Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
14
S- Nitroso compounds, formation, reactions and biological activity D. LYN H. WILLIAMS Chemistry Department, University of Durham, Durham, UK Fax: +44 191 384 4737; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. S-NITROSOTHIOLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Properties and Chemical Reactions . . . . . . . . . . . . . . . . . . . . . . . . . C. Biological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. S-NITROSOTHIOCARBONYL COMPOUNDS . . . . . . . . . . . . . . . . . . A. Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. FORMATION AND REACTIONS OF OTHER S-NITROSO COMPOUNDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. S-Nitrososulphides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. S-Nitrososulphinates (Sulphonyl Nitrites) . . . . . . . . . . . . . . . . . . . . . C. S-Nitroso Compounds with Inorganic Anions . . . . . . . . . . . . . . . . . . 1. Nitrosyl thiocyanate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nitrosyl thiosulphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Nitrosyl bisulphite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
665 666 666 669 673 674 674 675 676 676 677 678 678 678 679 680
I. INTRODUCTION
Nitroso compounds in general are quite well-known compounds, readily synthesized and their reactions have been studied. Some are important as intermediates in a number of important industrial processes, e.g. in diazotisation and azo dye formation, in caprolactam synthesis and in paracetamol manufacture. Compounds are very well-known in which the nitroso group is bound to carbon, nitrogen and oxygen sites within molecules. Much less well-known are those in which the nitroso group is bound to sulphur. These include principally S-nitrosothiols (sometimes called thionitrites), RSNO, generally henceforth referred to in this chapter as nitrosothiols. Other species including S-nitrosothiocarbonyl
665
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D. Lyn H. Williams
compounds are less familiar. Nitrosothiols have not been as widely studied as their oxygen counterparts alkyl nitrites, generally because of their more reduced stability. However, in recent years there has been much interest generated in the chemistry of nitrosothiols following the major discoveries made in the late 1980s and early 1990s concerning the part played by nitric oxide in a number of physiological process in human metabolism. Nitric oxide is believed to be formed naturally in vivo by an enzymatic reaction of L-arginine (leading to L-citrulline production) and also brought about in vivo by the administration of drugs such as glyceryl trinitrate (GTN), which has been used for over a century to treat problems in the blood circulatory system. Nitrosothiols (which have been detected in vivo) are believed to be involved in the nitric oxide saga in two ways: (a) as possible alternative (to GTN) NO-releasing drugs to make up for the deficiencies of spontaneous NO production in some clinical conditions, and (b) as a possible ‘storage’ area for nitric oxide in vivo in the mechanism of NO transfer within the body. II. S-NITROSOTHIOLS A. Formation
Nitrosothiols are very easily generated by simple electrophilic nitrosation of thiols1 (equation 1), just as alkyl nitrites are made from alcohols (equation 2), and N-nitrosamines from secondary amines (equation 3). The most convenient reagent is nitrous acid, generated from sodium nitrite and mineral acid in water or in mixed alcohol water solvents. In water the S-nitrosation of thiols is effectively irreversible, contrasting with the corresponding reaction of alcohols. This makes the product separation somewhat easier. The reason for the different behaviour is believed to arise from the differences in basicity (important in the reverse reaction) and nucleophilicity (important in the forward reaction) between the O- and S-sites. The reaction has been studied mechanistically2 and it shows all the characteristics of electrophilic nitrosation (including catalysis by non-basic nucleophiles such as halide ions, thiocyanate ion and thiourea) which are very familiar in N-nitrosation. However, since thiols are not significantly protonated in acid solution S-nitrosation is generally a faster process overall than in N-nitrosation. Some kinetic data (values of k in rate D k[HNO2 ][HC ][RSH]) are given in Table 1 for the acid catalysed nitrosation of some thiols with nitrous acid. These rate constants tend to approach 7000 dm6 mol2 s1 which is believed to be the diffusion controlled limit for the reaction of NOC with the thiols. Similarly, second-order rate constants for the reactions of ClNO, BrNO and ONSCN have been determined for some thiols and are given in Table 2. The by now well-established reactivity trend ClNO > BrNO > ONSCN is evident but the more reactive species are strangely well below the diffusion limit. HC
RSH C HNO2 ! RSNO C H2 O
(1)
HC
! ROH C HNO2 RONO C H2 O
(2)
HC
R2 NH C HNO2 ! R2 NNO C H2 O
(3)
Other nitrosating agents have been used successfully to synthesize nitrosothiols, notably alkyl nitrites3 , nitrosyl chloride4 , dinitrogen trioxide5 and dinitrogen tetroxide6 . In principle any carrier of NOC would suffice. One of the simplest nitrosothiols, CF3 SNO (a red unstable gas), has been made from both nitrosyl chloride and alkyl nitrites in reaction with CF3 SH7 . Use of these reagents in organic solvents has some advantage over the
14. S-Nitroso compounds, formation, reactions and biological activity
667
TABLE 1. Values of the third-order rate constant for the acid catalysed nitrosation of thiols with nitrous acid in water at 25 ° C k/dm6 mol2 s1
RSH Cysteine methyl ester Cysteine Glutathione Mercaptosuccinic acid Thioglycolic acid Mercaptopropanoic acid
213 443 1080 1334 2630 4764
TABLE 2. Second-order rate constants for the reactions of ClNO, BrNO and ONSCN with thiols in water at 25 ° C kdm3 mol1 s1
Cysteine methyl ester Cysteine Glutathione Mercaptosuccinic acid Thioglycolic acid Mercaptopropanoic acid
ClNO
BrNO
ONSCN
1.0 ð 106 1.2 ð 106 5.7 ð 106
4.9 ð 104 5.8 ð 104 2.9 ð 105 2.6 ð 104 1.1 ð 106 4.5 ð 105
7.0 ð 102 7.0 ð 102 1.9 ð 103
1.4 ð 107
2.5 ð 104
nitrous acid method when there are solubility difficulties in water. A well-tried successful procedure6 is to use N2 O4 in carbon tetrachloride, hexane, ether or acetonitrile at 10 ° C, when reaction is quantitative. Another excellent and more convenient procedure involves the use of t-butyl nitrite in organic solvents such as chloroform or acetonitrile8 where again excellent yields have been reported (equation 4). In mechanistic studies in water it has been shown that nitrosothiols are formed in solution by attack of the thiolate anion (in mildly alkaline solution) with a large range of alkyl nitrites9 (equation 5) and also with N-methyl-N-nitrosotoluene-p-sulphonamide10 . In both cases reaction appears to involve simple nucleophilic attack by the thiolate ion at the nitrogen atom of the nitroso group and, as expected, reactions are much facilitated by the presence of electron-withdrawing substituents in the alkyl nitrite. Neither reaction appears to have been much used synthetically. Some rate data are given in Table 3 which give the second-order rate constants k for the reactions of nine alkyl nitrites with three thiolate anions. The rate enhancement by electron-withdrawing groups within the alkyl nitrites is clearly seen. Nitrosothiols can also be formed from disulphides RSSR by photolysis and reaction with nitric oxide, but this does not seem to have much synthetic potential11 . CHCl3
t-BuONO C RSH ! RSNO C t-BuOH −
RONO + R′S
H+
R′SH
−
RO
H+
ROH
(4)
+ R′SNO
(5)
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D. Lyn H. Williams
TABLE 3. Second-order rate constants for the reaction of alkyl nitrites with the thiolate ions derived from three thiols in water at 25 ° C kdm3 mol1 s1 RONO Me3 CONO Me2 CHONO EtONO (Me)2 CH(CH2 )2 ONO EtO(CH2 )2 ONO Cl(CH2 )2 ONO Br(CH2 )2 ONO I(CH2 )2 ONO Cl2 CHCH2 ONO Cl3 CCH2 ONO
Cysteine
N-Acetylcysteine
Thioglycolic acid
1.7 11 28 27 169 1045 1055 1060 1.2 ð 104 Too fast to measure
1.8 12 31 30 169 1010 1030 1020
4.9 30 75 75 417 2260 2240 2260
Early workers isolated nitrosothiols of varying degrees of stability, including EtSNO4 , Ph3 CSNO12 and Me3 CSNO13 . However, in 1978 Field and coworkers14 prepared the nitrosothiol derived from N-acetyl-D,L-penicillamine (SNAP) which is indefinitely stable in the solid form as deep green crystals with red reflections. SNAP (1), because of its solid state stability, has been much used as the typical nitrosothiol in a large number of biological experiments. Similarly, the derivative from glutathione (2) is now widely available as a stable solid15 . The mounting interest in the biological activity of nitrosothiols SNO
SNO
Me
O
Me
H N
HO2 C
HN
N H
CO2 H NH2
Ac
O
(1)
(2)
Me
SNO
Me
SNO
Me
Me
Me +
NH3 Cl
Me
−
NHAc
HN CHO
(3)
(4) Me
Me
SNO
(5) CO2 H
O
ONS
N H NHAc (6)
SNO Me
Me
CO2 H
CO2 H
14. S-Nitroso compounds, formation, reactions and biological activity
669
has resulted in the isolation of a large number of stable nitrosothiols including 316 , 416 , 517 and the S,S0 -dinitrosothiol 617 . B. Properties and Chemical Reactions
The stable nitrosothiols are coloured either green or red. In general the tertiary structures (e.g. SNAP) are green. There is a general UV absorption band in the range 330 350 nm with extinction coefficients about 103 mol1 dm3 cm1 , which has been used to monitor reactions of nitrosothiols by spectrophotometry in kinetic studies. The UV-visible spectra have been analysed and the electronic transitions assigned18 . The infrared spectra of some nitrosothiols have also been analysed7 and the stretching (1480 1530 cm1 ) and bending frequencies of the NO group identified, as has the CS vibration in the 600 730 cm1 region. Both 1 H and 13 C NMR spectra of nitrosothiols have also been examined16 . There is a significant downfield shift of the ˛-protons upon nitrosation of thiols and there is a similar shift of the ˛-carbon resonances, which makes the techniques useful in showing whether S-nitrosation has occurred. The molecular structure of SNAP has been obtained by X-ray crystallography14 , and is shown in 7. The CS bond is rather long, but other features are as expected. 100.4°
° 1.214 A
C
N O
S °
1.841 A ° 1.771 A
113.2°
(7)
Since the discovery that nitric oxide is crucially involved in a range of physiological processes and indeed that it is synthesized in vivo from L-arginine (for review articles see References 19 22), there has been intense interest in a range of compounds which might act as NO donors. Consequently, the most studied reaction of nitrosothiols is that where decomposition to nitric oxide occurs. Nitrosothiols decompose photochemically and thermally to give the corresponding disulphides and nitric oxide18,23,14,24 (equation 6). In most cases the nitric oxide has not been identified as the primary product but rather as its oxidized form, nitrogen dioxide. h
2RSNO ! RSSR C 2NO
6
The reaction in water at pH 7.4 has been much studied since the discovery of the importance of nitric oxide. The products are as for the thermal and photochemical reactions, except that the final product is nitrite ion. This is to be expected since nitric oxide in aerated water at pH 7.4 also yields quantitatively nitrite ion25 , by it is believed the series of equations 7 9, which involves oxidation to nitrogen dioxide, further reaction to give dinitrogen trioxide which, in mildly alkaline solution, is hydrolysed to nitrite ion. Under anaerobic conditions it is possible to detect nitric oxide directly from the decomposition of nitrosothiols using a NO-probe electrode system26 . Solutions of nitrosothiols both in
670
D. Lyn H. Williams
water26 and in organic solvents6,14 will nitrosate, e.g. amines, probably via NO loss, oxidation and N2 O3 formation. In the absence of oxygen no nitrosation product is detected. Aryl halides are generated in excellent yields from nitrosothiols and arylamines at ambient temperatures in the presence of anhydrous Cu(II) halides in acetonitrile (equation 10)11 . This probably involves an initial NO group transfer, probably indirectly via NO formation, although no mechanistic studies have been carried out. 2NO C O2 D 2NO2
(7)
NO2 C NO D N2 O3
(8)
N2 O3 C 2OH D 2NO2 C H2 O
(9)
CuX2
ArNH2 C RSNO ! ArX C N2 C RSSR C R2 S3 CH3 CN
(10)
Kinetic studies of the reaction of nitrosothiols in water at pH 7.4 have been reported and reveal a large range of different rate forms and half-lives. However, in 1993 it was realized27 that reaction is brought about by catalytic quantities of Cu2C . There is a sufficient concentration of Cu2C in many samples of distilled water, and particularly buffer components, to allow reaction to occur. This accounts for the wildly erratic behaviour reported in the literature. When the concentration of Cu2C is carefully controlled sensible results emerge. There is a range of [Cu2C ] for most of the nitrosothiols studied for which the second-order rate equation (equation 11) applies. Values of the second-order rate constant k vary with the structure of the nitrosothiol in such a way which suggests that the copper needs to be bidentately linked (a) with the N of the NO group (or the S of the SNO group) and (b) with another electron-donating system such as a nitrogen atom or negatively charged oxygen atom at positions within the molecule which allow a six-membered ring to be formed26 . Both N-acetylation and the addition of a methylene group (which would give a 7-membered ring) resulted in sharp rate reductions. Very little reaction was discernible in the absence of function (b), e.g. for t-BuSNO. When Cu2C was rigorously excluded by complexation with EDTA, then again the reaction rate was reduced to a negligible value, even for reaction of the ‘normally very reactive’ nitrosothiols such as nitrosocysteine. 11 Rate D k[RSNO][Cu2C ] Outside a given [Cu2C ], zero-order behaviour (at high [Cu2C ]) and the presence of an induction period (at low [Cu2C ]) raised the possibility that the actual catalyst is CuC and not Cu2C , formed by reduction of the latter by thiolate ion, a well-known reaction28 (equation 12). This was confirmed by the use of a specific CuC -chelating agent neocuproine (8) which resulted in a sharp rate reduction, leading eventually to a complete suppression of the reaction. The spectrum of the CuC 8 complex was observed from the reaction mixture. Further, the increased reactivity brought about by the addition of a thiol species supported this suggestion. At low concentrations of added thiol there was a sharp increase in the rate constant for the reaction of SNAP, whereas at higher concentrations there was a gentle reduction leading eventually to a stabilization effect (see Figure 1). The initial catalysis represents an increase in rate of CuC formation (equation 12) whereas the subsequent rate reduction is believed to arise by complexation of Cu2C by thiolate (a well-known reaction29 ). This accounts for the contrasting literature reports, which state that in some cases added thiol increases the rate of decomposition whereas in other cases a stabilization effect is claimed. The outline reaction scheme is given in equations 13 15. Intermediate X1 is probably RSCuC and X2 is probably a structure similar to those given
14. S-Nitroso compounds, formation, reactions and biological activity
671
kobs (s−1) 0.0025
0.02
0.015
0.01
0.005
0 0
100
200
300
400
500
600
700
800
900
1000
106 [NAP]added (mol dm−3) FIGURE 1. Rate constant for decomposition of S-nitroso-N-acetylpenicillamine in the presence of added N-acetylpenicillamine (NAP)
in 9 and 10 for two different nitrosothiols. It is likely that here CuC is also coordinated to two water molecules. Details of how NO is released from 9 and 10 are not yet clear, and it is possible that coordination is at the sulphur atom rather than the nitroso nitrogen atom.
Cu2C C RS ! CuC C RSž ! RSSR
(12)
ž C ! Cu2C C RS X1 ! RS C Cu
(13)
RSNO C Cu
C
! X2 ! RS C Cu
2C
C NO
(14)
ž
RSNO C RS ! RSSR C NO
(15)
ž
or 2RS ! RSSR
H2 C H2 C
N
N
N
Me
Me (8)
H2 C
S
NH2 (9)
Cu+
S
C
O O
−
N O
O
+
Cu
(10)
Nitrosothiols are also readily decomposed by mercuric ion to the corresponding coordinated thiols and nitrous acid (in acid solution) as in equation 16. This reaction has been used as the basis of an analytical procedure for thiol determination30 . Mechanistic
672
D. Lyn H. Williams
studies have shown31 that this is quite a different reaction to the Cu2C catalysed reaction since (a) the Hg2C reactions are generally much faster, (b) the reactions with Hg2C are stoichiometric rather than catalytic, (c) no trace of NO was detected when the reaction was carried out anaerobically and (d) there is very little structure reactivity dependence which is so evident for the Cu2C reaction. All the evidence suggests that [RS(Hg)NO]2C is first formed and then undergoes nucleophilic attack by water at the nitroso nitrogen atom to release nitrous acid. A similar reaction can be achieved with an acid catalyst (equation 17) but only at fairly high acid concentration (¾2M H2 SO4 ) and only in the presence of a nitrous acid trap (such as sulphamic acid) which ensures the irreversibility of the process32 . RSNO C Hg2C C H2 O D RSHgC C HNO2 C HC
(16)
HC
RSNO C H2 O ! RSH C HNO2 (removed)
(17)
Nitrosothiols can also be reduced with sodium borohydride, leading (with SNAP14 ) to the disulphide formation (equation 18). NaBH4
ONSCMe2 CH(NHAc)CO2 H ! SCMe2 CH(NHAc)CO2 H]2
18
Oxidation is also a known reaction; examples are known where the reagents are fuming nitric acid33 or N2 O4 34 , the product being in each case the corresponding thionitrate (equation 19). HNO3
RSNO ! RSNO2
19
An important reaction of nitrosothiols is the exchange reaction of the nitroso group with another thiol, i.e. a transnitrosation. This has been demonstrated on a number of occasions6,35 . Often, the final product is not the new nitrosothiol but its decomposition product, the disulphide. All three possible disulphides, for example, have been identified in the product mixture of the reaction of nitrosoglutathione (GSNO) with cysteine (equation 20). It is, however, possible to identify spectrophotometrically the primary products of transnitrosation36,37 . Kinetic studies37 have shown quite clearly that the reaction involves attack by the thiolate anion, probably in a direct reaction, and is an example of nucleophilic substitution at the nitroso nitrogen atom. The process (equation 21) is thus very similar to that reported in Section II.A for the corresponding reaction of the thiolate anions with alkyl nitrites (equation 5). It seems likely that other powerful nucleophiles will react in a similar fashion, but there appear to be no reports in the literature. RSNO C R0 SH ! RSSR C R0 SSR C R0 SSR0 −
RSNO + R′S
H+
R′SH
−
RS
H+
RSH
(20)
+ R′SNO
(21)
14. S-Nitroso compounds, formation, reactions and biological activity
673
C. Biological Activity
Since 1986, a remarkable number of discoveries have been made concerning the physiological actions of nitric oxide. A large number of review articles have appeared (typically References 19 21) and a vast amount of research is being undertaken in this area. It is now known that nitric oxide is synthesized in vivo from L-arginine and controls, among other functions vasodilation in the blood circulatory system. Administered drugs such as glyceryl trinitrate (GTN, by far the most widely used) and other organic nitrates also generate nitric oxide in vivo and are effective as a treatment for angina and other circulatory problems. There is a problem with glyceryl trinitrate in that it quickly induces a tolerance in some patients, so that there is a need for other NO-releasing compounds which can be used medically. Nitrosothiols present an obvious alternative solution. There is no doubt that many nitrosothiols effect vasodilation38 and also have a powerful inhibition effect on platelet aggregation39 . Among those tested and shown to have significant activity are nitrosocysteine, SNAP, GSNO and nitrosocaptopril. Use is now made of these properties clinically by way of the administration of nitrosoglutathione (GSNO) (a) during coronary angioplasty40 to inhibit platelet aggregation and (b) to treat a form of pre-eclampsia in pregnant women41 . Details of the mode of action are not known, but a major factor is believed to be the ability to inhibit platelet aggregation at concentration levels which do not lower blood pressure, in contrast to some other NO-donors. It has been argued that the so-called Endothelium Derived Relaxing Factor is in fact a nitrosothiol42 and not nitric oxide itself. This, however, is not the generally held view at the present time. Nonetheless, it is quite likely that nitrosothiols are involved at some stage and the bulk of the nitric oxide in the blood43 and in other tissues such as the lung44 is found primarily in the form of nitrosothiol derivatives of proteins and peptides, notably GSNO. The anti-platelet aggregation effects of nitrosoproteins may involve lower molecular weight nitrosothiols following the known (equation 21) transnitrosation between nitrosothiols and thiols45 . New nitrosothiols are being synthesized and tested for activity. These include structures 1 6 in Section II.A as well as those derived from cysteine residues within proteins. One example of a S-nitrosocysteine within a polypeptide46 is remarkably stable in the solid form, contrasting with the marked instability of S-nitrosocysteine itself. The S,S0 dinitrosodithiol 11 has been shown to have platelet aggregation inhibition properties of the same order of magnitude as GTN and vasodilation properties somewhat less than those possessed by GTN17 . Me
Me
O
CO2 H SNO
ONS
N H
Me
Me
NHAc (11)
Nitrosothiols thus appear to have the necessary properties for clinical use as an alternative for GTN. There does not appear to be the same problem regarding tolerance47 . Much testing experiments in vivo remain to be undertaken. Little is known about the mode of action of nitrosothiols regarding their biological properties. There appears to be no direct connection between their reactivities towards nitric oxide loss and biological activity38,48 . However, the experiments which have been carried out in these studies relating to rates of nitric oxide formation do not recognize
674
D. Lyn H. Williams
the vital part played by Cu2C in these reactions and the quoted results may not represent a true reactivity sequence. It has been suggested49 that some of the biological activities result from NOC loss from RSNO, not in a unimolecular process (which would not make good chemical sense) but in the transnitrosation process discussed earlier in Section II.B (equation 21). One important result, however, does point to the fact that nitric oxide release from nitrosothiols is a necessary reaction for there to be biological activity50 . In a study using nitrosocysteine and GSNO it was shown that the specific copper(I) chelators neocuproine (8) and the structurally related bathocuproine sulphonate reduce the biological activity of both nitrosothiols. This indicates that copper(I) is required for biological activity, which ties in with the in vitro experiments described in Section II.B. The realization that copper plays such an important part in nitrosothiol decomposition accounts for the widely differing decomposition rates quoted in the literature, e.g. the half-life of nitrosocysteine has been reported as 15 min and also variously between 4 and 83 seconds. One of the factors important here, apart from the level of the [Cu2C ] present adventitiously, is the nature and concentration of the buffers used, since many of these, particularly those containing carboxylic acid groups, will themselves bind Cu2C and hence reduce the catalytic activity. It is clear that there is a long way to go before the biological activities of nitrosothiols (and of nitric oxide) are fully understood at the molecular level. III. S-NITROSOTHIOCARBONYL COMPOUNDS A. Formation
The sulphur atom of a thiocarbonyl compound is a powerful nucleophilic centre. Examples are to be found in the S-alkylation of thioamides and in the reaction of thioureas to give isothiuronium salts from alkyl halides. In a conventional SN 2 reaction thiourea is approximately as powerful a nucleophile as is iodide ion in polar solvents as measured by the Pearson nucleophilicity parameter51 . It is no surprise therefore that thiourea reacts with nitrous acid to give initially the S-nitrososulphonium ion (equation 22). This generates a red or yellow colour in solution, which is fairly characteristic of S-nitroso species. No salts have been isolated and the ion decomposes fairly readily in solution. In fact Werner52 showed that thiourea can undergo two reactions with nitrous acid, one leading to thiocyanate ion and nitrogen products (equation 23) and the other to the disulphide cation (equation 24). These findings can be rationalized in terms of N-nitrosation (at low acidities) leading to nitrogen formation, and S-nitrosation (at higher acidities) leading to the disulphide cation. HC + (NH2 )2 CS C HNO2 ! (NH2 )2 CSNO C H2 O
(NH2 )2 CS C HNO2 D SCN C N2 C HC C 2H2 O + + 2(NH2 )2 CS C 2HNO2 C 2HC D (NH2 )2 CSSC(NH2 )2 C 2NO C 2H2 O
(22) (23) (24)
The equilibrium constant for S-nitrososulphonium ion formation (equation 25) has been measured spectrophotometrically as 5000 dm6 mol2 at 25 ° C in water53 . This is a much larger figure than for the corresponding reactions leading to nitrosyl chloride, bromide and thiocyanate formation, reflecting the greater nucleophilicity of thiourea. The same effect is evident in the analysis of the rate constant for the nitrosation of thiourea by nitrous acid (equation 26). The value of the third-order rate constant k is 6900 dm6 mol2 s1 at 25 ° C, which is very close to that found for a large number of reactive aromatic amines
14. S-Nitroso compounds, formation, reactions and biological activity NOC
and is believed to be at the diffusion-controlled limit for reaction of with thiourea54 . Alkyl thioureas react with much the same rate constant. + (NH2 )2 CS C HNO2 C HC D (NH2 )2 CSNO C H2 O Rate D k[(NH2 )2 CS][HNO2
][HC ]
675
(or H2 NO2 C )
(25) (26)
As expected, other carriers of NOC such as nitrosamines55 , alkyl nitrites56 and a nitrososulphonamide57 will also generate the S-nitrososulphonium ion from thiourea. There appears to be little reported work on S-nitrosation reactions of simple thioketones. Thiocamphor when treated with iso-amyl nitrite in fact gives the oxime58 (formerly called ˛ isonitroso compounds), presumably via the tautomeric form of the thione, i.e. the enethiol. In this respect the reaction is very similar to the reactions of ketones59 which give oximes or C-nitroso compounds via the enol intermediates60 . B. Reactions
The S-nitrososulphonium ions derived from thiourea and its derivatives are not stable in solution but decompose to give the disulphide cation (C,C-dithiodiformamidinium) which has been isolated as its salts, e.g. the perchlorate and characterized by X-ray crystal analysis61 (equation 27). This is an example of the more general reaction whereby, eventually, thioureas and also thioketones and thiocarbonates can be converted to the stable -S-S-dication by a range of oxidizing agents both chemical and electrochemical62 . + + + 2(NH2 )2 CSNOD(NH2 )2 CSSC(NH2 )2 C 2NO
27
The decomposition reaction has been studied mechanistically63 and the kinetics have been interpreted in terms of the parallel pathways, one involving a bimolecular reaction + between two (NH2 )2 CSNO species (leading to a second-order kinetic term) and the other a reversible formation of a radical intermediate [(NH2 )2 CSSC(NH2 )2 ]Cž . At higher acidities the S-nitrosation reaction of thiourea leads to the formation of urea64 (equation 28) via, it is believed, the intermediate formation of the S-nitroso species. The reaction can also be brought about by nitrosamines or alkyl nitrites as the carriers of NOC . Reaction is thought to involve nucleophilic attack of the intermediate by water or the elimination of HSNO giving a carbodiimide, which is then hydrated. C
S
+
NO
C
+ S
NO
H2 O
C
O
(28)
An important property of the S-nitroso thiourea derivatives is the ability to effect electrophilic nitrosation of any of the conventional nucleophilic centres. This is manifest kinetically by the catalysis of nitrous acid nitrosation effected by added thiourea (equation 29). The situation is completely analogous to the catalysis of the same reactions by added halide ion or thiocyanate ion. The catalytic efficiency of thiourea depends on both the equilibrium constant KXNO for the formation of the intermediate and also its rate constant k with typically a secondary amine65 . Since KXNO is known (5000 dm6 mol2 ), it is easy to obtain + values of k. Values of k follow the trend (NH2 )2 CSNO < ONSCN < BrNO < ClNO whereas KXNO values follow the opposite trend. Since the range of KXNO values is very much larger than that of K values, the most efficient catalyst by far is thiourea. This is illustrated graphically in Figure 2 where the catalytic efficiencies of thiourea, thiocyanate
676
D. Lyn H. Williams 400
SC(NH2)2
Nitrosation of morpholine
104 k0 (s−1)
300
200
SCN −
100
0
Br − 5
10
15
20
25
103 [X − ] (mol dm−3) FIGURE 2. Catalysis by Br , SCN and (NH2 )2 CS in the nitrosation of morpholine
ion and bromide ion are compared in the nitrosation of morpholine by nitrous acid66 . A similar analysis has been carried out for the diazotisation of aniline67 and earlier for aliphatic amines68 . It appears that thiourea is the most efficient catalyst of nitrosation using aqueous nitrous acid. KXNO + ! HNO2 C HC C (NH2 )2 CS (NH2 )2 CSNO C H2 O
29 k + (NH2 )2 CSNO C PhN(Me)H ! PhN(Me)NO
IV. FORMATION AND REACTIONS OF OTHER S-NITROSO COMPOUNDS A. S-Nitrososulphides
It has been known for a long time that simple alkyl sulphides yield coloured (yellow or red) solutions when treated with alkyl nitrites or nitrous acid69 . The colours fade on standing and products have not been identified. It does, however, seem likely that the coloured products are in fact S-nitroso ions (equation 30) by analogy with the corresponding reaction of thiols, although in this case there is no suitable leaving group which would lead to a stable product. + R2 S C ‘NOC ’ D R2 SNO
30
There is indirect kinetic evidence that S-nitrosation of a sulphide occurs70 , followed by a S to N rearrangement of the nitroso group, leading finally to deamination (equation 31). The evidence is based on the much higher reaction rate when the sulphur atom is present.
14. S-Nitroso compounds, formation, reactions and biological activity
677
S to N transfer of the nitroso group has also been postulated on a number of other occasions53,71 to explain enhanced reaction rates. Detailed kinetic studies on the nitrosation of thioproline72 (12) and thiomorpholine73 (13) reveal that two pathways can exist, which depend on the reaction conditions, (a) a direct reaction at nitrogen and (b) a direct reaction at sulphur followed by S to N migration of the nitroso group. + CH2S
CH2SMe HNO2
C
Me
C
C
+ NH2NO
NH2
NH2
CH2SMe
CH2SMe
NO
C OH
31 S S N
CO2H
N
H
H
(12)
(13)
Sulphides should be capable of bringing about catalysis of nitrosation if the
+ S−NO
ion is formed and if it is itself an electrophilic nitrosating agent. This has been shown to be the case74 for the nitrosation of N-methylaniline in the presence of added dimethyl sulphide. The overall catalytic effect is approximately the same as that shown by bromide + ion, but no data are available for the value of the equilibrium constant for S−NO formation or for the rate constant for its reaction with the amine. Diazotisation of aniline is also catalysed by S-methylcysteine66 . Evidence that S-nitroso sulphides can be generated from nitrosamines and sulphides comes from the substantial nucleophilic reactivity of methionine (approximately the same level as bromide ion) in the denitrosation of an aromatic nitrosamine in acid solution in the presence of a ‘nitrite trap’ such as hydrazine75 . B. S-Nitrososulphinates (Sulphonyl Nitrites)
S-Nitrososulphinates can be made by treating sulphinic acids with N2 O4 at about 20 ° C in ether (equation 32)76 . Use of nitrous acid on alkyl nitrites leads to the formation of the corresponding hydroxylamines (equation 33) in a reaction where it is believed that the first formed nitrososulphinate nitrosates another molecule of the reactant sulphinic acid77 . Et2 O
RSO2 NO RSO2 H C N2 O4 ! °
(32)
RSO2 H C HNO2 D RSO2 NO
(33)
20 C
RSO2 NO C RSO2 H D (RSO2 )2 NOH The isolated nitrososulphinates are unstable brown crystals with the NDO IR absorption band near 1840 cm1 , i.e. at shorter wavelengths than in nitroso thiols (1490 1700 cm1 ) due to the powerful electron-withdrawing effect of the sulphonyl group. They decompose
678
D. Lyn H. Williams
upon warming, giving off nitric oxide and forming the hydroxylamine derivative. They are claimed to be the most powerful nitrosating agents known, although there are no quantitative data available. They react with alcohols giving alkyl nitrites, thiols to give Snitrosothiols and provide excellent reagents for deamination of aryl amines in acetonitrile containing anhydrous Cu(II) halides at room temperature78 . Nitrosamines are formed from secondary amines in high yield at room temperature11 . The most used reagent to date is 4-MeC6 H4 SO2 NO. The kinetics of the nitrosation of benzenesulphinic acid have been determined79 . The reaction is very rapid and requires stopped-flow techniques. This makes benzenesulphinic acid an excellent trap for free nitrous acid, on par with the more well-known hydrazoic acid and hydrazinium ion80 . In mildly acid solution reaction occurs via the sulphinic acid molecule and also the sulphinate ion. As expected, the latter is the more reactive and reaction takes place at the diffusion limit. All evidence points to the fact that the first nitrosation by NOC is the rate-limiting step. C. S-Nitroso Compounds with Inorganic Anions
1. Nitrosyl thiocyanate
When thiocyanate ions are added to nitrous acid in water, a pink colouration develops which is believed to be due to the formation of nitrosyl thiocyanate (equation 34), which is too unstable to be isolated but which can be used as a nitrosating agent in aqueous solution. Because the equilibrium constant for ONSCN formation81 is quite large (30 dm6 mol2 ) at 25 ° C, thiocyanate ion is an excellent catalyst for aqueous electrophilic nitrosation. The well established82 series is Cl < Br < SCN < (NH2 )2 CS. Thiocyanate ion is also a sufficiently powerful nucleophile to react in acid solution with nitrosamines in a denitrosation process (equation 35), which can only be driven to the right if the nitrosyl thiocyanate is removed by, e.g., reaction with a ‘nitrite trap’ such as hydrazoic acid. ! HNO2 C HC C SCN ONSCN C H2 O + PhN(Me)HNO C SCN ! PhNMeH C ONSCN Removed
(34) (35)
There are numerous examples of the demonstration of the catalytic activity of thiocyanate ion for a wide variety of substrates. In general the reaction of ONSCN is rate-limiting, but in some cases (just as for the nitrosyl halides) with very reactive substrates the formation of ONSCN can be rate-limiting. Although ONSCN has not been isolated, ab initio calculations83 and application of HASB theory suggest that the nitroso group is bonded to the sulphur atom. 2. Nitrosyl thiosulphate
A yellow solution is formed when nitrous acid is added to thiosulphate ion in water84 . This is believed to be due to the formation of nitrosyl thiosulphate [O3 SSNO] , although this has not been isolated and even in solution decomposition is fairly rapid. The equilibrium constant for its formation KXNO is 1.66ð107 dm6 mol2 at 25 ° C and the UV-visible absorption spectrum is very similar to that of other S-nitroso compounds85 . The rate constant for its formation is very large and is believed to represent a diffusion controlled process. Thiosulphate ion does appear to catalyse nitrosation but, over the range studied
14. S-Nitroso compounds, formation, reactions and biological activity
679
2
10 k0 (s−1) SCN
−
7
6
5
4
3 Br
−
2
1
0
2−
S2O3
0
1
2
3 103[Nucleophile] (mol dm−3)
FIGURE 3. Catalytic effect of added Br , SCN and S2 O3 2 in the nitrosation of N-methylaniline
for the reaction of N-methylaniline, there is no kinetic dependence of the rate constant upon [S2 O3 2 ] (see Figure 3)86 . This is because KXNO is so large that under the experimental conditions HNO2 is fully converted to O3 SSNO . A kinetic analysis reveals that O3 SSNO is not a very effective nitrosating agent, being several orders of magnitude less reactive than ONSCN. 3. Nitrosyl bisulphite
It has been known since 1894 that bisulphite ion reacts with nitrous acid to give hydroxylamine disulphonate87 (equation 36). It is believed that the nitrosyl bisulphite species is an intermediate which then nitrosates a further bisulphite ion. In this regard the reaction bears a striking resemblance to the nitrosation of sulphinic acids discussed earlier. This reaction has been important commercially for some time as the Raschig process88 for the production of hydroxylamine, since the disulphonate is readily hydrolysed to give the
680
D. Lyn H. Williams
free hydroxylamine. The results suggest that HO3 SNO is indeed a very reactive nitrosating species (just as the S-nitrososulphinates, see Section IV.B) but no kinetic studies have been reported on the possible catalytic activity of bisulphite ion in nitrosation reactions. NOC C HSO3 D HO3 SNO HC
HO3 SNO C HSO3 ! [(HO3 S)2 NO] ! (HO3 S)2 NOH
(36)
V. REFERENCES 1. 2.
D. L. H. Williams, Chem. Soc. Rev., 14, 171 (1985). L. R. Dix and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 109 (1984); P. A. Morris and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 513 (1988). 3. H. Lecher and W. Siefhen, Chem. Ber., 59, 1314, 2594 (1926). 4. H. S. Tasker and H. O. Jones, J. Chem. Soc., 95, 1910 (1909). 5. R. J. Phillips and H. Moor, Spectrochim. Acta, 17, 1004 (1961); R.J. Phillips, J. Mol. Spectrosc., 6, 492 (1961). 6. S. Oae, Y. H. Kim, D. Fukushima and K. Shinhama, J. Chem. Soc., Perkin Trans. 1, 913 (1978). 7. J. Mason, J. Chem. Soc. (A), 1587 (1969). 8. M. P. Doyle, J. W. Terpstra, R. A. Pickering and D. M. LePoire, J. Org. Chem., 48, 3379 (1983); S. A. Glover, A. Goosen, C. W. McClelland and F. R. Vogel, S. Afr. J. Chem., 34, 96 (1981). 9. H. M. S. Patel and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 37 (1990). 10. S. M. N. Y. F. Oh and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 755 (1989). 11. S. Oae and K. Shinhama, Org. Prep. Proced. Int., 15, 165 (1983). 12. H. Rheinboldt, Chem. Ber., 59, 1311 (1926). 13. G. Kresze and U. Uhlich, Chem. Ber., 92, 1048 (1959). 14. L. Field, R. V. Dilts, R. Ravichandran, P. G. Lenhert and G. E. Carnahan, J. Chem. Soc., Chem. Commun., 249 (1978). 15. T. W. Hart, Tetrahedron Lett., 26, 2013 (1985). 16. B. Roy, A. du M. d’Hardemare and M. Fontecave, J. Org. Chem., 59, 7019 (1994). 17. H. A. Moynihan and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 797 (1994). 18. J. Barrett, D. F. Debenham and J. Glauser, J. Chem. Soc., Chem. Commun., 248 (1965). 19. S. Moncada, R. M. J. Palmer and E. A. Higgs, Pharmacol. Rev., 43, 109 (1991). 20. A. R. Butler and D. L. H. Williams, Chem. Soc. Rev., 233 (1993). 21. P. L. Feldman, O. W. Griffith and D. J. Stuehr, Chem. Eng. News, 20, 26 (1993). 22. M. Fontecave and J -L. Pierre, Bull. Soc. Chim. Fr., 131, 620 (1994). 23. J. Barrett, L. J. Fitygibbones, J. Glauser, R. H. Still and P. N. W. Young, Nature, 211, 848 (1966). 24. H. Rheinbolt and F. Mott, J. Prakt. Chem., 133, 328 (1932). 25. D. A. Wink, J. F. Darbyshire, R. W. Nims, J. E. Saavedra and P. C. Ford, Chem. Res. Toxicol., 6, 23 (1993). 26. S. C. Askew, D. J. Barnett, J. McAninly and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 741 (1995). 27. J. McAninly, D. L. H. Williams, S. C. Askew, A. R. Butler and C. Russell, J. Chem. Soc., Chem. Commun., 1758 (1993). 28. I. M. Klotz, G. H. Czerlinski and H. A. Friess, J. Am. Chem. Soc., 80, 2920 (1958). 29. F. J. Davis, B. C. Gilbert, R. O. C. Norman and M. C. R. Symons, J. Chem. Soc., Perkin Trans. 2, 1763 (1983). 30. B. Saville, Analyst, 83, 670 (1958). 31. H. R. Swift and D. L. H. Williams, J. Chem. Soc. Perkin Trans. 2, (1996) to appear. 32. S. S. Al-Kaabi, D. L. H. Williams, R. Bonnett and S. L. Ooi, J. Chem. Soc., Perkin Trans. 2, 227 (1982). 33. H. Rheinboldt and F. Mott, Chem. Ber., 65, 1223 (1932). 34. Y. H. Kim, K. Shinhama, D. Fukushima and S. Oae, Tetrahedron Lett., 1211 (1978). 35. J. W. Park, Biochem. Biophys. Res. Commun., 152, 916 (1988). 36. D. J. Meyer, H. Kramer, N. Ozer, B. Coles and B. Ketterer, FEBS Lett., 345, 177 (1994). 37. D. J. Barnett, A. Rios and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 1279 (1995).
14. S-Nitroso compounds, formation, reactions and biological activity 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77.
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W. R. Mathews and S. W. Kerr, J. Pharmacol. Exp. Ther., 267, 1529 (1993) and references cited therein. J. Loscalzo, J. Clin. Invest., 76, 703 (1985); M. W. Radomski, D. D. Rees, A.Dutra and S. Moncada, Br. J. Pharmacol., 107, 745 (1992). E. J. Langford, A. S. Brown, R. J. Wainwright, A. J. de Belder, M. R. Thomas, R. E. A. Smith, M. W. Radomski, J. F. Martin and S. Moncada, Lancet, 344, 1458 (1994). A. de Belder, C. Lees, J. Martin, S. Moncada and S. Campbell, Lancet, 345, 124 (1995). L. J. Ignarro, H. Lippton, J. C. Edwards, W. H. Baricos, A. L. Hyman, P. J. Kadowitz and C. A. Gruetter, J. Pharmacol. Exp. Ther., 218, 739 (1981); G. M. Rubanyi, A. Johns, D. Wilcox, F. N. Bates and D. Harrison, J. Cardiovasc. Pharmacol., 17, S41 (1991). J. S. Stamler, O. Jaraki, J. Osborne, D. I. Simon, J. Keaney, J. Vita, D. Singel, C. R. Valeri and J. Loscalzo, Proc. Natl. Acad. Sci. U.S.A., 89, 7674 (1992). B. Gaston, J. Reilly, J. M. Drazen, J. Fackler, P. Ramdev, D. Arnelle, M. E. Mullins, D. J. Sugarbarker, C. Chee, D. J. Singel, J. Loscalzo and J. S. Stamler, Proc. Natl. Acad. Sci. U.S.A., 90, 10957 (1993). D. I. Simon, J. S. Stamler, O. Jaraki, J. F. Keaney, J. A. Osborne, S. A. Francis, D. J. Singel and J. Loscalzo, Arteriosclerosis Thrombos., 13, 791 (1993). P. R. Myers, R. L. Minor, R. Guerra, J. N. Bates and D. G. Harrison, Nature, 345, 161 (1990). J. A. Bauer and H -L. Fung, J. Pharmacol. Exp. Ther., 256, 249 (1990). E. A. Kowaluk and H. Fung, J. Pharmacol. Exp. Ther., 256, 1256 (1990). D. R. Arnelle and J. S. Stamler, Arch. Biochem. Biophys., 318, 279 (1995). M. P. Gordge, D. J. Meyer, J. Hothersall, G. H. Neild, N. N. Payne and A. Noronha-Dutra, Br. J. Pharmacol., 114, 1083 (1995). R. G. Pearson, H. Sobel and J. Songstad, J. Am. Chem. Soc., 90, 319 (1968). A. E. Werner, J. Chem. Soc., 101, 2180 (1912); M. E. Coade and A. E. Werner, J. Chem. Soc., 102, 1221 (1913). K. Al-Mallah, P. Collings and G. Stedman, J. Chem. Soc., Dalton Trans., 2469 (1974). P. Collings, K. Al-Mallah and G. Stedman, J. Chem. Soc., Perkin Trans. 2, 1734 (1975). D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 128 (1977). M. J. Crookes and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 759 (1989). J. R. Leis, M. E. Pe˜na and A. M. Rios, J. Chem. Soc., Perkin Trans. 2, 587 (1995). D. C. Sen, J. Indian Chem. Soc., 12, 751 (1935). O. Touster, in Organic Reactions (Ed. R. Adams), 7, Chap. 6, Wiley, New York, 1953, p. 327. J. R. Leis, M. E. Pe˜na, D. L. H. Williams and S. D. Mawson, J. Chem. Soc., Perkin Trans. 2, 157 (1988). O. Foss, J. Johnsen and O. Tvedten, Acta Chem. Scand., 12, 1782 (1958). R. L. Blankespoor, M. P. Doyle, D. M. Hedstrand, W. H. Tamblyn and D. A. Van Dyke, J. Am. Chem. Soc., 103, 7096 (1981). P. Collings, M. Garley and G. Stedman, J. Chem. Soc., Dalton Trans., 331 (1981). K. A. Jorgensen and S. O. Lawesson, Chem. Ser., 20, 227 (1982); J. W. Lown and S. M. S. Chauhan, J. Org. Chem., 48, 507 (1983). D. L. H. Williams, Nitrosation, Cambridge University Press, 1988, pp. 22 24 and references cited therein. T. A. Meyer and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 361 (1981). L. R. Dix and D. L. H. Williams, J. Chem. Res. (S), 97 (1984). M. Masui, C. Ueda, T. Yasuoka and H. Ohmori, Chem. Pharm. Bull., 27, 1274 (1979). E. M. Harper and A. K. Macbeth, Proc. Chem. Soc., 30, 15 (1914); A. K. Macbeth and D. D. Pratt, J. Chem. Soc., 119, 354 (1921). T. A. Meyer and D. L. H. Williams, J. Chem. Soc., Chem. Commun., 1067 (1983). J. W. Lown and S. M. S. Chauhan, J. Org. Chem., 48, 3901 (1983); T. Tahira, M. Tsuda, K. Wakabayashi, M. Nago and T. Sugimura, Gann, 75, 889 (1984). A. Castro, E. Iglesias, J. R. Leis, J. V. Tato, F. Meijide and M. E. Pe˜na, J. Chem. Soc., Perkin Trans. 2, 651 (1987). A. Coello, F. Meijide and J. V. Tato, J. Chem. Soc., Perkin Trans. 2, 1677 (1989). T. Bryant and D. L. H. Williams, J. Chem. Res. (S), 174 (1987). G. Hallett and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 624 (1980). S. Oae, K. Shinhama and Y. H. Kim, Tetrahedron Lett., 3307 (1979). C. S. Marvel and R. S. Johnson, J. Org. Chem., 13, 822 (1948); G. Kresze and W. Kort, Chem. Ber., 94, 2624 (1961).
682 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88.
D. Lyn H. Williams S. Oae, K. Shinhama and Y. H. Kim, Bull. Chem. Soc. Jpn., 53, 1065 (1980). T. Bryant and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 1083 (1985). G. P. Quinton and D. L. H. Williams, J. Chem. Res. (S), 209 (1987). G. Stedman and P. A. E. Whincup, J. Chem. Soc., 5796 (1963). Reference 65, pp. 10 24. K. A. Jorgensen and S. O. Lawesson, J. Am. Chem. Soc., 106, 4687 (1984). J. O. Edwards, Science, 113, 392 (1951). M. S. Garley and G. Stedman, J. Inorg. Nucl. Chem., 43, 2863 (1981). T. Bryant, D. L. H. Williams, M. H. H. Ali and G. Stedman, J. Chem. Soc., Perkin Trans. 2, 193 (1986). E. Divers and T. Haga, J. Chem. Soc., 65, 523 (1894). F. Raschig, Z. Angew. Chem., 17, 1398 (1904).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
15
Photochemistry of amines and amino compounds TONG-ING HO Chemistry Department, National Taiwan University, Roosevelt Road Section 4, Taipei, Taiwan (ROC) Fax: 886-2-363-6359; e-mail:
[email protected] and
YUAN L. CHOW Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada Fax: (604)291-3765; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. PHOTOCHEMISTRY INVOLVING TERTIARY AMINES . . . . . . . . . . A. With trans-Stilbene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. With Styrenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. With ˛,ˇ-Unsaturated Carbonyl Compounds . . . . . . . . . . . . . . . . . . D. With Other Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Tertiary Amines as Donors in Intramolecular Charge Transfer Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. PHOTOCHEMISTRY WITH SECONDARY AMINES . . . . . . . . . . . . . A. With Excited State trans-Stilbene . . . . . . . . . . . . . . . . . . . . . . . . . B. With Excited Styrenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. With Other Excited Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. PHOTOCHEMISTRY INVOLVING PRIMARY AMINES AND AMMONIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. PHOTOCHEMISTRY OF IMINE AND IMINIUM SALTS . . . . . . . . . . A. Photoinduced Electron Transfer Chemistry of Iminium Salts . . . . . . . B. The Aza-di--methane Rearrangement . . . . . . . . . . . . . . . . . . . . . . C. Photochemistry of Azirines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Stilbene-type Photocyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Other Reactions of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
683
684 685 685 686 687 692 693 698 698 700 702 704 710 710 715 717 717 720
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Tong-Ing Ho and Yuan L. Chow
VI. PHOTOCHEMISTRY OF AMIDES AND IMIDES A. Amides . . . . . . . . . . . . . . . . . . . . . . . . . . B. Imides . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . .
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722 722 730 740
I. INTRODUCTION
Perhaps the most important reaction for the amine is their ability to donate electrons. Since amines generally have low oxidation potentials, they are good electron donors in their ground state, and the donor ability is further enhanced by photoexcitation. The chemical consequence of this single electron transfer (SET) is the generation of the amine radical cations (aminium radicals) and an earlier review on the aminium radicals is available1 . The SET between amine and acceptor may be enhanced by photoexcitation and may lead to the formation of exciplexes2 or molecular complex with charge transfer character3 . The photochemistry between aromatic acceptors and amines via the exciplexes has been discussed earlier (Scheme 1)4 . CH3
NEt2
hν Et 3 N
H
CH2 N(CH3 )2
hν (CH3 )3 N
hν (CH3 )3 N
CH2 N(CH3 )2 SCHEME 1
The importance of tertiary amines in the photochemically induced electron transfer reactions has also been addressed5 . Direct irradiation of aromatic or aliphatic amines often leads to the scission of CN, NH or CH bonds that lead to the subsequent chemical reactions by radical pathways6 . In this section, photochemical reactions of amines reported since 1978 will be considered with emphasis on photoinduced electron transfer. Photochemical reactions of inorganic and organometallic compounds will not be included unless photochemistry of amine moieties is the primary interest.
15. Photochemistry of amines and amino compounds
685
II. PHOTOCHEMISTRY INVOLVING TERTIARY AMINES
Tertiary amines are known to react with excited aromatic compounds such as benzene7 , trans-stilbene8 , naphthalene9 , anthracene10 , phenanthrene11 and cyanoarenes12 . The addition of an amine ˛-CH bond to the aromatic compounds is interpreted as the consequence of consecutive electron transfer and proton transfer13 processes that involve several reactive intermediates including exciplexes2 and contact ion radical pairs (CIRP)13 15 from mechanistic considerations17 19 . The photoreaction of trans-stilbene (t-S) and a tertiary amine can serve as a model16 to illustrate the multistep process (Scheme 2). Ph
H + R3 N
H
hν
Ph
−
non - polar
+
( t-S /R3 N ) exciplex
emission
solvent
H+ polar solvent
Ph
Ph
Ph +
CNR2
Ph
Ph
Ph
Ph
+
NR2 Ph
Ph (4) radical pair
C
Ph
(1)
(2)
(3)
SCHEME 2
A. With trans-Stilbene
Quenching of t-SŁ by a tertiary aliphatic amine in non-polar solvents yields a fluorescent exciplex whose intensity and lifetime decreased with the increase of solvent polarity; preparatively, products 1, 2 and 3 also increase concurrently. The results have been interpreted as the increasing participation of proton transfer with increasing solvent polarity within the exciplex to give radical pair 4, which is the direct precursor for the observed chemical products. The random proton transfer from the aminium cations (R3 NCž ) to the stilbene anion radicals (t-Sž ) practically determines the product pattern20 (equation 1). However, the deprotonation of sterically hindered non-symmetrical tertiary amine cation radicals is regioselective13,21 23 as shown in equation 2. Singlet trans-stilbene reacts with ethyldiisopropylamine by the mechanism to give 5 predominantly (equation 2). It also reacts with amines of structure Me2 NCH2 R (R D CHDCH2 , CO2 Et, CCCH3 and CCH) in hexane solution to yield one single adduct PhCH2 CHPhCHRNMe2 in each case without involving the methyl group reaction21 . Ar
Ph
+ R3 N H
Ph
H Ar
Ar = p-XC6 H4 −
hν
+ Ph
C
NR2
(1) Ar
C
NR2
686
Tong-Ing Ho and Yuan L. Chow PhCH2 CHPh
PhCH2 CHPh t-S∗ + EtN(i-Pr)2
+ CH3 CHN(i-Pr)2
(CH3 )2 CN(i-Pr)C2 H5
(5) 92%
(2)
(6) 8%
Photoinduced intramolecular interaction of t-S and tertiary amine moieties linked with a polymethylene chain has also been studied24 . The photoexcitation of trans-stilbene in which a tertiary amine is attached to the ortho position with a (CH2 )1 3 linker leads to fluorescent exciplexes by intramolecular electron transfer, and results in no more than trans-cis isomerization. The failure to give adducts from the intramolecular exciplexes could arise from the unfavourable exciplex geometry to undergo the necessary bond formation. B. With Styrenes
Irradiation of styrenes in the presence of tertiary aliphatic amines resulted in the formation of adducts in fair to poor yield25 . Excited styrene7 reacted with triethylamine to yield diastereomeric adducts 12, 1-phenylethane 16 and 2,3-diphenyl butane 1926 (equation 3). R
R′ + N(CH2 R′′′)3
Ph
hν
R′′
(7) R = R′ = R′′ = H (8) R = R′′ = H; R′ = Me (9) R = Me; R′ = R′′ = H CHR′R′′
(10) R′′′ = Me (11) R′′′ = H
(3)
CHR′R′′ CHR′′′N(CH2 R′′′)2 + PhCHRCHR′R′′ + Ph
Ph R
(12) R = R′ = R′′ = H; R′′′ = Me (13) R = R′′ = R′′′ = H; R′ = Me (14) R = R′′ = H; R′ = R′′′ = Me (15) R = R′′′ = Me; R′ = R′′ = H
R (16) R = R′ = R′′ = H (17) R = R′′ = H; R′ = Me (18) R = Me; R′ = R′′ = H
2
(19) R = R′ = R′′ = H (20) R = R′′ = H; R′ = Me (21) R = Me; R′ = R′′ = H
The total product quantum yield is higher in acetonitrile than in hexane solution (0.34 vs 0.07); the adduct yield is lower in acetonitrile (9% vs 28% of total product). Irradiation of 8 with trimethylamine 11 yields the regiospecific adducts 13, 17 and 2027 . The reaction of 8 with triethylamine 10 in either hexane or acetonitrile solution (>290 nm) results in the formation of a single adduct 14 (24% yield) accompanied by comparable amounts of 17 (15%) and also 20 (78%)28 (equation 3). Regiospecific addition of triethylamine to ˛-methylstyrene 9 is also observed to give 15 (32%), 18 (11%) and 21 (8%)26 (equation 3). Intramolecular photoaddition of tertiary amine and styrene moieties has been extensively studied by Aoyama29 and Lewis’ group28,30,31 (equations 4 8). Equations 4 and 5 show that if the intramolecular additions result in the formation of a five- or sixmembered ring, the product yields are excellent. Highly regioselective intramolecular proton transfer is proposed to occur via least motion pathways from the lowest energy
15. Photochemistry of amines and amino compounds
687
folded conformations of the singlet exciplex intermediates in non-polar solvents31 . Ph
Ph
Ph N
hν
N Ph
Ph
(CH2 )n
Me
(CH2 )n
(4)
CH3
(5)
Ph
n = 2,3 CH3
CH3
N
CH3
hν
N Ph
Ph CH3
N
CH3 CH3 hν
N
CH3
CH3
N
+ CH3 Ph
Ph
Ph
CH3
CH3
(6)
4:1 (95%)
hν
Ph
Ph
N CH3
N
CH3
(7) CH3
80%
hν
Ph
+ Ph
N CH3 CH3
Ph N CH3 CH3
(8) N CH3 CH3 8:1 (80%)
C. With a,b-Unsaturated Carbonyl Compounds
Earlier reviews on the photochemistry of unsatured ketones and amines are available39,40 . The photoreactions of ˛,ˇ-unsaturated carbonyl compounds in the presence of amines have been reported to yield 1:1 amine adducts32,33 as well as photoreduction
688
Tong-Ing Ho and Yuan L. Chow
products (equation 9). The electron transfer from amine to the triplet enone leads to the formation of enone anion and aminium radical pair which has been demonstrated by CIDNP experiments34 . Detailed studies by laser flash photolysis concerning the reaction mechanism between triplet enone and amines were carried out by Schuster and coworkers35 38
O
O
+ Et3 N
O
hν
O
+
+
(9)
CHNEt2 2
CH3
It is shown that the less substituted ˛-CH bond of several tertiary amines added across the olefin bond of 2-cyclohexenone (Scheme 3). In the radical ion pair the proton of the less substituted hydrogen is transferred to the ˛-position of enones that leads to a predominance of products 23, 26, 29 and 32 (about 95% yield). O CHR′ R′ RN
O
O
+
+
CHR′′R ′′ 2
(22, 25, 28, 31) O
+
O
R′
R
C
NCHR′′R′′
+
R′′
R
C
NCHR′R′
R′
R′′
(23, 26, 29, 32)
(24, 27, 30, 33)
22, 23, 24: R = CH(CH3 )2 ; R′ = H; R′′ = CH3 25, 26, 27: R = CH(CH3 )2 ; R′ = H and CH3 ; R′′ = CH3 28, 29, 30: R = CH3 ; R′ = H and C3 H7; R′′ = H 31, 32, 33: R = CH3 ; R′ = H; R′′ = CH3 SCHEME 3
The effect of an ˛-silyl group attached to tertiary amine on 2-cyclohexenone photochemistry has been clarified by Mariano’s group42,43 , who illustrates the importance of
15. Photochemistry of amines and amino compounds
689
anions in the proton transfer processes (equation 10). O
O
hν
+ Et2 NCH2 SiMe3 R
O
NEt2
R
R
R = H or CH3
R
+
NEt2 R
SiMe3
(34)
R (35)
(10) Product 34 predominates in the polar aprotic solvent (acetonitrile), while in the polar protic solvent (methanol) products 35 are formed preferentially. The different products are caused by the relative rate of deprotonation against desilylation of the aminium radical, that is in turn governed by the action of enone anion radical in acetonitrile as opposed to that of nucleophilic attack by methanol. In an aprotic, less silophilic solvent (acetonitrile), where the enone anion radical should be a strong base, the proton transfer is favoured and leads to the formation of product 34. In aprotic solvents or when a lithium cation is present, the enone anion radical basicity is reduced by hydrogen bonding or coordination by lithium cation, and the major product is the desilylated 35 (Scheme 4). O
O
+ Et2 NCH2 SiMe3
−
+• Et2 N
hν
H CHSiMe3
• R
R
R
R = H or CH3
∼H
R
+
Nu
O
O H
H •
Et2 N
Et2 NCHSiMe3 • R
•
R
R
34
R
35 SCHEME 4
•
CH2
690
Tong-Ing Ho and Yuan L. Chow
The solvent-controlled differential reactivity was also applied to the intramolecular photoaddition of 36 and 37 (equations 11 and 12)45,46 . O
O
O
hν
hν
SiMe3
SiMe3
MeCN
N
MeOH
N Me
N Me
Me
(36)
(11) O O
O
hν
hν
MeCN
MeOH
N SiMe3
SiMe3
Me
(12)
N
N
Me
Me
(37) Substituent effects on the ˇ-(aminoethyl)cyclohexenone photochemistry were carried out to study the relative kinetic acidities of the tertiary aminium radical47 . The ease of the methylene hydrogen to be removed as HC increased in the order of X D alkyl < Si(CH3 )3 < CCH (equation 13). O
O R1 CH2 R1 N
N
CH2
(39)
H,
R2
= Si(CH3 )3
(40) R1 = H, R2 = C
CH2 R2
(13)
R2
(38) R1 = H, R2 = CH3 R1 =
hν
CH
(41) R1 = CH3 , R2 = H (34% in CH3 CN) (42) R1 = Si(CH3 )3 , R2 = H (76% in CH3 CN) (43) R1 = C CH, R2 = H (79% in MeOH)
The photosensitized electron transfer by 9,10-dicyanoanthracene (DCA) has been shown to initiate the addition of the ˛-silyl amine 44 to 4,4-dimethylcyclohexenone47 (equation 14). Intramolecular addition of ˛-silyl amine 45 was also shown to be feasible45,46 (equation 15). The primary step is electron transfer to give the aminium
15. Photochemistry of amines and amino compounds (44Cž )
691
(DCAž )
and anion radical; it is interpreted to be followed by the attack radical of 44ž on the enone after desilylation. Me
O
N
CH2 SiMe3
O hν
+
(14)
DCA
N Me
Me
Me
Me
(44)
Me
O
O
H hν, DCA
N
MeCN (89%)
N
CH2 Ph
H
(15) CH2 Ph
SiMe3 (45)
In the DCA-sensitized reaction of silyl amino esters 46 (equation 16) the formation of pyrrolidines 48 must be obtained through a desilylmethylation. This process can be prevented by attaching an electron-withdrawing group to the amine that obviously reduces its oxidation potential (equation 17)48 . O
O O
MeO
MeO hν, DCA
Me3 Si
+
MeCN−MeOH
MeO
(16) R
N
N
N
R
R (46)
(48)
(47)
O
O
Y
Y
Me3 Si
hν, DCA
(17)
MeCN−MeOH
N PhCH2 O2 C Y = Me, OMe n = 0, 1
(CH2 )n
N PhCH2 O2 C
(CH2 )n
692
Tong-Ing Ho and Yuan L. Chow
D. With Other Oxidants
By introducing a proper light-absorbing system, amines can be photoexcited to react with a ground state acceptor. For example, N,N-dimethylaniline is photooxidized by molecular oxygen in the presence of iron complex catalysts in acetonitrile to give a mixture of N-methylformanilide, 4,40 -methylenebis(N,N0 -dimethylaniline) and N-methylaniline (equation 18)49 . The amine N-dealkylation is usually used as a model for enzymatic and cytochrome P-450 oxidation reactions. The potential relationships between the photochemistry of flavin oxidation of amines and monoamine oxidases (MAO) has also been considered50 . Anthraquinone fluorescence quenching by electron transfer from amines51 and amine oxidation by triplet carbonyl compounds52 were also studied to clarify electron transfer and deprotonation process. PhNMe2
hν, Fe complex O2 , MeCN
PhNHMe + PhN CHO + Me
+
Me2 N
PhNCH2
NMe2
Me
CH2
NMe2
(18) Substituent effects on benzene photochemistry in the presence of amines are described53 in equations 19 21. The ˛-CH of an amine is shown to add photolytically to the 2,5positions of toluene (equation 19). In contrast, trifluoro-substituted benzene was excited to react with trimethylamine to give 50 and 52 by a side-chain substitution. This chemistry arose from facile defluorination of the anion radicals of 49 and 51. CH3
+ Et3 N
hν
(19) Me CH(Me)NEt2
H CF3
+ Et3 N
hν
(20) CF2 CH(Me)NEt2
(49)
(50)
CF3
CF3
+ Et3 N
hν
(21)
CF3 (51)
CF2 CH(Me)NEt2 (52)
15. Photochemistry of amines and amino compounds
693
The electron transfer reaction of excited benzophenone and trialkylamines has been applied to design photochemical cells54 . N,N-Dimethylaniline is demethylated by excited 3-nitrochlorobenzene55 (equation 22) in which the latter acts as the electron acceptor; subsequent proton transfer and hydrolysis complete the sequence. NMe2
Cl
NHMe
(22)
hν
+ NO2
E. Tertiary Amines as Donors in Intramolecular Charge Transfer Interaction
The photophysical aspects of inter- and intramolecular charge transfer interaction between benzenoid chromophores and tertiary amines continues to attract attention56 with the aim of clarifying the intermediates, e.g. exciplexes or radical ion pairs. There are many intramolecular charge transfer systems published in which tertiary amines are used as donors in the intramolecular charge transfer (ICT), twist intramolecular charge transfer (TICT) and in intramolecular exciplex formation. Typical examples are summarized in Scheme 5. For example, the emission states for compounds 56 (max D 586 nm, emission maxima in acetonitrile), 57 (max D 297, toluene), 65, 67, 74 (for n D 2, max D 369 nm, 524 nm in DMSO), 76 (max D 458 nm in ethyl acetate, max D 486 nm in CH3 CN) and 83 are classified as intramolecular exciplex systems, since the excitation is primarily on the donor or acceptor and the precursor states for exciplexes are locally excited states. The emission states for compounds 53 (max D 351 nm, 489 nm, CH3 CN), 54, 55, 58, 62, 73 (max D 486 nm, CHCl3 ; max D 508 nm in DMSO), 75 (max D 412 nm, 430 nm, in methylcyclohexane) are classified as TICT states because there is mesomeric interaction in the ground state and excitation will cause a twist movement accompanied by the change transfer. Compound 53 exhibits two fluorescence bands, the normal b band and the longwave a band. The a band appears only in polar solvents; it grows with the polarity of the solvent and shifts strongly to the red. Compound 77, in which the amine is immobilized N
N
CN , (53)57 62
N
COOEt (54)57
(55)57 SCHEME 5
694
Tong-Ing Ho and Yuan L. Chow N N
N N
N
(56)58
(57)59
(58)6 0
N
, (59)61 6 4 CN CN NC
CH
CH
N
N
(61)65
(60)63
CH3
(CH2 )3 N
O
O
(62)66
(63)67,75
SCHEME 5 (continued )
N
15. Photochemistry of amines and amino compounds
N
(CH2 )n
O
O
O
C
COCH3
(n = 1, 2, 3, 4, 5, 10) (64)68
N
(CH2 )n
(65)69
O
Cl Cl
N
(CH2 )n
N Cl O
Cl
(n = 2, 3, 4, 7) (66)70
(CH2 )n-NR2 NMe2
Ph
_ 73,77
(67)71
(68)74 SCHEME 5 (continued )
695
696
Tong-Ing Ho and Yuan L. Chow N N
Me
NC
CN
CO2 Et
CN (69)76
(70)76 H
N
(71)78
N CN CH2 H (72)79
O
N
O
(CH2 )nN
CHO
(73)80
( n = 1, 2, 3)
(74)81 SCHEME 5 (continued )
15. Photochemistry of amines and amino compounds
697 N
O O
O
NCH2 C
N
N (75)82
(76)83 (SiMe2 )n
(77)84 ,85
Me
NC
N
(n = 2,3,6 ) (78)86 N
(79)87
O
O
N
N
O
CHO N (80)88 (81)89
N
(
)n
( n = 1, 2, 3 ) (82)90
SCHEME 5 (continued )
NO2
O
CH3
698
Tong-Ing Ho and Yuan L. Chow Me N
N
Me (83)98
SCHEME 5 (continued )
in a five-membered ring, emits the b band only. For most compounds, the intramolecular electron transfer is involved in the photoexcitation process even though the extent of electron transfer might not be one hundred percent. III. PHOTOCHEMISTRY WITH SECONDARY AMINES
The intermolecular photochemical reactions of aryl olefins25,91 and arenes92,93 with secondary aliphatic amines result in the addition of an NH bond to the arenes. The products of the reduction and reductive dimerization of the aryl olefins are also observed. The mechanism8 proposed for the stilbene-secondary amine addition (Scheme 6) involves electron transfer quenching of singlet stilbene (t-S) by a ground-state amine to form a singlet exciplex which undergoes NH transfer to form a radical pair; this may either combine, disproportionate or diffuse apart22 . The absence of exciplex fluorescence from singlet stilbene and other arenes with secondary amines may be due to rapid NH transfer which occurs in both non-polar and polar solvents94 96 .
1
t-S*+ R2 NH
1
Ph
+ (t- S /R2 NH) ∗ −
NR2 Ph
Ph
Ph
Ph
Ph
Ph
Ph
+ Ph
NR2
Ph
SCHEME 6
A. With Excited State trans -Stilbene
Irradiation of o-methyl-trans-stilbene with diethylamine in acetonitrile solution results in the formation of two regioisomeric adducts in a 1:1 ratio, together with comparable
15. Photochemistry of amines and amino compounds
699
amounts of reduced stilbene24 (equation 23). Recent focus is on the intramolecular photochemistry of secondary (aminoalkyl) stilbenes24,28,97 . Irradiation of trans-2-[(Nmethylamino)methyl] stilbene 84 results in the slow formation of several products (equation 24). The major product can be converted to the aldehyde 86 (27% isolated yield). Irradiation of trans-2-[2-(N-methylamino)-ethyl] stilbene 87 results in the formation of Nmethyl-2-phenyltetrahydro-3-benzazepine 88 as the only significant product (equation 25).
NEt2
hν
+ Et2 NH
CH3 CN
Me
Me
(23)
NEt2 +
+
Me
CH3 Ph
Ph
H
hν
Ph
+
(24)
N
N
O
Me
Me
H (84)
(85)
(86)
Ph Ph H H
hν
N
Me
(87)
(88)
Me
(25)
700
Tong-Ing Ho and Yuan L. Chow
Irradiation trans-2-[3-(N-methylamino)propyl] stilbene 89 results in the formation of N-methyl-1-benzyltetrahydro-2-benzazepine 90 as the only significant primary photoproduct (equation 26), which in turn undergoes secondary photochemical Ndemethylation. The final mixture contains 90 (38%) and 91 (25%) at high (>95%) conversion. Intramolecular photoadditions of these (equations 24 26) secondary (aminoalkyl)-stilbenes are highly regioselective processes24 . Ph
Ph
Ph Me
H
H
N
H
N
hν
Me
hν
(89)
(90)
(91)
(26) B. With Excited Styrenes
Irradiation of styrenes in the presence of secondary aliphatic amines resulted in the regioselective addition of the NH bond to the styrene25 . The mechanism proposed for the formation of addition and reduction products from ˇ-methylstyrene and diethylamine is outlined by equation 2799 . Electron transfer quenching of singlet styrene by diethylamine followed by regioselective proton transfer to styrene ˇ-C yields a radical pair which combines with the adducts. The escaped ˛-styryl radical can disproportionate or combine. Irradiation of ˛-methylstyrene with diethylamine in deoxygenated hexane solution results in the formation of the regioselective adduct 92 and the reduction products 93 and 94 in approximately equal amounts100 (equation 28). +• − • Et2 NΗ
hν
+ Et2 NH Ph
Ph
•
Ph
+ Et2 N• Ph
NEt2 Ph
+
+ Ph
Ph
(27) + Et2 NH Ph
NEt2
hν
+
+ Ph
Ph
(92)
Ph Ph
(93)
(28)
(94)
15. Photochemistry of amines and amino compounds
701
Intramolecular secondary aminostyrenes 95 97 were also studied100 . N-2,2-Trimethyl3-phenyl-3-buten-1-amine 95 was irradiated to obtain the elimination product 98 (equation 29). Irradiation of N-methyl-4-phenyl-4-penten-1-amine 96 results in a single product 99 in 80% yield by GC analysis (equation 30). Similarily, irradiation of N-methyl5-phenyl-5-hexen-1-amine 97 results in the formation of a single product 100 in 70% yield (equation 31). The photochemistry of the (aminopropyl) indene 101 is also similar (equation 32). H
Me
Me
N
•N
hν
Ph
(29)
•
Ph
Ph
(95)
(98) 50% H hν
N Ph
Ph
Me
(CH2 )3
N
(30)
Me (96)
(99) H hν
N Ph
Me
(CH2 )4
Ph
(31)
N Me
(97)
(100)
N
HN CH2 Ph
(101)
CH2 Ph
(32)
hν
70%
achieved28,99
by irradiation of several High yields of nitrogen heterocycles have been ˇ-[N-methylaminoalkyl] styrenes in which the chain length (n D 1 to 5) (equation 33, n D 1 5) determines the yield, quantum yield and ratio of regioisomeric adducts. The product of addition of nitrogen to the benzylic carbon (b) is exclusive for n D 3, and is predominant for n D 1,2 or 5 (b:a > 10:1 in acetonitrile solution). However, a predominates for n D 4 (a:b D 7:1 in acetonitrile). When n D 1 or 2 the chain length may be too short to allow hydrogen transfer to the ˇ end of the styrene double bond. When the chain is sufficiently long, the intramolecular exciplex would be expected to display chemistry similar to that of intermolecular systems. For intermediate chain lengths (n D 3 or 4) the geometry of the exciplex, as determined by chain folding energies, may determine the regioselectivity of hydrogen transfer. The large isolated yield for n D 2 4 (60 80%) is
702
Tong-Ing Ho and Yuan L. Chow
promising for the synthesis of macrocyclic naturally occuring alkaloids. (CH2 )n
Me N
(CH2 )n hν
(CH2 )n
N
H
+ Ph
Ph n = 1−5
(33)
N
Me
Ph
Me
(a)
(b)
C. With Other Excited Systems
The substituent effects on the photochemistry between benzene and secondary aliphatic amines53 were studied. Irradiation of toluene or chlorobenzene with diethylamine results in the formation of mixtures of addition and substitution products (equations 34 and 35). Irradiation of anisole or benzonitrile with diethylamine gives the substitution product N,N-diethylaniline (equations 36 and 37). Irradiation of benzylfluoride with diethylamine results in a side-chain substitution (equation 38). The photoreaction of p-fluorotoluene with diethylamine gives both substitution and reduction products (equation 39). Me Me Et 2 NH
+
hν
Me
Me +
+
Me H
NEt2
NEt2
H
NEt2
H
NEt2
(34) Cl
Cl Cl Et 2 NH
+
hν
+ H
NEt2
NEt2
H
NEt2
(35) Cl +
+
+ Cl
CH Me
NEt2
H
NEt2
NHEt Et
OMe
H
Et N
(36) Et 2 NH hν
15. Photochemistry of amines and amino compounds Et
703
Et N
CN
(37)
Et 2 NH hν
CH2 F
(38)
Et 2 NH hν
CH2 NEt2 F
Me
Et 2 NH
(39)
+
hν
F H
Me
NEt2
NEt2
The intramolecular photochemistry of 9-[2-(N-substituted aminomethyl)-1-naphthyl]phenanthrenes has also been studied101 (equation 40). The pyrroline derivatives are obtained by the addition of the NH to the C-9 carbon atom of phenanthrene ring. Reasonable yields for the highly regioselective products are obtained by irradiation in benzene solution.
R1 CH2
CH2 N R2
hν
∆
R1
(40)
(102) R1 = C6 H5 , R2 = H (103) R1 = CH3 , R2 = H (104) R1 = C6 H11, R2 = H (105) R1 = t−C4 H9 , R2 = H
704
Tong-Ing Ho and Yuan L. Chow IV. PHOTOCHEMISTRY INVOLVING PRIMARY AMINES AND AMMONIA
The intermolecular fluorescence quenching of the singlet trans-stilbene and primary aliphatic amines have been studied8 . The free energy for electron transfer from ground state ethylamine to singlet stilbene was calculated to be endothermic (0.8 eV). Thus, neither electron transfer fluorescence quenching nor exciplex formation are observed for the ethylamine and stilbene system. The low observed rate constant for fluorescence quenching of styrene by butylamine is also due to the high oxidation potential of the primary amine99 . Direct irradiation of stilbene8 or styrene99 with a primary amine does not result in any addition products, while irradiation of primary styrylamine 106 in acetonitrile solution results in both isomerization and intramolecular addition to yield a mixture of a and b adducts (equation 41). The ratio of b/a is about 1.4.
hν
Ph
N
NH2
H
+ Ph
Ph (106)
(41)
N H
(a)
(b)
Intramolecular fluorescence quenching of phenylalkylamines 107 have been studied earlier102 but no exciplex was observed. An exciplex is believed to be an intermediate in the intramolecular styrylamine 106 photoreaction99 .
(CH2 )nNH2 n = 1, 2, 3 (107)
Photochemical addition of ammonia and primary amines to aryl olefins (equation 42) can be effected by irradiation in the presence of an electron acceptor such as dicyanobenzene (DCNB)103 106 . The proposed mechanism for the sensitised addition to the stilbene system is shown in Scheme 7. Electron transfer quenching of DCNBŁ by t-S (or vice versa) yields the t-S cation radical (t-S)C. . Nucleophilic addition of ammonia or the primary amine to (t-S)Cž followed by proton and electron transfer steps yields the adduct and regenerates the electron transfer sensitizer. The reaction is a variation of the electrontransfer sensitized addition of nucleophiles to terminal arylolefins107,108 . + NH2 R
+
hν
NHR
RNH2
DCNB
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(42) Irradiation of an equimolar mixture of t-S and DCNB in 9:1 acetonitrile water solution containing ammonia results in the formation of 1,2-diphenylethylamine in 46% yield106 .
15. Photochemistry of amines and amino compounds
705
hν, CH3 CN/H2 O +
t-S
t-S
− DCNB
DCNB
Ph
Ph
Ph
RNH2
Ph
NHR
+ NH2 R
SCHEME 7
The regiochemistry for the substituted t-S with ammonia and DCNB was also studied (equation 43). When there is an alkoxy substituent on the para position, the reaction yields selectively 1-amino-2-aryl-1-phenylamine (equation 44). NH2 CH
+ NH3
CHPh
hν
CH2 CHPh
DCNB
Xn
Xn (a)
(108)
(43) NH2 +
CHCH2 Ph Xn (b)
R1 R2
CH R3
R4 + NH3
CH
(109) R2
hν
DCNB
(44) R1
R3
CH2 CH NH2
R4
706
Tong-Ing Ho and Yuan L. Chow
The photoamination of t-S having a methyl or chloro group in the para position or a methoxy group in the meta or ortho positions gave non-selective adducts. Irradiation of the primary aminoethyl and aminopropylstilbenes in acetonitrile water solution in the presence of DCNB results in the formation of isoquinoline and benzazepine products in good preparative yields24,28 (equations 45 and 46). The preparation of benzazepine represents an improvement in overall yield when compared to previously reported nonphotochemical synthetic routes. Ph
Ph
hν, DCNB
NH2
NH
(45)
CH3 CN/H2 O
(110)
(111) Ph
Ph
NH2
NH
hν , DCNB
(46)
CH3 CN/H2 O
(112)
(113)
Photosensitized amination of several aromatic compounds including phenanthrene, anthracene, naphthalene with ammonia or primary amines has also been investigated106 (equations 47 49). NHR
+ RNH2 (or NH3 )
hν, m −DCNB MeCN−H2 O
(47) NR2
+
R2 NH (R = H or Me)
hν, DCNB MeCN−H2 O
(48) NH2
+ NH3
hν, DCNB MeCN−H2 O
NH2
+
(49)
15. Photochemistry of amines and amino compounds
707
Recently, a photosensitized synthesis of phenanthrene heterocycles from 1- and 9-(aminoalkyl)phenanthrenes has been achieved109 . Irradiation of 1-(2-aminoethyl)phenanthrene and m-DCNB in 9:1 acetonitrile water solution for 2 hours gives 70% of the aporphine 114 and 15% of the dehydroaporphine 115 with 87% conversion of starting material (equation 50). NH2 NH
NH
hν
+
CH3 CN/H2 O DCNB
(50)
(114) 70%
(115) 15%
Irradiation of the 9-(2-aminoethyl)phenanthrene (equation 51) under the same conditions but for 70 hours produces phenanthro[1,10-d,e]piperidine 116 and 9methylphenanthrene 117. NH NH2
Me hν, DCNB
+
MeCN−H2 O
(51)
(116) 30%
(117) 10%
Irradiation of the 1-(3-aminopropyl)phenanthrene (equation 52) for 3 hours results in the formation of the hexahydrophenanthro[10, 1-b,c]azepine 118 (68%) and 119 (12%) with 81% conversion. Irradiation of 9-(3-aminopropyl)phenanthrene (equation 53) for 4 hours results in the formation of 9,10-dihydrophenanthrene[9,10b]piperidine 120 (13%), phenanthro[9,10-b]piperidine 121 (22%) and 1-aza[5,6;7,8dibenzo]spiro[4,5]decane 122 (4%). NH2
NH
hν, DCNB
NH +
MeCN−H2 O
(118)
(52)
(119)
708
Tong-Ing Ho and Yuan L. Chow
NH2 hν, DCNB MeCN/H2 O
NH
(120)
(53)
NH +
+ NH
(121)
(122)
The triplet reaction of 2-nitrodibenzo[b,e][1,4]dioxin with primary amines (npropylamine and benzylamine) was studied110 in polar and apolar solvents. In polar solvents, the irradiation results in the formation of two isomeric compounds, (alkylamino)hydroxynitrodiphenyl ether and N-(alkylamino)-2-nitrophenoxazine (equation 54). In apolar solvents, only the nitrophenoxazine is obtained. In polar solvents, the exciplex formed between the 2-nitrodibenzo[b,e][1,4]dioxin triplet state and amines dissociates to the solvated radical ions, from which the diphenyl ether arises. 1Nitrodibenzo[b,e][1,4]dioxin is stable even on prolonged irradiation. OH
O
NHR
NO2 hν
O
RNH2 (R = n −C3 H7 ; PhCh 2 )
O (123)
NO2
(124) OH
NHR NH
+
+
O NO2 (125)
NO2
O (126)
(54)
15. Photochemistry of amines and amino compounds
709
The photochemical reaction between substituted benzenes and t-butylamine gave a mixture of addition and substitution products53 (equations 55 57). Cl Cl hν
+
t-BuNH2
+ Cl H
NHBu-t
H
NHBu-t (127)
(129)
(128)
NHBu-t (130)
(55)
Cl Cl +
+ H
NHBu-t
H
NHBu-t (132)
(131)
Cl
hν
(56)
t-BuNH2
NHBu-t CH2 F hν
+
t-BuNH2
CH
(57)
NHBu-t
CH2 NHBu-t
In the case of toluene and t-butylamine (equation 58), a novel acyclic adduct is obtained. Me Me hν t-BuNH2
+ Me NHBu-t
H
H
NHBu-t
Me +
Me
C Me
N
CH
CH
CH
CH
CMe2
(58)
710
Tong-Ing Ho and Yuan L. Chow
The solid state photochemistry of the salts of carboxylic acids with optically active primary amines has been studied111 . Enantiomeric excesses ranging from 14 80% can be achieved (equation 59). COOY COOY
EtOOC
COOEt
hν
COOEt
COOY
(59) +
H Y= H,
H
+ N
H
H
,
MeOOC
HOOC
H
+ N
+ N
H
,
HOCH2
V. PHOTOCHEMISTRY OF IMINE AND IMINIUM SALTS The photochemistry of imine chromophores shows similarity to the ethylenic or carbonyl group. For example, the imine double bond undergoes syn anti photoisomerization112 , photocyclization113 , cycloaddition114 and intramolecular hydrogen abstraction115 (equation 60). Earlier reviews on the photochemistry of imine compounds are available116 . More recent reviews on the photochemistry of imine and iminium salts are also available117,118 . Ph
Ph NHR
NR
(60)
hν
CH3
CH2
R = Ac
A. Photoinduced Electron Transfer Chemistry of Iminium Salts
The energies calculated for the electron transfer from electron-rich olefins to excited conjugated iminium salts are energetically favourable118 . Thus, electron-rich olefins are excellent fluorescence quenchers of 2-phenyl-1-pyrrolinium perchlorate 133119 . The
15. Photochemistry of amines and amino compounds
711
photochemistry between excited 133 and cyclohexene in methanol to obtain the addition product 134 and the methanol adduct 135 is illustrated in equation 61. ClO4 + N
Ph
−
Ph
hν
+
MeOH
N
H
H
(133)
(134) 31%
(61) Ph
OMe
+ N H (135) 18%
The mechanism for the photoreaction between 133 and cyclohexene can be summarized as in Scheme 8. The initiating electron transfer fluorescence quenching of 133 by cyclohexene resulted in the formation of an ˛-amino radical radical cation pair 136. Proton transfer from the 2-position of the cyclohexene radical cation to the nitrogen atom of the ˛-amino radical leads to another radical cation radical pair 137. Recombination of 137 at the radical site affords the adduct 134, while nucleophilic attack at the cation radical of 136 leads to another radical pair 138 which is the precursor for the adduct 135. Electron-poor olefins with higher oxidation potentials may decrease the rate of electron transfer and other processes competing for deactivation of the iminium salt excited states may increase. Alternate reaction pathways involving olefin-arene 2 C 2 cycloaddition may take place in the photochemistry of 133 with electron-poor olefins (equation 62)120,121 .
N + N
Ph Cl O4 −
H (133)
+
CH2
CRZ
hν
R
(139) R = H, Z = CN
Z
(140) R = H, Z = CO2 Me
H
(141) R = Me, Z = CO2 Me
+N R Z
H
(62)
H
(142) R = H, Z = CN (44%) (143) R = H, Z = CO2 Me (52%) (144) R = Me, Z = CO2 Me (54%)
712
Tong-Ing Ho and Yuan L. Chow +
+ N
ClO4
hν
+
Ph
Ph
N
SET
H
−
H
H
(136) (133)
−H+
Nuc
OMe
+ N H
Ph Ph
N
H
H (137)
(138)
Ph
OMe
Ph
+
N H
N H
H
(134)
(135) SCHEME 8
Intramolecular electron transfer initiated cyclization reaction of N-allyliminium salt systems may also generate 3-pyrrolidinyl ethers or alcohols in monocyclic and bridged or fused bicyclic systems (e.g. equations 63 65)122,123 .
+ N R
R = H or Me
N
hν
CHPh Me
MeO
H MeOH
H (63)
Me R
Ph
(25 − 28%)
15. Photochemistry of amines and amino compounds R Me
Me
hν
+ N
Ph
N
OR′
MeOH or H2 O
R
713
(64) Ph ( 22 − 58%)
R = H or Me
R
+ R N ClO − 4
hν
N
MeOH
(65) OMe
(58 − 68%)
R = Ph or CH C(Me)2
Selective generation of 2-aza-1,5-diradicals 146 through nucleophilic addition to the less substituted positions of the cation radicals 145 arising by intramolecular electron transfer was attributed to the cyclization regiochemistry (equation 66). H
H
N
+ •C R
N
Nu
C •
R
H
Nu
R
C •
(145)
Nu
R
N
(66)
R R
C •
(146)
The efficient photoaddition reactions between pyrrolinium perchlorate (133) and benzyltrimethylsilane (equation 67) or the allylsilane (equation 68) are examples of the initial electron transfer induced desilylation processes.
+ N
ClO4
−
+ PhCH2 TMS
Ph
Ph
hν MeOH
Me
+ PhCH2 CH2 Ph N
CH2 Ph
(67)
Me
(133) + N Me (133)
ClO4
−
Ph
+ TMSCH2 CH
CHTMS
Ph
hν MeCN
H
N Me
TMS
(68)
714
Tong-Ing Ho and Yuan L. Chow
The allylsilane-iminium salt photochemistry has been found useful for the development of novel spirocyclization methodologies (equation 69)124,125 .
Me
Me
+ N
TMS ClO4 −
RO
N
hν MeCN (90%)
RO
(CH2 )n
(CH2 )n
(147) R = Me, n = 1 (148) R = Me, n = 2
(149) R = Me, n = 1 (150) R = Me, n = 2 (69)
The iminium salt photoaddition reaction has been applied to the synthesis of Nheterocyclic systems (equation 70)126,127 .
N
+
ClO4 − N hν
(70)
(80%)
Me3 Si
Total synthesis of the representative protoberberines, (C)-xylopinine 151 (equation 71) and (C)-stylopine 152 (equation 72), have been achieved using silylarene-iminium salt photochemistry128 . The photochemical routes appear to be superior to alternative groundstate methods involving dipolar cyclizations. MeO
MeO N+
MeO
ClO4 −
N
MeO hν (70%)
Me3 Si
OMe
OMe
OMe
OMe (151)
(71)
15. Photochemistry of amines and amino compounds
715
O
O ClO4 −
N+
O
N
O hν
O
Me3 Si
(61%)
O
O
O (152)
(72) B. The Aza-di-p-methane Rearrangement
The extension of the di--methane rearrangement from 1,4-dienes and ˇ,-unsaturated ketones to the use of 1-aza-1,4-dienes has been achieved129 (equation 73).
hν
Ph
N
Ph
H3 O+
Ph
Ph
PhCOMe
Ph
Ph
CHO
Ph N
Ph
(73)
(40%)
Acyclic ˇ,-unsaturated oxime ethers are found to undergo both cis trans isomerization and NO bond fission130,132 (equations 74 and 75). Me
Me
Me
Me
Ph
Ph hν
(74)
N
Me
N
Me
Me
Me
OMe
MeO
Me
Me
Ph
Me Ph
O
EtOH
N
Me
Ph
hν
O MeO
OMe
Me
Me
Ph + N
CN
(75)
O
(18%)
(27%)
Cyclic ˇ,-unsaturated oximes 153 did undergo aza-di--methane rearrangement131 (equation 76). OH
OH
N
N
MeO hν R = H, Me
R (153)
MeO
R
(76)
716
Tong-Ing Ho and Yuan L. Chow
Various substituted ˇ,-unsaturated imines (equation 77) did undergo aza-di--methane rearrangements via triplet states132,133 . R3
R3
R3
R2 hν
Ph
Ph
R3 H3 O +
R2
Ph
N
R3
Ph
R1
R3
Ph R2
Ph N
O
(77)
R1 R1 = Ph, PhCH2 , (CH3 )2 CH − R2 = H, Me R3 = Me, Ph
The introduction of an electron-withdrawing group such as acetyl at the oxime oxygen will decrease the intramolecular electron transfer reaction from the nitrogen lone pair and will enhance the aza-di--methane rearrangement134 138 (equation 78). R2
R2
R2
R3 hν
R1
R1
Sens •
N OAc
R2
R1
R3
R1
(78)
N OAc R1 = Me, Ph
(20 − 90%)
R2 = Me, Ph R3 = H, Me
Other oxime ether derivatives, such as semicarbazones or benzoyl compounds, hydrazones undergo efficient aza-di--methane rearrangement139 (equation 79).
Ph
Ph
hν Sens •
N R
Ph
(79)
Ph N R
R = OCOPh , NHCOPh , NHCONH2
15. Photochemistry of amines and amino compounds
717
C. Photochemistry of Azirines
The irradiation of 2H-aryl azirines yields nitrile ylides which can be trapped by various dipolarophiles to form five-membered ring heterocycles116,140 142 (equations 80 82).
Ph Ph hν
N H
N
EtO2 CN
CO2 Et
N
(80)
NCO2 Et
CO2 Et
N
H
CO2 Et
CO2 Et NMe2
O
C
H Ph
Ph
(81)
hν
+
N
N NMe2
(60)% Ph
Ph
Ph
S
S +
N
O
hν
N
S
Ph
N
Ph N
(82)
S (86%)
Ph
D. Stilbene-type Photocyclizations
N-Phenylbenzylimines undergo stilbene-type photocyclizations (equation 83) to yield heterocyclic compounds143 . The reactions usually take place via the iminium salt and need oxidants like oxygen or iodine. Six-electron electrocyclic reactions have been observed for 1-aza-1,3-dienes144 (equation 84).
N
(83)
hν H2 SO4
N
718
Tong-Ing Ho and Yuan L. Chow
Ph
Ph hν
R
N
Ph
R
N
H
OCOPh
Ph
OCOPh
R = H, OMe, Cl, Me
(84)
Ph
R
N
Ph
(33-70%) Similar reactions have also been observed for 1-azadiene 154145 (equation 85), 4aryloxy-2-azabuta-1,3-dienes146 (equation 86), 1-styrylpyridinium salts147 (equation 87) and diaza-1,3-dienes148 (equation 88).
OMe
OMe
N
N hν
CONEt2 (154)
CONEt2 − MeOH (85)
OMe N
CONEt2 (80%)
15. Photochemistry of amines and amino compounds
Ph Ph
Ph
Ph hν
ArO2 C Ph
N + H − ClO4
719
Ph N
ArO2 C
H
Ph H2 O
(86)
Ph Ph N
O Ph
−
−
X + N
hν
X + N
O2
hν
(87) −
X + N
(60%)
720
Tong-Ing Ho and Yuan L. Chow
Ph N
Ph
OR
N
N
hν BF 3
N
Ph
(88)
OR
Ph R = H, PhCO
(13- 44%)
E. Other Reactions of Imines
Unlike ketones and alkenes, aliphatic imines are reluctant to undergo photoinduced (2 C 2) cycyoadditions. For example, the cyclohexanimines of acetone and its derivatives were studied149 . Compound 155 undergoes photoaddition with deuterated acetone, but the oxazetidine 156 decomposes to acetone and hexa-deuterioimine 157 (equation 89).
C6H11
Me Me C
C6H11 + N
(CD3)2 CO
hν
N
Me
CD3
O
Me
CD3
(155)
(156)
D3C
C6H11 C
+ (Me)2CO
N
D3C (157) (89) However, the cyclohexanimines of 1,3-difluoro-2-propane 158 do undergo photochemical 2 C 2 cycloaddition (equation 90).
CH2 F CH2 F
FH2 C C
N
FH2 C
C6 H11
hν acetone
N N
C6 H11 (158)
(100%)
C6 H11
CH2 F CH2 F
(90)
15. Photochemistry of amines and amino compounds
721
Intramolecular cycloaddition of an oxime ether 159 to yield an azapropellane 160 is also known150 (equation 91). CO2 Et
CO2 Et N
hν
(91)
N OMe
OMe (159)
(160) 70%
Photochemical Beckman rearrangement of oximes results in the formation of carboxamides as the major product151 (equation 92). N X
OH
C
O hν
X
C
H
NH2
(92) OH N +
X
C H
Recent studies with (C) fenchone or with (C) camphor (equation 93) indicated that 1:1 ratio of isomeric lactams is obtained152 . CONH2
H hν
+
MeOH
N
O N H
OH (32%)
(12%)
(93)
+
NH
+ O O
O (12%)
(6%)
Photochemical hydrogen abstraction reaction for the silylimine 161 give an oquinodimethane intermediate 162 which could be trapped with dimethyl fumarate, dimethyl maleate, trans-methyl cinnamate, methyl acrylate, acrylonitrile (equation 94)
722
Tong-Ing Ho and Yuan L. Chow
and imine 161 itself152 (equation 95).
Me hν
N H
CN
SiMe3
NHSiMe3
(161)
(162)
(94)
CN H2 N
CN
H
NHSiMe3 Me
161 + 162 N SiMe3 NHSiMe3 (95)
Me
N
VI. PHOTOCHEMISTRY OF AMIDES AND IMIDES A. Amides
Photoreactions of the amide group include the Photo-Fries rearrangement153 (equation 96), the photoaddition of formamide to a terminal alkene154 (equation 97), ˛-cleavage155 (equation 98), ˇ-cleavage156 (equation 99), electron transfer initiated cyclization157 (equation 100), stilbene-type oxidative cyclization158 (equation 101) and
15. Photochemistry of amines and amino compounds
723
Norris-type hydrogen abstraction159 (equation 102).
O NHC
NH2
NH
Me
MeC
NH2
0
COMe +
hν
(96)
cage
COMe NH2
+
CH3 (CH2 )7CH
CH2 + HCONH2
PhCON(Me)2 +
Ph
hν
(97)
CH3 (CH2 )9 CONH2
(67%)
hν
PhCOCH2 CH(Ph)2
(98)
Ph
PhCONH(CH2 )2 NEt2
hν
PhCONH2
HO
(99)
OH hν
−
Cl
+
HN
HN Cl O
O
HO NH O (100)
724
Tong-Ing Ho and Yuan L. Chow O O
O NH
O O
hν I2
O O
(101)
O NH
O
O (70%)
OH O
Me
Ph N(CHMe2 )2
hν
Me
Ph
O
O
(102)
N CHMe2
In addition, recent studies of amides include the 1,3-acyl migration of enamides to obtain the enamines through a photo-Fries like mechanism (equations 103160 and 104161 ). Me
Ph
Me
Me
Me
hν
H
N
O
NHMe
Ph
Me
(103)
O (100%) O R
O hν
R
N
(104) NH2
H R = Ph, Me
(85%)
Enamides 163 undergo photochemical conrotatory six-electron electrocyclic reactions to yield the dihydro intermediate 164, which in turn yields the trans-fused cyclic product 165 (equation 105) by a (1,5)-suprafacial hydrogen shift. Several natural product syntheses like that of benzylisoquinoline and indole type alkaloids can be achieved by this type of photocyclization (equations 106163 , 107164 , 108165 and 109166 ).
15. Photochemistry of amines and amino compounds
N
O
725
OH
N
H hν
163
H
(105) H
H [1,5]H
H
shift
N
O
N
OH
H
164
165
MeO MeO N
O
MeO
hν
+
N
O−
MeO O O
(106)
NaBH4
MeO N
O
MeO H H O
(77%) H
726
Tong-Ing Ho and Yuan L. Chow O−
O CH2 Ph N
+ N
hν
CH2 Ph
MeOH
R1
R2
R1
R2 I2
(107) O CH2 Ph N
R1
R2 (88%)
O OMe
N
CO2Me N H hν
(108)
O N
N H CO2Me (60%)
O
O
O
H H
N
H O N
Me
Me H hν
NaBH4
N R
N R
(109)
15. Photochemistry of amines and amino compounds
727
The enamide 166 react with the cation radical of cyclohexadiene, which is generated by sensitized electron transfer with the photoexcited dicyanobenzene (DCB), to generate a Diels-Alder type adduct (equation 110)167 . + Me
+
N
hν
Me
+
DCB
N
Ac
Ac
(166)
(110)
H
Me N
H
Ac
Dienamides such as 167 react by a different reaction pathway168 , namely by addition of the amide oxygen to the alkene by a radical addition reaction (equation 111).
O
hν
O
O NH
R
R R = Ar, Me
R
N
N
H
(167)
(111) Chiral induction to obtain the ˇ-lactam 169 by photolysis of the chiral crystal 168 in the solid state is possible (equation 112). O C
Ph
C O
Ph CHMe2
OH
hν
Me Me
N
N CHMe2
(168) (−)-crystal
O
(112)
CHMe2 (−)- (169)
The photoreaction of N-(12-dodecanoic acid)-benzoylformamide 170 in solution and in ˇ-cyclodextrin or carboxymethylamylose complexes indicated that major products are those of hydrolysis to mandelamide 171 and to the corresponding aldehyde 172 (equation 113)169 .
728
Tong-Ing Ho and Yuan L. Chow
O
OH
H N
Ph
CH2 (CH2 )10 CO2 H
CH
hν
NH2
Ph
C
O
O
(170)
(171)
(113)
O +
H
C (CH2 )10 CO2 H (172)
The intramolecular photochemistry of the vinylogous amide 173 in tert-butyl alcohol yielded a retro-Mannich type reaction product 174 (equation 114)170 .
O
O H hν
(CH2 )2 N H
N (174)
(173)
(114) Compared to amides, the photochemistry of thioamides was less studied. The 2substituted aryl thioamide 175 undergoes photocyclization to quinoline derivatives (equation 115)171 .
R2
R2 hν
N H
C
R1
(115)
N
1
R
S (175) Thioamides 176 react photochemically with 2,3-dimethyl-2-butene in the absence of oxygen to give ketones (equation 116)172 . In the absence of oxygen, the photoproducts of 176 include nitriles, 1,2,4-thiadiazole and isothiazoline (equation 117).
15. Photochemistry of amines and amino compounds
729
Me S
Me
ArC
Me
+
NH2
C
hν
C
Me
S
N2
Me
Me
Ar
(176)
Me
NH2 Me
(116)
hν
NH Ar
Ar
S
hν
C
O2
NH2
O
C
Ar
CHMe2 + N
C
Ar
S
−
C
CHMe2
ArC
N + S
ArCN
Ar N
Me Ar
N
(117)
Me
Ar
Me
N
S
S
Me
Primary thioamides undergo photochemical hydrogen sulphide extrusion in the absence of oxygen (equation 118)173 . S RC
NH2
hν
RC
N2
(118)
N + H2 S
Finally the effects of conformation, hydrogen bonding and Lewis acids on the intramolecular electron transfer, spectroscopy and photochemistry of amides were recently studied174 176 (equations 119 121). O R3 N X
R1
R2
R1 hν
X
R2
N
O
R3 X = H , CF3 , OMe R1 , R2 , R3 = H , Me
(119)
730
Tong-Ing Ho and Yuan L. Chow
Me
H N O
Me N
N H
N Me Me
O
(120)
O
O
Me
R N
N
Me
R
(121)
R = Me, C4 H9 , CH2 CH2 NMe2 , CH2 CH2 CH2 NMe2 , CH2 CH2 NMePh The first example of a counterthermodynamic one-way E ! Z photoisomerization based upon intramolecular hydrogen bonding was reported for the N-methyl-3-(2-pyridyl)propenamide systems. B. Imides
There are several reviews available on the photochemistry of imides177 . The photochemistry of N-alkylphthalimides (equation 122) has been extensively studied178 . Photochemical cyclization, ˇ-cleavage and hydrogen atom transfer reactions are caused by intramolecular υ-H atom abstraction from the T1 (Ł ) state of the phthalimide carbonyl group. The reaction is dependent on the solvent used. Benzazepinedione formation is observed in ethanol while ˇ-cleavage and H-transfer occur in acetone and acetonitrile. Both intermolecular and intramolecular electron transfers are important pathways for imides179 . For example180 , irradiation of N-allylphthalimide in methanol results in intramolecular electron transfer to yield the radical ion pair 177a followed by an anti-Markovnikov addition of the methanol to produce the biradical 177b. The cyclized products 178 and 179 are derived from the biradical intermediate (equation 123). The macrocyclic compound 180 was also synthesized using this methodology180 (equation 124). When a heteroatom such as nitrogen, oxygen or sulphur is introduced into the N-alkyl side chain of the phthalimide, photoinduced electron transfer to generate radical ion pairs becomes feasible181 . Proton transfer from the methyl or methylene group adjacent to the heteroatom gives a diradical which will cyclize the products (equation 125). When the substituent is methylthio (MeS) rather than dimethylamino (NMe2 ), the chemical yield increases and medium to large rings containing 38 atoms can be achieved182 .
15. Photochemistry of amines and amino compounds
731
O
O
N
(CH2 )2 CH3
hν
N
OH
O O O
O
N N
(122)
NH
HO HO
H
O
O NH
O O−
O
+ N
hν MeOH
N
O
O (177a) MeOH
OMe OH
HO OMe
(123)
N
N
O
O (177b)
(178) 41% OMe HO +
N
O (179) 41%
732
Tong-Ing Ho and Yuan L. Chow O O N (CH2 )n
O
O
CH2
CH
O
CHPh
MeOH hν
Ph
(124)
OMe O
HO O
(CH2 )n
N O O (180) 60%
O
N
(CH2 )nCH2
X
CH3 hν
O O
N
(CH2 )nCH2
+• X
CH3
• −H
O−
+
O
O
N
+
(CH2 )nCH2
•
• CH2 X
OH
N
X
CH3
OH
O
O
N
N
(CH2 )n CH2
HO
(CH2 )nCH2 •
•
CH2
CH2
X
(CH2 )n HO XMe
(78%; n = 4, X = S)
(6%; n = 4, X = S)
(125)
15. Photochemistry of amines and amino compounds
733
For the intermolecular interactions between N-methylphthalimide and alkenes, two reactions paths are possible183 . The first is the regio- and stereocontrolled 2C2 cycloaddition of the alkene to the CN bond to generate dihydrobenzazepinedione (equation 126), while the second is the electron transfer initiated addition(equation 127). O
O Me N
hν
Me +
(126)
Me
N
O
Me
O
O
N
Me
Me
Me
Me
Me +
O hν
O Me N
Me +
•
+
•
Me
Me Me
O−
O
HO
O
N Me
Me +
CH2
Me
N Me HO
(in MeCN)
CH2
Me OMe Me
(in MeOH)
(127) Intramolecular (2 C 2) photocycloaddition is possible for the bis-methacryl-Narylimide184 (equation 128). Me
O NAr
Me
O
Me hν
Me
O NAr
Me
O (major)
+
O NAr
Me
O
(128)
734
Tong-Ing Ho and Yuan L. Chow
Both saturated or unsaturated thioimides and dithioimides behave like thioketones in their photocycloaddition reaction with alkenes (equation 129) and alkynes (equation 130)185 .
Ph S
S Ph
Ph hν
NMe +
(129)
NMe
Ph O
O Ph S
S
Ph NMe + PhC
hν
CPh
(130)
NMe
O
O
Dithioamides behave similarly186 (equation 131) but, in the presence of steric hindrance in addition to the thiocarbonyl groups, the photoaddition will become regioselective187 (equation 132). Intramolecular photocycloaddition will lead to the formation of strained polycyclic thietanes188 (equation 133). Hydrogen abstraction by the thioamide functional group is also possible189 (equation 134).
Me S
Me
N
S
S +
N
S
hν
(131)
(86%)
S
S Me
Me Me
N
Me +
hν
N
Me
Me (132)
S
S
(50%)
15. Photochemistry of amines and amino compounds
735
Me S
S
Me (133)
hν
N
N S
S
(80%) Ph S
HS N
Ph
hν
(134)
N
S
O
Sulphenamides190 are photochemically active and undergo homolytic cleavage of the SN bond. The products are derived from the sulphur- and nitrogen-centred free radicals (equation 135). Oxygen atom transfer from a neighbouring nitro group to the sulphur is also observed191 (equation 136).
NHMe Me PhS
hν
N Ph
+ PhS
NHMe
SPh
(135)
NHMe + PhSSPh
+
Me S
N
Me O2 S
NMe2
N
NMe2
H2 N
O2 N hν
NO2
NO2 (136)
736
Tong-Ing Ho and Yuan L. Chow
Similarly to the sulphenamides, the photochemistry of isothiazole is initiated by the fission of the weakest SN bond192 (equation 137 and 138).
H O
S hν
S N
S•
O
Ph
•N
O
N Ph
Ph
(137)
S O N Ph O
O
Me
N
hν
Me
N• S•
S
O
O
NH
N
S
S H
Me
Me (60%)
(138) The photochemical deprotection of sulphonamides to free amines is synthetically useful193 . This process is caused by electron transfer from an electron-donating sensitizer such as 1,2-dimethoxybenzene or 1,4-dimethoxybenzene and the presence of reductants like ammonia or hydrazine is also required194 (equation 139).
15. Photochemistry of amines and amino compounds
737
MeO
MeO hν
N
MeO
NH CH3
SO2
MeO
CH2 Pr
CH2 Ph (100%)
(139) Extrusion of sulphur dioxide by a free radical mechanism can also lead to several ring-closing or ring-opening reactions. For example, intramolecular reaction of the enone 181 to the 3-substituted enone is accompanied by a phenyl shift195 (equation 140). Free radical ring closure may lead to the formation of useful heterocycles such as azetidine196 (equation 141) or carbazole197 (equation 142). In the absence of an external nucleophile such as n-butylamine, photochemical ring closure of sultam 182 affords a pyrrole. Trapping of the NS ruptured intermediate is also possible198 (equation 143). O
O•
R
R N
N SO2 Ph
hν
SO2 •
C6 H6
Ph (181)
(140) O
O NR
NHR
Ph
Ph (65%)
R = CHMe2
CH2 SO2
hν
N
N
Me
Me
N Me (60%)
(141)
738
Tong-Ing Ho and Yuan L. Chow SO2
hν
(142)
N N H
Ph
hν
SO2
SO2
N
N
NPh
Ph
(182)
Ph
(60%)
n-C4 H9 NH2
CH2 SO2 NH-(C4 H9 ) NPh (60%)
(143) Ring expansion of the sulphonamide reaction199 (equation 144) demonstrates the ability of a ruptured sulphur-centred free radical to undergo 1,3-Fries type migration200 (equation 145). Sulphur dioxide extrusion may also provide a synthetic route to ˇlactams201 (equation 146). Me Me O2 S
O2 S
(144)
N
Me
hν
N
Me N
H
N
Me
Me
SO2 Ph RN
NHR
NHR SO2 Ph
hν
(145)
+
SO2 Ph
15. Photochemistry of amines and amino compounds O2 S
739
Ph hν
N
N
+
O
O
(146)
N O
(major)
The amide functionality plays an important role in the physical and chemical properties of proteins and peptides, especially in their ability to be involved in the photoinduced electron transfer process. Polyamides and proteins are known to take part in the biological electron transport mechanism for oxidation reduction and photosynthesis processes. Therefore studies of the photochemistry of proteins or peptides are very important. Irradiation (at 254 nm) of the simplest dipeptide, glycylglycine, in aqueous solution affords carbon dioxide, ammonia and acetamide in relatively high yields and quantum yield (0.44)202 (equation 147). The reaction mechanism is thought to involve an electron transfer process. The isolation of intermediates such as N-hydroxymethylacetamide and N-glycylglycyl-methyl acetamide confirmed the electron-transfer initiated free radical processes203 (equation 148). + H3 N
CH2
C
NH
COO−
CH2
hν
CH3 CONH2 + CO2 + NH3
(147)
O O
− O
O
+ H3 NCH2 CNHCH2 C
− O
hν
O + H3 NCH2 CNHCH2 C •
O O•
• CH CNHCH • 2 2
O
O
O
CH3 CNHCH2 OH + CH3 CNHCH2 NHCH2 CNHCH2 CO2 H
(148) Terminal deamination is also a major step in gamma ray reactions with aliphatic oligopeptides in aqueous solution204 . This confirms that the amide group tends to react with the solvated electron. Ring opening of the pyrrolidine also occurs in the photolysis of pyrrolylglycine which is without a primary free amino group205 (equation 149). − O H N
+ N H
C
O hν
C C H2
H2 N(CH2 )4 CNHCH2 OH + CO2
(149)
O
O
As for the photophysical aspects for the bio-mimic photoinduced electron transfer systems, studies on amides206 and amino acid assemblies207 have recently begun to be popular.
740
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743
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T. Naito, N. Kojima, O. Miyata and I. Ninomiya, J. Chem. Soc., Chem. Commun., 1611 (1985). A. Couture and P. Grandclaudon, Synthesis, 576 (1986). T. Naito, E. Doi, O. Miyata and I. Ninomiya, Heterocycles, 24, 903 (1986). (a) T. Naito, Y. Tada, Y. Nishiguchi and I. Ninomiya, J. Chem. Soc., Perkin Trans. 1, 487 (1985). (b) I. Ninomiya, C. Hashimoto, T. Kiguchi and T. Naito, J. Chem. Soc., Perkin Trans. 1, 941 (1985). (c) T. Naito, Y. Hirata, O. Miyata and I. Ninomiya, J. Chem. Soc., Perkin Trans. 1, 2219 (1988). (d) I. Ninomiya and T. Naito, Photochemical Synthesis, Academic Press, New York, 1989, 176. 167. N. L. Bauld, B. Harirchian, D. W. Reynold and J. C. White, J. Am. Chem. Soc., 110, 8111 (1988). 168. C. Bochu, A. Couture, P. Grandclaudon and A. Lablache-Combier, Tetrahedron, 44, 1959 (1988). 169. W. G. Richard, C. A. Chesta and D. G. Whitten, Photochem. Photobiol., 54, 557 (1991). 170. F. M. Schell and P. M. Cook, J. Org. Chem., 49, 4067 (1984). 171. (a) P. de Mayo, L. K. Sydnes and G. Wenska, J. Chem. Soc., Chem. Commun., 499 (1979). (b) P. de Mayo, L. K. Sydnes and G. Wenska, J. Org. Chem., 45, 1549 (1980). 172. M. Machida, K. Oda and Y. Kanaoka, Tetrahedron Lett., 25, 409 (1984). 173. G. Crank and A. Mursyidi, J. Photochem. Photobiol. A: Chem., 53, 301 (1990). 174. F. D. Lewis, J. E. Elbert, A. L. Upthagrove and P. D. Hale, J. Org. Chem., 56, 553 (1991). 175. (a) F. D. Lewis, C. L. Stern and B. A. Yoon, J. Am. Chem. Soc., 114, 3131 (1992). (b) F. D. Lewis and B. A. Yoon, J. Am. Chem. Soc., 59, 2537 (1994). 176. (a) F. D. Lewis, S. V. Barancyk and E. L. Burch, J. Am. Chem. Soc., 114, 3866 (1992). (b) F. D. Lewis and E. L. Burch, J. Am. Chem. Soc., 116, 1159 (1994). 177. (a) J. D. Coyle, in Synthetic Organic Photochemistry (Ed. W. M. Horspool), Plenum Press, New York, 1984, p. 259. (b) Y. Kanaoko, Acc. Chem. Res., 11, 407 (1978). (c) H. P. Mazzocchi, Org. Photochem., 5, 421 (1981). 178. Y. Kanaoka, Y. Migita, K. Koyama, Y. Sato, H. Nakai and T. Mizoguchi, Tetrahedron Lett., 1193 (1973). 179. J. D. Coyle, Pure Appl. Chem., 60, 941 (1988). 180. (a) K. Maruyama, Y. Kubo, M. Machida, K. Oda, Y. Kanaoka and K. Fukuyama, J. Org. Chem., 43, 2303 (1978). (b) K. Maruyama and Y. Kubo, J. Am. Chem. Soc., 100, 7772 (1978). 181. (a) M. Machida, H. Kakechi and Y. Kanaoka, Heterocycles, 7, 273 (1977). (b) Y. Sato, H. Nakai, T. Mizoguchi and Y. Kanaoka, Tetrahedron Lett., 1889 (1976). (c) Y. Sato, H. Nakai, T. Mizoguchi, Y. Hatanaka and Y. Kanaoka, J. Am. Chem. Soc., 98, 2349 (1976). (d) C. R. King and H. L. Ammon, Tetrahedron Lett., 28, 2473 (1987). (e) J. D. Coyle and L. R. B. Bryant, J. Chem. Soc., Perkin Trans. 1, 2857 (1983). (f) M. Machida, S. Oyadomari, H. Takechi, K. Ohno and Y. Kanaoka, Heterocycles, 19, 2057 (1982). 182. (a) M. Machida, H. Takechi and Y. Kanaoka, Chem. Pharm. Bull., 30, 1579 (1982). (b) M. Wada, H. Nakai, K. Aoe, K. Kotera, Y. Sato, Y. Hatanaka and Y. Kanaoka, Tetrahedron, 39, 1273 (1983). 183. (a) C. Somich, P. H. Mazzochi and H. L. Ammon, J. Org. Chem., 52, 3614 (1987). (b) K. Maruyama, T. Ogana, Y. Kubo and T. Araki, J. Chem. Soc., Perkin Trans. 1, 2025 (1985). (c) M. Machida, K. Oda and Y. Kanaoka, Tetrahedron, 41, 4995 (1985). (d) P. H. Mazzochi and G. Fritz, J. Am. Chem. Soc., 108, 5362 (1986). (e) P. H. Mazzochi, S. Minamikawa and P. Wilson, J. Org. Chem., 50, 2681 (1985). 184. A. Alder, N. Buchler and D. Bellus, Helv. Chim. Acta, 65, 2405 (1982). 185. (a) J. D. Coyle, P. A. Rapley, J. Kamphuis and H. J. T. Bos, J. Chem. Soc., Perkin Trans. 1, 2173 (1986). (b) J. D. Coyle and P. A. Rapley, J. Chem. Soc., Perkin Trans. 1, 2273 (1986). 186. K. Oda, M. Machida and Y. Kanaoka, Synthesis, 768 (1986). 187. M. Machida, K. Oda and Y. Kanaoka, Chem. Pharm. Bull., 33, 3552 (1985). 188. (a) K. Oda, M. Machida, K. Aoe, Y. Nishikata, Y. Sato and Y. Kanaoka, Chem. Pharm. Bull., 34, 1411 (1986). (b) M. Machida, K. Oda, E. Yoshida and Y. Kanaoka, Tetrahedron, 42, 4619 (1986). 189. J. D. Coyle and P. A. Rapley, J. Chem. Res. (S), 142 (1986).
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(a) R. F. Bayfield and E. R. Cole, Phosphorus and Sulfur, 1, 19 (1976). (b) Y. Miura, H. Asada and M. Kinoshita, Bull. Chem. Soc. Jpn., 50, 1855 (1977). (c) T. Anda, M. Nojima and N. Tokura, J. Chem. Soc., Perkin. Trans. 1, 2227 (1977). 191. D. H. R. Barton, T. Nakano and P. G. Sammes, J. Chem. Soc., (S), 322 (1968). 192. (a) J. Rokach and P. Hammel, J. Chem. Soc., Chem. Commun., 786 (1979). (b) N. Kamigata, S. Hashimoto, S. Fujie and M. Kobayashi, J. Chem. Soc., Chem. Commun., 765 (1983). (c) N. Kamigata, H. Iizuka and M. Kobayashi, Bull. Chem. Soc. Jpn., 59, 1601 (1986). (d) N. Kamigata, H. Iizuka and M. Kobayashi, Heterocycles, 24, 919 (1986). 193. V. N. R. Pillai, Org. Photochem., 9, 225 (1987). 194. (a) T. Hamada, A. Nishida and O. Yonemitzu, J. Am. Chem. Soc., 108, 140 (1986). (b) T. Hamada, A. Nishida, Y. Matsumoto and O. Yonemitzu, J. Am. Chem. Soc., 102, 3978 (1980). (c) K. Oda, T. Ohnuma and Y. Ban, J. Org. Chem., 49, 953 (1984). 195. (a) J. Cossy and J. P. Pete, Tetrahedron, 37, 2287 (1981). (b) J. C. Arnould, J. Cossy and J. P. Pete, Tetrahedron Lett., 3919 (1976). (c) J. C. Arnould, J. Cossy and J. P. Pete, Tetrahedron, 36, 1585 (1980). 196. M. Lancaster and D. J. H. Smith, J. Chem. Soc., Chem. Commun., 471 (1980). 197. M. S. Ao and E. M. Burgess, J. Am. Chem. Soc., 93, 5298 (1971). 198. T. Durst and J. F. King, Can. J. Chem., 44, 1869 (1966). 199. C. V. Kumar, K. R. Gopidas, K. Bhattacharyya, P. K. Das and M. V. George, J. Org. Chem., 51, 1967 (1986). 200. (a) B. Weiss, H. Durr and H. J. Hass, Angew. Chem., Int. Ed. Engl., 19, 648 (1980). (b) A. Chakrabarti, G. K. Biswas and D. P. Chakrabotry, Tetrahedron, 46, 5059 (1989). 201. M. R. Johnson, M. J. Fazio, L. D. Ward and L. R. Sousa, J. Org. Chem., 48, 494 (1983). 202. D. Birch, J. D. Coyle, R. R. Hill, G. E. Jeffs and D. Randall, J. Chem. Soc., Chem. Commun., 796 (1984). 203. D. Birch, J. D. Coyle, R. R. Hill and G. E. Jeffs, J. Chem. Soc., Chem. Commun., 293 (1986). 204. F. Moriya, K. Makino, N. Suzuki, S. Rokushika and H. Hatano, J. Am. Chem. Soc., 104, 830 (1982). 205. J. D. Coyle, R. R. Hill and G. E. Jeffs, Tetrahedron Lett., 28, 2529 (1987). 206. J. -Y. Liu and J. R. Bolton, J. Phys. Chem., 96, 1718 (1992). 207. S. L. Mecklenburg, B. M. Peck, J. R. Schoonover, D. G. McCafferty, C. G. Wall, B. W. Erickson and T. J. Meyer, J. Am. Chem. Soc., 115, 5479 (1993).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
16
Photochemistry of nitro and nitroso compounds TONG-ING HO Department of Chemistry, National Taiwan University, Roosevelt Road Section 4, Taipei, Taiwan (ROC) Fax: 886-2-363-6359; e-mail:
[email protected] and
YUAN L. CHOW Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6 Fax: (604)-291-3765; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. PHOTOCHEMISTRY OF AROMATIC NITRO COMPOUNDS . . . . . . . A. Photoreduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Photosubstitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Intermolecular reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Intramolecular reactions (photo-Smiles rearrangements) . . . . . . . . C. Photorearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Intramolecular redox reactions . . . . . . . . . . . . . . . . . . . . . . . . . a. o-Alkylnitrobenzenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. o-Benzyl derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . c. Nitrobenzenes with ortho CDX bonds and their derivatives . . . d. Nitrobenzenes with ortho heteroatom substituents and their derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nitro nitrite rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Photoaddition and Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Photoisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Heterocyclic Compounds Containing Nitro Groups . . . . . . . . . . . . . G. Photoretro-Aldol Type Reactions and Photodecarboxylation to Generate Nitroaromatic Anions . . . . . . . . . . . . . . . . . . . . . . . . . H. Photoredox Reactions in Aqueous Solutions . . . . . . . . . . . . . . . . . . I. Photodissociation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J. Photonitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
747
748 748 748 753 753 758 760 760 760 764 770 773 776 776 778 780 782 785 787 789
748
Tong-Ing Ho and Yuan L. Chow
III. PHOTOCHEMISTRY OF NITRO-OLEFINS . . . . . . . . . . . . . . . . . . . IV. PHOTOCHEMISTRY OF ALIPHATIC NITRO COMPOUNDS . . . . . . . A. Simple Nitroalkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. aci-Nitronates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Geminally Substituted Nitroalkanes . . . . . . . . . . . . . . . . . . . . . . . V. PHOTOCHEMISTRY OF C-NITROSO COMPOUNDS . . . . . . . . . . . . A. Simple Nitrosoalkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Geminally Substituted Nitroalkanes . . . . . . . . . . . . . . . . . . . . . . . C. Aromatic Nitroso Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Other C-Nitroso Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. PHOTOCHEMISTRY OF ALKYL NITRITES . . . . . . . . . . . . . . . . . . VII. PHOTOCHEMISTRY OF N-NITRO AND N-NITROSO COMPOUNDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Nitrosamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Photolysis mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Photo addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Sensitized nitrosamine photoreaction by dual proton and energy transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitramines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Nitrosamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
792 795 795 795 798 803 803 803 806 807 810 810 810 810 812 814 816 816 817
I. INTRODUCTION Since the last review in the preceding volume published in 1982 by Chow on the photochemistry of nitro and nitroso compounds covering references up to 1979, there has accumulated significant amounts of data to require a follow-up review on this subject. This chapter is organized similarly to the last review, according to types of functional groups, i.e. the nitro and nitroso groups attached to carbon, oxygen and nitrogen. Both the synthetic and mechanistic research activities have expanded drastically in the last 15 years, and we focus our attentions more on the synthetic aspects unless it is required to do otherwise. II. PHOTOCHEMISTRY OF AROMATIC NITRO COMPOUNDS A. Photoreduction
The photoreduction of aromatic nitro compounds to the amino compounds can be carried out on the surface of semiconductor particles such as titanium oxide1 with H-atom donors (equation 1). At a shorter duration of the photoinduced reduction of pnitroacetophenone, the hydroxylamine intermediate can be obtained in about 30% yield. The reaction mechanism proposed is based on the photoexcitation of TiO2 to generate an electron and a positive hole (equations 2 and 3). Aliphatic nitro compounds such as 12-nitrododecanoic acid can be reduced to 12-amino dodecanoic acid in 90% yield by this method. NO2
NH2 hν, TiO2 EtOH
X
(1) X
X = H, p-CHO, p-COCH3 , p-CN, p-CH3 , p-CH3 O, m-CH
CH2 , m-COCH3 (80− 90%)
16. Photochemistry of nitro and nitroso compounds TiO2
hν
749
TiO2 (e, h+ ) O−
+ N
R
(2) OΗ 2e
−
2H+
R
N OH
O −H2 O
R
N
O
2e
−
2H+
R
N
OH
(3)
H 2e − , 2H+ −H2 O
R
NH2
The photoreduction of nitrobenzene derivatives by 10-methyl-9,10-dihydroacridine (AcrH2 ) occurs by a consecutive six-electron reduction process in the presence of perchloric acid to yield aniline derivatives and the 10-methyl acridinium ion2 (equation 4). In comparison, thermal reduction of these nitrobenzene by AcrH2 under comparable conditions yields hydroxylamine or aniline depending on the substituent3 . The photochemical reduction proceeds by electron transfer from AcrH2 to the n,Ł triplet excited state of nitrobenzenes to give, after secondary processes, nitrosobenzene as the first product. Subsequently nitrosobenzene is reduced in an acid-catalysed thermal reduction by AcrH2 to hydroxylaminobenzene and in the subsequent photoreduction of the hydroxylaminobenzene to aniline (Scheme 1). H
H + PhNO2 + 3H+
3 N Me
hν
(4)
(AcrH2 ) + PhNH2 + 2H2 O
3 + N Me (AcrH+ )
Intramolecular redox reactions for bichromophoric compounds containing nitro and amino (or amino acid) groups have also been examined. For example4 , irreversible
750
Tong-Ing Ho and Yuan L. Chow hν
PhNO2
1
PhNO2 *
ISC
3
PhNO2 *
PhNO2
AcrH2 + H+ 3
PhNO2 *
(AcrH2
+
PhNO2
+
AcrH + H2 O (AcrH2
+
PhNO2
−
−
+
AcrH2 + PhNO2 + H
)
+
PhNO
)
+
AcrH2 + H
AcrH fast
PhNHOH
hν A crH2 + H+
A crH+
PhNH2 SCHEME 1
intramolecular electron transfer from the aliphatic amine moiety to the photoexcited nitrophenyl group in p-nitrophenylalanine 1 and p-nitrophenylethyl amine 2 is more efficient for the former giving p-aminobenzaldelhyde in 80%. The presence of an ˛-carboxyl group facilitates electron transfer (equation 5). The proposed reaction mechanism is summarized in Scheme 2, in which intramolecular electron transfer from the amino group to the excited-state nitrophenyl moiety initiates the process to afford the internal radical ion pair 3. Decarboxylation and electron reorganization gives imine 4, which is hydrolysed to p-nitrosophenyl acetaldehyde 5. In basic medium, 5 undergoes deprotonation to 6 (max D 418) which slowly decomposes to p-aminobenzaldehyde.
NH2 O2 N
CH2 CH (1) R = CO2 H (2) R = H
R
hν pH 10
H2 N
CHO (5)
(80%)
Both CIDNP and ESR techniques were used to study the mechanism for the photoreduction of 4-cyano-1-nitrobenzene in 2-propanol5 . Evidence was obtained for hydrogen ž abstractions by triplet excited nitrobenzene moieties and for the existence of ArNHO, ž ArNO2 H and hydroxyl amines. Time-resolved ESR experiments have also been carried out to elucidate the initial process in the photochemical reduction of aromatic nitro compounds6 . CIDEP (chemically induced dynamic electron polarization) effects were observed for nitrobenzene anion radicals in the presence of triethylamine and the triplet mechanism was confirmed. Laser flash photolysis was also applied to study the anion radicals of trans-isomers of 4-nitro, 4,40 -dinitro- and 4-nitro-40 -methoxystilbenes, that are generated by triplet state quenching with 1,4-diazabicyclo[2.2.2]octane (DABCO) in polar solvents at room temperature7 . The study shows that electron transfer competes against the trans ! cis
16. Photochemistry of nitro and nitroso compounds
751 + NH2
NH2 CH2 CH
O2 N
CO2
−
e−
O2 N
CH2
(1)
CH
CO2
−
(3)
−CO2 −
O
−
CH2 CH
N
+
NH + H
H2 O
O
N
CH2 CHO
O (4)
OH
(5)
−
− O O
N
CHCHO
OH
−
N
CHOHCHO
H (6) 418 nm
(7) OH−
H2 N
CHO
SCHEME 2
isomerization and that the radical ions decay by back electron transfer to the ground state. Magnetic field effects have been observed for the intramolecular photoredox reaction of the bichromophoric compounds 8 and 9, that contain an electron donor and a nitro-aromatic moiety as excited electron acceptors8 . Irradiation of 8 and 9 will, by intramolecular redox reactions, afford 10 and 11 respectively (equations 6 and 7). The nitroso-aromatic products are characterized as cage products derived from a triplet biradical intermediate which originates from the triplet state nitroarene. Therefore, when an external magnetic field (0.64 tesla) is applied the cage nitroso product decreases by 8 9%. Similar observations have been made for the compounds containing tertiary amine and nitro-aromatic moieties connected by an alkyl chain 139 (equation 8).
752
Tong-Ing Ho and Yuan L. Chow P(Ph)2
O
O(CH2 )12
O2 N
(8)
(6)
hν
O(CH2 )12
ON
O P(Ph)2
O
(10)
O2 N
O(CH2 )12
N
hν
S
O(CH2 )11 CHO
ON
(7) (11)
(9)
H N + S (12) NMe2 O2 N
O(CH2 )n O n = 2 12
(13)
hν
NHMe
(8) ON
O(CH2 )nO (14)
+ O2 N
(15) X = NHCH3
O(CH2 )n O
(16) X = N(CH3 )CHO
X
16. Photochemistry of nitro and nitroso compounds
753
Time-resolved fluorescence studies were also carried out on a series of zinc(II) complexes of meso-tetraphenylporphyrins covalently linked to 1,3-dinitrobenzene and 1,3,5-trinitrobenzene as acceptors to study the photoinduced electron transfer process, which is the initial process for the photosynthesis10 . B. Photosubstitution
1. Intermolecular reactions
Nucleophilic substitution is the widely accepted reaction route for the photosubstitution of aromatic nitro compounds. There are three possible mechanisms11,12 , namely (i) direct displacement (SN 2ArŁ ) (equation 9), (ii) electron transfer from the nucleophile to the excited aromatic substrate (SR N 1ArŁ ) (equation 10) and (iii) electron transfer from the excited aromatic compound to an appropriate electron acceptor, followed by attack of the nucleophile on the resultant aromatic radical cation (SRC N 1ArŁ ) (equation 11). Substituent effects are important criteria for probing the reaction mechanisms. While the SR N 1ArŁ mechanism, which requires no substituent activation, is insensitive to substituent effects, both the SN 2ArŁ and the SRC N 1ArŁ mechanisms show strong and opposite substituent effects. ArXŁ C Y ! [ArXY] ! ArY C X h, e
X
(9)
Y
ArX ! [ArX]ž ! [Ar]ž ! [ArY]ž ! ArY C e e
(10)
Y
ArXŁ ! [ArX]Cž ! ArY or Ar(H)XY
(11)
When o-, m- and p-nitroanisole with 14 C-labelled at the methoxy group were irradiated under identical conditions in methanol in the presence of sodium methoxide, only m-nitroanisole underwent methoxy exchange, with the limiting quantum yield ( D 0.08) (equation 12)11 . Both the meta activation and labelled isotope experiments support a complex intermediate and indicate an SN 23 ArŁ mechanism (direct substitution in the triplet state) for this reaction (equation 12) and for 4-nitroveratroles (equation 13). Further evidence from quenching and lifetime experiments also support a direct displacement SN 2ArŁ mechanism for the photosubstitution reaction of nitroaryl ethers with hydroxide ions13 . NO2
NO2 hν
(12)
MeONa, MeOH
OCH3
O14 CH3
(φ = 0.08) NO2
NO2
hν MeONa, MeOH
(13)
O14 CH3 OCH3
OCH3 OCH3 (φ = 0.21)
754
Tong-Ing Ho and Yuan L. Chow
Regioselectivity in nucleophilic aromatic substitution reactions is also of interest. 4Nitroanisole reacts with n-hexylamine and ethyl glycinate, to give regioselective methoxy and nitro group photosubstitution (equation 14), respectively14 . Mechanistic evidence15 indicated that the latter is produced through a SN 23 ArŁ reaction pathway whereas the former arises from a radical ion pair via electron transfer from the amine to the 4-nitroanisole triplet excited state (SR N 1ArŁ mechanism). The regioselectivity for the photosubstitution of 4-nitroveratrole with amines (equation 15) is dependent on the ionization potential of the amine used. Both laser flash16 and steady-state photolyses17 have shown that amines with high ionization potential follow the SN 2ArŁ pathway, but amines with low ionization potential follow the SR N 1ArŁ mechanism. OMe
NH(CH2 ) 5 CH3 CH3 (CH2 ) 5 NH2 hν
NO2
NO2
(14) EtO2 CCH2 NH2
OMe
hν
NHCH2 COOEt OMe
OMe OMe
NH(CH2 )5CH3 hν
+ CH3 (CH2 )5NH2
NO2
NO2 N H
, hν
(15) N OMe
NO2
16. Photochemistry of nitro and nitroso compounds
755
The theory of ‘merging resonance stabilization’ was proposed to explain the difference in the regioselective displacement of 1-methoxy-4-nitronaphthalene by cyanide and methylamine18 (equation 16). The replacement of a nitro group by an electron-withdrawing cyano group must contribute to stabilize the transition states. The proposal’s usefulness has become limited since the replacement of the methoxy group by methylamin is shown to occur under non-photolytic conditions. Time-resolved transient spectroscopy was applied to study the mechanism of the nucleophilic substitution for 1methoxy-4-nitronaphthalene with amines19 . These studies indicated that primary amines cause the replacement of the nitro group whereas secondary amines displace the methoxy substituent (equation 17). The spectroscopic evidence shows the existence of the anion radical of 1-methoxy-1,4-nitronaphthalene in the secondary amine reactions, that give higher yields than the primary amine reactions. It was concluded that the reaction with secondary amines is an electron-transfer process (SR N 13 ArŁ ), and that with primary amines is simply an SN 23 ArŁ process.
OCH3
OCH3
hν CN
(16)
−
NO2
CN
OCH3
OCH3 hν RNH2 R = Me, C3 H7 , iso-C4 H9
NHR
NO2 hν, R2 NH, R = Me, Et, −(CH2 )4 −, −(CH2 )5 −
(17)
NR2
NO2 Dual mechanistic pathways are often implied for divergent products in nucleophilic aromatic photosubstitutions. For example, the photoreaction of 2-fluoro-4-nitroanisole with n-hexylamine gives rise to higher yield from the fluoride than from methoxy substitutions20 (equation 18); the former major process is ascribed to an SN 23 ArŁ mechanism occurring from the Ł triplet excited state, whereas the latter minor process has an SR N 13 ArŁ mechanism involving the n Ł triplet excited state.
756
Tong-Ing Ho and Yuan L. Chow OMe
OMe
NHC6 H13 NHC6 H13
F hν
+ n-C6 H13 NH2
F
+
(18)
NO2
NO2
NO2
The pH dependence of the regioselectivity for the nucleophilic photosubstitution of 3,4-dimethoxy-1-nitrobenzene by n-butylamine gives21 2-methoxy-5-nitro-N-butylaniline as the major product at pH D 11 (equation 19). At pH D 12, the ratio of the major product to 2-methoxy-4-nitro-N-butylaniline increases to 12:1; the increased selectivity is caused by hydroxide ion, which can either promote exciplex formation or act as a base catalyst in deprotonation steps following the -complex formation22 . NO2
OMe
hν BuNH2 pH = 11
OMe
NO2
NO2
NO2
+
+
NHBu
OMe NHBu
OMe (51%)
(19) OH OMe
(16%)
(11%)
Mechanistic studies also indicate that 4-nitroveratrole (equation 20) and 4,5dinitroveratrole (equation 21) undergo both singlet and triplet nucleophilic aromatic substitution with ethyl glycinate23 . An electron transfer process competes against the nucleophilic aromatic photosubstitution for singlet excited 4-nitroveratrole, causing a decreased product yield in equation 20. OMe
OMe OMe
NHCH2 CO2 C2 H5
+ H2 NCH2 CO2 C2 H5
hν SN 2 1A r*
(20)
NO2
NO2 (48%) OMe
OMe OMe + H2 NCH2 CO2 C2 H5
O2 N
NHCH2 CO2 C2 H5 hν
(21)
SN 2 3 A r*
O2 N NO2
NO2 (73%)
16. Photochemistry of nitro and nitroso compounds
757
Second-order kinetics have been confirmed in the photocyanation of 3,4-dimethoxy-1nitrobenzene with potassium cyanide24 (equation 22), that has lead to the assignment of the SN 23 ArŁ mechanism; this shows an interesting contrast to the SN 1ArŁ photocyanation of 2-nitrofuran to give 2-cyanofuran as judged by the quantum yield independent of the cyanide concentration25 . NO2
NO2
NO2
hν, KCN
+
H2 O −t-BuOH
OMe
(22)
CN
OMe
OH
OMe
OMe
(88%)
(<1%)
Ł
state of 3-bromonitrobenzene is shown to be responThe protonation of the triplet sible for the acid-catalysed promotion of halogen exchange which follows a SN 23 ArŁ mechanism26 (equation 23). Cationic micellar effects on the nucleophilic aromatic substitution of nitroaryl ethers by bromide and hydroxide ions have also been studied27 . The quantum efficiency is dependent on the chain length of the micelle. The involvement of counter ion exchanges at the surface of ionic micelles is proposed to influence the composition of the Stern-layer. Br
Cl
LiCl
(23)
hν
NO2
NO2 (φ = 0.02)
The effect of an o-methyl substituent on the photosubstitution of o- and p-nitroanisole by hydroxide ions28 (equations 24 26) can be ascribed to both electronic and steric effects that determine the reactivity and selectivity.
MeO
NO2
hν − OH
NO2 + MeO
HO
(φ = 0.111)
(φ = 0.020)
OH
(φ = 0.091)
(24) Me
MeO
Me
NO2
(φ = 0.005)
hν OH−
HO
NO2
(φ = 0.005)
(25)
758
Tong-Ing Ho and Yuan L. Chow MeO
NO2
hν − OH
HO
NO2 Me
Me (φ = 0.145)
(φ = 0.056) + MeO
(26) OH
Me (φ = 0.089)
Triplet exciplexes have been proposed to explain photolysis of 2-nitrodibenzo[b,e](1,4)dioxin in the presence of primary amines29 (equation 27). In polar solvents the exciplex dissociates to the solvated radical ions from which the diphenyl ethers formed; in apolar solvents only the nitrophenoxazine is obtained. In contrast, 1-nitrodibenzo [b,e] (1,4) dioxin is photostable in the presence of amines. O
OH RHN
NO2 hν
O
RNH2 (t-BuOH/H2 O)
O
NO2
(56%, R = n-C3 H7) (53%, R = PhCH2 ) OH RHN +
R N
(27) NO2
+
O
O NO2 (24%, R = n-C3 H7) (24%, R = PhCH2 )
(7%, R = n-C3 H7)
The nucleophilic aromatic substitutions of 2-fluoro-4-nitroanisole with amines have been shown to be useful as biochemical photoprobes30 . Nitrophenyl ethers such as 4nitroveratrole and 3- or 4-nitroanisole have also been explored as possible photoaffinity labels31 . 2. Intramolecular reactions (photo-Smiles rearrangements)
Excited-state intramolecular nucleophilic aromatic substitutions are known as photo-Smiles rearrangements. Ealier, these were reported for 2,4-dinitrophenyl ethers and s-triazinyl ethers32 . The exploratory33 and mechanistic34 studies on photo-Smiles rearrangements of p-(nitrophenoxy)-ω-anilinoalkanes were carried out (equation 28).
16. Photochemistry of nitro and nitroso compounds O2 N
O(CH2 )nNHPh
hν
O2 N
759
N(Ph)(CH2 )nOH
R
(28)
R
R = H, n = 2−5 R = OMe, n = 2− 4
Directive effects of the nitro group in photo-Smiles rearrangements have been systematically studied using a series ˇ-(nitrophenoxy)ethylamines 17, 19 and 22 as models35 ; the meta isomer 17 is photolysed to give the N,O-inverted product 18 cleanly in 75% (equation 29). However, photolysis of ortho (19) and para (22) isomers gave various by-products (such as 21, 24 and 25) in addition to the photo-Smiles rearrangement compounds 20 and 23 (equations 30 and 31). Predictably, both 19 and 22 are thermally rearranged in aqueous basic solution to give 20 and 23 cleanly. Apparently, excited nitrophenylic ether moieties preferentially undergo intramolecular nucleophilic attack by the amine group, wherein the m-nitro group can facilitate the collapse of the transition state to the product. Interestingly, the chain length has definite effects on the photochemical pattern of the nitro arene (acceptor) and amine (donor) moieties36 of the chain terminal. While nitrophenyl ethers with n D 2 6 (see equation 28) undergo photo-Smiles rearrangement, the higher (n 8) homologues show an intramolecular photoredox reaction (equation 32). Interestingly compound 26 with n D 7 exhibits neither photo-Smiles rearrangement nor intramolecular photoredox reactions. The photochemistry of N-(ω-(4nitro 1-naphthoxyl)alkyl) anilines 27 shows exactly the same chain-length control on the product pattern to give 28 for n 6, and 29 31 and aniline for n 8. NO2
NO2 hν
O
NH2
NaOH, H2 O
N H
(17)
(29)
OH
(18)
NO2
NO2 O
NH NH2
OH
hν NaOH, H2 O 0˚C
(19)
(20) 14%
(30)
NO2 O + N H (21) 8%
760
Tong-Ing Ho and Yuan L. Chow
NO2
NO2
NO2
hν
+
NaOH, H2 O
0˚C
O
NH HN
NH2 (22)
O
OH (23) 11%
(24) 14% NO2
(31)
+
OH
OH
N H (25) 25%
O2 N
O(CH2 )nNH
hν n≥8
ON
O(CH2 )n −1CHO
(26)
+ H2 N
(32)
C. Photorearrangements
1. Intramolecular redox reactions
a. o-Alkylnitrobenzenes. The photochemical investigation of 2,6-di-tert-butyl-1nitronaphthalene 32 was continued by Dopp and Wong37 to give binaphthylidene
Ph O2 N
O(CH2 )nNHPh
O2 N
N (CH2 )nOH
(27)
(28)
16. Photochemistry of nitro and nitroso compounds
O(CH2 )n−1CHO
ON
O2 N
761
O(CH2 )n−1CHO
(29)
(30) ON
O(CH2 )nNHPh
(31)
quinone 36 (equation 33) as the only isolable product.
NO2
O
N
O
hν π π∗
(32)
(33) − NO
O 1. Dimerization 2. −2H
(34)
[intermediate] (35)
O
O (36)
(33)
762
Tong-Ing Ho and Yuan L. Chow
It is proposed that 32 reacts from its Ł excited state by the nitro-to-nitrite (33) inversion followed by nitrite homolysis, when the naphthoxy radical must diffuse away from the cages to obtain the dimerization intermediate 35. However, the source of oxidizing agents is not identified. In comparison, o-nitro-tert-butylbenzenes 37 are excited to undergo intramolecular H-atom transfer and cyclization to give indol-N-oxides 40 (equation 34)38 . The discrepancy may arise from the nature of the excited state, e.g. that of 37 may react from its nŁ state.
NO2
HO2 N
CH2
HO
O− + N
hν ππ∗
R
Ο−
−H
R (37)
R (38)
+ N
2O
R (39)
(40)
R = H, 4- NHCOCH3 , 4- MeO, 4- Br, 4- CN, 4- NO2 , 4- CO2 H, 4- C6 H5, 5- C6 H5
(34) Photolysis of 1,4-bis-(2-chloro-1,1-dimethylethyl)-2-nitrobenzene 41 in solution and in the solid state39 preferentially causes intramolecular hydrogen abstraction from the adjacent chloromethyl group instead of the methyl group, leading to the formation of indole 1-oxide 44 as the primary product. This is hydrolysed subsequently to afford the hydroxamic acid 46 and also the lactam 47 (equation 35). The molecular geometry and packing from the X-ray crystallographic structure of 41 have provided the rationale for the intramolecular hydrogen abstraction efficiency that, in turn, provides the basis of the structure reactivity relationship. Such correlation is extended to 1-t-butyl-3,5-dimethyl-2,4,6-trinitrobenzene, 1-t-butyl-3,4,5-trimethyl-2,6-dinitrobenzene and 1-t-butyl-4-acetyl-3,5-dimethyl-2,6-dinitrobenzene40 .
Cl CH2 Cl
CHCl
NO2
N +
hν ππ∗
N +
O−
CH2 Cl
CH2 Cl (41)
OH
OH
(42)
O−
CH2 Cl (43) (35)
16. Photochemistry of nitro and nitroso compounds Cl
Cl
(43)
N + O−
− H2 O
763
OR
N ROH
OH
R = H, Me
CH2 Cl
CH2 Cl
(44)
(45)
(35 continued ) O
O NH
N OH +
CH2 Cl
CH2 Cl (46) 73% in MeOH
(47) 9% in MeOH
The light-induced yellowing of musk ambrette 48 is simulated41 by photolysis of 48 in 0.1 N methanolic sodium hydroxide solution to give the azobenzene 50 (through the intermediacy of azoxybenzene) and by-products 51 and 52, by intramolecular photocyclization (equation 36).
OMe
O−
MeO hν
NO2
O2 N Me
(48)
N
O2 N
N +
Me NO2
OMe
Me
(49)
(36)
764
Tong-Ing Ho and Yuan L. Chow
Me
MeO (49)
+
OMe NO2
N
+
N
O2 N
OMe
Me
NO2
N CH
O
(50) 40%
(51) 4%
(36 continued )
O +
CH N
O2 N Me (52) 6%
b. o-Benzyl derivatives. The photochemistry of o-nitrobenzyl derivatives carrying a well-placed heteroatom (see Scheme 3) has been reviewed thoroughly as a strategy in photoremovable protecting groups42 . When alkyl o-nitrobenzyl ethers were irradiated, they were converted into o-nitrosobenzaldehyde releasing the alcohol intact as shown (Scheme 3); o-nitrobenzyl ethers have been used to protect hydroxyl groups during the chemical modifications of carbohydrates and their portions in nucleosides and oligoribo nucleotides. N-(2-nitrobenzyl)-1-naphthamide 53 is photolysed at 78 ° C to NO2
NO
CH2 Y
O N +
hν
YH +
CHO
−
OH
NO H C
CHY
OH Y = OR, NRR′
SCHEME 3
Y
16. Photochemistry of nitro and nitroso compounds
765
give N-(˛-hydroxy-2-nitrosobenzyl)-1-naphthamide 54 (equation 37)43 as identifiable intermediate, which is decomposed slowly at room temperature to 1-naphthamide and 2-nitrosobenzaldehyde. CONH
CONH
CH2
CHOH NO
NO2 hν
(54)
(53)
CONH2
CHO NO +
(37) The derivatives of the o-benzylnitro group have been investigated by picosecond transient spectroscopy to examine the intermediates from the intramolecular hydrogen atom abstraction44 . While the o-quinonoid intermediates are formed from both the singlet and triplet excited state o-nitrobenzyl ethers, observed transient absorption at 460 nm from excitation of o-nitrobenzyl p-cyanophenyl ether has been assigned to the biradical intermediate (see Scheme 4)45 . Both 5-nitro-1,2,3,4-tetrahydro-1,4-methanonaphthalene 55 and 5-nitro-1,2,3,4-tetrahydro-1,4-ethanonaphthalens 56 incorporate structural contrasts that prohibit the contribution from the o-quinoid structure. Picosecond spectroscopy of the excited nitro-arenes gives46 transients with lifetimes of 770 ps and 410 ps that are assigned to the triplet excited state of 55 and 56, respectively. As photolysis of 56 affords nitrosoalcohol 57 (equation 38), the operation of the biradical route must provide the access to the product (Scheme 4).
hν
OH
H NO2 (56)
(38)
NO (57)
Recently, time-resolved resonance Raman spectroscopic studies47 of the excitation of 2(20 ,40 -dinitrobenzyl)-pyridine 58 and 4-(20 ,40 -dinitrobenzyl)pyridine have shown that three transient intermediates are involved: they are aci-nitro acid 59, aci-nitro anion 60 and NH
766
Tong-Ing Ho and Yuan L. Chow R
H +
H
H
hν
O
N
N
O
O S∗
−
ISC
O
+
O
+
H∗
R
H∗
R
H
N O
−
−
T∗
−H
−H
R
R
H
H OH
+
OH
+
N
N −
O
O o- quinonoid
−
R R
H
R
H
OH
H O
N
OH
N
O
N
OH
O biradical
SCHEME 4
quinoid tautomer 61, the transient max is shown in parentheses (equation 39). T1
NO2
NO2 ISC hν
N
S1
N
CH2 (58)
CH
NO2
N HO
(59) (370 nm)
O O
k1
NO2
(39)
−
N O k2
N
N
CH
CH
NO2
H (61) (565 nm)
+H
NO2 (60) (490 nm)
+
16. Photochemistry of nitro and nitroso compounds
767
o-Nitrobenzyl photorearrangements have been applied to the area of photocatalysis, microlithography and biosensors. For example, the photolytic generation of acid has been developed as a potential candidate for radiation-sensitive materials for microelectronics and coating industry48 . The systems of photogenerated acids from o-nitrobenzyl carboxylates49 and sulphonates50 have been applied as novel photoactive resists. The acid photogenerators based on the 2-nitrobenzyl rearrangement have been reviewed51 . Explorative studies of applying o-nitrobenzyl photochemistry to generate amines and diamines were reported, that is, to use the o-nitrobenzyloxy group as a masking group which can be photolytically detached52 . The quantum efficiencies of the photodecomposition of o-nitrobenzyl carbamates 62 and 64 (equation 40) have been studied in solution and in the solid state52 . The 2,6-dinitrobenzyl carbamates undergo photodecomposition most efficiently with quantum yields as high as 0.62 for 66, R1 and R2 D cyclohexyl; the photosensitivites are controlled by a complex combination of both steric and electronic effects. X
X R
O
CHO
CNR1R2
hν
COR + CO2 + HNR1R2
(40) NO2
NO2
(62) R = H, X = H (64) R = alkyl, X = H (66) R = alkyl, X = NO2
(63) R = H, X = H (65) R = alkyl, X = H (67) R = alkyl, X = NO2
Time-resolved resonance Raman spectroscopy has been used to study the photorearrangement of o-nitrobenzyl esters in polar and protic solvents53 ; in acetonitrile, the only primary photoproduct is nitronic acid 68 with a lifetime of 80 microsecond, while in methanol the nitronic acid exists in equilibrium with the nitronate anion 69, giving a lifetime of 100 microseconds (equation 41). O
O
CHROCR′
R CO
CR′
hν
(68) O R COCR′ + N (69)
OH
+ N
NO2
O− O
−
−
O
(41) R
+
H+
O
O + R′ C OH
NO
Photochemistry of (2-nitrophenyl)diazomethane 70 has been studied by excitation at 350 nm in argon matrix isolation system54 . That shows that at 10 K, 2-nitrosobenzaldehyde is formed by intramolecular oxygen migration from (2-nitrophenyl) carbene
768
Tong-Ing Ho and Yuan L. Chow
71. Further irradiation ( > 350 nm) of 2-nitrosobenzaldehyde causes secondary reactions to give a mixture of 2,1-benzisoxazol-3(1H)-one 72 and carbonylcyclopentadiene imine 73 along with carbon dioxide (equation 42). It was shown that oxazolone 72 undergoes decarboxylation to give 73 upon photolysis with shorter-wavelength light ( > 300 nm) but not with longer-wavelength light ( > 350 nm). Irradiation ( > 350 nm) of (4-nbutyl-2-nitrophenyl)diazomethane (74) in argon matrix at 10 K results in the formation of the oxazolone 77 and imine 78 that may be derived from intermediate 76 upon further irradiation (equation 43). Photoexcited nitrosobenzaldehyde 75 must undergo Hatom transfer to give intermediate 76, which could spontaneously cyclize from either diradicaloid or ketenoid forms to give oxazolone 77. However, it requires deep-seated rearrangements and corresponding energy to reach the ketimine stage; the nitrene and carbene species have been proposed to mediate the changes. CH
CHN2
CHO
A r2 hν
NO2
NO2
(70)
(71)
NO
hν (>350 nm)
(42)
O
hν
O N H
NH + CO2
C
>300 nm
(73)
(72)
CHO
CHN2 A r, 10 K >350 nm
NO2
n-Bu
NO
n-Bu
(74)
(75) O >350 nm
C
(43) N
n-Bu
OH
O
(76) hν
O
O N H
n-Bu
C OH N
n-Bu (78)
(77) n-Bu
C
+
NH
16. Photochemistry of nitro and nitroso compounds
769
The application of o-nitrophenylethylene glycol as a photolabile protective group of aldehydes and ketones was further discussed55 . The deprotection of 1,3-dioxolane group can be carried out by photolysis at 350 nm in an inert solvent such as benzene, giving fair to high yields. The isolation and characterization of onitroso-˛-hydroxyacetophenone demonstrates a mechanistic link with the known photorearrangement of o-nitrobenzaldehyde to o-nitrosobenzoic acid. The scope and limitation are also discussed mainly on the basis of its stability to bases and acids (equation 44).
NO2 hν
H
O−
O−
N + O
N + OH
H O
O
O R
R
R
O
O
R
R
O R
O−
OH
O
N + OH
N
N O
OH
(44) O
O
O
R
R
R
O
O
R
R
NO
O
R
NO
+ R
O
OH
R
OH O
O R
O R
A series of o-nitrobenzyl derivatives derived from glutamine, asparagine, glycinamide and -aminobutyramide linked through the amide nitrogen are photolysed to release free amides according to the common mechanism shown in equation 4656 . The quantum yield for the release of glutamine (equation 45) from the ˛-methyl derivative is 0.13 and that from the carboxy derivative is 0.24. The mechanism involved the aci-nitro anion intermediate 80 (equation 46); the half-lives for the ˛-methyl, ˛-carboxyl and ˛-H derivatives of glutamine at pH 7.5 are 360, 720 and 1800 microseconds respectively.
770
Tong-Ing Ho and Yuan L. Chow NO
NO2 hν
O
NHCO(CH2 )2 CHNH2 CO2 H
R
R
(45)
+ H2 NCO(CH2 )2 CHNH2 CO2 H R = H, CH3 , CO2 H O− N +
NO2
OH
hν
H
NHCOR′
NHCOR′ R
R
(79) O N +
−
NO O−
(46)
+ H+
OH
NHCOR′
NHCOR′
R
R (80) NO2
+ H2 NCOR′ O R
c. Nitrobenzenes with ortho CDX bonds and their derivatives. Mechanistic studies on the photochemistry of o-nitrobenzaldehyde by the matrix-isolation technique have provided evidence for the existence of a ketene intermediate57 on excitation at 313 or 350 nm (equation 47); the ketene is the precursor of the o-nitrosobenzoic acid and of the Nhydroxybenzisoxazolone. Excitation at 357 nm leads to the exclusive formation of the former acid.
16. Photochemistry of nitro and nitroso compounds O
771
O
C
C
H
OH
> 357 nm
NO2
NO
(47)
313 nm 350 nm
313 nm, 350 nm
O
O C
C 313 nm, 350 nm
O N
NO2 H OH
This photoreaction has been investigated by laser flash photolysis58 and quantum yield measurements that identify the triplet state ( D 6 nanoseconds) as the reactive species, and show intermediate 82 is sensitive to hydroxylic molecules, but the logical precursor biradical intermediate 81 could not be detected owing to a short lifetime (equation 48). O
O C + N
O C
Η
hν
+ N
O
+ N
OH
O−
O−
O−
(48)
(82)
(81)
OH
H2 O
CO2 H
+ N
OH N
OH
CO2 H
O
O−
OH NO
Application of similar photochemistry in the carbohydrate domain has been reported by Collins and coworkers who demonstrated that O-(2-nitrobenzylidene) sugars 83 and 85 can be sequentially decoupled by photolysis and oxidation to give hydroxy-O-2-nitrobenzoyl derivatives (84 and 86) that are specifically partially protected sugars59 (equation 49). In both cases, the first-stage photolysis specifically deprotects the C-3 equatorial OH group. Such a blocking deblocking sequence including the key-photoreaction step is
772
Tong-Ing Ho and Yuan L. Chow
applied to transform 87 to 88, during which the C-3 equatorial OH group is bared for the specific glucosylation60 to afford 89 (equation 50); this corresponds to the fully esterified methyl-3,4-di-O-(ˇ-O-glucopyranosyl)-˛-L-rhamnopyranoside (90, not shown). In a similar fashion, the fully protected ˇ-galactosyl-˛-galactoside derivative 91 is photolysed and oxidized to give the corresponding intermediate of 92 carrying the C-3 OH group61 . OMe Me O
OAc AcO
O
R
O
O
hν
AcO
O
OMe Me
O
Ar
OAc AcO
O
(49)
AcO
OH OCAc
NO2
R
O
O (83) R = α -OAc (85) R = β -OAc
(84) R = α -OAc (86) R = β -OAc
Ar =
OMe
OAc O AcO AcO
O
Me
OAc
O hν
O
O
H
(87)
Ar OMe
OAc O AcO AcO
O OAc OMe
OCAr O
(50) O
AcO AcO
Me
O O
OAc AcO
O
OCAr O
OAc OAc OAc (89) NO2 Ar =
O HO
(88) OAc O
Me
16. Photochemistry of nitro and nitroso compounds
O
OCOAr OCOCMe3 O
OCOCMe3 O
Ar
773
HO
O O
(CH2 )3 CO2 Me
O OAc
AcO
OAc
O
(CH2 )3 CO2 Me
O OAc
O
AcO
OAc
O AcO
AcO
(91)
(92)
d. Nitrobenzenes with ortho heteroatom substituents and their derivatives. The photocyclization of N-acyl-2-nitrodiphenylamines is an efficient reaction to give phenazine N-oxides as shown62 in equation 51. Irradiation of compound 97 gives N-oxides 98 and 99 in equal amounts (equation 52). When compound 95 is photolysed in the presence of trifluoroacetic acid, the acetyl group is eliminated efficiently to give 100 predominantly (equation 53); the acyl group must end up as the mixed anhydride. The overall reaction pattern involving equations 51 53 is summarized in Scheme 5, in which the key intermediate 103 can be trapped by 2,6-di-tert-butylphenol (DTBP) and triphenyl phosphine (TPP) to afford 104 and 105, respectively.
Ac N
N hν
X
NO2
H
X (51)
N O (94) X = H (80%) (96) X = NO2 (98%)
(93) X = H (95) X = NO2 Ac N
N
NO2
X
hν
NO2
(52)
N Y O
(97)
(98) X = NO2 , Y = H (99) X = H, Y = NO2
774
Tong-Ing Ho and Yuan L. Chow Ph N
Me
O NO2
Ph
Ph
N
Me
N
Me
O
O
O
O
N
N
O (101)
O (102)
TFA
H N Ph
Ph
N
N
Ph
D TBP
H O
Me
NO (104)
N
H
NO2
O
TPP
N
O (103)
Ph
N
N +
N
N Ph
PPH3
(105)
NO (106)
O SCHEME 5
H N 95
hν CF 3 CO2 H
96 (13%) + O2 N
(53) NO2 (100) 85%
Excitation of o-nitrophenyl alkyl ethers (107 and 108) causes the intramolecular hydrogen abstraction from the nŁ triplet state of the nitro group to give benzoxazoles 109 and 110 respectively63 according to the mechanism in equation 54.
16. Photochemistry of nitro and nitroso compounds H
O
OCH2 R
775
R
O
hν
NO2
N
(107) R = Ph (108) R = Me
O
OH
N
H R OH
O
(54) O
O hν
R
R
N
N (109) R = Ph (62%) (110) R = Me (61%)
O
Excitation of o-nitrodiphenylamine (111) and 3-nitro-2-phenylaminopyridine (112)64 causes the common intramolecular hydrogen abstraction, as the initial step, but subsequent steps involve the elimination of HNO2 and cyclization to give carbazole and ˛-carboline (113 and 114) in equation 55. OH NO2
N O
hν
X
N H
X
N
(111) X = CH (112) X = N + OH N O X
H −HNO2
N −
X
(55) X
N H (113) X = CH (114) X = N
N
776
Tong-Ing Ho and Yuan L. Chow
Irradiation of 1-alkoxy-4-t-butyl-2,6-dinitrobenzenes apparently gives aniline the aniline intermediates that undergo acyl migration to give the more stable anilide (equation 56)65 . OCH2 R O2 N
OH
OCOR NO2
O2 N
O2 N
NH2
NHCOR
hν
(56)
R = H, CH3 , C2 H5
2. Nitro nitrite rearrangement
Derivatives of 9-nitroanthracens 115 undergo the nitro nitrite rearrangement from their triplet n,Ł state to 9-anthrol derivatives 118 as shown66 in equation 57; nitrite photolysis is well known and ESR spectra for the anthryloxy radical 117 can be recorded at room temperature. N NO2
O
O
hν
X
X
(115) X = CN, C6 H5CO
(57)
(116) OH
O
+ NO
X (117)
X (118) X = CN, C6 H5CO
D. Photoaddition and Coupling
Irradiation of a mixture of styrene and a nitroarene, such as nitrobenzene, 2nitrothiophene or 2-nitrofuran, in acetonitrile gives the corresponding nitrone in high
16. Photochemistry of nitro and nitroso compounds
777
yields67 (equations 58 and 59). CHO Ar
+ N +
ArNO2
Ar = C6 H5 Ar = 2-Thiophenyl Ar = 2-Furanyl
+
I
(58)
O− (119) 73% (120) 78% (121) 80%
) (Ar = C6 H5 (Ar = 2-Thiophenyl) (Ar = 2-Furanyl)
NO2
S (122)
(59)
CHO
CHO I
+ N
S
+
+ N
S
O − (120) 27%
O − (123) 55%
Irradiation of 2-nitro-5-iodothiophene (122) in the presence of benzene or indene gives, instead of addition, the coupling products68 124 and 125 (equations 60 and 61). The latter photoreaction also gave a minor amount of the secondary product 126 through reduction of the CI bond69 in 125.
NO2 hν
+
NO2
I
S
(60)
S (122)
(124)
+ I
S (122)
NO2 hν
(61)
CH3 CN
+ S (125)
S
I (126)
778
Tong-Ing Ho and Yuan L. Chow
Interestingly, the photoreaction of indene with nitroarenes gives good yields of coupling products as shown in equation 62 (66% from 2-nitrothiophene and 52% from 2-nitrofurane). Nitrobenzene gives the reduction product. Strangely there is no reaction for p-nitrotoluene with indene. hν
+
ArNO2
Ar
CH3 CN
(62) Ar =
,
,
S
O
E. Photoisomerization
The effects of nitro substituents on the cis trans isomerization of stilbenes has been reviewed70 (equation 63). The trans-to-cis isomerization occurs from a triplet excited state, whereas the reverse cis-to-trans isomerization occurs through a main route which bypasses the triplet state. A nitro substituent usually causes a significant enhancement of the quantum yield of the intersystem crossing. Nitro substituent effects on the photoisomerization of trans-styrylnaphthalene71 (equation 64), trans-azobenzenes72 and 4-nitrodiphenylazomethines73 (equation 65) have been studied for their mechanisms. O2 N
O2 N hν
H C
H hν
C
C
Ph
H
(63)
C
H
Ph
O2 N
O2 N
hν
H C
hν
C
C H
H
X
C
(64) H
X
X hν
C
N
X = NO2 or H
C
hν
H
N
(65)
H X
The presence of a nitro substituent can enhance the intramolecular charge transfer in the excited state dramatically, so that the normal trans-to-cis isomerization of 1-[2(4-nitrophenyl)ethenyl]pyrene in cyclohexane is completely suppressed74 in polar solvents such as acetonitrile (equation 66).
16. Photochemistry of nitro and nitroso compounds O2 N
H
C
779 H
C
Py
hν (hexane)
H
C
C
H O2 N
Py
(66) Py =
Upon irradiation (>400 nm), 1-(9-anthryl)-2-nitroethylene 127 undergoes 4 C 2 and 6 C 6 as well as isomerization reactions75 (equation 67). H
O2 N NO2
H
hν
H
+
H
NO2
H H
(127)
(128) 3% H H O2 N (129) 56% (4π + 2π)
(67) H
H
H +
NO2
H O2 N
H
H
+
H
(130) 17% (6π + 6π)
NO2
H
H
H
H
(131) 12% (6π + 6π)
780
Tong-Ing Ho and Yuan L. Chow
F. Heterocyclic Compounds Containing Nitro Groups
Nanosecond laser flash photolysis was applied to study excited-state 2-nitrothiophene in polar and non-polar solvents76 : the transient absorption at 545 š 5 nm was assigned to its lowest triplet state. The rate constants of the interaction of this triplet excited state, with a number of substrates such as cyanide and hydroxide ions, have been determined77 . Similarly, the transient absorption at 490š5 nm was assigned to the lowest triplet excited state of 5-nitro-2-furoic acid78 , and that at 500 š 5 nm to that of N-(n-butyl)-5-nitro-2furamide79 . The photolysis of 2-methyl-5-nitro-1H-imidazoles 132 in a water-containing solvent80 gives oxime 133, which is in turn hydrolysed to 134 followed by a dehydrative cyclization to the 1,2,4-oxadiazole 135. Light-induced hydrolysis of 135 gives 136 (equation 68). R O2 N
R
N
Me
N
O
hν
N
Me N
HON (132)
(133) H2 O
O
O
RNH
N N HO
−H2 O
RNH
(68)
N
Me N
OH
Me O
(135) hν
(134)
H2 O
O NH2 RNH O (136)
The solvent effects on the relative stabilities of 4-nitroimidazole and 5-nitroimidazole exhibit interesting patterns81 . In the excited state the 5-nitro isomer is more stable than the 4-nitro isomer in aprotic solvents, while the stability order is reversed in the ground state. The photodimerization of 3-methyl-4-nitro-5-styrylisoxazoles 137 has been studied in the solid state82 . Truxillic acids 139 are prepared by the oxidation of the photodimers 138 (equation 69).
16. Photochemistry of nitro and nitroso compounds Is Ar
CO2 H
Ar
hν Solid State
Ar
KMnO4
Ar
Is
Ar
Is (137)
781
CO2 H
(138)
(69)
(139)
NO2
Me Is =
; Ar = C6 H5, 2-ClC6 H4 , 4-ClC6 H4 , 2,4-Cl2 C6 H3 N O
Nitroimidazoles (such as metronidazole and misonidazole) can enhance the porphyrin sensitized Type I photooxidations83 ; that is, electron transfer from the sensitizer to the oxygen molecule is facilitated to give more of the superoxide ion (Scheme 6). The Type II mechanism operates by energy transfer from the sensitizer to afford the singlet oxygen84 . Type I Sens C h ! 1 Sens ! 1 (Sensž /SCž ) 1 (Sensž /SCž ) ! Sensž C SCž Sensž C 3 O2 ! Sens C O2 ž SCž C O2 ž ! products 1 Sens C S
Type II Sens C h ! 1 Sens 3 1 2 ! Sens C O2 3 Sens C3 O ! Sens C1 O 2 2 1 O C S ! products 2 (Sens D Sensitizer, S D substrate) 1 Sens C 3 O
SCHEME 6
Whereas several 1-aryl-4-nitroimidazoles are found to be good sensitizers for superoxide ion formations85 (Type I photooxidation), only 1-phenyl-2-methyl-4-nitroimidazole 140 is a photosensitizer for singlet oxygen, i.e. by energy transfer of type II photooxidation (equation 70). O2 N N Me
Ph
N +
Me C
Me
Ph hν
C
O2
Me
CH2 C
HOO Me
(95%) (140)
(70)
C Ph
782
Tong-Ing Ho and Yuan L. Chow
G. Photoretro-Aldol Type Reactions and Photodecarboxylation to Generate Nitroaromatic Anions
Photolysis of p- or m-nitro phenylethyl alcohols 141 and 142 in aqueous solution causes retro-aldol type reactions, where the quantum efficiencies are pH dependent86 89 . In these compounds the nitro group is placed so that no intramolecular hydrogen abstraction can occur and the excited state must follow an alternative route. The m- or p-position of the nitro group controls the product pattern as shown in equation 71; while the p-nitro group promotes biphenyl formation, the m-nitro group gives predominantly m-nitrotoluene at pH D 14. Photolysis of 144 at pH 7 14 does not change the product pattern significantly. Photolysis of 141 at pH D 12 changes the 142/143 ratio to 20/80. However, the expected formaldehyde product was not isolated. Y
Y CH2 CH2 OH
X
hν
X CH3 + Y
X
pH = 14
(142) 2% (145) >95%
(141) X = NO2 , Y = H (144) X = H, Y = NO2
CH2 2
(143) 98% (146) <5%
(71) The photo-retro-aldol type reaction is general for appropriately substituted nitroaromatic compounds with a p- or m-nitrobenzyl carbanion moiety as the photolabile leaving group. Its mechanism is shown in equation 72, in which the reactive triplet nitrophenylethyl alcohol undergoes retro-aldol cleavage assisted by solvent water (or hydroxide ion) as the deprotonating base in the primary photoprocess. The photogenerated carbanion subsequently reacts to give the observed products (ArCH2 R and ArCHRCHRAr) in de-aerated solution. The photogenerated nitrobenzyl anion can transfer one electron to a suitable electron acceptor (including the original nitrobenzyl derivatives) to generate the anion radical, which can be observed by electron paramagnetic resonance (EPR) spectroscopy87,88,90 . The dimerization products (143,146) are derived from the nitrobenzyl radical. The yield of 146 is small owing to the fact that the m-nitrobenzyl anion is reluctant to give up its electron to form an m-nitrobenzyl free radical. The EPR experiment consistently shows very weak signals for the m-nitrobenzyl system. In aerated solution, the photogenerated carbanion reacts with oxygen by similar electron transfer to give hydroperoxides as the products (equation 73). H
3
S0
hν
S1
R ks t
ArCH
∗ OH − ArCHR + R2 CHO
O
(72)
CHR ArCH2 R + ArCHRCHRAr
OH ArCH2 CH-Ph
hν O2
Ar = 3- and 4-NO2 C6 H4
PhCHO + ArCH2 OOH
KI
ArCH2 OH
(73)
16. Photochemistry of nitro and nitroso compounds
783
Ketals 147, 148 and 149 cleanly photolysed to give the expected products 150 153 by an analogous photo-retro-aldol process in aqueous solution (pH 7) (equation 74).
O O Y
CH2
O
hν
C R
R
COCH2 CH2 OH
X (147) R = Ph, X = H, Y = NO2 (148) R = Ph, X = NO2 , Y = H (149) R = Me, X = H, Y = NO2 +Y
(150) R = Ph (151) R = Me
CH3 + Y X
(74)
CH2
2
X (152)
(153)
The product ratio for 152/153 is similar to those observed in compounds 141 and 144. The isolation of 150 and 151 implicates the formation of dioxocarbocation intermediates (154, 155) that can be trapped by water to give hemiorthoesters and ultimately the ester products (equation 75). The photogenerated p-nitrobenzyl anion also can be detected by the EPR spectrum of the corresponding radical anion through electron transfer88 .
147, 148, 149
hν
ArCH2 − + O
+
O
H2 O
R
O
O
HO
R (75)
(154) R = Me (155) R = Ph 150, 151 The photodecarboxylation of nitrophenyl acetate in aqueous media was also investigated recently89 92 , especially with respect to the kinetic and spectral properties of the photogenerated p-nitrobenzyl carbanion; its triplet state (max ca 290 nm) was identified to have a lifetime of 90 nanoseconds at pH > 5.0. The proposed reaction mechanism following 266-nm laser excitation of p-nitrophenyl acetate is summarized in Scheme 792 . The photodecarboxylation of p-(nitrophenyl) glyoxylic acid 156, which was studied by time-resolved and steady-state methods at room temperature93 , leads to p-nitrosobenzoic acid and carbon dioxide in good yields with D 0.28 in aqueous solution at pH 2 12 and excitation at 313, 280 or 254 nm (equation 76). An intermediate (max D 350, 2 ms) observed by nanosecond laser flash photolysis is assigned to the aci-form of the nitroketene
784
Tong-Ing Ho and Yuan L. Chow
O2 N
CH2 CO2
−
O2 N
CH2 CO2
−
S1(τ 1 ≤5 ps, φ = 0.6)
S0 CO2 + O2 N
CH2
−
ca 100 ps
O O2 N
CH2
C O−
T1 (τ ca 90 ns)
T1
pH > 3
CH2
CH2
−
pH < 3
CH2
CH3
−
Ο
N
+
−
Ο
−
Ο
+
N
Ο
p- nitrobenzyl anion H
N+ HO
+
NO2
−
Ο
aci-form
CH2 CH2
O2 N
NO2
SCHEME 7
derived from the excited-state decarboxylation and rearrangement.
O2 N
COCOOH
hν
ON
COOH + CO2
(156)
(76) Evidence for the trapping of a non-Kekule intermediate in m-nitro participation was obtained in a photo-retro-aldol type reaction94 . Photolysis of 157 in aqueous acid solution
16. Photochemistry of nitro and nitroso compounds (H2 SO4 , H0 D 1.65) leads to the formation of benzyl alcohol 160 in a high yield (equation 77).
CH2 CH
OH
Ph
785
3-(N-30 -nitrobenzyl-N-hydroxyamino)
CH2 OH
CH2 hν
+
NO2
−
O
(157)
N
HO
OH
N
OH
(158) − H2 O
H+(−H2 O)
CH2 OH
CH2 OH
CH2 OH 158
CH2
N OH
NO
N OH +
(159)
NO2 (160) 80% (77) The intermediacy of nitrobenzyl carbanions in such photolysis is general, and also has been found in the photooxygenation of a series of nitrobenzyl derivatives including 2-methoxy-(m- and p-nitrobenzyl) ethanols95 . H. Photoredox Reactions in Aqueous Solutions
The photoredox reaction of o-nitrobenzyl compounds is mediated by intramolecular hydrogen abstraction and subsequent redox oxygen transfer following excitation in various solvents, and even in the solid state, due to the proximity of the two functional groups. Such reactions do not appear to involve catalysis by either external acids or bases. Similar photoredox reactions of m- and p-nitrobenzyl derivatives also take place, but only in aqueous solution and are subject to catalysis96,97 . Irradiation of p-nitrobenzyl alcohol gives p-nitrosobenzaldehyde as the only product, in a reaction which is strongly catalysed by hydroxide ion97 (equation 78). m-Nitrobenzyl alcohol gives m-nitrobenzaldehyde as the major product by hydrogen ion catalysis98 (equation 78); the azoxy compound 161 is also obtained in this case.
786
Tong-Ing Ho and Yuan L. Chow Y
Y hν
CH2 OH
X
X
CHO
pH >11
O− +
N +
(78)
N
OHC
CHO (161)
X, Y = H or NO2
This new type of photoredox reaction of p- and m-nitro-substituted aromatic derivatives is not observed in organic solvents, and is99,100 extended to m-nitrobenzyl derivatives 162 containing alcohol, alkyl ether, ester or amine functions; these compounds undergo photooxidation to produce m-nitrobenzaldehyde (or m-nitroacetophenone) as the major isolable product100 (equation 79). XR1 C
R2
H
R3
COR3
hν +
NO2
(79)
NO2
(162) XR1 = OH , OMe , OEt , OCOMe , NH2 , OCH2 Ph , OPh , H R2 = H , CH2 OH , Me , CH2 CO2 Et , CH2 OPh , OMe , COCH3 R3 = H , Me , CH2 OH
A general reaction mechanism for m-nitrobenzyl derivative is proposed (Scheme 8) which involves a non-Kekule intermediate100 . The mechanism for the p-nitrobenzyl alcohol involves the highly polarized intermediate 163, which is consistent with the observed strong solvent effect and base catalysis of the reaction (equation 80). CH2 OH
CHOH
hν
S1
ISC
T1
CHO
CHO −H
2O
[OH− ]
NO2 HO
N+
O−
HO
N
OH
NO
(163)
(80)
16. Photochemistry of nitro and nitroso compounds
787
R
R OR
C
C hν
H
S1
ISC
T1
H+ slow
H
N
NO2
+
HO R C +
H
OR
O R
R OR
C
+
C
OR
OR
H2 O + 3O ) fast
−(H
N HO
+
O
−
N HO
+
N HO
OH
OH
COR
COR [O]
NO2
NO
SCHEME 8
I. Photodissociation
A new type of photodissociation for p-nitrobenzyl 9,10-dimethoxyanthracene-2sulphonate 164 has been reported to give 9,10-dimethoxy-anthracene-2-sulphonic acid 165, 9,10-dimethoxy-2-(p-nitrobenzyl)-anthracene 166 and p,p0 -dinitrobibenzyl101 (equation 81). It is suggested to occur from excited intramolecular electron transfer followed by radical ion decompositions and recombinations. OMe SO2 OCH2
NO2 hν
OMe SO3 H
OMe (164)
OMe (165)
(81)
788
Tong-Ing Ho and Yuan L. Chow OMe CH2 (165)
NO2
+
(81 continued ) OMe (166)
+
O2 N
CH2 − 2
Topologically controlled intramolecular coulombic interactions have been applied to study the photochemical cleavage reactions of a series of 4-nitrophenyl ethers linked through a methylene chain to a tertiary amine (e.g. 167, 170, 172 and 173). The product distribution is controlled by the chain length102,103 . The photoproduct pattern in aqueous basic media (pH D 12) is shown in equation 82, where the usual meta-substituted photoproduct 168 is the highest at n D 5 and decreased to ca 10% for n D 3 and to nil for n D 2. In contrast, 2-methoxy-4-nitrophenol, the p-substituted photoproduct, increases from a trace amount for n D 5 to quantitative yield for n D 2. The latter agrees with the clean photolyses of 173. As shown, the photocleavage of the p-alkyl ether linkage occurs preferentially for the substrate containing a short (two or three methylene units) link between donor and acceptor; this may arise from unusual stabilization of the intramolecular charge transfer state and constitute a new type of photocleavage reaction.
O2 N
O
(CH2 )n
N
R (167) n = 5, R = OMe (170) n = 3, R = OMe (172) n = 2, R = OMe (173) n = 2, R = H
O2 N
O
(CH2 )n
R (168) n = 5, R = OH (171) n = 3, R = OH
pH 12 hν
(82)
N
+ O2 N
OH R (169) R = OMe, H
New photochemical cleavage reactions of ortho-substituted CDC double bonds were reported by introducing a 2-nitrophenyl group to the double bond104 . Photolysis of 1(2-nitrophenyl)-1-alkenes 174 in methylene chloride solution without oxygen affords aryl
16. Photochemistry of nitro and nitroso compounds
789
and ˛,ˇ-unsaturated aldehyde in 30 80% yields (equation 83). h
ArCRDCH-(CHDCH)n -C6 H4 -ONO2 ! ArCR (DCH-CH)n DO CH2 Cl2 (175) R D H, Me; n D 0,1 (174) R D H, Me; n D 0,1
(83)
Ar D Ph, p-ClC6 H4 , p-MeC6 H4 , 1-C10 H7 , 2-C10 H7 Photolysis of 4- and 3-nitrophenyl acetates (176 ! 177; 178 ! 179) in neutral aqueous solution leads to the corresponding phenols with quantum yields 0.002 and 0.006105 (equation 84). A greater difference in the photoreactivity (quantum yields of 0.002 and 0.129, respectively) is shown between 2-methoxy-4-nitrophenyl acetate 180 and 2methoxy-5-nitrophenyl acetate 182. The nitro substituent clearly exhibits a meta-activating effect in the hydrolysis of phenyl acetates. NO2
NO2
hν
R1
R1
R2
(84)
R2
(176) R1 = H, R2 = OCOCH3 (178) R1 = OCOCH3 , R2 = H (180) R1 = OMe, R2 = OCOCH3 (182) R1 = OCOCH3 , R2 = OMe
(177) R1 = H, R2 = OH (179) R1 = OH, R2 = H (181) R1 = OMe, R2 = OH (183) R1 = OH, R2 = OMe
A new triplet diradical is detected by ESR from the photolysis of 2-nitrobiphenyl106 (equation 85). The spectrum shows a temperature dependence which implies that the observed triplet state is a ground state. O NO2
N
OH
(85) hν
J. Photonitration
The nitration reagents (NO2 Y) for electrophilic aromatic nitration span a wide range and contain anions Y such as nitric acid (Y D OH ), acetyl nitrate (Y D OAc ), dinitrogen pentoxide (Y D NO3 ), nitryl chloride (Y D Cl ), N-nitropyridinium (Y D pyridine) and tetranitromethane [Y D C(NO2 )3 ]. All reagents contain electron-deficient species which can serve as effective electron acceptors and form electron donor acceptor (EDA) complexes with electron-rich donors including aromatic hydrocarbons107 (ArH, equation 86). Excitation of the EDA complexes by irradiation of the charge-transfer (CT) absorption band results in full electron transfer (equation 87) to form radical ion
790
Tong-Ing Ho and Yuan L. Chow
pairs. Subsequent fragmentation to 184 (equation 88) and radical recombination gives the nitration products (equation 89). This photoinduced inner-sphere electron transfer provides a new method of photonitration107 and is a topic of current interest108 . The EDA complexes of tetranitromethane (the electron acceptor) with arenes can be photolysed to cause the nitration of the arenes such as anisole109 , anthracene110 , naphthalene111 , fluorene112 , benzene113 , dibenzofuran114 and others. The photonitration of naphthalene with tetranitromethane is summarized in Scheme 9108 . KEDA
ArH C NO2 Y
[ArH, NO2 Y]
(86)
hCT
Cž ž [ArH, NO2 Y]
[ArH , NO2 Y ]
(87)
fast
[ArHCž , NO2 Yž ] ! [ArHCž , NO2 ]Y (184)
(88)
184 ! ArNO2 C HY
(89)
When the naphthalene and tetranitromethane charge-transfer complex is photolysed in dichloromethane or acetonitrile at a low temperature, the nitro-trinitromethyl adducts 185, 186, 187 and hydroxy-trinitromethyl adduct 188 together accounted for 85 95% of the product mixture; the remaining products are 1- and 2-nitronaphthalene. The adduct 188 is a secondary product formed by hydrolysis of the corresponding nitrite during photolysis. Adducts 185, 186 and 187 are all unstable and easily undergo elimination to give mainly 1-nitronaphthalene, with 2-nitronaphthalene as minor product. In Scheme 9, the formation of the radical ion pair is followed by fast fragmentation of the tetranitromethane radical anion to give a ‘triad’. The initial chemical process is assumed to come from the trinitromethanide attack on naphthalene cation radical followed by the radical recombination (see equation 90). H
4 +
NO2
NO2
− + (O2 N)3 C
2 H
H
C(NO2 )3
C(NO2 )3
(185 and 186)
ONO
NO2
hydrolysis
H (188)
H OH C(NO2 )3
H
H ONO C(NO2 )3
H H
NO2 C(NO2 )3
(187)
(90) In the nitration of arenes with N2 O4 , the red-coloured transient arises from the metastable precursor complex [ArH, NOC ]NO3 which is formed in the prior
16. Photochemistry of nitro and nitroso compounds
+
ArH
C(NO2 )4
791
C(NO2 )4
CT Complex ArH hν
+
H
C(NO2 )3
−
+ NO2
ArH (NO2 )3 C NO2 ‘triad’
NO2
H − HC(NO
+
C(NO2 )3
H
C(NO2 )3
2 )3
,
NO2 H
NO2
O2 N
(185) H
,
(186)
C(NO2 )3
H
H NO2
C(NO2 )3 H
+
OH
(187)
(188) −H
2O
C(NO2 )3
SCHEME 9
H
792
Tong-Ing Ho and Yuan L. Chow
disproportionation of nitrogen dioxide induced by the aromatic donor115 (equation 91). Irradiation at this change-transfer absorption band at a low temperature results directly in aromatic nitration, which has been shown with 1,3,5-trimethylbenzene, toluene and others. +
ArH + NO2 (N2 O4 )
[ArH, NO ]NO3
hν
−
+
[ArH , NO ]NO3
−
(91) +
ArNO2 + H + NO3
−
III. PHOTOCHEMISTRY OF NITRO-OLEFINS
Photolysis of 4-nitro-2,5-cyclohexadienyl acetates in methanol gives 4-hydroxy-2,5cyclohexadienyl acetates stereospecifically116 although the mechanism (equation 92) involves the scission of the CN bond (and therefore, the possible loss of chirality) to form the cyclohexadienyl radical and nitrogen dioxide pair in a solvent cage 190. A recombination at the oxygen site (NO2 ) gives the corresponding nitrite 191, which is then further photolysed to give the alcohol 192 via the alkoxy radical. The clean retention of stereochemistry in nitrite 191 implies that the radical pair 190 in the cage maintains a tight relation on the same face. Me
NO2
NO2
Me Y
Me
ONO
Y
Y
hν MeOH
H
OAc
(189) Y = F, Cl, Me
H
OAc
H
OAc
(191)
(190)
Me
Me
O
OH
Y MeOH
H
OAc
+
H
CH2 OH
OAc
(192)
(92) The crystalline state of 193 was irradiated with sunlight at 5 ° C (equation 93) to afford the cyclobutanes 194 and 195 in a 3:1 ratio117 . Compound 195 obviously arose from the dimerization of the cis-isomer of 193. The disordered crystal structure of 193 permits isomerization of 193 to the cis-isomer which photolytically reacted with 193 to give 195. Interestingly, the crystalline state of compound 196 and 198 was photolysed to 197 and 198, respectively (equations 94 and 95), but ˇ-nitro-p-methylstyrene was photostable.
16. Photochemistry of nitro and nitroso compounds Ph NO2
Ph
NO2
hν
793
+
Ph NO2 Ph (193)
NO2
(93)
NO2 Ph
(194) Ar
CH3 O
(195) NO2
hν
(94)
CH3 O
NO2
NO2 Ar
(196) Cl
Ar
Cl
(197) Ar
hν
(95) NO2
NO2 NO2
(198) (199) Irradiation of 1-methyl-2-nitrocyclohexene 200 in benzene in the presence of methyl acrylate showed a dual pathway to give both isoxazoline 201 (54%) and the C-nitroso dimer 202 (22%)118 (equation 96). The isoxazoline 201 arose from an excited-state intramolecular cyclization and scission to give a nitrile N-oxide which is trapped by the acrylate. Concurrently, the photoinduced nitro nitrite inversion also occurs competitively to give the C-nitroso compound which is isolated as the dimer 202. −
O
+N
NO2
MeCO(CH2 )4
O Me
Me hν
N
CO2 Me
O (201) 54% CH2
(200) hν
[MeCO(CH2 )4 C
ONO
+ N
(96)
− O] O
O
O Me
CHCO2 Me
Me
hν or ∆
Me + N
Me + N
−O
O−
NO (202) 20%
794
Tong-Ing Ho and Yuan L. Chow
The functionalization of an unactivated but strategically located carbon can be initiated by intramolecular alkoxy radical hydrogen abstraction that can be induced by nitrite photolysis. Thus photolysis of 6ˇ-nitrocholest-4-ene 203 in methanol under nitrogen causes the nitro-to-nitrite conversion in the first step, followed by the secondary nitrite photochemical transformation to afford cholest-4-en-6-one 204 (7%) cholest-4-en-6ˇ-ol 205 (11%), and compounds 206 (24%) and 207 (7%)119 (equation 97). While a number of products is obtained, it is significant that ˇ-nitro configuration is stereospecifically retained in the nitrite intermediate, as can be judged from the ˇ-alcoholic configuration. A small amount of leakage to 4ˇ-nitrite (and 4ˇ-OH product 207) indicates a possibility of, but not the necessity of, the dissociative mechanism proposed in the nitro nitrite conversion in equation 92, although it must be mentioned that a CN bond homolysis is generally accepted in photoexcitation of nitroalkanes (see Section IV.A). C8 H17
NO2 (203) MeOH hν
+ ONO
ONO
O (204)
HON
+
HON
+
+
OH (205)
OH (206)
OH (207)
(97)
16. Photochemistry of nitro and nitroso compounds
795
IV. PHOTOCHEMISTRY OF ALIPHATIC NITRO COMPOUNDS A. Simple Nitroalkanes
The primary photochemical reaction for nitromethane in the gas phase is well supported by experiments to be the dissociation of the CN bond (equation 98). The picosecond laser-induced fluorescence technique has shown that the ground state NO2 radical is formed in <5 ps with a quantum yield of 0.7 in 264-nm photolysis of nitromethane at low pressure120 . The quantum yield of NO2 varies little with wavelength, but the small yields of the excited state NO2 radical increase significantly at 238 nm. In a crossed laser molecular beam study of nitromethane, it was found that excitation of nitromethane at 266 nm did not yield dissociation products under collision-free conditions121 . h
CH3 NO2 ! CH3 ž C NO2 ž
98
Two independent and complementary techniques, product emission spectroscopy and molecular beam photofragment translational energy spectroscopy, have been applied to confirm the CN cleavage as the primary process at 193 nm in the (Ł ) excitation122 . The majority of the NO2 radical produced is in the vibrationally excited 2 B state, and unimolecular dissociation to NO C O is revealed by molecular beam 2 studies. Several products (OH, HONO and NO2 ) were detected under one-photon and collision-free photoexcitation (222, 249 and 308 nm) of 2-nitropropane123 . The collision-free photolysis at 282 nm for nitroethane, 1-nitropropane, 2-nitropropane and tert-nitrobutane has indicated that the OH radical is formed in the primary process124 . The participation of a five-membered ring intermediate in the process is supported by relative yield data and by the observation that CH3 CD2 NO2 yields OH exclusively and no OD. No OH formation from nitromethane is observed. In marked contrast to the nitromethane photodissociation, no evidence is found for simple CN bond fission for nitromethyl radical (žCH2 NO2 ) which was studied using a fast beam photofragment translation spectrometer125 . Nitromethane was photolysed in solid argon at 14 K to give syn- and anti-CH3 ONO126 as identified by IR absorptions. On prolonged photolysis, nitromethanol, CO, NO, HNCO and the hydrogen-bonded complexes H2 CO Ð Ð Ð HNO and H2 OHNCO were detected by infrared absorption. When the enhanced role of cage recombinations is taken into account, the proposed mechanism in argon matrix is compatible with that determined from gas-phase studies of the photolysis of nitromethane. When nitromethane was exposed to ionizing irradiation in a solid martix and studied by ESR, the primary process was electron ejection127 . This is frequently followed by specific electron capture, so radical species are trapped in the rigid matrix. In dilute solutions of CD3 OD such a captive yields nitromethane radical anions, and in that of CFCl3 nitromethane radical cations. In marked contrast, the exposure of nitromethane liquid to gamma rays at 77 K gives mainly CH3 and NO2 radicals. B. aci-Nitronates
Further studies on the photochemistry of aci-nitronate anion have revealed that the reaction occurs from the Ł triplet excited states causing an oxygen migration to give hydroxamic acids128,129 . The photorearrangement gives regiospecific products with the retention of the configuration at the migratory terminus in high yields (equations 99 102).
796
Tong-Ing Ho and Yuan L. Chow O NO2
NHOH
hν
(99)
MeNH2
(208)
(209)
91%
OH
NO2 O
OEt
N
OEt
hν
(100)
EtONa
EtOH
(210)
(211) 75%
NO2 OH N
O
hν MeOH MeONa
AcO (212)
(213) 78%
(101)
+
(214) 17%
hν MeOH
MeNH2
N NO2 (215)
(102) O
OH (216) 95%
Correlative studies revealed that the faster the rate of nitronate formation, the higher the yields of the hydroxamic acids130 (equations 103 and 104).
16. Photochemistry of nitro and nitroso compounds H
797
H hν
O
NH3 , MeOH
(103)
N OH
NO2 Me
Me
(218) 47%, 99 de (76% EtOH EtONa) de = diastereomeric excess
(217)
H
H
R
R hν
X
NOH
X
NH3 , MeOH
(104)
NO2
O
H
H
(220) R = Ph, X = CH2 (81%, 99 de) (222) R = CONHBu, X = CH2 (62%, 99 de) (224) R = CONHBu, X = O (42%, 99 de)
(219) R = Ph, X = CH2 (221) R = CONHBu, X = CH2 (223) R = CONHBu, X = O
Photolysis of nitro-steroids 225 yields the aci-nitronate at 254 nm131 . This in turn gives various products, among them are ketone 226 and hydroxamic acid 227 (equation 105) which could be formed from the intermediate anions of the N-hydroxyoxaziridines, with a possible participation of gem-hydroxynitroso transient (or its anion; see Scheme 10). For comparison, N-butyl spiro-oxaziridine 228 in ethanol is photolysed at 254 nm (equation 106) to give N-butyl lactam 229 (50%) and the ketone 230 (25%). The former process is a well-known photoprocess of oxaziridine131 . R
+
hν EtONa, EtOH
HO
HO H
HO
H
H
(225) R = C9 H19
O
OH
O
NO2
N
(227) 15%
(226) 22%
(105) Bu N
O
O
O
N
Bu +
254 nm EtOH
AcO
H (228)
(229) 50%
(230) 25%
(106)
798
Tong-Ing Ho and Yuan L. Chow −
−
O
−
+ O N
O
N O
1
hν
R
1
R1
R
R2
R2
R2
(231) O N
−
O
O
−
O
Ν
1
1
1
1
O
R
R
R
R
R2 R2
R2
R2
SCHEME 10
Aliphatic nitro compounds can be photolytically converted into oximes in acetone in the presence of triethylamine in moderate yields (30 74%)132 , as shown by the examples in equation 107. OH
RCH2
hν
RCH2 CH2 NO2
N
Et 3 N acetone
(107)
H
(232)
(233) R = Ph (44%) (234) R = Indol-3-yl (41%)
C. Geminally Substituted Nitroalkanes
Both 2-nitro steroids 235 and 239 exist as the enols in ethanol, and are photolysed to give the corresponding ˛-diketones 237 and 238 (23% in 1:1 ratio)133 (equation 108) and 240 (equation 109), but different monoxime 236 and 241, respectively. On the contrary, 4-nitroketone 242 exists in the keto form, and is photolysed to give the ˛-oximino ketone 243 and its tautomer 244 without the diketones (equation 110). C8 H17 O2 N O2 N HO O
H
hν
(108)
EtOH
(235)
O
HO
O
+
+ HON
H
H (236) 12%
O
HO H (237)
H (238)
16. Photochemistry of nitro and nitroso compounds
O2 N
799
HO hν EtOH
HO Me
O
H Me
Me
(239)
H Me (240) 22%
(109) HON + O Me
H Me (241) 12%
hν EtOH
O
O
H NOH
H NO2
(243) 51%
(242)
(110)
+ O
H
H
N O (244) 25%
It is proposed that ˛-hydroxyimino ketones are derived from a reaction pathway initiated from the hydrogen abstraction by the nŁ triplet-excited nitro group of the keto form, while ˛-diketones are formed from the nitro nitrite photorearrangement of the enol forms133 . Photochemistry of the ˛-nitroketones located in a steroidal ring has been studied134 . The photoreaction of 245 (enol form) gives the corresponding cyclic N-hydroxy imide 247 (57 61%) (equation 111), whereas 250 (exclusively in the keto form) gives a cyclic imide which is formed from the ˛-oximinoketine 254 by light-promoted Beckmann rearrangement134 (equation 112). The mechanism of the formation of the N-hydroxy imide
800
Tong-Ing Ho and Yuan L. Chow
247 (see equation 111) can be visualized in analogy to that abserved in the nitronate rearrangement (e.g. Scheme 10); it is noteworthy that 245 reacts from its singlet excited enol (equation 114). Photoreactions of the seven-membered-ring ˛-nitrosteroidal ketone 255 in ethanol gave the corresponding ˛-hydroxyimino ketones in a low yield134 (equation 113). O
NO2
O
OH NO2 NO2
(111) (246) (245)
hν
O
O
OH N
OH
N
NOH
O +
+ O
(247) 57%
(248) 12%
(249) 19%
O
O hν
NH
NO2 O (250)
(251) 12%
(112) OEt +
O
O +
+ O
NOH
Me
(252) 11%
(253) 8%
(254) 5%
16. Photochemistry of nitro and nitroso compounds
801
C8 H17
(113)
hν
H
O
H
O
NO2
HON
(255)
(256) 28%
1
OH NO2
∗
OH NO2
hν
H
O
+
(114)
OH
O
N
OH O
N
hν
O Photolysis of six-membered steroidal ˛-nitro enones135 257 in protic solvents results in an unexpected ˛-cleavage of the carbonyl group to give 3-alkoxy-2-nitro-2,3secocholest-4-en-3-one 258 (equation 115) while irradiation of 259 gives the parent cholest-l-en-3-one 260 which is obtained by exchange of the nitro group with a hydrogen atom (equation 116). C8 H17
O2 N O
hν
O2 N
EtOH or MeOH
RO H
O (257)
(258) R = Et, Me (25−30%)
(115)
802
Tong-Ing Ho and Yuan L. Chow C8 H17
(116)
hν EtOH
O
O
H
H
NO2
(260) 37% (259)
In ethanol 2,4-dinitro-5˛-cholestan-3-one, 261, exists entirely as the enol, which is irradiated to give a mixture of diosphenols, 262, and its isomer, 263, in 55% yield (equation 117)136 . Similarly, photolysis of an equilibrium mixture of 264 and 265 gives 266 in 48% yield (equation 118). C8 H17 O2 N O2 N HO
H NO2
O
(100% in EtOH)
H
(261)
NO2
hν
(117)
HO
O +
O
HO
H
H
(262)
(263)
C8 H17
O2 N
O2 N
HO
O
H
(264)
NO2
hν
H NO2 (265)
O
HO
H (266)
(118)
16. Photochemistry of nitro and nitroso compounds
803
The mechanism for this efficient removal of the two nitro groups to give an ˛-diketone can be written in various ways with reference to existing proposals for allied compounds. It is noteworthy that it should specifically involve the homolysis of the CN bond of the 4-nitro group, which is assumed to occur in the initial stage upon excitation. V. PHOTOCHEMISTRY OF C-NITROSO COMPOUNDS A. Simple Nitrosoalkanes
Both the molecular potential energy137 and the photodissociation138 of nitrosomethane were studied by ab initio SCF-CI techniques. There are geometry changes induced by the excitation and nŁ transition of nitrosomethane; the single excited-state surface has an energy barrier along the dissociation coordinate138 . The first triplet state is not a dissociate state. The photoelectron spectra of nitrosomethane, 2-methyl-2-nitrosopropane and perhalogeno nitrosomethanes has been re-examined and re-assigned on the basis of ab initio SCF-CI calculations139 . Photoionization quantum yields140 have been measured for 2-methyl-2-nitrosopropane at wavelengths 147, 123, 105 and 107 nm. The results show that photoionization at energies up to 1.5 eV above threshold is of low probability. The data have been compared with those of recent photoelectron spectroscopy. Since the primary photochemical process for nitrosoalkane involves the homolytic dissociation of the CN bond to generate free radicals141 , recent studies on the photochemistry of nitrosoalkanes pay more attention to radical reactions and to the methods of detection, such as spin trapping studies coupled with ESR techniques142 . B. Geminally Substituted Nitroalkanes
The diastereomeric 2-chloro-2-nitroso-p-menthane and 3-chloro-3-nitroso-p-menthane (267) epimerize during photolysis143 (equation 119) and can concurrently give the nitroxide 269 as detected by ESR spectrometry, which confirms the mechanism for the photolysis of geminally substituted nitroso compounds (equations 120 and 121). Cl
NO hν
NO
Cl
hν
(268)
(267)
(119)
Cl R2 NO
R=
(269) Cl hν
R2 C NO
R2 CCl + NO
(120)
804
Tong-Ing Ho and Yuan L. Chow
Cl R2 CCl + R2 C
(121)
(R2 CCl)2 NO NO
Photolysis of the blue solid (C)-10-bromo-2-chloro-2-nitrosocamphane (270) with red light produces two nitroxide radicals 271 and 272 and 10-bromo camphor 273, 10-bromo2-chloro-2-nitro camphane 274 in addition to some minor products (equation 122). A complex reaction mechanism has been proposed144 .
Me
Me CH2 Br
Me
Me
O
CH2 Br
Cl
N hν
Cl
Me BrCH2 NO
Cl Me
(+)-(270)
(271) Me
Br CH2
Me CH2 Br O
N +
+
Me Me
Me
Me
O CH2 Br
(272)
(273) 40% Me
Me + BrCH2
Cl NO2
(274) 25% (122) Solid-state photochemistry of ()-2-chloro-2-nitrosocamphane 275 was studied145 by irradiation of the blue-crystal with red light to invert the configuration at C(2) (equation 123). This also causes a photochemically initiated Beckmann rearrangement to form chloroxime 276 to give nitroxide radical 278 (equation 124). The intermediate chloro oxime 276 is proposed to arise from the nŁ excitation and is believed to be the common intermediate for the photo-epimerization and Beckmann rearrangement. Extended
16. Photochemistry of nitro and nitroso compounds
805
irradiation produces two additional nitroxides 279 and 280, and camphor oxime 281, camphor 282, 2-chloro-2-nitro camphane 283 as well as 2-chloro-2-nitratocamphane 284 (equation 125). Me
Me Me
Me
Me
Me hν
Me N
NO
Me
Cl
Cl (−)-(275)
Cl Me
O
(276)
NO
(+)-(277)
(123) Me
Me
Me
Me − N Cl
Me N
Beckmann
C H2 C lO
N ClO
C
+C
O
(276) Me
Me
−
Me
Cl
Me
Me Me Me
N O
C
C H2
(124) C H2 OCl
O
Me
N O
C C H2 (278)
−
Me Me
806
Tong-Ing Ho and Yuan L. Chow Me
Me
hν
275
Me
N
Me
N
Me
Cl (279) 7.5% Me
(280) 7.5% Me
Me
+ OH N (281) 15%
Me
Me
+
+ Me
Me
O
Cl
Me
Me
+
O Me
Me
Me
Me
Me
(125) Me
Me
Cl NO2
O
(283) 15%
(282) 40%
Me
Me
+ Me
Cl ONO2
(284) 15% C. Aromatic Nitroso Compounds
Nitrosobenzene was studied by NMR and UV absorption spectra at low temperature146 . Nitrosobenzene crystallizes as its dimer in the cis- and trans-azodioxy forms, but in dilute solution at room temperature it exists only in the monomeric form. At low temperature (60 ° C), the dilute solutions of the dimers could be obtained because the thermal equilibrium favours the dimer. The only photochemistry observed at < 60 ° C is a very efficient photodissociation of dimer to monomer, that takes place with a quantum yield close to unity even at 170 ° C. The rotational state distribution of NO produced by dissociation of nitrosobenzene at 225-nm excitation was studied by resonance-enhanced multiphoton ionization. The possible coupling between the parent bending vibration and the fragment rotation was explored. The homolysis of the CNO bond and nitroxide formation147 have been studied using a series of sterically hindered aromatic nitroso compounds such as pentamethyl nitrosobenzene, 2,3,5,6-tetramethylnitrosobenzene, 2,4,6-trimethylnitrosobenzene and
16. Photochemistry of nitro and nitroso compounds
807
2,4,6-tri-tert-butyl nitrosobenzene. They are photolysed in (330 nm < < 500 nm) solvent, such as toluene, n-heptane, cyclohexane, p-xylene and diethyl ether148 , to give intense ESR signals of nitroxides. The latter are formed by hydrogen abstraction from the solvent and subsequent spin trapping (equations 126 128). NO Me
Me
Me
Me
hν
Me
(126)
+ NO
Me
Me
Me
Me Me
Me Me
CH2
H
Me
Me
Me
+ Me
+
Me
Me
Me
Me Me
(127) CH2
NO Me Me
Me
Me
+
CH2 Me
N
Me
O
Me
Me
Me
Me
(128) D. Other C-Nitroso Compounds
The photochemistry of di-tert-butyl nitroxide was studied149 . When di-tertbutylnitroxide (DTBN) is excited at 254 nm to the Ł state in pentane solution, it is cleaved to tert-butyl radical and 2-methyl-2-nitrosopropane (with quantum yield of 0.21). The tert-butyl radical is scavenged by DTBN to give di-tert-butyl-tert-butoxyamine150 (equation 129).
O N
O hν pentane
N
O
+
(129)
N
A solution containing DTBN and carbon tetrachloride was irradiated at 313 nm or 366 nm, when charge-transfer absorption, resulted in the efficient destruction of
808
Tong-Ing Ho and Yuan L. Chow
DTBN with a quantum yield of 1.7. The products of the photoreaction are 2-methyl-2nitrosopropane 285, isobutylene, tert-butyl chloride, di-tert-butyltrichloromethoxyamine 286 and di-tert-butylhydroxylammonium chloride 287 (equation 130). O N
hν
+ CCl4
+
NO (285) φ = 0.85
+
+ φ = 0.55
Cl φ = 0.3
OCCl3
OH
N
N+ +
(286) φ = 0.56
(130) Cl −
H (287) φ = 0.27
Irradiation at the DTBN chloroform charge-transfer absorption yields151 285 ( D 1.01), 287 ( D 0.6), tert-butyl chloride ( D 0.06), isobutylene ( D 0.99) and ditert-butyl (dichloromethoxy) amine 288 ( D 0.56) (equation 131). Also151 , irradiation of DTBN at 300 nm in methylene chloride gives 2-methyl-2-nitrosopropane and di-tertbutyl-tert-butoxyamine ( D 0.014) products characteristic of the locally excited (Ł ) state, and also 2-methyl-2-nitrosopropane ( D 0.11), 287 ( D 0.047), tert-butyl chloride ( D 0.004), isobutylene ( D 0.093) and di-tert-butyl (chloromethoxy) amine 289 ( D 0.05) (equation 132) from the DTBN CH2 Cl2 charge-transfer state. O N
OCHCl2 + CHCl3
hν
285 + 287 +
Cl +
N
+
(288)
(131) O
O N
+
CH2 Cl2
hν
285 +
N
Cl
+
OCH2 Cl +
+ 287
+
(132)
N
(289)
Mechanistically, the reaction in pentane with up to 35% methylene chloride is proposed to occur via ˛-cleavage (equations 133 and 134). Other reactions in chloroform, carbon tetrachloride and 65% methylene chloride are proposed to occur by electron transfer to the chlorocarbon with initial formation of di-tert-butyloxoammonium chloride 290 and
16. Photochemistry of nitro and nitroso compounds
809
Cln CH3n radical (equations 135 139). O N
hν
DTBN ∗
N
O
+
(CH3 )3 C
(133)
DTBN O (CH3 )3 C
+
DTBN
DTBN + CCl4
(134)
N
hν
+ (DTBN
− CCl4 )*
+ t-Bu2 N
− OCl
+ − DTBN + CCl4
(135)
+ CCl3
(136)
(290) CCl3 + DTBN 290
(137)
(286) N
+
O
DTBN + HCl
Cl
N
O +
+
HCl +
+
(138)
(139)
287
Laser flash photolysis at wavelengths within the charge-transfer absorption bands of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and carbon tetrachloride yields the oxoammonium chloride of TEMPO 291 (max D 460 nm) and the trichloromethyl radical in an essentially instantaneous (18 ps) process152 . The primary photochemical reaction is an electron transfer from TEMPO to carbon tetrachloride followed by immediate decomposition of the carbon tetrachloride anion radical to chloride and trichloromethyl radical (equation 140). The laser flash photolysis of TEMPO and of other nitroxides in a variety of halogenated solvents have confirmed the generality of these photoreactions152 .
+ CCl4 N
hν
+ N
O
∗ − CCl4
+ N
O
− Cl + Cl3 C
(291)
O TEMPO
(140) Photolysis of benzofurazan N-oxide 292 in chloroform generates the nitroxyl radical 393153 (equation 141), which is formed due to hydrogen abstraction from the solvent
810
Tong-Ing Ho and Yuan L. Chow
by the lowest triplet state of 292. The photoreaction of 292 in triethylamine provides the diethylnitroxyl radical derived from triethylamine through oxygen transfer (equation 142). ESR spectroscopy154 indicated involvement of an exciplex155 . O− N +
O N O
+
HCCl3
hν
+
O
CCl3
N
N
H (292)
(293)
(141) N 292 +
Et3 N
hν
O
+
Et2 N
O
+
Et
(142)
N
The stable nitroxyl radicals can be used for quenching the singlet excited naphthalene through an electron exchange mechanism156 . VI. PHOTOCHEMISTRY OF ALKYL NITRITES
The photolysis of methyl nitrite at low temperature in an argon matrix was studied157 . The products include formaldehyde, and nitroxyl HNO which also reacts to form N2 O and water. The 355-nm photodissociation of gaseous methyl nitrite has been studied by monitoring the nascent NO product using a two-photon laser-induced fluorescence technique158 . VII. PHOTOCHEMISTRY OF N-NITRO AND N-NITROSO COMPOUNDS A. Nitrosamines
Since the last review in this series, a number of reports has been published to clarify the primary photoprocess and to show the application of aminium radical reactions in syntheses. 1. Photolysis mechanisms
In the gas phase, N-nitrosodimethylamine (NND) is photolysed at the S0 S1 (n,Ł ) transition band at 363.5 nm, to cause NN bond scission with of unity159,160 ; the recombination of the two radicals is equally efficient to give NND leaving no photoproducts at all (Scheme 11). This is in good agreement with the photolysis in neutral solution where no chemical reaction is observed174 . Photolysis at the S0 S2 (p,pŁ ) transition band at 248.1 nm, however, causes elimination of HNO, and subsequent secondary reaction to give N-methyl methyleneimine160 (equation 143); similar photoreactions have been observed on irradiation with a low-pressure mercury lamp in cyclohexane to give slowly the timer of the imine174 . In low-temperature insert matrices, such irradiation give hydrogen-bonded complex 294 which can be detected by IR spectroscopy161 (equation 143). These reactions have been reviewed162 . The fast singlet
16. Photochemistry of nitro and nitroso compounds Me2 N
NO
H
+
Me2 N
......
NO
......
H+
(295)
hν hν
NO + Μe2Ν
811
H+
−30 °C
Me2 NH+ + NO
−150 °C
−150°C
pK = 6.5
+ N
NO
H 295A
r.t hν −150 °C
294 + HNO SCHEME 11
excited-state dissociation is probably the reason why no fluorescence has been detected from nitrosamines. (CH3 )2 N
NO
hν 248.1 nm
CH2
N. . . . . . HNO
(143)
CH3 (294)
In solution photochemistry in the presence of acids, the primary process is also the same except that both NND and the aminyl radical are protonated; the recombination of the aminium radical and NO to give 295A is too slow to compete with bond scissions174 (Scheme 11). The failure of oxygen to quench nitrosamine photoreactions in either solution (see below) or gas phases under various conditions must also mean a very short lifetime of singlet excited nitrosamines, in agreement with the fast dissociation159,160 . The molecular structure of nitrosamines is well described using NND and Nnitrosopiperidine (NNP) as the model. Their singlet and triplet excited stated are well defined163 . The triplet state can be generated by excitation at the S0 T1 (n,Ł ) transition at 450 nm, but not from the singlet excited state owing to its fast photodissociation. The triplet state does not show any chemical reactivity. A resonance stabilized nitrosamine in acidic solution is associated with a proton (or proton donor)164 ; this species is photolysed at the 342-nm band (n,Ł transition) to give aminium and nitric oxide radicals by a chain mechanism in methanol in either the presence or absence of an olefin at room temperature163 . Summarizing all available evidence, the primary photoreaction of a nitrosamine (NND) is shown in Scheme 11. It is most interesting to note that while the recombination of Me2 Nž and ž NO is extremely fast, that of an aminium radical (e.g. Me2 NHC ž) with ž NO to give 295A is slow, as shown by the lifetime of the piperidinium radical (>100 microsecond) in water164 . A competing reaction for the latter pair is the slow elimination according to equation 143. Also, estimations from flash photolysis show that these rates are slower than the hydrogen abstraction of Me2 NHC from methanol163 , that is <104 M1 s1 . Supported by simple INDO closed-shell calculation, this suggests that the N-protonated species 295A possesses much higher energy than the O-protonated species 295 owing to absence of resonance in the former. The low-temperature photolysis at 150 ° C in an ethanol methanol mixture containing trifluoroacetic acid (0.01 M) adds another dimension to nitrosamine chemistry163 ; irradiation at 313 nm under these conditions gives a new species showing absorption at 391,
812
Tong-Ing Ho and Yuan L. Chow
375 and 362 nm, which reverted to 295 partially on warming to 30 ° C. The absorption peaks suggest that the new species must be 295A, which is photolabile at 150 ° C, presumably undergoing an elimination similar to that shown in equation 143. Thus, while in the photolysis in the presence of an acid at room temperature the n,Ł excitation with a single photon causes the direct formation of an aminium radical and subsequent reactions, that at <150 ° C must be a biphotonic process to give chemical changes. 2. Photoaddition
Owing to the high electrophilic reactivity of aminium radicals, photolysis of nitrosamines under nitrogen in an acidic solution in the presence of an olefin results in the addition of a dialkylamino group and nitric oxide across the double bond. These C-nitroso compounds may form the dimers and are generally isolated as the tautomerized oxime if it is possible. Under oxygen, the photoreaction is not quenched but diverted to the formation of the corresponding nitrates instead of C-nitroso compounds; this arises from oxidation of nitric oxide to nitrogen trioxide during the photolysis. The reaction pattern has been described previously174 , and applications of this photoaddition under oxidative and non-oxidative conditions to a variety of olefins have since been reported165 168 . Some examples with subsequent modifications are shown in equations 144 and 145 to demonstrate its versatility. ONO2 H hν, O2 NO, H+
Me 2 N
NMe2
(296) N
hν, N1 Me 2 N
NO, H
+
NMe2
H
OH
(298)
(144)
H
H (297)
NMe2
R Me 2 N
R′
NO, H+
(145)
(299)
(300) R, R′ = NOH (301) R = ONO2 , R′ = H (302) R = OH, R′ = H
The non-oxidative photoaddition of NND to cis,trans-cyclodecadiene168 (296) and trans,trans,trans-cyclododecatriene166,168 (299) give the expected oximes 297 and 300
16. Photochemistry of nitro and nitroso compounds
813
in 85 and 76% yields, respectively, the former as a mixture of syn- and anti-oximes, but the latter is the syn-isomer. Under oxygen, the oxidative addition gives the expected nitrate isomers 298 and 301 in high yields and small amounts of the corresponding alcohols and ketones in both cases. Upon LAH reduction, the former gives ˛- and ˇ-alcohols168 in 65 and 13% (equation 144), respectively, while the latter 301 gives the open-chain aminoalcohol 303 as the major product in addition to minor yields of 302166 (equation 145). The LAH promoted cleavage of 301 has been explained with a reasonable mechanism169 . HO
NMe2 (303)
The oxidative photoaddition of NNP to 3-butenyl chloride and bromide in the presence of perchloric acid gave 2-nitrato-5-azoniaspiro [4,5] decane perchlorate (306) in 38 and 46% yield, respectively165 (equation 146). The yield of the salt is obviously much higher, but it is difficult to extract from aqueous solution. The oxidative photoaddition to 3butenol and its acetate gives 72 80% of the expected product 305, while that to various benzoate esters gives about 26 33% and that to p-toluenesulphonate gives no product. ONO2
X + (304) X = Cl, Br
N
NO
hν , O2 HClO4
+ HN
NNP (305)
Na 2 CO3
(146)
ONO2 + N
ClO4 −
(306)
Several examples of aromatic hydrocarbon sensitized additions of NNP to the same arenes were demonstrated to occur if an acid is present; this is in contrast to the failure of benzophenone to sensitize the photoreactions. Irradiation of anthracene in the presence of NNP and hydrochloric acid gives 308 in 70% yield and a small amount of 309 derived from the acid-catalysed elimination of piperidinium ion and addition of ethanol165 (equation 147). Anthracene possesses Es D 76.3 kcal mol1 , f D 0.27 and s D 5 ns, and can sensitize NNP (Es D 75 kcal mol1 ) readily to its singlet excited
814
Tong-Ing Ho and Yuan L. Chow
state to initiate the reaction; indeed, anthracene fluorescence is quenched by NNP with a diffusion-controlled rate constant. The azapolycyclic alcohol 311 can be prepared using intramolecular oxidative photoaddition as the key step165 , as in equation 148. X
H + NNP
hν , N2 , H+ EtOH
(307)
N
OH
(308) X = C5H10 N (309) X = OEt
(147) OH 1. hν , H+
O
(148)
2. LA H
O
O
N N
ON (310)
(311)
3. Sensitized nitrosamine photoreaction by dual proton and energy transfer
Singlet excited phenols are known to be very acidic; for example, singlet excited 1naphthol (313) has pKa D 0.5 C 0.2, Es D 91.3 kcal mol1 and s D 10.6 ns170 . The interaction of singlet excited 1-naphthol with NND may occur by proton transfer followed by energy transfer to give a singlet excited state of the phenol-NND-acid exciplex, and further to the aminium radical, nitric oxide and phenolate anion (equation 149). This intermediate complex, probably caged, reacts to give 1,4-naphthoquinone monoxime170 (314); under similar conditions, 2-naphthol (315) is self-nitrosated to give 1,2-naphthoquinone-1oxime (316). Likewise, 1- and 9-anthrols and 9-phenanthrol can be photonitrosated without added acid to give the respective quinone oximes in good yields (equations 150 152). *ArOH + O
N
*ArO− + Ο
NMe2
N
NMe2
(149) −
*ArO
+ Η+
O
N
O−
+
ArO− + NO + Me2 NH
NMe2
O
O Me 2 NH+
NO
(150) H (312)
NO
16. Photochemistry of nitro and nitroso compounds
815
O
OH
Me 2 NNO
(151)
hν
N (313)
OH
(314) OH Me 2 NNO hν
O N (315)
(152)
OH
(316)
The crucial requirement of excited-state proton transfer (ESPT) is suggested by the failure of 1-naphthyl methyl ether to undergo self-nitrosation under similar photolysis conditions. The ESPT is further established by quenching of the photonitrosation as well as 1-naphthol fluorescence by general bases, such as water and triethylamine, with comparable quenching rate constants and quantum yield. ESPT shows the significance in relation to the requirement of acid in photolysis of nitrosamines; and acid association is a photolabile species. Further studies of the self-nitrosation of 1-naphthol with NND reveal a high degree of stereospecificity in ESPT and the implication of at least two exciplexes in the excited state171 . In dioxane, 1-NpOH and NND form ground state complexes showing max at 380 450 nm with the association constant Ka D 7. Excitation of GSC (e.g. at 370 nm) shows weak exciplex fluorescence peaking at 480 nm, but gives no self-nitrosation product 312. On the contrary, excitation of 1-NpOH at 300 nm in the presence of NND causes the self-nitrosation according to equations 149 and 151. Fluorescence of 1-NpOH is quenched by NND without showing new exciplex emission, although an exciplex 317 must be assumed to rationalize ESPT and energy transfer (Scheme 12), and to connect
ArOH + ONNMe2
Ka
hν
(GSC)
hν′
∗(GSC)
hν
∗(ArO −...... Η+ON
∗ArOH + ONNMe2
(317)
ArO −
+
NO
+
Me2 NH+
SCHEME 12
NMe2 )
816
Tong-Ing Ho and Yuan L. Chow
with the mechanism in equation 149. The exciplex 317 from the dynamic diffusioncontrolled process and excited GSC do not interconvert to each other. The latter does not undergo ESPT, most probably owing to its geometry. It is deduced that exciplex 317 has a favourable geometry for ESPT. B. Nitramines
Nitramines are known to photodissociate from their ,Ł state to give aminyl and nitric oxide radicals; in the presence of an acid the aminyl radicals are protonated to give aminium radicals, which can initiate addition to olefins. As a synthetic reaction, photolysis of nitramines in the presence of acids can be conveniently run under oxygen to give oxidative addition similar to those shown in equation 145; indeed N-nitrodimethylamine is photolysed with triene 299 under such conditions to give a mixture of 301 and 302, similar to results observed in the oxidative nitrosamine photoaddition169 . To simplify the isolation, the crude products are reduced with LAH to form the open-chain amino alcohol 303. Some other oxidative photoadditions of N-nitro dimethylamine to other olefins are reported. As the photoreaction has to use a Corex filter and product yields are no better than those shown by nitrosamines, further investigations were scarcely carried out. C. Nitrosamides
Many intramolecular photoadditions of N-nitrosamides were published recently172 . Nitrosamides are photolysed to give amidyl and nitric oxide radicals, but thermalized to undergo the diazo ester rearrangement. In contrast to intermolecular reactivities, alkenyl amidyl radicals preferentially add intramolecularly to the inside double bond rather than abstract a C-5 hydrogen atom162 . An interesting entry to ˇ-lactam synthesis is the photolysis of 318 to give 319 in 59% (equation 153). Nitrosamide 320 is photolysed in CBrCl3 , which also act as a radical trapping agent, to give the bromoamide 321 in 89% (equation 154). OH N NO N
hν
N
O
O (318)
(319) H Br
NO N
H N
hν CBrCl3
O (320)
(153)
C6 H6
(154) O
H (321)
Owing to their importance in toxicology and as carcinogens, nitroamides must be considered seriously. The study of several N-nitroso-N-acetyl amino acids has been reported
16. Photochemistry of nitro and nitroso compounds CH3 CONHCHCH2 C6 H5
CH3 CONHCH
817
CHC6 H5
OCH3 (324)
(325)
to give unusual results173 . Photolysis of the nitrosamide 322 derived from phenylalanine in methanol under nitrogen at near 0 ° C gave both 324 and 325 in excellent yields in addition to a small amount of 327. These products are derived from 323 (equation 155), which is formed by decarboxylative elimination of HNO from excited state 322. Indeed MeOH is eliminated from 324 to give 325 during chromatography. Similar photolysis of 322 in acetonitrile in the presence of triethylamine gives 68% of oxadiazole 327, which is formed from 323 through the intermediacy of 326. The photoreaction must be run at a low temperature to avoid thermal reactions. The nitrosamides from other amino acids also show a similar reaction pattern if the thermal decompositions are suppressed173 . CH2 C6 H5
O CH3 C
N
CH
N
O
O
CO2 H
hν, Ν 2
CH3 C
CH3 OH −CO
N
CH
CH2 C6 H5 + HNO
(323)
(322)
(155) CH2 C6 H5
O CH3 C
N NH
CH N
CH2 C6 H5 O
(326)
H3 C
N O (327)
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Tong-Ing Ho and Yuan L. Chow P. Wan and S. Muralidharan, J. Am. Chem. Soc., 110, 4336 (1988). B. B. Craig and M. Dale Pace, J. Chem. Soc., Chem. Commun., 1144 (1987). B. B. Craig and S. J. Atherton, J. Chem. Soc., Perkin Trans. 2, 1929 (1988). B. B. Craig, R. G. Weiss and S. J. Atherton, J. Phys. Chem., 91, 5906 (1987). H. Gorner, L. J. Currell and H. J. Kuhn, J. Phys. Chem., 95, 5518 (1991). S. Muralidharan, K. A. Beveridge and P. Wan, J. Chem. Soc., Chem. Commun., 1426 (1989). P. Wan, S. Muralidharan, I. McAuley and C. A. Babbage, Can. J. Chem., 65, 1775 (1987). P. Wan and K. Yates, J. Chem. Soc., Chem. Commun., 1023 (1981). (a) P. Wan and K. Yates, J. Org. Chem., 48, 138 (1983). (b) G. G. Wubbels, T. F. Kalhern, D. E. Johnson and D. Campbell, J. Org. Chem., 47, 4664 (1982). P. Wan and K. Yates, J. Org. Chem., 50, 2881 (1985). P. Wan and K. Yates, Can. J. Chem., 64, 2076 (1986). K. Pafizadeh and K. Yates, J. Org. Chem., 51, 2777 (1986). T. Yamaoka, H. Adachi, K. Matsumoto, H. Watanabe and T. Shirosaki, J. Chem. Soc., Perkin Trans. 2, 1709 (1990). E. Cayon, J. Marquet, J. M. Lluch and X. Martin, J. Am. Chem. Soc., 113, 8970 (1991). J. Cornelisse and E. Havingna, Chem. Rev., 75, 353 (1975). H. Frey, Synlett, 215 (1990). P. Kuzmic, L. Pavlickova and M. Soucek, Collect. Czech. Chem. Commun., 51, 1293 (1986). K. Tanigaki, M. Yagi and J. Higuchi, Chem. Phys. Lett., 153, 57 (1988). J. K. Kochi, Acc. Chem. Res., 25, 39 (1992) and references cited therein. L. Eberson, M. P. Hartshorn, F. Radner and J. Svensson, J. Chem. Soc., Perkin Trans. 2, 1719 (1994) and references cited therein. (a) S. Sankararaman, W. A. Haney and J. K. Kochi, J. Am. Chem. Soc., 109, 5253 and 7824 (1987). (b) L. Eberson, M. P. Hartshorn and J. O. Svensson, Acta. Chem. Scand., 47, 925 (1993). J. M. Masnovi and J. K. Kochi, J. Org. Chem., 50, 5245 (1985). (a) S. Sankararaman and J. K. Kochi, J. Chem. Soc., Perkin Trans. 2, 1 (1991). (b) L. Eberson, M. P. Hartshorn and F. Radner, J. Chem. Soc., Perkin Trans. 2, 1799 (1992). (c) L. Eberson, M. P. Hartshorn and F. Radner, J. Chem. Soc., Perkin Trans. 2, 1793 (1992). (d) E. K. Kim, M. Bockman and J. K. Kochi, J. Chem. Soc., Perkin Trans. 2, 1879 (1992). L. Eberson, M. P. Hartshorn, F. Radner and W. T. Robinson, Acta. Chem. Scand., 47, 410 (1993). L. Eberson and M. P. Hartshorn, J. Chem, Soc., Chem. Commun., 1564 (1992). L. Eberson, M. P. Hartshorn, F. Radner, M. Merchan and B. O. Roos, Acta Chem. Scand., 47, 176 (1993). E. Bosch and J. K. Kochi, J. Org. Chem., 59, 3314 (1994). A. Fischer and P. N. Ibrahim, Tetrahedron, 46, 2737 (1990). G. R. Desiraju and V. R. Pedireddi, J. Chem. Soc., Chem. Commun., 1112 (1989). R. D. Grant and J. T. Pinhey, Aust. J. Chem., 37, 1231 (1984). H. Suginome, K. Takakuwa and K. Orito, Chem. Lett., 1357 (1982). P. E. Schoen, M. J. Marrone, J. M. Schnur and L. S. Goldberg, Chem. Phys. Lett., 90, 272 (1982). H. S. Kwok. G. Z. He, R. K. Sparks and Y. T. Lee, Int. J. Chem. Kinet., 13, 1125 (1981). L. J. Butler, D. Krajnovich and Y. T. Lee, J. Chem. Phys., 79, 1708 (1983). G. Radhakrishnan, T. Parr and C. Wittig, Chem. Phys. Lett., 111, 25 (1984). G. D. Greenblatt, H. Zuckermann and Y. Haas, Chem. Phys. Lett., 134, 593 (1987). D. R. Cyr, D. J. Leahy, D. L. Osborn, R. E. Continetti and D. M. Neumark, J. Chem. Phys., 99, 8751 (1993). M. E. Jacox, J. Phys. Chem., 88, 3373 (1984). M. C. R. Symons, Faraday Discuss. Chem. Soc., 86, 99 (1988). K. Yamada, T. Kanekiyo, S. Tanaka, K. Naruchi and M. Yamamoto, J. Am. Chem. Soc., 103, 7003 (1981). K. Yamada, S. Tanaka, K. Naruchi and M. Yamamoto, J. Org. Chem., 47, 5283 (1982). K. Yamada, K. Kishikawa and M. Yamamoto, J. Org. Chem., 52, 2327 (1987). G. J. Edge, S. H. Iman and B. A. Marples, J. Chem. Soc., Perkin Trans. 1, 2319 (1984). H. Takechi and M. Machida, Synthesis, 206 (1989).
16. Photochemistry of nitro and nitroso compounds 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174.
821
H. Suginome, Y. Kurokawa and K. Orito, Bull. Chem. Soc. Jpn., 61, 4005 (1988). H. Suginome and Y. Kurokawa, J. Org. Chem., 54, 5945 (1989). H. Suginome and Y. Kurokawa, Bull. Chem. Soc. Jpn., 62, 1343 (1989). H. Suginome and Y. Kurokawa, Bull. Chem. Soc. Jpn., 62, 1107 (1989). N. P. Ernsting and J. Pfab, Chem. Phys. Lett., 67, 538 (1979). R. Cimiraglia, M. Persico and J. Tomasi, J. Am. Chem. Soc., 107, 1617 (1985). N. P. Ernsting, J. Pfab, J. C. Green and J. Romelt, J. Chem. Soc., Faraday Trans. 2, 76, 844 (1980). C. A. F. Johnson, J. Chem. Soc., Faraday Trans. 2, 77, 2147 (1981). D. Forrest, B. G. Gowenlock and J. Pfab, J. Chem. Soc., Perkin Trans. 2, 576 (1979) K. Makino, J. Phys. Chem., 84, 1012 (1984). T. Bosch, G. Kresze and W. Hub, Justus Liebigs. Ann. Chem., 905 (1979). N. N. Majeed and A. L. Porte, J. Chem. Soc., Perkin Trans. 2, 1139 (1987). N. N. Majeed, G. S. Mac Dougall, A. L. Porte and I. H. Sadler, J. Chem. Soc., Perkin Trans. 2, 1027 (1988). M. Azoulay and E. Fischer, J. Chem. Soc., Perkin Trans. 2, 637 (1982). C. Chatgilialoglu and K. U. Ingold, J. Am. Chem. Soc., 103, 4833 (1981). D. Rehorek and E. G. Janzen, J. Photochem., 35, 251 (1986). (a) F. Genoud, Mol. Phys., 43, 1465 (1981). (b) D. R. Anderson, J. K. Keute, H. L. Chapel and T. H. Koch, J. Am. Chem. Soc., 101, 1904 (1979). D. R. Anderson and T. H. Koch, Tetrahedron Lett., 3015 (1977). J. S. Keute, D. R. Anderson and T. H. Koch, J. Am. Chem. Soc., 103, 5434 (1981). J. Chateauneuf, J. Lusztyk and K. U. Ingold, J. Org. Chem., 55 1061 (1990). S. K. Lin, J. Photochem. Photobiol. A: Chem., 45, 243 (1988). S. K. Lin and L. B. Feng, Chem. Phys. Lett., 128, 319 (1986). S. K. Lin and L. B. Feng, Spectrosc. Lett., 19, 883 (1986). S. A. Green, D. J. Simpson, G. Zhou, P. S. Ho and N. V. Blough, J. Am. Chem. Soc., 112, 7337 (1990). R. P. Muller, P. Russegger and J. R. Huber, Chem. Phys. Lett., 70, 281 (1982). F. Lahmani, C. Lardeux and D. Solgadi, Chem. Phys. Lett., 102, 523 (1983). G. Geiger, H. Stafast, U. Bruhlmann and J. R. Huber, Chem. Phys. Lett., 79, 521 (1981). G. Geiger and J. R. Huber, Helv. Chim. Acta, 64, 989 (1981). R. P. Muller, S. Murata and J. R. Huber, Chem. Phys., 66, 237 (1982). R. P. Muller and J. R. Huber, Rev. Chem. Interm., 5, 423 (1984). Y. L. Chow, Z. Z. Wu, M. P. Lau and R. W. Yip, J. Am. Chem. Soc., 107, 8196 (1985). W. S. Layne, H. H. Jaffe and H. Zimmer, J. Am. Chem. Soc., 85, 1816 (1963). Y. L. Chow, C. J. Colon, D. W. L. Chang, K. S. Pillay, R. L. Lockhart and T. Tezuka, Acta Chem. Scand., B 36, 623 (1982). Y. L. Chow, H. Richard and Y. Sakaino, Synthesis, 818 (1980). Y. L. Chow and Z. Z. Wu, Recl. Trav. Chim. Pays-Bas, 105, 312 (1986). Y. L. Chow, H. Richard and R. W. Lockhart, J. Chem. Soc., Perkin Trans. 1, 1419 (1982). Y. L. Chow, and H. Richard, J. Chem. Soc., Perkin Trans. 1, 1405 (1982). Y. L. Chow and Z. Z. Wu, J. Am. Chem. Soc., 109, 2560 (1987); 107, 3338 (1985). Y. L. Chow, Z. Z. Wu, M. L. W. Thewalt and T. W. Steiner, J. Am. Chem. Soc., 110, 5543 (1988). Y. L. Chow and R. A. Perry, Can. J. Chem., 63, 2203 (1985). Y. L. Chow and J. S. Polo, J. Chem. Soc., Perkin Trans. 2, 727 (1986). Y. L. Chow, Acc. Chem. Res., 6, 354 (1973).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
17
Radiation chemistry of amines, nitro and nitroso compounds WILLIAM M. HORSPOOL Department of Chemistry, The University of Dundee, Dundee DD1 4HN, Scotland Fax: +44 (0)382 34 5517; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . II. RADIOLYSIS OF AMINES . . . . . . . . . . . . . . . . . . . . A. Radiolysis of Aliphatic Amines . . . . . . . . . . . . . . . . B. Radiolysis of Aromatic Amines . . . . . . . . . . . . . . . . III. RADIOLYSIS OF AMINO ACIDS . . . . . . . . . . . . . . . . IV. RADIOLYSIS OF NITRO AND NITROSO COMPOUNDS A. Aliphatic Nitro Compounds . . . . . . . . . . . . . . . . . . B. Aromatic Nitro Compounds . . . . . . . . . . . . . . . . . . C. Nitroso Compounds . . . . . . . . . . . . . . . . . . . . . . . V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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823 824 824 826 828 832 832 832 834 835
I. INTRODUCTION
review1
A detailed of this area was published thirteen years ago as part of this series. Within that article a comprehensive coverage of the various methods for irradiating compounds was given. This included energy absorption, early events, dosimetry and reaction kinetics including free-radical reactions, radical scavenging and pulse radiolysis. That review suggested that the radiation chemistry of the species covered by this review was becoming an increasingly important area of study. There are indeed many citations dealing with radiation-induced reactions where amines, nitro and nitroso compounds are used as secondary reagents. More often than not the radiation process is utilized to produce a primary oxidant that then reacts with the substrate under discussion. The radiation process in these instances is not directly reacting on the amine or nitro compound. Thus a reviewer has many problems to wrestle with regarding inclusion or omission of articles. This review of the area has tried to provide a flavour of what is happening currently but is by no means exhaustive for the reasons given above.
823
824
William M. Horspool II. RADIOLYSIS OF AMINES
A. Radiolysis of Aliphatic Amines
Some studies have focused on the generation of the corresponding radical cations of methylamine, dimethylamine and N-methylpiperidine2,3 by -irradiation at low temperature. The radical cation of t-BuNH2 can be formed k D 3.4 ð 106 M1 s1 by oxidation with DMSOÐCl4 . Trimethylamine has been subjected to radiolysis studies. Thus the trimethylamine radical cation 1 can be produced by -irradiation (60 Co source) at 77 K in trichlorofluoromethane. This technique utilizes the facile generation of the radical cation of the trichlorofluoromethane. This radical cation then transfers an electron from the substrate to produce the radical cation of the amine. The EPR spectra of the radical cations were recorded. The cations produced under these conditions can be trapped indefinitely and do not undergo proton loss to give the radical 25 . In a pulse radiolysis examination in basic aqueous solutions saturated with N2 O and O2 two radicals 2 and 3 are seen in a ratio of 9:1. The radical 1 reacts readily with oxygen k D 3.5 ð 109 M1 s1 to yield the iminium ion 4. The electron transfer to yield 4 is preferred to the path that would yield the peroxy radical 5 followed by fission to 4. Trapping of 4 by hydroxide and hydrolysis of the hydroxymethyl dimethylamine accounts for the principal products, dimethylamine and formaldehyde, of the reaction6 . However, further study showed that the formation of a nitrogen-centred radical was the important first step. Thus attack by the hydroxy radical on the amine affords the radical cation 1 and hydroxide. The former species can be transformed into each of the others by hydrolytic processes yielding the alkyl radical 2 or, on protonation, the conjugate acid 6. The radical cation 1 is the stable species in acid7 . This reaction has also been discussed in a review article8 . Me3 N
+
Me2 NCH2
(1) + Me2 N
O2
2−
Me2 NCH2 O2
(2)
(3)
(5)
CH2
+ Me2 N
CH2
H (4)
(6)
Triethylamine can also be converted into the corresponding radical cation by irradiation at low temperature in trichlorofluoromethane5 or by oxidation with the 9 carbonate radical CO3 ž produced by pulse radiolysis. The radical cation of triethylamine has also been studied using time-resolved fluorescence detected magnetic resonance (FDMR). This work showed that the rate of formation of the radical cation was the same in n-hexane or in cyclohexane10 . Triethylamine has, of course, been used in many studies as a sacrificial electron donor. This is a common use in photochemical systems as well as in pulse radiolysis. A typical example of this is the use of triethylamine as an electron donor in the photoreduction of carbon dioxide to formic acid in nonaqueous polar solvents using oligo(p-phenylenes) as the photocatalyst11 , or the formation of hydrogen from water12 . The sacrificial use of triethylamine is also seen in the pulse radiolysis generation of captive electrons in glasses at low temperature. The glasses are ethanol/triethylamine and radiolysis brings about the ejection of an electron from the triethylamine thus producing the corresponding radical cation13 . Other studies have examined the temperature dependence of electron trapping in such glasses14,15 .
17. Radiation chemistry of amines, nitro and nitroso compounds
825
Silicon derivatives of these simple amines have also been studied using -irradiation in CFCl3 solution at 77 K. The radical cations 7 and 8 are formed in each of the cases. The EPR study showed that the singly filled MO of the radical cation was delocalized and extended into the silyl groups. The hydrazine derivative 9 also affords a radical cation 16 within which a twisted geometry exists with the two nitrogen tensors at an angle of 24° . + (Me3 Si)nNRm
n
m
R
+ (Me2 SiH)2 NH
(7)
1
2
Me
(8)
2
1
Me
3
0
−
2
1
H
Dopamine (10) has also been the subject of some study. Maity and coworkers17 have studied the pulse radiolysis or -irradiation induced reduction of the protonated form. In this instance the addition of an electron affords the radical anion 11 with a bimolecular rate constant for the reaction of 2.5 ð 108 M1 s1 . HO
(Me3 Si)2 N
+ N(SiMe3 )2
HO NH2
HO
(9)
−
(10) H N+
+ N
+
HO
NH3
(11)
H
H N +
(12)
(13)
(14)
The cyclic amines, aziridine and azetidine, can be converted to their radical cations 12 and 13, respectively, by -irradiation at 77 K in trichlorofluoromethane18 . In the case of the aziridine radical cation there is evidence that it opens to afford 14. There is a slight solvent dependency in the reaction of these systems and when the radical cation 13 of azetidine is irradiated in a matrix of CFCl2 CF2 Cl the radical cation converts into the neutral radical 15. With aziridine in the same matrix the radical 16 is obtained without the generation of the radical cation. Hindered secondary amines such as 2,2,6,6-tetramethylpiperidine are of interest as antioxidants. However, -irradiation (at 25 ° C with 72 rad min1 ) of well oxygenated dilute solutions of the piperidine 17 in 2,4-dimethylpentane has shown that these amines are not primary antioxidants19 22 . Studies have also examined the use of secondary amines for the protection of polymers against damage from -radiation23 . The stabilizers undergo oxidative transformations in the process. Hindered amine stabilizers, in combination with trivalent phosphorus melt processing stabilizers, are the stabilizers of choice. These are better than phenolic stabilizers since there is less discolouration of the polymer. Specifically polypropylene can also be protected against -initiated oxidation24 .
826
William M. Horspool
FDMR has also been used to detect the transient radical cations formed from secondary amines by pulse radiolysis. As mentioned earlier this technique has been used to study a variety of systems such as the radical cation of triethylamine. The radical cations of diethylamine, n-propyl amine and t-butylamine, have also been studied25 . The results have shown that the FDMR signal is enhanced with increasing alkyl substitution of the amine as in the pyrrolidines (18) and the piperidines (19)25 .
N
R Me Me
( )n
N H
Me Me
R
R
R
N
R
N H
H (15) n = 2 (16) n = 1
(18) R = H or R = Me
(17)
R
(19) R = H or R = N
-Irradiation at 77 K in trichlorofluoromethane of cyclic tertiary amines also affords radical cations that can be trapped indefinitely. In these systems there apparently is no reaction between the radical cations and free amine. The EPR spectra of the radical cations were recorded. The cations produced under these conditions can be trapped indefinitely and do not undergo proton loss to give the corresponding carbon-centred radical. Several systems (20 24) were examined in this way and all were found to be stable. In the bis amine (22, n D 1) evidence was obtained from the EPR study that there was weak N N interaction4 . The influence of silicon in 25 was also examined16 . ( )n + N Me
+ Me2 NCH2 NMe2
Me
N
+ N
Me
n = 1 or 2
(20)
(21)
(22) N
+ N
+ N
N
SiMe3
N + (23)
(24)
(25)
B. Radiolysis of Aromatic Amines
Triphenylamine (TPA), N,N,N0 ,N0 -tetramethyl-p-phenylenediamine (TMPD) and dimethylaniline (DMA) have been popular substrates for reaction under pulse radiolysis conditions. One of the earlier reports dealt with the formation of the radical cation of TMPD by reaction k D 3 ð 108 M1 s1 with the peroxy radical derived from oxidation of methylene chloride CHCl2 O2 by pulse radiolysis26 . DMA is also oxidized to its radical cation by the same reagent k D 2.5 ð 107 M1 s1 . Since then it has been
17. Radiation chemistry of amines, nitro and nitroso compounds
827
TABLE 1. Absolute rate constants for reaction of peroxyl radicals RO2 ž with TPMD R Me Et Bu i-Pr t-Bu ClCH2 Cl2 CH Cl3 C
k M1 s1 4.3 ð 107 3.3 ð 107 2.9 ð 107 9.2 ð 106 1.1 ð 106 4.2 ð 108 7.4 ð 108 1.7 ð 109
demonstrated that a variety of oxidants can be used to convert TMPD into the radical cation TMPDžC . The absolute rate constants for the formation of this species by reaction with alkyl and haloalkylperoxyl radicals RO2 ž have been determined27,28 (Table 1). Similar oxidation of amines occurs with pulse radiolysis of an aerated DMSO solution containing 5% CCl4 where the reactant species is DMSO Ð Cl. The effective production of the radical cations was concentration dependent but reached a plateau at 0.39 mmol/J. Radiolysis gave a higher plateau value of 0.42 mmol/J4 . Amines have also been oxidized by the use of sulphate radical anion obtained by pulse radiolysis in 95% acetonitrile solution. The rate constants were in the range of 107 109 mol1 s1 for the formation of the radical cation. Apparently these values are lower than those obtained from other solvent systems such as water29 . A publication has collated data re absolute rate constants for the reaction of peroxy radicals with organic solvents30 . The same amine substrates TPA and TPMD can also be converted into their radical cations k D 1010 M1 s1 by the use of bromine atoms generated by pulse radiolysis31 . TMPD k D 5.2 ð 108 M1 s1 , p-diaminobenzene k D 5 ð 107 M1 s1 and diphenylamine k D 1 ð 107 M1 s1 can all be readily converted into the corresponding radical cation by oxidation with pulse radiolysis generated SO3 ž . With higher redox potential amines such as aniline and N,N-dimethylaniline the oxidation to the radical cation fails32 . Rate constants have also been measured for conversion of the same amines 33 into their radical cations by reaction with SO4 ž . Indoles can be also be converted into their radical cations by the use of ClO2 ž as the oxidant produced by pulse radiolysis. From the reactivity of the resultant cation it was possible to establish the one-electron reduction potential of the indole in question. Typical results from this are illustrated in Table 234 . As can be seen, the one-electron reduction potential is influenced by alkyl substitution. A measure of the one-electron reduction potential of tryptophan at pH 7 has shown it to be 0.093 V more positive than the tyrosine radical35 . Further details on tryptophan and peptides, within which this moiety is present, have also been obtained using pulseradiolysis-generated N3 ž . This oxidant converts tryptophan into its radical cation with a 36 second-order rate constant of 3 ð 109 M1 s1 . Interestingly the indolyl radical cation is capable of oxidizing tyrosine to the phenoxy radical37 . Using this result and N3 ž as the oxidant it has been possible to examine the through-bond electron transfer in peptides where the tryptophan unit is separated by an insulator from a tyrosine. Again the formation of the radical cation of the tryptophan was the first event38 . Other studies39 have shown that the redox potential of the tryptophan unit is only slightly lowered from the value for tryptophan (Em D 1.05 V at pH 7) when it is incorporated into peptides40 . The
828
William M. Horspool TABLE 2. One-electron reduction potentials of some indoles E° (V)
Indole Indole N-Methylindole 2-Methylindole 3-Methylindole 2.3-Dimethylindole Tryptophan
1.24 1.23 1.10 1.07 0.93 1.24
TABLE 3. Absolute rate constants for the reaction of chloroalkylperoxy radicals with chlorpromazine Radical ž
CCl3 O2 CHCl2 O2 ž CHCl2 O2 ž CH2 ClO2 ž CH2 ClO2 ž
Solvent
Rate constant M1 s1
H2 O/i-PrOH/CCl4 ratio 90:10:0.06 H2 O/i-PrOH/CHCl3 ratio 90:10:0.1 H2 O/i-PrOH/CHCl3 ratio 9:81:10 H2 O/i-PrOH/CH2 Cl2 ratio 90:10:0.5 H2 O/i-PrOH/CH2 Cl2 ratio 66:33:1
5.2 ð 108 3.7 ð 108 3.4 ð 106 2.8 ð 107 1.7 ð 106
reduction potential determinations of biochemically important free radicals have been reviewed41 . Other important aromatic amines such as chlorpromazine (26) have also been subjected to oxidation studies using oxidants produced by pulse radiolysis. Typical among these is the use of chloroalkylperoxyl radicals formed by pulse radiolysis in a variety of solvents. These oxidants yield the corresponding radical cation. The rate constants (Table 3) for these reactions were determined42 . Other studies have determined the reactivity between chlorpromazine and Br2 ž in H2 O/DMSO in varying proportions. The rate constants for the formation of the radical cation of chlorpromazine were similar in value to those obtained from the peroxy radical reactions4 . S
N
Cl
NMe2
(26) III. RADIOLYSIS OF AMINO ACIDS
An excellent, fairly recent, review of this subject was published in 1987 as part of a text book dealing with radiation biology43 . Since that time several advances have been reported. Much of the work reported in earlier reviews draws on material published in the 1960s and 1970s and, of course, most of this was reviewed (up to 1982) in the earlier volume1 in this series. As with the other studies reviewed in this chapter, much of the work deals with the radiolytic generation of an oxidizing species that subsequently reacts with the substrate, in this section with amino acids. Typical of this is the description by M¨onig and coworkers44 of the reaction of hydroxy radicals, generated by -irradiation,
17. Radiation chemistry of amines, nitro and nitroso compounds
829
TABLE 4. Efficiency of decarboxylation of amino acids at pH 10.1 by hydroxy radicals G(CO2 ) CO2 yield versus radiation dose
Amino acid Glycine ˛-Alanine Valine Leucine Serine N,N-Dimethylglycine
4.0 5.2 3.6 3.9 4.5 5.4
with amino acids. This brings about an efficient decarboxylation of the acid provided that the reaction is carried out in basic aqueous solution. Under these conditions the lone pair of electrons on the nitrogen is not protonated and it is at this site that the hydroxy radical attacks via a three-electron bonded system as illustrated in 27. This intermediate collapses to hydroxide, carbon dioxide and the strongly reducing carbon-centred radical 28. The detailed study (some examples are shown in Table 4) showed that decarboxylation occurs only when the amino and the carboxyl groups are on the same carbon. Furthermore, the yield of carbon dioxide amounts to 60 100% of the hydroxy radicals present. RCHCOO−
RCHNH2
NH2 ∴ OH (27)
(28)
The introduction of phenyl groups affords another reaction path via the aryl group. Thus a typical example is that of phenylalanine (29) that can be hydroxylated radiolytically at the aryl group45 . Another study has examined the reaction of pulse-radiolysis-generated hydroxyl radicals with the same substrate. Hydroxy radical attack in this instance leads to the formation of hydroxycyclohexadienyl radicals that can be oxidized to tyrosines (30). The attack by the hydroxy radical is quite random, however, although the meta position appears to be disfavoured. With sulphate radicals decarboxylation is again an important process along with tyrosine formation46 . Apparently, sulphate radical attack generates a radical cation which either reacts with water to afford tyrosines or undergoes intramolecular electron transfer that results in decarboxylation. Conversion of the carboxylate into the corresponding radical occurs by electron transfer in situations where the ˛-amino group is protonated. These processes have been studied using Fe(VI) and Fe(V) employing pulse radiolysis. The rate constants for the reaction of Fe(VI) with the carboxylates is in the range of 10 103 M1 s1 while those for the reaction of Fe(V) are orders of magnitude greater47 . Other studies with metal ions have examined the decarboxylation and deamination of 2-methylalanine 31. This pulse study identified that the reaction of the carbon-centred radical 32 with Cu2C or CuC formed a transient. In the case of Cu2C the transient is suggested as 33, with a copper carbon bond. This decomposes by a ˇ-carboxyl elimination reaction yielding CuC , carbon dioxide and the salt 34 that hydrolysed into acetone. This mechanism is thought to describe a new pathway for biological damage induced by free radicals48 . The yield of radiation-induced radical formation in short peptides has also been measured and compared with the amino acids present49 .
830
William M. Horspool CH3
OH PhCH2 CHCO2 H
CH2 CHCO2 H
CH3 CCO2 −
NH2
NH2
+ NH3
(29)
(30)
CH3
CH3
CH2 CCO2
−
Cu III
(31) 2+
CH3
CH2 CCO2−
+ NH
CH2
C
NH3 +
3
(32)
(33)
+ NH3
(34)
Methionine (35) also undergoes decarboxylation affording the radical 36 by attack of hydroxy radicals at pH 350 . In this system the hydroxy radical attacks at sulphur in the first instance. This transient, with a three-electron SO bond, is converted into the transient 37 and it is from this, the five-membered transition state, that decarboxylation takes place. The free acid is essential since no decarboxylation occurs with the ester 38. A study of the transients in such systems has been carried out in frozen aqueous solutions at 77 K51 . With S-methylcysteine (39) there is no interaction between the sulphur and the nitrogen. The transient formed on hydroxy radical oxidation was proposed as 40 and no decarboxylation takes place52 . In the constrained methionine derivative 41 decarboxylation induced by hydroxy radicals is pH dependent53 . Again the oxidation takes place at the sulphur. However, the intermediate 42 has a constant lifetime in the pH range 2.5 8. At higher pH the key intermediate is 43 and it is this that undergoes decarboxylation into the radical 44. + S∴NH2
CO2 R CH3 SCH2 CH2 CHNH2
CO2
CH3 SCH2 CH2 CHNH2
(35) R = H
COOH
(36)
−
CH3 SCH2 CHNH2
(37)
(39)
(38) R = Et CH3
H +
S∴O
+
+ NH3
+ NH3
O
C
COO−
S
NH3 Me
(40)
S ∴O (41)
Me
(42)
O
17. Radiation chemistry of amines, nitro and nitroso compounds
+ NH3
Me
S. + . . OH
CO2
NH2
−
Me
S
(43)
Gly-Met
(44) O
+ H3 N
SMe NH
CO2
CO2
−
−
NH
CO2
Met-Glu O
SMe CO2
CO2
−
−
+ NH3
−
O NH
Met-Gly-Gly
CO2
NH O SMe O
Gly-Met-Gly
+ NH3
CO2
−
NH
C
CO2
−
NH O SMe O
SMe
NH2 Pro-Met
NH
CO2 Glu-Met
CO2
−
−
NH
+ H3 N
CO2
−
O SMe SCHEME 1
−
831
832
William M. Horspool
Other studies have examined the effect of pulse-generated hydroxy radicals on short peptides containing the methione unit. Transients involving S N interaction have been detected in L-methionyl-L-methionine54 . In -glutamylmethionine and the S-alkylglutathione derivatives decarboxylation is also observed. However, the decarboxylation is thought to proceed by two different routes involving either (i) electron transfer between the oxidized sulphur and the carboxyl group on the terminal C-atom when both reactants are within the same peptide unit or (ii) interaction between a hydroxy radical adduct and a protonated amino group sited ˛ to a carboxyl group. This results in a process referred to as N-terminal decarboxylation55 . The influence of peptide sequence has also been studied56 . Mechanistically the decarboxylation, when it occurs, is the same in these systems as in the shorter peptides or in methionine itself and involves electron transfer from the methionine carboxylate function to the oxidized sulphur function. The effect of the make-up of the peptide is seen with the following systems: Met-Gly, Met-Glu, Met-Gly-Gly, Gly-Met-Gly and Pro-Met where decarboxylation does not occur. However, 80% decarboxylation occurs with -Glu-Met (Scheme 1)56 . Amino acids and proteins have also been shown to undergo oxidation when exposed to oxygen free radicals generated by -irradiation. This treatment results in the formation of hydroperoxide groups in, e.g., bovine serum albumin (BSA) or lysozyme. Common amino acids such as glutamate, isoleucine, leucine, lysine, proline and valine also undergo this peroxidation with similar efficiency57 . The oxidation of BSA has also been studied 58 using a variety of pulse-radiolysis-generated oxidants such as Br2 ž . Other research has examined the reaction of hydroxy radicals, generated by 60 Co irradiation, with proteins either under an atmosphere of N2 O or of oxygen59 62 . IV. RADIOLYSIS OF NITRO AND NITROSO COMPOUNDS A. Aliphatic Nitro Compounds
Pulse-radiolysis-induced electron transfer to nitro groups has been studied in some detail. Thus 1,1-dinitrocyclohexane undergoes conversion to the corresponding radical anion 45 on radiolysis in t-BuOH/H2 O (20:80) at pH 7. This species collapses to the radical 46 with loss of nitrite63 . The products of the reaction result from the subsequent reactions of the radical 46 or of the nitronate 47 formed by addition of another electron to the radical. A later pulse-radiolysis study has examined64 the reactivity of 2,2-dinitropropane and 1,1-dinitrocyclopentane and has shown that a similar reaction path is followed as that for 1,1-dinitrocyclohexane. However, the loss of nitrite from the radical anions of 2,2-dinitropropane and 1,1-dinitrocyclopentane was shown to be faster than that for 1,1-dinitrocyclohexane. The radical cation of 1-cyano-1-nitrocyclohexane (48), formed by radiolysis, also decomposes rapidly by elimination of nitrite. The subsequent cyanocyclohexyl radical undergoes hydrogen abstraction reactions from solvent64 . NO2
−
NO2
NO2 −
NO2 NO2 (45)
−
CN (46)
(47)
(48)
B. Aromatic Nitro Compounds
Aromatic nitro compounds are also prone to undergo one-electron reduction on pulse radiolysis. The behaviour of the radical cation so formed is dependent upon the type of
17. Radiation chemistry of amines, nitro and nitroso compounds
833
substituent attached to the aromatic ring. For example, a study has examined temperature effects on the loss of halide from the radical anions of the benzyl derivatives (49)65 . X-radiation has also been used to induce transformations in aryl nitro derivatives isolated in argon matrices. Ionization under these conditions leads to radical cations that undergo intramolecular hydrogen transfer. The neutral products detected as a result of this are o-nitrosobenzoic acid and the isoxazolone (50). Both of these are produced by reaction of the ketene (51) initially formed by the hydrogen transfer66 . Other studies have examined the -radiolysis of nitrobenzene/carbon tetrachloride/water systems. The volatile products formed in these are dependent upon the composition of the reaction mixture. In the presence of high concentrations of carbon tetrachloride chlorobenzene is formed67 . R
R1
R3
X
C R
2
O2 N (49)
1
R
2
R
3
X
H
H
H
Cl
H
Me
H
Cl
H
Et
H
Cl
Me
But
H
Cl
Me
H
H
Br
But
H
H
Me
H
Me
Br
But
H
Me
Br
Br
Considerable interest has been reported in the radiolytic reactions of radiosensitizing nitroimidazoles such as Metronidazole, 2-methyl-5-nitro-1H-imidazole-1-ethanol (52). Again loss of the nitro function as nitrite appears to be one of the principal events. The formation of nitrite from -irradiation of the Ni(II) complex of the imidazole 52 arises by hydroxy radical attack to form the radical anion. This either eliminates nitrite or undergoes a four-electron reduction to a hydroxylamino derivative68,69 .
O C O
O− N+
N OH (50)
N
O O2 N
N
Me OH
OH (51)
(52)
Several studies have reported the influence of nitroimidazole derivatives on biological systems. Thus the influence of Misonidazole, 1-(2-nitro-1-imidazoyl)-3-methoxy-propan2-ol, on strand breaking in calf thymus DNA under ionizing radiation conditions has been assessed70 . Pulse-radiolysis studies of nitroheterocyclic compounds have examined
834
William M. Horspool
the interaction of the nitro radical with various cellular extracts and purified enzymes71 and copper oxidases72 . The imidazole derivatives (53) have also been tested as radiation sensitizers of hypoxic carcinoma cells73 .
R1
NO2
N
R3
SO2
N
R2
Me
(53)
R1
R
2
R3
Me Cl Cl Cl
Me Me Cl CO2 H
OCH2 CO2 H H H Cl
C. Nitroso Compounds
Radiation-induced electron transfer to nitroso compounds has also been studied. This technique, using electron expulsion from trichlorofluoromethane, provided data that the radical cation 54 is formed from nitrosobenzene at 77 K. Analysis of the EPR spectrum indicates that the singly occupied MO lies in the plane of the benzene ring and has high 2s character74 . Irradiation of the dimer 55 under the same conditions shows that a trace of the monomeric radical cation 56 is produced74 .
O+
N
(54)
Me3 CNO +
(Me3 CNO)2
(55)
(56) O
O C
O
(57)
N
N
OH
H (58)
X-radiation of o-nitrosobenzaldehyde also brings about intramolecular hydrogen transfer to yield the ketene 57. Cyclization within this affords 5866 .
17. Radiation chemistry of amines, nitro and nitroso compounds
835
V. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
C. L. Greenstock, ‘Radiation chemistry of amines, nitro and nitroso compounds’ in Supplement F: The Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives, Part 1 (Ed. S. Patai), Wiley, Chichester, 1982, p. 291. V. N. Belevsky, O. In Quan, S. I. Belopushkin and V. I. Feldman, Dokl. Akad. SSSR, 281, 869 (1985). V. N. Belevsky, S. I. Belopushkin and V. I. Feldman, J. Radioanal. Nucl. Chem. Lett., 107, 67 (1986). M. Kumar and P. Neta, J. Phys. Chem., 96, 3350 (1992). G. W. Eastland, D. N. R. Rao and M. C. R. Symons, J. Chem. Soc., Perkin Trans. 2, 1551 (1984). S. Das, M. N. Schuchmann, H. -P. Schuchmann and C. von Sonntag, Chem. Ber., 120, 319 (1987). S. Das and C. von Sonntag, Z. Naturforsch. B., Org. Chem., 41B, 505 (1986). C. von Sonntag and H. -P. Schuchmann Angew. Chem., Int. Ed. Engl., 30, 1229 (1991). R. E. Huie, L. C. T. Shoute and P. Neta, Int. J. Chem. Kinet., 23, 541 (1991). S. M. Lefkowitz and A. D. Trifunac, J. Phys. Chem., 88, 77 (1984). S. Matsuoka, T. Kohzuki, C. Pac, A. Ishida, S. Takamuku and M. Kusaba, J. Phys. Chem., 96, 4443 37 (1992). S. Matsuoka, H. Fujii, T. Yamada, C. Pac, A. Ishida, S. Takamuku, M. Kusaba, N. Nakashima, S. Yanagida, K. Hashimoto and T. Sakata, J. Phys. Chem., 95, 5802 (1991). J. Piekarskagolebiowska, C. Z. Stradowski and M. Szadkowskanicze, J. Photochem. Photobiol. A, Chem., 49, 325 (1989). J. Piekarskagolebiowska and J. Kroh, Bull. Pol. Acad. Sci., Chem., 39, 369 (1991). J. Kroh, Isotopenpraxis, 26, 461 (1990). C. J. Rhodes, J. Chem. Soc., Perkin Trans. 2, 235 (1992). D. K. Maity, H. Mohan and J. P. Mittal, J. Chem. Soc., Perkin Trans. 2, 919 (1994). X. -Z. Qin and F. Williams, J. Phys. Chem., 90, 2292 (1986). C. Crouzet and J. Marchal, Radiat. Phys. Chem., 40, 359 (1992). C. Crouzet and J. Marchal, Radiat. Phys. Chem., 40, 233 (1992). C. Crouzet and J. Marchal, Radiat. Phys. Chem., 41, 851 (1993). C. Crouzet, Radiat. Phys. Chem., 40, 233 (1992). P. P. Klemchuk, Radiat. Phys. Chem., 41, 165 (1993). S. Falicki, D. J. Carlsson, J. M. Cooke and D. J. Gosciniak, Polym. Degrad. Stab., 38, 265 (1992). D. W. Werst and A. D. Trifunac, J. Phys. Chem., 95, 1268 (1991). Z. B. Alfassi, S. Mosseri and P. Neta, J. Phys. Chem., 93, 1380 (1989). P. Neta, R. E. Huie, S. Mosseri, L. V. Shastri, J. P. Mittal, P. Maruthamuthu and S. Steenken, J. Phys. Chem., 93, 4099 (1989). P. Neta, R. E. Huie, P. Maruthamuthu and S. Steenken, J. Phys. Chem., 93, 7654 (1989). S. Padmaja, Z. B. Alfassi, P. Neta and R. E. Huie, Int. J. Chem. Kinet., 25, 193 (1993). P. Neta, R. E. Huie and A. B. Ross, J. Phys. Chem., Ref. Data, 19, 413 (1990). L. C. T. Shoute and P. Neta, J. Phys. Chem., 94, 2447 (1990). P. Neta and R. E. Huie, J. Phys. Chem., 89, 1783 (1985). S. Padmaja, Z. B. Alfassi, P. Neta and R. E. Huie, Int. J. Chem. Kinet., 25, 193 (1993). G. Mer´enyi, J. Lind and X. Shen, J. Phys. Chem., 92, 134 (1988). J. Butler, E. J. Land, W. A. Prutz and A. J. Swallow, J. Chem. Soc., Chem. Commun., 348 (1986). S. V. Jovanovic, A. Harriman and M. G. Simic, J. Chem. Phys., 90, 1935 (1986). M. Faraggi, M. R. DeFelippis and M. H. Klapper, J. Am. Chem. Soc., 111, 5141 (1989). M. R. DeFelippis, M. Faraggi and M. H. Klapper, J. Am. Chem. Soc., 112, 5640 (1990). M. DeFelippis, C. P. Murthy, M. Faraggi and M. H. Klapper, Biochemistry, 28, 4847 (1989). M. R. DeFelippis, C. P. Murthy, F. Broitman, D. Weinraub, M. Farragi and M. H. Klapper, J. Phys. Chem., 95, 3416 (1991). M. Faraggi and M. H. Klapper, J. Chim. Phys.-Phys.-Chim. Biol., 90, 711 (1993). Z. B. Alfassi, R. E. Huie, M. Kumar and P. Neta, J. Phys. Chem., 96, 767 (1992). C. von Sonntag, The Chemical Basis of Radiation Biology, Taylor and Francis, London, New York and Philadelphia, 1987, pp. 393 428. J. M¨onig, R. Chapman and K. -D. Asmus, J. Phys. Chem., 89, 3139 (1985).
836 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.
William M. Horspool C. Wiezorek, Radiat. Res., 100, 235 (1984). D. G. Wang, H. -P. Schuchmann and C. von Sonntag, Z. Naturforsch. B, Org. Chem., 48, 761 (1993). V. K. Sharma and B. H. J. Bielski, Inorg. Chem., 30, 4306 (1991). S. Goldstein, G. Czapski, H. Cohen and D. Meyerstein, Inorg. Chem., 31, 2439 (1992). C. Wiezorek, Int. J. Radiat. Biol., 45, 93 (1984). K. -O. Hiller and K. -D. Asmus, J. Phys. Chem., 87, 3682 (1983). M. H. Champagne, M. W. Mullins, A. O. Colson and M. D. Sevilla, J. Phys. Chem., 95, 6487 (1991). K. -D. Asmus, M. G¨obl, K. -O. Hiller, S. Mahling and J. M¨onig, J. Chem. Soc., Perkin Trans. 2, 641 (1985). L. K. Steffen, J. Am. Chem. Soc., 113, 2141 (1991). K. Bobrowski and J. Holcman, J. Phys. Chem., 93, 6381 (1989). K. Bobrowski, C. Sch¨oneich, J. Holcman and K. -D. Asmus, J. Chem. Soc., Perkin Trans. 2, 975 (1991). K. Bobrowski, C. Sch¨oneich, J. Holcman and K. -D. Asmus, J. Chem. Soc., Perkin Trans. 2, 353 (1991). S. Gebicki and J. M. Gebicki, Biochem. J., 289, 743 (1993). S. K. Kapoor and C. Gopinathan, J. Radioanal. Nucl. Chem., 171, 443 (1993). K. J. A. Davies, M. E. Delsignoret and S. W. Lin, J. Biol. Chem., 262, 9902 (1987). K. J. A. Davies, S. W. Lin and R. E. Pacifici, J. Biol. Chem., 262, 9914 (1987). K. J. A. Davies and M. E. Delsignoret, J. Biol. Chem., 262, 9908 (1987). K. J. A. Davies, J. Biol. Chem., 262, 9895 (1987). J. C. Ruhl, D. H. Evans, P. Hapiot and P. Neta, J. Am. Chem. Soc., 113, 5188 (1991). J. C. Ruhl, D. H. Evans and P. Neta, J. Electroanal. Chem., 340, 257 (1992). M. Meot-ner, P. Neta, R. K. Norris, and K. Wilson, J. Phys. Chem., 90, 168 (1986). J. Michalak, J. Gebicki and T. Bally, J. Chem. Soc., Perkin Trans. 2, 1321 (1993). J. Kuruc and M. K. Sahoo, J. Radioanal. Nucl. Chem., 173, 395 (1993). M. B. Roy, P. C. Mandal and S. N. Bhattacharyya, J. Chem. Soc., Dalton Trans., 2485 (1993). T. Kagiya, H. Ide, S. Nishimoto and T. Wada, Int. J. Radiat. Biol., 44, 505 (1983). G. W. Buchko and M. Weinfeld, Biochemistry, 32, 2186 (1993). N. Lougmani, A. Guissani, Y. Henry and B. Hickel, J. Chim. Phys. Phys.-Chim. Biol., 90, 931 (1993). N. Lougmani, A. Guissani, Y. Henry and B. Hickel, J. Chim. Phys.-Phys.-Chim. Biol., 90, 943 (1993). R. A. Egolf and N. D. Heindel, J. Heterocycl. Chem., 28, 577 (1991). H. Chandra, D. J. Keeble and M. C. R. Symons, J. Chem. Soc., Faraday Trans. 1, 84, 609 (1988).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
18
The electrochemistry of nitro, nitroso, and related compounds ALBERT J. FRY Wesleyan University, Middletown, Connecticut, USA Fax: (860)685-2211; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . II. GENERAL CONSIDERATIONS . . . . . . . . . . A. Mechanism of Electrochemical Reduction . . 1. Dependence of proton activity of medium 2. Other medium effects . . . . . . . . . . . . . III. SUBSTITUTED NITROAROMATICS . . . . . . IV. AROMATIC DINITRO COMPOUNDS . . . . . . V. ALIPHATIC NITRO COMPOUNDS . . . . . . . VI. RELATED PROCESSES . . . . . . . . . . . . . . . A. Nitro Compounds as Electrogenerated Bases B. Nitro Compounds as Protecting Groups . . . . VII. NITROSO COMPOUNDS . . . . . . . . . . . . . . VIII. ACKNOWLEDGMENTS . . . . . . . . . . . . . . . IX. REFERENCES . . . . . . . . . . . . . . . . . . . . . .
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837 838 838 838 843 845 847 849 851 851 852 854 854 854
I. INTRODUCTION
Nitro compounds have been popular subjects for investigation from the earliest days of organic electrochemistry. The reasons for this are not hard to find: they are available in profusion, are easily reduced without affecting other functional groups, and a variety of products can be produced, depending upon the exact nature of the experimental conditions. Studies on the electrochemical reduction of nitro compounds have produced important insights into the mechanistic pathways available to organic compounds generally. The electrochemical reduction of a given nitro compound may take a considerably different course when variables such as the pH, electrolysis potential or nature of the solvent are varied. This has made the study of their reduction mechanisms a popular and challenging research topic. Nitroso compounds are much less common than nitro compounds and have been studied far less. Nevertheless, their status as putative intermediates in the
837
838
Albert J. Fry
electrochemical reductions of nitro compounds has led to a number of studies of their behavior. II. GENERAL CONSIDERATIONS A. Mechanism of Electrochemical Reduction
It will be helpful at this point to review a few well-known features of the electrochemical behavior of nitro and nitroso compounds. The reader is referred to a previous review in this series for more detail on this point1 . The primary fact of which one must be aware of is that the electrochemistry of nitro compounds is exclusively cathodic: the high oxidation level of nitrogen in the nitro group means that while they are easily reduced, they generally cannot be oxidized. As a matter of fact, nitrobenzene and nitromethane have been used as solvents for electrochemical oxidations because of their stability under anodic conditions2 . Nitroso compounds are readily both oxidized and reduced, although the literature on these substances is much more sparse. 1. Dependence of proton activity of medium
Aryl nitro compounds are by far the most common such substances, and nitrobenzene (1) is the best known of these. Nitrobenzene exhibits a single four-electron voltammetric wave at pH 5 or above; a second two-electron wave is observed at more negative potentials at pH 4 or lower. The products of the electrochemical reduction of nitrobenzene in aqueous organic media were established a century ago in the classic work of Haber3 . Reduction at room temperature in weakly acidic media (roughly pH 5 to 7) consumes four electrons per mole of 1 and affords phenylhydroxylamine (2); reduction under more powerfully reducing conditions (pH 4 and more negative potentials) affords aniline by reductive cleavage of the NO bond of 2. If the reaction is carried out under more vigorous conditions (stronger acid, higher temperatures), the product is p-aminophenol, formed by acid-catalyzed rearrangement of 2 (the so-called Wallach rearrangement). Zuman has summarized the dependence of the ultimate fate of the arylhydroxylamine (that is, whether it is isolated or undergoes further transformation) on experimental conditions4 . In contrast to these multi-electron processes in protic media, 1 exhibits a one-electron wave followed by a second three-electron wave at more negative potentials. Controlled-potential electrolysis at relatively positive potentials affords a very stable radical anion in media of low proton availability (aprotic solvents or even aqueous alkali). Reduction in liquid ammonia as solvent affords not only the radical anion but also the corresponding nitrobenzene dianion, at more negative potentials5 . Similar behavior is observed in highly purified dimethylformamide6 . Preparative scale electrolysis in alkaline media usually affords azoxy compounds (3), although the corresponding azo compounds (4) and hydrazo compounds (5) have been isolated from some electrolyses. The reasons for the diversity of products under alkaline conditions is still not fully clear. Azoxy compounds are reduced to azo compounds relatively easily, hence it would appear unlikely that 3 could ever be isolated from such electrolyses, but it appears that part of the reason is the fact that azoxy compounds often precipitate from solution, protecting them against further reduction7 . In general these substances are produced by consecutive electrochemical reduction of 3 to 4 and finally to 5. O− C6 H5NO2
C6 H5NHOH
(1)
(2)
C6 H5N
NC6 H5 (3)
C6 H5N
NC6 H5 (4)
C6 H5NHNHC6 H5 (5)
18. The electrochemistry of nitro, nitroso, and related compounds
839
Aliphatic nitro compounds exhibit rather different behavior from nitroaromatic compounds. Secondary and primary nitro compounds tend to produce oximes because the intermediate nitroso compound quickly tautomerizes to the oxime (equation 1). Under aprotic conditions the radical anions of primary and secondary nitro compounds are relatively stable; those derived from tertiary nitro compounds, on the other hand, eject nitrite ion relatively readily (equation 2)8 . 2e
! R1 R2 CHNDO ! R1 R2 CDNOH R1 R2 CHNO2 C H
(1)
e
R1 R2 R3 CNO2 ! R1 R2 R3 CNO2 ž ! R1 R2 R3 Cž C NO2
(2)
Nitrogen in a nitro group is in the highest oxidation state which the element can exhibit while still bound to carbon. Under powerfully reducing conditions the nitro group can be reduced to an amino group, in which nitrogen exhibits its lowest oxidation state. A number of species of intermediate oxidation level are possible between these two extremes. The electrochemical reduction of nitro compounds does in fact give rise to a number of such intermediates. Some of these can be directly identified, while the existence of others can sometimes only be inferred. Furthermore, a variety of paths may interconnect the various intermediates, starting materials and products of the electrochemical reduction of a given nitro compound, depending on the particular experimental conditions being employed. Different nitro compounds may react by different paths under identical experimental conditions, and a given compound may give rise to the same product by several different paths under different experimental conditions. Consider the electrochemical reduction of nitrobenzene (1) to phenylhydroxylamine (2) in a weakly acidic protic medium. This process involves overall uptake of four electrons by 1. As we shall see, this can occur by a variety of mechanisms, of which only one possibility is shown in Scheme 1. This scheme C6 H5 NO2 C e ! C6 H5 NO2 ž (1) (6) 6 C HC ! C6 H5 NO2 Hž (7) 7Ce
! C6 H5 N(OH)O (8)
8 C HC ! C6 H5 N(OH)2 C OH (9) 9 ! C6 H5 NDO C H2 O (10) 10 C e
! C6 H5 NOž (11)
11 C HC ! C6 H5 NOHž (12) 12 C e ! [C6 H5 NOH] (13) 13 C HC ! C6 H5 NHOH SCHEME 1
840
Albert J. Fry
differs in one significant detail from the mechanism of reduction of 1 presented in the previous1 review in this series: it is now known that cleavage of the NO bond involves dehydration of an intermediate N,N-dihydroxy compound (9). Previously it had been suggested that nitrosobenzene (10) was formed by loss of hydroxide ion from intermediate 7. In essence, Scheme 1 describes the gradual decrease in the oxidation level of nitrogen as electrons are successively added to 1. Four electrons are added overall, but since this would build up an unacceptably high charge on 1 if no other change were to take place, the organic species responds by addition of protons at each stage to maintain its structure near neutrality. Scheme 1 works well to rationalize the known conversion of 1 to 2 in weak acid. However, it greatly misrepresents the complexity of the reactions taking place. For example, nitrosobenzene (10) is easier to reduce than 1, hence it does not build up in solution but rather is reduced immediately upon formation. But, if nitrosobenzene is easier to reduce than nitrobenzene, this means that the nitrobenzene radical anion (6) is itself thermodynamically capable of reducing 10 to its radical anion 11. One therefore really ought to add to Scheme 1 another line representing electron transfer from 6 to 10 to produce 11 and regenerate 1. Thus, there are two ways in which the reduction of 10 to 11 can take place, depending on whether electron transfer to 10 takes place from the electrode or from 6, respectively. Because the reactant and the various intermediates are produced and react in a narrow zone (the reaction layer ) close to the electrode surface, homogeneous solution electron exchange between 6 and 10 certainly does take place; in fact, it is probably the primary path for formation of 119 . Likewise, we should also note that 6 and 11 may undergo homogeneous solution electron exchange with other intermediates in the redox chain10 . One must also appreciate that in general the mechanism and even the products of reduction of any given nitro compound will be sensitive to reaction conditions, in particular pH and electrolysis potential. Often it is not readily apparent what the actual electroactive species is in a particular conversion. [An electroactive species is a chemical entity undergoing electron exchange from or to the electrode.] For example, one might legitimately inquire whether the actual electroactive material in the reduction of 10 is 10 itself or whether it is its conjugate acid, which being positively charged ought to be considerably easier to reduce than 10. This question is of particular mechanistic relevance for understanding electrolyses carried out in relatively strongly acidic solution, especially when one appreciates that a component of the medium, e.g. the protonated form of a compound, may be the electroactive substance even when it is present at very low equilibrium concentration11 . It is clear that working out the mechanism of the electrochemical reduction of nitro compounds represents a very challenging problem indeed. There has been a great deal of previous work in this area, largely summarized in previous reviews1,7b,12 . The electrochemical reduction of nitrosobenzene (10) to phenylhydroxylamine (2) and nitrobenzene (1) to the N,N-dihydroxy compound (9) can be used to illustrate another point. Complex organic electrochemical processes typically involve a series of individual reactions each of which is one of two types: (a) so-called ‘E’, or electron transfer steps (either homogeneous to or from another component of the medium depending on whether one is discussing oxidations or reductions, respectively or heterogeneous to or from the electrode) and (b) ‘C’ steps, i.e. chemical conversions (all reactions other than electron transfer). The conversion of 10 to 2 formally involves addition of the elements of hydrogen or, more specifically, two electrons and two protons, to 10. A major aim of mechanistic studies on organic electrode processes is the determination of the particular sequence of electron transfers and chemical steps involved in the overall reaction. For the conversion of 1 to 9 or 10 to 2, all combinations of two E steps and two C steps must a priori be considered as possible13 . Scheme 1 shows one possible way in which each of these conversions might take place, i.e. by alternate addition of electrons and protons to either 1 or 10. In the commonly used terminology of mechanistic electrochemistry, these
18. The electrochemistry of nitro, nitroso, and related compounds
841
are so-called ‘ECEC’ processes. The term ECEC is therefore a shorthand method for describing the sequence in which the electron transfer and protonation steps take place. If one includes all possible permutations of two proton and two electron transfers, there are six distinct mechanistic possibilities for the conversion of 1 to 9 and 10 to 2 (4!/2!2!), or twelve if one recognizes that the second electron transfer could be either homogeneous or heterogeneous. Some of these sequences are highly improbable on chemical grounds. We may expect, for example, that the mechanism of reduction of 1 and 10 in acid will probably not be EECC, because the species produced by the first electron transfer are likely to be strong bases and would surely react with a proton before the second electron transfer could take place. Likewise, it is unlikely that conversion of 1 to 9 (or 10 to 2) proceeds via a CCEE mechanism; this would imply that the electroactive species is doubly protonated nitrobenzene, whereas it is known that 1 and 10 are not strong bases. Even if such chemically unreasonable steps were to be omitted, it is clear that the number of discrete paths by which 1 might in principle be converted into 2 is very large. It would be very cumbersome to present all of the likely paths in a format similar to that of Scheme 1, i.e. as a series of chemical reactions written in text form. It turns out to be much more convenient to represent the various possible mechanistic paths in graphical form. This is done in the following way. Consider an electrochemical reaction involving the conversion of a substance A to a product B and requiring one electron transfer and one chemical step. There are two possible mechanisms (EC or CE) for this process, depending on the order in which the two steps occur. We can represent this as a so-called ‘square’ mechanism, represented as in Scheme 2. The EC path is represented by the top and right-hand equations while the CE process is represented by the left-hand and bottom reactions. EC process e−
A
A
−
H+
H+ A H+
e− B
CE process
SCHEME 2. Simplest (four-component) square mechanism
This type of representation is readily extended to cover more complex cases. A oneelectron, two-proton reduction can be described by a so-called ‘ladder’ scheme14 , whereas a two-electron, one-proton process can be described by a ‘fence’ scheme15 . Reactions involving uptake of the elements of H2 are relatively common in organic electrochemistry; in fact, we have already encountered the conversion of 1 to 9 and 10 to 2, which are examples of this type of process (see Scheme 1). Such processes may be represented by a nine-component square (Scheme 3). A number of features are common to schemes such as Schemes 2 and 3. All species in a given vertical column are in the same oxidation state but differ in their degree of protonation. Conversely, all species in a given horizontal row correspond to the same degree of protonation but are in different oxidation states. Each path which may be traced between any one species on the diagram and any other corresponds to a distinct electrochemical mechanism. The ECEC mechanism (A ! A ! AH ! AH ! AH2 ) which was mentioned previously as a mechanistic path from 1 to 9 and 10 to 2 can be seen from Scheme 3 to be only one of a number of paths by which this conversion might take place.
842
Albert J. Fry e
A
−
A
H+ +
e−
−
AH
AH
H+ e−
AH2
−2
H+
e−
H+ 2+
A
H+
AH
AH2
e−
−
H+ e−
+
AH2
SCHEME 3. Nine-component square mechanism
As mentioned earlier, reduction of nitro compounds to hydroxylamines is now known to involve a sequence involving initial two-electron, two-proton conversion to an N,Ndihydroxy compound (9), dehydration of 9 to the corresponding nitroso compound (10) and finally a second two-electron, two-proton reduction of 10. We may now recognize that two nine-component square schemes, separated by the intervening dehydration of 9 to 10, are required to represent all possible mechanistic paths for this process in acidic media. In point of fact, however, the doubly protonated nitro and nitroso compounds, which correspond to the lower left-hand corner of Scheme 3, are improbable intermediates in these reactions, because 1 and 10 are weak bases and their doubly protonated forms will therefore be present in vanishingly small amounts even in strong acid. Likewise, the nitrobenzene and nitrobenzene dianions (corresponding to the top right-hand corners of Scheme 3) are equally improbable intermediates because they would be formed via intermediate monoanions, which would be very short-lived in acidic solution. For this reason, the top right and bottom left corners of Scheme 3 are sometimes omitted when describing the reduction of nitro compounds in acid, leaving a seven-component diagram consisting of two four-component square mechanisms sharing a single corner (Scheme 4). The common intermediate between the two four-component squares in Scheme 4 is the RN(OH)OÐradical (7). e−
C6 H5NO2
C6 H5NO2
−
H+
H+ +
C6 H5NO2 H
e−
e−
C6 H5N(OH)O
−
C6 H5N(OH)O
7 H+
H+ +
C6 H5N(OH)OH
e−
C6 H5N(OH)2
SCHEME 4
One of the advantages of electrochemical methods over more conventional chemical methods is the fact that the actual electron transfer process can be carried out at an electrode with a far greater degree of control than with a solution reactant. By careful application of the appropriate electrochemical techniques, it is possible to define the sequence of chemical and electron transfer steps in a given electrochemical process with
18. The electrochemistry of nitro, nitroso, and related compounds
843
a high degree of specificity. Laviron has shown by such methods that the rate-determining step in the formation of the N,N-dihydroxy compound (9) is conversion of the radical ArN(OH)OÐ to 9. Using standard voltammetric techniques, he was able to conclude that the global mechanism for the reduction of ArNO2 to ArN(OH)2 changes from ECCE at pH D 0 to ECEC at pH D 5 (C is a protonation step) with the change in mechanism taking place at about pH D 316 . With 4-nitrobenzophenone the rate of dehydration of the N,N-dihydroxy compound controls the rate of the first reduction step in strongly acidic media H0 D 217 . The sequence of steps involved changes through CECE, ECCE and finally ECEC as the acidity of the medium increases from H0 D 5 to pH 10, and is EE at pH > 10. Dehydration of 9 is sometimes slow enough that the nitroso compound can be observed as a transient intermediate during electrolysis, for example at low temperature18 or with certain special structural types such as p-dinitrobenzene18 and the nitropyridines19 . Information obtained by voltammetric studies and preparative scale electrolyses can often be used to understand the course of reactions carried out with chemical reductants or oxidants. Nitro compounds provide an excellent illustration of this point. Organic chemists have known for many years that aryl nitro compounds can be reduced to a variety of compounds, depending on experimental conditions. For example, reduction to the corresponding aniline is often carried out using metallic tin or iron (strong reducing agents) and hydrochloric acid; this is consistent with the voltammetric data, which indicate that conversion of the hydroxylamine to the amine requires a relatively negative potential and a rather strongly acidic medium. Similarly, reduction of nitrobenzene (1) to azobenzene (4) is typically carried out using a strong reductant, for example metallic zinc, in alkaline medium20 ; we have seen that dimeric derivatives are formed only under basic conditions and that the initial dimer is normally the azoxy compound (3), which is reduced further to the azo compound. Finally, reduction of the nitro compound under basic conditions with a mild reductant affords the azoxy compound, which can likewise be obtained by electrochemical reduction in base under mild conditions. 2. Other medium effects
From the discussions up to this point it should be clear that reduction of nitrobenzene in acidic media affords phenylhydroxylamine, whereas reduction in basic media affords azoxy compounds and/or their secondary electrolysis products, azo or hydrazo compounds. Ohkubo recently made the very interesting observation that azoxybenzene is the major product (together with some azobenzene and a trace of hydrazobenzene) when the solvent for electrochemical reduction of nitrobenzene (acetonitrile) is saturated with carbon dioxide21 . The authors suggested that carbon dioxide emulates the effect of a proton in this reaction. This cannot be the entire answer, since addition of phenol to the medium instead of carbon dioxide results in formation of phenylhydroxylamine, not azoxybenzene22 . Carbon dioxide probably acylates the electrochemically-generated nitrobenzene radical anion, paving the way for NO bond breakage by loss of carbonate ion and providing an alternate route to azoxybenzene to that shown in Scheme 1. A possible mechanism is presented in Scheme 5. Thus far the solvent systems we have discussed are typical protic organic media, such as, for example, water ethanol mixtures containing an added supporting electrolyte. These solvents are presumably quite homogeneous on a microscopic level. However, a number of solvents have been developed in recent years which are heterogeneous on a microscopic scale. Micellar media are one example of such solvents. The electrochemical reduction of nitrobenzene in aqueous solutions containing polyoxyethylene lauryl ether, a substance known to produce neutral micelles, produces azobenzene (4) even at pH somewhat less than 723 . This is apparently the first case of formation of a dimeric product from electrolysis of nitrobenzene (1) in acidic media. Another striking example of this phenomenon
844
Albert J. Fry −
C6 H5NO2
e−
O C6 H5N + − O
e−
OCO2 C6 H5N
−
CO2
− CO3 −2
−
OCO2 C6 H5N + − O
C6 H5N
−
O
O
−
O e
−
−
C6 H5N
O
dimerization
C6 H5N
NC6 H5 −
O −
−
O CO2
C6 H5N
O NC6 H5 OCO2
− CO3 −2
C6 H5N +
NC6 H5
−
SCHEME 5
was recently observed during electrochemical reduction of 1 in a so-called ‘microemulsion’ consisting of 34% didodecylammonium bromide (DDAB), 51% hexane and 15% 5M aqueous HCl24 . Constant-current electrochemical reduction of 1 in this solvent affords a mixture of azobenzene and azoxybenzene! [Recall that these products are usually found only in electrolyses of nitrobenzene in alkaline meda.] Although microemulsions are thermodynamically stable and homogeneous on a macroscopic scale (for example, they do not scatter light), they are undoubtedly quite heterogeneous at the molecular level25 . Nitrobenzene is presumably concentrated in the hydrocarbon phase in both of these media and therefore its local concentration is undoubtedly higher than its nominal concentration. As was also recognized by Blount23 , this would favor dimerization, a bimolecular process. As noted at the outset, electrochemistry normally occurs in a thin layer of solution near the electrode surface. Electrochemical reactions frequently occur via adsorbed reactants and/or intermediates. Whether adsorption effects are observed in a given situation depends not only on the structure of the electroactive substance but also on the nature of the solvent and, very importantly, the composition of the electrode. Adsorption effects fall into a variety of categories: reduction of a substance may become either easier or harder, some transformations may be totally inhibited and chemical reactions in adsorbed films may proceed at rates different than in homogeneous solution. For example, deposition of small amounts of palladium on a gold surface results in an electrode in which the 4electron wave of some nitro compounds is shifted to more negative potentials and aniline formation is totally inhibited, but 3-nitro-1,2,4-triazole is easier to reduce than at pure gold, and the overall rate of reduction is controlled by the rate of dehydration of the ArN(OH)2 intermediate26 . Under similar conditions 2- and 4-nitroimidazole are reduced by parallel pathways: (a) electron transfer from the electrode to afford the ArN(OH)2 intermediate and (b) electrocatalytically by adsorbed hydrogen (see below)27 . Reductions at noble metal electrodes in acidic protic media often form adsorbed hydrogen, which is the actual reductant. For example, reduction of nitrobenzene at a Pd/C electrode in acetic acid methanol mixtures affords aniline via adsorbed hydrogen28 . This reaction is more closely related to catalytic hydrogenation of nitro groups than to the
18. The electrochemistry of nitro, nitroso, and related compounds
845
electrochemical process. The same might be said of electrochemical reductions of nitro compounds using Devarda copper29 , Raney nickel30,31 or Ti/TiO2 32 electrodes. Pintauro found that nitrobenzene could be reduced to aniline at Raney nickel when sodium tosylate is the supporting electrolyte, but that reduction went all the way to cyclohexylamine (!) when the supporting electrolyte is tetraethylammonium tosylate31 . III. SUBSTITUTED NITROAROMATICS
Laviron has studied an especially interesting class of nitro compounds containing a second basic site, e.g. 4-nitropyridine (14)33 . Even two-dimensional representations such as those encountered earlier (Schemes 2 4) are inadequate to represent this mechanistically very complex situation. Laviron showed, however, that the electrochemical conversion of 14 to the corresponding ArN(OH)2 species can be satisfactorily explained in terms of a modified so-called ‘bi-cubic’ diagram (Figure 1). Note that the each of the front and rear planes of the bi-cubic model consists of a seven-component reaction diagram analogous to that of
+
+
HNRNO2
HNRNO2
NRNO2
NRNO2 +
HNRNO2H+
.
Lower plane
.
+
+
HNRNO2H
.
NRNO2H+
.
.
NRNO2H +
.
HNRNO2H
NRNO2H
HNRN(OH)2+
+
Upper plane NRN(OH)2+
HNRN(OH)2
NRN(OH)2 +
HNRN(OH)(OH2+)
NRN(OH)(OH2+) −H2O k
R′NO Bi-cubic scheme 2e, 2H
+
(R′ = +HN or N) R′NHOH FIGURE 1. Bicubic mechanism for reduction of nitropyridines. Reproduced by permission of Elsevier Science SA from Reference 33
846
Albert J. Fry
Scheme 4. The compounds and intermediates on the ‘rear’ plane of the bicubic system (farthest from the reader) are protonated on the pyridine nitrogen atom; those on the ‘front’ plane (nearest the reader) are not. Laviron’s work has shown that the reduction of 14 and its corresponding N-oxide34 , and indeed probably most aryl nitro compounds, proceeds by an ECEC sequence leading to the neutral N,N-dihydroxy [ArN(OH)2 ] intermediate at all proton concentrations from H0 D 6 to pH 9.6. This substance then loses water to form the nitroso compound, which then undergoes a second sequence leading to the arylhydroxylamine. Pentahalonitrobenzenes (15) undergo electrochemical coupling to the corresponding octahalobiphenyls (16, equation 3)35 . There is an interesting mechanistic dichotomy between the fluorine and chlorine compounds (15a and 15b, respectively). The radical anion of 15a couples, then the resulting dimeric dianion ejects two fluoride ions to afford 16; in contrast, the radical anion of 15b ejects chloride ion to afford a neutral radical, which then dimerizes to 16. X5
X4 NO2
2 e−
O2 N
− 2 X−
NO2
(3) X4
(15a) X = F (16) (15b) X = Cl It was noted at the outset (Section II.A.1 that reduction of nitro compounds in basic media generally affords dimeric products (azoxy, azo or hydrazo compounds). It has been found, however, that reduction in 1N NaOH of nitroarenes bearing electron-supplying groups, especially hydroxy and alkoxy groups, affords amines in good yields36 . This is presumably because the intermediate hydroxylamine dehydrates readily to a quinoid substance, which then undergoes facile reduction to the amine (equation 4). Similar conversion to the amine was observed with a naphthalenic nitrosophenol (equation 5)37 . p-Nitrodiphenylamine is reduced all the way to the amine via dehydration of the intermediate hydroxylamine; however, reduction of the corresponding N-acylated compound stops at the hydroxylamine, which undergoes dehydration much less readily36b . In a related vein, it was reported that whereas 2-methyl-5-nitroaniline (17) exhibits a four-electron wave followed by a two-electron voltammetric wave in acidic medium, the closely related substance 4,6-di-t-butyl-2-methyl-3-nitroaniline (18) exhibits a single six-electron wave at the same pH. This suggests that the intermediate hydroxylamine from 18 is reduced to the corresponding amine faster than that from 17. The authors ascribed this difference to the larger number of alkyl groups in 18 causing the hydroxylamine formed from it to be more basic than that from 1738 . It seems more likely that the increased basicity arises because CH3
Bu-t NH2
NH2
t-Bu NO2 (17)
CH3 NO2 (18)
18. The electrochemistry of nitro, nitroso, and related compounds
847
the steric bulk of the t-butyl group in 18 forces the hydroxyl group of the hydroxylamino group out of the aromatic plane, thus reducing the degree of resonance interaction of the nitrogen with the benzene ring and making it easier to cleave the NO bond. NO2
NHOH
NH
NH2
(4)
OH
OH NO
O
OH NHOH
OH
OH
(5)
NH2 OH
IV. AROMATIC DINITRO COMPOUNDS
The behavior of dinitro compounds is of both synthetic and mechanistic interest. There is obvious synthetic value to selective reduction of a dinitro compound since the product has two readily differentiated groups for subsequent elaboration. One is also interested in the effect which one of the groups has on the other, and how this may change as one group is altered electrochemically. The observed effects depend on the nature of the structural relation between the two groups. It is necessary at this point to review the behavior of analogous benzenoid species. As mentioned previously nitrobenzene (1) undergoes one-electron reduction to a stable radical anion in aprotic media39 . The first polarographic reduction wave of meta-dinitrobenzene (19) is 0.25 V positive of that of 1. This substantial shift (1 V D 23.06 kcal mol1 ) is due to the effect of the second inductively electron-withdrawing nitro group on the reduction potential of the first. The second reduction potential of 19, on the other hand, is negative of the reduction potential of 1. This is presumably because in the radical anion formed at the first step the first nitro group now bears a negative charge40 and hence is inductively electron-supplying. Para- and ortho-dinitro benzenes (20 and 21), however, exhibit markedly different behavior. The first reduction potential of 20 is even more positive than that of 19, even though the second nitro group in 20 is further away
848
Albert J. Fry
from the first than in 19 and should exert less of an inductive effect. Furthermore, the second reduction potential of 20 is positive of that of the reduction potential of neutral nitrobenzene, even though in the case of 20 one is reducing a species already carrying a negative charge. ortho-Dinitrobenzene (21) behaves similarly, although the effects are less dramatic. The anomalous voltammetric behavior of 20 and 21 (and other aromatic compounds bearing unsaturated groups para or ortho to each other)41 has been ascribed7,9 to quinoidal contributions such as 22 to the structure of the dianions and corresponding monoanion radicals, thus providing a means of charge localization and stabilization in such species (presumably the effect is not as great in 21 because the two nitro groups are twisted somewhat out of planarity). The unusual ESR spectrum of the radical anion of 20 was also ascribed to a quinoidal contribution to the structure7 . Parker has obtained further evidence for the formation of quinoidal dianions from 20 and 2142 and quantum mechanical calculations (MP2, SCF) show that related monoanions also prefer a quinoidtype structure43 . On the other hand, it has been found that the radical anion of 1,4dinitrodurene prefers a structure in which one nitro is perpendicular and the other is parallel to the plane of the ring44 . The resonance stabilization of the quinoidal form is outweighed by the steric repulsions which arise if the nitro groups are both in the plane of the ring. The molecule apparently adopts a compromise in which only one nitro group is in the plane of the ring, thus preserving some stabilization in the semiquinoidal structure 23. NO2
NO2
NO2
NO2 NO2
O2 N NO2 (1)
(20)
(19)
−
Ο
+ N
O−
−
Ο
(21) −
+ N
O
H3 C
CH3
H3 C −O
N + (22)
CH3 +
O−
−
N
O
O (23)
These concepts were recently applied to an understanding of the electrochemical reduction of the mono and dinitro derivatives of the nonbenzenoid hydrocarbon 24a45 . Compound 24b exhibits a single one-electron wave at 1.08 V, while dinitro compound 25 exhibits two one-electron waves at 0.88 and 1.05 V46 . This behavior is quite similar to that exhibited by ortho-dinitrobenzene (21); it appears therefore that 25 is reduced to a dianion in which the quinoidal structure 26 is an important contributor to the resonance hybrid. The quinoidal structure 11 could be produced from 25 even though the
18. The electrochemistry of nitro, nitroso, and related compounds t-Bu
849
t-Bu
t-Bu
2 3
1
−
Me
X
10
4
9
5 Me
Me
Me
NO2
+
NO2
Me
O + N
−
O
6
8
O−
O
Me
−
O
7 t-Bu (24a) X = H (24b) X = NO2
t-Bu
t-Bu
(25)
(26)
two nitro groups are twisted out of the plane of the aromatic ring because overlap is still largely preserved between the adjacent ring carbon and nitrogen pi-orbitals in the twisted structure47 . Quantum mechanical calculations on 25 and its dianion were used to support these conclusions47 . V. ALIPHATIC NITRO COMPOUNDS
Electrochemical reduction of benzylic nitro compounds (27) in an ethanolic aqueous acetic acid buffer (35:65) affords a mixture of the corresponding oxime and hydroxylamine (equation 6)48 . The hydroxylamine can subsequently be oxidized back to the oxime (28) (via the intermediate nitroso compound); conversions as high as 90% can be obtained. R
R ArCHNO2 (27)
R
ArC
NOH
+
(6)
ArCHNHOH
(28)
Reduction of ˛,ˇ-unsaturated nitro compounds (29) affords the corresponding oximes (30) in high yields when electrolysis is carried out at 0.4 V (vs SCE) at a mercury or graphite electrode in aqueous isopropanol containing 0.1 M H2 SO4 (equation 7)49 . Reduction at 1.1 V affords the secondary amine (31) in fair yields. Isolated double bonds elsewhere in the molecule are not affected. NO2 Ar R (29)
R ArCH2 C (30)
R NOH
or
ArCH2 CHNH2
(7)
(31)
Electrochemical reduction of the ˛,ˇ-unsaturated nitro compounds 32 in acetonitrile containing tetraethylammonium tosylate affords the corresponding hydrodimer in 37%
850
Albert J. Fry
yield (equation 8)50 . An alternate route more often observed in the electrolysis was deprotonation of 32 by an electrogenerated base51 to afford a conjugated carbanion which attacks the starting material in a Michael-type reaction (equation 9). R NO2
2e
−
2H
O2 N
+
NO2
2 R
(8)
R (32)
(33) NO2
R 32
:B
−
R
−
NO2
1, 32 2. H
+
(9) R
NO2
1,2-Dinitro compounds are reduced to alkenes with elimination of two equivalents of nitrite ion (e.g. 34 to 35 equation 10)52 . More surprising, perhaps, is the reductive electrochemical coupling of 1,1-dinitro compounds such as 1,1-dinitrocyclohexane (36) to the corresponding dimeric vicinal dinitro compounds (34, equation 11). The process is initiated by reduction of 36 to a radical anion, which ejects nitrite ion to produce the ˛-nitrocyclohexyl radical (37), coupling of which leads to 348b,52 . What happens in the reduction of compounds 38 40, each of which bears an electronegative group bound to the carbon bearing the nitro group, depends upon the nature of the group8b . Compound 38 affords alkene 35; toluenesulfinate ion is ejected from the initial radical anion to produce radical 37, which reacts as shown above to afford 34 and ultimately 35 (equation 12). Reduction of 39 affords a mixture of nitrocyclohexane and cyanocyclohexane (equation 13); nitro ester 40, on the other hand, affords ester 41 (equation 14). Whether it is the nitro group or the hetero atom group which is lost upon reduction apparently depends on both the relative electronegativity of X and the electrolysis potential. NO2
(10)
O2 N (34) NO2 NO2
(35) NO2 e− −NO2
NO2
−
(36)
O2 N (37)
(34)
(11) NO2 SO2 -p-C6 H4 CH3 (38)
e− − −NO2
(37)
(35)
(12)
18. The electrochemistry of nitro, nitroso, and related compounds NO2 CN
NO2
e− − −NO2
851
H +
H
(13)
CN
(39)
NO2 CO2 Et
H
e− − −NO2
(14)
CO2 Et
(40)
(41)
Cobalt(III) macrobicyclic polyamine complexes normally exhibit electrochemical behavior analogous to that of nitroarenes, in that electrolysis at pH 0 or 4 affords hydroxylamines, and azoxy compounds at high pH53,54 . Their behavior in dry aprotic solvents resembles that of tertiary nitro compounds8 in that reduction affords a radical anion which ejects nitrite ion to afford a tertiary radical. The final product contains a hydrogen atom at the site originally occupied by the nitro group. The same reductive removal of a tertiary nitro group and replacement with hydrogen is observed upon reduction of a nitro derivative of the alkaloid vincristine55 . VI. RELATED PROCESSES A. Nitro Compounds as Electrogenerated Bases
Reduction of many organic weak acid compounds results in formation of the corresponding carbanions (equation 15). The alkylation of such species represents an attractive synthetic application56 . Niyazymbetov and Evans have explored the chemistry of ethyl nitroacetate (42)57 . As it happens, reductive cleavage of the ˛-nitro group occurs when 42 is reduced directly, but this problem was circumvented by using electrogenerated superoxide ion to deprotonate 42 (Scheme 6). (This is readily done: one simply exposes the electrolysis solution to the atmosphere during electrolysis; oxygen diffuses into the solvent and is immediately reduced to superoxide). The anion 43 is alkylated in high yield if the electrolysis is carried out in acetonitrile containing a tetraalkylammonium salt as supporting electrolyte; under these conditions ion-pairing is minimized and the carbanion is highly reactive. One can even effect dialkylation of 42 under these conditions. Anion 43 also reacts readily with Michael acceptors to afford the corresponding adducts in good yields. It is also possible to carry out alkylation and Michael addition in a single pot. Double Michael addition can be carried out also to produce adducts of type 44. Since these are tertiary nitro compounds, they are readily reductively denitrated (equation 16)58 . The nitro group is used temporarily to effect formation of the two carbon carbon bonds, and is then removed. R2 CHNO2 C e ! R2 C NO2 C 1/2 H2
(15)
O (42)
e −, O2
O X
EtO
NO2
X
X (44)
2e H
X
−
+
EtO
H
X
(16)
852
Albert J. Fry O2 C e ! O2 ž O2 ž C O2 NCH2 CO2 Et ! O2 NCH CO2 Et (42) (43) 43 C ‘E’ (electrophile) ! O2 NCH(E)CO2 Et SCHEME 6
Secondary nitro compounds can be converted into carbanions in similar fashion. Interesting highly functionalized adducts (46) were prepared by addition to levoglucosene (45) (equation 17)59 . Mixtures of diastereomeric adducts were generally formed60 . The adduct from nitromethane undergoes double Michael addition followed by aldol condensation to afford the novel adduct 47. O
O e−
O
O
RCH(R′)NO2
O
O
R (45)
(17)
NO2 R′ (46)
O OH
O
O
O2 N
O
O (47)
B. Nitro Compounds as Protecting Groups
The extreme ease of electrochemical reduction of nitro compounds suggests that they might usefully serve as protecting groups. Torii has shown that alcohols can be protected as their p-nitrobenzyl ethers. The group is removed by a two-step sequence involving catalytic reduction to the corresponding amine, followed by electrochemical oxidation of the amine, which is accompanied by hydrolysis of the intermediate Schiff base61 . The electrochemical behavior of a series of nitrobenzenesulfonamides (48 and 49) were examined by cyclic voltammetry and other techniques in connection with the use of such arenesulfonyl groups as protecting groups for amines. Interestingly, the behavior of the 2-nitro derivative 48a and the N,N-dialkyl 4-nitro derivative 49 differed from that of the 3-nitro and 4-nitro monosulfonamides 48b and 48c62 . Ortho-derivative 48a and 49
18. The electrochemistry of nitro, nitroso, and related compounds
853
O2 N SO2 NHBu
O2 N
(48a) X = 2−NO2 (48b) X = 3−NO2 (48c) X = 4−NO2
SO2 NBu2
(49)
are reduced to radical anions which are rather stable; they are however reduced at more negative potentials to dianions, which readily fragment with cleavage of the SN bond and ejection of the nitrobenzenesulfinate anion (this is exemplified for 49 in Scheme 7). The free amines are isolated in good yields (>70%). The initial radical anions from 48b and 48c fragment relatively readily with loss of a hydrogen atom to form a species which can be reduced further to a rather stable dianion (Scheme 8). Since the latter species does not undergo spontaneous cleavage of the SN bond at a useful rate, electrochemistry is therefore not useful for removal of the arenesulfonyl group with compounds such as 48b and 48c. The question naturally arises why different behavior should be exhibited by −2
O2 N
SO2 NBu2
e−
radical anion
e−
O2 N
SO2 NBu2
(49)
(50)
O2 N
(50)
H+
−
NBu2
SO2
−
+
−
NBu2
HNBu2 SCHEME 7
O2 N
−
SO2 NHBu
O2 N
− SO2 NBu
1. e 2. −H
(48b) X = 3−NO2 (48c) X = 4−NO2 O2 N
− SO2 NBu
e
−
−2
O2 N SO2 NBu
(51) SCHEME 8
854
Albert J. Fry
compounds as similar as 48a and, say, 48b. In effect, the question is: why does dianion 50 fragment while dianion 51 does not? The difference between the two is quite possibly the fact that dianion 50 has two electrons in an antibonding pi-orbital, whereas 51, which is a dianion radical, has only one electron in an antibonding pi-orbital. Furthermore, 51 can accommodate part of its negative charge on the relatively nonbasic sulfonamide nitrogen atom, while 50 has a doubly negative charge in its pi-system; these effects provide for a powerful driving force for cleavage of 50 which is absent from 51. On occasion such reductive deprotection processes can be quite selective. Electrochemical reduction of N,N0 -di-p-toluenesulfonyl-N-t-butoxycarbonyl derivatives of aliphatic and aromatic diamines selectively removed the p-toluenesulfonyl group attached to a primary amine site63 . Yields on the mono-protected products are fair to high; selective deprotection of the corresponding N,N0 -dibenzoyl derivatives occurred in yields 92%. VII. NITROSO COMPOUNDS
As can be seen from the preceding discussion, the existence of nitroso compounds as intermediates in the electrochemical reduction of nitro compounds is mostly inferential: nitroso compounds are easier to reduce than nitro compounds. Hence, they should be reduced as quickly as they are formed and would not be expected to be isolable. However, nitroso compounds have occasionally been isolated in unusual structural cases54 and the nitrosobenzene radical anion has been identified by ESR spectroscopy in at least one instance64 . It is possible to prepare nitroso compounds by a two-step sequence: one reduces the nitro compound electrochemically to the hydroxylamine, then electrochemically oxidizes the hydroxylamine to the nitroso compound65 . It has been suggested on thermochemical grounds that the radical cations of at least some nitroso compounds should be short-lived species. Such calculations suggest in fact that the CN bond dissociation energy of the radical cation of 2-nitroso-2-methylpropane should be close to zero66 . Direct electrochemical oxidation and reduction afford radical cations and radical anions, respectively, the ESR spectra of which have been characterized in a number of cases67 . Voltammetric studies have shown that the cationic micelle-forming surfactant cetyltrimethylammonium bromide inhibits the reduction of pnitroso-N,N-dimethylaniline to the corresponding arylhydroxylamine68 . One possibility, the ECEC path, i.e. alternating electron transfer and protonation steps, for the mechanism of reduction of nitrosobenzene to phenylhydroxylamine was discussed in Section II.A.1. It is pointed out there that this conversion might take place by a number of different paths. Laviron explored this question69 . He found that the mechanism is CECE in acidic media and ECEC in basic media and ECCE at intermediate pH. VIII. ACKNOWLEDGMENTS
Professors Dennis Evans and Petr Zuman kindly provided material in advance of publication. Financial support was provided by the National Science Foundation (Grant #CHE9413128). IX. REFERENCES 1. 2. 3.
A. J. Fry, in The Chemistry of Functional Groups, Supplement F: The Chemistry of Amino, Nitroso and Nitro compounds (Ed. S. Patai), Wiley, Chichester, 1982, pp. 319 337. A. J. Fry, ‘Solvents and Supporting Electrolytes’, in Laboratory Techniques in Electroanalytical Chemistry, 2nd ed. (Eds. P. T. Kissinger and W. R. Heineman), Marcel Dekker, New York, in press. F. Haber, Z. Elektrochem., 4, 506 (1989).
18. The electrochemistry of nitro, nitroso, and related compounds 4. 5. 6. 7. 8. 9. 10.
11. 12.
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.
855
(a) P. Zuman, in Electroorganic Synthesis (Eds. R. D. Little and N. L. Weinberg), Marcel Dekker, New York, 1991, p. 137. (b) P. Zuman, Z. Fijalek, D. Dumanovic and D. Suznjevic, Electroanalysis, 4, 783 (1992). W. M. Smith and A. J. Bard, J. Am. Chem. Soc., 97, 5203 (1975). B. S. Jensen and V. D. Parker, J. Chem. Soc., Chem. Commun., 367 (1974). (a) A. Darchen and C. Moinet, J. Electroanal. Chem., 68, 173 (1976). (b) F. D. Popp and H. P. Schultz, Chem. Rev., 62, 19 (1962). (a) J. C. R¨uhl, D. H. Evans, P. Hapiot and P. Neta, J. Am. Chem. Soc., 113, 5188 (1991). (b) J. C. R¨uhl, D. H. Evans and P. Neta, J. Electroanal. Chem., 340, 257 (1992). (c) H. Wang and O. Hammerich, Acta Chem. Scand., 46, 563 (1992). C. M. Amatore and J. M. Sav´eant, J. Electroanal. Chem., 86, 227 (1978). (a) B. Kastening, Electrochim. Acta, 9, 241 (1964). (b) B. Kastening, Coll. Czech. Chem. Commun., 30, 4033 (1965). (c) B. Kastening, Z. Anal. Chem., 224, 196 (1967). (d) B. Kastening, Ber. Bunsenges. Phys. Chem., 72, 27 (1968). L. Meites, Polarographic Techniques, 2nd ed., Wiley-Interscience, New York, 1965, p. 176. (a) H. Lund, in Organic Electrochemistry (Eds. H. Lund and M. M. Baizer), 3rd ed., Marcel Dekker, New York, 1991, pp. 401 432 (b) W. Kemula and T. M. Krygowski, in Encyclopedia of Electrochemistry of the Elements (Eds. A. J. Bard and H. Lund), Vol. 13; Chap. 2, Marcel Dekker, New York, 1979. (c) B. Kastening, in Progress in Polarography (Eds. P. Zuman and L. Meites), Vol. 3, WileyInterscience, New York, 1972, pp. 259 267. A. J. Fry, R. D. Little and J. Leonetti, J. Org. Chem., 59, 5017 (1944). E. Laviron, J. Electroanal. Chem., 124, 9 (1981). E. Laviron, J. Electroanal. Chem., 146, 1 (1981) E. Laviron and L. Roullier, J. Electroanal. Chem., 288, 165 (1990). E. Laviron, R. Meunier-Prest and R. Lacasse, J. Electroanal. Chem., 375, 263 (1994). A. Darchen and C. Moinet, J. Electroanal. Chem., 78, 81 (1977). A. Darchen and C. Moinet, J. Chem. Soc., Chem. Commun., 487 (1976). (a) C. D. Gutsche and D. J. Pasto, Fundamentals of Organic Chemistry, Prentice-Hall, Englewood Cliffs, N.J., 1975, p. 714. (b) G. M. Loudon, Organic Chemistry, Addison-Wesley, Reading, Mass., 1984, p. 1198. T. Ohba, H. Ishida, T. Yamaguchi, T. Horiuchi and K. Ohkubo, J. Chem. Soc., Chem. Commun., 263 (1994). D. H. Geske and A. H. Maki, J. Am. Chem. Soc., 82, 2671 (1960). G. L. McIntire, D. M. Chiappardi, R. L. Casselberry and H. N. Blount, J. Phys. Chem., 86, 2632 (1982). C. -W. Lee and A. J. Fry, unpublished research. (a) J. F. Rusling, Acc. Chem. Res., 24, 75 (1991) (b) M. Bourrel and R. S. Schecter, Microemulsions and Related Systems, Marcel Dekker, New York, 1988. (c) I. D. Robb (Ed.), Microemulsions, Plenum Press, New York, 1982. G. Kokkinidis, A. Papoutsis and G. Papanastasiou, J. Electroanal. Chem., 359, 253 (1993). A. Papoutsis and G. Kokkinidis, J. Electroanal. Chem., 371, 231 (1994). S. J. C. Cleghorn and D. Pletcher, Electrochim. Acta, 38, 425 (1993). G. Belot, S. Desjardins and J. Lessard, Tetrahedron Lett., 25, 5347 (1984). P. Delair, A. Cyr and J. Lessard, in Electroorganic Synthesis (Eds: R. D. Little and N. L. Weinberg), Marcel Dekker, New York, 1991, p. 129. P. N. Pintauro and J. R. Boutha, J. Appl. Electrochem., 21, 799 (1991). (a) C. Ravichandran, M. Noel and P. N. Anantharaman, J. Appl. Electrochem., 24, 965 (1994). (b) C. Ravichandran, D. Vasudevan and P. N. Anantharaman, J. Appl. Electrochem., 22, 1192 (1992). E. Laviron, R. Meunier-Prest, A. Vallat, L. Roullier and R. Lacasse, J. Electroanal. Chem., 341, 227 (1992). R. Lacasse and R. Meunier-Prest, J. Electroanal. Chem., 359, 223 (1993). C. P. Andrieux, A. Batlle, M. Esp´in, I. Gallardo, Z. Jiang and J. Marquet, Tetrahedron, 50, 6913 (1994). (a) K. J. Stutts, C. L. Scortichini and C. M. Repucci, J. Org. Chem., 54, 3740 (1989).
856
37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47.
48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69.
Albert J. Fry (b) M. Ciureanu, Rev. Roum. Chim., 38, 807 (1993). (c) M. M. Ellaithy and P. Zuman, J. Pharm. Sci., 81, 191 (1992). D. Vasudevan and P. N. Anantharaman, J. Appl. Electrochem., 24, 559 (1994). A. Ion-Carastoian, F. -G. Banica and M. Moraru, Rev. Roum. Chim., 38, 287 (1993). A. H. Maki and D. H. Geske, J. Chem. Phys., 33, 825 (1960). The negative charge in nitroarene radical anions is localized on the nitro group: (a) W. Kemula and R. Sioda, J. Electroanal. Chem., 7, 233 (1964). (b) A. H. Maki D. H. Geske, J. Am. Chem. Soc., 83, 1853 (1961). (a) Y. Kargin, O. Manousek and P. Zuman, J. Electroanal. Chem., 12, 443 (1966). (b) P. Zuman, O. Manousek and S. K. Vig, J. Electroanal. Chem., 19, 147 (1968). H. Wang and V. D. Parker, Acta Chem. Scand., 48, 933 (1994). S. Irle, T. M. Krygowski, J. E. Niu and W. H. E. Schwarz, J. Org. Chem., 60, 6744 (1995). S. Mahmood, B. J. Tabner and V. A. Tabner, J. Chem. Soc., Faraday Trans., 3253 (1990). T. Yamato, K. Fujita, H. Kamimura, M. Tashiro, A. J. Fry, J. Simon and J. Ochterski, Tetrahedron, 51, 9851 (1995). Potentials were measured relative to 0.1 M Ag/AgNO3 and converted to S.C.E. Orbital overlap is proportional to cos2 , where is the dihedral angle between the two orbitals. Since D 16.1° in 25, cos2 D 0.92, hence little overlap is lost by the twist of the nitro groups out of planarity. F. Miralles-Roch, A. Tallec and R. Tardivel, Electrochim. Acta, 38, 2379 (1993). M. Wessling and H. J. Sch¨afer, Chem. Ber., 124, 2303 (1991). R. D. Little, M. Schwabe and W. Russu, in Novel Trends in Electro-organic Synthesis (Ed. S. Torii), Kodansha, Tokyo, 1995, p. 123. A. J. Fry, Synthetic Organic Electrochemistry, 2nd ed., Wiley, New York, 1989, p. 308. (a) D. H. Evans and J. C. R¨uhl, in Electroorganic Synthesis (Eds. R. D. Little and N. L. Weinberg), Marcel Dekker, New York, 1991, p. 3. (b) W. J. Bowyer and D. H. Evans, J. Org. Chem., 53, 5234 (1988). A. M. Bond, G. A. Lawrance, P. A. Lay and A. M. Sargeson, Inorg. Chem., 22, 2010 (1983). P. A. Lay and A. M. Sargeson, Inorg. Chem., 29, 2762 (1990). L. Szabo, C. Szantay, E. G. Baitz and M. Mak, Tetrahedron Lett., 36, 5265 (1995). M. E. Niyazymbetov and D. H. Evans, Tetrahedron, 49, 9627 (1993). M. E. Niyazymbetov and D. H. Evans, J. Org. Chem., 58, 779 (1993). M. E. Niyazymbetov and D. H. Evans, Denki Kagaku, 62, 1139 (1994). A. L. Laikhter, M. E. Niyazymbetov, D. H. Evans, A. V. Samet and V. V. Semenov, Tetrahedron Lett., 34, 4465 (1993). Private communication from D. H. Evans and M. E. Niyazymbetov. K. Fukase, H. Tanaka, S. Torii and S. Kusumoto, Tetrahedron Lett., 31, 389 (1990). M. V. B. Zanoni and N. R. Stradiotto, J. Electroanal. Chem., 312, 141 (1991). L. Grehn, L. S. Maia, L. S. Monteiro, M. I. Montenegro and U. Ragnarsson, J. Chem. Res. (S), 144 (1991). C. Nishihara and M. Kaise, J. Electroanal. Chem., 149, 287 (1983). (a) P. Zuman and C. Karakus, Denki Kagaku, 62, 1306 (1994); P. Zuman and B. Shah, Chem. Rev., 94, 1621 (1994). M. L. Greer, H. Sarker, M. E. Mendicino and S. C. Blackstock, J. Am. Chem. Soc., 117, 10460 (1995). G. Gronchi and P. Tordo, Res. Chem. Intermed., 19, 733 (1993). N. C. Sarada, I. A. K. Reddy and K. M. Rao, J. Indian Chem. Soc., 71, 729 (1994). E. Laviron, A. Vallat and R. Meunier-Prest, J. Electroanal. Chem., 379, 427 (1994).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
19
Rearrangement reactions involving the amino, nitro and nitroso groups D. LYN H. WILLIAMS Chemistry Department, University of Durham, Durham, U.K. Fax: (191)-386-1127; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. REARRANGEMENT OF HYDRAZOBENZENES (THE BENZIDINE REARRANGEMENT) . . . . . . . . . . . . . . . . . . III. REARRANGEMENT OF AZOXYBENZENES (THE WALLACH REARRANGEMENT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. REARRANGEMENT INVOLVING PHENYLHYDROXYLAMINES A. The Bamberger Rearrangement . . . . . . . . . . . . . . . . . . . . . . . B. Other Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. REARRANGEMENT OF N-HALO COMPOUNDS . . . . . . . . . . . VI. REARRANGEMENT INVOLVING NITRO GROUPS . . . . . . . . . . A. The Nitramine Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . B. Rearrangement of Nitro Aromatics . . . . . . . . . . . . . . . . . . . . . C. Other Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. REARRANGEMENT INVOLVING NITROSO GROUPS . . . . . . . . A. The Fischer Hepp Rearrangement . . . . . . . . . . . . . . . . . . . . . B. Other Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
...
857
...
858
. . . . . . . . . . . . .
865 867 867 871 873 876 876 879 882 883 883 885 888
. . . . . . . . . . . . .
. . . . . . . . . . . . .
I. INTRODUCTION
Rearrangement reactions have greatly interested chemists for a long time (a) from the synthetic viewpoint as routes to new compounds and (b) from the mechanistic viewpoint, in order to discover how these reactions occur. This chapter is intended to update previous chapters in this series. No attempt has been made to be comprehensive in the treatment, and the effort has centred on new developments, particularly of understanding mechanisms, rather than on reporting additional examples of reaction types already known. Rearrangement reactions are constantly being reviewed; the most complete account is in
857
858
D. Lyn H. Williams
that chapter devoted to rearrangements covering the literature each year in the Organic Reaction Mechanisms series1 . A short account aimed at undergraduates has appeared within the Oxford Primer series2 . Two major new developments have occurred since the subject was last covered in this series and have been instrumental in being able to give definitive answers to mechanistic questions, which hitherto relied to some degree on speculation. The first is the ability to measure, with the necessary accuracy of measurement, heavy-atom kinetic isotope effects. Kinetic isotope effects (KIE) involving 1 H and 2 H isotopes have always played an important part in establishing reaction mechanisms, and such KIE values have been easy to measure experimentally, because of their relatively large magnitude. Isotope effects for bond breaking and making involving C, N and O isotopes particularly are now measurable and have been applied to the study of rearrangement reactions, particularly by Shine and his group at Texas Tech University. These studies have enabled chemists to decide in a rearrangement reaction whether bond breaking and bond making are synchronous processes, or whether the former precedes the latter resulting in at least a two-stage process with intermediate formation. The other technique is the application of the CIDNP effect, particularly by Ridd and coworkers. Enhancement of NMR signals is frequently an indication that radical pairs or radical ion-radical pairs are involved as intermediates. This ability to establish the nature of the intermediates clearly is a major tool in reaction mechanism studies. II. REARRANGEMENT OF HYDRAZOBENZENES (THE BENZIDINE REARRANGEMENT)
This is one of the most well-known (and unusual) rearrangement reactions involving amino groups and has probably received the most attention mechanistically speaking of all rearrangement reactions. It is set out formally in Scheme 1. The reaction is most wellknown under conditions of acid catalysis, although thermal and photochemical reaction pathways are also known. In acid solution hydrazobenzene 1 (more properly known as N,N0 -diphenylhydrazine) rearranges to give 4,40 -diaminobiphenyl (2) usually in about 70% yield together with 2,40 -diaminobiphenyl 3 (ca 30%). The common name for 2 is benzidine (after which the rearrangement is generally known) and for 3 diphenyline. Three other products have been detected usually with substituted hydrazobenzenes, and often in low yield. These are the 2,20 -diaminobiaryl 4, much more common from the reaction of hydrazonaphthalenes and the two arylaminoanilines 5 and 6 generally referred to as the ortho- and para-semidines, respectively. Often, products of disproportionation ArNH2 and
NH
NH
H+
H2 N
NH2
(1)
(2)
+
(70%)
H2 N
NH2 (3)
SCHEME 1
(30%)
19. Rearrangement reactions involving the amino, nitro and nitroso groups
859
NH R′
R NH2
R′
R
NH2
NH2
(4)
(5)
H2 N
NH R′
R (6)
ArNDNAr are also formed. Reaction occurs for a whole range of R and R0 substituents, often leading to a large spread of products if both 4- and 40 -positions are substituted. In some cases (for R D SO3 H, CO2 H) the substituent group R can be displaced. The reaction also can occur when there are N-substituents. Interestingly there is a recent report3 that when the rearrangement of 1 takes place in the presence of a rhodium(I) catalyst, the ortho-semidine product 5 is formed exclusively. Clearly the stereochemistry of the system when the catalyst is bound must be ideally set up for this product formation. The rearrangement was reviewed in this series in 19684 and 19755 and there have been many other important reviews6 8 . Interestingly from a historical viewpoint is the account of the very early history of the benzidine rearrangement which includes the possible contributions from the chemist/musician Borodin9 . Reaction is clearly intramolecular as shown by a range of experiments where no cross-over products were observed, and also by isotopic labelling experiments. Kinetic measurements showed that reaction was first-order in the hydrazo compound and both a first- and second-order dependence upon the acidity occurred depending on the reactant structure and the acidity of the medium. Various mechanisms have been postulated, but two emerged as the most likely contenders during the 1960s and 1970s. These were the -complex mechanism put forward and argued by Dewar10 , and later the Polar Transition State mechanism advocated by Banthorpe, Hughes and Ingold11 . Both mechanisms eventually attempted to incorporate reaction path+ ways via the monoprotonated reactant ArNHNH2 Ar and also via the diprotonated reactant + + ArNH2 NH2 Ar. A major breakthrough in the mechanistic investigation of this and many other rearrangements occurred when it became possible to measure, within the accuracy required, heavy-atom kinetic isotope effects, i.e. those involving bond breaking and making of bonds to elements other than hydrogen. In particular for the benzidine rearrangement, the ability to measure these KIE for 14 N 14 N/15 N 15 N for bond breaking, and the carbon isotope effects (for 12 C/13 C and 12 C/14 C) for bond making, has meant that for the first time definitive reaction pathways have been firmly established. This has been due to the pioneering work of Shine and his group, begun in 1976. Heavy atom KIE are necessarily small (typically 1% 5%) so it is not possible to obtain meaningful values by kinetic measurements of the isotopically substituted materials. All of the data were obtained by competition methods12 , using isotope-ratio mass spectrometry, whole-molecule-ion mass spectrometry and scintillation counting procedures. Details of the methods are given in the literature13 15 . An account of the results obtained up to 1989 has been given by Shine16 .
860
D. Lyn H. Williams
This also includes an excellent summary of earlier work, particularly on the position at various times of the -complex theory. The results obtained by the Shine group17 for the reaction of hydrazobenzene itself are given in Table 1. The main point of note is that for the bond-making process the KIE values are different for the formation of 2 and 3. There is a KIE of the expected magnitude on N,N bond breaking (although they are not the same) for both 2 and 3 formation. However, for CC bond formation (using both the 13 C and 14 C isotopes) 2 formation shows the expected KIE for a rate-limiting process whereas for 3 formation there is no measurable KIE. The clear conclusion is that rearrangement of 1 to 2 is a concerted process whereas that for 3 formation is not, the rate-limiting step being NN bond fission. There is no deuterium KIE for CH bond breaking from the 4- and 40 positions (other than a small inverse secondary effect), so this final proton loss must occur after the rate-limiting step. There is, as expected, no KIE for the 2,20 ,6,60 -13 C labelled material. Rearrangement to give 2 is clearly a concerted process and can be classified as an allowed [5,5]-sigmatropic rearrangement, to form the quinonoid intermediate from which rapid proton transfer to the solvent occurs to give the final product (Scheme 2). This idea was in fact suggested as a possibility some twelve years earlier by Schmid18 following elegant isotope work on the Claisen rearrangement. It is also in effect a part of the Polar Transition State mechanism. + NH2
+ NH2
+ NH2
+ NH2
Slow
H
H Fast
H2 N
NH2
(2) SCHEME 2 TABLE 1. Values of the KIE for the acid catalysed rearrangement of 1 to give 2 and 3 Label 15 N,15 N0
4,40 -13 C 4-14 C 2,20 ,6,60 -13 C 4,40 -2 H
Formation of 2
Formation of 3
1.0222 1.0209 1.0284 0.9945
1.0633 1.0006 1.0011 0.9953
a Measured for the disappearance of 1.
0.962a
19. Rearrangement reactions involving the amino, nitro and nitroso groups
861
Rearrangement to the diphenyline product 3, formally a forbidden [3,5] shift, must take place by a different mechanism in parallel to 2 formation. Previous mechanistic suggestions have attempted to explain the formation of both products within the same mechanistic framework. It is now apparent that 3 is formed by rate-limiting N-N bond fission to give an intermediate from which the product is formed. The nature of this intermediate is not yet known, but it has been suggested16 that it could be a -complex. The reaction of hydrazobenzene (1) refers to reaction via the doubly protonated form. The mechanism for the rearrangement via a mono protonated form was examined17 using 2,20 -dimethoxyhydrazobenezene (7). Again the KIE results for formation of the benzidine derivative 8 show that reaction is also concerted. It appears that there is no major difference between the one- and two-proton reactions. OMe
MeO
NH
MeO H+
NH
OMe
H2 N
(7)
NH2
(8)
Reactions leading to the semidine products have also been examined by the heavy-atom KIE method19 . The reaction of 9 gives both 10 and 11. As expected, a KIE on NN bond breaking was found for both products. For formation of 10 there was also a carbon KIE indicative of concertedness. The para-semidine rearrangement is then a [1,5]-sigmatropic shift. It was not possible to obtain the corresponding values for the formation of 11 (the ortho-semidine rearrangement). In an attempt to examine ortho-semidine formation the reaction of the 4,40 -dichlorohydrazobenzene (12) was studied20 . This reaction gives the ortho- (13) and the para- (14) semidines as well as a significant amount of the products of disproportionation 15 and 16 (Scheme 3). The formation of 14 is accompanied by loss of chlorine. There was no carbon KIE for bond formation for the formation of both semidine products 13 and 14 but the expected nitrogen KIE for both, so that in this case neither rearrangement product is formed in a concerted process.
MeO
NH
NH
(9) H+
MeO
NH
NH2 + MeO
NH2 NH
(10)
(11)
Details of the mechanism of the ortho-benzidine rearrangement were examined using the two hydrazonaphthalene derivatives 17 and 1817,21 . Both showed nitrogen and carbon
862
D. Lyn H. Williams
Cl
NH2
NH
Cl
NH
NH
Cl
Cl
(13)
(12) Cl
NH
NH2
(14)
Cl
N
N
NH2
(15)
+
2 NH2
Cl
(16) SCHEME 3
NH2 NH
NH
NH2
(17) NH
NH
NH2 (18)
NH2
19. Rearrangement reactions involving the amino, nitro and nitroso groups
863
isotope effects showing the reactions to be concerted and can be regarded as [3,3]sigmatropic shifts. One other set of experimental results has been reported giving the results of heavyatom KIE experiments in the benzidine rearrangement22 . A feature of percyclic reactions (including sigmatropic rearrangements) is that the motion of all the atoms involved are coupled. It follows that kinetic isotope effects should be found for atoms not directly involved in bond breaking or making, so that conventional secondary effects should be much greater than those normally encountered for the reactions. This has been tested in the reaction of hydrazobenzene itself using both carbon isotopes at the 1- and 10 -positions using 1-14 C and 1,10 -13 C2 labelled reactants. As predicted, there was a small but significant KIE for the reaction leading to the benzidine product (2) but no measurable KIE on the reaction leading to diphenylene (3). This is entirely consistent with the earlier findings and interpretation that 2 is formed in a concerted process whereas 3 is not but requires the formation of an intermediate. This paper22 also reports the results of the repetition of earlier experiments using 1 for 4,40 -13 C2 , 4-14 C and 15 N, 15 N0 labelled compounds. The results are somewhat different from those reported earlier, but it is argued that the more recent results are likely to be the more reliable given the better scintillation counting and mass spectrometric facilities available. As mentioned earlier, products of disproportionation often accompany the rearrangement products. This reaction is also acid-catalysed and it is a reasonable assumption that reaction proceeds via the protonated species. Experiments with the 4,40 diiodohydrazobenzene (19) showed that there were significant nitrogen and para-carbon kinetic isotope effects23 . This implies that disproportionation must take place after CC bonding has occurred, i.e. that the intermediate must be the quinonoid form 20 (and cannot, for example, be a -complex), which is then believed to react with another reactant molecule to give the disproportionation products (Scheme 4). As a result of these heavy-atom KIE experiments the principal features of the benzidine rearrangements have now been firmly established. The two main products arise from two parallel reactions one of which is concerted and the other is not. Other concerted processes have been identified and all of the concerted processes can be readily classified in the terminology of sigmatropic rearrangements within the general class of percyclic reactions. The benzidine rearrangements can also be brought about thermally, but very few mechanistic studies have been carried out. One set of heavy-atom KIE measurements has been made in the reaction of 2,20 -hydrazonaphthalene (18)21 . Substantial nitrogen (1.0611 for the [15 N, 15 N0 ]) and carbon (1.0182 for the [1,10 -13 C2 ]) KIE values were obtained showing that, just as for the acid catalysed reaction, this is a [3,3]-sigmatropic rearrangement, this time presumably of the non-protonated reactant. There continue to be a few examples reported where rearrangement has been used synthetically to develop new products sometimes important in the industrial world. Monomers for polyamides and polyimides (which are used for making moisture sensitive films, fibres and mouldings) have been synthesized24 by the reduction of a nitro compound, followed by a benzidine rearrangement of the resulting hydrazobenzene derivative as outlined in Scheme 5. Similarly, a number of 2-(2-arylhydrazino) tropones undergo the benzidine rearrangement when treated with HCl in EtOH to give 2-amino-5-(4-aminoaryl)tropones, which can be hydrolysed to the corresponding 5-aryl-tropolones. This is a useful route to a synthesis for open B ring colchine analogues25 . Quinamine Rearrangement
4-(Arylamino)-cyclohexadienones (21) rearrange in acid solution (often in alcohol or acetic acid solvents) to give 4-(aryloxy)-anilines (22) (Scheme 6). In some ways this
864
D. Lyn H. Williams
I
NH
NH
I
(19)
2H+
I
+ H2 N
+ NH2 I
(20)
20 + I
NH
NH
I
+ NH3
+
2
I
N
N
I
I
SCHEME 4 CF3 O
OCF3
NH
NH H+
CF3 O
Reduction
OCF3
OCF3 H2 N
NH2
Condensation
NO2 Polyamide
SCHEME 5
19. Rearrangement reactions involving the amino, nitro and nitroso groups
R
NH Me
O
NH2
R1
O
865
Me R1
R
(21)
(22)
SCHEME 6
reaction bears a formal resemblance to the benzidine rearrangement. Kinetic measurements have quantified acid catalysis and the lack of crossover products has shown the reaction to be intramolecular26 . There remained the question of whether rearrangement was concerted or not and this has been addressed by Boduszek and Shine27 , who measured the KIE for the [18 O], [15 N] and [4-14 C] (at the para position of the aniline ring) isotopes. The values obtained, k 16 O/k 18 O 1.0399, k 14 N/k 15 N 1.0089 and k 12 C/k 14 C 1.0501, confirmed that the rearrangement is concerted and is a [5,5]-sigmatropic shift. Other minor products are formed resulting from another concerted [3,3]-sigmatropic change. III. REARRANGEMENT OF AZOXYBENZENES (THE WALLACH REARRANGEMENT)
In some way formally similar to the benzidine rearrangement is the Wallach rearrangement of azoxybenzene 23 to give 4-hydroxyazobenzene 24 in concentrated (typically 95%) H2 SO4 . The 2-hydroxy isomer is sometimes formed in low yield with some substituted azoxybenzenes, and it is the main product in the photochemically induced reaction. Much of what is known about the reaction has been covered in earlier review articles28 30 . This contribution will report work published since 1981. + N
O−
H2 SO4
N N
N
(23)
(24)
OH
With 4,40 -substituted azoxybenzenes a range of different products has been reported. For example, with electron-withdrawing groups such as NO2 , COCH3 , CO2 H reaction gives the ‘normal’ 2-hydroxy isomer (25) plus the 40 -hydroxy product 26 believed to be formed by ipso-attack by water from the solvent and expulsion of the nitro group31 . Another example of ipso-attack at the 40 -position, this time followed by rearrangement, occurs in the reaction of 4,40 -dialkylazoxybenzene when the products are 27 and 28, believed to be HO O2 N
N N
(25)
NO2
866
D. Lyn H. Williams
O2 N
N N
OH
(26)
R
R
N N
N N
R
OH R
OH (27)
R
N
+ N
(28)
R OH
R
N
R N +
OH
(29)
generated from the intermediate 2932 . When the 4- and 40 -substituents are halogens, then the major product is that of reduction, the 4,40 -dihaloazobenzene33 . Interconversion of the isomers 30 and 31 occurs in the reactant during the rearrangement, involving an intermediate which is suggested as the bridged ion 32. This change occurs for X D Me and NO2 but strangely not when X D Br34 . A remarkable difference in reactivity exists between two such isomers in phenylazoxypyridine35 . The ˛ isomer (33) is virtually inert towards rearrangement in 95 100% H2 SO4 whilst the ˇ isomer (34) reacts ‘normally’ to give 4-(40 -hydroxyphenylazo) pyridine-N-oxide. The reactivity difference is so great, that from mixtures of 33 and 34 pure samples of 33 can be obtained when all 34 has rearranged. The Wallach rearrangement has been reported for perfluoro derivatives36 . Reactions are much slower, as expected, and in sulphuric acid the octafluoro compound 35 gave no rearrangement product, but in chlorosulphuric acid rearrangement did occur to give the 4-chlorosulphonate ester. Mechanistically speaking there have been no recent advances. What is known is that, at least for 4-OH formation, the reaction is intermolecular, requires two proton transfers at some stage and that a symmetrical intermediate is involved (often described as
19. Rearrangement reactions involving the amino, nitro and nitroso groups + N
O−
+ N
X X
N
(31)
+ OH
+ N
N N
O−
N
N
X
(32)
(33) F
+ N
O−
N
(30)
N
867
F + N
N
F
−
O (34)
F
O−
F
F
F
F
N
(35)
+ + ArNNAr). A number of possible reaction mechanisms have been suggested at different times and, at this time, the position is not settled. No heavy-atom KIE work has been reported for the acid catalysed reaction, but such experiments have been carried out for the photochemical reaction37 which gives the 2-hydroxy product and which is known to be intramolecular. There is an absence of a KIE when [15 N,15 N0 ] material is used, which at least reveals that if the proposed intermediate 36 is involved, then the rate-limiting step must be its formation and not its subsequent reaction since NO bond fission cannot be part of the slow step. N N O H (36)
IV. REARRANGEMENT INVOLVING PHENYLHYDROXYLAMINES A. The Bamberger Rearrangement
This is the best known rearrangement reaction of phenylhydroxylamines and is an acid catalysed reaction leading principally to the formation of 4-amino phenols 37, although a little of the 2-isomers 38 are also sometimes formed. Reaction proceeds quite smoothly in relatively dilute acid at room temperature. Reaction is quite general for a range of R and X substituents. Much of the early work was carried out by Bamberger38 and the position up to 1967 has been very well reviewed39 .
868
D. Lyn H. Williams RNH
PhNHOH
OH
RNH
H+
+
X
OH
X
X
(37)
(38)
In the presence of alcohols, the corresponding ethers are formed and added nucleophiles such as chloride ion40 or azide ion41 lead to the chloro- and azido-amine products, respectively. Rate constants are independent of the concentration of added nucleophile. Labelled 18 O from the solvent is incorporated in the product42 . All the evidence points to a reaction mechanism where water is lost from the O-protonated reactant to give a nitrenium ion iminium ion intermediate which is rapidly trapped by a nucleophile (H2 O in this case) to give the final product. This is shown in Scheme 7. Protonation at N- is likely to be more extensive, but there is no pathway to products from the N-protonated intermediate. +
H2 N OH
HNOH
H+
H+
+
+
HN
HNOH2
NH
NH
+ Slow
+ Fast H2 O
NH2
NH2 OH +
OH
SCHEME 7
19. Rearrangement reactions involving the amino, nitro and nitroso groups
869
2.5
6 + log kobs
2.0 H2SO4 −H2O 1.5 D2SO4 −D2O 1.0 2
1
−1
0 pH
−2
−3
−4
H0
FIGURE 1. Plot of log kobs vs H0 or pH for the rearrangement of N-phenylhydroxylamine in H2 SO4 H2 O and in D2 SO4 D2 O. Reproduced by permission of the Royal Society of Chemistry from Reference 44
More recent mechanistic studies43,44 have confirmed the general mechanistic framework. Acid catalysis is found at acidities up to ca pH 1, then there is an acid region where the rate constant is acid-independent, then at higher acidities acid catalysis occurs again. This is shown in Figure 1. The plateau region corresponds to effectively complete N-protonation. The pKa value measured spectrophotometrically (1.90) agreed with that derived from the kinetic measurements. Similar good agreement was obtained for the N-Et and 4-Me reactants and also for the unsubstituted phenylhydroxylamine in D2 O. The measured solvent KIE was also in agreement with the mechanism in Scheme 7. Acid catalysis at high acidity is believed + to arise from another reaction pathway involving the doubly protonated species Ph NH2 + OH2 for which there is support from polarographic measurements at high acidity45 . Kinetic experiments using 3-ring substituted derivatives43 gave a good log k vs m correlation yielding a value of 3.2, confirming NO bond fission in the sense leading to positive charge increase on the nitrogen atom in the transition state. N-Ethyl substitution had very little effect on the measured rate constant, whereas a 4-methyl substituent increased the rate constant by a factor of ca 100. In this case the initial product (identified by Bamberger) is the iminocyclohexadienol 39, which slowly hydrolyses to the quinone 40. These substituent effects suggest that in the transition state the developing positive change is located mostly at the 4-position (stabilized by the 4-Me substituent) and very little on the nitrogen atom (no stabilization by a N-Et substituent), so that the intermediate is more properly described by the iminium ion. This is supported by an earlier observation46 that whilst full incorporation of 18 O from the solvent H2 18 O occurs in the product, there is no detectable 18 O incorporation into the reactant phenylhydroxylamine.
870
D. Lyn H. Williams HNOH
NH
H
O
+
Slow H2 O
Me
Me
OH
Me
(39)
OH (40)
Further kinetic experiments with some sterically hindered phenylhydroxylamines gave results47 which suggest that under certain circumstances steric acceleration occurs, attributable to the buttressing effect of neighbouring 3-substituents. Thus the rate constants for the reactions of 41 and 42 are respectively greater than are those for 43 and 44. HNOH
HNOH Me(or Hal)
HNOH
HNOH Me
Me
Me (41)
(42)
Me
Me (43)
(44)
The rearrangement reaction continues to be of synthetic utility, often involved in industrial processes. Patent references (e.g. Reference 48) refer to the formation of 4-amino phenols. Often the reactant nitro compound is reduced (to the hydroxylamine) in an acid environment so that the two-stage reaction can be accomplished as a one-pot synthesis. 4-Amino phenol itself 45 can be made in high yield directly from nitrobenzene49 and the 4-methoxy aniline derivative 46 similarly from 2-methylnitrobenzene by hydrogenation in MeOH/H2 SO4 50 . NH2
NO2
Catalytic hydrogenation H+
OH (45) Me
NO2
NH2
Me Hydrogenation MeOH/H2 SO4
MeO (46)
19. Rearrangement reactions involving the amino, nitro and nitroso groups
871
At low acidities oxidation of phenylhydroxylamine occurs yielding azoxybenzene and other products. This competing reaction can be eliminated by working anaerobically and can also be much reduced by working at high acidities, suggesting that the oxidation occurs via the free base form of phenylhydroxylamine. An unusual kinetic result has been reported51 when phenylhydroxylamine reacted anaerobically with bisulphite anion. The product distribution was as expected, i.e. both 2- and 4-aminophenol and the 2- and 4-aminobenzenesulphonates were formed. Kinetic measurements showed a first-order dependence upon [bisulphite], in contrast to the earlier work with Cl and later with N3 . The authors propose a mechanism involving direct attack by the nucleophile at the 2- and 4-positions as the rate-limiting step, followed by proton transfers and solvent attack to form the sulphonate products. There has been considerable interest in the chemistry of hydroxylamines, since it is believed52 that the carcinogenicity of some arylamines results from the formation of the N-hydroxy species, which in turn generate nitrenium ions that react in a conventional electrophilic sense with nucleic acids. B. Other Rearrangements
A different mechanism probably operates for the reaction of N-hydroxy-Nphenylamides in the presence of (n-Bu)3 P, CCl4 and MeCN, with the 2-isomer in the product53 suggestive of some intramolecular pathway as outlined in Scheme 8. O
O RC RCNOH
O O
N
P(n−Bu)3
RCNH
+ OP(n−Bu)3
(n-Bu)3 P CCl4 , MeCN
O RCNH OH
SCHEME 8
O-Substituted phenylhydroxylamines also undergo rearrangement to give the 2-isomers. For example O-(arenesulphonyl) phenylhydroxylamines 47 readily form the 2-sulphonyl derivatives 48. Experiments with 18 O-labelled compounds led to the suggestion54 of a mechanism involving an ion pair which has only a very short lifetime. Heating O-phenylhydroxylamine 49 gave 2-aminophenol, though not in very high yield55 . A detailed mechanistic investigation of this reaction in trifluoroacetic acid has
872
D. Lyn H. Williams PhCONOSO2 R
PhCONH OSO2 R
(47)
(48)
ONH2
OH
OH NH2
TFA
+
NH2 (49)
50%
7%
been carried out56 . A little of the 4-isomer is formed, but the predominance of the 2isomer suggests that this reaction is very different from the Bamberger rearrangement. Cross-coupling experiments with 15 N labelled compounds showed that the 2-isomer is formed in an intramolecular process and that the formation of the 4-isomer has both intramolecular and intermolecular reaction pathways. Substituent effects in the aromatic ring gave a large negative value (7.8) from a Hammett plot using C values, indicating that a positive charge is being generated on the oxygen atom (delocalized into the ring to a considerable degree) in the transition state. The suggested mechanism outlined in Scheme 9 involves N-protonation followed by the formation of a tight phenoxenium + ONH3
ONH2 H+
Slow
O
OH
OH
NH2 intramolecular
intramolecular
+
: NH3
NH2 (50) SCHEME 9
19. Rearrangement reactions involving the amino, nitro and nitroso groups
873
ion ammonia pair (50) which can collapse to give the products. Reaction of the solvent (TFA) with the ion pair gives a solvent separated ion pair from which it is possible to rationalize the formation of the two minor by-products, catechol and hydroquinone. A synthetic application of this reaction has been reported57 when the rearrangement of 2-aryl-O-phenylhydroxylamines is followed by a ring enlargement to give an aryldihydroazepinone (Scheme 10). The 2-aryl-2-phenyl intermediate was also trapped out as the N-trifluoroacetamide. + ONH3
ONH2
O +
Ar
: NH3 Ar
Ar
O
O
NH2
NH
Ar
Ar
SCHEME 10
V. REARRANGEMENT OF N -HALO COMPOUNDS
The Orton rearrangement of N-chloroanilides is well known and the reaction mechanism, at least for reaction in aqueous acid solution, is well understood. The position is set out in Scheme 11. Protonation of the nitrogen atom is followed by nucleophilic attack by the chloride ion, generating chlorine which reacts with the anilide in a conventional electrophilic substitution reaction. The reaction is well documented and the reaction mechanism is well understood58 . Only a few recent developments have been reported. A good correlation between log k and has been obtained59 for reactions of 4-X reactants, giving a value of 0.79. This small value is consistent with the conflicting electronic demands of the two stages, the N-protonation and nucleophilic attack by chloride ion. Rearrangement occurs with N-chlorobenzanilide with acid catalysis and chlorine does not migrate to the aromatic ring of the benzyl group60 . That part of the reaction leading to de-chlorination has been studied separately61 using triethylamine as the nucleophile and pathways involving the protonated and non-protonated N-chloroacetanilide have been identified. Rearrangements of N-chloro compounds in heterocyclic systems have been studied. N-Chloroindole 51 gives62 the 3-chloro isomer 52. With pyrrole (53) there are two Cl
N
N
Cl (51)
H (52)
874
D. Lyn H. Williams + RCONHCl
RCONCl
H
+
X
RCONH Cl −
+ Cl2
X
X
RCONH
RCONH Cl +
X
X Cl
SCHEME 11
pathways63 , one thermal which is believed to be intramolecular giving the 2-chloro compound 54, and an acid-catalysed component leading to the 3-chloro (55) and 2,5-dichloro (56) products. The reaction of N-chlorocarbazole (57) gave a variety of products64 , the 3- and 1-chloro compounds and the 3,6- and 1,6-dichlorocarbazoles as well as carbazole itself. Reaction takes place in refluxing methanol and an intermolecular mechanism is argued on the basis of the product distribution. In the presence of added base only the carbazole product of de-chlorination is observed. This is taken to support the idea that the rearrangement reaction is acid-catalysed.
Thermal Intramolecular
N
Cl
H (54)
N Cl (53) Acid Catalysed Intermolecular
Cl + N
+ Cl
N
H
H
(55)
(56)
Cl
54
19. Rearrangement reactions involving the amino, nitro and nitroso groups
875
N Cl (57)
A quite different mechanism for rearrangement of N-chloro compounds occurs when reaction is carried out in the presence of silver ion. This reaction has been studied by Gassman as part of a quest to identify nitrenium ion intermediates in reactions. The work up to 1970 is covered in a review article65 . Rearrangement of the 2-azabicyclo [2.2.1]heptane derivative 58 occurs readily in a silver ion catalysed process to give the 1-aza derivative 59. Kinetic measurements indicated that heterolytic cleavage had occurred, giving the nitrenium ion and chloride ion. The former then undergoes a skeletal rearrangement typical of these bicyclic systems. Later66 the reaction of N-chloroaniline derivatives were studied, again in MeOH and silver ion assisted. With electron-donating ring substituents the final products are those derived by solvent attack at the ring 2- and 4-positions of the nitrenium ion imminium ion intermediate, but with electron-attracting substituents the corresponding 2- and 4-chloro substitution products are formed. For example, the reaction of 60 gave the 2-chloro isomer 61 (58% yield) together with the de-chlorinated product 62 (26% yield). All of these fit Scheme 12 with the formation of a nitrenium ion followed by nucleophilic attack at the 2- and 4-ring positions. It appears quite unusual that the chloro products are formed in the presence of silver ion, and the authors propose that a tight ionpair (63) is formed from which attack by chloride ion can occur. Kinetic measurements of substituted N-chloroanilines in the thermal reaction67 gave a good correlation of log k with C , giving a large negative value (6.35) consistent with the generation of a positive charge on nitrogen, which can be delocalized into the aromatic ring.
Cl
Ag+
N
MeOH
N Cl (58) t-Bu
Cl N
(59) t-Bu
H
t-Bu
N
H N
Cl +
CO2 Et (60)
CO2 Et (61)
CO2 Et (62)
876
D. Lyn H. Williams R
Cl
R
N
R
R
+ N
N
N +
X
X
X
X
+
MeOH or Cl −
Products
SCHEME 12
NR +
Cl − Ag+
(63)
VI. REARRANGEMENT INVOLVING NITRO GROUPS A. The Nitramine Rearrangement
The acid-catalysed rearrangement of N-nitroaniline derivatives continues to provide convenient synthetic routes to some nitro compounds which are difficult to obtain by other methods. A recent example68 is given in Scheme 13, where the introduction of the third nitro group into the aromatic ring is brought about by rearrangement of the Cl
HNCH2 CO2 H NO2
NO2 + H2 NCH2 CO2 H
NO2
NO2 HNO3 /H2 SO4
HNCH2 CO2 H O2 N
O2 NNCH2 CO2 H
NO2
NO2 H2 SO4
NO2
NO2
SCHEME 13
19. Rearrangement reactions involving the amino, nitro and nitroso groups
877
N-nitro glycine derivative. Another example69 to obtain a tetranitro compound is given in Scheme 14. Here the product was then used to generate polynitrodiazophenols. NH2
NHNO2 NO2 HNO3
NO2
O2 N
HOA c/H2 SO4 0˚C
NO2
O2 N
Me
Me Room Temp
H2 SO4
NH2 O2 N
NO2
NO2
O2 N Me
SCHEME 14
In the 1960s and 1970s there was something of a controversy regarding the mechanism of the nitramine rearrangement, and arguments were presented in favour of a ‘cartwheel’ mechanism and one involving the formation of radical pair intermediates. Now, two pieces of work, using modern techniques not available earlier, have produced conclusive evidence in support of the mechanism first put forward by White and coworkers70 (Scheme 15), in which the reactant is protonated at the amino nitrogen atom and NN bond fission occurs homolytically to give a radical radical ion pair 64. This intermediate can react within the solvent cage intramolecularly at the two positions of highest unpaired-electron density (i.e. the 2- and 4-positions) to give the observed products. This is the major pathway. Separation of the fragments of 64 allows reaction to occur also intermolecularly. This mechanism also can account for the formation of some of the minor products detected, e.g. the unsubstituted aniline formed by reduction of the radical cation. Ridd and coworkers71 have now shown unequivocally that radical pairs are indeed involved in this rearrangement by observation of strong enhancement of 15 N NMR signals in both the reactant and product, when reaction was carried out with 15 N-labelled nitro groups in both N-methyl-N-nitroaniline and also in N-methyl-N-nitro-2,5-dichloro (and dibromo) aniline. Further, Shine and coworkers72 have applied their heavy-atom kinetic isotope effect technique (widely applied in investigations into the mechanism of the bendizine rearrangement discussed in Section II of this chapter) to the nitramine rearrangement. Substantial nitrogen KIE values were recorded (for the formation of both 2- and 4-nitro products) when [15 NO2 ] labelled N-methyl-N-nitroaniline underwent rearrangement, whereas there was no ring carbon KIE (in both products) for the reaction of both [2-14 C] and [4-14 C] labelled materials. This means that NN bond fission and NC bond formation cannot occur in a single synchronous process as is proposed in the ‘cartwheel’ mechanism73 . On the other hand, the results are wholly consistent with the radical pair mechanism (Scheme 15), in which NN bond fission is the rate-limiting step.
878
D. Lyn H. Williams + RNHNO2
RNNO2
+ RNH
Side products
NO2 X
X (64) Intramolecular and Intermolecular pathways
RNH
RNH NO2 +
X
X NO2
SCHEME 15
NHNO2 Br
Br
R
N N
N
NHNO2
Br
R
N NO2
(65)
(66)
(67)
N
N
NO2
H
(68)
NO2
(69) NO2 + N H (70)
19. Rearrangement reactions involving the amino, nitro and nitroso groups
879
The nitramine rearrangement is also well known in heterocyclic systems. Fairly recent examples reported include the reaction of the pyridine derivatives74 65 and 66, and the tribromo-1-nitro-1H-pyrazole 67, which results in bromine displacement by the nitro group75 . Reaction is also known for N-nitroindazoles, N-nitrotriazoles and Nnitroimidazoles. N-Nitrocarbazole 68 rearranges to give the 1-nitro (69) and 3-nitro (70) products76 . Many of these reactions also take place thermally in organic solvents and also photochemically. The latter reactions are discussed elsewhere in this volume. B. Rearrangement of Nitro Aromatics
It has long been known that nitro-substituted aromatic compounds undergo positional rearrangements of nitro groups within the aromatic ring when treated with strong acids (usually H2 SO4 ) at high temperatures. Normally the reactions are quite slow, yields are low and the reactions are not suitable for synthesis. Now the use of trifluoromethanesulphonic acid (triflic acid CF3 SO3 H) has enabled reactions to proceed much more rapidly and the yields can often be quantitative. Normally in these reactions, a 1,3-migration of the nitro group occurs. Some examples77 79 are given below: Me
Me O2 N
NO2 CF 3 SO3 H 100 °C
Me
Me
OH
OH NO2
NO2 CF 3 SO3 H 100 °C
O2 N
NO2
In some cases80 where the nitro group is ortho to an ethyl group, there is a competing reaction which leads, via cyclization probably involving the nitronic acid form of the nitro group, to the corresponding anthranil 71. Me C
CH2 Me
O N
NO2 CF 3 SO3 H 100 °C
R
R (71)
Substituted 2-nitroanilines also rearrange in concentrated sulphuric acid at 110 ° C to give both products of rearrangement 72 and 73, where again 1,3-nitro group migration occurs81 .
880
D. Lyn H. Williams
NH2
NH2
NH2 O2 N
NO2 H2 SO4
+
110 °C
X
X
X
NO2 (72)
(73)
Labelling experiments using both 15 N and 2 H indicate that the rearrangement is intramolecular. Reactions are also acid-catalysed and are believed to occur via the Wheland intermediates 74 and 75. The most likely interpretation is that the rearrangement occurs within the Wheland intermediate by a direct 1,3-shift rather than by consecutive 1,2-shifts, and that the process can be regarded as a typical [1,5]-sigmatropic rearrangement.
R
R
R H
NO2 H
+
+
O2 N NO2
H
+
R
R
R
(74)
(75) −H +
R O2 N
R Nitro group rearrangements have also been postulated during aromatic nitration reactions, particularly those associated with reaction pathways involving ipso attack by the reagent (NO2 C or NO2 ). This topic is more fully discussed elsewhere in this volume and so just a few examples will be presented here. The nitronium acetate adducts 76 and 78, made by nitration with nitric acid in acetic anhydride, both undergo the nitro group rearrangements shown, to give 77 and 79 respectively82 . The former can be regarded as a [1,5]- and the latter as a [1,3]-sigmatropic shift. Similarly a 1,3-shift of the nitro group occurs in the nitration of aromatic amines. The nitration of 80 gives the ipso adduct 81 in quite high concentrations, detected and characterized by NMR measurements83 . This then reacts by rearrangement to give (after proton loss) the 2-nitro product 82. Similar reactions are common in the nitration of phenols and aromatic ethers84 .
19. Rearrangement reactions involving the amino, nitro and nitroso groups Me
881
R
NO2
H
H
OAc
OAc H NO2 X
X
(76)
(77)
Me
Me
NO2
Me
Me H CN H
NO2
OAc
CN H
(78)
OAc
(79) +
+
+
NMe2
HNMe2
HNMe2 NO2
NO2
+
Me
Me (80)
NO2
Me
(81)
(82)
Some insight into the mechanism of these 1,3-NO2 group shifts has been obtained from measurements of the 15 N CIDNP effect85 . There appear to be two mechanisms. During the reaction of 83 to give 84 there is a strong enhancement of 15 N nuclear polarization indicative of reaction via a radical pair, whereas for the reaction of the isomer 85 to give 86 there is no such enhancement, indicative of a mechanism which does not involve a radical pair. O
OH NO2
Me
NO2 (83)
Me (84)
882
D. Lyn H. Williams O
OH Me
O2 N
Me
NO2
(86)
(85)
C. Other Rearrangements
A 1,3-nitro group rearrangement from O to N has been reported86 . This occurs in the reaction of an imidate, 87 (generated from the chloro compound and silver nitrate in acetonitrile), which gives an N-nitroamide (88). Reaction is believed to be intramolecular involving a radical pair following ON homolytic bond fission. NO2 O
O
O NO2
Ar
Ar
NR
NR
Ar
N
NO2 R
(87)
(88)
A number of reactions of compounds containing the nitro group are postulated to occur by an isomerization to give the nitrite form NO2 ! ONO, which is often followed by ON homolytic bond fission releasing nitric oxide. The reaction has been extensively examined theoretically, for example in nitromethane. Calculations have led to values for the barrier height and characteristics of the transition state have been established (see, for example, Reference 87). The question of the nitro nitrite rearrangement within the O2 N
O2 N
Ph
Ph
NO2 Benzene
O
OH Me
Me (89)
O2 N
NO2
(90)
Ph
O2 N
Ph
O Me
OH
(92)
O Me
ONO
(91)
19. Rearrangement reactions involving the amino, nitro and nitroso groups
883
reaction of nitramide decomposition has been examined in a number of photochemical processes (which will not be discussed here) and thermal reactions. For example, in the pyrolysis of Me2 NNO2 88 two pathways have been established, one involving NN bond breaking and the other involving NO2 ! ONO rearrangement. Another area in which NO2 ! ONO rearrangement has been postulated is within aromatic nitration, again principally when ipso attack has occurred, in order to explain the formation of phenolic products. One example89 comes from the nitration of aromatic systems by N2 O4 /NO2 typically in benzene solution. This involves reaction of a nitrophenol derivative (89) to give the ipso adduct (90), rearrangement of the nitro group to the nitrite (91) followed by hydrolysis to give the OH product 92 (which in this system then reacts further with NO2 ). Nitrites are also believed to be intermediates in nitration reactions where nitronium ion is the nitrating agent. Hydroxy compounds analogous to 92 are often products from the nitration of alkyl phenols90 . Apart from the observation of hydroxy products there is convincing NMR evidence for the existence of the nitrite intermediates91 and there is also spectroscopic evidence for their existence during the photochemical nitration of 1,4,5,8-tetramethylnaphthalene using tetranitromethane as the nitrating agent92 . VII. REARRANGEMENT INVOLVING NITROSO GROUPS A. The Fischer Hepp Rearrangement
The case for an intramolecular mechanism for the rearrangement which takes place in parallel with a reversible denitrosation (Scheme 16) was presented in an earlier volume in this series93 . Denitrosation is brought about by nucleophilic attack by Y at the nitroso nitrogen atom forming the secondary amine and a free nitrosating agent YNO. Generally Y is a halide ion or, in their absence, the solvent, water or ethanol. The crucial experiments which supported this mechanistic framework were those carried out in the presence of a ‘nitrite trap’ (such as sulphamic acid, hydrazine, hydrazoic acid, urea etc.), which +
RNNO
RNHNO
H
+
RNH
Y
−
+ YNO
(94)
Intramolecular
RNH
NO (93) SCHEME 16
884
D. Lyn H. Williams
removes YNO and ensures the effective irreversibility of the denitrosation process. Under those circumstances when there is sufficient ‘nitrite trap’ present, a constant product ratio [93]/[94] was obtained as the concentration of the ‘nitrite trap’ was increased further. The ratio decreased as the concentration of [Y ] was increased and also as Y was made more nucleophilic (e.g. Cl ! Br ). These results are entirely consistent with the mechanism in Scheme 16, but cannot be accommodated by the earlier suggestion that 93 is formed by direct C-nitrosation of 94 by YNO. If that were the case, then the product ratio [93]/[94] should decrease towards zero as the concentration of the ‘nitrite trap’ is increased. Further experimental results have now been presented94 using 3-methoxy-N-nitrosoaniline (95) which gives a much higher [93]/[94] ratio than does N-methyl-N-nitrosoaniline (because of the activating effect of the OMe substituent). Table 2 shows the constancy of the % rearrangement product and of the rate constant (which will be the sum of the rate constants for denitrosation and rearrangement) over a range of different ‘nitrite traps’ and different concentrations. Table 3 shows the decreasing % rearrangement as the concentration of Br is increased; at 0.600 M Br , reaction is almost quantitatively that of denitrosation. Where it can be easily measured the rate constant increases with increasing [Br ] concentration, since the [Br ] term is included in the first-order rate constant for denitrosation. Similarly for different nucleophiles at the same concentration, % rearrangement decreases sharply as the nucleophilicity of Y increases. Similar results were obtained for reactions in HCl/EtOH and H2 SO4 /EtOH solutions using thiourea as the nucleophile and the solvent as the ‘nitrite trap’ (giving ethyl nitrite). MeNNO
OMe (95)
workers95
Some continue to regard the rearrangement as being intermolecular, using the evidence of the formation of 94 and products derived from YNO. This makes the common error that the detection of an intermediate does not necessarily mean that the intermediate is on the pathway to the product under consideration. The Fischer Hepp rearrangement generally gives only the 4-isomer and, apart from examples in the naphthyl series, the 2-isomer has rarely been identified. Now the 2-isomer has been characterized96 as the minor product from the reaction of the diphenylamine derivative 96. The 2-nitroso product gives the cyclized product 97 on treatment with hydrogen peroxide (Scheme 17). TABLE 2. Variation of the rate constant and % rearrangement with added ‘nitrite traps’ for the reaction of 95 in 3.5 M H2 SO4 Nitrite trap HN3 1 ð 103 M HN3 5 ð 103 M + NH3 NH2 1 ð 103 M + NH3 NH2 5 ð 103 M NH2 SO3 H 1 ð 103 M NH2 SO3 H 5 ð 103 M
% Rearrangement
103 k0 (s1 )
84 85
3.10 3.22
85
3.25
85 84 84
3.39 3.33 3.48
19. Rearrangement reactions involving the amino, nitro and nitroso groups
885
TABLE 3. Rearrangement yields and rate constants for the reaction of 95 (in 3.5 M H2 SO4 and 5 ð 103 M HN3 ) in the presence of added nucleophiles Nucleophile H2 O 0.077 0.077 0.077 0.077 0.004 0.008 0.016 0.032 0.077 0.100 0.600
M M M M M M M M M M M
% Rearrangement
103 k0 (s1 )
80 73 16 0 0 65 56 36 29 16 11 ca 2
3.27 3.51
Cl Br SCN SC(NH2 )2 Br Br Br Br Br Br Br
3.86 4.14 6.60 9.40
ON NO
NH
75%
NH
15%
OMe
N
NO
OMe (96)
H2 O2
OMe −
O
+N
OMe
N (97)
SCHEME 17
No evidence has been forthcoming on the nature of the intramolecular shift of the NO group to the 4-position (generally) in the aromatic ring. It would be helpful to have KIE values such as those obtained for the benzidine rearrangement as a first step in order to see if rearrangement is a concerted process. B. Other Rearrangements
Quite different from the Fischer Hepp rearrangement is the reaction of Nnitrosodehydromorpholine 98 which, in methylene chloride containing HCl, gives at room temperature 1-azo-4-oxa-3-oximinocyclohexene 99, which ring-opens on treatment
886
D. Lyn H. Williams
with aqueous acid97 . This is believed to be an intermolecular process, based on the results of cross-over experiments using 15 NO and ring deuterium labelling. The suggested mechanism involves C-protonation and that this ion 100 acts as a nitrosating agent reacting with the nitrosomorpholine derivative at the ring alkene position leading eventually to the oxime product 99. A similar rearrangement of N-nitrosodehydropiperidine to give also the 3-oximino derivative was reported earlier98 , but was not subjected to a mechanistic investigation. NO N
N HCl CH2 Cl2
O
O
(98)
(99)
NO
NOH
NO +N
N HCl
H
O
O
H
(100)
Examples continue to be reported of 1,2- and 1,3-rearrangements of the nitroso group in acyclic systems, showing that this is a widespread process. Scheme 18 shows the reaction of hydrazine derivatives (where G is an electron-withdrawing group). Evidence has been presented99 which suggests that the 1-nitroso compound is first formed, but that subsequently this rearranges to the more thermodynamically stable 2-nitroso isomer. A 1,3-shift has been reported for a nitrosourea 101 in CCl4 100 . Kinetic evidence based on the nature and slopes of Bronsted plots and the application of Eigen theory101,102 suggests that in the nitrosation of amides, ureas and carbamates by nitrous acid, the NO group becomes attached first of all to the oxygen atom of the carbonyl group, and after proton loss the nitroso group undergoes a 1,3-rearrangement to give the final N-nitrosoamide product (Scheme 19). It is known that other electrophilic reagents (e.g. HC and alkylating agents) attack the oxygen atom in amides preferentially. A similar rearrangement has been proposed (Scheme 20) for the mechanism of the nitrosation of tryptophan at low acidities103 . The evidence comes from the observation that at these acidities reaction rates are independent of the acidity and also are independent of added nucleophiles and NO2 R
NO2 NCONHCH2 Ph NO
(101)
CCl4 33 ˚C
R
NHCONCH2 Ph NO
19. Rearrangement reactions involving the amino, nitro and nitroso groups
887
HNO2
GC6 H4 NHNHCOR ! GC6 H4 N(NO)NHCOR ! GC6 H4 NHN(NO)COR SCHEME 18
N O
HNO2
RCONHR′
RC
O + NH R′
N O
O
NO RC
RCON
NR′
R′ SCHEME 19
R
R
NO
HNO2
N
N
+
H
H −H
R
+
R
N
NO
N
NO SCHEME 20
buffers. Under these conditions the nitroso group rearrangement is the rate-limiting step. There is also evidence104 that the nitrosation of nitronic acids to give nitroso introalkanes (pseudonitroles) or nitro oximes (nitrolic acids) also occurs by initial attack at an oxygen atom followed by an O to C rearrangement of the NO group (Scheme 21). Nitrosation at one site in a molecule (usually the most nucleophilic site) followed by NO rearrangement to give the final stable nitroso compound seems to be quite widespread.
888
D. Lyn H. Williams
Me2 C
+
OH
HNO2
N
Me2 C O
O
+
−
N
−
O ON
Me2 CNO2 NO SCHEME 21
Final examples of this report rearrangements from S to N. The diazotisation of amino acids containing the SR group appears to involve initial nitrosation at the very nucleophilic sulphur site, followed by a 1,4-rearrangement of the NO group, finally to give the alcohol product of deamination (Scheme 22)105 . Again the evidence here is kinetic, the reaction being ca 100 times faster than the corresponding reaction in the absence of the sulphur group. Similar S to N rearrangements have been proposed in the nitrosation reactions of thioproline106 and thiomorpholine107 . Me +
CH2 SMe
CH2 S HNO2
C
NO
C
NH2
NH2
CH2 SMe
CH2 SMe
C
C
+
NH2 NO
OH SCHEME 22
A large number of NO group rearrangements can also be brought about photochemically. These are not within the scope of this chapter and are discussed elsewhere in this volume. VIII. REFERENCES 1. A. W. Murray, in Organic Reaction Mechanisms (Eds. A. C. Knipe and W. E. Watts), Wiley, Chichester, 1993, pp. 437 559 and earlier volumes. 2. L. M. Harwood, Polar Rearrangements, Oxford University Press, Oxford, 1992. 3. C. J. Davies, B. T. Heaton and C. Jacob, J. Chem. Soc., Chem. Commun., 1177 (1995). 4. D. V. Banthorpe, in The Chemistry of the Amino Group (Ed. S. Patai), Wiley-Interscience, London, 1968, pp. 642 649. 5. R. A. Cox and E. Buncel, in The Chemistry of the Hydrazo, Azo and Azoxy Groups (Ed. S. Patai), Wiley, London, 1975, pp. 775 805. 6. H. J. Shine, in Aromatic Rearrangements, Elsevier, New York, 1967, pp. 126 179.
19. Rearrangement reactions involving the amino, nitro and nitroso groups
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7. D. V. Banthorpe, Top, Carbocyclic Chem., 1, 1 (1969); Chem. Rev., 70, 295 (1970). 8. M. J. S. Dewar, in Molecular Rearrangements, Part 1 (Ed. P. de Mayo), Interscience, New York, 1963, pp. 295 344. 9. H. J. Shine, J. Chem. Educ., 66, 793 (1989). 10. M. J. S. Dewar, The Electronic Theory of Organic Chemistry, Oxford University Press, Oxford, 1949, pp. 233 240. 11. D. V. Banthorpe, E. D. Hughes and C. K. Ingold, J. Chem. Soc., 2864 (1964). 12. L. Melander and W. H. Saunders, Reaction Rates of Isotopic Molecules, Wiley-Interscience, New York, 1980, p. 124. 13. S. M. Husain, J. McKenna and J. M. McKenna, J. Chem. Res. (S), 280 (1980); J. McKenna, J. M. McKenna and P. S. Taylor, J. Chem. Res. (S), 281 (1980). 14. P. Paneth, Talanta, 34, 877 (1987); Isot. Org. Chem., 41 (1992). 15. H. Kwart and J. Stanulonis, J. Am. Chem. Soc., 98, 4009 (1976); H. J. Shine, Isot. Org. Chem., 1 (1992). 16. H. J. Shine, J. Phys. Org. Chem., 2, 491 (1989). 17. H. J. Shine, H. Zmuda, K. H. Park, H. Kwart, A. G. Horgan and M. Breichbiel, J. Am. Chem. Soc., 104, 2501 (1982); L. Kupezyk-Subotkowska, H. J. Shine, W. Subotkowski and J. Zygmunt, Gazz. Chim. Ital., 117, 513 (1987). 18. G. Fr¨ater and H. Schmid, Helv. Chim. Acta, 53, 269 (1970). 19. H. J. Shine, H. Zmuda, H. Kwart, A. G. Horgan and M. Brechbiel, J. Am. Chem. Soc., 104, 5181 (1982). 20. E. S. Rhee and H. J. Shine, J. Am. Chem. Soc., 108, 1000 (1986); 109, 5052 (1987); J. Org. Chem., 52, 5633 (1987). 21. H. J. Shine, E. Gruszecka, W. Subotkowski, M. L. Brownawell and J. San Filippo, J. Am. Chem. Soc., 107, 3218 (1985). 22. W. Subotkowski, L. Kupezyk-Subotkowska and H. J. Shine, J. Am. Chem. Soc., 115, 5073 (1993). 23. H. J. Shine, J. Habdas, H. Kwart, M. Breichbiel, A. G. Horgan and J. San Filippo, J. Am. Chem. Soc., 105, 2823 (1983). 24. B. C. Auman and A. E. Feiring, U.S. Patent, US 5 175 367; Chem. Abstr., 119, 9319 (1993). 25. T. Nozoe, K. Takase, H. Saito, H. Yamamoto and K. Imafuku, Chem. Lett., 1577 (1986). 26. B. Miller, in Mechanisms of Molecular Migrations (Ed. B. Thyagarajan), Interscience, New York, 1968, p. 306. 27. B. Boduszek and H. J. Shine, J. Am. Chem. Soc., 110, 3247 (1988). 28. H. J. Shine, Aromatic Rearrangements, Elsevier, Amsterdam, 1967, pp. 272 284. 29. E. Buncel, Acc. Chem. Res., 8, 132 (1975). 30. D. L. H. Williams and E. Buncel, in Isotopes in Organic Chemistry, Vol. 5 (Eds. E. Buncel and C. C. Lee), Elsevier, Amsterdam, 1980, pp. 184 197. 31. I. Shimao and S. Oae, Bull. Chem. Soc. Jpn., 56, 643 (1983). 32. I. Shimao and S. Matsumura, Bull. Chem. Soc. Jpn., 49, 2294 (1976). 33. I. Shimao, K. Fujimori and S. Oae, Bull. Chem. Soc. Jpn., 55, 546 (1982). 34. J. Yamamoto, H. Aimi, Y. Masuda, T. Sumida, M. Umezu and T. Matuura, J. Chem. Soc., Perkin Trans. 2, 1565 (1982). 35. E. Buncel, S. R. Kuem, M. Cygler, K. I. Varaghese and G. I. Birnbaum, Can. J. Chem., 62, 1628 (1984). 36. G. G. Furin, O. I. Andreevskaya, A. I. Rezvukhin and G. G. Yakobson, J. Fluorine Chem., 28, 1 (1985). 37. H. J. Shine, W. Subotkowski and E. Gruszecka, Can. J. Chem., 64, 1108 (1986). 38. E. Bamberger, Chem. Ber., 27, 1347, 1548 (1894) and later papers. 39. H. J. Shine, Aromatic Rearrangements, Elsevier, Amsterdam, 1967, pp. 182 190. 40. H. E. Heller, E. D. Hughes and C. K. Ingold, Nature, 168, 909 (1951). 41. J. C. Fishbein and R. A. McClelland, J. Am. Chem. Soc., 109, 2824 (1987). 42. S. Okazaki and M. Okumura, unpublished work, cited by S. Oae, T. Fukumoto and M. Yamagami, Bull. Chem. Soc. Jpn., 34, 1873 (1961); 36, 601 (1963). 43. T. Sone, Y. Tokuda, T. Sakai, S. Shinkai and O. Manabe, J. Chem. Soc., Perkin Trans. 2, 298 (1981). 44. G. Kohnstam, W. A. Petch and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 423 (1984). 45. M. Heyrovsky, S. Vavricka, L. Holleck and B. Katening, J. Electroanal. Chem. Interfacial Electrochem., 26, 399 (1970).
890 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90.
D. Lyn H. Williams I. I. Kukhtenko, Russ. J. Org. Chem. (Engl. Transl.), 7, 324 (1971). T. Sone, K. Hamamoto, Y. Seiji, S. Shinkai and O. Manabe, J. Chem. Soc., Perkin Trans. 2, 1596 (1981). H. Landsheidt, A. Klausener and H. U. Blank, Eur. Pat-Appl. EP 569, 792; Chem. Abstr., 120, 163725 (1994). L. Cerveny and J. Toman, Chem. Prum., 42, 85 (1992); Chem. Abstr., 117, 236179 (1992). K. Miura, T. Kuvihara, K. Yanagida, Jpn. Kokai Tokkyo Koho JP 04 149, 160; Chem. Abstr., 117, 170969 (1992). L. A. Sternson, A. S. Dixit and A. R. Becker, J. Org. Chem., 48, 57 (1983). E. C. Miller, Cancer Res., 38, 1479 (1978). Y. Kikugawa and K. Mitsui, Chem. Lett., 1369 (1993). D. Gutshke and A Heesing, Chem. Ber., 106, 2379 (1973). M. A. Carter and B. Robinson, Chem. Ind., 304 (1974). N. Haga, Y. Endo, K. Kataoka, K. Yamaguchi and K. Shudo, J. Am. Chem. Soc., 114, 9795 (1992). Y. Endo, K. Kataoka, N. Haga and K. Shudo, Tetrahedron Lett., 33, 3339 (1992). H. J. Shine, Aromatic Rearrangements, Elsevier, Amsterdam, 1967, pp. 221 230. R. Onoda and H. Kawaguchi, Kagaku Kyoiky, 29, 220 (1981); Chem. Abstr., 95, 203032 (1981). M. D. Patwardhan, A. S. Mishra, S. S. Ghai and A. K. Mishra, J. Indian Chem. Soc., 58, 1084 (1981). G. R. Underwood and P. E. Dietze, J. Org. Chem., 49, 5225 (1984). M. De Rosa and J. L. Alonso Triana, J. Org. Chem., 43, 2639 (1978). M. De Rosa, J. Org. Chem., 47, 1008 (1982). M. De Rosa, A. Quesada and D. J. Dodsworth, J. Org. Chem., 52, 173 (1987). P. G. Gassman, Acc. Chem. Res., 3, 26 (1970). P. G. Gassman, G. A. Campbell and R. C. Frederick, J. Am. Chem. Soc., 94, 3884 (1972). P. G. Gassman and G. A. Campbell, J. Am. Chem. Soc., 94, 3891 (1972). K. U. B. Rao, R. K. Bhongle and S. Yoganarasimhan, Org. Prep. Proced. Int., 22, 113 (1990). R. L. Atkins and W. S. Wilson, J. Org. Chem., 51, 2572 (1986). W. N. White, J. R. Klink, D. Lazdins, C. Hathaway, J. T. Golden and H. S. White, J. Am. Chem. Soc., 83, 2024 (1961) and later papers. J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Chem. Commun., 261 (1982); A. M. A. AbuNamous, J. H. Ridd and J. P. B. Sandall, Can. J. Chem., 64, 1124 (1986). H. J. Shine, J. Zygmunt, M. L. Brownawell and J. S. Filippo, J. Am. Chem. Soc., 106, 3610 (1984). S. Brownstein, C. A. Bunton and E. D. Hughes, J. Chem. Soc., 4354 (1958). L. W. Deady, O. L. Korytsky and J. E. Rowe, Aust. J. Chem., 35, 2025 (1982). J. P. H. Juffermans and C. L. Habraken, J. Org. Chem., 51, 4656 (1986). J. B. Kyziol and Z. Daszkiewicz, Tetrahedron, 40, 1857 (1984). P. Barrow, J. V. Bullen, A. Dent, T. Murphy, J. H. Ridd and O. Sabek, J. Chem. Soc., Chem. Commun., 1649 (1986). J. V. Bullen, J. H. Ridd and O. Sabek, J. Chem. Soc., Perkin Trans. 2, 1681 (1990). J. V. Bullen and J. H. Ridd, J. Chem. Soc., Perkin Trans. 2, 1675 (1990). J. V. Bullen, J. H. Ridd, and O. Sabek, Gazz. Chim. Ital., 120, 291 (1990). J. T. Murphy and J. H. Ridd, J. Chem. Soc., Perkin Trans. 2, 1767 (1987). G. S. Bapat, A. Fischer, G. N. Henderson and S. Raymahasay, J. Chem. Soc., Chem. Commun., 119 (1983). F. Al-Omran, K. Fujiwara, J. C. Giffney, J. H. Ridd and S. R. Robinson, J. Chem. Soc., Perkin Trans. 2, 518 (1981). C. Bloomfield, A. K. Manglik, R. B. Moodie, K. Schofield and G. D. Tobin, J. Chem. Soc., Perkin Trans. 2, 75 (1983). J. H. Ridd, J. P. B. Sandall and S. Trevellick, J. Chem. Soc., Chem. Commun., 1195 (1988). E. Carvalho, J. Iley and E. Rosa, J. Chem. Soc., Chem. Commun., 1249 (1988). R. P. Saxon and M. Yoshimine, Can. J. Chem., 70, 572 (1992). E. S. Nigenda, D. F. McMillen and D. M. Golden, J. Phys. Chem., 93, 1124 (1989). M. P. Hartshorn, W. T. Robinson, J. Vaughan and J. M. White, Aust. J. Chem., 38, 575 (1985) and earlier papers for other examples. M. P. Hartshorn, H. T. Ing, K. E. Richards, K. H. Sulton and J. Vaughan, Aust. J. Chem., 35, 1635 (1982).
19. Rearrangement reactions involving the amino, nitro and nitroso groups 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107.
891
M. R. Amin, L. Dekker, D. B. Hibbert, J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Chem. Commun., 658 (1986). L. Eberson, J. L. Calvert, M. P. Hartshorn and W. T. Robinson, Acta Chem. Scand., 47, 1025 (1993). D. L. H. Williams, in The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives, Supplement F (Ed. S. Patai), Wiley, Chichester, 1982, pp. 133 140. D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 801 (1982). L. P. Nikitenkova, S. D. Karaktov, Y. A. Strepikheev and I. I. Naumova, Zh. Obshch. Khim., 54, 1375 (1984); Chem. Abstr., 101, 110052 (1984). S. P. Titova, A. K. Arinch and M. V. Gorelik, Zh. Org. Khim., 22, 1562 (1986); Chem. Abstr., 107, 39293 (1987). R. N. Loeppky and H. Xiong, J. Org. Chem., 60, 5526 (1995). R. E. Lyle, W. E. Krueger and V. E. Gunn, J. Org. Chem., 48, 3574 (1983). J. C. Kim and S. H. Han, Bull. Korean Chem. Soc., 15, 173 (1994). M. Tanno, S. Sueyoshi and S. Kamiga, Chem. Pharm. Bull., 38, 49 (1990). A. Castro, E. Iglesias, J. R. Leis, M. E. Pena and J. V. Tato, J. Chem. Soc., Perkin Trans. 2, 1725 (1986). A. Castro, M. Gonzalez, F. Meijide and M. Mosquera, J. Chem. Soc., Perkin Trans. 2, 2021 (1988). A. Castro, E. Iglesias, J. R. Leis, M. E. Pena, J. V. Tato and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 1165 (1986). E. Iglesias and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2, 1035 (1988). T. A. Meyer and D. L. H. Williams, J. Chem. Soc., Chem. Commun., 1067 (1983). T. Tahira, M. Tsuda, K. Wakabayashi, M. Nugao and T. Sugimura, Gann, 75, 889 (1984); A. Castro, E. Iglesias, J. R. Leis, J. V. Tato, F. Meijide and M. E. Pena, J. Chem. Soc., Perkin Trans. 2, 651 (1987). A. Coello, F. Meijide and J. V. Tato, J. Chem. Soc., Perkin Trans. 2, 1677 (1989).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
20
The synthesis and uses of isotopically labelled amino and quaternary ammonium salts KENNETH C. WESTAWAY Department of Chemistry, Laurentian University, Sudbury, Ontario, Canada P3E 2C6 Fax: 705-675-4844; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. THE THEORY OF KINETIC ISOTOPE EFFECTS . . . . . . . . . . . . . . . . A. Heavy-atom Kinetic Isotope Effects . . . . . . . . . . . . . . . . . . . . . . . . B. Primary Hydrogen Deuterium Kinetic Isotope Effects . . . . . . . . . . . . C. Secondary Alpha Hydrogen Deuterium Kinetic Isotope Effects . . . . . . III. USING KINETIC ISOTOPE EFFECTS TO ELUCIDATE THE MECHANISM OF BENZIDINE-TYPE REARRANGEMENTS OF AMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. USING KINETIC ISOTOPE EFFECTS TO MODEL THE SN 2 TRANSITION STATES FOR REACTIONS INVOLVING QUATERNARY AMMONIUM SALTS . . . . . . . . . . . . . . . . . . . . . . . . A. The Menshutkin Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. The SN 2 Reactions of Quaternary Ammonium Salts . . . . . . . . . . . . . V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
893 894 894 895 896 897 932 932 938 946
I. INTRODUCTION
This topic has been reviewed in ‘The Chemistry of the Functional Groups’ series published in 19821 . It is not the purpose of this chapter to provide a complete literature review. Rather, this chapter will discuss some of the new methods of measuring and interpreting kinetic isotope effects that have been used to determine the mechanisms of the reactions of amines and amine derivatives.
893
894
Kenneth C. Westaway II. THE THEORY OF KINETIC ISOTOPE EFFECTS
A. Heavy-atom Kinetic Isotope Effects
Several monographs2 5 have detailed discussions dealing with heavy-atom and primary and secondary hydrogen deuterium kinetic isotope effects. The monograph by Melander and Saunders5 covers the entire area particularly well. For this reason, only a brief summary of the theory of kinetic isotope effects as well as their important uses in the determination of reaction mechanism and transition-state geometry will be presented. The Bigeleisen treatment6 8 , based on Eyring and coworkers’ absolute rate theory9 , assumes that there is a single potential energy surface along which the reaction takes place, and that there is a potential energy barrier separating the reactants from the products. The reaction occurs along the path over the lowest part of the barrier with the transition state at the top of the barrier, i.e. it lies at the energy maximum along the reaction coordinate but at an energy minimum in all other directions. The transition state is assumed to be in equilibrium with the reactants and products and to have all the properties of a stable molecule, except that one vibrational degree of freedom has been converted into motion along the reaction coordinate. ! A C B
Transition ‡ ! Products state
1
The kinetic isotope effect for this reaction is: 1 Q1 ‡ QA2 QB2 k1 D Ð Ð Ð k2 2 Q2 ‡ QA1 QB1
2
where the subscripts 1 and 2 refer to the molecules containing the lighter and heavier isotopes, respectively, and the Qs are the complete partition functions for reactants A and B. Setting 1 D 2 and applying the harmonic approximation to all nonlinear gas molecules leads to an expression for Q2 /Q1 (equation 3), where S1 and S2 are the symmetry numbers of the respective molecules, the Ms are the molecular weights, the Is are the moments of inertia about the three principal axes of the n-atom molecules, and the s are the fundamental vibrational frequencies of the molecules in wave numbers. 3n6 1i 2i hc 1 exphc1i /kT N S1 IA2 IB2 IC2 1/2 M2 3/2 Q2 D N N Q1 S2 IA1 IB1 IC1 M1 2kT 1 exphc2i /kT i
3 Using various approximations, a solution to the isotopic rate ratio equation can be obtained. It is found that the isotope rate ratio, k1 /k2 , is dependent on the force constant changes which occur in going from the reactants to the transition state. Consequently, if CX bond rupture (where the isotopically labelled atom X can be halogen, sulfur, nitrogen, etc.) has not progressed at the transition state of the rate-determining step of the overall reaction, there is no change in the force constants involving the isotopic atom and the isotope rate ratio, k1 /k2 , will be equal to one. An isotope rate ratio greater than one will be observed if there is a decrease in the force constants at the transition state of the slow step. The greater the decrease in the force constant, the larger the magnitude of the isotope effect. The observation of a heavy-atom isotope effect, therefore, allows one to determine whether CX bond weakening (a decrease in force constant) has occurred when the reactant is converted into the transition state of the rate-determining step. Calculations by
20. The synthesis and uses of amino and quaternary ammonium salts
895
Saunders10 and by Sims and coworkers11 have shown that the magnitude of the leavinggroup heavy-atom isotope effect varies linearly with the extent of CX bond rupture in the transition state for concerted elimination reactions and for nucleophilic substitution reactions, respectively. Since the magnitude of the isotope effect is directly related to the amount of CX bond rupture in the transition state, these isotope effects provide detailed information about the structure of the transition state. B. Primary Hydrogen Deuterium Kinetic Isotope Effects
Although the zero-point energy differences between the isotopic molecules’ vibrations are not the only contribution to the isotope effect, they are, however, often the dominant term. This is particularly true for hydrogen deuterium kinetic isotope effects where the zero-point energy difference is large, and also for large molecules where isotopic substitution does not effect the mass and moment-of-inertia term significantly. It is usual to assume that the stretching modes are the most important in determining these isotope effects. This is based on the two assumptions: (i) that the bending vibrations are generally of a lower frequency and therefore have smaller zero-point energy differences for isotopic molecules, and (ii) the bending motions in the transition state will be similar to those in the substrates. Applying these approximations to the rupture of a single CH bond in a unimolecular process leads to equation 4, hc kH H D D exp 4 N kD 2kT where H and D are the ground-state symmetric stretching frequencies for the CH and CD bonds, respectively. Substitution of the appropriate frequencies into equation 4 gives an isotope effect of approximately seven at 25 ° C. For reactions involving a proton transfer from one molecule to another, however, the situation is more complex. Westheimer12 and Melander2 independently pointed out that, because bond formation and bond breaking are occurring concurrently, new stretching vibrations in the transition state which are not present in the reactants must be considered. They considered the reaction: AH C B ! [A- - -H- - -B]‡ ! A C HB
5
where [A- - -H- - -B] is a linear transition state. If this transition state is regarded as a linear molecule, there are two independent stretching vibrational modes which may be illustrated as follows: ? ! A- - -H- - -B Symmetric
! A- - -H- - -B Antisymmetric
Neither of these vibrations corresponds to stretching vibrations of AH or BH. The ‘antisymmetric’ vibrational mode represents translational motion in the transition state and has an imaginary force constant. The ‘symmetric’ transition-state vibration has a real force constant but the vibration may or may not involve motion of the central H(D) atom2,12,13 . If the motion is truly symmetric, the central atom will be motionless in the vibration and the frequency of the vibration will not depend on the mass of this atom, i.e. the vibrational frequency will be the same for both isotopically substituted transition states. It is apparent that under such circumstances there will be no zero-point energy difference
896
Kenneth C. Westaway
between the deuterium- and hydrogen-substituted compounds for the symmetric vibration in the transition state. Hence, an isotope effect of seven at room temperature is expected since the difference in activation energy is the difference between the zero-point energies of the symmetric stretching vibrations of the initial states, i.e. 1/2hH hD . In instances where bond breaking and bond making at the transition state are not equal, bond breaking is either more or less advanced than bond formation, and the ‘symmetric’ vibration will not be truly symmetric. In these cases, the frequency will have some dependence on the mass of the central atom, there will be a zero-point energy difference for the vibrations of the isotopically substituted molecules at the transition state and kH /kD will have values smaller than seven. It may be concluded that for reactions where the proton is less or more than one-half transferred in the transition state, i.e. the AH and HB force constants are unequal, the primary hydrogen deuterium kinetic isotope effect will be less than the maximum of seven. The maximum isotope effect will be observed only when the proton is exactly half-way between A and B in the transition state. This relationship is also found for carbon kinetic isotope effects where the isotopically labelled carbon is transferred between two atoms in the reaction10,11 . This makes interpreting carbon isotope effects difficult. C. Secondary Alpha Hydrogen Deuterium Kinetic Isotope Effects
In the preceding sections, the bond to the isotopic atom is broken or formed in the rate-determining step of the reaction. In these cases, the change in rate is referred to as a primary kinetic isotope effect. Isotopic substitution at other sites in the molecule has much smaller effects on the rate. These small isotope effects are collectively referred to as secondary kinetic isotope effects. As with primary isotope effects, the origin of secondary isotope effects is considered to be mainly due to changes in force constants upon going from reactants to the transition state. For the most part, secondary isotope effects depend on the change in zero-point energy (ZPE). Smaller force constants for the isotopic nuclei in the transition state than in the reactant lead to an isotope effect greater than one (Figure 1a). When the force constants are greater in the transition state than in the reactant, on the other hand, an isotope effect of less than one is observed (Figure 1b). Secondary alpha hydrogen deuterium kinetic isotope effects are determined when hydrogen is replaced by deuterium at the ˛- or reacting carbon. The generally accepted view originally proposed by Streitwieser and coworkers14 is that the alpha deuterium kinetic isotope effects are primarily determined by the changes in the out-of-plane bending vibrations in going from the reactants to the transition state. Solvolysis reactions proceeding via a carbocation are expected to give large normal isotope effects, kH /kD ˛ . The maximum kH /kD ˛ expected per deuterium for various leaving groups are 1.22 for fluoride, 1.15 for chloride, 1.13 for bromide, 1.09 for iodide, 1.19 for ammonia and 1.22 for benzenesulfonate15,16 . Smaller alpha deuterium isotope effects are observed for reactions proceeding via the SN 2 mechanism. This is due to steric interference by the leaving group and/or the incoming nucleophile with the out-of-plane bending vibrations of the C˛ H bonds. This leads to an increased force constant at the SN 2 transition state, 1 (see Figure 1b), where Nu is the nucleophile and LG is the leaving group in the SN 2 reaction. In fact, small or inverse isotope effects, kH /kD ˛-D D 0.95 1.04, are observed for the SN 2 reactions of primary substrates17 . Recently, Wolfe and Kim18 pointed out that the changes in the stretching vibrations played the major role in determining the magnitude of these isotope effects. However, a more recent study by Poirier, Wang and Westaway19
20. The synthesis and uses of amino and quaternary ammonium salts H H D
∆ZPE
897 ∆ZPE
D
E
E
H D
H D
∆ZPE
(a)
∆ZPE
(b)
FIGURE 1. (a) A reaction where ZPEreactant is greater than ZPEtransition state and kH /kD ˛ > 1.0. (b) A reaction where ZPEreactant is less than ZPEtransition state and kH /kD ˛ < 1.0
δ− Nu
δ+ δ− Cα LG (1)
showed that the magnitude of these isotope effects for reactions with a particular leaving group is determined by the nucleophile-leaving group distance in the SN 2 transition state, i.e. the changes in the out-of-plane bending vibrations as the reactant is converted into the transition state. III. USING KINETIC ISOTOPE EFFECTS TO ELUCIDATE THE MECHANISM OF BENZIDINE-TYPE REARRANGEMENTS OF AMINES
Shine and coworkers have used heavy-atom kinetic isotope effects to determine the mechanism of several electrophilic aromatic substitution reactions. The particular reactions of interest are the collection of reactions known as ‘benzidine rearrangements’. The four mechanisms that have been proposed for these rearrangements are shown in equations 6 9 using the benzidine rearrangement of hydrazobenzene as the model. One possibility is the concerted rearrangement via polar transition states that was proposed by Ingold, Hughes and Banthorpe20 (equation 6). A second possibility proposed by Dewar21 is a nonconcerted reaction via -complexes (equation 7). A third possibility is that the reaction proceeds via a pair of radical cation intermediates within a solvent cage22 (equation 8) and the final possibility is a rate-determining proton transfer to the benzene ring (equation 9). It is not known whether the rearrangement is concerted with the addition of the ring proton or proceeds via several fast steps after the rate-determining proton transfer to the benzene ring. It is also not known whether the proton adds to the benzene ring bearing the protonated nitrogen22 .
898
Kenneth C. Westaway
NH
+ NH2
2H +
NH
+ NH2
slow
NH2
NH2
H
+2
NH2
NH2
+
+
H
H
(6)
H −2H +
H2 N
NH2
NH
+ NH2
+ 2H+
NH
+ NH2
slow
NH2
NH2
+ H
NH2
NH2
+
+
H π − complex
H2 N
(7)
H −2H +
NH2
20. The synthesis and uses of amino and quaternary ammonium salts
NH
+ NH2
+ 2H+
NH
899
+ NH2
slow
(8) NH2
NH2
NH2
+
+
+
NH
−2H +
H
H
NH
+ H+
H2 N
NH2
+ NH2
NH
slow
H
H +
+ NH2
NH
and/or
+ NH2
+ NH −2H+
H2 N
(9)
NH2
Shine and coworkers have used an extensive set of kinetic isotope effects to determine the mechanism of the benzidine rearrangement (equation 10). The major product of the rearrangement, 4,40 -diaminobiphenyl, or benzidine (2), accounts for 70% of the product, while 4,20 -diaminobiphenyl or diphenyline (3) accounts for the rest. The reaction is second order in sulfuric acid, so the diprotonated hydrazobenzene is obviously an intermediate in this reaction. A large nitrogen isotope effect of 1.022223,24 indicated that NN bond rupture occurred in the rate-determining step of the reaction. It is worth noting that these isotope effects were measured by comparing the isotopic composition of the products formed from mixtures of the unlabelled and the labelled compound containing two 15 N isotopes per molecule, by whole-molecule isotope ratio mass spectrometry. This technique involves isolating the product from the reaction and analyzing it by mass spectrometry. In
900
Kenneth C. Westaway
these experiments, the isotopic ratio of the molecule (the ratio of the labelled to unlabelled molecules) was determined by measuring the isotopic composition of the molecule several thousand times. Typically, between 15,000 and 30,000 scans were used to determine the isotopic composition of the product. This very large number of scans was required because the heavy-atom isotope effects Shine and his coworkers measured were very small. H2 N
NH2 (2)
NH
NH
+ NH2
+ 2H+
+ NH2
(10) NH2 H2 N (3)
Whole-molecule isotope ratio mass spectrometry was also used to measure the secondary hydrogen deuterium kinetic isotope effect of 0.962 found for the formation of benzidine from mixtures of the undeuterated and 4,40 -dideuterohydrazobenzene. This isotope effect illustrated that the bonding to these hydrogens was altered in the rate-determining step of the reaction. Model calculations indicated that the hydrogen deuterium isotope effect would have been normal if the reaction had proceeded via the -complex mechanism. Finally, a k 12 /k 14 of 1.050 found for the formation of benzidine when the label was at C-4 of the hydrazobenzene, demonstrated that the C-4 carbon was also altered in the rate-determining step of the reaction. The nitrogen heavy-atom kinetic isotope effect of 1.0222 indicated that the NN bond is also breaking in the slow step of the reaction. Thus, finding a significant nitrogen, secondary hydrogen deuterium and carbon (C-4) kinetic isotope effect led the authors to conclude that the benzidene rearrangement of hydrazobenzene to benzidine occurs by the concerted mechanism shown in equation 6. The nitrogen kinetic isotope effect of 1.063 for the formation of diphenyline confirmed that rupture of the NN bond was also involved in the rate-determining step of this reaction. However, the magnitude of the nitrogen isotope effect found in the formation of the diphenyline is very different from the isotope effect of 1.022 found for the formation of benzidine. This clearly indicates that this reaction proceeds via a very different transition state than that for the formation of benzidine and it was concluded that it probably occurred via the -complex mechanism (equation 7). This conclusion is supported by the very small (effectively zero) carbon isotope effects found for the formation of diphenyline22 . In fact, a k 12 /k 13 of 1.0000 was found by whole-molecule isotope ratio mass spectrometery and a k 12 /k 14 of 1.0011 was obtained when a scintillation counter technique was used. This lack of a carbon isotope effect indicates clearly that carbon carbon bond formation does not occur in the rate-determining step of the reaction that forms diphenyline. Since NN bond rupture does occur in the slow step of the reaction to form diphenyline, but carbon carbon bond formation does not, it is obvious that diphenyline is not formed by a concerted
20. The synthesis and uses of amino and quaternary ammonium salts
901
mechanism but must involve the formation of an intermediate, and it was concluded that it occurred via the -complex mechanism (equation 7). Further confirmation of the -complex mechanism was provided by the calculated isotope effects for the -complex mechanism. The calculated nitrogen kinetic isotope effect for the formation of diphenyline by the dissociative -complex mechanism was 1.055, in excellent agreement with the 1.063 found experimentally. A rationale for the different mechanisms for the formation of benzidine and diphenyline was presented. The formation of benzidine is concerted because it occurs via an allowed [5,5] suprafacial sigmatropic shift whereas the concerted formation of diphenyline would occur via a forbidden [3,5] suprafacial reaction. The above results were interpreted in terms of the concerted mechanism shown in Scheme 1, although the authors state that one cannot determine whether the rings are bent (Figure 2) or planar in the transition state of the concerted reaction.
H N
+ N
2H+
H
H + H N H
N H
slow
H +
+ +
2+
NH2
N H
−2H+
H +
NH2
N H
SCHEME 1
+
H N
+
N
H H H
FIGURE 2. The possible bent configuration of the benzene rings for the concerted formation of benzidine
902
Kenneth C. Westaway
The labelled substrates required for this study were synthesized as follows. The hydrazobenzene doubly labelled with nitrogen-15 was prepared from the commercially available 15 N-labelled aniline (equation 11).
15 NH 2
+ MnO2
15 N
∆
aq. acetone
15 NH
15 N
(11)
Zn, NH4 Cl
15 NH
The 4,40 -dideuteroazobenzene was prepared with 97% d2 by the sequence of reactions shown in Scheme 2.
O2 N
HBF 4
NH2
NaNO2 , 0 °C
+ N
O2 N
N
Cu 2 O Na 2 CO3 D3 PO2
O2 N
Sn, HCl
D
H2 N
D
aq. MeOH Zn, NaOH
D
N
N
D
aq. acetone Zn, NH4 Cl
D
NH
NH
D
SCHEME 2
The 14 C-labelled compound was prepared from the 14 C nitrobenzene that was obtained by converting the commercially available 4-nitroaniline-1-14 C into the diazonium tetrafluoroborate and reducing it with hypophospous acid (Scheme 3)25 . The 4,40 -13 C2 azobenzene was prepared from the commercially available13 C-labelled acetone by the sequence of reactions shown in Scheme 4.
20. The synthesis and uses of amino and quaternary ammonium salts
*
O2 N
HBF 4
NH2
*
O2 N
NaNO2 , 0 °C
+ N
N
N
N
903
Na 2 CO3 Cu 2 O, H3 PO2
NO2 *
O2 N
H
* Zn, NaOH aq. acetone Zn, NH4 Cl
NH
*
NH
14 * = C
SCHEME 3
N
OH O C H
CH3 C* CH3
O + O2 N
N
*
N N
C Cl
N
C6 H5
−
C
C
C
N
K2 CO3 , acetone
O H
N
N NO2
O
*
C6 H5
40 ˚C
NO2
H2 , Pd/c
*
* MnO2
+
NH2
*
∆ NHOH
aq. acetone
* 13
*= C
SCHEME 4
N
NH
N
*
Zn, NH4 Cl
NH
*
904
Kenneth C. Westaway
The next benzidine-type rearrangement studied by Shine and coworkers was the p-semidine rearrangement of 4-methoxyhydrazobenzene26 . In this reaction, 4-methoxy hydrazobenzene rearranges in acidic medium to form p-semidine (4) and an o-semidine (5); see equation 12.
MeO
NH
NH 2H+
+ NH2
MeO
+ NH2
(12) NH2
MeO
NH
(4)
NH2
NH
OMe
(5)
These rearrangements are especially interesting because one of the nitrogens from the hydrazo group attacks the ortho- or the para-position of the activated benzene ring. Thus, an intramolecular, concerted mechanism seems even more unlikely in these rearrangements. Heesing and Schinke have shown, using substrates labelled with 15 N at both nitrogens, that both the 4-methoxy- and the 4-chlorohydrazobenzene rearrange in an intramolecular reaction27,28 . Some of these rearrangements involve a single proton while others require two protons. In the two-proton transfer reactions, the second proton is thought to add to the ipso position of the benzene ring producing a bent cyclohexyadienyl-like configuration that brings the para-position of the benzene ring close to the unprotonated nitrogen of the hydrazo linkage (Scheme 5). The formation of the o-semidine is also thought to involve ipso protonation of the benzene ring (Scheme 5). In the one-proton rearrangement, it is generally accepted that the protonation must occur at the nitrogen of the hydrazo group. Shine and coworkers synthesized 4-methoxyhydrazobenzene labelled with nitrogen-15 at both nitrogens and another sample labelled with carbon-14 at the 4-position of the unsubstituted benzene ring. The synthesis of the nitrogen-15 labelled substrate began with the commercially available 15 N-aniline (Scheme 6) while the carbon-14 labelled substrate was synthesized from 4-14 C-nitrobenzene that had been prepared earlier in Shine’s laboratory (Scheme 7). The products from the rearrangement in 60% aqueous dioxane under oxygen-free argon at 0 ° C at a pH of 4.43 were benzoylated, separated and analyzed by whole-molecule isotope ratio mass spectrometry. The nitrogen isotope effect for the formation of both the 4-amino-40 -methoxysemibenzidine (4) and 2-amino-3-methoxysemibenzidine (5) were 1.029 and 1.074, respectively. The carbon-12/carbon-14 isotope effect for the formation of the 4-amino-40 -methoxysemibenzidine was 1.039. The nitrogen and carbon isotope effects found for the formation of the 4-amino-40 -methoxysemibenzidine indicate that the nitrogen nitrogen bond is breaking and that the nitrogen carbon bond is forming in the slow step of the reaction forming the 4-amino-40 -methoxysemibenzidine. Obviously,
20. The synthesis and uses of amino and quaternary ammonium salts
905 H
X
NH
+
−2H +
NH2
NH2 + N H
2H +
X
NH
X
NH 2H +
N
H
NH2 +
−2H +
NH
+ NH2
X X
H
X = Cl, OCH3 SCHEME 5
this is only consistent with a concerted mechanism for the formation of 4-amino-40 methoxysemibenzidine. It is worth noting that the magnitude of these isotope effects are almost identical to those found in the concerted benzidine rearrangement (1.029 and 1.022 for the nitrogen isotope effects and 1.039 and 1.028 for the carbon isotope effects, respectively). The much larger nitrogen isotope effect of 1.074 found for the formation of the 2-amino3-methoxysemibenzidine suggests that this reaction occurs by a different mechanism. Thus, the authors concluded that the 2-amino-3-methoxysemibenzidine formed in a twostep mechanism with the nitrogen nitrogen bond rupture rate-determining. The nitrogen isotope effect in this reaction is similar to the isotope effect of 1.063 found for the twostep benzidine rearrangement. Finally, it is worth noting that the observed kinetic isotope effects were in good agreement with those calculated for the concerted and two-step rearrangements. Disproportionation (equation 13) is one of the side reactions that can occur in benzidine rearrangements. Shine and coworkers measured the nitrogen and carbon kinetic isotope effects for the disproportionation reaction of 4,40 -diiodohydrazobenzene, which only yielded disproportionation products, at 25 ° C in 70% aqueous dioxane that was 0.376 M in perchloric acid29 . The reaction was first order in hydrazobenzene and it has been assumed that an intermediate was involved in the disproportionation reaction. This intermediate must be one of: a radical ion30 (equations 14 and 15), a -complex31 (equation 16) or a quinonoid structure32 (equation 17).
906
Kenneth C. Westaway 15
NH2 + MnO2
15
∆
15
N
H2 O2
AcOH
15
N
15
N
N
O− H2 SO4
15
HO
15
N
N
(CH3 )2 SO4
15
CH3 O
15
N
N
SCHEME 6
∗
NO2
Zn HCl
∗
H2 N
∗
N
N
N
OCH3
OCH3
aq. acetone Zn, NH4 Cl
∗
N
N
∗ = 14 C
SCHEME 7
OCH3
O
20. The synthesis and uses of amino and quaternary ammonium salts NH
2
H
NH
907
+
NH2
2
(13) +
I
NH
I
+ NH2
N
+
+ 2H
N
+
I + 2H
NH
+ NH2
slow
I
−2H
+
(14)
I
NH2
2 I
I
NH
I
+
+ NH2
2 I
I
NH
NH
N
N
I
I
+
I + H
NH
+ NH2
NH
I
slow
I
(15)
+ NH2 + I
NH
−H
+
I
2 I
NH2
+ I
NH
NH
N
I
N
I
908
Kenneth C. Westaway I
NH
+
I + 2H
NH
+ NH2
+ NH2
I
I
slow
(16) 2+
I
I
I I
+
NH
NH
−2H
NH2 +
I
2
+
NH2
NH2
a π-complex
I
+ I
NH
N
+ NH2
I
I + 2H+
NH
I
N
+ NH2
I
slow
I
+ H2 N
+ NH2
(17)
I
− 2H +
2 I
I
NH
NH2 + I
NH
I
N
N
I
20. The synthesis and uses of amino and quaternary ammonium salts
909
4,40 -Diiodohydrazobenzene
labelled at both nitrogens with nitrogen-15 was synthesized from the commercially available 15 N-aniline (Scheme 8), and another sample, with carbon-13 at the 4-position of both rings, was synthesized from [1-13 C]-4-nitrophenol that was available in Shine’s laboratory (Scheme 9).
15
KH2 PO4
NH2 + KI + I 2
15
I
NH2
Na 2 HPO4 ∆ MnO2
15
I
15
N
N
I
Zn, NH4 Cl aq. acetone
15
I
NH
15
NH
I
SCHEME 8
Some 4,40 -diiodohydrazobenzene labelled with carbon-14 at one of the 4-positions of the phenyl rings was prepared from [4-14 C]azobenzene that had been synthesized previously in Shine’s laboratory (equation 18).
N
N
*
H2
H2 N
*
Pd/C
KH2 PO4 , Na 2 HPO4 KI, I 2
(18) I
H2 N
H2 N
*
I
MnO2 , ∆
I
* I
N N
aq. acetone Zn, NH4 Cl
I
NH NH
14 *= C
*
I
910
Kenneth C. Westaway
*
O2 N
NH2 NH2
OH
*
H2 N
Pd/C, ∆
OH
K2 CO3 , ∆
N
N
N
C
N
N
N
N
C N
O
Cl
C6 H5
*
C6 H5
H2
*
H2 N
Pd/C
NH2
H
KH2 PO4 , Na 2 HPO4 KI, I 2
I
*
N
*
N
I
MnO2
H2 N
∆
*
I
aq. acetone Zn, NH4 Cl
I
*
NH
NH
*
I
13 *= C
SCHEME 9
The nitrogen and carbon kinetic isotope effects were determined for the disproportionation reactions in 70% aqueous dioxane that was 0.376 M in perchloric acid. A nitrogen isotope effect of 1.037, a carbon-13 kinetic isotope effect of 1.023 and a carbon-14 isotope effect of 1.045 were observed for the disproportionation reaction forming 4,40 -diiodoazobenzene. The excellent agreement between the carbon-13 and carbon-14 isotope effects (the carbon-14 isotope effect should be 1.044 or 1.9 times the magnitude of the carbon-13 isotope effect33 ) which were measured by whole-molecule isotope ratio mass spectrometry and by scintillation counting, respectively, confirmed that the large carbon isotope effects were correct. Since the reaction is first order in substrate, these isotope effects demonstrated that an intermediate was formed and that nitrogen nitrogen bond rupture and the formation of the 4,40 carbon carbon bond both occurred in the rate-determining step of the decomposition of this intermediate. These results obviously rule out the radical ion and the -complex mechanisms because they only involve nitrogen nitrogen bond rupture in the rate-determining step of the reaction. Thus, the disproportionation reaction, like the benzidine rearrangement, is thought to proceed via a quinonoid intermediate that is formed in the slow step of the reaction. The quinonoid intermediate is then oxidized in a fast step by another hydrazobenzene
20. The synthesis and uses of amino and quaternary ammonium salts
911
molecule (equation 19). I
+ H2 N
+ NH2
+ 2H3 N
I
I
H N
(19)
+
H N I
I
N
N
I
I
The next reaction of this type investigated by Shine and coworkers was the nitramine rearrangement34 (equation 20). NO2
CH3
CH3
H
CH3
N
N
H N
NO2 H+
(20)
+
NO2
The rearrangements are first order in substrate and in acid and are mainly intramolecular in nature, although a small intermolecular component has been identified. Shine and coworkers investigated this reaction to try to prove that the process occurred by the nonconcerted (the favored) pathway (Scheme 10) rather than the concerted pathway (Scheme 11). The N-methyl-N-[15 N]nitroaniline, the N-methyl-N-nitro-[4-14 C]aniline and the N-methyl-N-nitro-[2-14 C]aniline required for this study were prepared using the reactions shown in Schemes 12 14. The nitrogen isotope effects were determined by whole-molecule isotope ratio mass spectrometry on the 2-nitro and the 4-nitro-N-methylanilines recovered from the reaction in 0.205 M hydrochloric acid at 30 ° C. The large nitrogen isotope effects of 1.045 and 1.039 observed for the formation of the 2-nitro and the 4-nitro-N-methylanilines, respectively, clearly demonstrate that nitrogen nitrogen bond cleavage occurs in the rate-determining step for the formation of both products. Although the carbon isotope effects were determined under conditions where a small amount of intermolecular reaction occurred, the isotope effects are effectively those for the intramolecular rearrangements. The carbon-12/carbon-14 isotope effects for the formation of both the 2-nitro- and the 4-nitro-N-methylanilines are, within experimental error, zero, i.e. they were 1.006 and 1.005 for the formation of the 2-nitro- and the 4-nitro-N-methylanilines, respectively, when the substrate was the N-methyl-N-nitro-[2-C14 ]aniline, and 1.008 and 1.005 for the formation of the 2-nitro- and the 4-nitro-N-methylanilines, respectively, when the substrate was the N-methyl-N-nitro-[4-C14 ]aniline. The absence of a carbon isotope effect clearly indicates that there is no carbon carbon bond formation in the rate-determining step of either of the nitramine rearrangements. Clearly, neither of the nitramine rearrangements
912
Kenneth C. Westaway CH3
H
CH3
NO2 N
NO2
H
CH3 N
N+ +
+H
CH3
+ N
+ NO2
+ N
CH3
H
CH3
H
CH3
H N
H
NO2
−H+
+
NO2
H N
+
NO2
H
NO2
SCHEME 10 NO2
CH3
CH3
N
H
CH3
NO2
H O N +
N+
N O
+H
CH3
+ N
+
H
CH3
H
N
N
H O
−H
O
+
N
NO2
O
N O
CH3
+ N
NO2
CH3
H
CH3
NO2
O
N
O
NO2 N
N −H
+
O
H
CH3
N
O
SCHEME 11
NO2
20. The synthesis and uses of amino and quaternary ammonium salts O C 6 H5 C
K15NO3
+ AgClO4
Ag15NO3
913
O
Cl
C6 H5C
− 15 °C
15NO 3
−15 °C 15NO 2
CH3
H
CH3 N
N
SCHEME 12
CH3 C O HC
O2 N
*
O
O OH, Et 3 N
5% Pd/C, 100 °C
C O
O HC NH
H
H2 N
*
−15 °C
*
methyl sulfide borane 0 °C
CH3
H
NO2
CH3
N
N O C6 H5 C NO3
*
* *=
14 C
SCHEME 13
is concerted, and the authors concluded that both reactions occur via a radical mechanism where nitrogen nitrogen bond rupture of the intermediate formed by protonation of the substrate is rate-determining (equation 21). H NO2
CH3
CH3
N
N+
NO2
CH3
+ N
H
(21) + H
+
slow
+ NO2
914
Kenneth C. Westaway
NH2 NO2
*
NO2
*
O
HC
*
OH, Et 3 N
NaNO2 , 0 °C
NH2
5% Pd/C, 100 °C
H3 PO2 , Cu 2 O CH3
C O O C O H −15 °C
CH3
CH3
H N O
*
O
*
C 6 H5 C
borane 0 °C
NH *
HC
NO2 N
NO3
methyl sulfide
*=
13 C
SCHEME 14
CH3
O O
C
Cl
O
OH 15NO 2
A g 15 NO3
15NO 2
(CH3 )2 SO4
CH3 CN
NaOH/MeOH
CH3
Zn
O OCH3
15NH 2
MnO2
OCH3 15N
∆
15N
aq, acetone Zn, NH4 Cl
OCH3
OCH3 15NH
15NH
SCHEME 15
20. The synthesis and uses of amino and quaternary ammonium salts
915
Confirmation of the radical mechanism was provided by Ridd and Sandall35 , who detected radical cations by nitrogen-15 NMR of the reaction mixture for the nitramine rearrangement of 2,6-dibromo-N-nitroaniline and of N-methyl-N-nitroaniline labelled with nitrogen-15 in the nitro group. The results did not allow the authors to indicate whether the products were formed within the solvent cage or from separated radicals. Shine and coworkers36 also investigated the mechanism of the one-proton benzidine rearrangement of 2,20 -dimethoxyhydrazobenzene. The doubly labelled 2,20 dimethoxy-[15 N,15 N]hydrazobenzene, the 2,20 -dimethoxy-[4,402 H2 ]hydrazobenzene and the 2,20 -dimethoxy-[4,4013 C2 ]hydrazobenzene required for this study were synthesized using the reactions in Schemes 15, 16 and 17, respectively. O CO2 H
C
O C
Cl
NH2
NH3
SOCl2
OCH3
OCH3
NO2
NO2
OCH3 NO2 NaOBr
+ N2
D
NH2
t-BuNO2
D3 PO2
BF 3 etherate
OCH3
OCH3
NO2
OCH3
NO2
NO2
H2 PtO
D
OCH3 MnO2
D
∆
N
OCH3
N
D
OCH3 NH4 Cl
NH2
Zn
OCH3
D
SCHEME 16
OCH3
NH
NH
D
CH3
CH3
CH3 O
O
13
N
N
N
C13 O + O2 N C−
H
N
Ph
H
CH3 O
NaOH
3 2 5°C
N a H, ∆
Ph
C O
C
O
CH3 O
OH
O
Ph
N
N
13
p ip erid ine
∆
C
CH3 O
KOH
O
O
13
K2 CO3
C 6 H5
N
N N
N
N
CH3 O
OH
OH
13
13
N2 H4
Raney-Ni
NH2
13
NO2
13
O
13
HO
O
SCHEME 17
∆
M nO2
NO2
CH2 N2
C6 H5
C
N N
N
N
NH2
13
C6 H5
Cl
C
O
13
NO2
(2 ) H2 O2
N N
C
N
C6 H5
N
(1) H2 SO4
N
N
OCH3 CH3 O
C6 H5
NH2
A c2 O
O
13
O
O
13
13
C6 H5
aq . aceto ne
Zn, NH4 Cl
C
O
13
NO2
NHCCH3
H2
Pd /C
C6 H5
CH3 O
NO2
OH
13
HN O 2
NH2
13
NH NH
OCH3
O C
Cl
N a O H, D M F
H2 SO4
H2 O
13
916
20. The synthesis and uses of amino and quaternary ammonium salts
917
Then, the nitrogen, the carbon and the deuterium kinetic isotope effects for these oneproton benzidine rearrangements (equation 22) were measured in buffered 60% aqueous dioxane at 0 ° C. The 2,20 -dimethoxybenzidine formed in the reaction was isolated and converted into its bis(trifluoroacetyl) derivative and analyzed by whole-molecule isotope ratio mass spectrometry. The nitrogen kinetic isotope effect was 1.029 š 0.005, the carbon-13 kinetic isotope effect was 1.029š0.005 and the secondary hydrogen deuterium kinetic isotope effect was 0.93 š 0.03. The substantial nitrogen and carbon isotope effects indicate that the nitrogen nitrogen bond is breaking as the carbon carbon bond is forming in the rate-determining step of the reaction. Thus, the rearrangement is a concerted reaction. The inverse secondary hydrogen deuterium kinetic isotope effect also confirms that the rearrangement is concerted. An inverse isotope effect is observed because carbon carbon bond formation changes the hybridization of the 4 and 40 carbon atoms of the benzene rings from sp2 - to sp3 -like in the transition state. Thus, the one-proton transfer benzidine reaction occurs by a pre-equilibrium proton transfer to nitrogen followed by a rate-determining concerted rearrangement. Finally, it is worth noting that all three of the isotope effects in this reaction are almost identical to those found for the two-proton benzidine rearrangement (Table 1). This suggests that the transition states for the oneproton and two-proton benzidine rearrangements are very similar. The authors suggest that the transition states have two bent cyclohexadiene-like rings. This brings the two reacting carbons close enough to react (Figure 3). OCH3 NH
CH3 O +
NH
H+
OCH3 + NH2
CH3 O
CH3 O
(22)
NH
OCH3
H2 N
NH2
TABLE 1. The nitrogen, carbon-13 and secondary hydrogen deuterium kinetic isotope effects found for the one- and two-proton benzidine rearrangements Rearrangement One-proton Two-proton
k 14 /k 15
k 12 /k 13
kH /kD
1.029 1.022
1.029 1.021
0.93 0.94
918
Kenneth C. Westaway
+
(H) N
+
N
H H H
FIGURE 3. The transition state for the one- and two-proton benzidine rearrangement
The thermal rearrangement of 2,20 -hydrazonapthalene has also been investigated by Shine and coworkers37 . This reaction was of interest because these compounds undergo (i) a high yield of the ortho,ortho0 -rearrangement with virtually no disproportionation in the normal acid-catalyzed reaction, and (ii) a clean thermal ortho,ortho0 -rearrangement (equation 23). In fact, it is believed that the carbazole product is formed from the diamine produced in the rearrangement reaction, so the kinetic isotope effects used to elucidate the mechanism of this reaction are determined only by the rearrangement reaction. NH NH
H+
(23)
NH2
+
NH
NH2
The 2,20 -hydrazonaphthalene doubly labelled with nitrogen-15 for the nitrogen isotope effect experiments and the [1,10 -13 C2 ]-2,20 -hydrazonaphthalene required for measuring the carbon isotope effect were synthesized by the reaction sequence shown in Schemes 18 and 19. The normal acid-catalyzed reaction was carried out at 0 ° C in 70% aqueous dioxane that was 1 ð 103 M in perchloric acid while the thermal rearrangement was carried out in 95% ethanol at 80 ° C. The nitrogen and carbon-13 kinetic isotope effects found in these two rearrangements are presented in Table 2. The large nitrogen and significant carbon13 kinetic isotope effects for both reactions indicate that both the acid-catalyzed and the thermal rearrangements are concerted. The larger nitrogen isotope effect for the acidcatalyzed reaction indicates that the transition state for the acid-catalyzed reaction has more
20. The synthesis and uses of amino and quaternary ammonium salts
919
15NH 2
OH 1.
15
NH4 Cl, A cONa, A cOH
2. H2 O
HCl, Na 15 NO2 15N
NH4 Cl, Zn
15NH
15N
aq. acetone
15NH
SCHEME 18 OH
Br
MgBr Mg
PBr3
dry ether
13
13
CH3
1. 13 CO2
2. HCl
O CH3
Zn (Hg)
13
CO2 H
MSA
HCl
10% Pd/C 13
CH3
13
13
CO2 H
Na 2 Cr2 O7
NH2 OH
H2 SO4
PPA
NaNO2 13
13
N
aq. acetone
N
Zn, NH4 Cl
13
13
NH
SCHEME 19
NH
HCl, 0˚C
NH2
920
Kenneth C. Westaway TABLE 2. The nitrogen and carbon-13 kinetic isotope effects for the acid-catalyzed and for the thermal benzidine rearrangement of 2,20 -hydrazonaphthalene in 70% aqueous dioxane at 0 ° C and in 95% ethanol at 80 ° C, respectively Reaction Acid-catalyzed Thermal
k 14 /k 15
k 12 /k 13
1.090 š 0.004 1.0611 š 0.0001
1.0086 š 0.0004 1.0182 š 0.0001
nitrogen nitrogen bond rupture than the transition state for the thermal rearrangement. Unfortunately, the small carbon isotope effect is consistent with a transition state with either very little or almost complete carbon carbon bond formation. Measuring the secondary hydrogen deuterium kinetic isotope effect for this reaction would probably differentiate between these two possibilities. Nitrogen, carbon-13 and carbon-14 kinetic isotope effects have been determined38 for the analogous acid-catalyzed ortho,ortho0 -rearrangement of the N-2-naphthyl-N0 phenylhydrazine (equation 24). The labelled compounds required for this study were prepared by the sequence of reactions shown in Schemes 20 22.
NH
NH
H+
(24)
NH2 +
NH
NH2
The isotope effects in Table 3 were measured at 0 ° C in 60% aqueous dioxane that was 0.1 M in perchloric acid. The nitrogen isotope effect was determined for both the doubly labelled nitrogen-15 substrate and using the nitrogen gas from a sample with the natural abundance of nitrogen in the starting material. The doubly labelled nitrogen isotope effect was determined by whole-molecule isotope ratio mass spectrometry while that for the unlabelled substrate was measured by converting the nitrogen into nitrogen gas and determining the isotopic composition by isotope ratio mass spectrometry. The carbon-13 isotope effect was obtained by isotope ratio mass spectrometry on CO2 while the carbon-14 isotope effect was measured by a scintillation counting technique. The nitrogen kinetic isotope effect of 1.0197 found using the substrate with the natural abundance of nitrogen isotopes corresponds to an isotope effect of 1.04 for the reaction of the doubly labelled compound. Thus, the nitrogen isotope effects found using two different analytical techniques to measure the isotope effect are in excellent agreement.
20. The synthesis and uses of amino and quaternary ammonium salts 15NH 2
+ O2 15 N 180˚C NaOH 15
15
N
N
aq. acetone Zn, NH4 Cl 15NH
15NH
SCHEME 20
13
13
NH2
N
+ O2 N
N
NaOH 180˚C
aq. acetone
Zn, NH4 Cl
13
NH
SCHEME 21 TABLE 3. The nitrogen, the carbon-13 and carbon14 kinetic isotope effects found for the acid-catalyzed ortho,ortho0 -rearrangement of N-naphthyl-N-phenylhydrazine in 60% aqueous dioxane at 0 ° C Isotope effect 15 N 15 N 15 N 13 C 14 C
N
kL /kH 1.043 š 0.005 1.0197 š 0.0009 1.0042 š 0.0001 1.0142 š 0.0005
NH
921
922
Kenneth C. Westaway +
NH2 O2 N
N2
14
14
O2 N
14
O2 N
HBF 4
H3 PO2
NaNO2
NaOH, 180 °C NH2
N
N
14
aq. acetone Zn, NH4 Cl
NH
NH
14
SCHEME 22
The carbon-13 kinetic isotope effect of 1.0074 estimated33 for this rearrangement using the equation 25 log (k 12 /k 14 )/ log (k 12 /k 13 ) D 1.9 is in reasonable agreement with the observed value of 1.0042. This agreement is satisfactory when one considers that (i) the two isotope effects are very small and that (ii) the carbon isotope effect indicates what is happening at the two carbons that are forming the new carbon carbon bond in the transition state. The nitrogen, carbon-13 and carbon-14 isotope effects clearly indicate that the rearrangement is concerted. However, the large nitrogen isotope effect accompanied by the small carbon isotope effects indicates that the transition state is unsymmetrical. It is worth noting that an unsymmetrical transition state with substantial nitrogen nitrogen bond rupture and a small carbon isotope effect was also found for the acidcatalyzed ortho,ortho0 -rearrangement of the closely related 2,20 -hydrazonaphthalene (vide supra). The nitrogen isotope effect for the 2,20 -hydrazonaphthalene rearrangement is approximately twice that for the N-naphthyl-N-phenylhydrazine rearrangement whereas the carbon-13 kinetic isotope effects are almost identical. The greater amount of nitrogen nitrogen bond rupture in the transition state of the 2,20 -hydrazonaphthalene reaction has been attributed to the fact that the 2,20 -hydrazonaphthalene rearrangement is a two-proton reaction whereas the N-naphthyl-N-phenylhydrazine rearrangement requires only one proton. Another possibility is that nitrogen nitrogen bond rupture has to be more advanced in the 2,20 -hydrazonaphthalene rearrangement so that the two large
20. The synthesis and uses of amino and quaternary ammonium salts
923
naphthalene rings will be close enough to form the new carbon carbon bond in the transition state. Rhee and Shine39 used an impressive combination of nitrogen and carbon kinetic isotope effects to demonstrate that a quinonoidal-type intermediate is formed in the rate-determining step of the acid-catalyzed disproportionation reaction of 4,40 -dichlorohydrazobenzene (equation 26). When the reaction was carried out at 0 ° C in 60% aqueous dioxane that was 0.5 M in perchloric acid and 0.5 M in lithium perchlorate, extensive product analyses indicated that the major pathway was the disproportionation reaction. In fact, the disproportionation reaction accounted for approximately 72% of the product (compounds 6 and 7) while approximately 13% went to the ortho-semidine (8) and approximately 15% was consumed in the para-semidine (9) rearrangement. NH2
Cl
N
N
Cl
(7) Cl (6) H+
Cl
NH
NH
Cl
(26)
H+
NH2 NH
Cl
Cl
NH
NH2
(9) (8) Cl
The doubly nitrogen-15 labelled substrate required for determining the nitrogen isotope effect for this reaction was obtained by the reactions shown in Scheme 2340 . The series of reactions used in the synthesis of the [4,40 -13 C2 ]-4,40 -dichlorohyrazobenzene is shown in Scheme 2440 , and the preparation of the [2-14 C]- and the [4-14 C]-4,40 dichlorohyrazobenzene are described in Schemes 25 and 26. The reaction was second order in acid and first order in substrate, so both rearrangements and the disproportionation reaction proceed via the doubly-protonated hydrazobenzene intermediate formed in a rapid pre-equilibrium step. The nitrogen and carbon-13 kinetic isotope effects were measured to learn whether the slow step of each reaction was concerted or stepwise. The nitrogen and carbon-13 kinetic isotope effects were measured using whole-molecule isotope ratio mass spectrometry of the trifluoroacetyl derivatives of the amine products and by isotope ratio mass spectrometry on the nitrogen and carbon dioxide gases produced from the products. The carbon-12/carbon-14 isotope
924
Kenneth C. Westaway O
Cl
+
C
O
NaOH
15NH Cl 4
Cl
C 15NH 2
Cl
NaOBr
15NH 2
Cl
MnO2
15N
Cl
∆
15N
Cl
aq. acetone Zn, NH4 Cl
15NH
Cl
15NH
Cl
SCHEME 23
O C H3 C
13
C
H NaOH
−
O + O2 N
H3 C
C
13
NO2
H ∆
O
Cl
13
HO
(PhO)3 PCl2
NO2
Sn HCl
Cl
13
NH2
MnO2 ∆
Cl
13
N
N
13
Cl
aq. acetone Zn, NH4 Cl
Cl
13
NH
NH
SCHEME 24
13
Cl
20. The synthesis and uses of amino and quaternary ammonium salts
925
NH2 14
14
NO2
14
NO2
NaNO2 , Cu 2 O
Et 3 N
0˚C, H3 PO2
10% Pd/C
NH2
HOA c A c2 O 14
14
14
NHAc
NH2
NHAc H2 O
NaOCl
H2 SO4
Cl
Cl MnO2 , ∆
NH2
Cl 14
Cl
N
N
aq. acetone
Cl
Zn, NH4 Cl
14
Cl
NH
NH
Cl
SCHEME 25 NO2
NaNO2 , HCl
SnCl2
0˚C, Cu 2 Cl2 14
NH2
NH2
NO2
HCl 14
14
Cl
Cl
MnO2 , ∆
NH2
Cl
Cl
N
aq. acetone
Cl
NH
SCHEME 26
N
14
Cl
NH4 Cl, Zn
NH
14
Cl
926
Kenneth C. Westaway
effects were determined by scintillation counting on the trifluoroacetyl derivatives of the products. The isotope effects for the formation of all three products are presented in Table 4. The nitrogen isotope effects measured by whole-molecule isotope ratio mass spectrometry and by isotope ratio mass spectrometry are in excellent agreement, i.e. the 15 N 15 N kinetic isotope effect should be twice the 15 N kinetic isotope effect for the formation of the disproportionation product and the para-semidine. The large nitrogen isotope effects indicate that there is substantial nitrogen nitrogen bond rupture in the transition state of the rate-determining step for the formation of all three products. However, all of the carbon isotope effects are, within experimental error, unity and the obvious conclusion is that there is no concomitant carbon carbon bond formation in the transition states of any of these reactions. The authors believe this simple explanation is correct for the formation of the ortho-semidine which would occur via an unacceptable concerted 1,3-sigmatropic shift that contravenes orbital-symmetry requirements. However, they are less willing to accept the obvious interpretation for the para-semidine reaction. The authors suggest that the lack of a carbon isotope effect in the formation of the para-semidine (9) might be observed because of the cancellation of two isotope effects. This seemed possible because the formation of 9 could arise by an allowed concerted 1,5-sigmatropic shift. Finally, the disproportionation reaction is thought to proceed by a multistep mechanism where the formation of the 4,40 -quinonoidal intermediate 10 (equation 27) is the slow step of the reaction. The para-semidine and the disproportionation products are then formed by a rapid oxidation of 10 by a second molecule of starting material (equations 28 and 29), respectively. + NH2
Cl
+ NH2
Cl
(27)
Cl
+ NH2
+ NH2
Cl
(10)
+ NH2
Cl
+ NH2
Cl
NH
NH2
Cl HCl + 2H+
H
H N
N Cl
Cl
(28)
Cl
N
N
Cl
1.028 š 0.007
1.026 š 0.003
15 N 15 Na
1.014 š 0.0015 1.0155 š 0.0003 1.0162 š 0.0005
15 Nb
1.033
1.028
(15 N)2 calc
Isotope effect
a These 15 N 15 N kinetic isotope effects were measured by whole-molecule isotope ratio mass spectrometry. b These 15 N and 12 C/13 C kinetic isotope effects were determined by isotope ratio mass spectrometry. c These 12 C/14 C kinetic isotope effects were determined by scintillation counting.
Disproportionation o-Semidine p-Semidine
Reaction 1.002 š 0.002 0.9993 š 0.0009 0.997 š 0.003
4,40 -13 C2 b
1.000 š 0.001 1.000 š 0.002
2-14 Cc
0.997 š 0.002 1.003 š 0.004 1.001 š 0.003
4-14 Cc
TABLE 4. The nitrogen, carbon-13 and carbon-14 kinetic isotope effects found for the acid-catalyzed formation of the disproportionation product, the orthosemidine and the para-semidine at 0 ° C in 60% aqueous dioxane that was 0.5 M in perchloric acid and 0.5 M in lithium perchlorate
927
928
Kenneth C. Westaway
+ NH2
Cl
Cl
+ NH2
H
H N
N
Cl
Cl
(29) + NH3
+
2
Cl
N
N
Cl
Cl
The most recent addition to Shine’s extensive study of the benzidine-type rearrangements41 involved remeasuring the nitrogen and the carbon-13 and carbon-14 kinetic isotope effects at the 4- and at the 4- and 40 -carbons as well as determining the carbon-13 and carbon-14 isotope effects at the 1- and at the 1- and 10 -carbons in the benzidine rearrangement of hydrazobenzene (equation 30). The reaction, which was carried out in 75% aqueous ethanol that was 0.1 M in hydrochloric acid and 0.3 M in lithium chloride at 0 ° C, gave an 86% yield of benzidine (11) and a 14% yield of diphenyline (12). The kinetic isotope effects found for the formation of benzidine and diphenyline under these reaction conditions are presented in Table 5.
H2 N
NH
NH
NH2 (11)
H+
NH2
(30)
H2 N
(12)
The significant nitrogen, carbon-13 and carbon-14 kinetic isotope effects at the 4- and at the 4 and 40 -positions for the formation of benzidine (11) indicate that benzidine is formed in a concerted reaction. The small, but real, carbon-13 and carbon-14 kinetic
20. The synthesis and uses of amino and quaternary ammonium salts
929
TABLE 5. The nitrogen, carbon-13 and carbon-14 kinetic isotope effects found for the acid-catalyzed benzidine rearrangement of hydrazobenzene in 75% aqueous ethanol that was 0.1 M in hydrochloric acid and 0.3 M in lithium chloride at 0 ° C Substratea
Isotope effect
15 N,15 N0
k 14 /k 15
4,40 -13 C2 4-14 C 1,10 -13 C2 1-14 C
k 12 /k 13 k 12 /k 14 k 12 /k 13 k 12 /k 14
Benzidine š 0.0009b
1.0410 1.0127 š 0.0011b 1.0121 š 0.0008c 1.0035 š 0.0010b 1.0051 š 0.0017c
Diphenyline 1.0367 š 0.0009b 1.001 š 0.001b 1.001 š 0.001c 1.000 š 0.003b 0.999 š 0.002c
a The preparation of these labelled substrates has been described previously. b The nitrogen and carbon-13 kinetic isotope effects found using the 15 N 15 N, the 1,10 13 C and the 4,40 -13 C substrates were measured by whole-molecule isotope ratio mass 2 2
spectrometry on the bis-(trifluoroacetyl) derivative. c The carbon-12/carbon-14 kinetic isotope effects found using the 1-14 C and the 4-14 C substrates were determined by scintillation counting on the bis-(trifluoroacetyl) derivative.
isotope effects found at the 1- and the 1- and 10 -positions in the formation of benzidine also suggest a concerted mechanism for the formation of benzidine. The reasonably large nitrogen isotope effect and small carbon isotope effects indicate that nitrogen nitrogen bond rupture is well advanced compared to carbon carbon bond formation, i.e. both the nitrogen nitrogen and the carbon carbon bonds are long and weak in the transition state of the rearrangement reaction forming benzidine (equation 31).
H δ+ N
NH
NH
H
H
+ NH2
2H+
H N δ+
+ NH2
2+
+ NH2
+ NH2
(31)
δ+
δ+
H
H −2H
H2 N
+
NH2
The absence of both carbon-13 and carbon-14 kinetic isotope effects at the 1-, the 1and the 10 -, the 4- and the 4- and 40 -carbons in the formation of diphenyline (12) confirms beyond any doubt that this compound is formed in a two-step rearrangement. Thus, the nitrogen nitrogen bond ruptures in the slow step of the reaction and then the product is
930
Kenneth C. Westaway
formed in a fast intramolecular step (equation 32).
NH
+ NH2
+ 2H+
NH
2
(32)
slow
+ NH2
+ NH2
NH2 −2H+
H2 N
Finally, it is interesting that the nitrogen isotope effects for the formation of benzidine and diphenyline are almost identical. This suggests that both reactions have almost the same amount of nitrogen nitrogen bond rupture in the transition state of the ratedetermining step. Boduszek and Shine42 studied the acid-catalyzed quinamine rearrangement of the quinamine, 6-bromo-2,4-dimethyl-4-(phenylamino)cyclohexa-1,4-dienone (13), to 40 -amino-6-bromo-2,4-dimethyldiphenyl ether (equation 33). This study involved synthesizing the quinamine 13 (Scheme 27) labelled at (i) the nitrogen with nitrogen15, (ii) the para-position of the phenyl ring with carbon-14, (iii) the ortho position of the phenyl ring with carbon-14 and (iv) the carbonyl oxygen with oxygen-18. Br Br
CH3 O NH
H+
H2 N
O
CH3
CH3
(33) (13)
CH3
The labelled substrates required for this study were obtained by substituting (i) the commercially available 15 N-aniline, (ii) the [4-14 C]aniline prepared by deaminating the commercially available 4-nitro[1-14 C]aniline and reducing the nitro group with tin and HCl, (iii) the [2-14 C]aniline formed by reducing the commercially available [2-14 C]nitrobenzene with tin and HCl and (iv) the 2,4-dimethyl[18 O]phenol, respectively, in the synthesis described in Scheme 27. The 2,4-dimethyl[18 O]phenol was synthesized by diazotizing 2,4-dimethylaniline with sodium nitrite and fluoroboric acid and treating the diazonium salt with oxygen-18 labelled water. Miller43 showed that the quinamine rearrangement was intramolecular and that the reaction was first order in both the quinamine and acid. The isotope effects found for this quinamine rearrangement were measured in 83.3% aqueous methanol at 25 ° C. The nitrogen isotope effect of 1.0089, the oxygen-18 isotope effect of 1.0399 and the carbon-14 isotope effect of 1.0501 at carbon-4 of the phenyl ring, found for this quinamine rearrangement, show that the nitrogen carbon-1 bond is breaking and that the carbon-4 oxygen bond is forming in the transition state of the rate-determining step of this reaction. This clearly indicates that the quinamine rearrangement is concerted. However, the nitrogen
20. The synthesis and uses of amino and quaternary ammonium salts
931
Br
HO
Br2
CH3
HO
CH3
CH3
CH3 Br2 , HOA c NaOA c, − 5 °C
Br
Br CH3
, NaOA c
NH2
CH3
O
O
− 5 °C
Br
NH
CH3
CH3 SCHEME 27
kinetic isotope effect is much smaller than either the oxygen-18 or the carbon-14 isotope effect at carbon-4 of the phenyl ring. This suggests the slow step of the quinamine rearrangment involves a [5,5]sigmatropic shift via an unsymmetrical transition state with only a slight amount of carbon nitrogen bond rupture but extensive carbon oxygen bond formation (equation 34).
CH3
NH
+ NH2
CH3
H+
Br
Br
CH3 O
CH3 O CH3
(34)
+
CH3 NH2
Br −H +
Br
CH3
CH3 O
O H
NH2
932
Kenneth C. Westaway
Finally, although a very small inverse k 12 /k 14 isotope effect of 0.990š0.008 was found when the substrate with carbon-14 at the 2-position of the phenyl ring was used, the authors concluded that there was no carbon-14 isotope effect in the quinamine rearrangement to the phenyl ether. This was expected because no bond forms at carbon-2 in the transition state of the concerted [5,5]sigmatropic rearrangement. The authors attributed this very small inverse isotope effect of 0.990 to a large k 12 /k 14 D 1.07 that was observed for the formation of a side product. The faster reaction of carbon-12 in forming the side product would enrich the unreacted substrate in carbon-14 and lead to the inverse isotope effect. IV. USING KINETIC ISOTOPE EFFECTS TO MODEL THE SN 2 TRANSITION STATES FOR REACTIONS INVOLVING QUATERNARY AMMONIUM SALTS A. The Menshutkin Reaction
Matsson and coworkers have measured the carbon-11/carbon-14 kinetic isotope effects for several Menshutkin reactions (equation 35) in an attempt to model the SN 2 transition state for this important class of organic reaction. These isotope effects are unusual because they are based on the artificially-made radioactive carbon-11 isotope. The radioactive carbon-11 isotope is produced in a cyclotron or linear accelerator by bombarding nitrogen14 atoms with between 18- and 30-MeV protons (equation 36). CH3 R
N
+
R′CH2
X
+ N
R′CH2
CH3 14 N
+
p+
11C
+
CH3 R X− CH3
(35)
(36)
He
The 11 C decays with a half-life of 20.34 minutes, to 11 B, by emitting a positron that can be detected in a scintillation counter. In spite of the difficulties in producing the carbon-11 isotope, preparing the labelled substrate and carrying out the reaction in a very short time, these carbon-11/carbon-14 kinetic isotope effects are a very useful addition to the arsenal of tools available to the physical organic chemist. This is because the difference in mass between the carbon isotopes is three in a mass of only eleven. As a result, these isotope effects can be as large as 25%, which is in the range of some of the larger secondary hydrogen deuterium kinetic isotope effects. This means that these extremely large heavy-atom kinetic isotope effects should be capable of detecting very small changes in the structure of SN 2 transition states. The first report of this new type of kinetic isotope effect in a Menshutkin reaction was published by Matsson and coworkers in 198744 . In this study, the alpha carbon k 11 /k 14 kinetic isotope effect was measured for the Menshutkin reaction between N,Ndimethyl-para-toluidine and labelled methyl iodide in methanol at 30 ° C (equation 35). The carbon-11 labelled methyl iodide required for this study was prepared from the 11 C atoms produced in the cyclotron in three steps45 (equation 37). 11
C C O2 !
11
LiAlH4
CO2 ! THF
11
HI
CH3 OH !
11
CH3 I
37
The carbon-14 labelled methyl iodide used to measure the k 11 /k 14 was commercially available.
20. The synthesis and uses of amino and quaternary ammonium salts
933
The very large carbon-11/carbon-14 isotope effect of 1.202 š 0.008 is almost twice the magnitude of the carbon-12/carbon-14 isotope effect of 1.12š0.01 measured for the same reaction at 48.5 ° C. This clearly illustrates the usefulness of this new type of very large heavy-atom isotope effect. A comparison of these two isotope effects is possible using the Swain Schaad equation33 . If one estimates the value of the k 11 /k 14 isotope effect using the Swain Schaad equation33 and the k 12 /k 14 D 1.12, the k 11 /k 14 isotope effect should be 1.21. Given that the Swain Schaad equation is only approximate, the agreement with the observed k 11 /k 14 D 1.0202 is excellent and it is safe to conclude that the Menshutkin reaction has a very large alpha carbon isotope effect and a fairly symmetrical transition state. Matsson and coworkers also used BEBOVIB IV calculations to model the transition state for this reaction46 . The calculations and their observed k 11 /k 14 D 1.0202 suggested that the transition state is early with a nitrogen alpha carbon bond order of approximately 0.3 and an alpha carbon iodide bond order of approximately 0.7. It is worth noting that Yamataka and coworkers47 also found large (near the theoretical maximum) alpha carbon kinetic isotope effects for the Menshutkin reactions between 3,5-disubstituted pyridines and methyl iodide (equation 38, Table 6). Although the alpha carbon kinetic isotope effects increase slightly as more electronwithdrawing substituents are added to the nucleophile, they are all large and effectively constant for a wide range of nucleophiles. For example, the isotope effect only changes by 0.013 when the rate constant decreases 340 times, i.e. the rate of the reaction with 3,5dimethylpyridine is 340 times larger than the rate of the reaction with 3,5-dichloropyridine. This suggests that the transition state for the Menshutkin reaction is not very susceptible to changes in the structure of the reactants. Other types of kinetic isotope effects have been measured in an attempt to determine the structure of the transition states of Menshutkin reactions. For example, Bourns and Hayes1 and Kurz and coworkers48,49 found very small incoming nucleophile nitrogen kinetic isotope effects in Menshutkin reactions (Table 7). These very small isotope effects, which are only slightly larger than the error of the measurements, are not affected significantly by a change in the leaving group, the solvent or even the substrate. It is important to note, however, that these very small incoming nucleophile nitrogen kinetic isotope effects indicate that the transition state is early with only a small amount of nitrogen alpha carbon bond formation. In fact, BEBOVIB IV calculations suggest that the nitrogen alpha carbon bond order in these transition states is between 0.2 and 0.3. This is in excellent agreement with the results from Matsson’s BEBOVIB IV calculations46 . Other workers have concluded that the transition state for the Menshutkin reaction is late with more nitrogen alpha carbon bond formation than alpha carbon leaving group bond rupture. For instance, Harris and coworkers51 found that the secondary alpha deuterium kinetic isotope effects (Table 8) decreased when a poorer nucleophile was used in the SN 2 reactions between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25 ° C (equation 38, Table 8).
X N Y
+
CH3
I
CH3
+ N
I−
(38)
934
Kenneth C. Westaway TABLE 6. The alpha carbon-12-carbon-13 kinetic isotope effects for the Menshutkin reaction between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25 ° C 3-X
5-Y
(k 12 /k 13 )˛
CH3 CH3 H Cl Cl
CH3 H H H Cl
1.063 š 0.004 1.062 š 0.002 1.066 š 0.005 1.074 š 0.002 1.076 š 0.016
TABLE 7. The incoming nucleophile nitrogen kinetic isotope effects in Menshutkin reactions with various amines in several solvents Nucleophile (amine) 4-Methylpyridine Pyridine
3-Acetylpyridine 2,6-Dimethylpyridine Quinuclidine N,N-Dimethyl-4-toluidine Et3 N Me3 N
a
Substrate
Solvent
k 14 /k 15
CH3 OMs CH3 OTf CH3 OMs CH3 OTs CH3 OTf CH3 OTs CH3 OTf CH3 OTs CH3 OTf CH3 OTf CH3 OTf CH3 Cl CH3 Br CH3 I CH3 ThC CH3 ThC CH3 OMs CH3 OBr CH3 OMs CH3 OTs CH3 OTf CH3 OMs CH3 OMs CH3 OMs CH3 OMs BzOBs CH3 I CH3 CH2 I CH3 CH2 Br
H2 O MeCN H2 O H2 O H2 O H2 O H2 O H2 O H2 O MeCN DCE H2 O H2 O H2 O H2 O MeCN H2 O H2 O H2 O H2 O MeCN H2 O MeCN MeCN (wet) MeCN Me2 CDO Benzene Benzene Benzene
0.9969 0.9937 0.9971 0.9978 0.9965 0.9978 0.9965 0.9978 0.9965 0.9946 0.9942 0.9960 0.9972 0.9950 0.9976 0.9964 0.9972 0.9972 0.9978 0.9977 0.9941 1.0002b 0.9962b 1.0024b 1.0027b 1.0028c 1.0009d 1.0015d 0.9991d
a Reference 48. b Reference 49. c Reference 50. d Reference 1.
TABLE 8. The secondary alpha hydrogen deuterium kinetic isotope effects for the Menshutkin reaction between 3,5-disubstituted pyridines and methyl iodide in 2-nitropropane at 25 ° C 3-X
5-Y
(kH /kD )˛
CH3 CH3 H Cl Cl
CH3 H H H Cl
0.908 0.851 0.850 0.835 0.810
20. The synthesis and uses of amino and quaternary ammonium salts
935
The important observation is that all of the isotope effects are large and inverse. Thus, the transition states in these reactions must obviously be very crowded, i.e. the C˛ H(D) out-of-plane bending vibrations in the transition state must be high energy19 . As a result, these workers concluded that nitrogen alpha carbon bond formation is more advanced than alpha carbon iodine bond rupture in the transition state. It is interesting, however, that these authors also concluded that the NC˛ bond formation is approximately 30% complete in the transition state. In another study, Paneth and O’Leary52 measured the incoming nucleophile nitrogen and the secondary alpha hydrogen deuterium kinetic isotope effects for the Menshutkin reaction between N,N-dimethyl-para-toluidine and methyl iodide in methanol at 25 ° C. They found a very small nitrogen kinetic isotope effect of 1.0019 š 0.001 in good agreement with the isotope effects reported by Kurz and coworkers48,49 . The secondary alpha deuterium kinetic isotope effect for this reaction was 0.83 š 0.04, in good agreement with the isotope effects reported by Harris and coworkers51 . This indicated that the transition state was sterically crowded and Paneth and O’Leary concluded that the transition state was symmetrical or slightly late with nitrogen alpha carbon bond formation advanced with respect to alpha carbon iodide bond rupture. Ando, Tanabe and Yamataka53 measured both the carbon-12/carbon-14 and the secondary alpha hydrogen-tritium kinetic isotope effects for the Menshutkin reactions between substituted N,N-dimethylanilines and substituted benzyl benzenesulfonates in acetone at 35 ° C (equation 39). They found large carbon-12/carbon-14 isotope effects and small secondary alpha tritium isotope effects for these reactions (Table 9). The carbon-12/carbon-14 isotope effects for these reactions are all large, i.e. they are near the theoretical maximum for these isotope effects. Thus, these isotope effects agree, in general, with the large k 11 /k 14 isotope effect reported by Matsson and coworkers (vide supra). It is important to note that the carbon isotope effects go through a maximum when the leaving group is changed in the reactions between benzyl para-substituted benzenesulfonates and N,N-dimethyl-paratoluidine. This was the first illustration that alpha carbon kinetic isotope effects in SN 2 TABLE 9. The carbon-12/carbon-14 and secondary alpha hydrogen tritium kinetic isotope effects for the SN 2 reactions between Y-substituted N,N-dimethylanilines and Zsubstituted benzyl X-substituted benzensulfonates in acetone at 35 ° Ca Z D m-Br Y p-CH3 O p-CH3 O p-CH3 O p-CH3 p-CH3 p-CH3 p-CH3 p-CH3 H H H m-CH3 p-Br m-NO2
ZDH
X
k 12 /k 14
(kH /kT )˛
k 12 /k 14
(kH /kT )˛
p-Cl H p-CH3 m-NO2 p-Cl H p-CH3 p-CH3 O m-NO2 p-Cl H p-Cl p-Cl m-NO2
1.130
1.033
1.061
1.151 1.148 1.137 1.141 1.141
1.041 1.026 1.030 1.031
1.142 1.140 1.148 1.119 1.149 1.162 1.156 1.147 1.158 1.143 1.135
1.129 1.117
1.033
1.139 1.127
1.056 1.055 1.043 1.033 1.035 1.042 1.048
a The errors in the k 12 /k 14 are between š0.003 and š0.005 while those for the (k /k ) range from H T ˛ š0.008 to š0.012.
936
Kenneth C. Westaway
reactions pass through a maximum as the theoretical calculations suggested10,11 .
N(CH3 )2 Y
+
CH2
O
SO2 X
Z
(39) + CH2 N(CH3 )2
O
SO2 X
Y
Z
The secondary alpha tritium isotope effects, on the other hand, are small. Benzyl substrates have looser SN 2 transition states than methyl substrates (vide infra) and thus these reactions would be expected to have slightly larger isotope effects than methyl substrates. Thus, these tritium isotope effects are in general agreement with those found by Paneth and O’Leary52 and by Harris and coworkers51 in other Menshutkin reactions (vide supra). It is worth nothing that the tritium isotope effects are smaller for the meta-bromobenzyl benzenesulfonates than for the benzyl benzenesulfonates. This is expected because the transition state is invariably tighter with a shorter nucleophile-leaving group distance, when a more electron-withdrawing substituent is on the phenyl ring on the alpha carbon. Finally, although the transition states in these Menshutkin reactions appear to be slightly looser than those found for the methyl substrates in other studies, these isotope effects are consistent with a transition state with significant nitrogen alpha carbon bond formation and less alpha carbon oxygen bond rupture. The newest type of isotope effect that has been used to characterize the transition state of the Menshutkin reaction is a secondary incoming nucleophile hydrogen deuterium kinetic isotope effect54 . These isotope effects involve using primary amines labelled with deuterium at the nitrogen as the nucleophile (equation 40). In fact, Lee and collaborators54 measured both the secondary alpha hydrogen deuterium and the secondary hydrogen deuterium incoming nucleophile kinetic isotope effects for four different Menshutkin reactions (Table 10). The secondary alpha deuterium isotope effects for the benzyl benzenesulfonate reactions are fairly large and normal, indicating that these reactions have a loose transition state with long nucleophile alpha carbon and alpha carbon leaving group bonds. The methyl and ethyl substrate reactions, on the other hand, have inverse secondary alpha deuterium isotope effects like those found in the other Menshutkin reactions (vide supra). These inverse isotope effects indicate that these reactions have tight transition states with short nucleophile alpha carbon and alpha carbon leaving group bonds. NL2 + RCH2 OSO2
Y
Z
(40) + RCH2 NL2 L = H, D
Y
OSO2
Z
20. The synthesis and uses of amino and quaternary ammonium salts
937
TABLE 10. The secondary alpha deuterium and secondary incoming nucleophile deuterium kinetic isotope effects found for the SN 2 reactions between para-substituted anilines and benzylamines with benzyl, methyl and ethyl para-substituted benzensulfonates in acetonitrile at 30 ° C Substituent on the nucleophile
para-Substituent on the leaving group
(kH /kD )˛
(kH /kD )aNucl
Benzyl para-substituted benzenesulfonates with para-substituted anilines CH3 1.089 š 0.005 0.973 m-NO2 CH3 1.096 š 0.009 0.955 p-CH3 O m-NO2 NO2 1.095 š 0.010 0.951 NO2 1.102 š 0.010 0.898 p-CH3 O Benzyl para-substituted benzenesulfonates with para-substituted benzylamines CH3 0.966 m-NO2 CH3 0.952 p-CH3 O NO2 0.953 m-NO2 p-CH3 O NO2 0.940 Methyl para-substituted benzenesulfonates with para-substituted anilines CH3 0.971 š 0.009 0.963 š 0.009b m-NO2 p-CH3 O CH3 0.990 š 0.008 0.978 š 0.008b m-NO2 NO2 0.974 š 0.007 0.968 š 0.009b p-CH3 O NO2 0.993 š 0.007 0.984 š 0.007b Ethyl para-substituted benzenesulfonates with para-substituted anilines CH3 0.963 š 0.009 0.851b m-NO2 p-CH3 O CH3 0.978 š 0.008 0.862b m-NO2 NO2 0.968 š 0.009 0.858b p-CH3 O NO2 0.984 š 0.007 0.869b a The authors did not give error limits for most of these isotope effects. They imply that the error is less
than 1%.
b At 65 ° C.
The secondary incoming nucleophile deuterium kinetic isotope effects are all inverse. This is because both the NH(D) bending and stretching vibrations become higher in energy in the transition state as the steric crowding increases (the nitrogen alpha carbon bond forms). Obviously, when the nitrogen alpha carbon bond formation is more complete in the transition state, the steric crowding around the NH(D) bonds will be greater and the isotope effect will be more inverse. Thus, these new isotope effects are useful because they indicate the degree of nitrogen alpha carbon bond formation in the transition state. The authors concluded that the transition states for the Menshutkin reactions of the benzyl substrates were early (reactant-like) with nitrogen alpha carbon bond formation lagging behind alpha carbon oxygen bond rupture. The transition states for the Menshutkin reactions with the methyl and ethyl substrates, on the other hand, are tight (product-like) with nitrogen alpha carbon bond formation greater than alpha carbon oxygen bond rupture. Finally, it is worth noting that the substituent effects are different on the two types of Menshutkin reactions as well. For the benzyl substrates, changing to a better nucleophile, i.e. changing the substituent on the nucleophile from the meta-nitro to a para-methoxy substituent, leads to a later, more product-like transition state with more inverse secondary incoming nucleophile deuterium kinetic isotope effects. However, the same change in nucleophile in the reactions with the methyl and ethyl substrates leads to an earlier transition state and less inverse secondary incoming nucleophile deuterium kinetic isotope effects.
938
Kenneth C. Westaway TABLE 11. The carbon-11/carbon-14 kinetic isotope effects for the SN 2 reactions between several amine nucleophiles and the labelled methyl iodide in dimethoxyethane or acetonitrile at 15 ° C and 30 ° C, respectively Nucleophile (CH3 CH2 )3 N Quinuclidine 2,6-Lutidine 2,4-Lutidine
Solvent
Temperature
k 11 /k 14
pKa
DME DME acetonitrile acetonitrile
15.00 15.00 30.00 30.00
1.221 š 0.006 1.220 š 0.005 1.220 š 0.009 1.189 š 0.012
10.65 10.95 6.77 6.72
Finally, Persson, Berg and Matsson55 measured the k 11 /k 14 isotope effects for the SN 2 reactions between several amine nucleophiles and labelled methyl iodide in dimethoxyethane or acetonitrile at 15 ° C and 30 ° C, respectively, to determine how sterically crowded nucleophiles affected the structure of the transition state of a Menshutkin reaction. The results in Table 11 show that the k 11 /k 14 isotope effects for these reactions are large. In fact, they are all near the theoretical maximum value for these isotope effects. Secondly, the isotope effect for the reaction with the more sterically hindered amine, 2,6-lutidine, is larger than that for the less sterically hindered 2,4-lutidine. It is worth noting that 2,6-lutidine and 2,4-lutidine have almost the same pKa , so there is little or no electronic effect in these reactions. Le Noble and Miller56 found a larger chlorine leaving group isotope effect (k 35 /k 37 D 1.0038 š 0.0003) for the 2,6-lutidine methyl chloride reaction than for the corresponding pyridine reaction (k 35 /k 37 D 1.00355 š 0.00008) in bromobenzene at 100 ° C. Thus, it appears that the carbon chlorine bond rupture is more advanced in the reaction with the more sterically crowded nucleophile, although the difference could be due to the fact that 2,6-lutidine is also a better nucleophile than pyridine. Also, the nitrogen incoming nucleophile kinetic isotope effects measured by Kurz and coworkers48,49 and by Bourns and Hayes1 (see above) indicated that nitrogen alpha carbon bond formation is not well advanced in the transition state. These isotope effects suggest that the transition state for the reaction with the more sterically hindered nucleophile is loose with longer nitrogen-alpha carbon and alpha carbon-chlorine bonds. Finally, theoretical calculations also suggested a looser transition state should be found when a more sterically crowded nucleophile was used in this reaction, and the authors concluded that the transition state for these reactions were early but that the reaction, with the more sterically crowded nucleophile and the larger alpha carbon k 11 /k 14 isotope effect, was looser. Unfortunately, the same trend in the k 11 /k 14 isotope effects is not observed in the triethylamine/quinuclidine reactions with methyl iodide, although it is possible that the identical isotope effects may be due to the cancellation of two effects, a steric effect and an electronic effect, i.e. triethylamine is both a stronger base and a more sterically crowded nucleophile. It is interesting that the chlorine leaving group kinetic isotope effects are also different for these two reactions. Swain and Hershey57 found a larger chlorine leaving group isotope effect in the reaction of the less sterically hindered nucleophile, quinuclidine (k 35 /k 37 D 1.0071 š 0.0001), than for the corresponding triethylamine methyl chloride reaction (k 35 /k 37 D 1.00640 š 0.00009). B. The SN 2 Reactions of Quaternary Ammonium Salts Westaway and coworkers have measured the secondary alpha deuterium and nitrogen leaving group kinetic isotope effects for the SN 2 reactions between thiophenoxide ions and benzyldimethylphenylammonium ion to learn how ion-pairing, a change in solvent or substituents in the nucleophile, the substrate and the leaving group affect the structure of SN 2 transition states.
20. The synthesis and uses of amino and quaternary ammonium salts
939
In one study to determine how a change in nucleophile affected the structure of the SN 2 transition state, the secondary alpha deuterium and nitrogen leaving group kinetic isotope effects for the SN 2 reactions between several para-substituted thiophenoxide ions and benzyldimethylphenylammonium ion (equation 41) were measured at 0 ° C in DMF containing a high concentration of sodium nitrate to keep the ionic strength constant, so accurate rate constants could be determined58 . Surprisingly, the nitrogen leaving group and the secondary alpha deuterium kinetic isotope effects for these reactions (Table 12) were identical. Two explanations for the identical secondary alpha deuterium and nitrogen kinetic isotope effects are possible. One possibility is that the transition states do not change when the substituent on the nucleophile is altered. This suggestion seems highly unlikely, however, because no one has observed this behavior in any study, and it is unreasonable to conclude that a change in nucleophile, which changes the rate constant by a factor of 6.4, would not alter the energy (structure) of the transition state, thereby causing a change in the isotope effects. The second, more likely, possibility is that the change in nucleophile changes the transition state but that the changes that occur in transition state structure do not cause a change in the isotope effect. If one assumes that the nitrogen leaving group kinetic isotope effects can be interpreted in the usual fashion, i.e. that the magnitude of the isotope effect increases with the percent C˛ - - -N bond rupture in the SN 2 transition state10 , then all three reactions have identical amounts of C˛ - - -N bond rupture in the transition state. If this is the case, interpreting the secondary alpha hydrogen deuterium isotope effects is not straightforward. If a SN 2 transition state were unsymmetrical and the bond to one of the nucleophiles was very long, the magnitude of the isotope effect would be determined by the length of the shorter reacting bond, because the second nucleophile in the SN 2 transition state is too far away to affect the C˛ H(D) out-of-plane bending vibrations that determine the magnitude of the isotope effect19 (Figure 4). S− + C6 H5CH2
Z
+ N(CH3 )2 C6 H5
(41) Z
S
CH2 C6 H5 + (CH3 )2 NC6 H5
The nitrogen (leaving group) kinetic isotope effects indicate that there is no change in the amount of C˛ - - -N bond rupture in the SN 2 transition state when the substitutent in the TABLE 12. The nitrogen (leaving group) and secondary alpha hydrogen deuterium kinetic isotope effects for the SN 2 reactions between several para-substituted sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at 0 ° C para-Substituent on the thiophenoxide ion CH3 O H Cl
k 14 /k 15 š 0.0007a
1.0162 1.0166 š 0.0004 1.0166 š 0.0005
(kH /kD )˛ 1.221 š 0.012b 1.215 š 0.011 1.215 š 0.013
a The standard deviations of the mean of at least four separate experiments. b The error in the isotope effect D 1/k [k 2 C k /k 2 ð k 2 ]1/2 D H H D D where kH and kD are the standard deviations for the rate constants for the
undeuterated and deuterated substrates, respectively.
940
Kenneth C. Westaway H
S
Cα
N
FIGURE 4. Showing how the magnitude of a secondary alpha hydrogen deuterium kinetic isotope effect can be determined by the length of the shorter reacting bond rather than by the nucleophile leaving group distance in an unsymmetrical SN 2 transition state
nucleophile is altered. Moreover, the amount of C˛ - - -N bond rupture in the SN 2 transition state is not large because the nitrogen isotope effect is only approximately one-third of the theoretical maximum nitrogen leaving group kinetic isotope effect of 1.04459 . Also, the nitrogen isotope effects found when thiophenoxide ion was the nucleophile in these reactions (k 14 /k 15 D 1.0166 š 0.0004) is significantly smaller than the 1.0200 š 0.0007 found for the same reaction in DMF at an ionic strength of 0.64 (Table 13)60 . Thus, it appears that C˛ - - -N bond rupture is not well advanced in these transition states (the transition states are reactant-like). The secondary alpha hydrogen deuterium kinetic isotope effects for these reactions, on the other hand, are very large, indicating the transition states are very loose with long S- - -N distances. Since the C˛ - - -N bonds are short, the S- - -C˛ bonds must be very long in these transition states. This conclusion is warranted because the secondary alpha hydrogen deuterium kinetic isotope effects found for the reaction with thiophenoxide ion in this study [kH /kD ˛ D 1.22 š 0.01] is the largest that has been found for an SN 2 reaction of a quaternary ammonium ion. Moreover, the kH /kD ˛ of 1.22 š 0.01 found in this study is significantly larger than that [kH /kD ˛ D 1.179 š 0.0071 ] found for the same reaction at an ionic strength of 0.640 (Table 13). The Hammett D 1.62 š 0.01 in the reaction where kH /kD ˛ D 1.22, whereas a larger Hammett value of 1.76 š 0.19 was found in the reaction with kH /kD ˛ D 1.179. Since a larger value is observed when the change in charge on going from the reactants to the transition state is larger, i.e. when there is more nucleophile alpha carbon bond formation in the transition state, the reaction with the larger (kH /kD )˛ must have the longer S- - -C˛ transition state bond. TABLE 13. The secondary alpha hydrogen deuterium and primary nitrogen kinetic isotope effects for the SN 2 reaction between sodium thiophenoxide and benzyldimethylphenylammonium nitrate at different ionic strengths in DMF at 0 ° C Ionic strength 0.904 0.64
(kH /kD )˛ 1.215 š 0.011a 1.179 š 0.007a
k 14 /k 15 š 0.0004b
1.0166 1.0200 š 0.0007b
Hammett 1.62 š 0.01c 1.79 š 0.19c
a The error in the isotope effect D 1/k [k 2 C k /k 2 ð k 2 ]1/2 where k and k D H H D D H D
are the standard deviations for the rate constants for the undeuterated and deuterated substrates, respectively. b The standard deviation of the mean of five different measurements. c The correlation coefficients for the Hammett plots found by changing the para-substituent in the nucleophile are 1.000 for the reaction at an ionic strength of 0.904 and 0.994 for the reaction at an ionic strength of 0.64.
20. The synthesis and uses of amino and quaternary ammonium salts
941
The most reasonable explanation for the constant nitrogen and secondary alpha deuterium kinetic isotope effects found in these reactions is that changing the substituent in the nucleophile does not affect the amount of C˛ - - -N bond rupture in the transition state but changes the length of the S- - -C˛ transition state bond significantly. However, these changes in the length of the S- - -C˛ transition state bond occur too far from the alpha carbon to affect the C˛ (H)D out-of-plane bending vibrations (the magnitude of the secondary alpha hydrogen deuterium kinetic isotope effect). As a result, the magnitude of the secondary alpha deuterium kinetic isotope effect is only determined by what happens to the shorter C˛ - - -N bond when the substituent is changed and, since the C˛ - - -N bond does not change when the substituent in the nucleophile is altered, the magnitude of the secondary alpha deuterium kinetic isotope effect does not change when the substituent on the nucleophile is altered. These conclusions are interesting because they are consistent with the predictions of the ‘Bond Strength Hypothesis’61 which suggests that ‘there will be a significant change in the weaker reacting bond but little or no change in the stronger reacting bond in an SN 2 transition state when a substitutent in the nucleophile, the substrate, or the leaving group is altered in an SN 2 reaction’. Since the carbon sulfur bond is weaker than the carbon nitrogen bond in these SN 2 reactions61 , the ‘Bond Strength Hypothesis’ would predict that adding an electron-withdrawing group to the nucleophile should not affect the alpha carbon-leaving group (C˛ - - -N) bond significantly but should lead to a significant change in the length of the weaker S- - -C˛ bond. It is interesting that these are the exact changes suggested on the basis of the isotope effects. Finally, another interesting conclusion is that the shortest bond in these SN 2 transition states is the strongest bond, i.e. the stronger C˛ - - -N bond is the shorter reacting bond and the weaker S- - -C˛ bond is longer in the transition state. The nucleophile in the SN 2 reactions between benzyldimethylphenylammonium nitrate and sodium para-substituted thiophenoxides in methanol at 20 ° C (equation 42) can exist as a free thiophenoxide ion or as a solvent-separated ion-pair complex (equation 43)62,63 . The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for these SN 2 reactions were determined to learn how a substituent on the nucleophile affects the structure of the SN 2 transition state for the free ion and ion-pair reactions64 . −
Z
S
+ C6 H5CH2
+ N(CH3 )2 C6 H5
(42) Z
+
xM
+
−
x SC6 H5
S
+
CH2 C6 H5 + (CH3 )2 NC6 H5 −
[M (solvent)y SC6 H5] x
(43)
The secondary alpha deuterium kinetic isotope effects for both the ion pair and the free ion reactions (Table 14) decrease when a more electron-withdrawing para-substituent is on the nucleophile. Since the magnitude of the secondary alpha deuterium kinetic isotope effect is directly related to the S- - -N distance in the SN 2 transition state19 , adding a more electron-withdrawing substituent to the nucleophile leads to a transition state with a shorter S- - -N distance. The primary leaving group nitrogen kinetic isotope effects for the free ion and the ion-pair reactions (Table 14), on the other hand, increase very slightly when a more electron-withdrawing substituent is added to the nucleophile. Therefore, the
942
Kenneth C. Westaway TABLE 14. The secondary alpha deuterium kinetic isotope effects and primary leaving group nitrogen kinetic isotope effects for the free ion and ion-pair SN 2 reactions between benzyldimethylphenylammonium nitrate and para-substituted thiophenoxide ions in methanol at 20 ° C para-Substituent
k 14 /k 15
(kH /kD )˛
The nucleophile is the free thiophenoxide ion CH3 O H Cl
1.271 š 0.013a 1.222 š 0.013 1.121 š 0.014
1.0162 š 0.0005b 1.0166 š 0.0008 1.0169 š 0.0005
The nucleophile is a solvent-separated ion-pair complex CH3 O H Cl
1.216 š 0.012a 1.207 š 0.008 1.150 š 0.009
1.0161 š 0.0005b 1.0162 š 0.0010 1.0166 š 0.0003
a The error in the isotope effect is 1/k [k 2 Ck /k 2 ðk 2 ]1/2 , D H H D D where kH and kD are the standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates, respectively. b Standard deviation for the average kinetic isotope effect.
C˛ - - -N transition state bond length increases slightly as a more electron-withdrawing substituent is added to the nucleophile. The relative length of the S- - -C˛ transition state bond can be deduced from the primary nitrogen and the secondary alpha deuterium kinetic isotope effects. When a more electron-withdrawing substituent is added to the nucleophile, the C˛ - - -N transition state bond increases slightly while the S- - -N distance shortens. Therefore, the S- - -C˛ transition state bond must be much shorter when a more electronwithdrawing substituent is added to the nucleophile in both the free ion and the ion-pair reactions. The relative transition state structures are shown in Figure 5 using the free ion as the nucleophile. The earlier transition states, found when a more electron-donating substituent is added to the nucleophile, may be found because a better nucleophile would not have to come as close to the alpha carbon to distort the C˛ NC bond and cause reaction. The greater change in the S- - -C˛ bond with substituent can be understood in terms of the Bond Strength Hypothesis61 . The SC˛ bond is weaker than the C˛ NC bond and the Bond Strength Hypothesis predicts that the greatest change will occur in the weaker δ− CH3 OC6 H4 S
Cα
δ+ N(CH3 )2 C6 H5
(kH / kD)α = 1.27 k14 /k15 = 1.0162
δ− HC6 H4 S
Cα
δ+ N(CH3 )2 C6 H5
(kH / kD)α = 1.22 k14 /k15 = 1.0166
δ− ClC6 H4 S
Cα
δ+ N(CH3 )2 C6 H5
(kH / kD)α = 1.12 k14 /k15 = 1.0169
FIGURE 5. The relative transition state structures for the SN 2 reactions between benzyldimethylphenylammonium ion and free para-substituted thiophenoxide ions in methanol at 20 ° C
20. The synthesis and uses of amino and quaternary ammonium salts
943
S- - -C˛ bond and that there will be little or no change in the stronger C˛ - - -N bond when the para-substituent on the nucleophile changes. A second observation is that the substituent effect is greater in the free ion reactions than in the ion-pair reactions, i.e. the (kH /kD )˛ (Table 14) changes by 15% in the free ion reactions but by only 7% in the ion-pair reactions. The corresponding change in the k 14 /k 15 is 0.0007 in the free ion reaction but only 0.0005 in the ion-pair reactions. A possible explanation for this is that the change in charge on the nucleophilic sulfur atom with substituent is greater in the free ions than in the ion-pairs. A CNDO/2 calculation64 shows that the decrease in charge on the sulfur of the free ion is 0.0208 but is only 0.0171 for the ion-pair when the para-substituent is changed. Since the substituent effect on the negative charge on the sulfur atom is 22% greater for the free ion, it is not surprising that the substituent effect is greater in the free ion reactions. Finally, the changes in transition state structure found in this study can be used to test the theories for predicting the substituent effects on the transition state structure. Unfortunately, Thornton’s Reacting Bond Rule65 , the More O’Ferrall Jencks Energy Surface Method66,67 and the Pross Shaik Method68 all fail to predict the change in transition state structure that was found in this study. Only the Bell, Evans and Polanyi Principle69 , which predicts an earlier transition state when a better nucleophile is used, and the Bond Strength Hypothesis61 , which predicts there will be a significant change in the weaker S- - -C˛ reacting bond and little or no change in the stronger C˛ - - -N reacting bond when the para-substituent in the nucleophile is changed, are consistent with the experimental results. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for the free ion and ion-pair reactions in Table 15 show how ion pairing affects the structure of the transition state for the SN 2 reactions between benzyldimethylphenylammonium nitrate and sodium para-substituted thiophenoxides in methanol at 20 ° C. The TABLE 15. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects and the Hammett values for the ion-pair and free ion SN 2 reactions between benzyldimethylphenylammonium nitrate and sodium parasubstituted thiophenoxides in methanol at 20 ° C para-Substituent
Free ion
Ion-pair
k 14 /k 15
k 14 /k 15
š 0.0005a
CH3 O H Cl
1.0162 1.0166 š 0.0008 1.0169 š 0.0005 (kH /kD )˛
1.0161 š 0.0005a 1.0162 š 0.0010 1.0166 š 0.0003 (kH /kD )˛
CH3 O CH3 H Cl c
1.271 š 0.013b 1.237 š 0.008 1.222 š 0.013 1.121 š 0.014 0.85 š 0.14d
1.216 š 0.012b 1.213 š 0.013 1.207 š 0.008 1.150 š 0.009 0.84 š 0.11d
a Standard deviation for the average kinetic isotope effect. b The error in the isotope effect is 1/k [k 2 C k /k 2 ð k 2 ]1/2 , D H H D D where kH and kD are the standard deviations for the rate constants for
the reactions of the undeuterated and deuterated substrates, respectively. c The Hammett values were obtained by changing the para-substituent in the nucleophile. d The standard error of coefficient of the value.
944
Kenneth C. Westaway
primary nitrogen leaving group kinetic isotope effects for the free ion and the ion-pair reactions (Table 15) are identical within the experimental error of the method. Although the incoming nucleophile sulfur kinetic isotope effects have not been measured, one can deduce how the S- - -C˛ bond changes with ion pairing by combining the information provided by the secondary alpha deuterium and the primary nitrogen kinetic isotope effects. The magnitude of the secondary alpha deuterium kinetic isotope effect is determined by the S- - -N distance in the SN 2 transition state19 and, since the nitrogen isotope effects show that the C˛ - - -N transition state bond is not changed by ion pairing, the change in the secondary alpha deuterium kinetic isotope effect caused by ion pairing must be due to a change in the S- - -C˛ transition state bond. Therefore, the secondary alpha deuterium kinetic isotope effects indicate that the free ion S- - -C˛ bond is significantly longer than the ion-pair S- - -C˛ bond when the nucleophile is the p-methoxythiophenoxide ion, is longer than the ion-pair S- - -C˛ bond when the nucleophile is the p-methylthiophenoxide ion, is slightly longer than the ion-pair S- - -C˛ bond when the nucleophile is thiophenoxide ion but is shorter than the ion-pair S- - -C˛ bond in the p-chlorothiophenoxide ion reaction. Finally, the identical Hammett values, found by changing the para-substituent on the nucleophile for the free ion and ion-pair SN 2 reactions (Table 15), indicate that the change in charge on the nucleophilic sulfur atom in going to the transition state is identical for the free ion and ion-pair reactions, and therefore, that the S- - -C˛ transition state bond is not altered significantly when the nucleophile changes from a free ion to an ion-pair. The identical values for the free ion and ion-pair reactions may be observed because, on average, the S- - -C˛ bond for the free ion reaction is identical to the S- - -C˛ bond in the ion-pair reactions. One explanation for the longer S- - -C˛ bond in the free ion transition state is that the sodium ion reduces the electron density on the sulfur atom64 , making it a poorer nucleophile. This would lead to a more product-like transition state (vide supra). Unfortunately, this is not true for the p-chlorothiophenoxide ion reaction which has a shorter S- - -C˛ bond in the free ion transition state. Two other observations are obvious when one considers how ion-pairing affects the structure of the SN 2 transition state. First, the major change in bonding occurs in the weaker S- - -C˛ bond and there is little or no change in the stronger C˛ - - -N reacting bond as the Bond Strength Hypothesis61 predicts. The final observation is that the greatest change in transition state structure is found in the reaction with the best nucleophile, and the effect of ion-pairing becomes smaller as a more electron-withdrawing substituent is added to the nucleophile. This probably occurs because the decrease in the electron density on the sulfur atom, that occurs when a more electronwithdrawing substituent is added to the nucleophile, reduces the strength of the ionic bond between the solvent-separated sodium ion and the sulfur anion of the para-substituted thiophenoxide ion significantly. This means that the difference between the electron density on the sulfur atom of a free ion nucleophile and an ion-pair nucleophile will be smaller when a more electron-withdrawing substituent is on the nucleophile. As a result, the difference between the free ion and the ion-pair secondary alpha deuterium kinetic isotope effects should be smaller when a more electron-withdrawing group is added to the nucleophile. This trend is found when the nucleophile is the p-methoxythiophenoxide ion, the p-methylthiophenoxide ion and the thiophenoxide ion. Unfortunately, the effect of ion-pairing on the transition state for the p-chlorothiophenoxide ion reaction does not fit this trend. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects (Table 16) were determined for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at 0 ° C60 and in methanol at 20 ° C64 to learn how a change in solvent affects the structure of the SN 2 transition state. Unfortunately, the isotope effects were measured at different temperatures. Applying an average temperature dependence of 0.008 per 20 ° C to the secondary alpha deuterium
20. The synthesis and uses of amino and quaternary ammonium salts
945
TABLE 16. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at 0 ° C and in methanol at 20 ° C Solvent Methanol DMF DMF
Temp (° C)
(kH /kD )˛
k 14 /k 15
20 0 20
1.215 š 0.012b 1.179 š 0.010 1.17e
1.0162 š 0.0010c 1.0200 š 0.0007 1.019e
Hammett valuea 0.84 š 0.11d 1.70 š 0.05
a The Hammett value was obtained by changing the para-substituent on the nucleophile. b The error in the isotope effect is 1/k [k 2 C k /k 2 ð k 2 ]1/2 , where k and k are the D H H D D H D
standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates, respectively. c Standard deviation of the average kinetic isotope effect. d The standard error of coefficient of the value. e The kinetic isotope effects are estimated at 20 ° C.
kinetic isotope effect of 1.179 found at 0 ° C in DMF70,71 suggests that this kinetic isotope effect would be approximately 1.17 at 20 ° C. The temperature dependence of a nitrogen isotope effect would appear to be small1 , i.e. a change of 20 ° C would change the isotope effect by less than one percent. Thus, the nitrogen isotope effect for the reaction in DMF would be 1.019 at 20 ° C. The larger secondary alpha deuterium kinetic isotope effect of 1.215 in methanol indicates that the S- - -N transition state distance is greater in methanol than it is in DMF. The primary leaving group nitrogen kinetic isotope effect, on the other hand, is smaller in methanol than in DMF, indicating that the C˛ - - -N transition state bond is considerably shorter in methanol than in DMF. Because the transition state in methanol has a longer S- - -N distance but a shorter C˛ - - -N bond, the S- - -C˛ bond must be much longer in methanol than in DMF. Therefore, an earlier transition state with a much longer S- - -C˛ and a shorter C˛ - - -N bond is found in methanol (Figure 6). The Hammett values found by changing the para-substituent on the nucleophile in DMF and methanol (Table 16) support this conclusion. The larger value in DMF indicates that the change in charge on the nucleophilic sulfur atom is greater on going from the reactant to the transition state in DMF. Therefore, the S- - -C˛ transition state bond is shorter in DMF than in methanol. The earlier transition state in methanol can be rationalized as follows. The SN 2 transition state for this reaction will primarily be solvated at the sulfur atom because the partial In methanol: −
+
δ S + (Na )
δ Cα
+
δ N
(kH/kD)α = 1.215 k14 /k15 = 1.0162
In DMF: −
δδ S + (Na )
+
δ Cα
+
δδ N
(kH/kD)α = 1.17 k14 /k15 ≥ 1.019
FIGURE 6. The relative transition state structures for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF and in methanol
946
Kenneth C. Westaway
positive charges on the alpha carbon and on the nitrogen atom are sterically hindered to solvation. The second assumption is that the structure of the transition state will depend on its stability in that solvent, i.e. that the transition state that is the most stable in each solvent will be found. An early transition state would be more stable than a product-like transition state in methanol, because solvation of the sulfur atom by hydrogen bonding would lower the energy of an early transition state where there is a greater negative charge on the sulfur atom, i.e. the solvent stabilizes an earlier transition state more than a late transition state. As a result, a transition state with a longer and weaker S- - -C˛ transition state bond would be expected in methanol. In DMF, a late, less ionic (dipolar) transition state which would be more strongly solvated by DMF, is expected. Finally, the secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate were measured at two different ionic strengths in DMF at 0 ° C (Table 17)58 . The larger secondary alpha deuterium and the smaller nitrogen leaving group kinetic isotope effect found in the high ionic strength reaction indicate that the S- - -N distance in the transition state is greater and that the C˛ - - -N bond is shorter in the reaction at a high ionic strength. This means that the S- - -C˛ bond is longer in the transition state for the high ionic strength reaction. The earlier, more ionic, transition state is probably found at the high ionic strength because the more ionic transition state will be more stable (more highly solvated) in the more ionic solvent. The important observation, however, is that inert salts that are used to increase the ionic strength in reactions so that accurate rate constants can be measured, change the structure of the transition state markedly. TABLE 17. The secondary alpha deuterium and primary leaving group nitrogen kinetic isotope effects and the relative transition state structures for the ion-pair SN 2 reactions between sodium thiophenoxide and benzyldimethylphenylammonium nitrate in DMF at different ionic strengths at 0 ° C (kH /kD )˛
k 14 /k 15
0.640
1.179 š 0.010a
1.0200 š 0.0007b
0.904
1.215 š 0.011a
1.0166 š 0.0004b
Ionic strength
Relative transition state structure υυ υυC S- - -C- - -- - -N υ υC S- - -- - -C- - -N
a The error in the isotope effect is 1/k [k 2 C k /k 2 ð k 2 ]1/2 , where k and k are D H H D D H D the standard deviations for the rate constants for the reactions of the undeuterated and deuterated substrates, respectively. b The standard deviation for the average kinetic isotope effect.
V. REFERENCES 1. 2. 3. 4. 5. 6.
P. J. Smith and K. C. Westaway, in The Chemistry of the Functional Groups, Supplement F: The Chemistry of Amino, Nitroso and Nitro Compounds and Their Derivatives (Ed. S. Patai), Wiley, London, 1982, pp. 1261 1312. L. Melander, Isotope Effects on Reaction Rates, Ronald Press, New York, 1960. E. Caldin and V. Gold (Eds.), Proton Transfer Reactions, Chapman and Hall, London, 1975. W. W. Cleland, M. H. O’Leary and D. B. Northrup (Eds.), Isotope Effects in Enzyme-catalyzed Reactions, University Park Press, Baltimore, 1977. L. Melander and W. H. Saunders, Jr., Reaction Rates of Isotopic Molecules, Wiley-Interscience, New York, 1980. J. Bigeleisen, Proceedings of the International Symposium on Isotope Separation, North-Holland, Amsterdam, 1958.
20. The synthesis and uses of amino and quaternary ammonium salts 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
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J. Bigeleisen and M. Wolfsberg, Adv. Chem. Phys., 1, 15 (1958). J. Bigeleisen, J. Chem. Phys., 17, 675 (1949). S. Glasstone, K. J. Laidler and H. Eyring, The Theory of Rate Processes, McGraw-Hill, New York, 1941. W. H. Saunders, Jr., Chem. Scr., 8, 27 (1975). L. B. Sims, A. Fry, L. T. Netherton, J. C. Wilson, K. D. Reppond and W. S. Cook, J. Am. Chem. Soc., 94, 1364 (1972). F. H. Westheimer, Chem. Rev., 61, 265 (1961). R. A. More O’Ferrall, J. Chem. Soc. (B), 785 (1970). A. Streitwieser, Jr., R. H. Jagow, R. C. Fahey and S. Suzuki, J. Am. Chem. Soc., 80, 2326 (1958). K. C. Westaway and S. F. Ali, Can. J. Chem., 57, 1089 (1979). S. R. Hartshorn and V. J. Shiner, Jr., J. Am. Chem. Soc., 94, 9002 (1972). H. Humski, V. Sendijarevic and V. J. Shiner, Jr., J. Am. Chem. Soc., 96, 6187 (1974). S. Wolfe and C. -K. Kim, J. Am. Chem. Soc., 113, 8056 (1991). R. A. Poirier, Y. Wang and K. C. Westaway, J. Am. Chem. Soc., 116, 2526 (1994). C. K. Ingold, E. D. Hughes and D. V. Banthorpe, J. Chem. Soc., 2864 (1964). M. J. S. Dewar and A. Marchand, Annu. Rev. Phys. Chem., 16, 338 (1965). H. J. Shine, H. Zmuda, K. H. Park, H. Kwart, A. G. Horgan and M. Brechbiel, J. Am. Chem. Soc., 104, 2501 (1982). H. J. Shine, H. Zmuda, K. H. Park, H. Kwart, A. G. Horgan, C. Collins and B. E. Maxwell, J. Am. Chem. Soc., 103, 955 (1981). H. J. Shine, G. N. Henderson, A. Cu and P. Schmid, J. Am. Chem. Soc., 99, 3719 (1977). S. H. Korzeniowski, L. Blum and G. W. Gokel, J. Org. Chem., 42, 1469 (1977). H. J. Shine, H. Zmuda, H. Kwart, A. G. Horgan and M. Brechbiel, J. Am. Chem. Soc., 104, 5181 (1982). A. Heesing and U. Schinke, Chem. Ber., 105, 3838 (1972). A. Heesing and U. Schinke, Chem. Ber., 110, 3819 (1977). H. J. Shine, J. Habdas, H. Kwart, M. Brechbiel, A. G. Horgan and J. San Filippo, Jr., J. Am. Chem. Soc., 105, 2823 (1983). G. S. Hammond and J. S. Clovis, J. Org. Chem., 28, 3283 (1963). M. J. S. Dewar, The Electronic Theory of Organic Chemistry, Oxford University Press, Oxford, 1949, p. 239. D. V. Banthorpe and J. G. Winter, J. Chem. Soc., Perkin Trans. 2, 868 (1972). C. G. Swain, E. C. Stivers, J. F. Reuwer, Jr. and L. J. Schaad, J. Am. Chem. Soc., 80, 5885 (1958). H. J. Shine, J. Zygmunt, M. L. Brownawell, and J. San Filippo, Jr., J. Am. Chem. Soc., 106, 3610 (1984). J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Chem. Commun., 261, (1982). H. J. Shine, K. H. Park, M. L. Brownawell and J. San Filippo, Jr., J. Am. Chem. Soc., 106, 7077 (1984). H. J. Shine, E. Gruszecka, W. Subotkowski, M. Brownawell and J. San Filippo, Jr., J. Am. Chem. Soc., 107, 3218 (1985). H. J. Shine, L. K. Subotkowski and W. Subotkowski, J. Am. Chem. Soc., 107, 6674 (1985). E. S. Rhee and H. J. Shine, J. Am. Chem. Soc., 108, 1000 (1986). H. J. Shine and E. S. Rhee, J. Labelled Compd. Radiopharm., 21, 569 (1984). W. Subotkowski, L. K. Subotkowski and H. J. Shine, J. Am. Chem. Soc., 115, 5073 (1993). B. Boduszek and H. J. Shine, J. Am. Chem. Soc., 110, 3247 (1988). B. Miller, J. Am. Chem. Soc., 86, 1127 (1964). B. S. Axelsson, B. Langstrom and O. Matsson, J. Am. Chem. Soc., 109, 7233 (1987). B. Langstrom, G. Antoni, P. Gullberg, C. Halldin, P. Malmborg, K. Nagren, A. Rimland and H. Svard, J. Nucl. Med., 28, 1037 (1987). B. S. Axelsson, O. Matsson and B. Langstrom, J. Phys. Org. Chem., 4, 77 (1991). T. Ando, T. Kimura and H. Yamataka, in Nucleophilicity (Eds. J. M. Harris and S. P. McManus) Chap. 7, American Chemical Society, Washington, DC, 1987, p. 108 J. L. Kurz, M. W. Daniels, K. S. Cook and M. M. Nasr, J. Phys. Chem., 90, 5357 (1986). J. L. Kurz, J. E. Pantano, D. R. Wright and M. M. Nasr, J. Phys. Chem., 90, 5360 (1986). T. Ando, H. Yamataka and E. Wada, Isr. J. Chem., 26, 354 (1985). J. M. Harris, M. S. Paley and T. W. Prasthofer, J. Am. Chem. Soc., 103, 5915 (1981). P. Paneth and M. H. O’Leary, J. Am. Chem. Soc., 113, 1691 (1991).
948 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.
Kenneth C. Westaway T. Ando, H. Tanabe and H. Yamataka, J. Am. Chem. Soc., 106, 2084 (1984). I. Lee, H. J. Koh, B. -S. Lee, D. S. Sohn and B. C. Lee, J. Chem. Soc., Perkin Trans. 2, 1741 (1991). J. Persson, U. Berg and O. Matsson, J. Org. Chem., 60, 5037 (1995). W. J. Le Noble and A. R. Miller, J. Org. Chem., 44, 889 (1979). C. G. Swain and N. D. Hershey, J. Am. Chem. Soc., 94, 1901 (1972). V. T. Pham, M.Sc. Dissertation, Laurentian University, Sudbury, Ont., Canada, 1993. A. Maccoll, Annu. Rep. A. Chem. Soc., (London), 71, 77 (1974). K. C. Westaway and S. F. Ali, Can. J. Chem., 57, 1354 (1979). K. C. Westaway, Can. J. Chem., 71, 2084 (1993). Z. G. Lai and K. C. Westaway, Can. J. Chem., 67, 21 (1989). K. C. Westaway and Z. G. Lai, Can. J. Chem., 66, 1263 (1988). W. Jiang, M.Sc. Dissertation, Laurentian University, Sudbury, Ont., Canada, 1996. E. R. Thornton, J. Am. Chem. Soc., 89, 2915 (1967). R. A. More O’Ferrall, J. Chem. Soc. (B), 274 (1970). W. P. Jencks, Chem. Rev., 72, 705 (1972). A. Pross and S. S. Shaik, J. Am. Chem. Soc., 103, 3702 (1981). M. J. Dewar and R. C. Dougherty, The PMO Theory of Organic Chemistry, Plenum Press, New York, 1975, pp. 219, 220. V. J. Shiner, Jr., W. Dowd, R. D. Fisher, S. R. Hartshorn, M. A. Kessik, L. Milakofsky and M. W. Rapp., J. Am. Chem. Soc., 91, 4838 (1969). K. M. Koshy and R. E. Robertson, J. Am. Chem. Soc., 96, 914 (1974).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
21
Displacement and ipsosubstitution in nitration J. P. B. SANDALL Department of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK Fax: (+44) 1392 263434; e-mail: J.P.B.
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. FORMATION OF ipso-ADDUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . III. FURTHER REACTIONS OF ipso-INTERMEDIATES AND ADDUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Solvolysis of Adducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Further Addition to the ipso-Species . . . . . . . . . . . . . . . . . . . . . . . IV. REARRANGEMENT OF ipso-SUBSTITUTED GROUPS . . . . . . . . . . . V. DISPLACEMENT OF ipso-SUBSTITUTED GROUPS . . . . . . . . . . . . . VI. CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
949 950 957 957 961 964 969 970 970
I. INTRODUCTION
This review covers the literature from about 1980, the year of publication of Schofield’s1 book on nitration which includes a chapter on ipso-attack in nitration. The use of the term ipso dates back to 1971 when Perrin and Skinner2 applied it to systems undergoing attack at a substituted position in an aromatic ring. This process has always been regarded as unusual in electrophilic processes such as nitration, since the requirement of a positively charged leaving group results much more often in loss of a proton than loss of a less stable positively charged species. However, this view is partly a consequence of seeing the nitration reaction only as a method of introducing the nitro group; when one considers all the possible reactions that might result from attack at an ipso-position, then it is clear that the process is of considerable importance. In nucleophilic substitution of course ipso-substitution is the norm, since the reversed polarity of the reaction results in loss of a stable negatively charged substituent (e.g. halide ion) much more commonly than a hydride ion, although this latter process can be competitive in special circumstances. Another reason for the greater attention paid to reaction at an ipso-position recently is that modern analytical techniques enable the characterization of less stable or transient
949
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J. P. B. Sandall
species, or compounds only present in small amounts, leading to a much fuller description of complicated mechanisms. The general consequences of ipso-attack in a nitration reaction may be briefly outlined. Usually the aromatic substrate will have two substituent groups, one of which, not necessarily the more electron releasing, will direct an incoming electrophile to attack at a substituted position; thus, for example, 1,4-dimethylbenzene will react with nitronium ion, in a sufficiently acidic medium, to generate the 1,4-dimethyl-1-nitro-benzeneonium ion. For 4-chloroanisole, the dominant ipso-products will arise from attack at the position bearing halogen. This positively charged species may react to form a more stable species in several ways, for example by losing a proton from a suitable position, e.g. formation of 4-methyl-4-nitro-cyclohexa-2,5-dienone (often called an ipso-intermediate) from 4-methylphenol as starting material. Alternatively it may be stabilized by capture of a negatively charged species usually derived from the solvent, e.g. acetate ion from acetic acid, usually called an ipso-adduct. The ipso-species formed by either of these routes may dissociate again (possibly homolytically, generating nitrogen dioxide); either the ipsosubstituent or the nitro group may rearrange (conceivably either homo- or heterolytically) resulting in either nuclear or side-chain substitution or it may undergo solvolysis. Other reactions include further addition to its carbon carbon double bonds. Finally, a suitable substituent, e.g. iodo, may simply be displaced by the incoming electrophile. It must also be remembered that the substrates suitable for ipso-attack are often among the most reactive; this frequently gives rise to the possibility of nitrous acid catalysed nitration as a further complication or even direct reaction with nitrogen dioxide. Examples illustrating all these types of behaviour have been recently investigated. II. FORMATION OF ipso-ADDUCTS
Major work in this field has been carried out by Fischer, Henderson and their coworkers3 12 . The behaviour of 1,4-dimethylbenzene on nitration may be taken as a typical example4 . This substrate, when nitrated in acetic anhydride, gives rise to a diastereomeric pair of adducts involving the formal addition of nitronium acetate across the 1,4-positions (1). In earlier work, attempts were made to assign the configuration of such adducts by using proton NMR shift reagents, but with only limited success. However, relative configurations of the acetates, and dienols derived from these, had been obtained. Myhre and coworkers13 had attacked a similar problem by synthesizing 1,4-dialkyl-4nitrocyclohexadienols by addition of methyllithium to a 4-alkyl-4-nitrocyclohexadienone. This reaction is somewhat stereoselective, and one would expect the predominant isomer to have (Z) configuration, since addition trans to the nitro group is preferred. This is the isomer which (as acetate) is formed in smaller amount in the nitration process. Fischer and coworkers prepared the two diastereoisomeric 1,4-dimethyl-4-nitrocyclohexa-2,5-dienyl acetates and separated them by low temperature chromatography (overall yield 90%, ratio approximately 7:3). The acetates were stereospecifically reduced to the corresponding dienols (aluminium hydride) and these, again stereospecifically, were methylated to give the ethers. The 2,6-dideuterio-1,4-dimethyl-4-nitrocyclohexadienols were prepared using the method of Myhre and coworkers, separated, and the 13 C NMR spectra assigned for both isomers of the alcohol, the ether and the acetate. Comparison with the spectra of the isomeric acetates derived from direct nitration allowed the assignment of the major isomer to the (E) configuration (2). Sufficiently good crystals of the (E)-1,4-dimethyl4-nitrocyclohexa-2,5-dienol were obtained to carry out an X-ray structure analysis; the cyclohexadiene ring is almost flat with the methyl groups trans as expected. It may be noted that the stereochemistry of these acetates and ethers is wrongly assigned in an earlier paper by Shosenji and coworkers14 .
21. Displacement and ipso-substitution in nitration Me
NO2
Me
NO2
Me
951
NO2 H OAc
AcO
Me (1)
AcO
Me (2)
(3)
Whilst aromatic compounds substituted 1,4- with alkyl groups will give mainly 1,4ipso-adducts by nitration at low temperatures, a complication arises with many other substituents, e.g. a halogeno group para to alkyl. This is the possible formation of 1,2adducts (3), as well as the normal 1,4-addition observed with 1,4-dialkylbenzenes (except when one group is t-butyl). Thus nitration of 4-fluoromethylbenzene in acetic anhydride at low temperature10 gives the expected pair of diastereomeric 1,4-nitronium acetate adducts, but in addition the cis-1,2-adduct is observed. In this case the ratio of 1,4-addition to 1,2addition is about 10:1. However, replacement of the 4-fluoro-substituent by 4-chloro or 4-bromo results in only formation of the 1,2-adduct being observed, with the nitro and acetate groups again being cis to each other. In both cases, the NO2 group is attached to the activated ipso-methyl position and not the ipso-halogen position. This behaviour may be rationalized by the relative activations of the ipso and unsubstituted positions towards the electrophile using simple additivity of the partial rate factors for the appropriate monosubstituted benzenes including the rate factors for the ipso positions. The nitro and acetate groups in these 1,2-adducts are always cis; the authors conclude that the addition is stereoselective, being in all cases syn addition. This was confirmed by an X-ray crystal structure determination in the case of the 4-bromo product. Presumably the ipsointermediate carbocation does not escape from the substrate/nitronium acetate encounter pair. The authors also comment on the interesting regioselectivity mentioned above: with both 1,4-dimethylbenzene and 4-fluoromethylbenzene the addition is effectively 1,4; for the other 4-substituents investigated (chloro, bromo, methoxy) addition is almost completely 1,2. This similarity in behaviour for fluoro and methyl does not parallel either the inductive or resonance (or total) electronic effects of the substituents on an electrophilic process. In an attempt to investigate further this regioselectivity, the group of Fischer and Henderson11 looked at the nitration of a series of 2- and 3-substituted 4-methylanisoles and phenols. The product distribution by and large followed the expected pattern calculated from the partial rate factors for halogen and nitro substituents on the observed ratios of attack on 4-methoxymethylbenzene. The largest deviations from the expected regioselectivity occurred with a nitro group in the 2-position: it was expected that this should slightly increase ipso-attack; in fact it significantly decreased it, possibly due to steric effects. However, an examination of the relative amount of capture of the presumed 4-methoxy ipso-cation at the 2-, 4- and 6-positions showed some interesting anomalies. The extent of 4-capture versus 2/6 is again not related to the electronic effects of the substituents in the 3-position, nor is the fact that selectivity between the 2- and 6-positions reversed by exchanging a 3-chloro for a 3-nitro substituent easily explained. Although the grouping of fluoro and methyl substituent effects referred to above suggests the possibility of a radical process, the marked sensitivity of the reactions to substituent effects generally would seem to preclude this. Whereas capture of the ipso-cation by acetate in acetic acid solution continues to be one of the best methods of isolating such adducts, its capture by water is, of course, of great importance during normal nitration in aqueous acid. For example, in 60% H2 SO4 1,2dimethylbenzene gives no less than 33% of mono- and di-nitro-3,4-dimethyl phenols15 .
952
J. P. B. Sandall
The general process is one of loss of nitrous acid from the adduct (4); in highly substituted aromatics the initially formed adduct may well also rearrange either by hydroxyl or other group migration. The second major route to ipso-species formation may be formulated as loss of a proton (generally from a hydroxyl or amino group) from the initially formed cation. For example, in the nitration of 2,6-dichloro-4-methylphenol, the major initial product was shown to be 4-methyl-4-nitro-2,6-dichlorocyclohexa-2,5-dienone16 as early as 1900. A more recent example, investigated by Ridd and coworkers17 , is of formation of ipso-intermediates during the nitration of N,N-dimethyl-p-toluidine and some related compounds. The authors showed that the major product from the toluidine itself (2-nitroN,N-dimethyl-p-toluidine, 78%) was formed in two stages; the intermediate was clearly demonstrated by both 1 H and 13 C NMR to be the ipso-adduct (5). The marked upfield shifts of the 4-methyl group protons (0.3 ppm) and the methyl carbon itself (38 ppm) are completely in accordance with the change from sp2 to sp3 hybridization at this position. The spectrum of the corresponding 4-ethyl-N,N-dimethylaniline also showed the same phenomenon as did N,N-2,4,6-pentamethylaniline where the alternative possibility of an ortho ipso-intermediate was shown to be absent. The solvent used was a typical nitrating mixture (HNO3 in 70% H2 SO4 ) and the intermediates had half-lives up to several hours at 0 ° C. The clean separation of the 1 H NMR peaks for the 4-methyl group in starting amine, intermediate and the final product enabled a kinetic study to be carried out on the formation of both intermediate and product. This showed that formation of the intermediate was an autocatalytic reaction, inhibited by hydrazine and strongly catalysed by traces of nitrous acid. It is clear therefore that the intermediate is formed not by nitronium ion attack at the 4-position, but by a process involving catalytic quantities of nitrous acid, which can be formed by side-reactions. This kinetic behaviour parallels exactly that of N,N-dimethylaniline18 which, under the same conditions, gives almost exclusively N,N,N,N-tetramethylbenzidines by dimerization of the cation radical PhNMe2 Cž which is formed by electron transfer to the NOC ion. The possible alternative mechanism, nitrosation at the 4-position followed by oxidation, was rejected on the grounds that benzidine formation could not be explained. Further confirmation of the oxidizing function of nitrous acid (NOC at this acidity) is given by the observation during the reaction of the ESR spectrum of an organic free radical shown by simulation to be the N,N-4-trimethylanilinium cation radical. Although the authors noted at the time that the observation of the radical did not prove it was on the reaction path, later work showed that the intermediate and final nitro product exhibited a CIDNP effect which confirmed the postulated mechanism. Formation of the ipso-product by NO2 C attack also occurs at appropriate acidities. The rearrangement step will be considered later.
Me
+ NMe2
NO2
Me
CH3
HO
H (4)
+ NMe2
NO2
Me (5)
Me
Me
NO2 (6)
The example outlined above is a particularly clean reaction; most ipso-attacks in amines and phenols are rarely as simple as this. Two other substrates might be used as examples
21. Displacement and ipso-substitution in nitration
953
at this point: N,N-2,4,6-pentamethylaniline and N,N-2,4-tetramethyl-6-nitroaniline19 . At 0 ° C in 70% HNO3 the former compound undergoes ipso-attack at the 4-position to form initially the relatively stable intermediate (6). This can be crystallized out of solution as a hexafluorophosphate, or, if the acid solution is somewhat diluted (40%), it can capture water to generate the 2,4,6-trimethyl-4-nitrocyclohexa-2,5-dienone (7) by the slow displacement of the dimethylamino group. On the other hand, substitution of the 6-methyl group by 6-nitro leads to a completely different final product. Here the analogous ipsointermediate is seen only as a transitory species; the major product (8) may be formulated as arising by the formal addition of one molecule of water across the 5,6 double bond in the ipso-intermediate corresponding to 6. + NMe2
O
O
NO2 Me
Me
Me
NO2 (7)
H H HO
Me
NO2 (8)
Me
NO2 (9)
The nitration of 4-methylphenol provides an interesting example of how the existence of a reasonably stable ipso-intermediate (9) modifies the nitration process and also is markedly affected by the exact reaction conditions. Coombes and coworkers20 investigated products and kinetics for this reaction using HNO3 in 60 80% H2 SO4 . The amount of the expected product, 2-nitro-4-methylphenol, although approaching 100% at high acidities, was much less at lower acidities unless a more efficient nitrous acid trap (sulphanilic acid) was used than the sulphamic acid, which was the trap required for the kinetic studies. The results of the kinetic study showed that the ipso-intermediate (9) was formed by a process first order with respect to nitric acid, and that it decomposed by an overall first order process at a rate (although dependent on overall acidity) independent of nitric acid concentration. In the presence of nitrous acid catalysis, presumably, a much greater fraction of the reaction went by the ipso-intermediate route other reactions of this species would reduce the yield of the final nitro product. This reaction was subsequently investigated21 in acetic anhydride as solvent, using nitronium acetate as the nitrating agent. Under these conditions nitrous acid catalysed nitration is the almost exclusive route to both the ipso-intermediate (30%) and the 2nitro-4-methylbenzene (70%). The temperature at which the ipso-compound was formed was sufficiently low to preclude its rearrangement to the final nitro product. Both 15 N and 13 C CIDNP effects were seen. A strong emission signal in the 15 NMR spectrum corresponding to the ipso-nitro compound (9) was observed, as were an enhanced 13 C NMR absorption signal for C-4 and an emission signal for C-1. The starting material also showed a CIDNP effect in its 13 C spectrum, the reverse of that for the intermediate, i.e. the C-4 signal in emission and the C-1 signal in enhanced absorption. In order to interpret these effects, Kaptein’s rules22 were applied, using the known g values for NO2 and the 4-methylphenoxy radical; the signs of the necessary hyperfine coupling constants were derived for C-1 and C-4 from semi-empirical molecular orbital calculations. The agreement between the observed phase of all the polarized signals and that deduced from the mechanism (Scheme 1) is complete. Thus, the results are only consistent with a mechanism in which the polarization of the ipso-intermediate arises from diffusion
954
J. P. B. Sandall + O
OH
H+
Me
NO2
Me
NO2 Path C
Path A
O
+ NO2
Path B
OH
NO2
OH
NO2
Me OH
+
Me
Me NO2
Me SCHEME 1
together with the 4-methylphenoxy radical and NO2 , not by direct electron transfer to the nitronium ions, nor from the radical pair generated by electron transfer to the nitrosonium ion. Also, the not inconsiderable polarization found in the substrate shows that there must be a significant probability of escape from the radical pair (Path A, Scheme 1) and that the initial oxidation step must also be reversible. This reversibility in the primary oxidation step had already been deduced from a kinetic study23 under quite different conditions, i.e. for nitrous acid catalysed nitration in aqueous nitric acid. The subsequent rearrangements (Paths B and C) will be dealt with later. Formation of ipso-intermediates by reaction of aromatic compounds with nitrogen dioxide is, of course, limited to the more reactive substrates such as phenols. Hartshorn’s group24 33 , also recently in conjunction with Eberson34 39 , having investigated the reactions of ipso-compounds formed from many different substituted phenols using mainly fuming nitric acid as nitrating agent, wished to determine whether nitrogen dioxide would give a similar pattern of reactivity27 . In a typical experiment, a suspension of 3,4,5-tribromo-2,6-dimethylphenol was suspended in cyclohexane, the solvent deoxygenated by a flow of nitrogen, and pure nitrogen dioxide was bubbled through the stirred suspension. A detailed study of the reaction has demonstrated the occurrence of the appropriate 4-nitrocyclohexa-2,5-dienone, as well as a product, 6-hydroxy-2,6-dimethyl3,4,5-tribromocyclohexa-2,5-dienone, which further reacted with NO2 to generate two isomeric dinitro ketones (10, cis- 56%; 11, trans- 31%). The possible sequence of reactions is illustrated in Scheme 2. Several points of interest arise here: some will have to be
21. Displacement and ipso-substitution in nitration Br
Br
955 Br
Br
Me
Br
Me
Br
Me
Br
OH
Br
O
Br
O
Me
Me
NO2
Me
Br
Br Me
Br
Br
Me
Br
O
NO2
Br NO2
ONO
O Me
OH
Me
OH
SCHEME 2
Br
Br
Br
Me NO2
Br NO2
O Me
OH (10)
Br
NO2 Me
Br NO2
O Me
OH (11)
deferred to a later moment when we consider the rearrangements of ipso-intermediates. The suggested route to the formation of the ipso-intermediate, hydrogen atom abstraction from the hydroxy group of the phenol by NO2 , to generate the corresponding phenoxy radical which then combines with a further molecule of NO2 , is reminiscent of the radical process which occurs in nitrous acid catalysed nitration (vide supra). That this completely homolytic process, carried out in a non-polar solvent such as cyclohexane, should generate the same final products, 10 and 11, in the same ratio (10, 54%; 11, 30%) as the reaction in fuming nitric acid, is remarkable. Confirmation of this mechanism, first proposed by Brunton and coworkers40 , for the generation of the ipso-intermediates from phenols by NO2 has been produced by Coombes and collaborators41,42 . They examined the kinetics of the reactions of phenol, 4-methylphenol and some 2,4,6-trialkylphenols with NO2 in cyclohexane. For example, the reaction of 2,6-di-t-butyl-4-methylphenol with NO2 forms the corresponding 2,6-di-t-butyl-4-methyl-4-nitro-cyclohexa-2,5dienone (12) with a second order dependence of rate on the concentration of NO2 ; this is in accordance with the mechanism outlined in Scheme 3. On the other hand, the same reaction of 2,4,6-trimethylphenol is independent of the concentration of NO2 . This behaviour is only explicable if in the latter case the formation of the ipso-intermediate occurs by a rate limiting process from some other, rapidly formed, intermediate. In order to investigate this process further, 2,4,6-tri-t-butylphenol
956
J. P. B. Sandall But
Me
ArOH + NO2
NO2 O
ArO + HNO2
ArO + NO2
(12)
But (12)
SCHEME 3
was reacted with NO2 ; it generated a small quantity of 2,6-di-t-butyl-p-benzoquinone (3%), the expected ipso-intermediate (67%) and a compound (22%) shown by spectroscopic data to have structure 13. This same compound can be formed in 42% yield using NO2 in carbon tetrachloride solution but not apparently in benzene28 . A kinetic study on the rate of formation of these compounds, together with data for the rate of reaction of NO2 with the 2,4,6-tri-t-butylphenoxy radical43 , was completely consistent with Scheme 4, with the radical lying on the reaction path. It was suggested that the intermediate in this scheme may be identified with the ipso-intermediate generated by addition of NO2 at the 2- rather than the 4-position; this intermediate could be observed at low temperatures in deuteriochloroform; it isomerized to the 4-ipso-product as the temperature was raised. In the case of the more bulky t-butyl groups, the rate of isomerization becomes relatively fast. O But
But
ArOH + NO2 OH H NO2 NO2
But
ArO + HNO2
ArO + NO2
(12, tris-But ) + Intermediate
Intermediate
(13)
(13)
SCHEME 4
Coombes and coworkers42 have also investigated the reaction of 4-methylphenol with NO2 in cyclohexane as solvent. The reaction at room temperature give 32% 4-methyl-4nitrocyclohexa-2,5-dienone and 68% 4-methyl-2-nitrophenol. This may be compared with the 30% and 70% respectively reported above for the nitrous acid catalysed process in acetic acid; again a fascinating similarity. The kinetics could only be explained in terms of a second intermediate, A in Scheme 5; such intermediates have been observed previously in the nitration of 2,5-dimethylphenol. In confirmation of this, a primary kinetic isotope effect was observed in the nitration of phenol itself at a relatively low NO2 concentration; and the product ratio of ortho- to para-substitution was shown to be almost identical to that for the nitrous acid catalysed nitration mechanism. Clearly, the product determining stage for both this NO2 attack and for the nitrous acid catalysed process is the addition reaction of the phenoxy and NO2 radicals. In fact, the observed product ratio is close to that predicted by relative magnitudes of the calculated (VAMP44 , V.5.01, AM1 and PM3) annihilated spin densities (32, 36, 32) of the phenoxy radical at the 2-, 4- and 6-positions. In general, it would appear that the process of ipso-intermediate formation of the more reactive substrates such as phenols and amines is dominated by nitrous acid catalysed
21. Displacement and ipso-substitution in nitration
957
O•
OH NO2 •
+ HNO2
CH3
CH3 NO2 •
NO2 •
O
O H NO2
Me
CH3
NO2
(A) SCHEME 5
nitration, unless specific precautions are taken for this to be eliminated, and that this radical process also gives higher yields of the intermediates when the necessary substituent groups are in the 1,4-positions. In the case of dialkylbenzenes and halogenoalkylbenzenes, the classical Ingold mechanism appears more probable, although it is unlikely that the incipient ipso-carbocation escapes from the encounter pair in solvents such as acetic anhydride at low temperatures. III. FURTHER REACTIONS OF ipso -INTERMEDIATES AND ADDUCTS A. Solvolysis of Adducts
In this section we will emphasize the solvolytic behaviour of the ipso-adduct, although discussion of rearrangements cannot be avoided, since the latter are concurrent, competing reactions. Again, to some extent, the behaviour of the adducts arising from the nitration of 1,4-dimethylbenzene may be used as a general example. Several groups have investigated the solvolysis of 1,4-dimethyl-4-nitrocyclohexa-2,5-dienyl acetate (1, 14) and its corresponding dienol. Myhre and collaborators45 examined both products and kinetics in aqueous ethanol as solvent, comparing product formation for these systems with that in 50% 80% aqueous sulphuric acid. The E and Z isomers of both ester and alcohol were prepared and characterized as outlined above and subjected to solvolytic elimination in aqueous ethanol (40% 75%). Both isomeric acetates generated 2,5-dimethylphenyl acetate in at least 99.5% yield; no detectable amounts of the corresponding 2,4-isomer were found. The decomposition was first order in adduct, the E isomer being more reactive (by a factor of about 3). In acid solution, the products were, depending on the acid strength, a mixture of 2,5-dimethylnitrobenzene and the side-chain substitution product, p-tolualdehyde. Thus in greater than 77% acid, the nitro compound was obtained in quantitative yield, whereas in 64% acid, while the total yield was still quantitative, it comprised 72% nitro compound and 26% aldehyde. At still lower acid concentrations, the yield of nitro compound fell off drastically, with no further increase in aldehyde production, although other side-chain
958
J. P. B. Sandall
substituted compounds were observed. The kinetics in these solutions were too fast to measure by conventional techniques. The results in aqueous ethanol were discussed in terms of Scheme 6. The rate limiting process is the rate of the solvolytic elimination of nitrous acid which depends on the ionizing power of the solvent; no primary isotope effect was observed. The migration of the acetate group had previously been shown to be intramolecular and involving a 1,2-shift46 , although work with pseudocumene47 has shown the possibility of a 1,3-shift of the acetoxyl group in dilute acid. The bridged cation is suggested on the basis of the known stability of such structures. The kinetic data for the aqueous alcoholic solvolysis of the dienol are more difficult to interpret since the reaction is more complex, producing about 30% 2,4-dimethylphenol, 50% 1,4-dimethylcyclohexadiene-1,4-diol together with smaller quantities of other species. The results were however thought to be consistent with Scheme 7, where the methyl group migrates more easily than the hydroxyl group. Possible routes to the variety of products obtained in acid solution are also outlined in this work. A thorough re-examination of the products of solvolysis in aqueous organic solvents of the acetate (14) and its corresponding dienol and methyl ether was carried out by Fischer, Henderson and Smyth9 . In order to maximize the solvolysis of the nitro group, 50% aqueous methanol was used. For up to 10 half-lives for the initial solvolysis, the products from the nitro dienol consisted of mainly methoxy dienol (15) and dienediol (16) together with the two phenols 17 and 18 (Scheme 8). At very long reaction times, the initially formed dienes were aromatized forming dimethylphenols and anisoles. In the presence of base, the rearomatization was suppressed; in trifluoroacetic acid, the dienediol gave close to 100% of the phenol (17). All the products were accounted for in terms of the reactions of the substituted 1,4-dimethyl-4-nitro-2,5-cyclohexadienyl cation, which can undergo 1,2- or 1,4-nucleophilic addition generating new cyclohexadienes. It is also suggested that the cation can also undergo competing rearrangements of the methyl group with the acetyl, hydroxyl or methoxyl substituents. Finally, the cation may lose a proton from the methyl side-chain to generate a triene, which in turn will undergo side-chain substitution via a benzylic cation. The variation in product yields with reaction conditions could be rationalized on this basis. Further light has been thrown on the mechanism of solvolysis of ipso-adducts in aqueous acid solution by kinetic studies48,49 . In order that the reactions should proceed at a measurable rate, substrates with more electron withdrawing groups than alkyl had to be used. The authors examined the kinetics and products of aqueous sulphuric acid solvolyses of 2-cyano-3,4-dimethyl-4-nitro-cyclohexa-2,5-dienyl acetate (19) and 5-chloro-2-methyl2-nitrocyclohexa-3,5-dienyl acetate (20, a 1,2-adduct). When 20 was heated in acetic acid50 , 2,3-dimethylbenzonitrile and 2,3-dimethyl-5-nitrobenzonitrile were formed and it was suggested that the nitro group migration was, somewhat unusually, an intramolecular 1,3-migration more often these are 1,2-shifts. Moodie and coworkers48,49 therefore investigated both kinetics and products in aqueous acid solution in the hope of clarifying these points. Their general mechanism is set out in Scheme 9, where the primary process is considered to be a competition between the elimination of nitrous acid (E1) to generate the Wheland type intermediate (21) that is the precursor of the aromatic ester, and the acid catalysed hydrolysis of the acetate group (AAl 1) to form the ipso-cation (22). The cation underwent extensive capture by water particularly at low acidities and a 1,2-rearrangement of the nitro group, rather than the 1,3-shift, observed on heating. These rearrangements will be discussed later. A very similar picture was obtained for the ipso-adduct 20: competing acid-catalysed elimination of nitrous acid and ester solvolysis. The ipso-cation generated by this solvolysis is identical to that obtained by attack on 4-chloromethylbenzene; no less than 59% of primary attack by nitronium ion takes place at C-1 in this compound.
21. Displacement and ipso-substitution in nitration Me
Me
NO2
959
Me
+
−NO2 −
H O
Me
Me
OAc
OAc
Me O
+ C
(1)
Me
Me Me +
−H +
OAc
Me H
Me
OAc
SCHEME 6
Me
NO2
−
+
OR
Me
OH
ROH - H +
Me
NO2
Me
Me
∼Me - H+
+
Me Me
OH
Me
OH
OH ∼OH - H
+
Me
OH Me SCHEME 7
960
J. P. B. Sandall Me
A
Me
Me
A
OMe
+
Me
NO2
Me
OH
Me
OH
+
Me
Me
(14)
OH (15)
(16)
(A = OAc, OH, OMe) ∼ OH
∼ Me
OH
A H
Me
Me
+
Me OH +
Me
Me
Me
(17)
(18)
SCHEME 8 Me
NO2
H Me
AcO
Me Me
CN
CN
+
Cl (20) E
Me
Me
H
NO2
OAc
OH
(21)
Me
CN H
OAc
A A l1
O2 N
Me
Me
(19)
Me
Me
CN
CN
+
(22)
SCHEME 9
21. Displacement and ipso-substitution in nitration
961
It is clear that these solvolytic reactions of ipso-adducts are markedly dependent on reaction conditions: strongly acidic conditions and electron withdrawing substituents will favour a heterolytic process; lower acidity, higher temperatures and electron releasing substituents probably favour homolytic processes. With so many factors involved, each substrate under each set of conditions gives rise to its own particular behaviour. B. Further Addition to the ipso -Species
This aspect of the behaviour of ipso-species has been extensively investigated by Hartshorn’s group. Again, it is impossible to review in any detail all the substrates that have been examined; a few examples will however illustrate the principle processes observed. A typical substrate, 4,5-dichloro-2-methylphenol24 , on treatment with concentrated nitric acid gives 2,2,5-trinitro-3,4-dichloro-6-methylcyclohex-3-enone (23). An exactly analogous compound was observed and completely characterized by X-ray crystallography from the nitration of 4,6-dibromo-2,5-dimethylphenol. The IR, and 1 H and 13 C NMR spectra were fully in accord with this structure; the relative stereochemistry at C5 and C6 was assumed by analogy with that known for the dibromo analogue. Nitration of 4,5-dichloro-2-methyl-6-nitrophenol gave the identical compound. Further evidence for the structure comes from the behaviour of this adduct on heating in tetrachloroethylene: Cl Cl
NO2
Cl
H
NO2
H
O
O2 N Me
CN
Cl O
Me
NC
Me
Me
OH
Me
(23)
O
O2 N
O
O2 N
NO2
Me
OH (24)
(25) O
CN
O
CN Me
NC
NC
CH2 ONO2
NC
Me
Me
Me
CH2
Me
Me O2 N
O Me
OH (26)
Me
Me
(27)
(28)
CN
CN Me
CN
NO2
CN
NO2 Me
Me Me
O
O2 N Me
Me (29)
Me
O
O2 N Me
Me (30)
962
J. P. B. Sandall
the ˛-diketone (24) is formed with evolution of nitrogen dioxide. This type of addition reaction to the first generated ipso-intermediate is quite general and not restricted to phenols: another example may be found in the nitration of 3,4,5,6-tetramethylbenzene1,2-dicarbonitrile. This substrate was first investigated by Suzuki’s group51 who reported the formation of several compounds (25, 26, 27 and 28) on nitration in fuming nitric acid. The structures given for 25 and 26 are not analogous to that, for instance, given above (23). This led Hartshorn and coworkers30 to repeat the reaction; they identified two isomeric dinitroketones (29, 30) and the two corresponding isomeric hydroxy nitro ketones, in addition to the compounds 37 and 38. It will be noted that in this case, all the products have undergone a methyl group migration; the tendency of an ipso-substituted alkyl group to undergo a displacement will be discussed in the next section. The elimination of nitrogen dioxide from the trans dinitro ketone by refluxing in petroleum ether gives the cyclohexa-2,4-dienone (31); regeneration of the cyclohex-3-enones by treatment with nitrogen dioxide gives an approximately equimolar mixture of the cis and trans isomers, 29 and 30. Likewise, the cis dinitroketone rearranges to the trans at 20 ° C in chloroform. These rearrangements, and the formation of the hydroxy ketones, were considered to take place via a radical pair intermediate (Scheme 10), the hydroxyl groups arising from hydrolysis of the nitrito ketones. CN NC
CN Me
NO2
NO2
NC
Me 29
Me
Me O
O2 N Me
Me
Me
Me
CN
CN NC
O
O2 N
Me
ONO
NC
Me Me Me
O Me
O
O2 N
Me
Me
Me
(31)
SCHEME 10
The effects of a quite small change in structure of the substrate may be illustrated by the behaviour of the 2,3,5,6-tetramethylbenzonitrile30 . Here, on treatment with fuming nitric acid, the 6-nitro compound is formed as expected; two other products are the addition compounds 32 and 33, again the cis and trans isomers. Again both compounds can be generated by direct addition of nitrogen dioxide to the 2-cyano-3,4,6,6-tetramethylcyclohexa-2,5-dienone (34). However, the cis dinitroketone dissolves on heating in chloroform to give solely the trans dinitroketone: clearly in this case a mechanism involving homolytic loss of nitrogen dioxide is most unlikely such a process would surely lead to loss of some nitrogen dioxide and formation of 34. In order to explain the retention of the NO2 moiety during reflux in chloroform, the authors suggest hetero- rather than homolytic cleavage of the C4NO2 bond. Thus the rearrangement in this isomer takes place via
21. Displacement and ipso-substitution in nitration Me
Me
O2 N
Me
Me
CN
963
CN
CN
Me
O2 N
Me H O2 N
H O2 N
O Me
Me
O Me
(32)
O
Me
Me
(33)
Me (34)
an ion pair formed from a nitronium ion and a resonance-stabilized carbanion. Recombination of the two ions with inversion at C-4 gives the required isomer. This difference in behaviour from compounds 29 and 30 above is marked; the extra stabilization of the carbanion is suggested to arise from the ˇ-keto nitrile structure which is noted for the ability to stabilize a carbanionic centre at the ˛-carbon atom this structural feature is absent in 30. Presumably this outweighs the extra stability which may arise in 30 from the second electron withdrawing cyano group. The reaction was also carried out in the presence of mesitylene; no nitromesitylene was formed, demonstrating that the nitronium ion does not escape from the ion pair. If a more reactive polyalkylphenol is used as substrate, then nitrogen dioxide becomes a useful reagent for the generation and subsequent addition reactions of the ipsointermediates. Thus reaction of 2,4,6-trialkylphenols31 with nitrogen dioxide generates first the 4-alkyl-4-nitro-2,5-cyclohexadienone which can rearrange to the corresponding 6-nitro compound. Further reaction of this latter compound is by either 1,2- or 1,4addition of two moles of nitrogen dioxide to form the isomeric trinitro compounds 35 and 36, the final product depending on the sizes of the alkyl groups at C-2 and C-4. Hydroxyketones are also among the products when 4-chloro-2,3,6-trimethylphenol33 is used. In order to characterize these, a reaction was first carried out with nitric acid in acetic acid which favours formation of these compounds relative to the trinitro adducts; four hydroxy ketones were characterized by X-ray crystallography. When the same substrate was reacted with nitrogen dioxide in benzene, in addition to the hydroxy ketones, four isomeric trinitroketones (37 40) were isolated and characterized. These compounds accounted for some 60% of the products and hydroxy ketones for 12%. Comparison of the behaviour of this substrate with that of 3-chloro-2,4,6-trimethylphenol and 2,3,4,6tetramethylphenol enabled a comparison of the effect of the 3-substituent to be carried out. Essentially the reaction can be explained in terms of the recombination of the phenoxy and NO2 radicals to form either nitro or nitrito compounds, the latter giving rise to hydroxy ketones, the former to nitroketones (Scheme 11), both these species capable of further addition of NO2 . For 3-methyl substituted phenols, the pattern of attack was that arising from formation of an ipso-intermediate at the 6-position; for the 3-chlorosubstituted phenol, attack must have been at the 2-position. As well as this change in the regiochemistry of the addition, the chloro substituent promotes the formation of R1
R2
NO2
R1
R2
NO2 H O2 N
H O R3
NO2 (35)
O2 N
O R3
NO2 (36)
964
J. P. B. Sandall Me
Cl
Me
Cl
NO2 Me
NO2 Me
O2 N
O Me
O2 N
NO2
Me
Cl
NO2 Me
O Me
(37)
O2 N
NO2
O Me
(38)
NO2 (39)
Me
Cl
NO2 Me O2 N
O Me
NO2 (40) Cl
Me
NO2•
NO2•
Me Cl
Me
Me
O• Me
O Me
ΟΝΟ•
Products
NO2
Cl
Me
Me
NO2•
Products
O Me
OH
SCHEME 11
hydroxy ketones, either by favouring radical recombination via ONO, or by facilitating the hydrolysis. IV. REARRANGEMENT OF ipso -SUBSTITUTED GROUPS
The migration of ipso-substituted groups, whether those attacked (e.g. alkyl) or those attacking (such as nitro or acetoxyl), is a fertile ground for investigation. The behaviour of a typical ipso-adduct may be conveniently illustrated by the behaviour of the cyclohexadiene adducts arising from the nitration of 4-ethyltoluene in acetic anhydride5 . Here all four possible adducts, the diastereoisomeric pairs of the 4-ethyl-1-methyl-4-nitro- and 1ethyl-4-methyl-4-nitrocyclohexa-2,5-dienyl acetates, were obtained (41, 42) and separated. The authors formulated the migration steps as occurring via the cyclohexadienyl cation. All possible rearrangement products can be realized under appropriate conditions; that is methyl, ethyl, acetoxyl and nitro groups were all observed to migrate. In strongly acidified methanol, the formation of the nitrocyclohexadienyl cation is favoured; in methanol itself, or, better, aqueous methanol, the acetoxycyclohexadienyl cation is produced. The reaction
21. Displacement and ipso-substitution in nitration Me
OAc
Me
NO2
Et
NO2
Et
OAc
(41)
965
(42)
is further complicated by capture of the methoxy group also being of importance, not to mention migrations into the side-chain. However, Fischer and Henderson were able to establish that, for example in the 4-acetoxy-4-alkylcyclohexadienyl cation, 1,2-migration of acetoxyl is faster than alkyl migration, but 1,2-alkyl migration is faster than that of hydroxyl or methoxyl in the corresponding cations. Nitro group migration appears always to take preference over other possibilities. Much more detailed mechanistic studies have been carried out on the ipso-intermediates, 4-methyl-4-nitrocyclohexa-2,5-dienones (substituted 2-methyl, 3-methyl and 2-nitro), formed by nitration of the corresponding phenols. Here, only nitro group migration is important, and that only from the 4- to the 2-(6-)position. The first careful mechanistic study of such systems was carried out by Barnes and Myhre52 who examined the behaviour on rearrangement of the 4-methyl-, 3,4-dimethyl- and 3,4,5-trimethylcyclohexa2,5-dienones in both non-polar organic, aqueous and aqueous-acid solvents. In contrast to the 4-alkyl-4-nitro adducts discussed above, a 1,3-shift of the nitro group rather than a 1,2shift was observed in all solvents. The reaction was faster in non-polar organic solvents than in water and kinetically first order in ipso-intermediate: the rate of formation of the product 2-nitro compound was equal to the rate of disappearance of the intermediate. The activation entropy was small and positive and radical scavengers lowered the yield of nitro product. Methyl groups substituted in the 3- and 5-positions slowed the reaction down. 15 N labelling of the nitro group demonstrated substantial but incomplete scrambling of the label. All these facts were held to be consistent with a radical dissociation recombination process, with extensive loss of NO2 from the solvent cage. An acid-catalysed route for the rearrangement was also found. The work of Coombes and coworkers20 on the formation of the 4-methyl-4-nitro intermediate has already been discussed above. Here the solvent was aqueous sulphuric acid with acid concentration ranging from 55% to 90%. The final product, 4-methyl-2nitrophenol, was formed by the expected two routes: about 40% via the ipso-intermediate and 60% directly. Their kinetic studies enabled the acidity dependence of the ipsorearrangement to be examined; they argued that this dependence demonstrated that the rate-limiting stage of the conversion involved the protonated ipso-intermediate (43). They Me
NO2 +
OH (43)
966
J. P. B. Sandall
argued that, unlike the reaction in less acidic media, already established as a radical process, the catalysed process involved a rate-limiting reversion to the nitronium ion/phenol encounter pair, followed by heterolytic fission of the CN bond and fast formation of product. They pointed out that if this acid catalysed process were homolytic, then effectively one must assume that electron transfer from phenol to nitronium ion must take place during encounter pair formation, an earlier suggestion by Perrin53 . Later, some evidence that this acid catalysed process did not involve dissociation to the nitronium ion was produced by Myhre54 . In an attempt to clarify these processes further55 , the rearrangement of the 4-methyl-4nitrocyclohexa-2,5-dienone was followed in situ in an NMR spectrometer, to establish the presence of CIDNP effects. The formation of this ipso species has already been discussed; under the conditions of these experiments it is formed essentially by the nitrous acid catalysed radical nitration process, to the extent of approximately 70%, the major side-product being the 4-methyl-2-nitrophenyl acetate (the phenolic product of the rearrangement is acetylated rapidly in the acetic anhydride solvent). The nitrocyclohexadienone also reverts to 4-methylphenyl acetate during this period to the extent of 20%. The reactions are shown in Scheme 1. The rearrangement was followed by 1 H NMR; it gave first order kinetics and no sign of any 1 H nuclear polarization. Both the uncatalysed and acid-catalysed processes could be distinguished under these conditions; about 4% added sulphuric acid was required to give a reaction proceeding through the catalysed route to the extent of 90%. Substituent effects on this first order rate were also obtained: a 2-methyl substituent increased the rate by 20%, 3-methyl decreased it by about a factor of two and a 2-nitro group increased it by a factor of approximately 20. There was no marked difference between the substituent effect on the catalysed and uncatalysed processes. 15 N NMR spectra were then taken during the rearrangement, again under both acid catalysed and non-acid catalysed conditions. The various enhancement factors for the nitrogen nucleus in both reactant and product could be extracted mathematically for all possible routes illustrated in Scheme 1. This showed unambiguously that both the acid catalysed route and the simple thermal rearrangement both give rise to CIDNP effects and both must take place by homolytic dissociation of the CN bond. This is also in accord with the substituent effects mentioned above. It is also clear from these studies that there is a significant return to the initial cyclohexadienone from the radical pair. Although the results require the acid catalysed rearrangement to have a homolytic component, obviously some contribution from a heterolytic process (Path C, Scheme 1) cannot be ruled out. As we have noted so frequently before, it is important not to extrapolate too far in attempting to deduce a mechanism even when only small structural changes in substrate are involved. The rearrangement of the nitro group in the ipso-intermediates derived from some 2-methylphenol provides an interesting example56 . Here the intermediates, variously substituted 2-methyl-2-nitrocyclohexa-3,5-dienones (44), rearrange rapidly and regiospecifically to the corresponding 6-nitro-2-methylphenols unless the 6-position is O
O NO2
R
Me
Me NO2
R
R = 3-Me, 4-Me, 5-Me, 6-Me 4-NO2 , 6-NO2 (44)
(45)
21. Displacement and ipso-substitution in nitration
967
blocked. The same regiospecificity is found in the nitro group rearrangements of substituted 2-nitrophenols in trifluoromethanesulphonic acid57 , where the rearrangement occurs via the Wheland intermediate. By analogy with the rearrangement of the 4-methyl-4nitrocyclohexa-2,5-dienones outlined above, one would expect a homolytic mechanism, but a radical pair process involving NO2 is not normally expected to be regiospecific. Such radical pairs as 45, when generated either by rearrangement of an ipso-intermediate or by nitrous acid catalysed nitration, result in attachment of NO2 at both ortho and para positions as would be expected from the very similar spin densities at these sites. Previous workers investigating these substrates had noted the regiospecificity and suggested two possible explanations: either a homolytic process involving the transient formation of phenyl nitrate20 or a 1,5 sigmatropic shift58 . By generating the 15 N labelled ipsointermediate and following the 15 N NMR spectrum during its rearrangement, it was shown that no CIDNP effect was observable unless the 6-position was blocked, in which case rearrangement takes place to the 4-position with a CIDNP effect. Both the regiospecific 2 6 rearrangement and the clearly homolytic 2 4 rearrangement undergo acid catalysis to much the same extent. It seems that it is most unlikely that completely different mechanisms apply to these two rearrangements: in each case then the first step must involve homolysis of the CN bond. Extensive semi-empirical calculations failed to detect a transition state for a 1,5 sigmatropic process; the NO2 group always appears to move away from the 6-position as the CN bond is stretched. The explanation for the absence of a CIDNP effect, and the marked regiospecificity for the 2 6 rearrangement, must presumably be sought elsewhere. The calculations mentioned above suggested that the barrier to movement of the NO2 towards the 4-position is greater than that for movement towards the oxygen atom of the phenoxy radical. Perhaps then no escape from the radical pair undergoing the 2 6 shift takes place because of stabilizing interactions between the phenoxy oxygen atom and the NO2 nitrogen atom as previously suggested by Coombes and collaborators20 . It is worth emphasizing that although the presence of a CIDNP effect can be diagnostic of the presence of a radical pair on the reaction path59 , the absence of such effects does not preclude a homolytic reaction. It is also necessary for some escape from the radical pair to take place, for there to be a reasonable electron spin density on the nucleus under observation and for the relaxation time of that nucleus to be sufficiently long. It is for these reasons that the observation of 15 N CIDNP effects in nitration processes involving NO2 is easier than with other nuclei in the system. If the ipso-position attacked during nitration is already substituted by a nitro group, then the consequences of such a process will not be recognized unless the attacking nitrating agent or the original group is labelled (most conveniently with 15 N). Thus ipso-attack at the 4-position in 4-nitrophenol was investigated60 and shown to occur to the extent of 20%. The conditions used involved nitric acid in trifluoroacetic acid in the presence of nitrous acid catalysed nitration, so it is not unexpected that the formation of the ipso-intermediate should be a free radical process. The rearrangement of the nitro group to the 2-position was also shown to be a homolytic process, involving the NO2 4-nitrophenoxy radical pair. This was demonstrated by 15 N labelling of the 4-nitrophenol and treating this with unlabelled nitric acid; the migrating nitro group in the 2-position showed a CIDNP effect of the appropriate phase. Another interesting aspect of this reaction, although not directly relevant to ipso-attack, is that the 2,4-dinitrophenol which is produced directly, even in conditions when nitrous acid catalysed nitration is prevented, also forms by a homolytic process. The authors suggest that this is possibly via nitronium attack on the phenolic oxygen atom to generate phenyl nitrate, which can then undergo a rearrangement akin to the nitramine rearrangement which is typically a homolytic process. It seems unlikely that this observation of a CIDNP effect arises from direct electron transfer from phenol to nitronium ion, since no such effect is observed with mesitylene, which is expected to be just as easily oxidized.
968
J. P. B. Sandall
The exchange of nitro groups is not restricted to that at the 4-position relative to the hydroxyl group. Konior and coworkers61 have nitrated both 2,6-dinitrophenol and picric acid with 15 N labelled nitric acid in acetic anhydride. The product from both nitrations (picric acid) showed the presence of the label in all three positions of the nitro group; indeed, in the picric acid derived from the dinitrophenol, the nitro group in the 4-position was also labelled 14 N. No precautions were taken to eliminate nitrous acid catalysed nitration so that it is possible that both formation of the ipso-intermediates and their rearrangement proceed via a radical pair. However, as pointed out by Moodie62 , increasing the number of electron withdrawing substituents in the ring may well increase the extent of heterolysis as opposed to homolysis during the apparently very similar nitramine rearrangement; for example, significant heterolysis occurs during the rearrangement of N-2,4-trinitroaniline to picramide. Yet another way in which an ipso nitro group may rearrange is to generate a nitrito compound. Thus when 2,3,4,5-tetrabromo-6-methylphenol is nitrated in fuming nitric acid, Hartshorn’s group26 noted the formation of the product 2,3,4,5-tetrabromo-6methyl-6-hydroxycyclohexa-2,4-dienone (46). They suggested that this is produced via the corresponding 6-nitrito intermediate, which could not be isolated since it is hydrolysed during the work-up of the reaction products. Such hydroxy compounds are frequently observed on nitration of alkyl phenols. Confirmation of the existence of these nitrito ipsointermediates and their facile hydrolysis to the corresponding hydroxy compounds has been gained from analysis of the 1 H and 15 N NMR spectra obtained63 during the nitrous acid catalysed nitration of 2,6-dichloro-4-methylphenol. Four products were characterized by NMR: 47 50. The 4-nitro-4-methyl ipso-intermediate could be isolated from the nitration; when dissolved in wet chloroform two other compounds are formed in the first five minutes with the disappearance of about half the starting material. One of these is the hydroxy compound 48, the other is clearly an ipso-intermediate. When 15 N labelled starting material is used, only two signals are observed; one for the starting material and one at very low field (υ 600 p.p.m.) typical of nitrites. Further evidence for the nature of this compound and for its equilibrium with the nitro intermediate was obtained by treating the hydroxy compound with nitrous acid dissolved in chloroform and again O
O
HO
O
Cl
Br
Cl
Cl
Cl
Me Br
Br Me
Br (46)
NO2
Me
(47)
(48) OH
O Cl
Cl
Me
ONO (49)
OH
Cl
Cl
CH2 NO2 (50)
21. Displacement and ipso-substitution in nitration
969
following the reaction with 1 H NMR. As expected, the spectra of both the nitrito and nitro compounds are observed. The equilibrium can therefore be approached from either side. The reaction mixture is unstable, losing oxides of nitrogen; after several hours the major product visible has a spectrum corresponding to the arylnitromethane 50. More recently Eberson, Hartshorn and coworkers36 have observed such nitrito compounds spectroscopically, during the photochemical nitration of 1,4,5,8-tetramethylnaphthalene with tetranitromethane. These were observed during the first hour of the reaction, subsequently disappearing. V. DISPLACEMENT OF ipso-SUBSTITUTED GROUPS
Many examples may be found in the literature1 of the displacement of substituents other than hydrogen during nitration with concurrent formation of aromatic nitro compounds. Often these displacements are from highly activated substrates, and one frequently suspects that the dominating mechanism of formation of the final nitro product is nitrous acid catalysed nitration, the product-determining stage being attack of NO2 radical rather than nitronium ion on the ipso-position. An interesting use of ipso-displacement of a tert-butyl group by nitro is exemplified by the approach of Verboom and collaborators64 to the functionalizing of calixarenes. Calix[4]arenes are often functionalized at the upper rim by nitration of free positions para to the hydroxyl group on the lower rim or by ipso nitration of p-sulphonate groups. Thus nitration of tetra-t-butyl-tetramethoxycalix[4]arene, where the t-butyl groups are para to the methoxyl groups, resulted in a good yield of the corresponding tetra-nitro compound. Dialkylated calix[4]arenes reacted much more quickly than the tetra-alkylated species to give regiospecific products where nitro-det-butylation occurs para to hydroxyl not methoxyl; this product, under more forcing conditions, then gives the expected tetra-nitro derivative. In this way, by control of the oxygenated function at the lower rim, a variety of usefully functionalized calixarenes may be prepared. Another interesting system that has been investigated by Yamato and coworkers65 comprises a series of 1,n-bis(5-t-butyl-2-methoxy-3-methylphenyl)alkanes where n ranges from 1 to 4, together with the corresponding biphenyl. Even in the absence of the 3methyl group, the para-directing influence of the methoxyl group was sufficient to give significant amounts (13%) of the mono-5-nitro compound (n D 2). With the 3-methyl substituent blocking the other activated position, both mono- and di-nitro-de-t-butylation occurred with yields ranging up to 93%. The authors suggest that the high yields may be explained by one aromatic ring stabilizing the other areneonium ring arising from the ipso-attack of the nitronium ion. Displacement of groups undergoing ipso-attack in indoles under both nitrating conditions and nitrosating conditions has been investigated by Colonna, Greci and Poloni66 . Indoles are reactive species to electrophilic attack which occurs mainly at the 3-position. If this position is substituted by the N2 C6 H5 , CH2 OH, COCH3 or CHO groups, all could be displaced by treatment with 70% nitric acid mixed with twice its volume of acetic acid, to give the corresponding 3-nitro compound, often in addition to the 3,4- and 3,6dinitro species. They failed to isolate any ipso-adduct, but deduced its presence from the deep colour observed on addition of the nitric/acetic acid solution. The reaction of the same substrates with sodium nitrite in acetic acid also gave the 3-nitro compounds; since the authentic 3-nitroso derivative could be oxidized by nitrous acid through to the corresponding 3-nitro compound, they deduced that the mechanism was one involving the 3-nitroso compound as an intermediate. However, the 3-nitrosoindole gives both the 3-nitro- and 3,5-dinitroindoles under these conditions; this was ascribed to the possibility of the ipso-cation undergoing both direct nitration in the 5-position as well as nitro-denitrosation. When carrying out the reactions in the cavity of an ESR spectrometer, a signal
970
J. P. B. Sandall
ascribed to the NO2 radical was sometimes observed. In these cases an electron transfer mechanism to generate the substrate cation radical, followed by radical pair collapse, was suggested. A sequence of leaving abilities of the various groups in the 3-position, based on yields and reaction times, is also given. In a later paper67 , this work is extended to 4-substituted N,N-dimethylanilines and indolizines: further confirmation of the radical process was obtained. As a final example in this section, we may consider the ipso-displacement of the nitro group itself. Liu and Zhao68 have investigated the substitution of the nitro group in a series of 4-nitrobenzoate esters by the phenylthiolate anion. Here the process again involves radical species, but now it is the radical anions of the nitro compounds which are observed as well as the thiophenoxyl radical which could be trapped. VI. CONCLUSION
Of necessity, only a few of the many papers published in this area have been examined in detail in this review. Clearly, the area of aromatic nitration is still full of surprises38 and ipso-attack of nitrating species on substituted aromatics is proving useful in elucidating many of the subtle mechanistic details37 . VII. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
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M. P. Hartshorn, H. T. Ing, K. E. Richards, K. H. Sutton and J. Vaughan, Aust. J. Chem., 35, 1635 (1982). M. P. Hartshorn, R. J. Martyn, W. T. Robinson, K. H. Sutton, J. Vaughan and J. M. White, Aust. J. Chem., 36, 1589 (1983). M. P. Hartshorn, W. T. Robinson, K. H. Sutton and J. Vaughan, Aust. J. Chem., 38, 161 (1985). M. J. Gray, M. P. Hartshorn and J. Vaughan, Aust. J. Chem., 39, 59 (1986). M. P. Hartshorn, J. M. Readman, W. T. Robinson, C. W. Sies and G. J. Wright, Aust. J. Chem., 41, 373 (1988). J. W. Blunt, M. P. Hartshorn, R. G. Jensen, A. G. Waller and G. J. Wright, Aust. J. Chem., 42, 675 (1989). M. P. Hartshorn, M. C. Judd, R. W. Vannoort and G. J. Wright, Aust. J. Chem., 42, 689 (1989). J. L. Calvert, M. P. Hartshorn, W. T. Robinson and G. J. Wright, Aust. J. Chem., 46, 1629 (1993). L. Eberson, M. P. Hartshorn and F. Radner, J. Chem. Soc., Perkin Trans 2, 1799 (1992). J. L. Calvert, L. Eberson, M. P. Hartshorn, R. G. A. R. Maclagan and W. T. Robinson Aust. J. Chem., 47, 1211 (1993). L. Eberson, J. L. Calvert, M. P. Hartshorn and W. T. Robinson, Acta Chem. Scand., 47, 1025 (1993). L. Eberson, M. P. Hartshorn, F. Radner and J. O. Svensson, J. Chem. Soc., Perkin Trans 2, 1719 (1994). L. Eberson, M. P. Hartshorn and F. Radner, Acta Chem. Scand., 48, 937 (1994). C. P. Butts, L. Eberson, G. J. Foulds, K. L. Fulton, M. P. Hartshorn and W. T. Robinson, Acta Chem. Scand., 49, 76 (1995). G. Brunton, H. W. Cruse, K. M. Riches and A. Whittle, Tetrahedron Lett., 20, 1093 (1979). R. G. Coombes, A. W. Diggle and S. P. Kempsell, Tetrahedron Lett., 34, 8557 (1993). R. G. Coombes, A. W. Diggle and S. P. Kempsell, Tetrahedron Lett., 35, 6373 (1994). C. D. Cook and R. C. Woodworth, J. Am. Chem. Soc., 75, 6242 (1953). G. Rauhut, J. Chandrasekhar, A. Alex, T. Steinke and T. Clark, Centrum f¨ur Computer-Chemie der Universitat Erlangen-Nurnberg, 1993. J. T. Geppert, M. W. Johnson, P. C. Myhre and S. P. Woods, J. Am. Chem. Soc., 103, 2057 (1981). A. Fischer and J. N. Ramsay, Can. J. Chem., 52, 3960 (1974). H. W. Gibbs, R. B. Moodie and K. Schofield, J. Chem. Soc., Perkin Trans. 2, 1145 (1978). C. Bloomfield, R. B. Moodie and K. Schofield, J. Chem. Soc., Perkin Trans. 2, 1003 (1983). C. Bloomfield, R. B. Moodie and K. Schofield, J. Chem. Soc., Perkin Trans. 2, 1793 (1983). A. Fischer and C. C. Greig, Can. J. Chem., 52, 1231 (1974). H. Suzuki, A. Inoue, M. Koge and T. Hanafusa, Bull. Chem. Soc., Jpn., 51, 1172 (1978). C. E. Barnes and P. C. Myhre, J. Am. Chem. Soc., 100, 973 (1978). C. L. Perrin, J. Am. Chem. Soc., 99, 5516 (1977). P. C. Myhre, Report 1985, ARO-17572.1-CH-H; cf. Gov. Rep. Announce Index (U.S.), 85(24), Abstr. No. 555 257, 1985. J. H. Ridd, S. Trevellick and J. P. B. Sandall, J. Chem. Soc., Perkin Trans. 2, 1535 (1992). J. H. Ridd, S. Trevellick and J. P. B. Sandall, J. Chem. Soc., Perkin Trans. 2, 1073 (1993). J. V. Bullen and J. H. Ridd, J. Chem. Soc., Perkin Trans. 2, 1675 (1990). A. Fischer and G. N. Henderson, Tetrahedron Lett., 21, 4661 (1980). J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Chem. Commun., 402 (1981). A. H. Clemens, J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Perkin Trans. 2, 1667 (1984). R. J. Konior, R. I. Walter, U. L. Bologa, M. T. Capriogu, N. Negoita and A. T. Balaban, Polish J. Chem., 68, 2451 (1994). R. B. Moodie, in Aromatic Nitration (Ed. K. Schofield), Chap. 15, Cambridge University Press, 1980. M. R. Amin, L. Dekker, D. B. Hibbert, J. H. Ridd and J. P. B. Sandall, J. Chem. Soc., Chem. Commun., 658 (1986). W. Verboom, A. Durie, R. J. M. Egberink, Z. Asfari and D. N. Reinhoudt, J. Org. Chem., 57, 1313 (1982). T. Yamato, H. Kamimura, K. Noda and M. Tashiro, J. Chem. Res. (S), 424 (1994). M. Colonna, L. Greci and M. Poloni, J. Chem. Soc., Perkin Trans. 2, 628 (1981). M. Colonna, L. Greci and M. Poloni, J. Chem. Soc., Perkin Trans. 2, 165 (1984). Y. -C. Liu and W. -Y. Zhao, Acta Chimica Sinica, 49, 615 (1991).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
22
Nitric oxide from arginine: a biological surprise ALAN H. MEHLER Department of Biochemistry and Molecular Biology, Howard University, Washington, DC, USA
I. ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . II. ABBREVIATIONS AND DESIGNATIONS USED IN BIOCHEMISTRY . . . . . . . . . . . . . . . . . . . . III. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . A. Early Reports on NO . . . . . . . . . . . . . . . . . B. Mechanism of NO Formation . . . . . . . . . . . . C. Content of Folate and the Origin of Oxygen . . IV. INDIVIDUAL NOS . . . . . . . . . . . . . . . . . . . . . A. bNOS cDNA . . . . . . . . . . . . . . . . . . . . . . . B. eNOS cDNA . . . . . . . . . . . . . . . . . . . . . . . C. iNOS cDNA . . . . . . . . . . . . . . . . . . . . . . . V. LOCALIZATION OF THE HUMAN GENE . . . . A. bNOS in the Human Gene . . . . . . . . . . . . . . B. eNOS in the Human Gene . . . . . . . . . . . . . . C. iNOS in the Human Gene . . . . . . . . . . . . . . D. Three Genes come from Three Chromosomes . VI. FORMATION OF NO AND CITRULLINE . . . . . VII. COMPLEXITIES OF NOS . . . . . . . . . . . . . . . . A. Role of BH4 . . . . . . . . . . . . . . . . . . . . . . . B. Iron in NOS . . . . . . . . . . . . . . . . . . . . . . . C. Subunits and Dimers . . . . . . . . . . . . . . . . . . D. Complications of Many Cofactors . . . . . . . . . E. Inhibitors of NOS . . . . . . . . . . . . . . . . . . . F. Factors for Growth of NOS . . . . . . . . . . . . . VIII. PHYSIOLOGICAL FUNCTIONS OF NOS . . . . . IX. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . X. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . .
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974
Alan H. Mehler I. ABBREVIATIONS
bNOS BH4 cDNA cGMP EDRF eNOS FAD FMN iNOS NADPH L-NAME NO NOS
brain nitric oxide synthase tetrahydrobiopterin, tetrahydrofolate complementary DNA 30 ,50 -cyclic phosphate of guanylic acid endothelial-derived relaxing factor endothelium nitric oxide synthase flavin adenine dinucleotide flavin mononucleotide inducible nitric oxide synthase nicotinamide adenine diphosphate phosphate reduced NG -nitro-L-arginine methyl ester nitric oxide nitric oxide synthase
II. ABBREVIATIONS AND DESIGNATIONS USED IN BIOCHEMISTRY
Biochemists started more than 50 years ago to name familiar molecules by abbreviations. They have not been dissuaded by the change in terminology nor the alterations in names. Therefore, the current list of short-hand abbreviations that are used now takes several pages. The sort of names used in this chapter is quite varied and is illustrated below. For distance along nucleotide length, the dimension is kilobases, kb. The nomenclature for the weight of proteins is one of several possibilities. The one used is Kilodaltons, Kd. The position of genes upon a chromosome is given by either p, for the shorter portion from the centromere, or q, for the longer portion. Within the p or q, the distance is given as staining bands with the Giemsa stain, as for example 7q35 7q36 represents the 7th chromosome, position 35 36 of the distance away from the centrosome. The designation qter represents the terminal portion of the chromosome. DEAE is the abbreviation for DiEthyl Amino Ethyl, the binding group of a substitution on cellulose. SDS/PAGE is a technique for naming the material used for electophoresis in which SDS represents sodium dodecyl sulfate solution that is used with PolyAcrylimide Gel Electrophoresis (PAGE). TATA and CCAAT arc the names where, in general, the polymerase binds to DNA, but these factors are sometimes missing. The other binding sites for the many factors that activate the polymerase, Sp1, AP-1, etc., have many diverse meanings. SOD is superoxide dismutase. The abbreviations as part of the names such as NG - or Nω - for the L-NAME indicate the nitrogen atoms listed as either the guanido nitrogen (G) or the terminal nitrogen ω (two ways for listing the same nitrogen atoms). III. INTRODUCTION A. Early Reports on NO
The discovery that a biological catalyst was nitric oxide (NO) was a surprising event. This finding was in part due to the persistence of Furchgott1 , who discovered in 1987 that what he called EDRF (endothelium-derived relaxing factor) was probably this molecule and Ignarro2 , who determined in the same year that EDRF and NO had the same halflife and were released in the same order by various treatments of arterial or venous substrates; cGMP was induced and the materials were bound by hemoglobin. These two findings were reported in a symposium organized by Vanhoutte3 and were the first findings
22. Nitric oxide from arginine: a biological surprise
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that a new era was dawning. Inspired by this discovery, Moncada and collaborators in the Wellcome Research Laboratories4 tried a group of physical approaches that also favored the existence of nitric oxide as the material proposed by Furchgott and by Ignarro. It should be emphasized that all of the experiments reported by 1988 were pharmacological and were of primary interest to pharmacologists. However, from that time until the present (1995), many papers have involved biochemists, physicians and other scientists and the number of papers on the subject of nitric oxide has reached over 1000 in 1994. The first paper by Furchgott on EDRF was published in 19805 . This work showed that acetylcholine was effective in producing the effect of a relaxation of rabbit thoracic aorta only if endothelial cells were still present and that these were easily removed. It is necessary to recall that the endothelial cells are only a single layer on the internal surface of a much larger muscle layer. However, the single layer of endothelial cells comprises the essential components for producing the active principle. The production of NO was not completely unexpected. Some 10 years prior to Furchgott and to Ignarro’s discovery, in a review by Murad’s group6 , the efficiency of NO was shown upon cGMP and the inhibition by hemoglobin was also demonstrated. However, the technical tools necessary for determining the source and even the identity of this compound were not available. This was true even though Keilin and Hartree had shown that catalase formed NO back in 19547 . While the statements that EDRF was really NO were still in progress, Moncada and collaborators started studies that gave further evidence that the active ingredient was in fact the simple gas. In a series of papers in 1987, Radomski, Palmer and Moncada showed that material released from endothelial cells and NO were similar in their passage through a cascade and decomposed at similar rates8,9 . A parallel study showed that platelets10 and vascular smooth muscle were effected in the same way by both EDRF and NO11,12 . The activation by superoxide dismutase (SOD) and inhibition by hemoglobin (Hb) were similar for both of these11,12 . In these experiments, the concentration of NO was determined by chemiluminescence following the reaction with ozone11 . It should be noted that many of the data of Moncada were confirmations of the data of others. Thus, the work of Furchgott showed that Hb inhibited EDRF action12 16 . The laboratory of Murad had very early shown the effects of many nitro compounds, including NO, on the stimulation of cyclic guanylic acid (cGMP)17,18 and Craven and DeRubertis19 had shown that NO along with a number of related compounds was capable of stimulating cGMP and that nitrohemoglobin had a similar effect. Gruetter and coworkers20 and Mellion and collaborators20 22 reported that NO is a good inhibitor of platelet aggregation based on work of Needleman’s group23,24 . Ignarro25 28 found NO was liberated from nitrosothiols and activated guanylate cyclase, elevated the vascular and platelet level of cGMP, caused vascular smooth muscle relaxation, inhibition of platelet aggregation and hypotension in anesthetized animals. B. Mechanism of NO Formation
By the year 1987, there was intense excitement about the biosynthesis of NO. The discovery that the active molecule was derived from arginine was strange enough. This was first shown by Hibbs and coworkers29 , who showed that mouse macrophages required L-arginine for cytotoxic activated macrophages (CAM) and also for inhibition of aconitase and uptake of [3]-thymidine into DNA. The reaction was also given by L-homoarginine and some derivatives of L-arginine and N-monomethyl arginine (NG MMA) was particularly inhibitory. Shortly after, the same group30 showed that arginine was converted to citrulline.
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Alan H. Mehler
Iyengar and coworkers31 found that the oxidation of L-arginine led to citrulline, actually before Hibbs and collaborators30 . At this point in time, Palmer’s group11 showed that NO was indeed formed from the guanido nitrogen of arginine. This led to a series of confirmations; the first was Ignarro and collaborators32 , who demonstrated that NO was the same as EDRF. Then in 1988 Marletta and coworkers33 showed that nitric oxide was formed and that NO2 and NO3 were formed from it. In their reaction L-arginine MgCC and NADPH were required. The enzyme was soluble in mouse macrophage, the RAW 264.7 cells. Later in 1988, Hibbs and collaborators34 showed that mouse macrophages formed NO from arginine and that NO was the precursor of NO3 . This was confirmed in 1989 by Stuehr’s group35 , who showed that the production of NO from L-arginine was responsible for CAM and that the process was inhibited by NG , NG -dimethyl-Larginine. C. Content of Folate and the Origin of Oxygen
The complexity of NO-synthase was emphasized by Tayeh and Marletta36 and Kwon, Nathan and Stuehr37 , who isolated dihydro- and tetrahydrofolate as the endogenous compounds that stimulated the oxidation from 20 30% to 100%. Kwon and coworkers38 followed this finding with mass spectrometric data, which showed that the oxygen of citrulline formed from arginine contains the oxygen of air. Leone’s group39 demonstrated that both the citrulline and NO oxygen are derived from molecular O2 by showing that both methylate citrulline and nitrosomorpholine contained the isotope of the oxygen gas. This was found to be true for the three types of NO synthetase (see below) except for the NO from brain, which was not recovered as a morpholine derivative. IV. INDIVIDUAL NOS A. bNOS cDNA
The presence of NO in mammalian brain was first proposed by pharmacologists. Using cerebellar cells, Garthwaite and collaborators40 determined that EDRF was produced by N-methyl-D-aspartate (NMDA) and that NO was the probable nature of the EDRF. While this work was under way, Knowles and coworkers41 demonstrated the synthesis of NO and citrulline in a crude synaptosomal cytosol from rat forebrains. This work established that NADPH was required, that a number of simple arginine derivatives were effective, that hemoglobin was inhibitory and that L-methylarginine prevented the activity. Within months of the work of Knowles, Bredt and Snyder42 purified an enzyme from cerebella of 10-day-old rats that synthesized NO. The technique involved the formation of citrulline, since this compound can be easily determined. This work was continued and Bredt and Snyder43 within a few months of their previous study had purified the brain NOS. This work was dependent upon a couple of factors: first, the requirement of calmodulin for the enzyme and, second, the elution of the enzyme from 20 ,50 -ADP agarose with NADPH. The use of calmodulin is important for the role of calcium as an activator of the enzyme. The first elution gave a six-fold purification on DEAE. The second step, 20 ,50 -ADP agarose, allowed the bulk of the protein to be eliminated with 0.5 M NaCl followed by elimination of NO synthase with 10 mM NADPH. The isolation of NOS led to the cloning and expression of the cDNA for this enzyme. NOS was purified as before and tryptic fragments were isolated. Bredt’s group44 then continued to isolate the cDNA by a complex method. The two larger peptides (17 and 18 amino acids) were formed, then a 599-bp product was synthesized from the two of these. This 599-bp product was then used to screen 106 cDNA clones and three clones
22. Nitric oxide from arginine: a biological surprise
977
had an open reading frame of 4,287 bases. This corresponded to a molecular mass of about ¾160K and incorporated all of the 21 peptides given by trypsin. The cDNA was inserted into human kidney cells with cytomegalus virus and gave a single Coomassie blue stain, which produced citrulline from arginine, produced nitrite from arginine and produced NO, which gave increased endogenous cGMP synthesis. The cDNA showed a 10.5 Kb band in total cerebellar RNA, which indicates that over half the mRNA is not expressed. NOS RNA was not expressed in kidney, liver, skeletal muscle, stomach or heart. The largest amounts were present in cerebellum, then less so in olfactory bulb, colleculi, hypocampus and cerebral cortex. Comparing the structure with those in Gene Bank, this was found to resemble cytochrome P-450. The amino acids from the C-terminal portion, 641 amino acids, have a homology with the cytochrome P450; there is a 36% identity and 58% close homology. The fact that both enzymes use both FMN and FAD suggests that there is a mechanism for transferring between them. This finding was confirmed by Mayer and coworkers45 . Using pork cerebellum, they employed similar purification to obtain a 45-fold enzyme. The factors responsible for activation were the same as those for rat: NADPH, CaCC plus calmodulin, FAD and, in an unknown way, BH4 . The molecular weight was also 160,000 kDa. A similar purification from rat cerebellum was made by Schmidt and collaborators46 , who also obtained similar values although they claimed four major factors were given by SDS/PAGE. The difference might have been attributable to the use of generic cerebella by the latter workers. B. eNOS cDNA
The success of Bredt’s group44 in cloning NOS from cerebellum raised questions about the similar cloning of endothelial cell NOS, largely because these two have roughly identical properties. In 1988, Palmer and Moncada47 and Schmidt and coworkers48 independently found that endothelial cells formed NO from L-arginine. Pollock’s group49 purified the enzyme from bovine aorta. The preparation was 95% insoluble but was converted to a form that was soluble on treatment with 3-[(3-cholamidopropyl) dimethylaminoniol]-propane sulfate (CHAPS). The soluble form with CHAPS was used. The purified enzyme required BH4 for maximum activity, CaCC and calmodulin and NADPH for any activity. Arginine was converted to citrulline, NO3 was created and the preparation had EDRF activity. The molecular weight was 135 kDa. The cDNA responsible for the aortic protein from bovine source was purified by four groups simultaneously, namely by Janssen’s group50 , by Sessa’s group51 , by Lamas and coworkers52 and by Nishida’s group53 . All four derived the same sequence of bases. Those include methionine, which is in a consensus sequence for initiation54 . Also included are a calmodulin site, an FMN site, a pyrophosphate and an FAD site for the dinucleotide and the NADPH sites for ribose and adenine. The three cDNAs made NO according to different assays, including NADPH diaphorase, a cyclic GMP assay, interfered with by NAME, synthesis of citrulline from arginine and NO synthase in COS cells. The fact that this 135 kDa protein was associated with the cell structure was pointed out by the authors as due to a myristyl site, which was not found in the brain cDNA. The report of Nishida showed a sheer stress in the cDNA. Endothelial NOS was found to be associated with cell membranes and this property was associated with the finding that the cDNA contained the structure for binding myristic acid55 . Busconi and Michel56 used bovine aortic endothelial cells to demonstrate that the myristoylated protein was found. When the second amino acid, glycine, was converted to alanine, the addition of myristic acid was prevented and the enzyme remained soluble. Sessa and coworkers51 carried out the same experiments simultaneously and found the same results. However, in both cases the enzyme was not purified, although the protein
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Alan H. Mehler
was found to include myristic acid. The protein was shown to be modified by Liu and Sessa57 . They found the endothelial NOS was indeed myristylated, that the myristic acid was not modified during the binding and that the binding is an amide linkage. Of course, the N-terminal methionine is lost during the preparation of the enzyme for myristoylation. C. iNOS cDNA
Macrophages were among the first cells found to produce NO29 . On purification, the macrophages from various animals were found to be similar to the neural43 and endothelial cells47,49 in that they contained an enzyme that decomposed arginine to citrulline and NO31,39 . The enzyme used NADPH for the reaction39 ; molecular oxygen was the source of the oxygen included in the products38,39 and the enzyme was only partially active in the absence of BH4 36,37 . The major difference between the enzymes was the complete lack of effect of CaCC and the independence of the activity upon calmodulin58,59 . Another difference was the inducibility of the macrophage enzyme60 62 . Both interferon- and lipopolysaccharide were required for maximum expression of activity63 and, contrary to the short half-life of the neuronal enzyme (seconds), the half-life of the macrophage was hours64 . The lack of calmodulin in the macrophage enzyme was explained by the work of Cho and coworkers65 , who reported that the purified enzyme contained calmodulin bound through noncovalent bonds. This followed the report by Stuehr’s group58 that the macrophage enzyme was purified from RAW 264.7 cells derived from mice and that this enzyme had, in addition to the features above, both FAD and FMN. This work strengthened the report of Yui and collaborators66 , which described the enzyme from rat macrophages but did not find evidence for calmodulin or flavins. A similar report from Hevel and coworkers67 described the purification from mouse macrophages of an enzyme that contained 1 FMN and 1 FAD; this also oxidized arginine to citrulline and NO better in the presence of BH4 . At this stage of discovery, the encouragement was set for cloning of the macrophage enzyme. This was carried out independently by three groups, Lyons and coworkers68 , Xie and collaborators63 and Lowenstein’s group69 . The first group68 showed the gene contained FMN, FAD and NADPH, the second group63 showed in addition the calmodulin binding site. Lowenstein’s group69 confirmed the findings of Xie and coworkers and showed the picture of spleen cells with both red pulp and, less, in white pulp. All three teams showed the molecular weight of 130,000. V. LOCALIZATION OF THE HUMAN GENE A. bNOS in the Human Gene
The localization of bNOS to the human genome was accomplished by Kishimoto and coworkers70 . These investigators used a rat cerebellar cDNA to obtain a human cDNA from Clontech. This cDNA was hybridized to Southern blots containing DNA from a battery of human-rodent somatic cell DNA. Since the blots had been shown to be selective, the authors showed that the cDNA hybridized to chromosome 12. By using restriction nucleases EcoRI and Hind III the assignment was made to 12 q14-qter. One or two copies were indicated in vivo but reducing the hybrid conditions showed more bands. It is necessary to conduct further studies to see whether the other cDNA are derived from this or another clone. A more complete analysis of human neuronal NOS gene was made by Hall’s group71 . It is a gene of 29 exons; a flanking region of over 1500 bp was determined 5- and several
22. Nitric oxide from arginine: a biological surprise
979 CaCC /calmodulin
poly (A) are found as far as nt 6632: A region for heme in exon 6, in exons 13 and 14, FMN in exon 18, FAD in exons 21, 22 and 23 and NADPH in exons 25, 26 and 27. Although promoters have yet to be determined in vivo, diversity is suggested by the occurrence of AP-2, TEF-1/MCBF, CREB/ATF/cFOS, NRF-1, Ets, NF-1 and NF-B in the 5-region. B. eNOS in the Human Gene
Janssens and coworkers50 cloned the cDNA for endothelial NOS from human tissues. The cDNA contained the FMN, FAD and NADPH sequences attributed to these cofactors. The enzyme was CaCC -dependent and this was blocked by L-NAME. More than 95% of the enzyme sedimented in the particulate fraction. The enzyme made cGMP in reporter cells, corresponding to NO synthesis, and this was antagonized by L-NAME. These properties of cDNA from human endothelial NOS were basically confirmed with several differences noted by Marsden’s group72 in the process of isolating and characterizing the human gene and locating it in 7q35 7q36. The gene was isolated from human clones in a bacteriophage library. This gene lacks the TATA box but includes a CCAAT box, Sp1 sites, GATA sites and reverse sites; AP-1 site, AP-2 site, physical stress elements and heavy metal sequences were found. Steroid binding sites were lacking. The consensus sequence for RNA polymerase III was found. The chromosome map was determined with human-rodent pairs at 7q32 7qter and was done more accurately with the FISH determination with metaphase chromosomes. This latter analysis showed that the gene was 7q35 36. The same authors also obtained a more precise location of the human bNOS as 12q24.2. This gene also contained the calmodulin/calcium site and the FMN, FAD and NADPH binding sites. Zhang and coworkers73 confirmed the work in eNOS of Marsden’s group72 with about 10 differences in the 50 -region, none of which was a promoter box. They found the number of promoters and Sp1 and GATA sites were effective. There is a likelihood of several others participating also. Busconi and Michel74 tested eNOS for membrane targeting and found that only the myristyl portion of the molecule, not the polybasic region, is responsible for membrane association. Venema and collaborators75 grew the eNOS in baculovirus. They found less than theoretical FAD and FMN and hope to find conditions for putting these flavins in the enzyme in proper quantities. C. iNOS in the Human Gene
A human gene for hepatic inducible NOS was isolated in 1993 by Geller and coworkers76 . Hepatocytes were isolated from an operative wedge resection, which were over 98% pure. The cells were stimulated with cytokines TNF-˛, IL-1 and IFN-. The purified cDNA, in addition to FMN, FAD and NADPH factors, also contained a calmodulin site. This site retained some activity in the presence of calcium inhibitors. There are also phosphorylation sites at 232, 576 and 890 residues. In a paper completing the series, Xu’s group77 confirmed the structure of human endothelial NOS as occupying 7q35 36 and found the gene for human inducible NOS as being on chromosome 17. This was a short paper that made the point that each of human genes for NOS, brain, endothelial are inducible, as a separate product of similar but related genes. A more complete paper by Chartrain and coworkers78 isolated the gene from human foreskin fibroblasts. The gene was shown to reside on chromosome 17 cenq11.2. A comparison of hepatic cDNA for NOS with the gene sequence showed 99.7% identity and the 0.3% difference is attributed to polymorphism, since the sources differed.
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D. Three Genes come from Three Chromosomes
In the few years since NOS was shown to be an ubiquitous enzyme, the enzyme had been purified, the mRNA was identified and the gene had been isolated and mapped to human chromosomes. The findings were the sort predicted from the beginning: the three types of NOS were indeed different from each other and were represented by three closely related, but distinct, genes occurring on three chromosomes in man. The three genes are large structures and it is possible that many introns will be responsible for types of one or more of the types. It should be noted, however, that only one gene exists of each type. VI. FORMATION OF NO AND CITRULLINE
The formation of citrulline from arginine led Hibbs and collaborators34 to postulate that the reaction known to occur in microorganisms was also found in eukaryotes. They proposed that the reactions shown in Figure 1 occurred. The reaction was specific for L-arginine and was also given by L-homoarginine but by no other guanidino compounds. A short time later, Iyengar’s group31 showed that the mixture of NO2 /NO3 was derived from the guanidino groups of L-arginine and that, since citrulline was probably a product, only a single N contributed. Since NO3 is not derived from NO2 , the synthesis of these compounds is conjectural. They wrote the reaction as shown in Figure 2. Palmer and Moncada79 found a similar reaction in porcine aortic endothelium but were reluctant to designate the same reaction as Hibbs and coworkers39 because they thought there was little point in reducing the nitrogen to ammonia before oxidizing it. They found NNMA to be a powerful inhibitor. Kwon, Nathan and Stuehr37 found tetrahydrofolic acid (BH4 ) to serve as a cofactor for the production of NO from mouse macrophages. This compound had been established Deminase
L-arginine
C H2 O ! citrulline C NH3 oxidase
NH3 C 1 12 O2 ! NO2 C H2 O C HC FIGURE 1
H2 15N H2 15N
+ NH3 + C
NCH2 CH2 CH2 CH H − COO
15
−
NO2 + 15NO3
−
O
O N 15
N O
N H FIGURE 2
22. Nitric oxide from arginine: a biological surprise NADPH
NADP
981
+
Dihydrofolate reductase
MTX H2 Biopterin H4 Biopterin
NA D(P)H
Q−H2 Biopterin
Dihydropteridine reductase
−
NMA
NO2 + − NO3
NO −generating Enzyme(s)
O2
NADPH(?) L−Arginine
NO + L−Citrulline
FIGURE 3 + H2 N
+ H2 N
NH2 NH
+ H3 N
+ H2 N
NHOH
+ H3 N
−
L-Arginine
O
NH
NH
COO
N
+ H3 N
−
COO
−
COO
NG-oxo-L-arginine
L-NHA
N
O
H
O2 H2 N
NH
+ H3 N
N
−
COO
L-citrulline
FIGURE 4
+ H2 N
H2 O
O C
+ H3 N
C
NH
−
COO
NO2
−
NO3
NO
−
N
+ H3 N
−
COO
982
Alan H. Mehler OH
+ H2 N
N CH3 ΝΗ
+ H2 N
+ H2 N
NHCH3 H+
ΝΗ
N
CH3
+ H3 N
−
COO
ΝΗ + H2 N
+ H3 N
−
COO
+ H3 N
H N
CH2
ΝΗ
−
COO
L-NMA
−
H3 N
COO
OH
+ H2 N
NH
CH2
ΝΗ
+ H3 N
−
COO
Carbanolamine −Η 2 Ο
+ H2 N
CH2
N ΝΗ
+ Η 3Ν
−
COO imine
FIGURE 5
22. Nitric oxide from arginine: a biological surprise
983
as the cofactor for phenylalanine hydroxylation to tyrosine80 as well as tyrosine and tryptophan hydroxylation81 . Kwon and coworkers37 not only found that the production of NO was stimulated, but found that a reduction of the pterin could be accomplished if FAD and GSH were added. Therefore, they included in their article the picture shown in Figure 3 to illustrate the reaction. Actually, Tayeh and Marletta36 had also found BH4 to be a cofactor for mouse macrophages one month previously but had emphasized the NO synthesis. In the picture that they had included, the first hydroxylated arginine was shown as N-hydroxyl-L-arginine although this compound had not yet been published. The reactions leading to NO and citrulline are shown in Figure 4. The synthesis of NG -hydroxy-L-arginine was published by Pufahl and Marletta82 . This compound was shown to be a substrate for the production of nitrite and nitrate, for the production of NO and for the synthesis of citrulline. When 15 N-NHA was used as substrate, the NO2 /NO3 produced were found to contain undiluted 15 N. Therefore, they concluded that the NG -hydroxy-L-arginine is a true substrate in NO synthesis. Hibbs and coworkers34 had reported that the NG -methyl-L-argine was a potent inhibitor of macrophage nitrite generation. This was subsequently studied by Olken and collaborators83 . They found that NG -methyl-L-arginine is indeed an inhibitor with a Ki approximately equal to the Km of arginine (4 2 mM for the methyl compound and 7.4 mM for arginine). Two of the mechanisms of the inhibitor are illustrated in Figure 5. They also included a third mechanism of a peroxide formation. The lower case given, in which a Michael acceptor is shown, seems unlikely since the authors state that this should give formaldehyde and L-arginine, which should overcome the inhibition. V. COMPLEXITIES OF NOS A. Role of BH4
The role of BH4 was made contentious by the finding that it is not recycled in the brain NOS. Giovanelli’s group84 used the enzyme prepared according to Bredt and Snyder43 and showed that the protein responded to BH4 . The results of Giovanelli’s group84 showed that the BH4 acts in very low concentration (<1.0 mm) and that it does not have to be reactivated during the catalysis. Each BH4 molecule is responsible for >15 moles of product. They conclude that the function may be allosteric or it may serve to maintain some groups in a reduced state required for activity. The above conclusion84 was negated by the findings of Hevel and Marletta85 . These authors used mouse macrophages to study the effect of BH4 on NOS. With the purification used in the past, they found only a small portion of the BH4 relative to other cofactors and in this case they found a considerable activation on adding more BH4 to the reaction. However, when 5ðM BH4 was added to the solutions used for preparation of the enzyme, they found essentially a 1:1 ratio of BH4 to the enzyme and no effect of adding more BH4 . They concluded that BH4 is used in an oxidative reaction of the macrophage NOS. Of course, a possibility as to the difference between the results of Giovanelli’s’ group89 and of Hevel and Marletta85 is the use of bNOS and iNOS, respectively. B. Iron in NOS
Iron was first found in NO synthase by Mayer and coworkers86 . Probably because the amount of enzyme obtained from brain was small, they reported the iron as non-heme. The next year, however, the iron was reported by White and Marletta87 as heme iron. The heme was identified at a mixture of high-spin and low-spin states with a shoulder at
984
Alan H. Mehler +
NADPH O2
Fe
NADP H2 O
+++
H2 N
+++
(FeO)
NOH
H2 N
NH
+ H3 N
NH2 N
−
COO
+ H3 N
−
COO
FIGURE 6
406 nm, previously shown by Nardi and Fulco88 to be due to FMN and FAD bound to the enzyme. White and Marletta87 proposed that the iron might work as a carrier of oxygen and be responsible for the formation of NG -hydroxy-L-arginine. They also demonstrated that the porphyrin was protoporphyrin IX and presented the CO spectrum. The work was with mouse macrophage NOS and a partially purified bNOS was said to have similar properties. This is shown in Figure 6. In an article published independently at the same time, Stuehr and Ikeda-Saito89 used the purified bNOS and iNOS to reach the same conclusions. While the paper was under review, the authors mention that White and Marletta had reported earlier that the iron was a heme and was used as an oxidant. Using the same type of study, they found that the iron prophyrin and its CO derivative had the expected properties and proposed that the iron is penta-coordinated, with a cysteine thiolate as the fifth coordinate. A third publication confirmed the results when McMillan and coworkers90 used bNOS grown in human kidney cells. These workers obtained similar data for the light absorption of the enzyme and its CO spectrum. They also speculate on very similar sequences in the three types of purified enzyme that might be the porphyrin binding site. Mayer and collaborators45 also found biopterin in NOS and found iron, which they claimed was non-heme. The biopterin they postulated was reduced by NADPH. Therefore, they proposed the mechanism shown in Figure 7 to account for the overall reaction.
22. Nitric oxide from arginine: a biological surprise
985
NH R
L-arginine
C NH2
NADP
+
H4 Biopterin
O2
(Fe) +
H + NADPH
9-H2 Biopterin
H2 O NOH
NADP
+
FADH2
O2
O2
R
C NH2
O R
NH2
HO2 O2
FADH
L-Citrulline
C
NO.
H2 O ∗
N +
H + NADPH
HO2 + R
FAD
C
H NH2
O
O R
C
O
H
H NH2
H2 O2
FIGURE 7
Stuehr and coworkers91 synthesized NG -hydroxy-L-arginine and suggested the scheme shown in Figure 8 to make up the action of NOS. Using bNOS, Klatts’ group92 determined that the BH4 gave five times the rate of NADPH and that Fe was part of the enzyme. Without deciding where the BH4 reacted, they proposed the scheme shown in Figure 9. Pufahl and Marletta82 , with the NG -hydroxy-L-arginine that they had synthesized, gave the outline of the scheme presented in Figure 10. Using a spectrophotometric method, McMillan and Masters93 obtained evidence that bNOS contained a heme group that reacted with L-arginine and with NG -hydroxy-Larginine (an intermediate) and NG -methyl-L-arginine (an inhibitor). They therefore concluded that the heme was an oxygen donor. In a minireview, Marletta94 postulated the series of reactions in Figure 11. The reactions show the details of the iron porphyrin reaction and are concerned with the formation of NO. In a review without references, Feldman and coworkers95 proposed a very similar scheme to Marletta94 but with the nitrogen of hydroxyarginine assuming an iminoxyl radical that is converted to NO. Korth’s group96 accept the scheme published by Marletta94 but proposed that the NG -hydroxy-L-arginine must be oxidized according to the mechanism of Figure 12. This sequence of reactions argues against the participation of the iminoxyl radical of NOH as the reductant because it is likely to lose a proton more rapidly, and therefore reactions A, B, F, G, H and I are proposed. Using a purified bNOS, Campos and collaborators97 studied the hydroxylation of Larginine by the enzyme minus NADPH. They found 0.16 mole of NOH per mol of NOS. The presence of reducing agents in the purified bNOS was measured as much less than the NOH formed. Possible reagents that could have been responsible are flavin and BH4 .
986
Alan H. Mehler NADPH
0.5 NADPH
O2
O2 BH4
! N-hydroxy-L-arginine !
L-arginine
NOž C citrulline
FIGURE 8 + NH3
NH2 RN H NH2 RN
C
C
O
C
NHR NH3
+ 3+ O + Fe
N
HN
Fe
3+
Fe
3+
HN
C
NHR
OH +
H + NO
NH2 RNH
C H
+ O (Fe
N
e
+ NH3
3+
O)
Fe
2+
+ ΗΝ
H2 O2 , O2
H2 O
−
+
RNH
C H
+ 2+ − O Fe O2
N
e
C H
+ NH3 O2
Fe
2+
ΗΝ
−
NH2 RNH
− O2
− O2
+ 2+ O Fe O2
N
Fe
3+
ΗΝ
RNH
C H
− O2
N
Fe
2+
ΗΝ
C
NHR
+
H2 O + NH3
+ NH3
FIGURE 9
NHR
2H
+
C
C
+ NH3
H
RNH
NHR
−
O2 + 2+ O Fe
C
+ NH3
e
NH2
NHR
O2
2H NH2
C
Fe N
OH
3+
(O
3+
Fe)
ΗΝ
C
NHR
22. Nitric oxide from arginine: a biological surprise L-arginine
NADPH
NADPH
O2
O2
987
! NG -Hydroxy-L-arginine ! citrulline C NO
FIGURE 10
PPIX H2 N
+++
Fe + NH2
PPIX Fe H2 N
NH
+++
N
OH
H2 N
NH
COO
−
++
Ο2
N
PPIX Fe
OH
H2 N
NH
+++
−
OO
N
OH
NH
1 NA DPH 2
NA DPH O2
+ H3 N
PPIX Fe
O2
+ H3 N
COO
+ H3 N
−
COO
+ H3 N
−
COO
−
NHA
PPIX Fe
+++
H2 N • NO +
PPIX Fe
+++
O
O H2 N NH
H3 N
O N NH
COO
−
+ H3 N
O
−
COO
−
FIGURE 11
C. Subunits and Dimers
Although the first purification of bNOS was a monomer, it is now clear that the enzyme in all cases is effective as a dimer. A purified macrophage iNOS was used by Baek and coworkers98 to separate the holoenzyme from the monomers. The subunits do not have NOS activity but do have the ability to oxidize reduced triphosphopyridine nucleotide with either ferricyanide, cytochrome c or dichlorophenolindophenol. When all of the missing factors are present, but not when any is missing, the authors find recombination, as shown in Figure 13. Ghosh and Stuehr99 found the two subunits combined in a head-to-head fashion. They consider that the two tails could be free or could be somehow bound. Raman spectra were performed by Wang’s group100 . They found the heme to have a 5-coordinate high spin configuration. The fifth ligand was an axial bond to the thiolate, which was confirmed by the FeCO bending mode at 562 cm1 .
988
Alan H. Mehler PPIX Fe
+++
1 NA DPH 2 − 1 NA DP 2
PPIX Fe
++
O2
PPIX Fe
+++
OO
PPIX Fe A
+ PPFe
+++
OOH
PPIX Fe
OO
O
F + H3 N
NOH
+ H3 N
C
NH
+++
B
+++
N
OH
+ H3 N
D
NH
O•
N
H
O
O
H3 N
N
G
NH
NH
+++
+ PPIX Fe OO +++ − PPIX Fe OO −
H3 N
COO
−H
+ H3 N
−
COO
+ H3 N
−
+ PPIX Fe
+++
+
− OO −
COO
+ H3 N
−
E
H
H2 N
−H
O
PPFe + N
O
+
PPIX Fe COO
−
FAD
Fe N
FMN
N Arginine 2
FMN FAD CAM
H4B
H4B N
N CAM
N +2 +2
FIGURE 13
FAD
FMN
Fe N
OH
+ H − H2 O
CAM N
+++
I
FIGURE 12
N
−
+
NH
+ H3 N
COO
N
N Fe
N H4B
N
+++
22. Nitric oxide from arginine: a biological surprise
989
The activity of bNOS is firmly bound to the amino acids that comprise the enzyme and is able to withstand separation of the two halves by tryptic cleavage. Sheta and collaborators101 separated ca 79 and ca 89 fractions from bNOS and found that one fraction (ca 79) had the heme and the other (ca 89) had the flavin and was able to reduce cytochrome c. When the two domains of the enzyme were held together with calmodulin, the appearance of the two domains was prevented. The finding of retained activity of the two halves was confirmed by McMillan and Masters102 , who produced the heme component and the flavin-binding component with and without the calmodulin site as proteins produced in E. coli. The workers showed the heme had spectral properties of NOS and that the fifth ligand was Cys415 by changing this to histidine in a site-specific mutation: the mutant did not bind heme. Chen and coworkers103 prepared mutants of the eNOS and grew them in COS-1 and baculovirus cells. Alanine instead of cysteine in positions 235 and 441 retained the heme and NOS activity of the enzyme, but these changes at cysteine 99 and 241 gave no NOS activity. The authors picked Cys184 as being responsible, because the peaks with CO were missing whereas the Cys99 still gave the CO change. At the same time that Chen’s group103 reported the above, Richards and Marletta104 reported the findings with neural NOS and the C415H mutant. Heme at 7 ð M gave a 7-fold greater activity and there was about a 50% increase with BH4 in the assay. The C415H mutation gave no NOS activity and the enzyme was devoid of heme. The flavin spectra in the region 450 to 500 mm were normal. This was the first evidence that the Cys 415 binds the heme. D. Complications of Many Cofactors
By resonance Raman methods, Wang and coworkers105 showed NO bound to both ferric and ferrous heme of bNOS. Hurshman and Marletta106 used iNOS and spectrophotometric methods to show similar reactions, although the physiological effects will depend on the effects of arginine and oxygen in vivo. Using neuronal NOS, Matsuoka and collaborators107 observed that arginine apparently reacted with the heme to reduce the rate of CN or CO reacting. The reaction of L-arginine CAM
1
O2
2 NADPH e−
FAD, FMN
e−
O2 heme Fe
−
+++
Arginine
NO
cytochrome c Fe(CN)6 FIGURE 14
990
Alan H. Mehler
is shown to take place with the iron instead of the H2 O. Calmodulin does not affect the iron but permits electrons to flow from the flavins. NO in the concentrations formed by NOS from brain were shown by Griscavage and coworkers108 to inhibit the synthase about 1,000ð more than CN . This effect was attributed to binding to the ferric heme and could be reversed by BH4 but not by other reducing agents. Mayer’s group109 used a Clark-type nitric oxide electrode to follow the reaction of bNOS and found also a strong inhibition by BH4 . They conclude that BH4 reacts with SOD to peroxynitrite. Abu-Soud and coworkers110 were able to remove heme and BH4 from NOS by dialysis with 2 M urea. The remaining enzyme retained the ability to reduce ferricyanide and cytochrome c. The reduction of cytochrome c was about 9ð in the presence of calmodulin. The two sites of calmodulin for influencing the reaction are shown in Figure 14. Hobbs and coworkers111 used a specific chemiluminescent reaction to measure NO. With this they determined that the reaction measured by citrulline formation was not affected by SOD but that NO was increased. E. Inhibitors of NOS
A further study by Olken and collaborators112 describes inactivation of mouse iNOS by NG -methyl-L-arginine. The inactivation occurs only in the presence of oxygen. Only a small amount of 3 H or 14 C label from the labeled methyl group of NG -methyl-L-arginine
PPIX H2 N
Fe
+++
PPIX
NOH
Fe
+++
H2 N
OO−
PPIX
Fe
+++
NOH
NH
O
O
H2 N
NH
N −
OH
NH
HOOH
+ H3 N
−
COO
+ H3 N
+ H3 N
−
COO
L-NHA
Ferric nitroxyl PPIX
Fe
+++
NO−
PPIX
Fe
Fe
+++
λmax440, 578 nm
NH
NO
O2 (aerobic) HOOH
NO2
FIGURE 15
+ NO −
O
H2 N Ferrous nitrosyl PPIX
+++
−
NO3
−
+ H3 N
−
COO
−
COO
22. Nitric oxide from arginine: a biological surprise NADPH
e−
FAD, FMN
heme Fe
991
+++
− CAM + CAM
NADPH
e
FAD, FMN
e
Arginine
O2
CAM −
−
heme Fe
Thiocitrulline NAME
+++
e−
O2
−
NO
Dithionite FIGURE 16
was included, showing that the reaction is varied. A large amount of the heme was lost in inactivation. Simultaneous studies by Abu-Soud group113 with three inhibitors, Nω -methyl-L-arginine, Nω -nitro-L-arginine methyl ester and thiocitrulline, affected both neuronal and macrophage NOS. Whereas the Nω -methyl-L-arginine was similar to Larginine in that it did not prevent the reduction of heme, both Nω -nitro-L-arginine and thiocitrulline did. The inhibition by both of these compounds seems to block at two points, shown in Figure 15. A variety of L-arginine-based inhibitors was tested by Komori and coworkers114 . They found NG -methoxy-L-arginine as well as NG -hydroxy-L-arginine and L-arginine itself to oxidize NADPH. The mechanism of the effects remain to be determined. The ability of murine macrophage NOS to use peroxides in place of oxygen was studied by Pufahl and collaborators115 . Cumene hydroperoxide and tert-butylhydroperoxide were inactive but hydrogen peroxide supported product formation. Interestingly, L-arginine was not used but NG -hydroxy-L-argine was a substrate. The authors proposed the mechanism for the hydrogen peroxide in Figure 16. Several specific inhibitors of NO synthetases have been found. The species of all three human NOS was found by Garvey’s group116 to be inhibited by isothioureas, with ethylthioruea the most powerful. Furfine and coworkers117 found S-methyl-L-thiocitrulline and S-ethyl-L-thiocitrulline were effective vs neuro NOS in human, but there seems to be difficulty in in vivo studies. Narayanan’s group118 reported on several S-alkyl-L-thiocitrullines from rat with nNOS and iNOS. The methyl compound is most potent and is reversible. Another type of inhibitor was found by Wolff and Griben119 to be imidazole and its phenyl derivatives and120 also substituted nitroindazole, especially the 7-nitroindazole. Wolff and Lubeskie121 reported that aminoguanidine is a mechanism-based inhibitor of the three types of NOS. F. Factors for Growth of NOS
Hartneck and coworkers122 grew rat bNOS in baculovirus. Calcasi and collaborators124 found that the bNOS gives a burst of superoxide when stimulated by N-methyl-D-aspartate. This is arachadonic-independent and is suppressed by L-arginine or NG -nitro-L-arginine. The superoxide gives cell death. Xie’s group123 measured two closely linked but separable promotors for iNOS. Lowenstein and coworkers125 reported that bacterial lipopolysaccharide (LPS) promotes iNOS
992
Alan H. Mehler
and that IFN- does not by itself but with LPS gives a big stimulation. This was confirmed by Weisz and coworkers126 . Balligand’s group127 detected the iNOS in single myocytes. Two distinct pathways for generating expression of iNOS in rat cells were demonstrated by Kunz and coworkers128 . Xie and collaborators129 reported that NF-B is essential for LPS induction of iNOS in the mouse. They found two NF-B, one in the 50 -region, NF-Bu, and one in the downstream location, NF-Bd. The downstream NF-Bu is responsible for the induction of LPS. Chu’s group130 described a large series of human iNOS that varied in the initial codons, many lacking the first exon. Xie and coworkers131 cloned the NOS from RAW264.7 cells and found two sets of cDNA. The smaller set was 22 amino acids shorter. They found that this cDNA did not produce NOS. By removing amino acids, they found Phe reduced the level to 41%, removing the Ile1121 further reduced the level to 95% and further removal lost all NOS activity. This is the first example of the importance of the COO region. The eNOS has been purified from many tissues. Human NOS was purified from placenta by Garvey collaborators132 . Balligand’s group133 found rat eNOS in myocytes and showed it to be responsible for cholinergic and ˇ-adrenergic regulation and muscular contraction. The eNOS of guinea pigs was shown to be dependent on sex hormones by Weiner and coworkers134 . This was the first evidence that the eNOS was inducible. A human colon adenocarcinoma was found by Jenkins and collaborators135 to be stimulated by eNOS. Schmidt’s group136 reported that two of the arginine derivatives inhibit NOS, NG methyl-L-arginine and NG -nitro-L-arginine, and are taken up by cationic amino acid transporter and neutral amino acid transporter of macrophages. The same authors137 found that peroxynitrite produces the same change in hemoglobin as NO, but that it does not interfere with the Clark-type determination of NO. Peroxynitrite was also found to be the compound that inactivates aconitase. In a couple of papers published together in J. Biol. Chem., Hausladen and Fridovich138 and Castro’s group139 reported that this ironcontaining enzyme is not inhibited by NO but is inhibited by peroxynitrite. Hecker and coworkers140 described an adduct of NG -hydroxyl-L-arginine with NO as the product made by IL-1ˇ in rat muscle that yields NO immediately with NOS. VIII. PHYSIOLOGICAL FUNCTIONS OF NOS
The two most surprising aspects of NO are the large number of alterations of metabolism controlled by a simple gas and the most extensive list of diseases that may be caused by either an increase or decrease in the concentration of the molecule. The second function, the clinical function of NO, has occupied the attention of both the preclinical and clinical investigators and is responsible for the growth in the literature. To attempt to cover the clinical literature is far beyond the scope of this review but the outlines of the subject cannot be ignored. The scope of this branch of the literature is expanding while this chapter is being written, and the impact of NO on medicine is just arriving. The early studies on NOS in macrophages suggested to the authors that the synthesis of NO was responsible for the killing of tumor cells and certain pathogens28 . It is now clear that the application of nitroglycerin and related compounds is due to the release of NO141 and that eNOS carries out this function in vivo. However, NO also is responsible for killing neuronal cells. Zhang and coworkers142 have determined that NO was capable of damaging the DNA of sensitive cells and, by activating poly (ADP-ribose) synthetase, kill the cells by energy depletion. The finding of a brain NOS42,43 led to speculation that various neurological disorders were due to this molecule. Therefore, it was of great significance when Huang and collaborators143 produced a strain of mice completely lacking bNOS. These mice had
22. Nitric oxide from arginine: a biological surprise
993
only minor lack of the enzyme: homozygous mutant animals have stomachs with 1.5 3ð the stomachs of littermates and pyloric stenosis. They grow normally and breed at normal levels. Their brains appear normal. Except for the NOS, they appear to have the usual enzymes and the mutant mice seem to have the expected functions. Vasodilation of vascular penile beds does not depend upon the bNOS and the animals mate normally. Prior to knockout mice, a number of neural functions were ascribed to NO function. The fact that these have not appeared does not mean that the functions do not exist but that more than one function can apply. Thus, in penile tissue of rates NOS nerves are prominent144 and electrical stimulation produced penile erection145,146 . Normal mating of knockout mice suggests that this function can take place without NO participation, but this leaves the NO function to be assigned to an auxiliary role, perhaps to play a more important role when the alternative neuroexciter is deficient. Similarly, Huntington and Alzheimer diseases might occur when two different neurotransmitters are deficient. The second mice to undergo a deficiency of iNOS were produced by MacMicking’s group147 . These animals were again, like the bNOS, grossly normal. When tested against certain toxic elements (Listeria, lymphoma cells), the iNOS were more susceptible, showing that the NO produced had an effect but was not the difference that some of the experimenters had anticipated. Testing against septic shock, the drop in arterial pressure was only 15% in 2 hours with LPS and the animals survived whereas wild-type mice lost 64%, of the arterial pressure and all died. However, the death due to killed Propionobacterium acne, a granuloma-forming bacterium, was the same for mutant and wild-type mice. In this case it is clear that the NO does not deal with all of the functions of live bacteria and that iNOS can affect only those properties protected against by NO. The third eNOS has very recently been knocked out in mice in work that has yet to be published by P. L. Huang. Although he cannot give the data of the paper, he indicates that the animals are fertile and that they have higher blood pressure than their littermates. Since this form of NOS is primarily concerned with blood pressure, this is the feature that is emphasized in the preliminary paper. Within the past two years, NOS has been shown in a variety of invertebrates, from slime molds148 through molluscs149 . The exact function of NO in invertebrates is still unknown and is part of the puzzle of the purpose of this material in biology. According to Nathan and Xie150 , it is quite within the scope of biology for some modifications to be met on purification of the invertebrate enzymes. The nomenclature of the mammalian enzymes studied in the present situations is suggested by these authors to be mathematical in place of alphabetical. Thus bNOS, or ncNOS, would be referred to as I, iNOS would be called II and eNOS, or ecNOS, would be called III. IX. CONCLUSIONS
From 1987 until now only a few years have passed, but in that time a new physiological mediator has been found, NO. In this short time the three enzymes that individually mediate this reaction in mammals have been characterized and the occurrence of similar enzymes in invertebrates have been determined. It is not only new, but surprising, that this physiological agent is a gas that is formed in one cell and spreads its function to nearby cells, but that its function is limited by oxidation. In the case of brain, Verma and coworkers151 have recently suggested that carbon monoxide may be a similar activator of cGMP. The period of surprises is not yet over. X. REFERENCES 1. R. F. Furchgott, in Vasodilatation: Vascular Smooth Muscle, Peptides, Autonomic Nerves and Endothelium (Ed. P. M. Vanhoutte), pp. 401 414. Raven Press, New York, 1988.
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Alan H. Mehler
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Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
23
Reactions of nitrosoarenes with SH groups P. EYER and D. GALLEMANN Walther-Straub-Institut fur ¨ Pharmakologie und Toxikologie, Ludwig-Maximilians¨ Munchen, Universitat Nuˇbaumstr. 26, D-80336 Munchen, Germany ¨ ¨ Fax: (089)-51452-224
I. INTRODUCTION AND HISTORICAL REMARKS . . . . . . . . . . . . . . . . II. REACTION PRODUCTS AND PATHWAYS . . . . . . . . . . . . . . . . . . . . . A. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Formation of the Semimercaptal Intermediate . . . . . . . . . . . . . . . . . . 1. Structural elucidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Kinetic aspects of semimercaptal formation . . . . . . . . . . . . . . . . . . C. Formation of the N-Hydroxyarylamine and its Secondary Products . . . . 1. N-Hydroxyarylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The bifurcation at the semimercaptal stage . . . . . . . . . . . . . . . . . . 3. Secondary products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. The Sulfenamide Cation Descendants . . . . . . . . . . . . . . . . . . . . . . . . 1. The sulfinamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a. Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. Formation mechanism and kinetics . . . . . . . . . . . . . . . . . . . . . 2. Sulfenamide and arylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . a. Formation and identification . . . . . . . . . . . . . . . . . . . . . . . . . . b. Remarks on the formation mechanism . . . . . . . . . . . . . . . . . . . 3. Thio ether . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. N-Sulfenylquinonimines and resultant products . . . . . . . . . . . . . . . a. Monocyclic products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. Bicyclic products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . c. N-Sulfenylquinonimine formation from nitrosophenols and nitrosoanilines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Formation of N-Hydroxysulfonamide . . . . . . . . . . . . . . . . . . . . . . . . F. Reaction Pathways Involving Radical Intermediates . . . . . . . . . . . . . . III. BIOLOGICAL SIGNIFICANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Monocyclic Nitrosoaromatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
999
1000 1001 1001 1001 1001 1003 1007 1007 1007 1009 1009 1009 1009 1010 1011 1011 1012 1014 1015 1015 1016 1018 1019 1019 1020 1020 1022
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P. Eyer and D. Gallemann
1. Nitrosobenzene generated from nitrobenzene and aniline . . . . . . . . . 2. Nitroso-procainamide from procainamide . . . . . . . . . . . . . . . . . . . 3. 3-Nitrosobenzamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Nitroso derivatives of chloramphenicol . . . . . . . . . . . . . . . . . . . . . 5. Nitroso derivatives of chloroanilines . . . . . . . . . . . . . . . . . . . . . . 6. Nitroso derivatives of sulfonamide drugs . . . . . . . . . . . . . . . . . . . 7. Nitroso derivatives of dinitrobenzenes . . . . . . . . . . . . . . . . . . . . . 8. 4-Nitrosophenetol from 4-phenetidine . . . . . . . . . . . . . . . . . . . . . 9. 4-Nitroso-N,N-dimethylaniline . . . . . . . . . . . . . . . . . . . . . . . . . . C. Polycyclic Nitrosoaromatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 4-Nitrosobiphenyl from 4-aminobiphenyl . . . . . . . . . . . . . . . . . . . 2. 2-Nitrosofluorene from 2-acetamidofluorene . . . . . . . . . . . . . . . . . D. Heterocyclic Nitrosoaromatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Nitrosoimidazoles from nitroimidazoles . . . . . . . . . . . . . . . . . . . . 2. Heterocyclic N-oxygenated compounds derived from food mutagens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1022 1023 1023 1024 1026 1026 1028 1029 1029 1030 1030 1031 1031 1031 1033 1035
I. INTRODUCTION AND HISTORICAL REMARKS
The reaction of the aromatic nitroso group with thiols was unknown in organic chemistry until the sixties of this century. Thus, in 1969 Furuya and coworkers attempted to investigate the mechanism of thio etherification of 4-nitrosophenol in more detail when they reacted it with ethylmercaptan1 . The products they observed, however, most probably resulted from the interaction of the nitroso group with the thiol. This gap in organochemical knowledge is quite amazing since reactions of nitrosoarenes with thiols are exothermic and kinetically uninhibited at ambient temperature. Furthermore, these reactions obviously parallel the semiacetal formation of carbonyls reacting with alcohols. Moreover, similar reactions of nitrosoaromatics with active hydrogen compounds are well known2,3 . Thus, a semiacetal-like product was identified in 1901 by Bamberger and Rising4 while reacting nitrosobenzene with 4-toluenesulfinic acid. However, until the late seventies there are only a few papers superficially dealing with the interaction of nitrosoarenes with thiols. To our knowledge, this reaction was first mentioned by Smentowski in 19635 . He investigated the reaction of nitrosobenzene with 2-naphthylthiol and reported the thiol disulfide and the corresponding azo(xy)aromatics to be the main products. A variety of products have been observed by several groups: thiol disulfide5,6 , azo(xy)aromatics5 7 , arylamines6,8 , an adduct of nitrosoarene with thiol which could be hydrolyzed to the corresponding arylamine by acid or alkali treatment9 11 and a thio ether8,12 . Despite this mysterious medley of different products emerging from the reaction of nitrosoaromatics with thiols, no detailed investigation was undertaken to illuminate the obviously complex reactions until toxicologists took an interest in that topic. This interest arose when it became clear that nitrosoarenes and the N-hydroxyarylamines are biological reactive intermediates that are involved in toxic, allergic, mutagenic and carcinogenic effects. Hence, interactions with cellular thiols, predominantly with glutathione (GSH) and protein SH groups, were considered to be important for the detoxication of nitrosoarenes. In 1977, Neumann and coworkers11 were the first to present a hypothetical scheme illustrating how a labile nitrosoarene/thiol adduct9 11 may liberate the arylamine. In 1958, Kiese and coworkers for the first time detected nitrosobenzene in the blood of dogs after aniline administration, and it was his group who discovered N-oxygenation and the site of action in vivo13 16 . Finally, Kiese initiated17 and extended the research in the metabolic fate of nitrosobenzene in erythrocytes10 and encouraged one of the authors
23. Reactions of nitrosoarenes with SH groups
1001
to participate in this field18,19 . Hence, we greatfully took the opportunity to maintain this tradition by collecting the pertinent data and presenting a comprehensive review on chemical reactions of the aromatic nitroso group with thiols. Detailed investigations in well defined chemical systems revealed these reactions to be very complex, and a lot of items remain in the dark until today. Since scientists of chemical toxicology are expected to be among the most interested readers of this chapter, the biological significance of these reactions is presented in more detail, too. II. REACTION PRODUCTS AND PATHWAYS A. Overview
Scheme 1 summarizes the main reaction pathways proposed for the interaction of nitrosoarenes with thiols in aqueous, neutral solvents as deduced from product patterns and kinetic data. Accordingly, the first reaction step is the formation of an addition product (1), termed ‘semimercaptal’. This labile intermediate is cleaved by a second thiol molecule yielding the corresponding N-hydroxyarylamine (2). Alternatively, the semimercaptal NO bond may be broken with formation of an electrophilic sulfenamide cation (3). Both reaction pathways compete for each other, depending on aryl substituent(s), pH of the reaction medium, and concentration and pKa of the thiol. The ramification of the reaction pathway at the sulfenamide cation stage is even more complex since the positive charge is delocalized through the aromatic system, depending on the aryl substituent(s). Generally, three electrophilic centers (the sulfur atom and the o- and p-position of the aromatic ring) can react with various nucleophiles (excess thiol, solvent H2 O and the reaction product arylamine 8), giving rise to a variety of intermediates and end products such as sulfinamides (4), sulfenamides (5 and 6), thio ethers (7), arylamines (8) and Nsulfenylquinonimines (9 and 10). Again, the preference of a distinct pathway depends on the aryl substituent(s) and the thiol concentration. Beside the pathways summarized in Scheme 1, a few additional reaction possibilities are reviewed in Sections II.E and II.F. B. Formation of the Semimercaptal Intermediate
1. Structural elucidation
According to the different electronegativity of nitrogen and oxygen, the nitroso group is polarized in analogy to the homologous carbonyl group† . Similar to alcohols reacting with carbonyls, the addition of thiols to nitrosoarenes yields a semiacetal-like N-hydroxysulfenamide which was first postulated by Youssefyeh21 .
Ar
N
O + RSH
k 1 (fast) k −1
S Ar
R k 2 (slow)
N
products
(1)
OH
The family of the N-hydroxysulfenamides has been commonly termed ‘semimercaptal’22 31 , despite the potential confusion with carbonyl/thiol adducts (see, for example, Reference 32). With few exceptions, semimercaptals are very unstable and give various † Molecular orbital calculations on the electrostatic potential of the aromatic nitroso group revealed an uneven charge distribution at the nitroso-nitrogen, enabling both electrophilic and nucleophilic attack20 . Accordingly, the major negative region is located at the outside of the CAr NDO angle within the molecular plane, reflecting the nitrogen lone electron pair. A significant build-up of a positive potential was calculated to be inside the CAr NDO angle below and above the molecular plane.
(2)
RA /D
N
+ RSH − RSSR
H
(1)
O + RSH
OH
N
N
OH
O
S
R
−
RSH
(9)
−OH
N
S
+ H2 O + − RD H / H
RD
RD
RA /D
RA /D
R
+
(3)
RD
+
N
N
+ N
N
R
R
R
R
RSH
(10)
N
−
RD
RA /D
(6)
+RS , RSH
−
+
+ RS
−H
+ H2 O
−RSSR
RD + − RDH / H
S
S
S
+ S
N
N H
S
S
(5)
(4)
R
R
RD
S S
+ RSH − RSSR
R
R
RD
S
+ RSH
S
(7)
− RSSR
N H
R
N H
O
NH2
R
(8)
NH2
SCHEME 1. Main reaction pathways during interaction of nitrosoarenes with thiols (RA denotes electron acceptor substituent and RD electron donor substituent)
RA
RA /D
1002
23. Reactions of nitrosoarenes with SH groups
1003
products depending on the nature of their aryl substituent(s). Therefore, this family has only been hypothesized for about ten years11,18,21 23,25,33 37 before it could be isolated in substance. In our laboratory, Klehr reacted nitrosobenzene with 1-thioglycerol in methanol at 40 ° C and confirmed the proposed structure by 13 C-NMR, FAB-MS and UV spectroscopy24,38 . In the meantime some other semimercaptals have been proved structurally29,38,39 . Semimercaptals (1) exhibit a variety of spectroscopic characteristics. The most typical property is a strong FAB-MS signal at m/z D [MCH18]C (positive ion mode), thereby enabling a clear distinction from the isomeric sulfinamide (4)24,29,38,39 . Obviously, the N-hydroxy group is particularly prone to proton impact and subsequent loss of water. Further discrimination from the sulfinamide is given by the absence of an IR absorption at D 1060 cm1 which is typical for the SDO double bond29 . The semimercaptal exhibits maximum UV absorption in the region of 255 270 nm18,24,30,38,40 . The 13 C-NMR chemical shift of the ipso carbon atom of N-hydroxy-N-(1-thioglycerol-S-yl)-aniline was found to be similar to that of N-hydroxyaniline (152 ppm). The signal of the aliphatic carbon atom vicinal to the sulfur atom (37 ppm) appeared between the corresponding signals of the parent thiol and the sulfenamide, indicating a relatively weak electron withdrawal at the sulfur atom24,38 (Table 1). Characteristic 1 H-NMR signals29 of semimercaptals, containing NS conjugated cysteinyl residues, are summarized in Table 1. On separation by reversed-phase HPLC, semimercaptals are eluted subsequent to the respective sulfin- and sulfenamides24,38 . 2. Kinetic aspects of semimercaptal formation
The formation of the semimercaptal has been shown to be reversible18,22,30,36,38,40 . First indications came from a simple observation: nitrosobenzene18,38 and nitrosochloramphenicol22 , respectively, having reacted with GSH to complete disappearance of their characteristic UV absorption, could be recovered from the reaction mixture by extraction with ether. During reaction of various nitrosoarenes with thiols, no isosbestic points were detected between the UV spectra of the nitrosoarenes and their end products, indicating formation of a labile intermediate18,22,38,40 . Correspondingly, absorbance of most nitrosoarenes decreased biphasically when reacted with excess thiol18,22,30,36,40 . A rapid initial fall in optical density reflecting the establishment of the semimercaptal equilibrium was followed by a slower decrease due to consecutive reactions of the semimercaptal with concomitant readjustment of the preceding equilibrium (see equation 1). Similarly, the rapid build-up and the slower decrease of the semimercaptal can be observed in the region around 260 nm18,30 (the maximum absorbance of the semimercaptals). Forward and reverse reaction rates have been shown to increase with rise in pH18,30,38 , but no indications for general acid or base catalysis were found30 . Therefore, the thiolate anion is assumed to be the nucleophile ultimately reacting during the forward reaction (Scheme 2). This conclusion is corroborated by the rate constants of semimercaptal formation with various thiols (Table 2). The marked differences in reactivities at pH 7.4 are obviously largely due to the different degree of dissociation, except for t-butylthiol, hemoglobin cysteine (ˇ 93) SH groups (HbSH) and thiophenol. (With t-butylthiolate 46 48 , steric hindrance may cause the low reaction rates. The low reactivity of and HbS phenylthiolate is attributed to resonance stabilization of the negative charge, as indicated by the Hammett reaction constant for dissociation of substituted thiophenols ³ 249 ). In the back reaction, the NS cleavage of the semimercaptal anion (pKa estimated as ³ 1030 ) is suggested to be the rate-determining step (Scheme 2). Forward and
SDO not existing
[M C H]C , [M C H H2 O]C
CAryl NS: 152 NSCAlkyl : 37
cys ˇ1 : 3.0 cys ˇ2 : 3.4
13 C-NMRh
1 H-NMRj
255 270
IR: (cm1 )
R
>
Rt
N H
S
R
? ³
R1
Rt
N
cys ˇ1 : 2.7 3.0 cys ˇ2 : 3.1 3.2
CAryl NS: 149 NSCAlkyl : 42
SDO not existing [M C H]C , [M C H SR]C
244 255f 280 304f 5 7
OH
SO2 R
cys ˇ1/2 : 4.8
[M C H]C , [M C H O]C
SO2 ³ 1165/1360
³ 250
ArNH2 C RSSR C RSO2 Hd ArNO C RSO2 H ArNH2 C RSSR C RSO2 Hd 24 ArNO C RSO2 H ArNH2 C RSSR
R1
>
Rt c
N
O
H
S* R
cys ˇ1 : 3.4 3.6i cys ˇ2 : 3.6 3.7i
CAryl NS: 139 142 NSCAlkyl : 56 58i
SDO ³ 1060 [M C H]C , [M C H ArNH]C
230 245f,g 271 288f 8 14
ArNH2 C RSO2 H ArNH2 C RSO2 H
R1
cys ˇ1 : 3.64 cys ˇ2 : 3.87
[M C H]C , [M C H SR]C
412
N
Rt
4-aminophenol, thio ether
>
O
S
R
h Data of derivatives from nitrosobenzene reacted with 1-thioglycerol, 2-thioethanol and cysteamine (in CD OD). The corresponding signal of the original thiols are located at 3 ³27 ppm24,42 . i With chiral thiols, signals are doubly splitted. j Data of derivatives containing NS conjugated cysteinyl residues (in CD OD, D O or mixtures of both). The corresponding signals of GSH, for example, are located at cys ˇ : 3 2 1 2.88 š 0.04 ppm and cys ˇ2 : 2.93 š 0.03 ppm in D2 O35,44 .
a For references compare the respective text parts. b Retention times (R ) compared according to24,26,38,43,45 . t c With chiral thiols, double peaks may be obtained at high chromatographic resolution. d Originally, RSOH will result which disproportionates according to equation 7. e In MeOH/H O. 2 f Corresponding sulfen- and sulfinamides exhibit about 15 nm difference in their absorption maxima; -donor substituted sulfen- and sulfinamides reveal a slight bathochromic shift38 . g For the probable glutathione sulfinamide of the polycyclic 3-nitroso-1-methyl-5H-pyrido[4,3-b]indole, the UV maximum was reported at 262 nm41 .
υ (ppm)
υ (ppm)
OH
S
Ar-NH-SO-R ArNH2 C RSO2 H ArNH2 24 Ar-NHOH C RSSR
Rt
N
FAB-MS
UV/Vise max 1 (nm) max 2 (nm) ε1 /ε2
Reversed-phase HPLCb Neutral hydrolysis Acidic hydrolysis Alkaline hydrolysis Reaction with RSH
R1
TABLE 1. Comparison of characteristic properties of NS conjugates emerging during the reaction of nitrosoarenes with alkanethiolsa
1004
23. Reactions of nitrosoarenes with SH groups RSH
K a (RSH)
1005
RS− O Ar
N
S
k1
Ar
N
k −1
R −
O
S Ar
R
N
K a (−NOH)
OH
SCHEME 2. Mechanism of semimercaptal formation (from Kazanis and McClelland30 , with modification) TABLE 2. Second-order rate constants of the semimercaptal formation for various thiols reacting with nitrosobenzene (conditions unless otherwise specified: pH 7.4, 37 ° C, nitrogen) Thiol
k1,obs a (M1 s1 )
pKa (SH)
Cysteine Cysteamine Glutathione 1,2-Ethanedithiol 1-Thioglycerol Benzylthiol Thioethyleneglycol Thiophenol HbSH t-Butylthiol
12 ð 103 12 ð 103 5 ð 103 4.5 ð 103 1.7 ð 103 1.5 ð 103 1.3 ð 103 32 5.5c 4
8.6 8.349 8.8 9.149 9.549 9.449 9.6 6.5 >1151 11.149
k1,thiolate b (M1 s1 )
Reference
2.0 ð 105 1.0 ð 105 1.2 ð 105 2.2 ð 105 2.1 ð 105 1.5 ð 105 2.1 ð 105 40 >2.2 ð 104 2.0 ð 103
36 25 25 38 38 36 25 25 40 25
ak
1 Ð [RSH]1 . 1, obs D -d[nitrosobenzene]/dt Ð [nitrosobenzene] bk 1 Ð [RS ]1 . D -d[nitrosobenzene]/dt Ð [nitrosobenzene] 1, thiolate c pH 7.4, 25 ° C, carbon monoxide.
reverse reaction are affected by pH in the same manner so that the equilibrium itself is unimpaired† . The semimercaptal formation rates of substituted nitrosobenzenes reacting with GSH25,30,36 and Hb-SH27,40 , respectively, have been shown to obey a Hammett correlation. As far as -electron donors are not considered, a good fit is achieved using Hammett constants [k1 GSH D C1.930 ]. However, inclusion of definite electron donor substituents such as o- or p-alkoxy or dialkylamino groups require the Hammett C scale25,27,36,40 [C k1 GSH D C2.1, C k1 Hb-SH D C1.727 ] (Figure 1). These substituents significantly slow down the semimercaptal formation rates, presumably as -electron donation results in a second resonance structure (11) disabling the nitrosothiol interaction: − R2 N
δ+ N −
δ− − O −
+ R2 N
N −
−− O −
(11) † A similar mechanism of addition was presumed for the reaction of nitrosobenzene with OH . However, the resulting adduct is not protonated at the pH of reaction, but additionally deprotonated to the dianion, giving rise to a completely different product pattern3,50 .
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P. Eyer and D. Gallemann
(a) 3-NO2
4-COMe 1 3-Cl
σ −2
−1.5
−1
−0.5
4-Cl 4-Cl 3-OMe
4-CHOHMe 3.5-Me2
3.4-Me2
0.5
3-Me 4-Me −1
−2
ρ = 1.95 (r 2 = 0.95)
logk 1 /k 1 0
4-OEt
−3 4-NMe2 −4
(b) 4-COMe
1
3-Cl
σ+ −2
−1.5
3-NO2
−1
4-Cl 4-Cl 3-OMe
−0.5 3.5-Me2 3.4-Me2
0.5
3-Me 4-Me −1
ρ = 2.01 (r 2 = 0.99)
−2
log k 1 /k 1 0
4-OEt
−3 4-NMe2 −4
FIGURE 1. Hammett plots [ (a) and C (b), respectively] for the formation of semimercaptals from GSH and substituted nitrosobenzenes. Log k1 /k1 0 values were calculated from the rate constants reported for pH 7.4, 37 ° C18,22,36 and pH 7.49, 25 ° C, ionic strength 1 M30 . Correction for pH is unnecessary as k1 and k1 0 are affected in the same manner. Correction for the different temperatures has been revealed to be insignificant. (The Hammett parameter appears to vary with 1/T while seems to be independent of temperature54 . Hence, log k1 /k1 0 has been assumed to correlate with 1/T.) For want of for the complex nitrosochloramphenicol substituent (20), of 4-CHOHMe was used55
23. Reactions of nitrosoarenes with SH groups
1007
This resonance effect is a well-known phenomenon of -donor substituted nitrosoarenes, and the batho- and hyperchromic UV shifts40,52 , increased dipole moments2,52 and molecular geometry20,53 have been attributed to it. In addition, molecular orbital calculations have shown a significant decrease of the positive electrostatic potential at the nitrogen atom of the nitroso group in the presence of -donating substituents20 (see footnote in Section II.B.1). Reverse reaction rates and equilibrium constants of the semimercaptal formation have been shown to fit a Hammett correlation ( -scale), too30 . Since an investigation of the latter kinetic parameters has not been possible for nitrosoarenes bearing -donating substituents (because of the kinetic instability of such semimercaptals, see Section II.D), the fit cannot be proved on the C -scale. The Hammett reaction constants were reported to be k1 GSH D 1.4 and K1 GSH D C3.230 . Thus, electron acceptor groups give rise to rapid establishment of the equilibrium while electron donor groups distinctly slow down this reaction. The relatively high and positive -value of the equilibrium constant (K1 ) reflects the strong dependence of the semimercaptal equilibrium on the nature of the aryl substituent(s). C. Formation of the N-Hydroxyarylamine and its Secondary Products
1. N-Hydroxyarylamine
The formation of N-hydroxyarylamines (2) has been reported for a variety of nitrosoarenes reacting with thiols18,24,33,36,38,41,43 . In the case of electron acceptor substituted nitrosoarenes, N-hydroxyarylamines are usually the main end products22,25,28,29,36,41 . In contrast, -donor substituted nitrosobenzenes have not been observed to form N-hydroxyarylamines25,36,38,39,56 . Similarly, N-hydroxy derivative formation could not be detected during the reaction of the electron-rich 1-methyl2-nitrosoimidazole with GSH57 . Thus, the electronic effects of the aryl residue play a crucial role not only for the initial reaction rates, but also for the further reaction pathways. In addition, N-hydroxyarylamine formation is substantially affected by the thiol concentration and the pH of the solvent. At an educt stoichiometry of 1:1, N-hydroxyarylamines were hardly detected3,18,22,29,38,43 . From this point of stoichiometry, increasing thiol proportions were found to result in increasing yields of the N-hydroxyarylamines18,22,28,29,36,38,43 . In the case of electron acceptor substituted nitrosoarenes, stoichiometric amounts of thiol disulfide are formed18,22,36 . Thus, the Nhydroxyarylamines have been presumed to be formed from the labile semimercaptal by thiolytic cleavage of the NS bond18,22,24,25,28,29,33,36 (see Scheme 1). 2. The bifurcation at the semimercaptal stage
Some detailed work has been done to investigate the dependence of branching ratios at the semimercaptal step on thiol concentration, pH, and the nature of the aryl substituent(s). Thus, Eyer and coworkers18,22,25,36 determined product ratios of the stable end products, N-hydroxyarylamine (2) and sulfinamide (4), while Kazanis and McClelland30 conducted kinetic investigations. Not included in all these studies were -donor substituted nitrosoarenes, as their semimercaptals form a variety of additional products36 (see Scheme 1). Furthermore, as already mentioned in Section II.B.2, the establishment of the semimercaptal equilibrium is distinctly slowed down by these substituents. Besides, consecutive reactions are accelerated, thereby obscuring the biphasic reaction kinetics. Thus, a sufficient kinetic distinction between (fast) semimercaptal formation and (slower) subsequent reactions is not feasible (see equation 1). This effect is
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P. Eyer and D. Gallemann
also displayed by sterically hindered thiols as t-butylthiol since kinetics of the initial step are drastically slowed down38 (cf Table 2). [Reaction kinetics of nitrosoarenes with CIgroups can be corrected for incomplete establishment of the semimercaptal equilibrium as shown by Kazanis and McClelland30 ]. Observation of the slow kinetic component at the maximum absorption of the semimercaptals revealed a pseudo first-order decrease, consisting of a thiol-dependent and a thiol-independent component30 : k2 (slow) D k2 RSH Ð [RSH] C k2 (rearr)
2
The first term obviously reflects the thiol-dependent N-hydroxyarylamine formation while the second term stands for the rearrangement to the sulfinamide (see Scheme 1). Correspondingly, product ratios were found to correlate with thiol concentrations in the following manner22,25 : K1 Ð [NOAr] Ð [RSH] Ð k2 RSH Ð [RSH] [N-hydroxyarylamine] D D p Ð [RSH]; [sulfinamide] K1 Ð [NOAr] Ð [RSH] Ð k2 (rearr) pD
k2 RSH k2 (rearr)
(3)
At constant pH, the parameter p is dependent on the electronic effects of the nitrosoarene substituent(s). Using only definite acceptor substituted nitrosoarenes, a Hammett correlation on the scale was obtained25 . Separate investigation of k2 RSH and k2 (rearr) for a wider selection of nitrosoarenes reacting with GSH revealed reasonable correlation with Hammett constants only for k2 RSH ( D C1.4). However, k2 (rearr) was found to fit better on the Hammett C scale (C D 3.530 [for further discussion of k2 (rearr) see Section II.D.1.b]. Substantial dependence of the bifurcation ratio p on pH, buffer concentration and temperature was noticed, too18,25,30,33 . For the thiol-dependent reaction, a linear correlation of log k2 RSH with pH was obtained (slope D 0.9), indicating the thiolate to be the reacting species30 . A similar dependence of k2 RSH on the thiol pKa is to be expected, but, except for a few indications33 , detailed data are lacking hitherto. General acid-base catalysis could be excluded, and a distinct negative entropy of activation was found. Thus, the detailed mechanism of N-hydroxyarylamine formation seems to proceed via a nucleophilic attack of the thiolate anion at the semimercaptal sulfur atom, forming a properly orientated transition state. The subsequent displacement of the N-hydroxyarylamine anion is probably not assisted by proton transfer, as indicated by the absence of buffer catalysis and the positive Hammett value30 (Scheme 3). RSH
Ka (RSH)
− RS
S Ar
N OH
R
k 2 RSH
RSSR + Ar
− N
−
H Ar
OH
SCHEME 3. Mechanism of N-hydroxyarylamine formation (from Kazanis and modification)
N OH
McClelland30 ,
with
23. Reactions of nitrosoarenes with SH groups
1009
Recently, some doubts have appeared on this widely accepted mechanism, because sulfenamides, but not N-hydroxyarylamines, were found upon addition of thiols to isolated semimercaptals (from nitrosobenzene and 4-chloronitrosobenzene reacted with 1-thioglycerol or 2-thioethanol)27,38 . During the direct reaction of the nitrosoarenes with excess thiols, however, N-hydroxyarylamines were formed as the main products27,38 . On the other hand, semimercaptals from 3- and 4-nitronitrosobenzene reacting with Nacetylcysteine methyl ester or GSH were reported to be thiolytically cleaved as expected29 . These contrasting observations have remained without any well-founded explanation hitherto. Possibly, there exists an additional pathway, e.g. via radicals, leading from the nitrosoarene to the N-hydroxyarylamine, as discussed below in Section II.F. 3. Secondary products
Azo- and azoxyarenes have been repeatedly observed during reactions of nitrosoarenes with thiols5 7,11,29,33,35,36,38 . The latter family presumably emerges from the interaction of the N-hydroxyarylamine with unreacted nitrosoarene, a reaction proceeding even in neutral solutions2,6,58 . The formation of azoarenes may be due to condensation of the end-product arylamine with still unreacted nitrosoarene59 . D. The Sulfenamide Cation Descendants
1. The sulfinamide
a. Identification. In the reaction of a great variety of nitrosoarenes with alkanethiols, formation of a stable adduct has been repeatedly observed. This adduct was identified as Naryl-S-alkylsulfinamide (4) due to a lot of characteristics. Radioactive experiments26,35 as well as 1 H-NMR spectra18,35,43 revealed a 1:1 adduct of nitrosoarene and thiol. NS bond formation was indicated as ring substitution was excluded by 1 H-NMR data and hydrolysis experiments: On acidification9,10,18,22,28,35,38,41,60,61 and alkalization11,24,33,43 the adduct liberated the corresponding arylamine and the sulfinic acid18,33,60,62 . In neutral aqueous solutions and in the presence of excess thiol, the adduct remained stable35,38 . Only the glutathione sulfinamides of the heterocyclic 3-nitroso-1-methyl-5H-pyrido[4,3-b]indole41 and 2-nitroso-6-methyldipyrido[1,2-a:30 ,20 -d]imidazole43 were observed to decay slowly at neutral conditions. Elemental analysis24,38 and FAB-MS spectra24,35,37,38,43,60 displayed the same mass as the respective semimercaptal, but no fragmentation corresponding to the loss of water was observed (see Table 1). IR spectra18,24,35,38,43 exhibited a broad intense peak at ³ 1060 cm1 indicative of a sulfoxide stretching vibration. Characteristic UV9,24,38,40,41,43,61 , 13 C-NMR24,38 and 1 H-NMR data35,43,63 are summarized in Table 1. Among all products formed during reactions of nitrosoarenes with thiols, the sulfinamides display one special characteristic. Because of the stereostable pyramidal conformation at the sulfur atom, two enantiomeric forms are possible64 66 . (Sulfenamides contain a stereogenic SN axis which, however, is stereolabile; therefore, enantiomers are not observable in many cases67 . Most likely, this holds true for semimercaptals and N-hydroxyarylamines as well.) Therefore, nitrosoarenes reacting with optically active thiols as, for example, the physiological substrates L-cysteine or GSH (L-glutamyl-Lcysteinylglycine) will result in diastereomeric sulfinamides, provided the chirality of the thiol does not control the formation ratio24,38,61 . In fact, doubling of NMR signals has been observed with sulfinamides containing chiral thiols24,35,38,43,61 . Because of the relatively high inversion barrier of the stereogenic sulfur center65,66 , the diastereomers are stable enough to allow isolation. Thus, distinct sulfinamides are eluted as double peaks,
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P. Eyer and D. Gallemann
as observed with GSH26,68 , L-cysteinyl-L-prolinyl-L-tyrosine61 , L-cysteinyl-glycine63 and 1-thioglycerol38 by high-resolution HPLC. In contrast, sulfinamides from achiral thiols displayed one single HPLC peak63 . b. Formation mechanism and kinetics. Exclusive formation of sulfinamides was observed during decomposition of isolated semimercaptals in aqueous solutions24,38 . Some efforts have been undertaken to elucidate the mechanism leading from the semimercaptal to the isomeric sulfinamide in more detail. Using 1-thioglycerol38 and GSH30 , the respective N-(thiol-S-yl)aniline-S-oxides have been synthesized in 18 O-enriched water as solvent. Investigation of the products by FAB-MS revealed the sulfinamide molecular peak to be shifted to 2 higher mass units, indicating the incorporation of one 18 Oisotope. Therefore, the rearrangement was suggested to proceed by NO bond fission of the semimercaptal (Scheme 4). The liberated sulfenamide cation will partly allocate its positive charge to the more electropositive sulfur atom, and addition of a water molecule with subsequent proton rearrangement will result in the sulfinamide.
Ar S Ar
N
+ S
R O
R H2 O
N
k 2 0 (rearr)
OH
Ar +
H
+ N
S
Ar
R
N H
S
R
k2 H(rearr)
HA k2 HA (rearr) SCHEME 4. Mechanism of the semimercaptal sulfinamide rearrangement (from Kazanis and McClelland30 , with modification)
A couple of additional findings support the intermediate occurrence of a sulfenamide cation. Thus, the isolated semimercaptal shows a prolonged lifetime in solvents of reduced polarity24,38 since the transition state cation is less stabilized by solvation. Kinetic investigations at different pH values and buffer concentrations revealed a general acid catalysis. Both decreased pH18,22,25,30 and increased buffer concentrations30 have been found to accelerate the NO bond cleavage (see Scheme 4), thereby raising the sulfinamide portion. Thus, the rate constant for the rearrangement reaction has been separated into three terms, reflecting the different types of NO cleavage30 : k2 (rearr) D k2 0 (rearr) C k2 H (rearr)[HC ] C k2 HA (rearr)[HA]
4
The first term considers an unassisted cleavage of the hydroxide ion while terms two and three imply catalysis by HC and buffer acids, respectively. At physiological pH, the uncatalyzed pathway will account for the main part of the reaction, as deduced from the individual kinetic constants reported for N-(glutathion-S-yl)-aniline-S-oxide formation30 . The proton-catalyzed reaction path contributes only at pH below 6, and catalysis by H2 PO4 is relevant from about 10 mM upwards. Under physiological conditions, the high concentrations of buffering protein amino acid residues (histidine: pKa ³ 6.569 , terminal ˛-amino groups: pKa ³ 8.069 ) and carbonic acid (pKa D 6.470 ) will also contribute to the latter term. Kinetic constants for these buffers, however, are lacking hitherto.
23. Reactions of nitrosoarenes with SH groups
1011
A Brønsted plot for the sulfinamide rearrangement of N-(glutathion-S-yl)-Nhydroxyaniline revealed a slope of 0.6, indicating that the proton is not fully transferred to the hydroxy group in the transition state30 . The developing positive charge is obviously highly delocalized, thereby enabling the hydroxide anion to leave without catalysis. In addition to the neighboring sulfur atom, the aromatic ring provides a large system for delocalization. A Hammett correlation for the sulfinamide rearrangement revealed a reasonable fit only for C constant and a reaction constant of C D 3.530 . These findings once more corroborate a substantial build-up of a positive charge in the transition state and a significant stabilizing contribution of the (substituted) benzene ring. Accordingly, a couple of metabolites could be attributed to ring-localized nucleophilic addition reactions to the sulfenamide cation (see below). For comparison with the analogous Bamberger reaction of N-phenylhydroxylamine and N-imidazoylhydroxylamines the account of Kazanis and McClelland30 is recommended. The significant inverse correlation of sulfinamide formation with thiol concentration18,22,24,25,28 30,33,35,36,38 has already been discussed in Section II.C.2. Accordingly, the rearrangement pathway from the semimercaptal to the sulfinamide is favored at low thiol concentrations at the expense of N-hydroxyarylamine formation (see equation 2). In the case of bulky thiols as t-butylthiol38 or Hb-SH40 the sulfinamide is the main product since reduction by a second thiol is sterically hindered. The reaction of nitrosoarenes with alkanethiols may provide a new and simple synthetic route to N-aryl-S-alkylsulfinamides which has not been mentioned hitherto62 . Nitrosoarenes are frequently accessible by simple redox reactions of the commercially available arylamines or nitroarenes2,71 . High yields of the desired sulfinamide may be achieved by adjusting stoichiometry, pH and solvent polarity. With aryl thiols, however, this method may not be applicable because of the very sluggish reaction (see Table 2). Whether such a synthetic route can be extended to alkylnitroso compounds remains to be established. 2. Sulfenamide and arylamine
a. Formation and identification. During reaction of various electron-rich nitrosoarenes with physiological thiols, several indications of a further, metastable adduct arose which liberated the corresponding arylamine on prolonged incubation33,35,72 . Again, radioactive experiments26,35 and 1 H-NMR data24,35,72 revealed a 1:1 adduct without ring substitution. MS spectra24,35,72 and elemental analysis24 indicated a product containing one oxygen atom less than the sulfinamide, and IR spectroscopy24,35,38 proved the sulfoxide structure to be absent. Correspondingly, 1 H-NMR35,72 , 13 C-NMR24,38 and UV data24,38,72 indicated a lower electron withdrawal of the sulfenyl sulfur compared to the sulfinamide (see Table 1). According to these spectroscopic characteristics and the chemical behavior described below, this family was identified as N-aryl-S-alkylsulfenamides (6). The instability of N-aryl-S-alkylsulfenamides observed in the reaction mixture was shown to be due to hydrolysis and a more rapid reaction with nucleophiles. In the presence of millimolar concentrations of GSH isolated sulfenamides yielded the arylamine and the thiol disulfide within a few minutes35,72 . Ar
NH
−
SR + RS
+
+ H
Ar
NH2 + RSSR
(5)
(6)
Klehr argued against this thiolytic cleavage of sulfenamides, as he did not observe accelerated aniline formation from PhNHSR in the presence of 1-thioglycerol24,38 . However,
1012
P. Eyer and D. Gallemann
this negative result was probably due to the distinct higher pKa and, therefore, lower reactivity of 1-thioglycerol (see Table 2). In fact, thiolytic cleavage of aromatic sulfenamides does not always proceed spontaneously and requires proton catalysis73 . Moderate instability of various isolated N-aryl-S-alkylsulfenamides towards hydrolysis was observed24,35,72 with formation of one equivalent arylamine and 2/3 equivalent thiol disulfide38 . This decomposition may be rationalized by protonation of the sulfenamide nitrogen atom and subsequent sulfenylation of a solvent molecule24,35,38 .
Ar
NH
SR
+ H+
Ar
+ NH2
SR
H2 O + −H
Ar
NH2 + RSOH
(6)
The sulfenic acids formed thereby are known to be highly unstable and were presumed to disproportionate to 2/3 thiol disulfide equivalent and 1/3 sulfinic acid38,74 77 . 2RSOH ! RSO2 H C RSH RSOH C RSH ! RSSR C H2 O 3RSOH ! RSO2 H C RSSR C H2 O
(7)
The proposed mechanism of sulfenamide hydrolysis is consistent with various findings on the reactivity of sulfenamides. Thus, protonation of sulfenamides is widely suggested to occur at the nitrogen atom, both from theoretical calculations78 and from experimental results79 82 . Accordingly, the reaction of sulfenamides with electrophiles involves the coordination of the electrophile with the nitrogen atom and subsequent nucleophilic attack on the sulfur atom83 . This mechanism of hydrolysis could also explain the apparent high instability of the sulfenamide of 2-nitroso-6-methyldipyrido[1,2-a:30 ,20 d]imidazole37,43 (see Section II.E): The electron-rich heterocyclic N-aryl substituent may drastically raise the pKa of the sulfenamide nitrogen atom as observed with donor substituted sulfenanilides80 . Despite all these indications, the postulated reverse hydrolysis mechanism of proton-assisted cleavage of the thiol with liberation of a nitrenium ion35 may not be totally excluded. The sulfenamide N-(glutathion-S-yl)-2-amino-1-methyl-6phenylimidazo[4,5-b]pyridine was observed to hydrolyze spontaneously with formation of the 5-hydroxyarylamine84 . This reaction might be rationalized by addition of water to the highly resonance-stabilized nitrenium ion85 . b. Remarks on the formation mechanism. Klehr observed the formation of sulfenamides from isolated semimercaptals in the presence of excess thiol24,38 . Thus, reduction of the semimercaptal does not only lead to N-hydroxyarylamines (see Section II.C), but also to the sulfenamides (Scheme 1). Formation of the latter product or the subsequent arylamine has been reported for a variety of electron-rich nitrosoarenes24,26,33,35,37 39,43,72 , but has hardly been observed in the case of acceptor substituted nitrosoarenes at neutral conditions29,36,38 . Nevertheless, in an acidic milieu formation of 3-nitroaniline was reported to be a main pathway during the reaction of 3-nitrosonitrobenzene with GSH29 (the probable intermediate sulfenamide will rapidly hydrolyze at the pH of reaction). These data suggest the sulfenamides to emerge from thiol-mediated reduction of the sulfenamide cation which is preferentially formed from electron-rich nitrosoarenes and/or at low pH (see Section II.D.1). Accordingly, high concentrations35,38 and low pKa 33 of the thiol favored the sulfenamide-arylamine pathway at the expense of the sulfinamide route. The occurrence of an intermediate N,N-bis(thiol-S-yl)-arylamine (full mercaptal) has been repeatedly surmised to be involved in the semimercaptal reduction25,29,33,37
23. Reactions of nitrosoarenes with SH groups
1013
(Scheme 5, pathway 1). Analogously, thioacetal/-ketal formation is known to proceed from the unstable hemithioacetals/-ketals of carbonyls58 . However, this kind of a 1:2 adduct has not been observed hitherto during reactions of nitrosoarenes with thiols37 . In addition, reaction of the isolated semimercaptal PhN(OH)SR1 with different thiols 24,38 R2 SH never did yield PhNHSR2 but always PhNHSR1 (Scheme 5). Molecular orbital calculations on the semiempirical level (MNDO) conducted for the N-(methylthiolS-yl)-4-anisidine cation and N-(methylthiol-S-yl)-aniline cation revealed a significant negative total charge density at the nitrogen atom (Scheme 6). Conceivably, this is due to the high electronegativity of nitrogen compared to its neighboring atoms in the sulfenamide cation. Therefore, a significant contribution of the NC -localized resonance structure (Scheme 5) is not to be expected, and a thiolate may not react to give the full mercaptal. Accordingly, full mercaptal formation was achieved just the other way by sulfenylation of sulfenamides79 . Taken together, these indications argue against the occurrence of a full mercaptal in the semimercaptal-sulfenamide reaction path. OH RD
SR1
N
−OH −
+ N
RD
SR2
R2 S − 1
RD
SR
N SR1
1
RD
+
N
SR1
2 R2 S −
RD N
SR1
N H
SR1
R2 S
+ R2 SH
− R2 SSR2
+ H2 O − R2 SOH
RD
SCHEME 5. Mechanism of the semimercaptal
sulfenamide reduction
1014
P. Eyer and D. Gallemann Me
Me S + 0.44
− 0.21 + 0.16
N − 0.07 +
− 0.14 + 0.18
S + 0.35 − 0.23
+ 0.08
+ 0.15
− 0.11
− 0.17
N − 0.06 + 0.11
+
− 0.22 O
− 0.19 + 0.38 Me
SCHEME 6. Charge distribution in two different sulfenamide cations (total charge densities as revealed by MNDO calculation; H. -U. Wagner in Reference 56)
Kazanis and McClelland, in their outstanding work30 , have proposed a detailed mechanism of semimercaptal reduction (Scheme 5, pathway 2). Accordingly, a thiolate may add to the p-position of the sulfenamide cation, resulting in an unstable ipso-adduct. Attack of a second thiolate with elimination of thiol disulfide will restore aromaticity in the sulfenamide. This thiolytic cleavage of the ipso-adduct implicates a 1:1 stoichiometry in the formation of sulfenamide and thiol disulfide. However, the initial sulfenamide formation during the reaction of 4-nitrosophenetol with GSH (0.1 and 0.5 mM, respectively, pH 7.4, 37 ° C, argon atmosphere) was accompanied by formation of only about 1/5 equivalent glutathione disulfide (GSSG)56 . Therefore, an alternative route of hydrolytic cleavage of the ipso-adduct has been proposed (see Scheme 5)24,56 , as already mentioned for sulfenamide decomposition. In summary, the ipso-adduct mechanism reflects plausibly the events occurring during semimercaptal reduction. According to this mechanistic conception, -donor substituted nitrosoarenes exhibit a strong correlation between sulfenamide and arylamine yield, respectively, and the thiol concentration employed38,56 . In the case of nitrosobenzene and 4-chloronitrosobenzene, however, the 1-thioglycerol proportion (1:2 and 1:25, respectively) had virtually no effect on the sulfinamide/sulfenamide ratio at pH 6 938 . As to our understanding, this effect lacks any reasonable explanation. 3. Thio ether
Formation of some other products during reaction of the donor substituted 4nitrosophenetol and N,N-dimethyl-4-nitrosoaniline with GSH has been implicated26,36 . In fact, a stable glutathione conjugate was isolated from reaction mixtures of 4nitrosophenetol and GSH in low yields68 . FAB-MS analysis revealed the same molecular mass as the corresponding sulfenamide, but the UV spectrum was distinctly different, and acidic milieu did not decompose this compound. UV data, pKa value and 1 H-NMR spectra indicated this product to be 4-ethoxy-2-(glutathion-S-yl)-aniline68 . The formation of this adduct is consistent with the postulated intermediate occurrence of a resonancestabilized sulfenamide cation which is prone to nucleophilic ring addition of thiolate (see Scheme 1). The resulting 4-ethoxy-2,N-bis-(glutathion-S-yl)-aniline (5) has now been isolated and structurally confirmed by FAB-MS, 1 H-NMR and chemical reactivity45 . As already mentioned above, the sulfenamide group is sensitive to thiolytic and hydrolytic cleavage, yielding the stable arylamine thio ether (7). A similar mechanism was proposed
23. Reactions of nitrosoarenes with SH groups
1015
for the formation of the main product 2-amino-5-(glutathion-S-yl)-1-methylimidazole during reaction of 1-methyl-2-nitrosoimidazole with large excess of GSH57 . Formation of ring-substituted arylamine thio ethers occurs also by proton-catalyzed thermal rearrangement of the corresponding sulfenamides73,82,83 . This alternative pathway may not completely be excluded in thio ether formation from nitrosoarenes, but it seems unlikely since these thio ethers were produced at neutral pH and low temperatures68 . The discovery of the bis-conjugate additionally favors the pathway of nucleophilic ring addition of thiolate to the sulfenamide cation. Hitherto, thio ether formation has clearly been proved only in the case of the donor substituted 4-nitrosophenetol and the electron-rich 1-methyl-2-nitrosoimidazole. The low yields of this adduct (about 2% at 1:1- and about 10% at 1:5-stoichiometry for 4-nitrosophenetol reacting with GSH56 ) may be the reason for its rare discovery. However, other nitrosoarenes should yield this family, too. Semiempirical molecular orbital calculations (MNDO) indicate a similar positive charge at the o-position of the N(methylthiol-S-yl)-aniline cation and -4-anisole cation as well (Scheme 6). Furthermore, formation of 1-(glutathion-S-yl)-2-naphthylamine was reported to occur in mixtures of 2-nitrosonaphthalene and GSH12 . 4. N -Sulfenylquinonimines and resultant products
Formation of several colored products during reaction of nitrosoarenes with thiols has been repeatedly observed12,26,68 . Two different orange-colored conjugates were found during HPLC separation of mixtures of 4-nitrosophenetol and GSH. The UV spectra were indicative of a quinoid structure, and further studies revealed these adducts to be a monocyclic and a bicyclic conjugate. In both cases the reactive quinoid structure gives rise to formation of secondary, stable end products. a. Monocyclic products. An identical monocyclic conjugate was formed, both from 4nitrosophenetol reacting with GSH as well as from 4-nitrosoanisole and 4-nitrosophenol, indicating an exchange of the p-substituent by an identical group. Accordingly, the signals of the p-substituent were lost in the 1 H-NMR spectrum. Characteristically, 4 different aromatic signals, each splitted into a double doublet by o- and m-coupling, were observed. These findings are consistent with the structure of N-(glutathion-S-yl)-4benzoquinonimine (Scheme 7, 9a) because the hindered rotation around the imino bond86 causes magnetic inequivalence of the quinoid protons. FAB-MS analysis corroborated the proposed structure. The isolated conjugate reacted with excess GSH with formation of various products. Mild reduction yielded the corresponding sulfenamide 12 followed by formation of 4-aminophenol (13) while addition to the quinoid system resulted in thio ethers of 4-aminophenol (14). However, these secondary products have not been observed directly in reaction mixtures of 4-nitrosophenetol and GSH, presumably because of the low yield of the quinonimine derivative (9a) (maximum 5% of theory)45 . Under mechanistic aspects, discovery of the quinonimine derivative was not unexpected. The sulfenamide cation of 4-nitrosophenetol (3a) gives rise not only to ring addition of GSH but of other nucleophiles, too. Especially the p-position seems to be prone to nucleophilic attack since this aromatic carbon atom obtains additional positive charge by the I-effect of the adjacent oxygen atom as revealed by semiempirical molecular orbital calculations (see Scheme 6). The ethoxy group is known to be quite a good leaving group58 . Thus, addition of H2 O with concomitant loss of a proton may produce an unstable ipso-adduct which is prone to release either hydroxide or ethoxide, presumably with proton assistance (Scheme 7). A similar reaction pathway has already been described for the N-(thiophenol-S-yl)-4-anisidine cation87 .
1016
EtO
P. Eyer and D. Gallemann
+
N
SG
+ H2 O / −H + + H + / − H2 O
HO N
SG
EtO − EtOH
(3a)
SG O
N
(9a)
GSH
HO
N H
SG
SG HO
N H
SG
(12)
SG HO
NH2
(13)
HO
NH2
(14)
SCHEME 7. Formation of N-(glutathion-S-yl)-4-benzoquinonimine and subsequent reactions
b. Bicyclic products. In analogy to the monocyclic quinonimine derivative, reaction of the main end-product 4-phenetidine (see Scheme 1) with the sulfenamide cation (3a) produces N-(40 -ethoxyphenyl)-N0 -(glutathion-S-yl)-4-benzoquinone diimine (Scheme 8, 10a). The corresponding 2-thioethanol and t-butylthiol derivatives exhibited MS spectra corroborating the presumed structure68 . 1 H-NMR spectra of the three derivatives, however, were not sufficiently meaningful since the aromatic signals of 8 protons overlapped mutually68 . Therefore, the pentafluorophenyl derivative 10b was synthesized56 . (As pentafluoroaniline hardly reacted with the sulfenamide cation 3a, because of the low nucleophilic amino nitrogen, another route was pursued: 4-nitrosophenetol was reacted with pentafluoroaniline under acid catalysis3,88 , giving pentafluoro-40 -nitrosodiphenylamine in low yield. Transformation with GSH delivered the desired benzoquinone diimine derivative 10b.) Chemical behavior of the 4-ethoxyphenyl (10a) and the pentafluorophenyl (10b) derivatives was similar, and FAB-MS analysis revealed the expected mass. The 1 H-NMR spectrum exhibited 8 aromatic double doublets with a relative intensity of 0.5 proton
23. Reactions of nitrosoarenes with SH groups
EtO
EtO
+
N
1017
NH2
SG −H
+
(3a) H N
EtO
N
SG
N
SG
EtO −EtOH
EtO
N
(10a)
GSH SG H N
EtO
N H
SG
H N
EtO
(15)
N H
SG
(17)
SG H N
EtO
NH2
H N
EtO
(16)
NH2
(18)
SCHEME 8. Formation of N-(40 -ethoxyphenyl)-N0 -(glutathion-S-yl)-4-benzoquinone diimine and subsequent reactions
each, reflecting the E Z isomerism of N,N0 -disubstituted quinone diimines56 . Further confirmation of the proposed structure of 10a came from chemical reactivity as described elsewhere68 . F5C6
SG N
SG N
N
N
F5C6 (10b)
The bicyclic quinone diimine 10a exhibits the same product pattern in the reaction with excess GSH as the monocyclic quinonimine 9a. Reduction results in slow formation of
1018
P. Eyer and D. Gallemann
4-amino-40 -ethoxydiphenylamine
(16) with intermediate occurrence of a metastable compound, probably the corresponding sulfenamide 15. Besides, ring addition of various thiols ultimately resulted in the formation of 4-amino-40 -ethoxy-2-(thiol-S-yl)-diphenylamine (18), presumably via the corresponding sulfenamide 1768 (Scheme 8). The quinone diimine 10a was discovered in incubates of 4-nitrosophenetol with about 2.5-fold excess of GSH. At higher GSH concentrations, this product was hardly formed because 4-nitrosophenetol and hence the sulfenamide cation (3a) had completely reacted before significant amounts of 4-phenetidine were formed (see Scheme 1)56 . However, when GSH was slowly generated by an enzymic reaction in the presence of 4-nitrosophenetol, quinone diimine yields increased markedly56 . Similarly, high yields of the quinone diimine 10a were obtained when authentic 4-phenetidine was present from the beginning in the mixtures of 4-nitrosophenetol and GSH. This path may provide a new and simple synthetic route for distinct N-sulfenylquinonimines which has not been mentioned hitherto86 . In fact, a variety of N-sulfenylquinone diimine derivatives were obtained during reaction of 4-nitrosophenetol with other primary arylamines and other thiols. Because of the weaker nucleophilicity of acceptor substituted anilines and alkylamines, these amines presumably can hardly compete with the other nucleophiles for the sulfenamide cation56 . c. N-Sulfenylquinonimine formation from nitrosophenols and nitrosoanilines. Because of the ionizable proton of the aryl substituent, nitrosophenols and -anilines presumably will display a somewhat different metabolic pattern (Scheme 9). The semimercaptals of these -donor substituted nitrosoarenes will almost exclusively yield the sulfenamide cation which is prone to simple and rapid stabilization: Dissociation of the proton at the substituent oxygen and nitrogen results in the corresponding N-sulfenylquinone mono- and
HX
N
O
+ R2 SH
OH HX
N SR2 − OH −
X = O, N R1
+
HX
N
SR2
N
SR2
− H+
X
N
OH
X
R2 SH
R2 SH
?
sulfenamide arylamine thio ethers
SCHEME 9. Tentative pathways of nitrosophenols and nitrosoanilines reacting with thiols
23. Reactions of nitrosoarenes with SH groups
1019
4-ethoxy-40 -nitrosodiphenylamine
diimine, respectively. In fact, during the reaction of and pentafluoro-40 -nitrosodiphenylamine with equivalent amounts of GSH the quinone diimines 10a68 and 10b56 were the main products. However, in the reaction of 4nitrosophenol with varying proportions of GSH, the quinonimine 9a was formed only as a minor product45 . Most probably, the quinoid resonance structure of the parent nitrosoarene decelerates the rate of the nitroso/thiol interaction36 (see Section II.B.2) and gives rise to further nucleophilic reaction centers besides the nitroso group. These pathways, however, remain to be elucidated in detail. E. Formation of N-Hydroxysulfonamide
Recently, a new product was discovered during reaction of the polycyclic 2-nitroso-6methyldipyrido[1,2-a:30 ,20 -d]imidazole with GSH and cysteine, respectively43 . Structural elucidation by UV/Vis, 1 H-NMR, IR and FAB-MS and the stability towards hydrolysis71 (see Table 1) revealed an N-hydroxysulfonamide. The authors suggested it to be formed by addition of the nitrosoarene to sulfinic acid, emerging by hydrolysis of the metastable sulfinamide. In fact, nitrosoarenes are known to react with aryl-3,4,7,71,89 as well as with alkylsulfinic acids7,90 to form stable N-hydroxysulfonamides. However, the glutathione sulfinamide decay in neutral solution probably proceeded too slowly to deliver the large amounts of glutathione sulfinic acid required within a few minutes. In addition, a sulfinamide was not observed during the reaction with cysteine. Both thiols, however, formed large amounts of the corresponding arylamine. Its precursor sulfenamide was detected immediately after the reaction start by FAB-MS37 , but it was not observed 10 min later by HPLC, despite the low thiol proportions employed43 . Therefore, the sulfenamide is probably the unstable ancestor of the sulfinic acid (see equations 6 and 7). Transferred to other nitrosoarenes, formation of an N-hydroxysulfonamide is only to be expected from electron-rich nitrosoarenes forming the sulfenamide, provided the sulfenamide exhibits a particularly marked instability towards hydrolysis (see Section II.D.2). F. Reaction Pathways Involving Radical Intermediates
Formation of hydronitroxide radicals during nonenzymic reduction of nitrosobenzene, 2-nitroso-1-naphthol and 2-nitroso-1-naphthol-4-sulfonic acid with reducing agents such as NADH, GSH, cysteine, N-acetylcysteine and other thiols has been observed by ESR spectroscopy5,91,92 . The reaction was carried out with 5 mM nitrosoarene and 5 mM thiol in 0.1 M phosphate buffer, pH 7.4, under either air or nitrogen. Radical formation did not depend on atmospheric oxygen. Interestingly, in the presence of higher concentrations of the reducing agents, e.g. 10 mM thiol, no ESR signal was detected. These data have been interpreted as being indicative of a one-electron reduction of nitrosoarenes leading to the hydronitroxide radical as the initial reaction product, followed by reduction of the radical to the hydroxylamine with excess thiols91 93 . ž ž
ArNO C RSH ArNHO C RS
(8) ž
ArNHO C RSH ArNHOH C RS ž
(9)
Formation of phenylhydronitroxide radicals, DMPO (5,5-dimethyl-1-pyrrolineN-oxide)/glutathiyl and DMPO/hemoglobin thiyl free radical adducts has been detected in erythrocytes of rats in vivo after administration of nitrosobenzene and phenylhydroxylamine, respectively92,94 . The data, however, could also be interpreted in a different way: ArNO C 2RSH ! ArNHOH C RSSR
(10)
1020
P. Eyer and D. Gallemann ž
ArNO C ArNHOH 2ArNHO
(11)
In fact, neutral, partially aqueous solutions containing nitrosobenzene and phenylhydroxylamine yielded phenylnitroxide radicals95 . However, excess thiol will reduce the nitrosoarene completely, thereby excluding the comproportionation reaction 11. Reaction 9 is thermodynamically highly unfavored, and formation of thiyl radicals could be only demonstrated in the presence of high concentrations of the spin trapping agent DMPO, e.g. at 100 mM92 . Since the yields of spin adducts of thiyl radicals were much higher when phenylhydroxylamine instead of nitrosobenzene was reacted with GSH in buffer or with red cells, it was proposed that the species responsible for the oxidation of the thiols to produce the thiyl free radicals in vivo and in vitro was the phenylhydronitroxide radical generated in the reaction of phenylhydroxylamine with oxyhemoglobin92 . Hence, the radical pathway of reaction 8 appears less likely, and the radicals detected stem probably from the reaction chain 10, 11, 9. III. BIOLOGICAL SIGNIFICANCE A. Introduction
Overt external exposure of living organisms to nitrosoarenes is a rare event, and chemists are usually aware of the hazard potential of C-nitroso compounds. Nonetheless, we are daily exposed to nitrosoarenes that are generated within our cells. To maintain a proper milieu int´erieur, our body is faced with eliminating efficiently the useless or harmful ballast of foreign compounds incorporated daily. Since lipophilic xenobiotics are usually not excreted by the kidneys, higher organisms have evolved a variety of metabolic reactions to produce more hydrophilic derivatives that are easily eliminated by the renal route. The liver is the central organ to fulfill this task, but other organs may share it, too. In doing so, the organism runs some risk because reactive intermediates can be formed which may injure the cells where they arise, or if sufficiently stable some distant sensitive organs they reach while travelling through the body. Aromatic amines and nitroaromatics are typical representatives of lipophilic compounds undergoing extensive metabolism. These substances are widely used in industrial manufacturing of dyes, pesticides, plastics and ammunition, constitute significant environmental pollutants, which are also produced in cigarette smoke, and are constituent moieties of various drugs. Finally, a variety of heterocyclic aromatic amines with a remarkably mutagenic potential are prepared daily in our kitchen while cooking or frying food. Irrespective of their origin, all these compounds have to be considered as being potentially responsible for allergic, toxic, mutagenic and carcinogenic effects. Of the various metabolic pathways involved, N-oxygenation and nitroreduction are generally accepted as being the most important toxication reactions that occur in the body of mammals (for reviews see References 16 and 96 99). The reactive intermediate oxidation states of this class of compounds, namely, the N-hydroxyarylamines and nitrosoarenes, are in rapid metabolic equilibrium. The nitrosoarenes are readily reduced to the corresponding N-hydroxyarylamines, both enzymically and nonenzymically, and the N-hydroxyarylamines are quickly re-oxidized by autoxidation and, particularly effective, by oxyhemoglobin17,19,34,100 . Scheme 10 depicts the most important reactions of N-oxygenated arylamines as detected in red blood cells27 . The most important elimination reaction of N-hydroxyarylamines in blood is the co-oxidation with oxyhemoglobin under formation of the nitroso compound. Depending on substituents, the nitrosoarenes can (A) reversibly bind to the hemoglobin iron like gaseous ligands40 , are (B) enzymically reduced to the parent N-hydroxyarylamines by methemoglobin reductase (NADPH) thereby sustaining the
23. Reactions of nitrosoarenes with SH groups HO
1021
SG N
D HO
SHb N
C
A O
GSH HbFe2 +
NO
HbSH
HbFe2+ O2
NADPH + H+
N
O2
HbFe3+ B
NADP +
HbFe2+ O2 H
OH N
SCHEME 10. Reaction pathways of N-oxygenated arylamines in erythrocytes
catalytic cycle (Kiese cycle17,101 ) of methemoglobin formation, or (C, D) undergo addition reactions with thiols. Of these, the reactive cysteine residues in hemoglobin (in human hemoglobin only cys 93 of the ˇ-chain) (C) and the abundant reduced glutathione (GSH) (D) are of primary importance. For the last years, covalent binding of nitrosoarenes to hemoglobin SH groups with formation of a sulfinamide that can be hydrolyzed in vitro has attracted particular interest102,103 . Biomonitoring of hemoglobin-bound residues has been proposed as a suitable approach to control exposure to, and toxication of, potential carcinogenic arylamines and nitroarenes in persons at risk104 108 . Although hemoglobin adducts of aromatic amines and nitroarenes appear to be good dosimeters for the biologically effective dose of a carcinogen delivered as N-hydroxy or nitroso compound and to correlate with target tissue DNA adduct formation109 , several factors probably intervene to limit the quality of such a correlation108 . In this context also nongenotoxic actions on tissue-specific tumor formation by arylamines or nitroarenes
1022
P. Eyer and D. Gallemann
have to be considered110 . As recently shown in isolated liver mitochondria, the initiating and promoting hepatocarcinogen 2-acetylaminofluorene starts, after transformation into 2-nitrosofluorene, a redox cycle, thereby disturbing the intramitochondrial thiol status. The mitochondrial insult due to thiol depletion and calcium release may lead to cell death, entailing stimulation of cell proliferation that may amplify the altered clone with the genotoxic hit111 . Hence, cellular actions of N-hydroxyarylamines other than on DNA should gain more interest in carcinogenicity studies. This overture highlights only some aspects which, in the opinion of the authors, shed light on the biological, mostly toxicological implications related to the reactions of nitrosoarenes with thiols. The following part presents more in-depth information on selected topics that may exemplify some general principles of reaction pathways occurring under physiological conditions. It covers by no means all of the pertinent literature. Particular emphasis has been put on substituent effects that govern distinct reaction pathways with cellular thiols. B. Monocyclic Nitrosoaromatics
1. Nitrosobenzene generated from nitrobenzene and aniline
The capacity of aniline and, to a less extent, nitrobenzene to produce hemolysis, methemoglobin and denaturated hemoglobin (Heinz bodies) following poisoning is well known and has been linked to the hepatic biotransformation of these substances into proximate toxic compounds such as phenylhydroxylamine14,16,101,112 . This derivative, entering red blood cells within the liver, reacts very fast (k D 2 ð 103 M1 s1 ) with oxyhemoglobin to yield ferrihemoglobin and nitrosobenzene (Scheme 10, reaction B)100 . The latter, being a better ligand for the ferrous iron of hemoglobin than dissolved molecular oxygen40 , is rapidly sequestered from further reactions (Scheme 10, reaction A) and thus can escape the liver via red blood cells34,113 . Nitrosobenzene itself hardly produces any ferrihemoglobin in solutions of purified oxyhemoglobin but gives rise to many equivalents of ferrihemoglobin in red cells under normal metabolic conditions. In doing so, nitrosobenzene has to be reduced to phenylhydroxylamine, which in turn is co-oxidized with oxyhemoglobin to yield ultimately nitrosobenzene and ferrihemoglobin (Scheme 10, reaction B). Since reactive reduced oxygen species, expectedly superoxide and hydrogen peroxide derived thereof, did not influence ferrihemoglobin formation100 , the co-oxidation process was suggested to be more complex, including formation of phenylhydronitroxide radicals and compound I- and II-type hemoglobin intermediates92,114,115 . Formation of free phenylhydronitroxide radicals was observed in live mice immediately after injection of nitrosobenzene116 and in blood in vitro upon addition of nitrosobenzene117 . The intermediate phenylhydronitroxide radical arising from the cooxidation of phenylhydroxylamine and oxyhemoglobin92 is reduced by thiols, yielding thiyl radicals that were detected as DMPO (5,5-dimethyl-1-pyrroline-N-oxide)/glutathiyl free radical adducts and DMPO/hemoglobin thiyl free radical adducts (for reaction details see Section II.F). These adducts were observed in rat and human blood in vitro, and in rats in vivo after administration of aniline, phenylhydroxylamine, nitrosobenzene and nitrobenzene, respectively92 . Conceivably, these thiyl radicals may react with oxygen under formation of reactive oxygen species or with adjacent amino acid residues, thus explaining hemoglobin denaturation and membrane damage that underly Heinz body formation, hemolysis and reduced life span112 . Of course, impaired antioxidative capacity such as in glucose-6-phosphate dehydrogenase deficiency will enhance the susceptibility of red cells towards nitrosoaromatics, whether formed from arylamines or nitroarenes118 .
23. Reactions of nitrosoarenes with SH groups
1023
When nitrosobenzene was incubated with human red cells, GSSG was formed together with glutathione adducts which, upon acid treatment, liberated aniline and glutathione sulfinic acid. In addition, nitrosobenzene was bound to the globin moiety (Scheme 10, reaction C). Acid hydrolysis liberated aniline (about 70%) and stoichiometric amounts of cysteic acid (after total hydrolysis of the globin), indicating formation of a sulfinamide19 . It should be mentioned, however, that some radioactive material from [U-14 C]-labelled nitrosobenzene remained bound to the globin moiety even after extensive acid hydrolysis10,19 . The nature of these adducts remains still to be elucidated. Conceivably, a sulfenamide cation may have added to nucleophilic sites under formation of stable adducts (see Section II.D.3). Collectively, the data from in vitro and in vivo experiments confirm the reactions of nitrosobenzene with thiols as observed in mere chemical systems. 2. Nitroso-procainamide from procainamide
Procainamide [19; 4-amino-N-(2-diethylaminoethyl)benzamide], used as an antiarrhythmic drug, is associated with the highest incidence of drug-induced Lupus erythematodes and with agranulocytosis (4% incidence)119 . Procainamide is metabolized by rat and human microsomes and by leucocytes to yield N-hydroxy-procainamide120 . In the presence of oxygen the [14 C]-label of N-hydroxy-procainamide was found to be bound to proteins, which was prevented by ascorbic acid, NADPH and GSH. In the reaction with GSH a compound was isolated that liberated parent procainamide and glutathione sulfinic acid and exhibited a molecular mass consistent with a glutathione sulfinamide. Besides, a labile compound was detected that regenerated procainamide in the presence of GSH and, therefore, was tentatively assigned as a sulfenamide60 . In addition, nitroso-procainamide reacted with cysteine and GSH under physiological conditions with formation of Nhydroxy-procainamide and stoichiometric amounts of the disulfides. Nitroso-procainamide also was found to bind irreversibly to mouse hemoglobin121 . O H2 N
C
N H
CH2 CH2 NEt2
(19)
Binding of N-hydroxy-procainamide (in the presence of oxygen) to histone proteins of white blood cells was markedly reduced by ascorbic acid, but the material bound was not liberated by acid treatment120,122 . Hence, it was suggested by the authors that nitrosoprocainamide may have reacted with something other than sulfhydryl groups, particularly since histone proteins contain very few sulfhydryl groups60,120,122 . Binding of nitroso-procainamide to histone proteins may perturb chromatin structure or catabolism, resulting in immunogenic forms of DNA-free histones. In fact, all sera of patients (n D 24) with procainamide-induced Lupus showed IgG and IgM antibody activity against various histone components of chromatin (chromosome subunits)122 . The nature of the procainamide adduct to histone proteins still awaits elucidation. 3. 3-Nitrosobenzamide
3-Nitrosobenzamide and 6-nitroso-1,2-benzopyrone are among the most active C-nitroso compounds that inactivate the eukariotic nuclear protein poly(ADP-ribose) polymerase at
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one zinc finger site, thereby completely suppressing the proliferation of leukemic and other malignant human cells. The cellular event elicited by these C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesium-dependent endonuclease123 . The most probable mechanism underlying the destabilization of zinc coordination to poly(ADP-ribose) polymerase was related to the oxidation of the cysteine ligands in the zinc finger peptide by the C-nitroso compounds124 . 3-Nitrosobenzamide gained even more interest when it was found that the compound inhibited acute infection of cultured human lymphocytes by human immunodeficiency virus type 1. The retroviral nucleocapsid protein of HIV-1 contains two domains, each of which binds zinc stoichiometrically with three cysteine thiols and one histidine imidazole group. These zinc complexes and the protein folding that they stabilize are essential for viral genome recognition during budding, genomic RNA packaging, and early events in viral infection. Since these zinc finger sequences are completely conserved and essential for viral replication they appeared as a prime target for antiviral chemotherapy. Treatment of HIV-1 with 3-nitrosobenzamide resulted in a loss of zinc from the virion, as well as from synthetic HIV-1 zinc finger polypeptide, coincidental with viral inactivation125,126 . The mechanism of zinc deprivation by 3-nitrosobenzamide was elucidated most recently. When the reconstituted nucleocapsid protein p7 of HIV-1 (15 mM) was incubated with 3-nitrosobenzamide (300 mM) at pH 7.5, three disulfide bonds per protein molecule were formed while 3-nitrosobenzamide was reduced to the hydroxylamine. Molecular masses of p7 adducts augmented by one or two 3-nitrosobenzamide residues were observed by electrospray ionization MS, consistent with covalent bond formation between cysteine sulfur and the nitroso nitrogen atom127 . These findings point to intermediate semimercaptal formation of 3-nitrosobenzamide with one of the three cysteine residues per domain followed by intramolecular thiolytic cleavage by an adjacent cysteine residue of the triad that normally forms the ligand for the zinc atom. The carboxamide substituent meta to the nitroso group ( m D C0.2855 ) should favor hydroxylamine formation by thiolytic cleavage at the expense of the sulfinamide pathway. In addition, intramolecular reactions with a properly orientated second thiol group will greatly facilitate the observed reaction. Nevertheless, sulfinamide formation should equally result in loss of zinc binding capacity, and the observed masses would be consistent with a sulfinamide structure, too. Possibly, quantitative data will be provided in future to foster the proposed127 mechanism. 4. Nitroso derivatives of chloramphenicol
Chloramphenicol [20; CAP; D-()-threo-1-(p-nitrophenyl)-2-(dichloroacetamido)-1,3propanediol] is an important antibiotic due to its broad activity against a number of clinically relevant microbial pathogens and its ability to penetrate easily the blood brain barrier. Besides human application, CAP became widely and routinely used in veterinary practice and is used in Europe in most animal productions including fish128 . However, the use of CAP was soon restricted after its association with bone marrow depression and aplastic anemia. The underlying biochemical lesion is still obscure, and adequate animal models are lacking. Since thiamphenicol, a CAP analogue where the nitro function has been replaced by a MeSO2 -group, has never been associated with aplastic anemia, Yunis and coworkers suggested that the p-nitro group of CAP may be involved in the development of aplastic anemia129,130 . When the nitroso analogue became available131 this hypothesis was tested experimentally. Nitroso-CAP has proved to be considerably more toxic to cultured human bone marrow cells than CAP and to irreversibly inhibit DNA synthesis as well as the growth of
23. Reactions of nitrosoarenes with SH groups NO2
1025
NO2
HO
C
H
O
H
C
NH
C
CH2 OH (20)
CHCl2
O
C
H
C
O NH
C
CHCl2
CH2 OH (21)
pluripotential hematopoetic stem cells. Moreover, 500-times more [14 C]-labelled nitrosoCAP was irreversibly bound to viable bone marrow cells than [14 C]-labelled CAP132 . From all these data it seemed reasonable to suspect nitroso-CAP as the most probable candidate responsible for the bone marrow cell injury. Although nitroso-CAP was not detected in vivo, there is ample evidence for nitro reduction of CAP133,134 . Nitroso-CAP reacts very rapidly with GSH in chemical systems with formation of a semimercaptal-type intermediate (k D 5.5 ð 103 M1 s1 , pH 7.4, 37 ° C) which gives rise to a sulfinamide22 . Nitroso-CAP is rapidly eliminated from human blood in vitro, 90% in less than 15 s. Only 5% is covalently bound to plasma proteins, mainly albumin, the remainder being metabolized in red cells by the very rapid adduct formation with GSH. Preferentially, the sulfinamide but also N-hydroxy-CAP rapidly give rise to amino-CAP in the blood23 . It is thus conceivable that part of amino-CAP observed in the blood after CAP administration may have originated from intermediate nitroso-CAP as suggested most recently134 . In any event, nitroso-CAP, whether formed by microorganisms in the intestine or produced in the liver, will be degraded in blood before reaching the bone marrow23,130,135 . Interestingly, another CAP metabolite emerged as a favorite proximate toxic candidate, dehydroCAP (21)135 . This compound is fairly stable in blood and can readily reach the bone marrow cells. DehydroCAP itself inhibits myeloid colony growth136,137 . Perhaps the most important aspect of dehydroCAP is that, in contrast to CAP, it is readily reduced by human bone marrow homogenate even under aerobic conditions130,138 . One can assume that the 4-nitrosopropiophenone derivative will react with GSH in a similar way as 4-nitrosoacetophenone to give quite exclusively the hydroxylamine and GSSG25,36 , thereby inducing a marked oxidative stress. Further investigations will show whether this metabolic pathway is indeed responsible for the CAP-induced aplastic anemia. New aspects of CAP exposure and toxicity arose when residues of CAP metabolites were detected in kidney, liver and muscles of chickens that had received oral doses of CAP 12 days before being slaughtered139 . Of these, nitroso-CAP, dehydroCAP and dehydroCAP base [1-(p-nitrophenyl)-2-amino-3-hydroxypropanone] appear of particular toxicological importance. The results, however, should be confirmed since it is quite unexpected that a reactive compound such as nitroso-CAP can be detected in organs 12 days after dosing with CAP. Finally, a toxicological impact is given by the fact that CAP readily decomposes in aqueous solution when exposed to sunlight UV or tungsten light140 . Decomposition of CAP has also been observed in vivo when CAP-dosed rats were exposed to UV-A light. Of the degradation products detected, p-nitrosobenzoic acid appears to be most relevant because it induces methemoglobinemia and inhibits DNA synthesis in rat bone marrow
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P. Eyer and D. Gallemann
cells. Moreover, covalent binding of [ring-3 H]-CAP to tissue of ears and skin of the back of rats was several times higher when the animals were exposed to light compared with controls kept in the dark141 . The influence of UV-A on covalent binding of xenobiotics to endogenous material in the skin is considered an important aspect of the occurrence of photoallergic effects141 . Since p-nitrosobenzoic acid has been shown to have a half-life of some 4 min in rat blood, this intermediate, once formed in the capillaries of the irradiated skin, may meet the requirement of sufficient stability to reach sensitive targets as the bone marrow while travelling through the blood141 . The reactivity of p-nitrosobenzoic acid with thiols appears not to have been tested hitherto. From the known Hammett constant ( p D C0.4555 ) one may deduce that the compound will show a reactivity in between the reactivities of nitrosobenzene and p-nitrosoacetophenone. Taken together, CAP may yield different nitroso derivatives through widely varying pathways. Depending on the substituent, sulfinamides may be formed that deplete cellular thiols and give rise to haptenization of macromolecules, thereby inducing antigenicity. Thiol-mediated reduction of the nitroso compounds, yielding autoxidizable hydroxylamines, may induce oxidative stress with formation of reactive oxygen species that could well be responsible for DNA toxicity. 5. Nitroso derivatives of chloroanilines
Propanil (3,4-dichloropropionanilide) is an important arylamide herbicide that is used in rice, barley, oat and wheat fields. The 3,4-dichloroaniline moiety is also found in the N-substituted phenylureas linuron, diuron and neburon. Hence, exposure to 3,4-dichloroaniline derivatives will be common and has been associated with methemoglobinemia in humans142 . N-Hydroxy-3,4-dichloroaniline has been identified as microsomal metabolite and detected in the blood of propanil-treated rats. Its amount appeared sufficient to account for the hemolytic activity of the parent compound and to be largely responsible for the methemoglobinemia observed143 . Interestingly, 3,4-dichloroaniline itself has been shown to produce ferrihemoglobin in bovine red cells in vitro with formation of 3,4-dichloronitrosobenzene144 , confirming the peroxidative activity of oxyhemoglobin leading to N-oxygenation145 . Moreover, intraperitoneal administration of 3,4-dichloronitrosobenzene to rats produced ferrihemoglobin over much longer periods than an equivalent dose of nitrosobenzene146 . This finding is consistent with the behavior of 3,4-dichloronitrosobenzene in the reaction with GSH. At the usual GSH concentration found in red cells, i.e. 2 mM, about 90% of the nitroso compound forms the hydroxylamine that can re-enter the Kiese cycle while side reactions leading to the sulfinamide are small25 . Nevertheless, binding of 3,4-dichloroaniline to hemoglobin of rats was observed143,147 . 6. Nitroso derivatives of sulfonamide drugs
Dapsone (22; 4,40 -diaminodiphenyl sulfone) is an established antileprotic and antiinflammatory drug that is also effective in the therapy of Pneumocystis carinii pneumonia O H2 N
S O (22)
NH2
23. Reactions of nitrosoarenes with SH groups
1027
and against chloroquine-resistant Plasmodium falciparum148 . Its use is often limited by its dose-dependent toxicity, such as methemoglobinemia and hemolysis. It is also responsible for occasional life-threatening disorders such as agranulocytosis149 . The toxicity of dapsone is due to the cytochrome P-450-catalyzed oxygenation leading to N-hydroxydapsone. This major metabolite enters red cells and is co-oxidized with oxyhemoglobin to generate a nitroso derivative and methemoglobin148 . GSH levels of red cells were diminished upon incubation with N-hydroxydapsone only when glucose was absent, or in glucose-6-phosphate dehydrogenase-deficient red cells150 . On the other hand, oxidation of purified hemoglobin was greatly enhanced by GSH151 . Prior depletion of GSH by diethylmaleate led to a fall in both methemoglobin and dapsone formation compared with untreated cells148 . Hence, it was suggested by the authors that GSH, rather than NADPH methemoglobin reductase, was chiefly responsible for the process of methemoglobin generation and parent amine formation from N-hydroxydapsone in human red cells. Two GSH-dependent pathways were proposed: reduction of the nitroso derivative by GSH to yield the hydroxylamine together with GSSG, and adduct formation to yield a labile sulfenamide that ultimately gives rise to dapsone152 . The latter pathway appears less likely, considering the electron-withdrawing sulfonamide substituent with a Hammett p constant of C0.5855 . Rather, the nitroso derivative of dapsone is suggested to react in a similar way as 4-nitrosoacetophenone ( p D C0.5555 ) which has been shown to yield nearly exclusively the N-hydroxy derivative and GSSG25,36 . Two other routes for the GSH-mediated amine formation are conceivable. The enhanced formation of Nhydroxydapsone facilitates its enzymic reduction to the amine16,17 . In addition, the amine could be formed by enzymic cleavage of the sulfinamide as detected for nitrosobenzene19 . Sulfamethoxazole [23; N1 -(5-methylisoxazol-3-yl)sulfanilamide] is a clinically important sulfonamide that is mainly used together with trimethoprime in fixed combination (cotrimoxazole). The use of this sulfonamide has been associated with a variety of idiosyncratic reactions, including fever, lymphadenopathy, skin rash, hepatitis, nephritis and blood dyscrasias153 . The incidence of these reactions is in the range of 1:5000 in the normal population but is much more common in patients with AIDS154 . Sulfamethoxazole is metabolized to the N-hydroxy derivative by cytochrome P-450 and peroxidases, e.g. of white blood cells. Under physiological conditions the N-hydroxy derivative appears to be rapidly and spontaneously oxidized to yield the nitroso compound that is more reactive and more toxic than the N-hydroxy precursor155 . When 1 mM GSH was added to 50 mM nitroso-sulfamethoxazole quantitative formation of N-hydroxy-sulfamethoxazole was observed. At much lower concentrations of GSH, e.g. 100 mM, significant quantities of a sulfinamide were formed together with a short-lived intermediate which was tentatively assigned as a semimercaptal28 . O H2 N
S O
H N N
Me O
(23)
These data, e.g. predominant thiolytic cleavage of the semimercaptal at physiological GSH concentrations, is in line with the expected behavior in considering the positive Hammett constant of the sulfonamide substituent ( p D C0.5855 ). It is to be expected that cells with lowered GSH content or impaired enzymic capacity to reduce GSSG will be
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P. Eyer and D. Gallemann
more susceptible towards conjugate formation and thus depletion of GSH. Such a vitious cycle may underly cellular toxicity of HIVIII-B -infected lymphocytes and hypersensitivity reactions154 . Sulfasalazine [24; 4-hydroxy-40 -(2-pyridylsulfamoyl)azobenzene-3-carboxylic acid] is commonly used for the treatment of inflammatory bowel disease. The drug consists of two moieties, sulfapyridine [N1 -(2-pyridyl)sulfanilamide] and 5-aminosalicylic acid, which are linked by an azo bond. Sulfasalazine is hardly absorbed in the intestine and reaches the colon unchanged where bacteria cleave the azo link, liberating sulfapyridine which is absorbed, while 5-aminosalicylic acid is thought to exert its antiinflammatory effects locally. The moiety responsible for its toxicity is considered to be sulfapyridine which can be metabolized to yield N-hydroxy-sulfapyridine (for review see Reference 156). A wide range of adverse effects of sulfapyridine has been reported, including leucopenia, intravascular hemolysis, particularly in glucose-6-phosphate dehydrogenase deficient patients, and methemoglobinemia in up to 40% of the patients. COOH HO O N
N
S O
N H
N
(24)
N-Hydroxy-sulfapyridine was shown in vitro to produce ferrihemoglobin and to be cytotoxic to mononuclear leucocytes. Co-incubation with ascorbic acid, GSH, or Nacetylcysteine did abolish cytotoxicity but did not inhibit ferrihemoglobin formation156 , indicating that the nitroso derivative may be the ultimate cytotoxic agent for leucocytes while in red cells the Kiese cycle16,101 may be still operating. These data are suggestive that nitroso-sulfapyridine is mainly reduced to the N-hydroxy derivative at high concentrations of GSH as found in human red cells. 7. Nitroso derivatives of dinitrobenzenes
1,3-Dinitrobenzene is an intermediate employed in chemical syntheses of a large number of compounds used in the dye, explosives and plastics industry. The compound is known to induce methemoglobinemia and to cause testicular toxicity with the Sertoli cell being the major target. Nitro reduction was observed in erythrocytes, in rat Sertoligerm cell cocultures and in rat testicular subcellular fractions, and it was shown that 3-nitrosonitrobenzene was formed that was considerably more toxic. Testicular toxicity was enhanced when the intracellular thiol levels were reduced by pretreatment with diethylmaleate. In turn, pretreatment with cysteamine or ascorbate reduced the toxicity of 1,3-dinitrobenzene and 3-nitrosonitrobenzene. These findings suggest that formation of 3-nitrosonitrobenzene and the corresponding hydroxylamine may elicit a futile redox cycle, using up reduced cofactors such as GSH and NADPH in the Sertoli cell (for literature see Reference 157). The strong electronwithdrawing properties of the nitro group ( m D C0.7; p D C0.855 ) are in line with this view. Accordingly, the semimercaptal will be stabilized29,157 and the hydroxylamine pathway will be favored. From this it becomes clear that low molecular thiols will not lead to eventual detoxication of these nitrosonitroaromatics but will sustain a redox cycle that may be
23. Reactions of nitrosoarenes with SH groups
1029
detrimental. The reported beneficial effects of added thiols on the testicular toxicity of 3-nitrosonitrobenzene thus remain to be explained. One can speculate that stable protein adducts of a semimercaptal structure may be cleaved by low molecular thiols, followed by restitution of the protein sulfhydryl by another low molecular thiol. Similarly enigmatic is the fact that only 1,3-dinitrobenzene, but not 1,2- or 1,4-dinitrobenzenes, elicit the observed testicular toxicity157 . 8. 4-Nitrosophenetol from 4-phenetidine
4-Phenetidine (4-ethoxyaniline) is one of the metabolites of the previously widely used analgesic/antipyretic drug phenacetin which has been accused to cause methemoglobinemia, particularly in infants, and serious kidney lesions following long-term treatment. In addition, phenacetin has been made responsible for an increased rate of cancer in the urinary tract. Hence, phenacetin has been displaced from analgesic formulations in most countries. Neither phenacetin nor 4-phenetidine is toxic per se, but the latter is a suitable substrate for several drug metabolizing enzymes, such as cytochrome P-450s, peroxidases and prostaglandin synthase (for literature see Reference 158), and even for oxyhemoglobin144 . N-Hydroxy-4-phenetidine and its autoxidation product 4-nitrosophenetol formed during cytochrome P-450 oxidation of 4-phenetidine were attributed to the methemoglobinemia and hemolysis observed159 162 . The mechanism of ferrihemoglobin formation, however, is much more complicated than considered formerly163 165 . Moreover, N-hydroxy-4phenetidine binds to DNA72 and is directly mutagenic166,167 , whereas 4-nitrosophenetol did not react with DNA72 but binds covalently to proteins, predominantly to sulfhydryl groups40,168 . The reaction of 4-nitrosophenetol with thiols is extremely complex as deduced in Section II. Formation of the semimercaptal39 , the sulfinamide36 and the sulfenamide72 have been described. Formation of GSSG was clearly observed (0.44 mM) when 4nitrosophenetol (1 mM) was allowed to react with GSH (2 mM) under physiological conditions36 . On the other hand, GSSG hardly increased when isolated rat hepatocytes were exposed to 0.2 mM 4-nitrosophenetol while GSH had dropped markedly and resulted in cell death158 . Similarly, total GSH of isolated perfused rat livers was depleted by 4nitrosophenetol with a small increase in GSSG and mixed glutathione/protein disulfides. The bile flow of the livers was significantly inhibited and the excretion mechanism for GSSG impaired169 . These results suggested that glutathione adducts might be formed that compete with the GSSG excretion mechanism25 . Interestingly, transport systems of glutathione conjugates in human red cells were similarly inhibited by metabolites of 4-nitrosophenetol170 . Possible candidates for this inhibitory action are two thio ethers, 4-ethoxy-2-(glutathion-S-yl)-aniline (7) and 4-amino-40 -ethoxy-2-(glutathion-S-yl)diphenylamine (17)68 . When 4-nitrosophenetol reacted with human red cells formation of acid-stable hemoglobin adducts was observed. The amount of these adducts was markedly increased when the reduction of GSSG was inhibited. These findings suggest GSH-mediated formation of the sulfenamide cation that is not consumed by further GSH-mediated reactions but is available for ring addition reactions56 . 9. 4-Nitroso-N ,N -dimethylaniline
4-Nitroso-N,N-dimethylaniline has been reported to be bactericidal and mutagenic to Salmonella typhimurium TA 100 tester strains. In addition, this compound has proved to
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P. Eyer and D. Gallemann
be carcinogenic to male mice and rats171 . 4-Nitrosodimethylaniline was shown to be cytotoxic to isolated rat hepatocytes and to deplete cellular GSH. Pretreatment with diethylmaleate, which reduced hepatocyte GSH by 85%, enhanced 4-nitrosodimethylaniline toxicity172,173 . The reaction of 4-nitrosodimethylaniline with GSH is quite slow and leads to formation of N,N-dimethyl-p-phenylenediamine and 2 molecules GSSG together with hitherto unknown glutathione conjugates36 . The disappearance of 4-nitrosodimethylaniline in the presence of GSH was clearly enhanced by glutathione S-transferase. No attempts have been reported on isolation of such a reaction product172 . Formation of quite stable glutathione S-conjugates derived from 4-nitrosodimethylaniline have already been suggested to explain the inhibitory effect on biliary GSSG excretion25 . It should be noted that the N,N-dimethyl-p-quinone diiminium cation, which is easily formed during autoxidation of N,N-dimethyl-p-phenylenediamine, also reacts rapidly with GSH with formation of a typical Michael addition product174 . These data show that 4-nitrosodimethylaniline can deplete GSH in the liver by multiple reactions that are not exclusively related to the nitroso function, and it appears that the slow reactivity towards thiols correlates with the strongly negative Hammett constant p C D 1.755 . C. Polycyclic Nitrosoaromatics
1. 4-Nitrosobiphenyl from 4-aminobiphenyl
4-Aminobiphenyl (25) is a carcinogenic aromatic amine detected in cigarette mainstream and sidestream smoke and found to increase the risk of smokers for bladder cancer. In addition, 4-aminobiphenyl induces methemoglobinemia in various animal species. A prerequisite for these toxic actions appears to be N-hydroxylation175 . The extent of covalent binding of radiolabelled 4-aminobiphenyl to rat hemoglobin was extraordinarily high and amounted to 5% of the dose103 . This high binding index was correlated with an exceptionally high rate of N-oxygenation of 4-aminobiphenyl by rat liver microsomes176 .
NH2
(25) The fate of N-hydroxy-4-aminobiphenyl in rat erythrocytes in vitro was studied in more detail177 . It was found that both N-hydroxy-4-aminobiphenyl and 4-nitrosobiphenyl had rapidly disappeared while ferrihemoglobin formation still proceeded. Acid treatment of the hemolysate liberated only one third of the expected 4-aminobiphenyl, indicating a binding type different from a sulfinamide linkage. 3-Hydroxy-4-aminobiphenyl was considered a probable ferrihemoglobin-forming candidate which, after oxidation to an o-quinonimine, may form an acid-stable conjugate with hemoglobin146 . Upon reaction of 4-nitrosobiphenyl with thiols, its negative Hammett constant p C D 0.1855 is expected to facilitate formation of a sulfenamide cation that may delocalize its positive charge partly to C3 , C20 and C40 . Hence formation of aminophenols and acid-stable hemoglobin adducts would be conceivable.
23. Reactions of nitrosoarenes with SH groups
1031
2. 2-Nitrosofluorene from 2-acetamidofluorene
2-Acetamidofluorene (26), which was initially intended to be used as an insecticide178 , is one of the most extensively studied chemical carcinogens. This aromatic amide as well as its amine and nitro derivatives induce tumors in a wide variety of sites, including liver, urinary bladder, mammary gland, intestine and forestomach. The initial activation involves the formation of N-hydroxy intermediates179,180 .
H N COMe
(26) The observation that 2-nitrosofluorene, under physiological conditions, readily reacts with GSH to yield a water-soluble product that liberated 2-aminofluorene upon mild acid treatment is probably the first report in the literature pointing to sulfinamide formation. At that time, however, no further attempts were made to identify this compound9 . Formation of two glutathione conjugates from 2-nitrosofluorene was reported later on35 . These authors succeeded in isolation and identification of N-(glutathion-S-yl)-2-aminofluoreneS-oxide (sulfinamide) and N-(glutathion-S-yl)-2-aminofluorene (sulfenamide). These conjugates made up >90% of the 2-nitrosofluorene applied (10 mM GSH, pH 7), indicating that hydroxylamine formation is a minor pathway if at all. This behavior can be expected, considering the strong -donor character of the fluorenyl moiety30 p C D 0.4855 . D. Heterocyclic Nitrosoaromatics
1. Nitrosoimidazoles from nitroimidazoles
Misonidazole [27; 1-methoxy-3-(2-nitroimidazol-1-yl)-2-propanol] and the model compound 1-methyl-2-nitroimidazole have been used as radiosensitizers in the treatment of certain types of human tumors. One important property of these compounds is that they are more toxic to hypoxic cells than to aerobic cells, indicating that reductive metabolism of the drug is involved in the toxicity. Results of a number of studies suggest that intracellular thiols play a significant role in the hypoxic cell toxicity, and it was found that reduction products formed stable thio ethers with GSH (for literature see References 181 183). The reaction mechanism of thio ether formation has not been fully established. It has been suggested that the 4-electron reduction product was involved in thio ether formation181,184,185 , and that the hydroxylamine rather than the nitroso derivative was the reactant. On the other hand, an intermediate nitroso derivative is expected to give a sulfenamide cation (see Scheme 1) which easily allows thio ether formation.
CH2 CHOHCH2 OMe
CH2 CH2 OH
N O2 N
N Me
N (27)
NO2 N (28)
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P. Eyer and D. Gallemann
An extensive proposal of the underlying reaction mechanisms has been presented by McClelland’s group57,186,187 . Unlike phenylhydroxylamine, these hydroxylamines do not exhibit an acid-catalyzed NO cleavage as in the Bamberger rearrangement. In contrast, NO cleavage becomes predominant at neutral pH when the imidazole nitrogen is no longer protonated. The resulting nitrenium ion is considerably stabilized since the positive charge is highly delocalized into the imidazole system under predominant formation of an imminium ion. Nucleophilic attack of GSH to the resonance contributing carbenium ion at the C5 atom easily explains formation of a stable thio ether30,187 . Noyce188 has determined C constants defining the accelerating effect of heterocyclic ring systems in reactions that result in the formation of a carbenium ion center adjacent to the ring. The C values so obtained were 0.82 for the 1-methyl-2-imidazole and 1.02 for the 1-methyl-5-imidazole group188 . It has been predicted that N-hydroxy-4-anisole C D 0.7855 should have a reactivity similar to that of 2-(hydroxylamino)-1-methylimidazole, thereby undergoing a neutral Bamberger rearrangement187 . In fact, the structural analogue N-hydroxy-4-phenetidine quickly yielded high amounts of 4-aminophenol when kept in phosphate buffer at pH 7.4 under argon189 . When 1-methyl-2-nitrosoimidazole became available190 it was found that addition of excess GSH to solutions of 1-methyl-2-nitrosoimidazole led to a rapid loss of the characteristic absorbance at 360 nm within a few seconds. Preliminary experiments suggested that formation of GSSG and the hydroxylamine was followed by formation of stable thio ethers. It should be noted, however, that detection of free hydroxylamine was unsuccessful57 . In cell-free systems 1-methyl-2-nitrosoimidazole reacted with excess GSH to form adducts in a 1:3 stoichiometric reaction191 . 1-Methyl-2-nitrosoimidazole was by two orders of magnitude more toxic to CHO cells than the nitro and hydroxylamine compound. Circumstantial evidence suggested that GSH might reduce cytotoxicity190 . Similar observations were reported with HT-29 human colon cancer cells. Depletion of cellular GSH with buthionine sulfoximine before incubation with the nitrosoimidazole resulted in enhanced susceptibility192 . Since the DNA damage by the nitrosoimidazole in HT-29 colon cancer cells was probably not a result of a direct interaction of the nitroso compound, a possible activating effect of GSH to yield the ultimate electrophile was discussed193 . Interestingly, mixtures of the nitrosoimidazole with GSH gave rise to DNA strand breaks in the plasmid assay194 . These data suggest that 1-methyl-2-nitrosoimidazole is responsible for the cytotoxicity elicited by 1-methylnitroimidazole191 . Whether the hydroxylamine-derived nitrenium/carbenium ion and/or the nitroso-derived sulfenamide cation are responsible for the DNA effects remains to be elucidated. Metronidazole [28; 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole] and other 1-alkyl5-nitroimidazoles are important antibiotics for the treatment of anaerobic bacterial and protozoal infections. Evidence suggests that their activity is due to inhibition of the DNA function and that reduction of the nitro group is required for the antiparasitic activity of the drugs195 . They are also bacterial mutagens and rodent tumorigens (for literature see Reference 196). The 2-electron reduction model compound 1-methyl-4phenyl-5-nitrosoimidazole was found to have properties consistent with the biologically active form of a 5-nitroimidazole and to bind to DNA, but at a rate too slow to account for its bactericidal effect. In the presence of physiological concentrations of thiols such as cysteine and GSH, however, binding to lambda-phage DNA and polynucleotides was enhanced by 2 3 orders of magnitude, which was quantitatively sufficient to account for its bactericidal effect197 . The authors concluded that a semimercaptal-like intermediate might yield a highly reactive cation that binds to DNA. These data suggest that
23. Reactions of nitrosoarenes with SH groups
1033
the nitrosoimidazole might still be a penultimate reactive intermediate in the bioactivation of nitroimidazoles which by interaction with thiols would give the ultimate reactive species that binds to DNA. Whether a semimercaptal-type intermediate is formed, which upon loss of the hydroxyl group may produce a sulfenamide cation, or whether a neutral Bamberger rearrangement of the hydroxylamine species occurs, has to await further investigations. 2. Heterocyclic N-oxygenated compounds derived from food mutagens
In the past 15 years, analyses of pyrolyzed amino acids and proteins198 and of cooked protein-containing foods199 have led to the discovery of several classes of highly mutagenic heterocyclic aromatic amines. The most common class of mutagens in foods in the Western diet appears to be aminoimidazoazaarenes, characterized by having 1 or 2 heterocyclic rings fused to an aminoimidazo ring. This class of compounds was also obtained in model reactions by heating creatin(in)e (from muscle) together with an amino acid. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (29; PhIP), usually the most abundant product of food-derived mutagens, is formed by heating creatine and phenylalanine at 200 ° C200 . This compound is modestly mutagenic in the Ames test, but is a potent carcinogen in rats and mice, causing breast and colon cancers. NH2 N
Me
Me N NH2 N (29)
N
N (30)
PhIP is a hydrophobic procarcinogen that is inactive per se, but is metabolized in vivo to highly reactive electrophiles that bind covalently to DNA (for literature see Reference 201). The initial bioactivation step responsible for PhIP-DNA adduct formation appears to be the N-oxidation of PhIP to form N-hydroxy-PhIP which undergoes further activation to yield N-acetoxy, N-sulfonyloxy and N-glucuronide derivatives. Using isolated rat hepatocytes it was shown that pretreatment of the hepatocytes with 1-bromoheptane and buthionine sulfoximine, depleting GSH and preventing its resynthesis, respectively, resulted in a 15-fold increase in the formation of PhIP-DNA adducts, as well as in a high level of unscheduled DNA synthesis202,203 . These data suggest that GSH may either intervene in DNA binding of reactive metabolites, e.g. by reaction with the putative nitrenium ion, or inhibit formation of the activated N-hydroxy conjugate. Interestingly, formation of an unstable N-(glutathion-S-yl)-PhIP (sulfenamide) was observed on reacting N-acetoxy-PhIP with GSH. The conjugate disappeared upon further purification to yield the stable end-product 5-hydroxy-PhIP84 . These data suggest that the intermediate sulfenamide may lead to a nitrenium ion which is in resonance with a highly electrophilic carbenium form85 . In this pathway GSH provides a metastable conjugate but not a detoxification product. No details on possible reaction pathways have been presented hitherto. 2-Amino-3-methylimidazo[4,5-f]quinoline (30; IQ) is formed at modest yields by heating creatinine together with an amino acid (glycine, serine, phenylalanine) at 200 ° C200 .
1034
P. Eyer and D. Gallemann
This compound requires metabolic activation by liver microsomes to yield highly mutagenic derivatives in the Ames test204 . In addition, IQ is a multipotent animal carcinogen that is metabolized by prostaglandin-H synthase205 and the hepatic cytochrome P-450 system204 . Blood protein binding of IQ was found in rats dosed intragastrally with the labelled compound. The same adducts, though in much higher yields, were found when purified rat serum albumin was exposed either to N-hydroxy-IQ or incubated with parent IQ in the presence of a microsomal system. A tripeptide was isolated which contained N-(cystein-S-yl)-IQ-S-oxide (sulfinamide) that easily liberated IQ on acidification. Pretreatment of albumin with p-chloromercuribenzoate reduced covalent binding drastically61 . The authors concluded that the reactant most likely to yield this structure is 2-nitroso-3-methylimidazo[4,5-f]quinoline, which is probably formed by autoxidation of N-hydroxy-IQ. The 3-amino-1-methyl-5H-pyrido[4,3-b]indole derivatives (31; Trp-P-1) and (32; TrpP-2) were found as tryptophane pyrolysates in broiled fish and meat and in pyrolysates of protein and amino acids by Sugimura and coworkers198 . These mutagens are heterocyclic amines and exhibit mutagenicity in the Ames test supplemented with S-9 mix198 . The pyridoindole derivatives Trp-P-1 and Trp-P-2 are N-hydroxylated at the exocyclic amino group to form proximate reactive compounds. Me
Me N
N NH2
N H
NH2
N H
Me
(31)
(32)
Thiols, particularly GSH, modify the mutagenic activity and covalent binding to DNA by at least two mechanisms. The first one involves glutathione S-transferase which, in the case of N-hydroxy-Trp-P-2, produced a stable C-conjugate and two labile Nconjugates, one of which decomposed into Trp-P-2 while the other liberated the parent N-hydroxy-Trp-P-2. This latter conjugate was found to be outstandingly mutagenic41,204 . The second pathway starts with the nitroso derivative leading to the putative sulfenamide and sulfinamide41 . Alternatively, both labile compounds could also be stereoisomeric sulfinamides, particularly since they showed nearly identical UV maxima. N N
NH2
N N
N
N
(33)
(34)
NH2
Me
2-amino-dipyrido[1,2-a:30 ,20 -d]imidazoles
The (33; Glu-P-1) and (34; Glu-P-2) were first isolated from glutamic acid pyrolysates. As observed with Trp-P-1 and Trp-P-2,
23. Reactions of nitrosoarenes with SH groups
1035
mutagenic activity was shown after microsomal N-oxygenation at the exocyclic amino group to yield the reactive N-hydroxy and nitroso derivatives204 . Most interestingly, upon reaction of nitroso-Glu-P-1 with GSH also an N-hydroxysulfonamide was apparently formed besides sulfinamide, sulfenamide and arylamine37,43 (see Section II.E). IV. REFERENCES 1. Y. Furuya, I. Urasaki, K. Itoho and A. Takashima, Bull. Chem. Soc. Jpn., 42, 1922 (1969). 2. J. H. Boyer, in The Chemistry of the Nitro and Nitroso Groups (Ed. H. Feuer), Interscience Publishers, New York, 1969, p. 215. 3. P. Zuman and B. Shah, Chem. Rev., 94, 1621 (1994). 4. E. Bamberger and A. Rising, Chem. Ber., 34, 228 (1901). 5. F. J. Smentowski, J. Am. Chem. Soc., 85, 3036 (1963). 6. E. G¨ulbaran, Finish Chem. J., 37, 229 (1964). 7. E. Y. Belyaev, L. M. Gornostaev and G. A. Suboch, Khim. Tekhnol. Polim., 4, 60 (1975). 8. E. Boyland, P. L. Grover and D. Manson, Ann. Rep. Brit. Emp. Cancer Campaign, 44, 2 (1966). 9. P. D. Lotlikar, E. C. Miller, J. A. Miller and A. Margreth, Cancer Res., 25, 1743 (1965). 10. M. Kiese and K. Taeger, Naunyn-Schmiedeberg’s Arch. Pharmakol., 292, 59 (1976). 11. H. -G. Neumann, M. Metzler and W. T¨opner, Arch. Toxicol., 39, 21 (1977). 12. D. Manson, J. Chem. Soc., Perkin Trans. 1, 192 (1974). 13. M. Kiese, Angew. Chem., 70, 93 (1958). 14. M. Kiese, Naunyn-Schmiedeberg’s Arch. Exp. Pathol. Pharmacol., 235, 354 (1959). 15. M. Kiese and H. Uehleke, Naunyn-Schmiedeberg’s Arch. Exp. Path. Pharmacol., 242, 117 (1961). 16. M. Kiese, Pharmacol. Rev., 18, 1091 (1966). 17. M. Kiese, D. Reinwein and H. D. Waller, Arch. Exp. Path. Pharmacol., 210, 393 (1950). 18. P. Eyer, Chem.-Biol. Interact., 24, 227 (1979). 19. P. Eyer and E. Lierheimer, Xenobiotica, 10, 517 (1980). 20. P. Politzer and R. Bar-Adon, J. Phys. Chem., 91, 2069 (1987). 21. R. D. Youssefyeh, J. Chem. Soc., Perkin Trans. 1, 1857 (1975). 22. P. Eyer and M. Schneller, Biochem. Pharmacol., 32, 1029 (1983). 23. P. Eyer, E. Lierheimer and M. Schneller, Biochem. Pharmacol., 33, 2299 (1984). 24. H. Klehr, P. Eyer and W. Sch¨afer, Biol. Chem. Hoppe-Seyler, 366, 755 (1985). 25. P. Eyer, in Biological Oxidation of Nitrogen in Organic Molecules: Chemistry, Toxicology and Pharmacology (Eds. J. W. Gorrod and L. A. Damani), Horwood, Chichester, 1985, p. 386. 26. H. Klehr, P. Eyer and W. Sch¨afer, Biol. Chem. Hoppe-Seyler, 368, 895 (1987). 27. P. Eyer, Xenobiotica, 18, 1327 (1988). 28. A. E. Cribb, M. Miller, J. S. Leeder, J. Hill and S. P. Spielberg, Drug Metab. Dispos., 19, 900 (1991). 29. M. K. Ellis, S. Hill, P. Matthew and D. Foster, Chem.-Biol. Interact., 82, 151 (1992). 30. S. Kazanis and R. A. McClelland, J. Am. Chem. Soc., 114, 3052 (1992). 31. P. Eyer, Environ. Health Perspect., 102 (Suppl. 6), 123 (1994). 32. H. P. T. Ammon, C. J. Estler and F. Heim, Biochem. Pharmacol., 16, 769 (1967). 33. B. D¨olle, W. T¨opner and H. -G. Neumann, Xenobiotica, 10, 527 (1980). 34. P. Eyer, H. Kampffmeyer, H. Maister and E. R¨osch-Oehme, Xenobiotica, 10, 499 (1980). 35. G. J. Mulder, L. E. Unruh, F. E. Evans, B. Ketterer and F. F. Kadlubar, Chem.-Biol. Interact., 39, 111 (1982). 36. C. Diepold, P. Eyer, H. Kampffmeyer and K. Reinhardt, in Biological Reactive Intermediates II. Chemical Mechanisms and Biological Effects (Eds. R. Snyder, D. V. Parke, J. J. Kocsis, D. J. Jollow, C. G. Gibson and C. M. Witmer), Plenum Press, New York, 1982, p. 1173. 37. K. Saito and R. Kato, Biochem. Biophys. Res. Commun., 124, 1 (1984). 38. H. Klehr, PhD Thesis, Ludwig-Maximilians-Universit¨at M¨unchen, 1988. 39. H. Klehr and P. Eyer, Naunyn-Schmiedeberg’s Arch. Pharmacol., 335 (Suppl.), R 12 (1987). 40. P. Eyer and M. Ascherl, Biol. Chem. Hoppe-Seyler, 368, 285 (1987). 41. K. Saito, Y. Yamazoe, T. Kamataki and R. Kato, Carcinogenesis, 4, 1551 (1983). 42. H. -O. Kalinowski, S. Berger and S. Braun, 13 C-NMR-Spektroskopie, Thieme Verlag, Stuttgart, 1984.
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Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
24
Analytical aspects of amino, quaternary ammonium, nitro, nitroso and related functional groups JACOB ZABICKY and SHMUEL BITTNER Institutes for Applied Research and Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel Fax: 927-7-472969, 972-7-472943; e-mail:
[email protected] [email protected]
I. ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . II. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . III. ELEMENTAL ANALYSIS . . . . . . . . . . . . . . . . . A. Automatic Organic Elemental Analysis (CHNOS) 1. General . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nitrogen . . . . . . . . . . . . . . . . . . . . . . . . . 3. Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . B. Digestion Methods . . . . . . . . . . . . . . . . . . . . C. Nitrogen Responsive Detectors for GC . . . . . . . D. Stable Isotope Analysis . . . . . . . . . . . . . . . . . IV. AMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Isotope Analysis . . . . . . . . . . . . . . . . . . . . . . C. Gas Chromatography . . . . . . . . . . . . . . . . . . . D. Liquid Chromatography . . . . . . . . . . . . . . . . . 1. General . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Underivatized analytes . . . . . . . . . . . . . . . . 3. Pre-column and post-column derivatization . . a. Reaction with dicarboxaldehydes . . . . . . . b. Oxazole derivatives . . . . . . . . . . . . . . . . c. N-Acylation and N-sulfonation . . . . . . . . d. Reaction with isothiocyanates . . . . . . . . .
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Jacob Zabicky and Shmuel Bittner e. N-Arylation . . . . . . . . . . . . . . . . . . . . . . f. Schiff bases . . . . . . . . . . . . . . . . . . . . . . g. Miscellaneous reactions . . . . . . . . . . . . . . 4. Chiral purity . . . . . . . . . . . . . . . . . . . . . . . 5. Fossil dating . . . . . . . . . . . . . . . . . . . . . . . E. Electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . F. Spectrophotometric Methods . . . . . . . . . . . . . . . G. Enzymatic Biosensors . . . . . . . . . . . . . . . . . . . H. Miscellaneous Methods . . . . . . . . . . . . . . . . . . I. Derivatization . . . . . . . . . . . . . . . . . . . . . . . . QUATERNARY AMMONIUM COMPOUNDS . . . . A. Chromatography . . . . . . . . . . . . . . . . . . . . . . . B. Miscellaneous Methods . . . . . . . . . . . . . . . . . . NITRO COMPOUNDS . . . . . . . . . . . . . . . . . . . . A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Aromatic Nitro Compounds . . . . . . . . . . . . . . . 1. General . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Monocyclic arenes . . . . . . . . . . . . . . . . . . . 3. Polycyclic aromatic hydrocarbons (PAH) . . . . . 4. Phenols . . . . . . . . . . . . . . . . . . . . . . . . . . . a. HPLC and GC without derivatization . . . . . b. HPLC and GC with precolumn derivatization c. Miscellaneous methods . . . . . . . . . . . . . . 5. Aromatic amines . . . . . . . . . . . . . . . . . . . . 6. Miscellaneous aromatic compounds . . . . . . . . C. Nitrofurans . . . . . . . . . . . . . . . . . . . . . . . . . . D. Miscellaneous Heterocyclic Compounds . . . . . . . E. Aliphatic Compounds . . . . . . . . . . . . . . . . . . . F. Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Nitramines . . . . . . . . . . . . . . . . . . . . . . . . . . . NITROSO COMPOUNDS . . . . . . . . . . . . . . . . . . A. General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitrosoarenes . . . . . . . . . . . . . . . . . . . . . . . . . C. Nitrosamines . . . . . . . . . . . . . . . . . . . . . . . . . 1. Gas chromatography . . . . . . . . . . . . . . . . . . 2. Liquid chromatography . . . . . . . . . . . . . . . . 3. Miscellaneous methods . . . . . . . . . . . . . . . . D. Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . . HYDROXYLAMINES . . . . . . . . . . . . . . . . . . . . . A. Quantitative Analysis . . . . . . . . . . . . . . . . . . . . B. Structural Analysis . . . . . . . . . . . . . . . . . . . . . C. Derivatization . . . . . . . . . . . . . . . . . . . . . . . . AMINO-OXYLS . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . .
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I. ABBREVIATIONS
AAS AED AFID AOAC
atomic absorption spectroscopy atomic emission detector(ion) alkali FID Association of Official Analytical Chemists
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1085 1085 1086 1089 1092 1093 1096 1102 1105 1109 1114 1116 1118 1122 1122 1125 1125 1127 1129 1133 1133 1134 1134 1135 1137 1139 1140 1141 1142 1142 1143 1143 1143 1144 1144 1146 1148 1150 1151 1151 1152 1152 1153 1154
24. Analytical aspects CE CI-MS CLD CLND CMC CZE DON DSC DTA ECD EI-MS ELCD ELISA ELS EPA FAB FASD FIA FID FLD FPD GC-. . . GCE HPTLC ICP IEC LIF LLE LOD LOQ MEKC MSTS NAA NDIR NICI-MS NIOSH NOC NPD OFID OSHA PAH PON PSP-MS RIA RID RP-. . . RSD
capillary electrophoresis chemical ionization MS chemiluminescence detector(ion) chemiluminescence nitrogen detector(ion) critical concentration for micelle formation capillary zone electrophoresis dissolved organic nitrogen differential scanning calorimetry differential thermal analysis electron capture detector(ion) electron impact MS electrolytic conductivity detector(ion) enzyme-linked immunosorbed assay evaporative light scattering Environmental Protection Agency (USA) fast atom bombardment flameless alkali-sensitized detector(ion) flow injection analysis flame ionization detector(ion) fluorescence detector(ion) flame photometric detector(ion) gas chromatography combined with special detectors glassy carbon electrode high-performance TLC inductively coupled plasma ion-exchange chromatography laser-induced fluorescence liquid liquid extraction limit(s) of detection limit(s) of quantation micellar electrokinetic chromatography mainstream tobacco smoke nitroso amino acids nondispersive infrared negative ion chemical ionization MS National Institute for Occupational Safety and Health (USA) nitroso organic compounds (nitrosamines) nitrogen phosphorus detector(ion) oxygen FID Occupational Safety and Health Administration (USA) polycyclic aromatic hydrocarbon(s) particular organic nitrogen plasma-spray MS (discharge-assisted TSP-MS) radioimmunoassay refractive index detector(ion) reversed-phase combined with other items relative standard deviation
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Jacob Zabicky and Shmuel Bittner RTECS SCE SFE SIM SIMS SNR SPE SPME SSTS TCD TDN TEA TGA TOF TSD TSNA TSP-MS USP UVD UVV VNOC XPS XRD
Registry of Toxic Effects of Chemical Substances (NIOSH/OSHA) standard calomel electrode supercritical fluid extraction selected-ion monitoring mode of MS secondary ion MS signal-to-noise ratio solid-phase extraction solid-phase microextraction sidestream tobacco smoke thermal conductivity detector(ion) total dissolved nitrogen thermal energy analyzer thermogravimetric analysis time of flight thermionic specific detector(ion) tobacco-specific N-nitrosamines thermospray MS US Pharmacopea UVV photometric detector(ion) ultraviolet-visible volatile NOC X-ray photoelectron spectroscopy X-ray diffractometry
II. INTRODUCTION The present chapter deals with amino, nitro and nitroso groups, quaternary ammonium compounds, and with several minor related functional groups. Analytical aspects concerning these functional groups were reviewed in the past to various extents1 3 . The present chapter will deal with certain general aspects and especially with advancements that took place in the last few years. The technological importance of organic compounds containing amino and nitro groups is outstanding, both as chemical intermediates and as products that are used in other manufacturing industries, agriculture and medicine. They have found application as drugs, dyestuffs, pesticides, explosives, additives, modifiers and others. Manufacture of these chemicals requires development of analytical methods for process and quality control. Examples of such compounds that have found industrial application are listed in various tables below. Automatization of all stages of the analytical process is a trend that can be discerned in the development of modern analytical methods for chemical manufacture, to various extents depending on reliability and cost-benefit considerations. Among the elements of reliability one counts conformity of the accuracy and precision of the method to the specifications of the manufacturing process, stability of the analytical system and closeness to real-time analysis. The latter is a requirement for feedback into automatic processcontrol systems. Since the investment in equipment for automatic online analysis may be high, this is frequently replaced by monitoring a property that is easy and inexpensive to measure and correlating that property with the analyte of interest. Such compromise is usually accompanied by a collection of samples that are sent to the analytical laboratory for determination, possibly at a lower cost. A different approach is required in biological research, pharmacology, forensic investigations, occupational hygiene and environmental protection. Often one confronts samples that are difficult to deal with because of their small size, unstability, the low concentration
24. Analytical aspects
1045
of analyte or the nature of the matrix. Many advances of modern analysis are concerned with pushing down the limits of detection and quantation (LOD, LOQ) using smaller and smaller samples, frequently in the mM or nM range, with only picomoles or even femtomoles of analyte. These advancements are the result of improved selectivity of reagents and media, development of sensors with increased sensitivity that are backed-up by reliable electronic system and optimization of the analytical methodology. Some advances are concerned with making the analytical equipment cheaper, easier to handle and more time efficient (see, for example, Reference 4). It should be pointed out that the LOD and LOQ concepts are used rather loosely in the literature and are sometimes interchanged. Furthermore, LOD are given in extensive as well as intensive terms (e.g. mmol vs nM/mL). Except for cases where sample size was reported and a lower limit concentration could be discerned, extensive LOD are given as reported. The present chapter is subdivided according to the nature of the various analytical methods, emphasizing the importance of chromatography including the various detection methods. Structural analysis is treated only briefly here and is left mostly to other chapters dealing with spectral properties. III. ELEMENTAL ANALYSIS
Compounds bearing the functional groups of the present chapter are usually analyzed for the characteristic N heteroatom and less frequently for O. In this section some recent advances in the analysis of these heteroatoms are presented. A critical review appeared of the analysis of the nutrient elements C, N, P and Si, and their speciation in environmental waters, including sample collection and preservation, sample preparation and methods for end analysis5 . A. Automatic Organic Elemental Analysis (CHNOS)
1. General
A recent brief review showed the working principles of various automatic analyzers6 . A modified account of N and O analysis will be presented here. Today there exist in the market instruments that perform organic elemental analyses in a few minutes. The ease and speed of such analyses enable the use of such instruments for routine analysis. Although some operational details vary from model to model and between one manufacturer and another, all these instruments can be considered as exalted versions of the classical Pregl determination of C and H by conversion to CO2 and H2 O, together with Dumas’ method for N by conversion to N2 , the calorimetric bomb method for S by conversion to SO2 and SO3 and Schultzes’ method for O by conversion to CO. This is combined with modern electronic control, effective catalysts and instrumental measuring methods such as IR detectors and GC analyzers. A method for rapid organic C and N analysis in natural particulate materials consists of eliminating carbonates with HCl solution and determining these elements in an automatic analyzer7 . 2. Nitrogen
Instruments are available for determination of N alone, CHN, CNS and CHNS. N determination in one of the CHN models involves removal of all nonnitrogenous combustion products, including halogens and various oxides, reduction of N oxides to N2 , removal of excess oxygen, dilution with helium and measurement with a thermal conductivity
1046
Jacob Zabicky and Shmuel Bittner
detector (TCD)8 . In a simultaneous CHNS analyzer the combustion gases are reduced to a mixture of N2 , CO2 , H2 O and SO2 , carried in a helium stream and determined by GC-TCD9 . Automatic Dumas determinations of N in plant tissue were consistently higher than the corresponding Kjeldahl determination in a comparative study. A correlation between both results was proposed10 . Significantly higher values were also obtained from a LECO FP428 nitrogen analyzer when comparing the results with those of the Kjeldahl method for the determination of N in various oil-bearing seeds. The automatic analyzer was adopted for routine analysis of these materials11 . The same instrument was fitted with a liquid injector for determination of total N in milk. The intense production of steam resulted in poor N recoveries. This was improved by slow injection and filling the combustion tube with CeO2 . Results were about 6.7% higher than by the Kjeldahl method12 . A dual-channel analyzer for the determination of N in water was developed, based on chemiluminescence detectors (CLD). One channel is for total dissolved N (TDN) and the other for Nox (e.g. NO2 , NO3 ). The difference between the two channels is taken as organic N. Total N analysis of waste waters takes 2 4 min, in manual or automatic mode; operational range: 10 ppb to 200 ppm N as Nox , 60 ppb to 200 ppm total N and 90 ppb to 200 ppm organic N13 . 3. Oxygen
Oxygen elemental analyzers are usually sold as adaptation kits for the CHN analyzers. In one commercial model all the oxygen-containing compounds are converted to CO, which is measured with a nondispersive infrared (NDIR) photometer8 . A recent development in GC is the oxygen flame ionization detector (OFID), incorporating a reactor in which the C of organic matter is retained and O appears ultimately as methane and is measured by FID. The OFID exhibits over 105 O-to-C selectivity14 . B. Digestion Methods
Nitrogen in forest soil extracts and surface waters may belong dominantly to the socalled dissolved organic nitrogen (DON), which is difficult to measure by the Kjeldahl method. An accurate, fast, simple and inexpensive alternative is based on persulfate oxidation followed by conductometric measurement of the nitrate ion15 . Nitrogen in sediments can be determined by persulfate oxidation in a strongly alkaline environment in a bomb at high temperature and pressure. End analysis of the resulting nitrates is by ion-exchange chromatography (IEC)16 . Determination of DON and dissolved organic phosphorus was carried out in a flow injection analysis (FIA) system by oxidation promoted by UV light, successively in acid and alkaline media. At the 2 40 mM level, recovery was 60 100% for spiked deionized water and 40 80% for seawater17 . A method for TDN in water is based on photooxidation of inorganic and organic nitrogen with alkaline peroxodisulfate. The nitrate formed is reduced by Cd to nitrite. The latter participates in diazotation and coupling reactions, followed by spectrophotometric determination at 540 nm. The FIA method is relatively fast and inexpensive; LOD 0.03 mg N/L with linearity up to 3 mg/L18 . The alkaline peroxodisulfate digestion of TDN in a bomb may yield nitrate as the sole product. End analysis can be by ion chromatography. The method showed a recovery higher than 90%, relative standard deviation (RSD) 4.62% for urea and ammonium chloride and 3.62% for natural water samples19 . Determination of total particulate organic nitrogen (PON) and phosphorus is based on the standard persulfate digestion method at 120 ° C, yielding nitrate and phosphate for end analysis. The modification is efficient for cell cultures and natural
24. Analytical aspects
1047
seawater and is suitable for routine analysis in shipboard laboratories20 . PON was determined by persulfate oxidation using 0.2 mm Teflon membrane filters. The results obtained for seawater were 20 90% higher than those obtained with the coarser glass fiber filters, so it was concluded that submicron particles contribute significantly to PON21 . Possible interferences in the analysis of TDN in seawater by the persulfate oxidation stem from the presence of bromide ions. These are eliminated by reducing the bromate ion product to bromide, oxidizing to bromine and expelling the latter from the solution22 . A review of the Kjeldahl method has appeared23 . A Cu catalyst was investigated instead of the standard Hg catalyst for the Kjeldahl determination of N in meat products, according to AOAC Method 928.0824 . Microwave drying was demonstrated for rice leaves and did not affect the N analysis25 . The presence of organic nitrogen interferes with the determination of ammonium ions in organic fertilizers when ammonia is distilled off from suspensions alkalinized with NaOH. No such interference was noted when MgO was used as the base. The specific ammonium electrode was found to be unsatisfactory for the end analysis of ammonia. The residue left after distilling off ammonia could be used for Kjeldahl determination of organic N26 . Total nitrogen determinations in barley and malt gave slightly higher results by the Dumas than by the Kjeldahl method. The Dumas method was adopted as the reference method by the Analysis Committee of the Institute of Brewing27 . Comparison of the results obtained by the Kjeldahl method with those of automatic N analyzers is mentioned in Section III.A.2 above. Pyrochemiluminescence was adopted by AOAC International, as a method for determination of total N in urine. The reaction of ozone with the products of oxidative pyrolysis is measured with a CLD; average recovery of total N in urine in a collaborative study of twelve laboratories was 99.9% with RSD ranging from 3.66 to 9.57%28 . C. Nitrogen Responsive Detectors for GC
Gas chromatography is idealy suited for identification and determination of individual compounds, but samples with overlapping and coincidental peaks may confuse the analysis. Combinations such as GC-MS or GC-FTIR are now commonplace; however, these instruments may be unwieldy for most routine analyses. In such cases element-specific detectors may be of help, as they greatly simplify complex chromatograms. These detectors have been reviewed6,29,30 including ones that respond specifically to nitrogen-containing species: Alkali flame ionization detector (AFID)31 33 , flameless alkali-sensitized detector (FASD)34 38 , chemiluminescence detector (CLD)39 42 , electrolytic conductivity detector (ELCD)43,44 and electron capture detector (ECD)45 49 . A nitrogen-specific chemiluminescence detector (CLND) is based on total conversion of N to NO, which undergoes a chemiluminescent reaction with ozone. This was applied to the analysis of nitrosamines, pesticide residues, food flavoring compounds, pharmaceuticals and petroleum distillates50 . A new thermionic ionization chemiluminescence-measuring device is sensitive to S, N and P. In this detector sulfur-containing compounds produce SO and the chemiluminescence produced on mixing this species with O3 is measured. Independent response channels lead to chromatograms for the S channel and for the NP channel51 . Recent examples of GC analysis using specific response detectors for N are mentioned also in Sections IV.C and VI.A. Atrazine (1a) was determined in freeze-dried water samples containing simazine (1b) by GC combined with a nitrogen phosphorus detector (NPD). This method and direct rapid-magnetic particle-based enzyme-linked immunosorbed assay (ELISA) gave comparable results at levels between 0.1 to 5 mg/L of water. A clean-up step before ELISA was advantageous52 . Organophosphorus and nitrogen-containing pesticides,
1048
Jacob Zabicky and Shmuel Bittner N
EtNH N
Cl N
(a) R = i-Pr (b) R = Et
NHR (1)
e.g. simazine (1b), in ground and drinking water were determined after concentration by solid-phase extraction (SPE) and elution with an organic solvent. Recovery was 75 90% from 1 2.5 L samples containing 0.1 5 mg/L of analytes. GC-NPD and GC-MS in selected-ion monitoring (SIM) mode were compared, the latter being more sensitive; LOD 0.08 0.60 mg/L vs 0.03 0.13 mg/L, respectively53 . 2-Methoxy-3-alkylpyrazines (2) were determined in carrots by combining a selective stripping method with GC-NPD. Concentrations of 2a as low as 0.029 ng/g were measured54 . Traces of aldicarb (3a) and its metabolites (3b c) were determined in oranges by extraction with aqueous solvents, partitioning with dichloromethane and a combination of reversed phase (RP) HPLC, using a gradient mobile phase, GC-NPD and GC combined with a flame photometric detector (FPD); LOD 0.4, 0.8 and 0.4 ppb for 3a, b and c, respectively55 . N
N
OMe
R
Me (a) R = i-Pr (b) R = i-Bu (c) R = s-Bu
(2)
MeY
C Me
CH
N
(a) Y = S O2 CNHMe (b) Y = SO (c) Y = SO2 (3)
Nitrogen-containing components of gasoline were determined by simulated distillation (a GC procedure) using a CLND56 . The effect of SPE was studied on analytical reproducibility in the determination of thirteen drugs by GC-NPD in whole blood. Reproducibility was good as long as limiting factors such as volatility or chromatographic behavior did not interfere57 . A study was made of the effectiveness of SPE with a C18 adsorbent for P- and N-containing pesticides, using GC-NPD for the end analysis. Recoveries varied from 0 to 91%, depending on the physicochemical properties of the analyte58 . D. Stable Isotope Analysis
A comparative study was made between determinations of the 15 N content of plant and soil samples, using the methods of the International Atomic Energy Agency Laboratories, based on MS, a novel automatic N analyzer coupled to a mass spectrometer and a microprocessor-controlled emission spectrometer. Although the latter instrument is fast, its precision may be insufficient to determine 15 N in soil59 . Enrichment of the 15 N content has become part of various powerful research techniques. For example, uniform labeling with 15 N was used for sequence-specific assignments and secondary structure determination of certain proteins by NMR60 and tracing of complicated processes including the increase of DON in soil61,62 . An inexpensive piston-action ball mill for the rapid preparation of plant and soil material for automated 15 N and 13 C analysis enables one to process 150 samples per hour to
24. Analytical aspects
1049
particle sizes that are at least 50% under 105 mm. This allows a precision better than 1% for the determination of 15 N isotope enrichment in an automated, continuous flow, N and C isotope-ratio mass spectrometer63 . A method for purification of nanomole quantities of N prior to determination of the isotope ratio was described, based on the absorption of various impurities on calcium oxide and copper at high temperature64 . Problems arose with ammonia diffusion techniques for concentration of low N-content samples, before 15 N analysis, such as nonquantitative recovery and isotopic fractionation, to which no solutions were found. Therefore, evaluation of the ammonia diffusion technique for representative sample types and use of standard curves are recommended for overcoming such problems65 . Some elemental analysis methods involve conversion to N2 and a direct method that does not require standards was developed based on the (2,0) band of the second positive system emitted by the N2 molecule in a high-frequency discharge. The band heads of 14 N14 N and 14 N15 N molecules were resolved in a monochromator and the peak intensities measured; RSD <4% in the 15 N concentration range of 0.36 to 24%66 . The precision of these molecular spectroscopy measurements has been limited by the variability of the spectral background. Imaging of the isotopic bandhead region with a diode array allowed making corrections for the spectral background and increasing the analytical precision67 . A study was made of the effects of derivatization on the 13 C analysis of amino acid enantiomers. Conventional isotope ratio MS and GC-isotope ratio MS were used. The latter method requires volatilization of the analytes, which was accomplished by introducing O-isopropyl and N-trifluoroacetyl groups, causing a change in the 13 C analysis of the original analytes. It was proposed to use a set of known standards for such analyses, which are applied in geological studies68 . IV. AMINES A. General
Amines, including the amino acids, peptides and proteins, are mentioned in this Section. Tables 1 3 list primary, secondary and tertiary amines of industrial relevance. Compounds
TABLE 1. Examples of environmental, occupational and quality control protocols for industrial primary amines Compound and CAS registry number a
Safetyb
Amino group attached to saturated aliphatic carbon 1-Adamantanamine [768-94-5] 117D L-Alanine [56-41-7] 83D e Amikacin 2-Aminoethanol [141-43-5] 1547B 2-(2-Aminoethylamino)ethanol 168B [111-41-1]f 1-(2-Aminoethyl)piperazine 172B [140-31-8]f 2-Amino-2-ethyl-1,3-propanediol [115-70-8] 2-Aminoheptane [123-82-0] 177C 6-Aminohexanoic acid [60-32-2] 149B
Spectrac
I(3)409D, N(1)276C I(1)571B
Various protocolsd
I(3)423D, N(1)291B I(3)437D, N(1)304C
YD1925000, USP USP USP KJ5775000 KJ6300000
I(3)437D, N(1)330C
TK8050000
I(1)348B I(3)374A, N(1)490C I(1)578D, N(1)247C
MQ5425000, USP MO6300000, USP (continued overleaf )
1050
Jacob Zabicky and Shmuel Bittner
TABLE 1. (continued ) Compound and CAS registry number a 2-Amino-2-methyl-1-propanol [124-68-5] 1-Amino-2-propanol [78-96-6] Amphetamine sulfate [60-13-9] (28) Amphotericin B [1397-89-3] Ampicillin [69-53-4] L-Arginine [74-79-3] (8) Bacampicillin hydrochloride [37661-08-8] n-Butylamine [109-73-9] s-Butylamine [13952-84-6; 33966-50-6]g t-Butylamine [65-64-9] Capreomycin sulfate [1405-37-4]e (R)-(C)-Cycloserine [68-41-7] Cyclohexylamine [108-91-8] L-Cysteine hydrochloride monohydrate [7048-09-6] (115) Diethylenetriamine [111-40-0]e,f L-DOPA [59-92-7] Dopamine [62-31-7] (19b) Doxorubicin hydrochloride [25316-40-9] Ethylamine [75-04-7] Ethylenediamine [107-15-3]e L-Glutamic acid [56-86-0] (34b) Glycine [56-40-6] Histamine phosphate [51-74-1] (6) L-Histidine [71-00-1] L-Isoleucine [73-32-5] Isopropylamine [75-31-0] Kanamycin sulfate [133-92-6; 25389-94-0]e L-Leucine [61-90-5] L-Lysine monohydrochloride [657-27-2] (144)e L-Methionine [63-68-3] Methylamine [74-89-5] ˛-Methyl-L-DOPA [41372-08-1] Natamycin [7681-93-8] (š)-Norephedrine hydrochloride [154-41-6] (79) D-Penicillamine [52-67-5] DL-Phenylalanine [150-30-1] L-Phenylalanine [63-91-2] (45) 2-Phenylethylamine [64-04-0] (33) Pimaricin [7681-93-8]g Primaquine phosphate (148) [63-45-6]f
Safetyb
Spectrac
Various protocolsd
194B
I(3)425D, N(1)294B
UA5950000
215D
I(3)425A, N(1)293B
247A 302D
I(1)786A, N(1)658B
UA5775000 SI1750000, USP BU2625000, USP XH8350000, USP CF1934200, USP SH8490000, USP
302D 615B
I(3)364D, N(1)239B I(3)368B, N(1)243A
EO2975000 EO3325000
615C
I(3)369B, N(1)244A
970C 1000C
I(1)810D, N(1)678C I(3)402A, N(1)270C I(1)592A, N(1)499B
EO3330000 USP NY2975000, USP GX0700000 HA2275000, USP
1207D
I(1)396A, N(1)266B I(2)257B I(1)1294A, N(1)1098B
IE1225000 AY5600000, USP UX1092000, USP Q19295900, USP
1569C 1604B 1776A 1786D 1877C 1877D 2024A 2031B
I(3)364B, N(1)237D I(3)374D, N(1)248A I(1)590A, N(1)497B I(1)563A, N(1)481A
KH2100000 KH8575000, USP LZ9700000 MB7600000, USP NI5425000, USP MS3070000, USP NR4705000, USP NT8400000 NZ3225000, USP
2116D 2172B
I(1)575B, N(1)489B I(1)588B, N(1)495B
OH2850000, USP OL5650000, USP
2232D 2283D
I(1)594C, N(1)501B I(3)363D I(2)258D
PD0457000, USP PF6300000 AY5950000, USP TK3325000, USP DN4200000, USP
1499A
2838C 2624C 2689b 2755D 2756B 2741C 2838C 2942C
I(2)621D, N(2)493B I(1)575D, N(1)489C I(3)368A, N(1)242C
I(1)1273A, N(1)1079D I(1)592C, N(1)500A I(2)250C, N(2)248B I(2)251A, N(2)248C I(3)1164C, N(1)1075C I(2)864B, N(2)741A
YV9425000, USP AY7535000, USP SG8750000 TK3325000 VA9660000, USP
24. Analytical aspects
1051
TABLE 1. (continued ) Compound and CAS registry number a
Safetyb
n-Propylamine [107-10-8] 2961D L-Serine [56-45-1] 3085C 3261B Tetraethylenepentamine [112-57-2]e,f D-Thyroxine [51-49-0] 3349C L-Thyroxine [51-48-9] 3349B Triethylenetetramine [112-24-3]e,f 3431D (+)-3,30 ,5-Triiodo-L-thyronine 3467B sodium salt [55-06-1] L-Tyrosine [60-18-4] (46) 3565B Amino group attached to carbon carbon double bond 154C 2-Amino-3-chloro-1, 4-naphthoquinone [2797-51-5]g Mitomycin C [50-07-7] 2470B Amino group attached to aromatic carbon Aclonifen [74070-46-5]g Acrisorcin [7527-91-5] Amiloride hydrochloride [17440-83-4]e 2-Aminobenzoic acid [119-92-3] 2-Aminobenzoic acid methyl ester [134-20-3] (165) 4-Aminobenzoic acid [150-13-0] 4-Aminobenzoic acid n-butyl ester [94-25-7] 4-Aminobenzoic acid ethyl ester [94-09-7] (165) 4-Aminobiphenyl [92-67-1] 2-Amino-4-chlorophenol [95-85-2] DL-Aminoglutethimide
[125-84-8] 4-Aminohippuric acid [61-78-9] 1-Aminonaphthalene [134-32-7] 2-Aminonaphthalene [91-59-8] 2-Aminophenol [95-55-6] 4-Aminophenol [123-30-8]
4-Aminosalicylic acid [65-49-6] Amprolium Anileridine [144-14-9]f Aniline [62-53-3] Asulam [2302-17-2]g Atrazine [1912-24-9] (1a)e,g Basic fuchsin [569-61-9; 632-99-5]e Benzidine [92-87-5] (32)e Chloramben [133-90-4]g 2-Chloroaniline [107-47-8]
Spectrac
Various protocolsd
I(3)364C, N(1)238D I(1)580B I(3)398D, N(1)268A
UH9100000, EPA USP KH8585000
I(2)254A I(2)254B I(3)498B, N(1)267C I(2)253D
USP YP2833500, USP YE6650000 USP
I(2)255D, N(2)254B
YP2275600, USP
I(2)81A, N(2)87A
QL7350000
I(2)1068A
CN0700000, USP
USP USP 282B 2295A
I(2)189A, N(2)186B I(3)1371A, N(2)284A
CB2450000 CB3325000
138B
I(2)198C, N(2)195B
DG1400000, USP DG1530000, USP
1571A
I(3)1372B, N(2)287D
DG2450000, USP
143D 789A
I(3)1157B, I(1)1228A, N(1)1038A I(2)404A, I(2)378B, N(2)355A N(1)1058B
DU8925000, EPA SJ5700000
149B 196D 197A 206C 207A
MA4026950, USP USP QM1400000, EPA QM2100000, EPA SJ4950000 SJ5075000
225A
I(3)1115D, N(1)997B I(1)1210B, N(1)1013A I(2)219C, N(2)215C
270A
I(3)1109A, N(1)987A
338C, 339A
I(2)963B, U126, 129
CX9850000, CX9850100, USP DC9625000, EPA
732D
I(3)1114C, N(1)995A
BX0525000
VO1225000, USP USP USP BW6650000, EPA
(continued overleaf )
1052
Jacob Zabicky and Shmuel Bittner
TABLE 1. (continued ) Compound and CAS registry number a
Safetyb
4-Chloroaniline [107-47-8]
733B
3-Chloro-4-fluoroaniline [367-21-5]
782A
3-Chloro-4-methylaniline [95-74-9]
797C
2-Chloro-4-nitroaniline [121-87-9]
815D
4-Chloro-2-nitroaniline [89-63-4]
816B
Dapsone [80-08-0] 1,2-Diaminobenzene [95-54-5]e
212A 2773A
1,3-Diaminobenzene [106-50-3]e
2773B
1,4-Diaminobenzene [106-50-3]e
2773C
2,4-Diaminotoluene [95-80-7]e
1059C
3,4-Dichloroaniline [95-76-1]
1112C
3,30 -Dichlorobenzidine [91-94-1]e 2,6-Dichloro-4-nitroaniline [99-30-9]g 2,6-Diethylaniline [579-66-8]
1196C
2,4-Dimethylaniline [95-68-1] 2,6-Dimethylaniline [87-62-7]
1348C 1349A
Dinitramine [29091-05-2]f,g Fluroxypyr [69377-81-7]g Methotrexate [59-05-2]e,f 2-Methoxy-5-methylaniline [120-71-8] 2-Methylaniline [95-53-4] 4-Methylaniline [106-49-0]
129C 2252C 3371C 3372D
2-Methyl-5-nitroaniline [99-55-8]
2388C
2-Nitroaniline [88-74-4]
2549C
3-Nitroaniline [99-09-2]
2550A
4-Nitroaniline [100-01-6]
2550C
Procainamide hydrochloride [614-39-1]f Procaine hydrochloride [51-05-8]f Sulfadiazine [68-35-9] (111) Sulfamethazine [57-68-1] Sulfathiazole [72-14-0] Triamterene [396-01-0]e
2942D
Spectrac I(3)1126C, N(1)1010A I(3)1137A, N(1)1025D I(3)1138C, N(1)1026B I(3)1365D, N(1)1168D I(3)1211A, N(1)1169A I(2)490B, N(2)815C I(1)1154A, N(1)1045C I(1)1154D, N(1)1048A I(1)1242B, N(1)1051B I(3)1155B, N(1)1049A I(3)1139D, N(1)1029A
Various protocolsd BX0700000, EPA EPA XU5111000, EPA BX1400000 BX1575000 GA0875000, USP SS7875000 SS7700000 SS8050000, EPA XS9625000, EPA BX2625000 DD0525000, EPA
2943B 3195A
I(3)1131C, N(1)1019A I(3)1135B I(3)1131A, N(1)1018C
I(2)896D I(3)1144A, N(1)1033B I(3)1112D, N(1)992D I(3)1121B, N(1)1005B I(1)1364B, N(1)1167C I(3)1185C, N(1)1134D I(3)1189B, N(1)1139A I(3)1193C, N(1)1144C I(2)373B, N(2)350C I(2)303D, N(2)349D I(2)836C
3322B 3389C
BX3500000, EPA ZE8925000 ZE9275000, EPA
MA1225000, USP BZ6720000 XU2975000, EPA XU3150000 XU8225000, EPA BY6650000, EPA BY6825000, EPA BY7000000, EPA CV2295000, USP DG2275000, USP WP1925000, USP WO9275000, USP WP2360000, USP UO3470000, USP
24. Analytical aspects
1053
TABLE 1. (continued ) Compound and CAS registry number a
Safetyb
Spectrac
Various protocolsd
2,4,5-Trichloroaniline [636-30-6]
3407A
I(3)1152B, N(1)1043A I(3)1114B, N(1)994B
XU8225000, EPA
3-Trifluoromethylaniline [98-16-8]
141A
XU9210000, EPA
a Nomenclature may vary from source to source. See also Reference 69. b Entry number in Reference 70. c Codes beginning with I,N and U denote FTIR spectra in Reference 71, NMR spectra in Reference 72 and UVV
spectra in Reference 73, respectively. d A code of two letters followed by seven digits is a reference to Registry of Toxic Effects of Chemical Substances (RTECS) of National Institute for Occupational Safety and Health/Occupational Safety and Health Administration (NIOSH/OSHA). Standard samples are commercially available for most compounds with reference to protocols of the US Environmental Protection Agency (EPA) and the US Pharmacopea (USP)74 . e The compound has two or more amino groups of the same type. f The compound has several types of amino groups. g A pesticide, see Reference 75.
TABLE 2. Examples of environmental, occupational and quality control protocols for industrial secondary amines Compound and CAS registry number a
Safetyb
Spectrac
Amino group attached to two saturated aliphatic carbons 168B I(3)466B, N(1)304C 2-(2-Aminoethylamino)ethanol [111-41-1]f 1-(2-Aminoethyl)piperazine 172B I(3)437D, N(1)330C [140-31-8]f Desipramine hydrochloride [58-28-6]f Dicyclohexylamine [101-83-7] 1177C I(3)402D, N(1)272C Diethanolamine [111-42-2] 1183D I(3)431B, N(1)297D Diethylenetriamine [111-40-0]f 1207D I(1)396A, N(1)266B Dobutamine hydrochloride [49745-95-1] (1R,2S)-(-)-Ephedrine 1513A I(1)1277C, [299-42-3] (30) N(1)1078C (R)-(-)-Epinephrine [51-43-4] (21b) 1518C I(1)1296A, N(1)1099C Iminodiacetic acid [142-73-4] 1976A I(1)564B, N(1)483B (š)-Isoproterenol hydrochloride 2043D I(1)1296B, [949-36-0] (21c) N(1)1099D (š)-Ketamine hydrochloride [1867-66-9] 2470B I(2)1068A Mitomycin C [50-07-7]f Morpholine [110-91-8] 2477C I(3)472A, N(1)335C Oxamniquine [21738-42-1]f (R)-(-)-Phenylephrine hydrochloride 2776D I(1)1286A, [61-76-7] (51) e Piperazine [57-47-6] 2843D I(3)463B, N(1)326A Piperazine dihydrochloride 2844C [142-64-3]e 2844A I(1)371B, N(1)326B Piperazine hexahydrate [142-63-2]e
Various protocolsd
KJ6300000 TK8050000 USP HY4025000 KL2975000 IE1225000 USP KB0700000, USP DO2625000, USP AI2975000 DO1930000, USP GW1400000, USP CN0700000, USP QD6475000 USP DO7525000, USP TK7800000, USP TL4025000 TM0850000 (continued overleaf )
1054
Jacob Zabicky and Shmuel Bittner
TABLE 2. (continued ) Compound and CAS registry number a L-Proline [147-85-3] (š)-Propranolol hydrochloride [3506-09-0] (1S,2S)-(+)-Pseudoephedrine hydrochloride [345-78-8] (180a) Sarcosine [107-97-1] Tetraethylenepentamine [112-57-2]e,f Triethylenetetramine [112-24-3]e,f
Safetyb 2946A 2961A
Spectrac I(1)583C I(1)1300D, N(1)1104B
2983D
Various protocolsd TW3584000, USP UB7526000, USP UL5950000, USP
3070A 3261B
I(1)570A I(3)398D, N(1)268A
VQ2897000 KH8585000
3431D
I(3)498B, N(1)267C
YE6650000
Amino group attached to one saturated aliphatic carbon and one carbon carbon double bond Flurtamone [96525-23-4]g Amino group attached to one saturated aliphatic carbon and one aromatic carbon Benzonatate [104-31-4] USP Butralin [33629-47-9]g Chloroquine [54-05-7] VB2360000, USP Cyanazine [21725-46-2]e,g UG1490000 Desmetryn [1014-69-3]e,g Dinitramine [29091-05-2]f,g Ethoxyquin [91-53-2]g N-Ethyl-m-toluidine [102-27-2] 1660B I(3)1117C, N(1)999D XU6400000 N-Ethyl-o-toluidine [94-68-8] I(3)1113A XU6440000 Hydroflumethazide [135-09-1] USP Oxamniquine [21738-42-1]f USP Pendimetalin [40487-42-1]g Primaquine phosphate [63-45-6] 2942C I(2)864B, N(2)741A VA9660000, USP (148)f Quinacrine hydrochloride hydrate 3020C I(2)877A, N(2)751D AR7875000, USP [6151-30-0]f Amino group attached to one aromatic carbon and one carbon carbon double bond Bromocriptine mesylate KE8250000, USP [22260-51-1]f f Reserpine [50-55-5] 3039C I(2)1069C, N(2)945A ZG0350000, USP Vinblastine sulfate 3598B YY8400000, USP [143-67-9](102b)f Amino group attached to two aromatic carbons Amodiaquine [86-42-0] (146)f Carbazole [86-74-8] Diphenylamine [122-39-4]g Fluazinam [79622-59-6]g
681B
I(2)679C
USP FE3150000, EPA JJ7800000, EPA
a Nomenclature may vary from source to source. See also Reference 69. b Entry number in Reference 70. c Codes beginning with I, N and U denote FTIR spectra in Reference 71, NMR spectra in Reference 72 and UVV
spectra in Reference 73, respectively. d A code of two letters followed by seven digits is a reference to RTECS of NIOSH/OSHA. Standard samples are commercially available for compounds with reference to protocols of EPA and USP74 . e The compound has two or more amino groups of the same type. f The compound has several types of amino groups. g A pesticide, see Reference 75.
24. Analytical aspects
1055
TABLE 3. Examples of environmental, occupational and quality control protocols for industrial tertiary amines Compound and CAS registry number a
Safetyb
Spectrac
Amino group attached to three saturated aliphatic carbons Acetophenazine maleate [5714-00-1]e,f Alphaprodine hydrochloride [14405-05-1; 49638-24-6] 1-(2-Aminoethyl)piperazine 172B I(3)437D, N(1)330C [140-31-8] Aminotriptyline hydrochloride [549-18-8] Amodiaquine [86-42-0] (146)f Anileridine [144-14-9]f Apomorphine hydrochloride hemihydrate [41372-20-7] (54) Atropine sulfate monohydrate 320A I(2)286B, N(2)274B [5908-99-6] (159) Azatadine maleate [3978-86-7] Bensultap [17606-31-4]g Benztropine mesylate [132-17-2] 277B I(1)381D Benzyldimethylamine [103-83-3] 1357B I(3)1167D, N(1)1067D Bromocriptine mesylate [22260-51-1]f Bromodiphenhydramine hydrochloride [1808-12-4] Bromopheniramine maleate [980-71-2] Bupivacaine hydrochloride [18010-40-7] (11) Buspirone [33386-08-2; 36505-88-7] (27)f Butorphanol tartrate [58786-99-5] Cartap [15263-53-3]g Chlorcyclizine hydrochloride [1620-21-9; 4362-31-3]e Chlorphenoxamine hydrochloride [562-09-4] Chlorpromazine hydrochloride 871A [69-09-0]e Chlortetracycline hydrochloride 871B [64-72-2]e Clindamycin hydrochloride [21462-39-5] Clomiphene citrate [50-41-9] Cocaine [50-36-2] (23a) Codein [76-57-3] Cyclizine [82-92-8]e Cyclomethycaine sulfate [50978-10-4] Cyproheptadine hydrochloride 999C sesquihydrate [41354-29-4] Dibucaine hydrochloride [61-12-1] 1095C
Various protocolsd
OB4180000, USP TN7101000, USP TK8050000 USP USP USP CE0700000, HQ1750000, USP CK2455000, USP DE8025500, USP YM3150000, USP DP4500000 KE8250000, USP USP US4025000, USP TK6060000, USP USP USP TL2200000, USP KR3155000, USP SO1750000, USP QI7800000, USP GF2275000, USP YE0875000, USP YM2800000, USP QD0893000, USP USP USP TM7050000, USP GD3325000, USP (continued overleaf )
1056
Jacob Zabicky and Shmuel Bittner
TABLE 3. (continued ) Compound and CAS registry number a
Safetyb
Spectrac
2-(N,N-Diethylamino)ethanol [100-37-8] Diethylenetriaminepentaacetic acid [67-43-6]e Diphenhydramine hydrochloride [147-24-0] Diphenylpyraline hydrochloride [132-18-3] Dodemorph [1593-77-7]g Erythromycin [114-07-8] Ethopropazine hydrochloride [1094-08-2]f Ethylenediaminetetraacetic acid [60-00-4]e Ethylenediaminetetraacetic acid, calcium disodium salt hydrate [23411-34-9]e Fenpropidin [67306-00-7]g Fenpropimorph [67564-91-4]g Flupropadin [81613-59-4]g Haloperidol [52-86-8] Hexamethylenetetramine [100-97-0]e D,L-Homatropine hydrobromide [51-56-9] Morphine sulfate [64-31-3] (55) Naloxone hydrochloride dihydrate [51481-60-8] (S)-(-)-Nicotine [54-11-5]g Noscapine [128-62-1] Pargyline hydrochloride [306-07-0] Physostigmine [57-47-6]f Procainamide hydrochloride [614-39-1]f Procaine hydrochloride [51-05-8]f Promethazine hydrochloride [58-33-3]f Propamocarb hydrochloride [25606-41-1]g Quinacrine hydrochloride hydrate [6151-30-0]f Quinidine sulfate [6591-63-5] Quinine sulfate [6119-70-6] (160) Reserpine [50-55-5] Scopolamine hydrobromide [114-49-8] Strychnine [57-29-9]g Tetracycline hydrochloride [64-75-5] Thioridazine hydrochloride [130-61-0]f
1208D
I(3)432B, N(1)299B
KK5075000
1208A
I(1)543C
MB8205000
Various protocolsd
1450A
KR7000000, USP
1461A
TM7823600, USP I(1)703B
1551B
KF4375000, USP SO5002000, USP AH4025000, USP
1605D
EV7700000, USP
1852B
I(2)471D, N(2)332D
EU1575000, USP MN4725000, USP
1882B
I(2)286A, N(2)274C
YM5602000, USP QC8750000, USP QD2275000, USP
2541A
I(3)1537B, N(2)647B
QS5250000 RD2625000, USP DP6650000, USP TJ2100000, USP CV2295000, USP
2423C 1533B 2942D
I(2)948C, N(2)964A I(2)1065C, N(2)392D I(2)373B, N(2)350C
2943B 2948C
I(2)303D, N(2)349D
DG2275000, USP SO8225000, USP
3020C
I(2)877A, N(2)751D
AR7875000, USP
3023A 3023D 3039C 3073B
I(2)866A, I(2)865C, I(2)1069C, N(2)945A I(2)286C, N(2)274D
VA6950000, USP VA8440000, USP ZG0350000, USP YM4550000, USP
3180C 3252B 3337C
I(2)1066B, N(2)942D I(2)421C I(1)1316D
WL2275000 QI9100000, USP SP2275000, USP
24. Analytical aspects
1057
TABLE 3. (continued ) Compound and CAS registry number a
Safetyb
Spectrac
Various protocolsd
Tridemorph [81412-43-3]g Triethanolamine [102-71-6] 3426B I(3)434C, N(1)301D KL9275000 Tubocurarine chloride pentahydrate 3556D YO5100000, USP [41354-45-4] (205)f Vinblastine sulfate [143-67-9] 3598B YY8400000, USP (102b)e,f Amino group attached to one carbon carbon double bond and two saturated aliphatic carbons Mitomycin C [50-07-7]f 2470B I(2)1068A CN0700000, USP Amino group attached to two carbon carbon double bonds and one saturated aliphatic carbon Propyliodone [587-61-1] USP Amino group attached to one aromatic carbon, one carbon carbon double bond and one saturated aliphatic carbon Nalidixic acid [389-08-2] 2485D I(2)889B, N(2)763B QN2885000, USP JI5075000 Oxolinic acid [14698-29-4]g Amino group attached to one aromatic carbon and two carbon carbon double bonds 3018C I(2)873C Pyrvinium pamoate [3546-41-6]f Amino group attached to one aromatic carbon and two saturated aliphatic carbons Ametrin [834-12-8]e,g Benfluralin [1861-40-1]g Buspirone [33386-08-2; 36505-88-7] (27)f Crystal violet [548-62-9]e 929B I(2)1029D, U239 N,N-Diethylaniline [91-66-7] 1196B I(3)1111C, N(1)991B 3-(Dimethylamino)phenol [99-07-0] 1341D I(3)1120C, N(1)1004B N,N-Dimethylaniline [121-69-7] 1347D I(3)1111A, N(1)990D Dipyridamole [58-32-2]e 1472B Ethalfluralin [55283-68-6]g Isopropalin [33820-53-0]g Methotrexate [59-05-2]f 129C I(2)896D 2344C I(2)887D, U448 Methylene blue [7220-79-3]e Methyl yellow [60-11-7] 2464D U472 Oryzalin [19044-88-3]g Physostigmine [57-47-6]f 1533B I(2)1065C, N(2)392D Profluralin [26399-36-0]g Propachlor [1918-16-7]g Pyrvinium pamoate [3546-41-6]f 3018C I(2)873C 3598B Vinblastine sulfate [143-67-9] f (102b)
VC3543500, USP EPA EPA USP BO9000000, USP BX3400000 SL1050000, USP BX4725000, EPA KK7450000, USP EPA EPA MA1225000, USP SO5600000, USP BX7350000, USP TJ2100000, USP EPA VC3543500, USP YY8400000, USP
Amino group attached to two aromatic carbons and one saturated aliphatic carbon Acetophenazine maleate OB4180000, USP [5714-00-1]f Antazoline phosphate USP Bromethaline [63333-35-7]g Desipramine hydrochloride USP [58-28-6]f Ethopropazine hydrochloride 1551B SO5002000, USP [1094-08-2]f (continued overleaf )
1058
Jacob Zabicky and Shmuel Bittner
TABLE 3. (continued ) Compound and CAS registry number a
Safetyb
Promethazine hydrochloride [58-33-3]f Thioridazine hydrochloride [130-61-0]f
2948C 3337C
Spectrac
Various protocolsd SO8225000, USP
I(1)1316D
SP2275000, USP
a Nomenclature may vary from source to source. See also Reference 69. b Entry number in Reference 70. c Codes beginning with I, N and U denote FTIR spectra in Reference 71, NMR spectra in Reference 72 and UVV
spectra in Reference 73, respectively. d A code of two letters followed by seven digits is a reference to RTECS of NIOSH/OSHA. Standard samples are commercially available for compounds with reference to protocols of EPA and USP74 . e The compound has two or more amino groups of the same type. f The compound has several types of amino groups. g A pesticide, see Reference 75.
containing the amino group are important intermediates in the manufacture of organic chemicals. Many of the pharmaceuticals listed in these tables stem from biological systems, possibly with some minor chemical modification. Some amines, including amino acids, are also traced in environmental samples to assess ecologic interaction of living organisms and pollution by industrial chemicals. Nanomolar concentrations of low molecular weight amines and organic acids dissolved in seawater can be preconcentrated up to 1000-fold by diffusion across hydrophobic membranes and collecting in HCl or NaOH solutions, respectively. Of a set of 25 amines investigated, excepting pyrrole, all showed practically quantitative trapping efficiency76 . A comparative study was carried out between diffusive (passive) and pumping (active) sampling of airborne contaminants, including factors such as retention volumes, uptake rate, concentration, recovery by thermal desorption and sampling efficiency. Diffusive sampling gave precise and accurate results according to NIOSH standards (š25% accuracy), and the method is sensitive enough to measure benzene, aniline and nitrobenzene at concentrations as low as 0.1 mg/m3 . Diffusive sampling has practical advantages and is cost effective77 . Interlaboratory studies were carried out on the precision characteristics of the analytical methods used for determination of certain biogenic amines in fish and fish products, as required by German law. These included putrescine (4a), cadaverine (4b), tyramine (5) and histamine (6)78 . CH2 CH2 NH2 CH2 CH2 NH2 NH2 (CH2 )nNH2 (a) n = 4, (b) n = 5, (c) n = 6 (4)
N N H
HO (5)
(6)
24. Analytical aspects
1059
B. Isotope Analysis
In Section III.D various methods were mentioned for determination of the 15 N to 14 N isotope ratio. Some applications to amines that appeared in the recent literature are presented here. Isotope dilution with a known aliquot of labelled compound allows solving some of the problems related to nonquantitative recovery yields of analyte in the analytical processing of a sample. However, the possibility of isotopic fractionation has to be taken into consideration. Isotopic analysis of amino acids containing natural abundance levels of 15 N was performed by derivatization, GC separation, on-line combustion and direct analysis of the combustion products by isotope-ratio MS. The N2 gas showed RSD better than 0.1‰ for samples larger than 400 pmol and better than 0.5‰ for samples larger than 25 pmol. After on-column injection of 2 nmol of each amino acid and delivery of 20% of the combustion products to the mass spectrometer, accuracy was 0.04‰ and RSD 0.23‰79 . Nitrogen uptake studies in plants can be made based on 15 N labelling, taking advantage of developments in MS and automated on-line separation. 15 N can be precisely analyzed in samples of plant extract containing as little as 5 50 mg of N, with isotope enrichment close to the natural abundance level, and then be ascribed to N pools in the plant, such as nitrate, amino acids and soluble protein80 . Individual amino acids can be determined out of mixtures in the natural 13 C abundance range by addition of 13 C-labelled amino acid, derivatization to the N-acetyl propyl ester, GC separation, combustion and determination of 13 C. Up to nine amino acids could be determined in 200 mg of a mixture. The global 13 C of casein calculated from individual amino acids differed by less than 1.5‰ from the directly determined value81 . Characteristic line pairs of the following isotopically enriched amino acids were investigated by MS-SIM: [˛-15 N] and [ε-15 N]lysine, [1-13 C] and [15 N]alanine and leucine, and [1-13 C], [2-13 C], [3-13 C] and [4-13 C]aspartic acid. Enrichments from 0.14 to 36% were determined with high precision82 . A method of high precision and accuracy for determining 15 N enrichment of eighteen common plasma amino acids and urea was proposed, based on derivatization with t-butyldimethylsilyl chloride (7) followed by a single GC analysis combined with electron impact (EI) MS-SIM detection. The monitored ions contained all the N atoms of the original compounds, except for arginine (8) that lost one of the guanidino nitrogens. The method was applied to human metabolism studies83 . Me CO2 H
HN t-Bu
Si Me (7)
Cl
CNH(CH2 )3 CH H2 N
NH2 (8)
A sensitive method for determination of branched-chain L-amino acids is based on labelling individual species with 13 C or 2 H, isolating the amino acid by IEC and applying the derivatization scheme depicted in reaction 1. The L-amino acid is converted
1060
Jacob Zabicky and Shmuel Bittner
enzymatically to the corresponding ˛-keto acid which, on reaction with o-phenylenediamine, yields a branched chain quinoxalinol. After SPE and O-trimethylsilylation the isotope enrichment is determined by GC using chemical ionization (CI) MS-SIM with ammonia and monitoring the [MH](C) and [MH C 1]C ions84 . H3 N
+
CHR O
O
R
O
OH
L-leucine dehydrogenase
O
NH2
(1)
NH2
N
R
N
R
N
OSiMe3
Me 3 SiCl
N
HO
Determination of the 15 NH4 C :(15 NH4 C C 14 NH4 C ) ratio in samples enriched with can be performed by IEC with post-column derivatization according to reaction 7 (Section IV.D.3.a) and fluorescence measurement. The working principle is based on the slightly longer (1.2%) retention time of 15 NH4 C . This is insufficient for peak resolution, but causes a slight retardation to the emergence of the peak maximum, that can be correlated with the concentration of the heavier isotope in the 25 75% range85 . The problem of indigeneity assessment of organic matter in fossils can be solved by determining 13 C and 15 N for the enantiomers of each amino acid. These values should be the same for all amino acids in the fossil sample in indigenous organic matter, while a divergence points to contamination of the sample. The technique involves LC-MS for 15 N, combustion of the eluted amino acids and determination of the 13 C content86 . See also Section IV.D.5. GC-MS analysis of the organic matter in hot water extracts from the Murchinson meteorite showed substantial enrichment of the heavier isotopes of the ‘organic’ elements over the terrestrial values: 2 H C1221‰, 13 C C22‰ and 15 N C93‰. However, a lower value was found for ammonia 15 N C69‰. The total amino acids separated from the extracts had 15 N C94‰. The 15 N values of the soluble organic compounds found in the meteorite are consistent with their formation, or formation of their precursors, by interstellar chemistry87,88 . 15 NH C 4
C. Gas Chromatography
Innumerable applications of chromatographic methods to the analysis of amines appeared in the recent literature concerning biogenic amines, drugs and their metabolites, pesticides and industrial intermediates; however, due to the nonvolatile nature of many amines, application of the LC methods in Section IV.D became preponderant. In Section III.C various detectors were mentioned that respond selectively to nitrogencontaining compounds; some applications to amines follow. A nonlinear calibration curve
24. Analytical aspects
1061
for the NPD was proposed as to be more suitable than a linear one, when this detector is applied to the GC determination of amino acids89 . A collaborative validation study of EPA method 507 was conducted for the GC-NPD analysis of traces of fourty-five pesticides containing N and P in reagent water and finished drinking waters. The results were processed with an EPA computer program to assess recovery, precision and effect of the water type. Method 507 was found to be acceptable for the tested analytes, except for merphos, that decomposed in the injection port of the gas chromatograph. Several pesticides exhibited statistically significant matrix effects for finished drinking water90 . Lidocaine (9) and bupivacaine (11) and their main metabolites resulting from dealkylation of the amino group (10 and 12) in plasma were determined by liquid liquid extraction (LLE) followed by GC-NPD, using a capillary column; LOD was as low as 15 mg/L for the four compounds studied. Simultaneous ingestion of caffeine (13) or carbamazepine (14) interfered with the determination of 10 and 12, respectively91 . Me
Me
Et2 NCH2 CONH
EtNHCH2 CONH Me
Me
(9)
(10) Me
Me
CONH
CONH
N
N Me
Bu
Me
H
(11)
(12)
Me O N N Me O (13)
N
N
Me
CONH2 (14)
Embutramide (15), a general anesthetic, was determined in biological matrices after extraction and GC-NPD, using ambucetamide (16) as internal standard; LOD 40 mg/L, linearity from 0.1 to 3 ppm, with recovery of about 80% from blood of dogs that underwent euthanasia with formulation T6192 .
1062
Jacob Zabicky and Shmuel Bittner
MeO Et CCH2 NHCOCH2 CH2 CH2 OH
MeO
CHCONH2
Et
NBu2 (15)
(16)
The calcium antagonist nicardipine (17) and its pyridine metabolite M-5 were determined in plasma after LLE and concentration. End analysis was by capillary GC-NPD with temperature gradient; LOD 0.5 mg/L for both compounds93 . See also reaction 27 in Section IV.H for electrochemical processes undergone by similar compounds. NO2
Me
H CO2 CH2 CH2 N
MeO2 C
CH2 Ph Me
N H
Me
(17)
The sensitivity of FID and ECD toward perfluoroacyl derivatives of amino, hydroxy and mercapto compounds was investigated. Thus, the FID signal of the perfluorovaleryl derivative of a compound increased with the size of the alkyl substituent, but was reduced as compared with the signal of an analogous hydrocarbon. The sensitivity of ECD toward the derivatives varied within two orders of magnitude, depending on the size of the alkyl substituents94 . Determination of biogenic amines in aqueous medium was based on a scheme consisting of derivatization with 3,5-bis(trifluoromethyl)benzoyl chloride (18), LLE, hydrolysis of phenolic esters present in the extract, silylation of the free hydroxy groups and GC combined with negative ion chemical ionization (NICI) MS. It happened that the molecular ion carried more than 60% of the ionic current, making the method highly specific, with potential LOD below the picogram level. This method revealed that the principal amines in bovine retina are dopamine (19b), tyramine (5) and serotonine (20)95 , and in the COCl
CH2 CH2 NH2 HO HO
F3 C
CF3
(CH2 )n NH2 NH
HO (a) n = 1, (b) n = 2
(18)
(19)
(20)
24. Analytical aspects
HO
CHCH2 NHR OH
(a) R = H (b) R = Me (c) R = i-Pr
1063
HO
CHCH2 NH2 OH
HO (21)
(22)
thoracic nervous system of a locust species are the same ones in addition to norepinephrine (21a) and octopamine (22)96 . The presence of hexamethylenediamine (4c) in hydrolyzed human urine is indicative of exposure to hexamethylene diisocyanate. The diamine was determined after derivatization with heptafluorobutyric anhydride followed by GC-CI-MS, using ammonia as the ionizing reagent and deuterated hexamethylenediamine as internal standard; LOD 0.5 mg/L urine97 . A screening program was proposed for the analysis of cocaine (23a) and its metabolite benzoyl ecgonine (23b) in the meconium of newborn infants, of mothers suspect of cocaine use during pregnancy. The method consists of SPE from a methanolic extract of the meconium, silylation of 23b with N,O-bis(trimethylsilyl)trifluoroacetamide (24) and analysis by GC-MS. The method was sensitive to less than 0.25 ppm of 23a and 0.5 ppm of 23b in the meconium, and is preferable for screening to the more involved fluorescence polarization immunoassay determination of these compounds98 . See also the beginning of Section IV.D.2 for an alternative analysis of cocaine.
CO2 R NMe
(a) R = Me O2 CPh (b) R = H (c) R = Et (23)
NSiMe3 CF3 C OSiMe3 (24)
Attention should be paid to the appearance of spurious peaks in the fragmentation patterns of amines determined by GC-MS, when the analytes came into contact with methanol or ethanol as solvents. Thus, for example, Schiff bases may be formed on condensation of a primary amine with traces of formaldehyde or acetaldehyde present in the solvent. Although the peaks of such product may be unresolved in the chromatogram, they may appear as ions with mass increments of C12 or C26 in the mass spectrogram, complicating the identification of the analyte, as was the case with some amphetamine drugs99 . Simultaneous screening and determination of benzodiazepines (e.g. diazepam, 25a) and other anxiolytic drugs in plasma were carried out on 1 mL samples by SPE onto a C8 RPsorbent, reextraction with AcOH/MeOH and GC-NPD-ECD analysis with twin columns, using prazepam (25b) as internal standard. Application of SPE instead of the usual LLE proved to be of advantage in the case of imidazopyridine drugs (e.g. alpidem 26a and zolpidem 26b). The LOQ of the method allowed toxicological and pharmacological determinations, except for buspirone (27) that allowed determinations only at toxic blood levels100 . Volatile amines from C1 to C6 and ammonia were separated on a PoraPLOT column, with or without a temperature gradient, depending on volatility. The method is applicable to determination of the purity of manufactured amines. Trace analysis of these amines can be performed by capillary GC-FID and of ammonia by GC-ELCD101 .
1064
Jacob Zabicky and Shmuel Bittner R O
N
Cl
(a) R = Me (b) R = CH2
N Ph (25)
N X X
N CH2 CONR2 (a) R = Pr, X = Cl (b) R = X = Me (26) N
O N
N
N
N O
(27)
Determination of the lower tertiary aliphatic amines in environmental samples, such as river water and bottom sediments, may be performed easily and with good selectivity by distillation of the amines followed by headspace GC-MS; LOD in mg/L for 40 mL samples were 1.25 for Me3 N, 0.25 for Et3 N, 0.125 for All3 N, 0.25 for Pr3 N and 0.125 for Bu3 N, with recovery over 70% and standard deviation of the recoveries below 12% n D 5102 . A method for determination of volatile methylamines in urine, proposed as an aid for detection of the fish odor syndrome, is based on headspace GC analysis103 . Volatile amines dissolved in water or sediments were determined by preconcentration in a Cavett diffusion flask, by adding strong alkali and cyclopropylamine as internal standard to the water or the solution in the pores of the sediment. The evolved amines were collected in a small volume of HCl. After neutralizing the acid, the amines were determined by GC-NPD, using cyclobutylamine as internal standard; LOD 7.3, 54.0 and 703 ng/L of MeNH2 , Me2 NH and Me3 N, respectively, for 5 mL injection; linear range 1 ð 106 to 7 ð 104 M104 . Acetic anhydride is a useful GC pre-column derivatizing reagent for amines, phenols and alcohols. In the presence of aqueous base only amines and phenols are derivatized, but
24. Analytical aspects
1065
under anhydrous conditions also alcohols undergo acetylation. The acetylated derivatives are useful for GC and GC-MS analysis of biogenic amines, antidepressants, antipsychotics and some of their metabolites105 . A comparison was made between variations of the full scan GC ion-trap MS method for detection of amphetamine (28) and similar drugs in urine. Thus, the fragmentation patterns obtained by methane-CI-MS of underivatized methamphetamine (29), ephedrine (30), pseudoephedrine (30) and phentermine (31) have more characteristic peaks that help making positive identifications, than those obtained by EI-MS of the N-(heptafluorobutyryl) or N-(-(ethoxycarbonyl)hexafluorobutyryl) derivatives; LOD 2.4 and 2.6 mg/L of 28 and 29 for CI-MS vs 0.7 and 1.4 mg/L for EI-MS, respectively; also LOQ are slightly higher for CI-MS than EI-MS106 . A polymeric reagent was proposed for derivatizing primary and secondary amines, consisting of a polystyrene matrix with attached pentafluorobenzoyl groups via anhydride moieties. Analysis of amines at picogram levels was by capillary GC with thermionic specific detection (TSD) on N mode or ECD107 or with NICI-MS-SIM; LOD 1 mg BuNH2 /L for 2 mL injection, with linearity in the 5 250 mg/L range108 . Detection of benzidine (32) and its conjugates in urine can be performed after hydrolysis of the conjugates, LLE, adding benzidine-d8 as internal standard, derivatizing with pentafluoropropionic anhydride and end analysis by GC-NICI-MS-SIM; LOD 0.5 mg/L urine; linearity between 2 and 200 mg/L. This test was applied for toxicological monitoring of workers in polyuretane manufacture109 .
CH2 CHCH3
PhCH2 CH(Me)NHMe
PhCH(OH)CH(Me)NHMe
NH2 (28)
(29)
PhCH2 C(Me2 )NH2
(30)
H2 N
NH2
(31)
(32)
A sensitive method for primary amines is shown in reaction 2, leading to the corresponding N-benzenesulfonyl-N-trifluoroacetyl derivatives. These can be determined by GC-ECD using SE-30 columns; LOD 1 5 pg, which is about 200 times more sensitive than GC-FID. The method was applied for determination of phenethylamine (33) in urine110 . This analysis was performed also by LLE into n-pentane, derivatization to the benzenesulfonamide and GC-FPD using a capillary column; recoveries of aliphatic primary amines in urine were 91 107%, RSD 0.2 4.5%111,112 . Amines in environmental waters and sediments were determined after LLE with dichloromethane, derivatization with benzenesulfonyl chloride and GC-SIM-MS; LOD 0.02 2 mg/L of water and 0.5 50 ng/g of sediment113 .
SO2 Ph RNH2
PhSO2 Cl
RNHSO2 Ph
(CF 3 CO)2 O
R
N
(2)
COCF3
1066
Jacob Zabicky and Shmuel Bittner PhCH2 CH2 NH2 (33)
More extensive derivatization schemes than reaction 2 are necessary for GC analysis of amino acids. A method was proposed for detection of amino acids and dipeptides at the femtomol level. After LLE the analytes were N-alkylated with pentafluorobenzyl bromide, N-acylated with heptafluorobutyric anhydride and esterified with N,Obis(trimethylsilyl)trifluoroacetamide (24). Of the twenty amino acids studied, only glutamic acid (34b) and arginine (8) could not be detected by this scheme. Dipeptides with neutral side groups were more easy to derivatize. End analysis was by GC-NICIMS. Recoveries of phenylalanine, lysine and threonine were 76, 55 and 34% respectively; LOD was less than 150 fg for MS-SIM at signal-to-noise ratio (SNR) 80. The method was applied to urine samples114 . A sensitive and specific method for detecting the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5,b]pyridine (35) adducted to DNA in living tissues consists of alkaline hydrolysis of the tissue, LLE, production of the bis(pentafluorobenzyl) derivative and GC-MS combined with ECD; LOD 0.03 fmol of 35/mg DNA (1 adduct/108 nucleotides). Evidence for the adduct was found in samples of human colon but not of human pancreas or urinary bladder115 . Me CO2 H HO2 C(CH2 )nCH NH2
Ph
N
(a) n = 1 (b) n = 2
NH2 N
N (34)
(35)
Amines, aminoalcohols and amino acids in aqueous medium can be derivatized before GC analysis by treatment with alkyl chloroformates116 . A method proposed for protein amino acids uses ethyl chloroformate which, under optimal conditions, reacts within a few seconds with all the reactive moieties of the molecule. Amino acid GC analysis is finished within five minutes in a capillary column, including pre-column derivatization time. Arginine (8) fails to react to completion and is not eluted from the column117,118 . Of the alkyl chloroformates investigated for derivatization of amino acids, isobutyl chloroformate gave the most sensitive derivatives for determination by GC-FID and GC-MS119 . A procedure proposed for protein and nonprotein amino acids consists of pre-column isobutyloxycarbonylation of amino, alcohol and mercapto groups with isobutyl chloroformate, SPE, producing the t-butyldimethylsilyl ester with t-butylchlorodimethylsilane (7) and end analysis by GC-MS. Temperature-programmed retention indexes for DB-5 and DB-17 capillary columns were determined. The method was applied to determination of amino acids in almond, walnut and sunflower seeds120 . The analytical and synthetic applications of reagent 7 were reviewed121,122 . Azo dyes extracted from waste sludges can by identified by GC-MS after H2 /Pd cleavage to aromatic amines according to reaction 3, in a microreactor mounted on the injector123 . H2 /Pd
ArNDNAr0 ! ArNH2 C Ar0 NH2
3
The offensive odor emitted by fish meal processing plants is due mainly to aliphatic amines. The degree of environmental damage can be measured from a correlation between
24. Analytical aspects
1067
an odor organoleptic test and the results of GC fitted with a semiconductor sensor, with trimethylamine serving as reference compound124 . A combination of column adsorption chromatography on basic alumina and GC of the eluate served for characterization of the trace fraction of nitrogen-containing compounds in hydroprocessed naphtha. These were subdivided into groups of four types, namely pyridines, pyrroles (the most abundant), anilines and indoles125 . D. Liquid Chromatography
1. General
Intense research activity is taking place at all times on LC separation of biologically active amines in general and amino acids in particular. All aspects of the analytical problem are focused in these studies, such as sampling, nature of sample, pre- and postcolumn treatment with well established and new reagents, separating phases, carrying liquids and their composition gradients, and detection methods. Various important LC methods for amino acid, peptide and protein analysis were reviewed and evaluated126,127 . A review of HPLC methods for the analysis of selected biogenic amines in foods appeared, including methods for extraction and for elimination of interfering compounds128 . A study comprising five laboratories was carried out on the accuracy and precision of protein amino acid analysis. An important conclusion reached was that it is necessary to examine both accuracy and precision to achieve maximum improvement in either129 . A commercially available single-cell protein, Pruteen, was proposed as reference material for the determination of amino acids and other substances in food. This recommendation was the result of a five-year-long study on the stability of this particular protein130 . Some recovery problems encountered during hydrolytic extraction of amino acids from environmental samples were discussed. A way was proposed for compensating for differential losses of neutral, acidic and basic amino acids, consisting of adding various nonprotein amino acids before the hydrolysis, that act as charge-matched recovery standards131 . The stability under long-term storage of biogenic amines dissolved in Krebs Ringer Henleit saline solution, usually employed for studying the release of such compounds, was examined by LC with electrochemical detection, with 3,4dihydroxybenzylamine (19a) serving as reference compound. Although every amine shows a peculiar behavior, all are affected by temperature, pH of the solution and length of storage. Catecholamines such as dopamine (19b), epinephrine (21b) and norepinephrine (21a) were stable for weeks in acidic solution under refrigeration, while indolamines such as serotonine (20) underwent fast degradation under the same conditions. At room temperature and pH 7.81, marked reductions in the concentration of the catecholamines were observed, but not of serotonin. Under freezing, at pH 1.96, the catecholamines remained intact and serotonin disappeared after two weeks132 . At the low concentrations required for detection by thermal lens spectrometry, catecholamines can undergo immediate oxidative cyclization with hexacyanoferrate ions to aminochromes (36), at pH 7. These are intensely colored quinonoid dyes. At higher concentrations a lower pH is required to avoid polymerization of the dyes, and the process becomes slower and inadequate for HPLC detection; LOD ca 1 mg/L in urine133 . See Section IV.D.3.g for an alternative application of aminochromes to the analysis of catecholamines. A universal eluent system was proposed for analysis of amino acids in biological fluids by IEC on the cation exchange resin Ostion LG ANB134 . A study was carried out on the effect of the carrier pH on RP-HPLC of amines, using a C8 column and octyl sulfate as ion pairing reagent. Optimal results were obtained for the analysis of catecholamines
1068
Jacob Zabicky and Shmuel Bittner
R +
−
N
O
R′
O
R′′ (36)
in urine by a pre-column cleanup with alumina and chromatography with the mobile phase at pH 5.4135 . A comparative study of the analysis of aliphatic amines by GC-FID, GC-TSD and HPLC with refractive index detector (RID), using isopropylamine as internal standard, gave good results in all cases. Determination of trimethylamine oxide by HPLC with a pulsed amperometric detector was problematic136 . A study involving twenty-six laboratories was carried out to assess the quality of amino acid analysis, using samples of urine and lyophilized plasma. Coefficients of variation ranged from 13% for glycine to 65% for methionine. Automated IEC followed by ninhydrin detection (37) seemed to perform better than other methods; however, there was no clearly superior method and no analyzer clearly outperformed the others. This seems to point to the importance of personal proficiency and expertise in the performance of such analyses137 .
O
O
N
O
OH (37)
A general approach was described to the analysis of traces of nitrogen- and phosphoruscontaining pesticides in environmental samples, using on-line and off-line SPE, followed by LC with TSP-MS-SIM detection. The assignments of various pesticides were reconfirmed by a variety of MS techniques138 . Preconcentration of traces of thirty-four pesticides and various transformation products was performed on-line by SPE on extraction disks or a packed column, followed by LC-TSP-MS-SIM of the positive ions [M C H]C and either [M C NH4 ]C or [M C CH3 CN]C or the negative ions [M H] and [M C HCO2 ]; LOD 0.01 0.4 mg/L for 100 mL samples, depending on the analyte and mode of operation. The method was applied to determination of trace levels of pesticides in river waters139 . 2. Underivatized analytes
The standard urine immunoassay for detection of cocaine (23a) abuse during the gestation period of newborn babies was frequently found to yield negative results in cases where positive results were shown by extraction of meconium with a solvent, followed by HPLC. The drug and metabolites such as norcocaine (23b) and cocaethyline (23c) were detected140 . See Section IV.C for an alternative analysis of cocaine.
24. Analytical aspects
1069
Results of high-performance silica gel, cellulose and RP-bonded silica gel for eighteen amino acids were compared with previous reports on IEC, RP-LC and paper chromatography. Determination was by scanning densitometry of the product (presumably 37) obtained after applying ninhydrin141,142 . Determination of amino acids in pig plasma by IEC and detection by the ninhydrin method is influenced by the protein and lipophilic compounds present, causing lower resolution. This is avoided on addition of sulfosalicyclic acid followed by SPE. An increase was observed in the results for threonine, asparagine, glutamic acid, glutamine, glycine, alanine, valine and lysine, whereas those for phenylalanine and tryptophane showed a decrease with this modification143 . IEC was applied to determine biogenic polyamines such as putrescine (4a), cadaverine (4b), tyramine (5), histamine (6), spermidine (38), agmatine (39) and tryptamine (40), contained in aqueous trichloroacetic extracts of leafy vegetables, such as cabbage and lettuce. A cation exchange column loaded with potassium ions and a special buffer were used. Spermidine (38) was the major amine detected in this group (7 15 mg/g fresh weight)144 . NH
NH2 (CH2 )4 NH(CH2 )3 NH2
NH2 CH2 CH2 CH2 CH2
(38)
NH
NH2
(39) CH2 CH2 NH2
N H (40)
Underivatized amino acids were analyzed in a FIA system including a high-performance IEC column and a CLD cell. The chemiluminescence generated on a GCE was measured when Ru(II) ions in the carrier solution were oxidized to Ru(III) and reacted in situ with the amino acid. LOD ranged from 100 fmol for proline to 22 pmol for serine (SNR 6)145 . A study of fifty-five aliphatic, aromatic and heteroclyclic amines showed that twentyeight of them could be detected in a FIA system at concentrations in the range of 1.0 ð 1010 to 4.0 ð 106 M (SNR 3, 20 mL injection), without derivatization, by HPLC-CLD, taking profit of the chemiluminescence produced in the presence of aryl oxalate and sulforhodamine 101 (41). The method was applied to the determination of histamine (6) in fish146 . See reaction 24 in Section IV.G. HPLC on a Cosmosil 5 C18 column, using a perchloric acid acetonitrile eluent (pH 7.6), followed by CLD in the presence of hydrogen peroxide and bis(2,4,6-trichlorophenyl) oxalate (42), was applied to the determination of 1-aminopyrene (43a) and various diaminopyrenes (43b d). Ascorbic acid was added to avoid oxidative degradation of the aminopyrenes in the presence of metals; LOD in the sub-fmol range (SNR 3)147 . A fast (less than 10 min) HPLC-ELCD method was proposed for determination of dopamine (19b) and its metabolites in microdialysates, using packed fused silica capillary columns; LOD 0.05 mg/L of dopamine in a 2 mL sample, RSD 3% (n D 10)148 .
1070
Jacob Zabicky and Shmuel Bittner SO3 −
SO3 −
N+
O
N
(41) Cl
Cl Cl
O
O
O
O
Cl
Cl
Cl (42)
NH2 N 3 8
(a) (b) (c) (d)
X X X X
= = = =
H 3-NH2 6-NH2 8-NH2
Ru(III) N
X 3
6 (43)
(44)
Tris(2,20 -bipyridine)ruthenium(III) complex ions (44) produce a chemiluminescence in the presence of amino acids in a FIA system. Amino acids containing secondary amino groups have the strongest response; LOD 20 pmol for proline to 50 nmol for asparagine149 . Nitrogen-containing compounds are easily detected by CLND, without pre- or postcolumn derivatization. Thus, peptide mapping by RP-HPLC using CLND gave the correct results as for the chain size, against the results of UV visible (UVV) detection (UVD), which were biased by the presence of strong UV chromophores150 . A method for determination of the aromatic amino acid phenylalanine (45), tyrosine (46) and tryptophan (47) content of peptides at low microgram levels is based on sizeexclusion HPLC combined with UVD using a diode array, and data processing of the
24. Analytical aspects PhCH2 CH(NH2 )CO2 H
1071
p-HOC6 H4 CH2 CH(NH2 )CO2 H
(45)
(46) CH2 CH(NH2 )CO2 H
N H (47)
spectra to yield the second-order derivative. Comparison of the derivative spectra with those of standards consisting of the aromatic amino acids and their heterodipeptides, using spectral features such as amplitude and wavelength of primary and secondary minima and intersection with the abscissa, helps corroborating and quantifying their presence151 . The series of regioisomeric amines 48 50, methamphetamine (29) and phentermine (31), can be identified in forensic screening analyses by RP-HPLC-UVD (254/280 nm dual accessory) using a C18 stationary phase and a mobile phase buffered at pH 3.0. The capacity factors and retention times increase in the order 48 < 49 < 29 < 31 < 50. Other methods for identifying these compounds failed; for example, the base peak in MS is m/z D 58 for all five compounds, corresponding to a loss of a benzyl group from the molecular peak; also their IR and UVV spectra are too similar to be useful for this purpose152 . PhCH2 CH2 NHEt (48)
PhCH2 CH2 NMe2 (49)
PhCH2 CH(Et)NH2 (50)
Analysis of a wide range of amines, in dialysate aliquotes taken from experimental animals, was carried out by isocratic HPLC with detection on a series of eight coulometric electrodes, measuring from 0 to 0.490 V with increments of 0.070 V. A parallel analysis was carried out after pre-column derivatization according to reaction 7 (Section IV.D.3.a), isocratic elution on a different column and measurement with a series of four electrodes set at 0.250, 0.450, 0.550 and 0.650 V. Compounds were identified by retention time and electrochemical profile along the arrays. Analyses were complete within 25 min. Among the compounds examined were isoproterenol (21c), phenylephrine (51), methoxamine (52), hydralazine (53), apomorphine (54), morphine (55) and its 3-glucoronide metabolite; for these compounds LOD 0.215 10.65 mg/L, at SNR 3, with linearity in the 0.5 500 mg/L range. For amino acids LOD ca 0.75 mg/L, at SNR 3, with linearity in the 0.25 20 mg/L range153 . RP-HPLC determination of trace impurities of the toxic 4-aminopyridine in the central system-stimulating drug 3,4-diaminopyridine can be performed on condition that the impurity has a lower retention time. This was accomplished on applying ion pairing with dodecanesulfonate to maximize selectivity; LOD 50 ppm of the impurity in the drug154 . OMe Me CHCH2 NHMe
CHCHNH2
OH
OH
HO (51)
MeO
(52)
1072
Jacob Zabicky and Shmuel Bittner
OH
NHNH2 HO
N N
N
H
Me
(53) (54) CH3 N OH H
O
HO
(55) Methods were described for HPLC determination of the mutagenic and carcinogenic ˛carbolines (56,57), -carbolines (58,59)155 160 , and other products of amino acid pyrolysis found in cigarette smoke, diesel exhaust and cooked foods and phenazines (60, 61) present as impurities of certain pesticides161 . These compounds were also determined in human plasma, urine and bile161,162 . The use in consumer products of azo dyes that yield carcinogenic amines under reductive conditions is illegal in Germany. Detection of such carcinogenic amines in textiles is problematic, and a method was proposed combining TLC, automatic multiple development
Me
N H
NH2
N
(56)
N H (57)
Me
Me N
N H (58)
NH2
N
N NH2
N H (59)
NH2 Me
24. Analytical aspects
1073
N
OH
N
NH2
N (60)
NH2
N (61)
NH2
and assessment by means of a scanner163 . Azo dyes present in sludges can be determined after extraction with dichloromethane, reduction with sodium hydrosulfide or tin(II) chloride and HPLC-MS164 . See also discussion of reaction 3 in Section IV.C. A sensitive HPLC method used coulometric detection for the simultaneous determination of catecholamines, indoleamines and related metabolites. Oxidative and redox modes were applied to the various analytes, using arrays containing one to four coulometric working electrodes165 . Pulsed amperometric detection following HPLC of the underivatized amino acid is sensitive but has a limited range of linear response. Application of ELCD before amperometric detection extends the dynamic range of amino acid determination166 . Pulsed amperometric detection after IEC was found to be more sensitive (0.01 1.2 mM) than ninhydrin derivatization with UVD (4.5 55.0 mM)167 . Determination of the amino saccharides glucosamine, mannosamine and galactosamine in microbial polymers, chitin, animal waste, sewage, plant residues and soil was performed by HPLC using a strong ion-exchange column, an alkaline eluent and a pulsed amperometric detector. The latter was superior to RID. More than 3% of the total nitrogen in alfalfa and 20% in straw stems from amino saccharides168 . A glassy carbon electrode (GCE) modified by electrodeposition of Ru(III,IV) oxides was used for the amperometric determination of cystine, cysteine, methionine, glutathione and glutathione disulfide after HPLC using a strong cation exchange column. Unmodified electrodes are unfit for analysis of these compounds. For methionine, sensitivity was 20 š 0.3 nA/mM/cm2 ; linearity over the range of 0.6 180 mM at pH 2, 7.5 mL sample, 1 mL/min flow169,170 . A constant potential amperometric detector was used in a FIA system for the determination of carbohydrates and amino acids. The working electrode is an Eastman-AQ electrode chemically modified by Ni(II) ions. The mechanism shown in reactions 4 6 was proposed, where reaction 5 is rate limiting171 . Ni(OH)2 C OH ! NiO(OH) C H2 O C e ž
NiO(OH) C RH ! Ni(OH)2 C R ž
NiO(OH) C R ! Ni(OH)2 C products
(4) (5) (6)
A comparison was made between Ag, Au, Co, Cu, Ni and Pt electrodes for constantpotential amperometric detection of carbohydrates, amino acids and related compounds in FIA systems. Cu electrodes showed the best performance as for their range of linear response, LOD, stability and long life172 . Two electro-oxidation processes of amino acids at a Cu electrode are possible, depending on the applied potential and the conditions of the solution: In neutral or slightly basic solution, at very low potentials measured against an Ag/AgCl electrode, the process is related to complex formation between the amino acid and Cu(II) ions. In a strongly alkaline solutions, at 0.4 0.8 V the process involves electrocatalytic oxidation. The latter process is better for constant-potential amperometric detection of underivatized amino acids and peptides in FIA chromatographic systems; LOD 1 10 pmol for most amino acids and simple peptides173 . Nitrogen-containing analytes in a FIA system, e.g. amino acids, as they emerge from the LC column, are introduced into a pyrolysis oven under argon atmosphere. The products
1074
Jacob Zabicky and Shmuel Bittner
are converted to nitrate by potassium peroxidisulfate, and determined with malachite green using a UVD at 650 nm174 . Determination of iodo amino acids by HPLC with inductively coupled plasma (ICP)MS detection had LOD 35 130 pg of I, which is about one order of magnitude lower than with UVD usually applied for these compounds175 . Amino acids and peptides containing sulfur, such as cysteine, cystine, methionine and glutathione, can be determined after HPLC separation by pulsed electrochemical detection, using gold electrodes176 . It is usually a very difficult task to introduce chemical modifications in the solid phase filling the chromatographic column. On the other hand, the possibilities of modifying the carrying fluid used for elution are practically unlimited. This includes solvent composition in isocratic and gradient regimes, buffers and other additives. For RP-HPLC on C18 columns, ion interaction reagents such as octylammonium salycilate or orthophosphate are used to modify the properties of the absorbing surface, improving the resolution of many mixtures. Thus, trace levels of aromatic amines can be determined without derivatization. Applying this method to the analysis of a commercial brown hair dye revealed the presence of more than 7000 ppm of p-phenylenediamine177,178 . The same two ion interaction reagents were applied to the RP-HPLC-UVD determination of the food-related biogenic amines tyramine (5), histamine (6), 2-phenethylamine (33) and tryptamine (40). The elution sequence was different for both additives; LOD 400 ppb for 5 ( 230 or 280 nm), 900 ppb for 6 ( 230 nm), 500 ppb for 33 ( 254 nm) and 20 ppb for 40 ( 280 nm)179 . RP-HPLC using alkylammonium salicylates as ion interaction reagents is effective in the separation of amines from inorganic analytes such as nitrite and nitrate ions. However, care should be taken that alkylamine analytes should be of shorter chain-length than the ion interaction reagent. By this method 0.50 ppm of pphenylenediamine and 0.20 ppm of nitrate could be determined in seawater180 . RP-ion pair chromatography of amino acids was performed using 1-naphthylamine as ion-interaction reagent with sodium heptanesulfonate as hydrophobic counterion, to enhance the capacity ratio of the column for all amino acids tested181 . Amino acids and peptides yield under physiological conditions carbamates of structure 62, which are presumed to be neurotoxic agents. A correlation was found between the propensity of these compounds to undergo such transformation and their RP-LC behavior in the presence of cetrimide (63), a cationic surfactant that makes the separation technique sensitive to the negative charge on 62182 . CO2 − H NHCO2 −
R
Me n-C16 H33
+
N
Me Br−
Me (62)
(63)
Determination of halogenated 2-aminobenzophenones (64a c), which are metabolites of psychotropic drugs, was performed by HPLC with amperometric detection (GCE vs Ag/AgCl); LOQ 750 ng of metabolite/L of biological fluid (urine or serum), with recovery better than 97%183 . The impurities of H-acid (65), an intermediate for various synthetic dyes, include Koch’s acid (66), omega acid (67), chromotropic acid (68) etc. They were determined by RP-HPLC-UVD at 235 nm, using as mobile phase a 0.3 M aqueous solution of sodium sulfate184 . The chemiluminescence of the reaction of hydrogen peroxide with luminol (69) is catalyzed by metalloporphyrins 70a and 70b. This chemiluminescence is quenched by
24. Analytical aspects X
O
1075
NH2 (a) X = Y = Cl (b) X = H, Y = Cl (c) X = F, Y = Br Y (64)
OH
NH2
HO3 S
HO3 S
SO3 H
HO3 S
SO3 H
(65)
(66) NH2
HO3 S
HO
NH2
OH
SO3 H
OH
SO3 H
HO3 S
(67)
(68) O
NH2
NH NH O (69) Ar (a) M = Fe, Ar = N Ar
+
N Me
N Ar
M N
N (b) M = Mn, Ar = Ar (70)
SO3
−
1076
Jacob Zabicky and Shmuel Bittner
the presence of amines that form complexes with the metal ions and reduce the catalytic effect of the porphyrine complexes. This abatement is the working principle of a method proposed for determination of amino acids in a FIA system following LC185 . The mutagenic aminophenazines 71 are present as impurities of carbendazim (72) fungicides and its formulations. They were determined by HPLC-UVD (diode array), using 0.02% sulfuric acid in MeOH, and measuring at 270 and 453 nm186 .
N
NH2
N NHCO2 Me
Y
N (71)
Y = NH2, OH
N H (72)
The neutral nitrogen-containing components in diesel oil were selectively retained by an alumina HPLC column and were eluted by a gradient mobile phase of hexane dioxan. Identification and determination was carried out by a combination of MS and UV diode array detectors, showing that these components were mainly alkylcarbazoles and alkylindoles187 . Aromatic and sulfur-containing amino acids were separated by HPLC, and subjected to post-column UV irradiation before electrochemical detection with GCE vs AgCl/Ag electrodes. The analytes showed different behavior during lamp off and on periods. Thus, for example, tyrosine (46) and tryptophan (47) showed inherent electrochemical response at C0.80 V, but none at C0.60 V; however, on turning on the UV lamp they showed sensitive response at both potentials126 . 3. Pre-column and post-column derivatization
Pre-column derivatization procedures fulfil several important analytical functions. However, some problems are involved such as separation of the analytes from the matrix with the inherent recovery problems; modification of the analyte to improve chromatographic resolution with the inherent problems of functional specificity, derivatization yields of individual analytes, stability of the derivative and the necessity of removing excess reagents. Although automatization of pre-column treatment is now commonplace, this is not usually a requirement. Post-column derivatization is performed mainly for labelling the analyte to better fit the installed detector and is frequently applied in FIA systems. This requires fast and effective reactions with minimum excess reagent or a means for removal of excess to avoid interferences. Additional targets may also be sought in post-column derivatization, such as modification of retention times in a second chromatographic cycle. A comparative study was made of the RP-HPLC analysis of free amino acids in physiological concentrations in biological fluids, with pre-column derivatization by one of the four major reagents: o-phthalaldehyde (73) in the presence of 2-mercaptoethanol, 9fluorenylmethyl chloroformate (90), dansyl chloride (92) and phenyl isothiocyanate (97, R D Ph) (these reagents are discussed separately below). Duration of the analysis was 13 40 min. Sensitivity with the latter reagent was inferior to the other three; however, its use is convenient in clinical analysis, where sample availability is rarely a problem. The derivatives of 73 were unstable and required automatized derivatization lines. Only 92 allowed reliable quantation of cystine. All four HPLC methods compared favorably with the conventional ion-exchange amino acid analysis188 . Some examples of derivatization used in LC are shown here and in Sections IV.D.4 and IV.E.
24. Analytical aspects
1077
a. Reaction with dicarboxaldehydes. Primary amines react with o-phthalaldehyde (73) in the presence of 2-mercaptoethanol, as shown in reaction 7, yielding fluorescent isoindole products (74)189,190 . This reaction affords a very frequently used pre-column and postcolumn derivatizing scheme.
CH
O +
CH
HSCH2 CH2 OH
H2 NR
NR (7)
O SCH2 CH2 OH
(73) (74) Some problems and solutions involved in the automatization of pre-column derivatization of amino acids applying reaction 7 to biological samples were discussed191 . Solid media and conditions were examined for enrichment by SPE of the lower aliphatic amines in aqueous solution, prior to HPLC with fluorometric detection of the o-phthalaldehyde derivative. The best medium was the weak cation exchanger Spheron C 1000, and desorption with methanolic perchloric acid. Concentration limits for the determination were in the nM range, with enrichment factor of 240 in the preconcentration step192 . The problem of the stability under laser-induced fluorescence (LIF) of the fluorescent species 74, derived from amino acids and peptides in biological samples, in the concentration range of 1012 to 1015 M was addressed193 . N-Acetylcysteine was proposed as replacement for 2-mercaptoethanol, to avoid its unpleasant odor194 ; -glutamylcysteine provided its own mercapto group, as shown in reaction 8193 . See also references to reaction 7 in Section IV.D.4. O CH
O
HO2 C +
CH
O
H2 N
NH HSCH2
CO2 H
CO2 H
(8)
N
S NH O CO2 H A study of residual analysis of thirty pesticides and their transformation products was based on SPE on-line with HPLC-UVD or post-column derivatization with ophthalaldehyde (73) and fluorescence detection (FLD), according to EPA method 531.1 and others. The method allowed determination of many pesticides in river and well waters at 0.01 to 0.5 mg/L levels195 . An automatized procedure was proposed for determination
1078
Jacob Zabicky and Shmuel Bittner
of amino acids in plasma based on pre-column derivatization with this reagent that was claimed to be fast and stable for long series of analyses; the coefficient of variation was <3% for most of the thirty physiological amino acids tested196 . Biogenic amines such as -aminobutyric acid, spermidine (38), spermine (75) and hexamethylenediamine (4c) were determined by pre-column derivatization according to reaction 7, gradient elution LC and amperometric detection at C650 mV, using GCE vs Ag/AgCl electrodes. On column detection limits are at the low picomole range197 . A method was evaluated for determination of amines in wine, such as polymethylene diamines (4a c), tryptamine (40) and 2-phenethylamine (33), based on pre-column derivatization with o-phthalaldehyde (73), RP-HPLC with gradient elution and coulometric detection with an array of sixteen electrodes at increasing potentials198 . The same derivatization served for determination of biogenic amines in wine by RP-HPLC-FLD on a C18 column; ex 356 nm, fl 445 nm, recovery 84.0 108.3%, RSD 3.0 8.2%199 . Amino acids in cultured cells were determined by RP-HPLC-FLD; ex 330 nm, fl 450 nm, LOD 0.5 pmol, linearity in the 1 800 pmol range200 . Determination of -aminobutyric acid in cerebrospinal fluid requires special care, because of its relatively low concentration as compared to other amino acids and the possibility of distorting results on degradation of homocarnosine (76). A procedure was proposed consisting of deproteinization with sulfosalicyclic acid, separation by IEC, post-column derivatization according to reaction 7 and FLD measurement201 . A method for determination of ε-aminocaproic acid in body fluids consists of deproteinization with zinc sulfate, addition of D-valine as internal standard, derivatization according to reaction 7 and HPLC-FLD using a mobile phase containing 2.5 mM of the Cu(II) complex of L-proline. As low as 50 mg/L of the analyte could be detected, using 100 mL samples of urine or plasma202 . H2 NCH2 CH2 CH2 CONH CHCO2 H N
NH2 (CH2 )3 NH(CH2 )4 NH(CH2 )3 NH2 (75)
N H (76)
Fast determinations of amino acids in plasma, cerebrospinal fluid and other media were based on reaction 7 and RP-HPLC. In one of them, taking 17 min per run, including times for derivatization and column re-equilibration, recovery of amino acids spiked into plasma was 96 106%, except for tryptophan (47, 89%). The method had within run precision of 1.8 6.4%, between run precision of 2.1 7.2% and was linear in the 5 800 mM range for all amino acids203 . RP-HPLC with electrochemical detection, using a multistep polarity gradient, resolved the derivatives of twenty-three amino acids and physiological dipeptides in less than 25 min204,205 . A fast variation claimed runs of less than 5 min for simultaneous determination of the neurotransmitter amino acids glycine, aspartic (34a), glutamic (34b), taurine (77) and -aminobutyric acid in brain tissue; LOD 2.5 pmol for all five amino acids206 . A modification allowed improved resolution and sensitivity and shorter performance times. This was applied to determination of sixteen amino acids in plasma and cerebrospinal fluid207 . H2 NCH2 CH2 SO3 H (77)
24. Analytical aspects
1079
Amino acids and other nitrogen-containing compounds affect chlorine consumption in the treatment of drinking water. Such amino acids from three French rivers were determined in the raw samples and, after each treatment step in a plant, by pre-column derivatization by reaction 7 and HPLC-FLD. The main compounds detected were glycine, serine, alanine, aspartic acid, glutamic acid, threonine and valine. The global amino acid content was 20 90 mg N/L, causing a consumption of 0.4 1 mg Cl2 /L208 . Use of a basic citrate buffer for the pre-column derivatization step of amino acids in seawater avoids precipitation of Ca and Mg hydroxides209 . Post-column application of reaction 7 was used to bind the ε-amino groups of lysine residues in a hemoregulatory peptide, for determination by HPLC-FLD; LOD 1 ng, LOQ 20 mg/L for 0.25 mL plasma samples; response was linear for 20 4000 mg/L of plasma210 . Reaction 7 was also applied to amino acids in seawater in a FIA system. Determination of ammonia vs primary amines could be accomplished in the system by a buffer change from pH 7 to pH 10.5, respectively211 . A fast method for determination of biogenic amines is important for assessing the freshness of sea food and its possible allergenic and toxic effects. The simultaneous detection of histamine (6), agmatine (39) and other polyamines poses a difficult problem. A method for determination of these compounds uses sodium hexanesulfonate as ion pairing agent in RP-HPLC and post-column derivatization with o-phthalaldehyde (73)212 . Perchloric acid extraction, RP-HPLC-UVD (diode array) using post-column derivatization by reaction 7 was applied in the determination of the biogenic amines putrescine (4a), cadaverine (4b), tyramine (5), histamine (6) and phenethylamine (33) in meat products; LOD 0.5 mg/kg with 96 113% recoveries213 . Biogenic amines 4a, 4b, 5, 6, 33, serotonine (20), tryptamine (40), spermidine (38), spermine (75) and agmatine (39) were determined simultaneously in beer after microfiltration, RP-HPLC, post-column derivatization with 73 and FLD; LOD 0.30 0.40 mg/L except for 20 and 75, which were slightly higher. Linearity, precision, sensitivity and recovery were satisfactory, and the interference from amino acids and other amines was assessed214 . The effect of SPE was studied on the determination of thirty pesticides and their transformation products was based on derivatization by reaction 7, using UVD or FLD (EPA method 531.1). The method was used for analysis of river waters of Spain and France195 . A variant of reagent 73, naphthalene-2,3-dicarboxaldehyde (78), was used for determination of amino acids in tobacco215 . Analytes containing more than one primary amino group show a much diminished quantum efficiency, which can be corrected by coordinated deposition of the LC effluent on a TLC plate and performing a second fluorometric measurement of the immobilized derivatives216 . An HPLC-CLD method was proposed, based on measurement of the chemiluminescence emitted by the pre-column 78-derivatives of the analytes in the presence of a diaryl oxalate (42) and hydrogen peroxide, for determination of ultratrace amounts of amphetamine (28), norephedrine (79) and p-hydroxyamphetamine (80) in urine, using phenethylamine (33) as internal standard; LOD 0.1 1.5 ð 1015 mol217 . See discussion of reaction 24 in Section IV.G. CHO Ph CHO (78)
CH HO
CHMe
4-HOC6 H4 CH2
NH2 (79)
CHMe NH2
(80)
The painstaking procedures and special instrumentation required for manipulating nanoliter range volumes were described for the determination of amino acids in single cells218 and the amino acid analysis of subnanogram amounts of protein219 . The amino acid extract
1080
Jacob Zabicky and Shmuel Bittner
of a single cell was derivatized with 78 in the presence of cyanide ions, leading to products of probable structure 81, which were both fluorescent and electroreactive. Separation was by open tubular microbore LC and the derivatives were measured electrochemically218 . Using norleucine as internal standard, and the various amino acids contained in the hydrolyzate of a 5 nL sample of protein solution were determined by the method just described219 . A high-sensitivity LIF-based detector for HPLC was developed incorporating a HeCd laser, which responds specifically to amines derivatized with 78 in the presence of cyanide ions; LOD ca 1012 M220 . CN
NR
(81) Peptides containing a tryptophan residue at the N-end can be determined by pre-column derivatization with glyoxal and RP-HPLC-FLD, as shown in reaction 9, giving single fluorescent peaks; LOD 0.55 3.82 nM (SNR 3) for 100 mL injection volume221 .
CONH
peptide
NH2 N H
CH
O
CH
O
(9) CONH
peptide
N N H CH2 OH
See also reaction 15 in Section IV.E. b. Oxazole derivatives. Various oxazole-based reagents have been proposed for tagging amines and thiols. For example, 2-fluoro-4,5-diphenyloxazole (82a) and 2-chloro-4,5bis(p-N,N-dimethylaminosulfonylphenyl)oxazole (82b) for pre-column derivatization of amino acids followed by HPLC-FLD; LOD for the 82a derivatives of thirteen amino acids is in the 19 64 fmol range (SNR 2). Amino acids with thiol substituents had LOD of one order of magnitude lower. Chemiluminescence with hydrogen peroxide/oxalate esters also afforded very sensitive determinations222,223 . Sodium benzoxazole-2-sulfonate (83) itself is not fluorescent, but with amines and amino acids the derivatives exhibit an intense blue fluorescence224 . c. N-Acylation and N-sulfonation. By pre-column benzoylation in biological fluids, the hydroxy groups of sugars become esterified and neutral amino acids are converted to the corresponding 5-benzoyloxy-2-phenyloxazoles (84). No protein precipitation takes place and no pyridine or drying are required. Determination by HPLC-MS has LOD ca 1 pmol (SNR 2)225 . Benzoylation followed by RP-HPLC on a C18 column detects biogenic amines in fish, including putrescine (4a), cadaverine (4b), phenethylamine (33), spermidine (38),
24. Analytical aspects
1081
Y N
N X
(a) X = F; Y = H (b) X = Cl; Y = SO2 NMe2
SO3 Na O
O Y (82)
(83)
spermine (75), histamine (6), tyramine (5) and agmatine (39)226 . Mixtures of industrial polyvalent amines (85) were determined by RP-HPLC-UVD after derivatization with benzoyl chloride or m-toluyl chloride227,228 . Ferrocenecarboxylic acid chloride (86) was used for tagging primary and secondary amines, amino acids and peptides. End analysis was by LC with electrochemical detection for electro-oxidation of ferrocene; LOD 500 fmol229 . COCl
R
N Fe
PhCO2
O (84)
Ph
H2 N(CH2 CH2 NH)nH (85) n = 1 5
(86)
Compound 87 in acid-hydrolyzed urine serves as a tracer for occupational exposure to the corresponding diisocyanate. It was derivatized with pentafluoropropionic anhydride and determined by LC using TSP-MS and plasmaspray (PSP) MS (discharge-assisted TSP-MS). The [M 2] ion was measured; instrumental LOD 0.1 pg/mL; LOD about 0.2 mg/L urine, RSD 10% for 0.5 mg/L230 . Another determination of 87 in urine is with isobutyl chloroformate231 .
NH2
CH2
NH2
(87)
A determination of traces of low (C1 to C4 ) aliphatic amines in the atmosphere consists of passing air through an absorber containing phosphorous acid, derivatizing with m-toluyl chloride and end analysis by HPLC-UVD; LOD 1 5 pmol of amine, corresponding to concentrations lower than 0.1 mg/m3 of air, in a 300 L sample232 . Various benzoxadiazole reagents have been proposed for fluorescent labelling of alcohols, phenols, thiols and amines. Reagent 88 was used for derivatization of various substrates, including aliphatic and aromatic amines233,234 . Derivatization of alcohols and amines with reagent 89 affords flourescent labeling of these compounds, when excitation and fluorescence were essentially the same for all alcohols and amines tested with both reagents. Using LIF (ArC emission at 488 nm) improves the sensitivity of the method (LOD 2 10 fmol) as compared with a conventional Xe lamp (LOD 10 500 fmol). See also Section IV.D.4 for other benzoxadiazole reagents.
1082
Jacob Zabicky and Shmuel Bittner SO2 NMe2 N
SO2 NMe2
O
N N
O N
N Me
COCl
N CH2 COCl (88)
(89)
9-Fluorenylmethyl chloroformate (90) yields with primary and secondary amines the corresponding 9-fluorenylmethyl carbamates. Primary and secondary biogenic amines and amino acids can be derivatized with 90 in a fully automated pre-column system and determined by LC with spectrophotometric detection235 . This method was applied to food analysis236 . In one automatic system reaction time was 45 s allowing good determinations of amino acids at <10 pmol levels237,238 . Derivatization with 90 enabled the separation and determination of twenty-seven free amino acids in extracts from green coffee with a recovery of 99.8%239 . A complete amino acid analysis of collagen can be performed within 35 min by derivatization with 90 and RP-HPLC-FLD. The response is linear over the range 1 800 pmol. The method allows complete analysis on a 100 ng sample of collagen, corresponding to 1 pmol of protein chain240 . A protocol was proposed for identification of protein binders used in art (e.g. casein, glue, egg), based on derivatization with 90 and HPLC-FLD of certain amino acids241 . A pre-column automatic derivatization method for the amino acids in plasma was proposed, involving reaction 7 for the primary ones, followed by derivatization with reagent 90 for the secondary ones242 . A polymeric reagent (91) was synthesized that attaches the same tabbing to primary and secondary amines as does 90. Aliphatic amines in the air of various industrial environments were collected by adsorption on silica gel
CH2 O2 CCl (90)
NO2 O OCO2 CH2
(91)
24. Analytical aspects
1083
(ca 100 L of air), desorbed with dilute acid and determined by injection of a 5 10 mL sample into a reactor containing 91, on-line with HPLC-FLD243 . Reactive polymers were synthesized for tagging amines with 9-fluorenylmethoxycarbonyl, 4-nitrobenzoyl and acetylsalicyl groups. The reactive polymers were combined into a mixed bed reactor for on-line pre-column derivatization in HPLC analysis of amines. The objective of multiple pre-column tagging was to aid identification of unknown analytes in a complex matrix. The method was demonstrated for amphetamine (28) in human urine with acceptable accuracy and precision244 . Nineteen biogenic amines in wine were determined by derivatization with dansyl chloride (92), SPE and HPLC-UVD. Linearity was observed for amine concentrations in the 0.5 20 ppm range; LOD 50 150 mg/L (SNR 3), which is typical of dansyl derivatives. Addition of standard amines showed recoveries better than 85% for ethanolamine, phenethylamine (33), putrescine (4a), cadaverine (4b), tyramine (5) and histamine (6)245,246 . The dansyl derivatives of the latter five biogenic amines, tryptamine (40), spermidine (38) and spermine (75) were separated by TLC on silica gel plates. None of the twelve solvent systems studied could resolve the mixture; however, application of two-dimensional TLC did, using extraction with acetonitrile and spectrofluorometry. The method was applied for analysis of fish and dry sausage samples247 , and also for analysis of biogenic amines in fermented olives248 . After post-column addition of tris(2,20 bipyridyl)ruthenium(II) complex (44) and electrochemical oxidation in a flow cell to Ru(III), this ion reacts with the dansyl derivatives in situ and the chemiluminescence of the reaction can be measured249 . An HPLC-CLD method based on measurement of the chemiluminescence emitted by the pre-column dansyl derivatives of the analytes in the presence of bis(2,4,6-trichlorophenyl) oxalate (42) and hydrogen peroxide was proposed for determination of ultratrace amounts of methamphetamine (29), amphetamine (28), norephedrine (79), p-hydroxymethampetamine (93) and p-hydroxyamphetamine (80) in urine, using phenethylamine (33) as internal standard; LOD 1 3 ð 1014 mol217 . A simplified automated procedure for pre-column derivatization of amino acids with 92 was proposed250 . SO2 Cl
4-HOC6 H4 CH2
CHMe NHMe
NMe2 (92)
(93)
A good correlation between experimental retention times and calculated selectivities and molecular connectivities was found using the PRISMA model for seventeen dansylated biogenic amines present in foodstuffs and animal fodder251 . Derivatization with dabsyl chloride (94) was applied for the separation of primary amino acids in physiological samples, prior to determination of their specific radioactivity. The derivatization is easy to perform and the derivatives are stable252 . N-Acylation can be preformed with esters of N-hydroxysuccinimide; N-succinimidyl 4-nitrophenylacetate (95) was used to derivatize the primary and secondary amines conferring bad odor to water253 . Derivatization of amines with the ester of Nhydroxysuccinimide with N-(quinolin-6-yl)carbamic acid (96) gives excellent yields of
1084
Jacob Zabicky and Shmuel Bittner
Me2 N
N
N
SO2 Cl
(94)
unsymmetric ureas. The selective fluorescence of the derivatives allows direct injection of the reaction mixture with no interference of the excess reagent; LOD from 40 fmol for phenylalanine to 800 fmol for cystine, linear response in the 2.5 200 mM range. Good amino acid analyses could be obtained from protein hydrolysates containing as little as 30 ng of sample254 . By derivatization with reagent 96 nineteen amino acids were separated in 35 min with resolution of at least 1.6, seventeen of which showed linearity at concentrations of 25-500 mM255 . A study of the long-term repeatability and consistency of amino acid analyses showed that derivatization with 96 was superior to that with phenyl isothiocyanate (reaction 11)256 . See also Section IV.E for other acylating reagents derived from N-hydroxysuccinimide (134, 135). O
O
N-O2 CCH2 -C6 H4 -NO2 -p
N
O
NH O
O
N
O (95)
(96)
d. Reaction with isothiocyanates. Primary and secondary amines in general react with isothiocyanates (97) to yield the corresponding thioureas, as in reaction 10; however, ˛amino acids can undergo further cyclization to the corresponding thiohydantoins (98), the classical Edman reaction 11. S RNH
S
C
NHR′
R ′ NH2
R
N
C
S
R ′R ′′ NH
RNH
C
NR′R′′
(97)
(10) O R′ R
N
C
S + H2 N
CHCO2 H
R
N NH
(11)
R′ S (97)
(98)
Derivatization with phenyl isothiocyanate (97, R D Ph) followed by HPLC was compared with IEC followed by the ninhydrin reaction for over ninety compounds. The former method was favored for speed, sensitivity and equipment versatility257 . Phenylthiocarbamyl derivatives of amino sugars and amino sugar alcohols (reaction 10) were
24. Analytical aspects
1085
resolved by RP-HPLC258 . Twenty-two protein amino acids underwent derivatization with butyl isothiocyanate (97, R D Bu) and were determined by RP-HPLC-UVD; RSD of the molar response relative to the methionine peak was less than 5% for all except cysteine; asparagine and serine were not resolved from one another259 . RP-HPLC on a C18 column with a multistep linear gradient of two solutions was investigated for the phenyl isothiocyanate derivatives of twenty-six amino acids260 , and also for determination of amino acids in deprotenized blood261 . Modifications were proposed to make it faster, for the analysis of nutritionally important amino acids in serum and internal organs262 . It was claimed that RP-HPLC of the phenyl isothiocyanate derivatives of plasma and urine amino acids, followed by electrochemical detection, virtually eliminates interferences of other components in the sample and enables the determination of secondary amino acids263 . Methods based on derivatization with phenyl isothiocyanate were proposed for determination of free amino acids in wine and must264 and infant food265,266 . The derivatives obtained on treatment of amino acids with 4-nitrophenyl isothiocyanate are stable and suitable for subsequent HPLC-UVD analysis267 . A study was made of RP-HPLC with constant-potential (1.2 V vs SCE) and pulsedpotential amperometric detection using platinum or gold electrodes, of the derivatives of the common amino acids, obtained from phenyl and methyl isothiocyanates. All the thiohydantoins (98) were oxidized at both electrodes; LOD was less than 0.2 mM for lysine and glycine, for 50 mL injection268 . e. N-Arylation. A comparative study was carried out for the analysis of amino acids in serum by pre-column derivatization with o-phthalaldehyde (73) and N,N-diethyl2,4,dinitro-5-fluoroaniline (99) followed by HPLC, and IEC followed detection by the ninhydrin method (37) in an amino acid analyzer. Good agreement was found for the three methods, but pre-column derivatization was more sensitive and faster. Good resolution was found for thirty amino acids with 73 and thirty-eight with 99269 . See also reagents 127 in Section IV.D.4. F NO2
Et2 N NO2 (99)
f. Schiff bases. Measurement of the chemiluminesce of Schiff base formation (reaction 12) can be applied for determination of primary amines, by post-column derivatization in a FIA system. Sodium bis(2-ethylhexyl) sulfosuccinate (100) is also added to form reversed micelles to accelerate the reaction270 . The chemiluminesce of the oxidation of Schiff bases with the Fenton reagent in a FIA system was proposed; LOD 1.5 ð 108 M for hexylamine and 1.4 ð 107 for alanine, with linear behavior in the 105 103 M range. The mechanism depicted in reaction 13 was tentatively proposed, where PhCHOŁ is a benzaldehyde molecule in a triplet state271 . PhCH2 CH
O + H2 NR
PhCH2 CH
NR + H2 O
(12)
1086
Jacob Zabicky and Shmuel Bittner n-Bu CO2 CH2 CHEt
NaO3 S
CO2 CH2 CHEt n-Bu (100)
PhCH2 CHO + H2 NR
PhCH2 CH
Fenton reagent
NR
H2 O2 / Fe(II)
(13) Ph
NHR PhCHO∗ + RNHCHO O
O
1-Pyrenecarboxaldehyde (101) was used for derivatization of primary aromatic amines to the corresponding Schiff bases, for their determination by HPLC-FLD; LOD 1 2 pmol272 . CH
O
(101)
g. Miscellaneous reactions. Catecholamines were oxidized to aminochromes (36) with hexacyanoferrate(III) ion and the products were separated on a C18 column using a micellar mobile phase containing sodium dodecylsulfonate. Detection was by thermal lens spectrophotometry, using the 488 nm line of an ArC laser; LOD ca 4 mg/L. The method was applied for determination of unconjugated catecholamines in urine, using isoproterenol (21c) as internal standard273 . The PRISMA model274 and factorial experimental design were applied in the development of a one-dimensional overpressured layered chromatography separation method for the anti-neoplastic bis-indole alkaloids vincristine (102a), vinblastine (102b) and some derivatives275 . Diazotization and formation of diazo dyes affords a general approach to pre-column derivatization, to be followed by direct phase or RP-HPLC with UVD or FLD. Thus,
24. Analytical aspects
N
OH
N H MeO2 C
(a) R = CH (b) R = Me
1087
Et
N H Et
O OAc
N
MeO
R
HO
CO2 Me
(102)
sulfanylamide (103), p-aminobenzoyl-ˇ-alanine (104) and p-aminobenzoic acid served as model compounds for diazotization and coupling with 2-aminoanthracene (105). The method was applied for determination of p-aminobenzoic acid in urine. The method was unsuitable for 4-hydroxy or alkyl derivatives of aniline276 . Modifications of the Bratton Marshall method277 were proposed for precolumn derivatization, by which primary aromatic amines are diazotized and coupled with N-(1-naphthyl)ethylenediamine (106). The diuretics hydrochlorothiazide (107), bendroflumethazide (108) and furosemide (109) were determined in urine after hydrolysis, diazotization and coupling with 106, with p-aminobenzoic acid serving as model compound. Substituted indoles such as 5-hydroxyindole-3-acetic acid (110) and tryptophan (47) underwent N-nitrosation and interfered with the determination. End analysis was by HPLC with UVD or thermal lens spectrophotometry, using a micellar carrier; LOD for the diuretics was ca 5 nM for the NH2 4-H2 NC6 H4 CONHCH2 CH2 CO2 H
4-H2 NC6 H4 SO2 NH2 (103)
(104) (105) NHCH2 CH2 NH2
O
O S
NH2 O2 S
NH
Cl
NH
(106)
(107)
O
CO2 H
O S
NH2 O2 S
NH
F3 C
NH (108)
O NHCH2
CH2 Ph
H2 NO2 S Cl (109)
1088
Jacob Zabicky and Shmuel Bittner CH2 CO2 H
HO
N SO2 NH
H2 N
N
N H (110)
(111)
latter detector, which was 20 50-fold more sensitive than UVD278 . The necessity of preparing fresh solutions of unstable nitrite is avoided in a FIA system where nitrate is reduced to nitrite in situ by Cd/Cu, followed by diazotization and coupling with reagent 106. This was applied to fast analysis of sulfadiazine (111), with a throughput of 72/h. UVD measurements at 542 nm were linear in the 0.5 50 ppm range279 . 1-(2,4-Dinitrophenyl)pyridinium chloride (112) is a versatile display reagent after planar chromatography (e.g. TLC and paper chromatography), revealing as colored areas on a yellow background. The reagent can be applied for detection of nucleophilic analytes such as primary and secondary amines, thiols, thiolactones and carboxylic acids, as shown in reaction 14280 .
Nu H
N
+
N
Nu:
NO2
NO2
NO2
NO2 (112)
Nu+
Nu
(14)
N
N NO2
NO2
NO2 O−
N+
O−
24. Analytical aspects
1089
4. Chiral purity
See Section IV.I for alternative methods of chiral resolution. Partial chemical hydrolysis of proteins and peptides with hot 6 M HCl, followed by enzymatic hydrolysis with pronase, leucine aminopeptidase and peptidyl D-amino acid hydrolase, avoids racemization of the amino acids281 . The problems arising from optical rotation measurements of chiral purity were reviewed. Important considerations are the nonideal dependence of optical rotation on concentration and the effect of chiral impurities282 . Determination of chiral purity using chromatographic methods has been reviewed283 . The feasibility of using a circular dichroism spectrophotometer as LC detector for chromophore-bearing chiral molecules was critically examined. Using UVD in tandem with such spectrophotometer may be of advantage284 . The sensibility of the chromatographic detectors and the good yields usually attained with derivatizing reagents make it possible to analyze small samples containing low concentrations of chiral amines, such as biological fluids and environmental samples. Usually, methods are based on precolumn derivatization with a chiral reagent, for example SC-Mosher’s acid chloride (113)285,286 , followed by destruction of excess reagent, chromatographic resolution and detection of the diasteroisomers. Derivatization of amino acids with the C form of 1(9-fluorenyl)ethyl chloroformate (114) affords dioasteroisomers that can be resolved and determined by RP-ion pair HPLC. Of the nineteen amino acids investigated tyrosine (46), tryptophan (47) and cysteine (115) could not be detected due to their weak reaction with the derivatizing reagent. The method was applied to the study of amino acids in the nervous system of crustaceans287 .
F3 C
COCl
MeO Ph
HSCH2 CH(NH2 )CO2 H
MeCHO2 CCl
(113)
(114)
(115)
The enantiomeric purity of protected amino acids used in peptide synthesis can be determined by pre-column partial deprotection followed by derivatization with Marfey’s reagent (116). The Marfey diastereoisomers can be easily resolved and determined by RP-HPLC using an ODS-Hypersil column288 . Fifteen amino acids collected from mammalian tissues were derivatized with Marfey’s reagent and subjected to two-dimensional TLC. Each individual spot (enantiomeric mixture of a diasteroisomer) was then resolved by RP-HPLC. Except for tyrosine (46) and histidine (117), subnanomole quantities of enantiomers could be analyzed289,290 . F
CONH2
H3 C C H
CH2 CHCO2 H
N N H
NH2
NO2 N H
O2 N (116)
(117)
1090
Jacob Zabicky and Shmuel Bittner
A fully automated derivatization system for determination of enantiomeric purity of amino acids is based on derivatization with o-phthalaldehyde (73) in the presence of the chiral thiol N-isobutyryl-L-cysteine (118a) or its D enantiomer (see reaction 7). The diasteroisomeric isoindole derivatives of fourty-one amino acids were separated on a C18 RP-column. The fluorescence allowed detection of 1 2 pmol of an amino acid enantiomer; linearity was good in the 25 1000 pmol range291 . Derivatization by reaction 7, using N-t-butyloxycarbonyl-L-cysteine (118b) as mercaptol, was applied to enantiomeric analysis of the free amino acids in brain tissue, revealing the presence of a large amount of free D-serine (0.22 mmol/g, 25% of the free serine found) while D-alanine and D-aspartate are present at trace levels292 . Similarly, thiosugars were proposed as chiral thiol reagents for pre-column derivatization of enantiomeric mixtures of 2-amino-1-alcohols. The reaction takes place within 1 min and resolution by RP-HPLC with fluorescence detection is efficient; LOD is less than 1 mM for 10 mL injection293 .
HSCH2 CHCO2 H RNH
(a) R = Me2 CHCO (b) R = t-BuO2 C (c) R = Ac
(118) A comparative study was carried out of the effectiveness of three commercially available chiral columns and nonchiral derivatives of amino acids such as N-(3,5-dinitrobenzoyl) esters (119), phenylurea esters (120), hydantoins (121) and thiohydantoins (98). Although good separations were obtained, no column was universally effective294 .
O
O2 N
R CONHCHCO2 R′ R
PhNHCONHCHCO2 Me
Ph
N NH
R
O2 N
O (119)
(120)
(121)
Derivatization of secondary amino acids with 9-fluorenylmethyl chloroformate (90), followed by HPLC using a modified cyclodextrin-bonded phase and a nonaqueous polar mobile phase, served to determine enantiomeric impurities which were in some cases as low as 1 ppm of the main enatiomer. The derivatizing group served both as a tracer and as a means for avoiding further racemization of imino acids295 . The enantiomeric purity of esters of amino acids derivatized with reagent 90 could be separated on Chiralcel-OD with large separation factors (1.5 2.2). FLD had LOD below 0.05% down to the ppm range. Inversion of the elution order was observed for certain proline and tryptophan enantiomers296 . The chiral reagent 122 was proposed for derivatization of enantiomeric mixtures of amino acids. Good HPLC separations were obtained for the diasteroisomer derivatives of a series of amino acids, including some unusual ˛-amino acids with long or bulky side chains, aryl and hetaryl groups, and ˇ-substituted ˇ-amino acids297 . Nonchiral columns can be used with nonchiral derivatization for better detectability of the analytes, using chiral modifiers of the carrier solvent. For example, RP-HPLC resolution of dansylated (92) D,L-amino acids using L-phenylalanine Cu(II) complex
24. Analytical aspects
1091 O
PhCH2 O2 CNHC*H(i-Pr)CONHCMe2 CO2 N
O (122)
as chiral modifier298 . The Cu(II) complex of (R,R)()-N,N0 -dicyclohexyl-trans-1,2cyclohexanediamine (123) was also proposed as chiral modifier. This was applied to the RP-HPLC resolution of free or dansylated amino acids and to further assist the separation of diasteroisomers299 . NHHex-c
NHHex-c (123)
The concept of two-dimensional chromatography was applied to LC in columns for determination of enantiomeric composition of complex mixtures of amino acids, as occurring in biological fluids and foods. The first run performed was IEC with LiCl Li citrate buffer. Each eluted peak corresponding to an amino acid was reinjected into an RPC18 column and eluted with an aqueous solution containing chiral Cu(II) complexes with various derivatives of L-phenylalanine (124 126), which undergo partial ligand exchange with the amino acid enantiomers and perform chiral discrimination. Advantages of the method are that only the chiral mixtures of interest are separated and each one of these can be treated with a different chiral reagent. Detection was by fluorometry, after post-column derivatization with 4-chloro-7-nitrobenz-2,1,3-oxadiazole (127a) for proline and hydroxyproline and, according to reaction 7, for the other amino acids. It was possible to detect chiral impurities as low as 0.1% in the nM concentration range300 . Precolumn derivatization of amino acids with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (127b) followed by HPLC-FLD (ex 470 nm, fl 530 nm) showed separation factors of 1.27 and 1.17 for the derivatives of the enantiomers of phenylalanine and leucine, respectively; LOD ca 30 fmol301 ; phenylcarbamylated ˇ-cyclodextrin stationary phases were also used301,303 . The fluorogenic benzoxadiazolyl isothiocyanate Edman reagents (128) were proposed for pre-column derivatization of amino acids, followed by HPLC-FLD. No racemization took place on derivatization304 . Pre-column derivatization of alcohols and amines with the chiral proline derivative reagent 129 affords fluorescent labeling of these compounds for LC-FLD. Excitation at about 450 nm and fluorescence at about 560 nm were essentially the same for all alcohols and amines tested; instrumental LOD (SNR 2) and detection using a conventional Xe lamp was 10 500 fmol, and 2 10 fmol with LIF, using the ArC emission at 488 nm234 . See other benzoxadiazole reagents above (88, 89). PhCH2 CHCONH2 NMe2 (124)
PhCH2 CHCONH2 NHMe (125)
PhCH2 CHCONHCH2 CH2 NHCOCHCH2 Ph NHMe
NMe2 (126)
1092
Jacob Zabicky and Shmuel Bittner X
SO2 NMe2
SO2 NR2 N
N
N O
(a) X = Cl (b) X = F
O
O
N
N
N
NO2
N
N=C=S
(128) R = H, Me
(127)
COCl
CO.N
(129)
The enantiomeric composition of the amino acids of a pyoverdine hydrolyzate was determined by RP-HPLC of their derivatives with ˇ-D-glucopyranosyl isothiocyanate tetraacetate (130a). However, the L-configuration of threo-ˇ-hydroxyhistidine (131), a rare amino acid, was established with amino acid oxidases305 . Derivatization with the tetrabenzoate analogue (130b) gave excellent resolution in the RP-HPLC of a variety of enantiomeric amino acids and ˇ-adrenergic blockers on a standard C18 column, while the tetrapivalate analogue (130c) gave unsatisfactory results306 . Derivatization with reagent 130a followed by RP-HPLC was proposed for determination of the enantiomers of cyclic imino acids and ˇ-substituted ˇ-alanines307 . CH2 OY O N=C=S OY YO
N
(a) Y = Ac (b) Y = Bz (c) Y = t-BuCO
CH N H
OY (130)
HO
CHCO2 H NH2
(131)
HPLC, using a Crownpack CR column containing an 18-crown-6-type chiral crown ether, served to separate and resolve the enantiomers of 5,6-dihydroxy-2-aminotetraline (132a) and 6,7-dihydroxy-2-aminotetraline (132b) at pH 2.0; LOQ for enantiomeric impurities was <0.1%308 . ∗ NH2
7 X
(a) X = 5-OH (b) X = 7-OH
HO 5 (132)
5. Fossil dating
A dating technique for fossils is based on the measurement of the D:L ratio of amino acids extracted from the fossil sample. The hypothesis is that over very long periods
24. Analytical aspects
1093
epimerization takes place, and the enantiomeric ratio can be correlated with age. This has some advantages over 14 C radioisotope dating, as several easily resolved tracers (amino acids) are available for mutual reconfirmation or discovery of unusual features. The rate of racemization is affected by temperature, pH, catalysts etc., but these factors can be eliminated by correlating D:L ratios in fossils of a locality with 14 C dating. This was done for about one-hundred known fossil specimens collected in Hungary, and the calibration curves were applied to estimate the age of specimens, based on two to three amino acids309 . See also end of Section IV.B. Besides providing a dating tool for samples older than the limit of radiocarbon dating (4 5 ð 104 year), enantiomer ratio can be applied to dating of recent samples, where the 14 C method is also insensitive. Thus, the rate of epimerization of aspartic acid allows dating of deposits less than 350 years old310 . Assessment of indigeneity of fossil samples can be carried out by analyzing the soluble organic matter. Each peptide is separated and submitted to amino acid analysis and differentiation using multivariate statistics. Besides dating, also the molecular phylogeny of the fossils can be asserted311 . Determination of the ‘I/A’ ratio (L-isoleucine to D-alloisoleicine) requires very small samples, e.g. snail shells were individually analyzed and shown to belong to a mixed-aged deposit, aided by 14 C dating312 . The effect of temperature on the rate of racemization of amino acids in fossils was investigated and the implications of the findings on fossil dating were analyzed313 . The high rate of conversion of L-aspartic acid into its D-isomer, observed in uncontaminated bone samples taken from catacombs in Rome (IV century BC) was attributed to collagen decomposition due to the humidity of the catacombs314 . E. Electrophoresis
Refractive index may afford a sensitive universal detection method for capillary electrophoresis (CE). An important part of the setup is a refractive index matching fluid in which the capillary is submerged. The method was tested for a saccharide mixture including N-acetylglucosamine and N-acetylgalactosamine315 . An intensity-modulated 257 nm pump laser-induced refractive index changes inside a 25 mm bore capillary used in CE. These changes were monitored with the aid of a probe laser beam oscillating at 663 nm. This RID was demonstrated for dansyl (92) derivatives of amino acids: total sample 350 pg, with detection volume <10 pL316 . The effectiveness of nine background electrolytes, providing both buffering action and background absorbance, was assessed for CE separation of twenty common amino acids. p-Aminosalicylic acid and p-(N,N-dimethylamino)benzoic acid were the best317 . Low molecular weight amines can be separated and determined by CE using an electrolytic system based on Cu(II)318 . Potential-amperometric detection of amino acids and peptides separated by CE was carried out by electro-oxidation at a Cu electrode in alkaline medium. The method was applied to determination of amino acids in urine, L-aspartylL-phenylalanine methyl ester (aspartame) in soft beverages and pentapeptides from a solid-phase synthesis process319 . Primary amines are derivatized readily and quantitatively as illustrated in reaction 15. CE and detection by LIF had LOD in the low attomol 1 ð 1018 range for amino acids and amino sugars320,321 .
1094
Jacob Zabicky and Shmuel Bittner CO2 H
O + Η2 NCHRCO2 H N
CHO
(15) CO2 H
NCHRCO2 H N
Amino acids derivatized with 9-fluorenylmethyl chloroformate (90) were separated by CE and determined by LIF with a pulsed laser; LOD 0.5 nM (SNR 2)322 . A sensitive technique for amino acids is capillary zone electrophoresis (CZE) combined with LIF of their fluorescein isothiocyanate (133) derivatives. Not all amino acids give good resolution. LOD for proline and arginine were 0.3 and 0.5 nM, respectively323 . N=C=S
CO2 H
HO
O
O
(133)
The chiral purity of amino acids at large enantiomeric excess can be determined automatically by derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (127b) followed by CE with cyclodextrin chiral selectors and detection of the LIF excitation at 488 nm. Lod 140 ppm of L-phenylalanine in D-phenylalanine324 .
24. Analytical aspects
1095 O
O N O N
O
N
S
Me2 N
S
O
O
Me
O
(134) O
Et2 N
O
O O
N
O (135)
O
Pre-column derivatization with either 134 or 135 followed by CZE and LIF detection was proposed for amino acids. The amino group of the analyte displaces the succinyloxy moiety of the reagent yielding a carboxamide325 . See also Section IV.D.3.c for other acylating reagents derived from N-hydroxysuccinimide (95 and 96). Rifamycin B (136), a macrocyclic antibiotic of the ansamycin class, associates enantioselectively with amino alcohols. As 136 bears a carboxyl group, it can be used as a host molecule to resolve enantiomeric mixtures by CE. This was applied to analyze a variety of drugs, including terbutalin (137), bamethan (138), norphenylephrine (139), Me O
O
HO2 CCH2 O
HO
O
CHCH2 NHBu-t Me OH Me
O
OH
OMe Me
OH
HO (137)
OAc
OH
Me OH
Me
Me
(136)
HO
CHCH2 NH2
CHCH2 NHBu-n
OH
OH (138)
HO (139)
1096
Jacob Zabicky and Shmuel Bittner
isoproterenol (21c), epinephrine (21b), norepinephrine (21a), pseudoephedrine (30) and octopamine (22)326 . Micellar techniques can increase the concentration of a component in the disperse phase and the ionic mobility due to lower specific surface for a given specific charge. Pre-column derivatization with 90 was followed by micellar electrokinetic chromatography (MEKC) and LIF detection. Combined derivatization with 73 and 90, to attach fluorescent markers to primary and secondary amino acids in biological samples, was investigated327 . Derivatization with 78 in the presence of cyanide afforded fluorescent derivatives of amino acids that were separated by MEKC; LOD of 0.9 amol (attomol, 1018 mol) at SNR 2, using LIF, at 200 mM concentrations, with injections of ca 2.5 nL328 . The analysis of thirty dansyl (92) derivatized amino acids by MEKC was investigated. Sodium dodecylsulfate micelles were used for neutral and acidic amino acids, attaining separation efficiency between 210,000 and 343,000 theoretical plates; LOD was 3 6 fmol, RSD 0.09 0.70% for migration times and 0.85 3.41% for peak area. Sodium cholate micelles were used for basic amino acids. The method was demonstrated for determination of amino acid composition in foodstuffs and skin329 . Applicability of CZE to the Edman phenylthiohydantion derivatives of amino acids (140) is limited because the neutral amino acids cannot be resolved by this method and by the reduced thickness of the sample requiring relatively high concentrations of the fluorescent material for detection. These limitations may be overcome by a micellar technique that confers mobility to neutral 140 species and by application of thermotropic detection that allows one to detect a few tens of fmol of the derivative, obtained after injecting ca 0.5 nL, at a concentration of ca 1 mM330 . O R Ph
Me2 N
N
N
N
NCS
NH S (140)
(141)
The thiohydantoin derivatives of amino acids obtained from 4-(4-dimethyaminophenylazo)phenyl isothiocyanate (141) and fluorescein isothiocyanate (133) can be separated by CZE. Lowering the absolute detection limits of thiohydantoin derivatives of the amino acids is a basic requirement for the development of highly sensitive protein sequencer based on Edman-like processes. Thus, the absolute LOD of thiohydantoin derivatives are at present of the order of 1016 mol for 141 and 1021 mol for 133331 . The basic material in seeds that is extractable with trichloroacetic acid solutions is ascribed to nonprotein nitrogen when the acid is in the 0.4 1.0 M concentration range. Gel electrophoresis on a sodium dodecylsulfate polyacrylamide medium pointed to the presence of 12 kDa polypeptides in soybean meal and 7, 10, 12 and 28 kDa in almond meal332 . F. Spectrophotometric Methods
Aromatic amines can be determined by measuring the difference of their UVV absorption spectra, taken at identical concentrations but different pH of the solution. Also, standard mixtures and samples of the amines isolated from coke processing products were tested; LOD 0.1 1 ppm. The procedure is potentially useful for waste waters and industrial effluents, where techniques such as GC and nonaqueous titrations may prove difficult to apply333 . A determination of certain metabolites symptomatic of pancreatitis
24. Analytical aspects
1097
consists of basic hydrolysis of urine, followed by spectrofluorimetric determination of p-aminobenzoic acid and p-aminosalicylic acid334 . o-Aminophenol undergoes oxidative dimerization followed by hydrolysis, yielding the intensively colored 2-hydroxy-3H-phenoxazin-3-one, as shown in reaction 16. Halogensubstituted o-aminophenols in urine were determined by the same reaction335 . N
NH2
OH
Fe(III)/H+
2
(16)
OH
O
O
Modifications of the Bratton Marshall method mentioned in Section IV.D.3.g can be used for sensitive spectrophotometric detection and determination of primary aromatic and heterocyclic amines. Thus, a simple spectrophotometric determination of the cardioprotective agent acadesine (142) was developed, to measure concentrations of the drug in plasma during intravenous infusion to patients undergoing coronary artery bypass graft surgery336 . CONH2 N
H2 O3 PO
N
CH2 O H H
H H
HO
OH
NH2
(142)
Amino acids can be determined according to reaction 17. The resulting dithiocarbamates have two specific absorption bands at max 255 and 285 nm. Lysine and cysteine have almost double the molar aborbance because of reaction of the additional NH2 and SH group, respectively337 . The kinetics of this reaction can be used for the determination of secondary amines, by measuring the absorbance of the Cu(II) complex with the N,Ndialkyldithiocarbamate, at max 440, in a stop-flow cell. The products of primary amines are unstable. The reaction rate of n-alkylamines is faster than that of isoalkylamines. Micelle formation by addition of Triton X-100 improved the method338 . RCHNH2 CO2 H
CS2 /NaOH
RCHNHCS2 − CO2 −
(17)
A spectrophotometric method for determination of primary and secondary amines requires development for each particular compound, determining the kinetics of reaction of the amine with sodium 1,2-naphthoquinone-4-sulfonate (143) and the UVV absorption spectrum of the product, under a set of fixed conditions. The procedure was applied to determination of ephedrine (30) and amphetamine (28) in pharmaceutical samples339 . Reagent 143 in a FIA system was used for the fast determination of lysine (144) in commercial feed samples by multivariate calibration techniques, without need of chromatographic separation340 .
1098
Jacob Zabicky and Shmuel Bittner O O CH2 CH2 CH2 CH2 CHCO2 H NH2
NH2 SO3 Na (143)
(144)
Reaction 7 (Section IV.D.3.a) was applied for the automatic kinetic-fluorometric determination of primary amine pharmaceuticals, using N-acetylcysteine (118c) as thiol and a stop-flow technique for data acquisition194 . A FIA system was designed for determining the total free amino acids in seawater, based on reaction 7 and measurement of LIF (ex 337 nm, fl 455 nm) using a diode array. The signals of dissolved ammonia and urea are weak. Possible interference by ammonia can be eliminated by the time-resolved fluorescence technique, because the fluorescent lifetime of the ammonia derivative is 9 ns vs 21 ns for that of all the amino acid derivatives. Linearity was observed in the 1 500 nM range of alanine equivalent. The method is suitable for real-time analyses in on-board laboratories341 . The results from this FIA method compared well with HPLC determination of the free amino acids. Only in the case when ammonia concentration strongly overbalanced that of the free amino acids (ratio × 10) did the FIA method fail342 . The electron acceptor 7,7,8,8-tetracyanoquinodimethane (TCNQ, 145) is capable of abstracting one electron from a donor molecule, yielding deeply colored solutions of a OH
HN
NC
CN
NC
CN (145)
Cl
N (146)
Me Et2 NCH2 CH2 CH2 CHNH
Cl
N
N NHCHCH2 CH2 CH2 NH2 Me
(147)
(148)
CH2 NEt2
24. Analytical aspects
1099
stable radical anion that can be measured spectrophotometrically. This was applied to the determination of the antimalarial drugs amodiaquin (146) hydrochloride, chlorodiaquin (147) phosphate and primaquin (148) phosphate in pharmaceutical formulations343 . A solution containing an amino acid is passed through a polymeric bed containing Cu(II) ions, forming a complex which is further reacted with zincon (149) and the blue color measured at 600 nm in a FIA system. This was applied for fast determination of amino acids in pharmaceutical formulations344 .
CO2 −
OH H N
N N
N
SO3 − (149)
A sensitive method for the spectrocolorimetric determination of primary or secondary amino functions attached to a solid support consists of derivatizing with either 2iminothiolane (150, Traut’s reagent) or sulfosuccinimidyl 3-(4-hydroxyphenyl)propionate (151). The products contain one mercapto or phenolic OH group attached to each amino site, which are capable of reducing Cu(II) to Cu(I) in alkaline medium. Thus, the derivatized sample is incubated with the so-called 2,20 -bicinchoninic acid copper protein reagent, containing 152 and Cu(II) ions, yielding an intensely colored chelate complex with Cu(I) ions345 . Derivatization with 150 and 5,5-dithiobis(2-nitrobenzoic acid) (153, Ellman’s reagent) as the chelating agent was also recommended for determination of primary amino groups attached to the surface of solid supports346 . O
SO3 H
p-HOC6 H4 CH2 CH2 CO2 N NH
S
O
(150)
(151)
HO2 C
CO2 H
O2 N N
CO2 H
HO2 C SS
N (152)
(153)
NO2
1100
Jacob Zabicky and Shmuel Bittner
The lysine and hydroxylysine sites of gelatin were determined by combining their free amino groups with fluorescamine (154) and measuring the induced photoluminescence347 . Primary amino groups covalently attached to the surface of glass were determined by derivatization with the same reagent and measurement of the fluorescence348 .
O
O O O
(154)
Latent fingerprints on paper have been revealed by combining the amino acids present with reagents such as ninhydrin (see 37), dansyl chloride (92), fluorescamine (154), 4chloro-7-nitrobenzofurazan (127a) and o-phthalaldehyde (see reaction 7). To avoid some problems encountered with these reagents it was proposed to use 1,8-diazafluorenone (155), leading to the formation of highly fluorescent ylides (156)349 .
N + N H
δ−
N N
N
δ−
N
N O (155)
(156)
HC )]
Amines form ion associates of the type [dye (amine or [dye (amine HC )2 ] with sulfonphthalein-type dyes, such as bromophenol blue (157a) or bromocresol green (157b). Spectrophotometry using these ion associates may give wrong results if the amines were once dissolved in halogenated solvents, due to quaternization between the amine and the solvent. This was demonstrated for a series of amines such as ephedrine (30), tropine (158), atropine (159), quinine (160) and ajmaline (161), and a series of solvents such as CH2 Cl2 , CHCl3 , CCl4 and ClCH2 CH2 Cl350 . A series of calixarenes bearing azo groups, such as 162a c, are potential detectors of aliphatic primary amines, as they showed bathochromic shifts of 37 100 nm from max 382 with these compounds. No shift was shown in the presence of aniline or pnitroaniline351 .
24. Analytical aspects Br
Br R
O
1101
O−
Br
Br
(a) R = H (b) R = Me
NMe
OH
SO3 −
R
(158) CH
CH2
(157) N CHOH
CH2 OH NMe
O2 CCH
MeO Ph
(159)
N (160) HO
N OH
N Me Et (161)
Primary amines form fluorescent Schiff base complexes in the presence of salicylaldehyde (163) and Be(II) ions, that can be measured in a FIA-FLD system. The reaction is fast, allowing up to 30 determinations per hour. Analytical range: MeNH2 6 ð 106 to 6 ð 103 M, RSD 3%; EtNH2 , n-PrNH2 and n-BuNH2 3 ð 105 to 8 ð 103 M. Secondary and tertiary amines do not react. This was applied to the determination of traces of MeNH2 (0.007 0.008%) in commercial Me2 NH352 . A fast and sensitive method for determination of 4-aminoantipyrine (164) consists of coupling this compound with diazotized p-nitroaniline in a FIA system and measuring spectrophotometrically at 380 nm. About 50 determinations per hour could be carried out; LOD was 0.05 ppm (SNR 3), RSD 0.61% for 4 ppm and 0.27% for 50 ppm, with linearity up to 50 ppm353 . Surface-enhanced Raman scattering using a silver-coated alumina support selectively enhanced the spectrum of p-aminobenzoic acid. This allowed the determination of this compound at low ppm levels in vitamin B complex354,355 . LIF excitation spectra were recorded for alkyl aminobenzoates (165) under free jet conditions. The partially resolved band contours were different for the various compounds
1102
Jacob Zabicky and Shmuel Bittner
N
N
link
N
N
OH
OH CH2
CH2
CH2
CH2
OH
OH
N
N N
N
link
2
Links (a) Me
Me
(b)
(c)
O
(162)
O CH
O
H2 N
R
Me
OH O
R = Me, Et n = 3,4
N Me N Ph
(163)
O
(164)
n-H2 N (165)
and could be assigned to conformers of the molecule. Differences in band contour were ascribed to changes in hybridization caused by the conformational structure356 . G. Enzymatic Biosensors
Amperometric biosensors incorporating certain enzymes on the electrode for the determination of D- and L-amino acids were investigated. The parameters included enzyme immobilization procedure, composition of the immobilizing matrix, amount of enzyme,
24. Analytical aspects
1103
pH, flow rate and injection volume. The immobilized enzymatic system consisted of a D- or an L-amino acid oxidase producing hydrogen peroxide, and hydrogen peroxide reductase. The efficiency of the electrocatalytic reduction of hydrogen peroxide starts to increase from C600 mV towards negative potentials, and levels off at 100 mV, measured against a Ag/AgCl electrode. The 20 most common L-amino acids could be detected357 . Specific amperometric amino acid sensors were based on a Clark oxygen electrode, with specific or nonspecific enzymes immobilized on the gas-permeable membrane. L-Glutamic acid was determined using L-glutamate oxidase, by measuring the oxygen consumption of reaction 18. For L-lysine, L-arginine and L-histidine the corresponding decarboxylases catalyzed reactions 19 21. The liberated carbon dioxide was consumed by autotrophic bacteria leading to oxygen consumption that was measured in the detector358 . HO2 CCH2 CH2 CHCO2 H + O2 + H2 O
oxidase
HO2 CCH2 CH2 CCO2 H + NH3 + H2 O2 (18) O
NH2 decarboxylase
H2 N(CH2 )4 CHCO2 H
H2 N(CH2 )5NH2 + CO2
(19)
NH2 H2 NCNH(CH2 )3 CHCO2 H NH
decarboxylase
H2 NCNH(CH2 )4 NH2 + CO2 NH
NH2
CH2 CH2 NH2
CH2 CHCO2 H NH2 N H
(20)
decarboxylase
N H
+ CO2
(21) Polyaniline-modified electrodes allow electrometric determination of hydrogen peroxide produced in aminooxidase systems, without interference of electroreactive amino acids, such as cysteine, histidine, methionine, tyrosine and tryptophan359 . An interdigitated array of microelectrodes in a small volume helped to significantly reduce the LOD of electrochemically reversible redox materials360,361 . This was applied to the determination of p-aminophenol by small volume immunoassay, by sandwiching layers of a supported enzyme with the microelectrodes. A steady-state signal was obtained for the array, showing a linear relationship between the concentration and the limiting current over the range of 1 1000 mM. Less than 1 min detection time was required for 2 10 mL samples362 . A biosensor was designed where a dehydrogenase and an enlarged coenzyme are confined behind an ultrafiltration membrane. The amino acid is determined indirectly, by measuring the fluorescence of the reduced coenzyme (ex 360 nm, fl 460 nm) produced in reaction 22, with the aid of an optical fiber. The coenzyme is regenerated with pyruvate in a subsequent step, as shown in reaction 23. This biosensor was proposed for determination of L-alanine and L-phenylalanine for monitoring of various metabolic diseases and for dietary management363 .
1104
Jacob Zabicky and Shmuel Bittner L- Phenylalanine dehydrogenase
PhCH2 CHCO2 H + NAD+ + H2 O
PhCH2 CCO2 H
NH2
O
(22)
+ NH3 + NADH + H+ NADH + MeCCO2 H + H+
NADH+ + MeCHCO2 H
O
(23)
OH
Amino acids may be determined by measuring the amines obtained after the action of a carboxylase with a specific electrode for amines, which is based on a poly(vinyl chloride) membrane containing sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (166) as ion exchanger and tricresyl phosphate as solvent mediator. LOD was 20 and 50 mM for tyroxine and phenylalanine, determined as tyramine (5) and phenethylamine (33), respectively364 . F3 C B− Na+ F3 C
4 (166)
The hydrogen peroxide produced in a FIA system coupled with a bioreactor containing an amino acid peroxidase can be determined by the chemiluminescence it produces in the presence of phenyl 10-methylacridinium-9-carboxylate (167). Thus, for example, a throughput of 200 samples of glutamate per hour was achieved with LOD 0.5 mM (SNR 3)365 . Hydrogen peroxide, generated on degradation of amino acids by L-amino acid oxidase immobilized in a reactor, can be determined by measuring the chemiluminescence in the presence of luminol (69) and hexacyanoferrate ions. The method was applied to the determination of free amino acids in cheese, with a throughput of 40 samples per hour366 . This method was preferable to derivatization procedures with either trinitrobenzenesulfonic acid or by applying reaction 7367 . CO2 Ph
N+ Me (167)
A sensitive method of determination of H2 O2 is by the so-called peroxalate reaction luminescence (reaction 24) by which hydrogen peroxide reacts with an aryl oxalate
24. Analytical aspects
1105
forming 1,2-dioxetanedione (168); this reacts with a fluorophore , leading to an excited state (169), that eventually returns to the ground state emitting a photon368 . The effectiveness of the method depends on the readines by which 169 is formed and the nature of the fluorophore. For example, 2,4,6-trichlorophenyl oxalate (42) catalyzed by imidazole (170) is frequently used. The method was reviewed369 . A modification claimed to be 10 times more sensitive uses 1,10 -oxalyldiimidazole (171) as reagent and an immobilized form of 3-aminofluoranthene (172); LOD 10 nm of H2 O2 in water, for 0.5 pmol (50 mL) injection370 . O H2 O2 +
CO2 Ar
O
CO2 Ar
O
+ 2ArOH O (168) O O +Φ
O
(24)
Φ +
− O (169)
Φ + hν
2CO2 + Φ
N
N
N N
N H
N O
(170)
O (171)
CO2 CH2 CH2 OCH2 CHCH2 NH CCH2
n
OH
Me
(172) H. Miscellaneous Methods
Carbon paste and graphite epoxy electrodes modified with RuO2 can be used for detection of amino acids and peptides in FIA systems. Optimal conditions are in strongly alkaline solutions at C0.45 V vs Ag/AgCl electrode, with a fast and linear response. Carbon paste electrodes can be modified also with Co3 O4 371 . Colorimetric methods for the determination of amino groups attached to a solid support may give erroneous values
1106
Jacob Zabicky and Shmuel Bittner
due to nonspecific adsorption of chromophores on the solid surface. An amperometric determination of primary amino groups was based on derivatization with glutaraldehyde followed by oxidation of the resulting dienamine (reaction 25). The amino group concentration is proportional to the oxygen consumption, that is monitored by a Clark oxygen electrode; RSD is 3.2% for AH-Sepharose 4B372 . R NH2
3RCH2 CHO
N
CH2 R R
O2 oxidation
(25) R
N+
CH2 R R
Amino acids enhance the oxidation peak of Cu(0) obtained with a carbon paste electrode incorporating Cu(II) cyclohexylbutyrate. The increased current is proportional to the amino acid concentration at trace levels in the mM range373 . The behavior of such electrodes was investigated for cysteine (115). On scanning potentials in the positive direction, the amino acid is accumulated on the electrode as the Cu(I) complex at C0.90 V vs a standard calomel electrode (SCE), in acetate buffer at pH 4.5; linear range is 2 ð 109 to 1 ð 107 M, 1 min accumulation, RSD 3% (n D 5)374,375 . Amino acids can be determined in a two-step process (reaction 26). The SO2 produced can be determined by measuring the S2 emission of an N2 H2 flame in a molecular emission cavity. Carbon was found to be better than iron for building the cavity376 . pH 11.7
H2 NCHRCO2 H C ArSO2 Cl ! ArSO2 NHCHRCO2 CHC
! ArNHCH2 R C CO2 C SO2 Ar D 2,4,6-(O2 N)3 C6 H2
(26)
Radioimmunoassay (RIA) may sometimes be the method of choice for certain amines. Thus an 125 I RIA method was developed for the specific detection of D-amphetamine (28) and D-methamphetamine (29) in urine, with LOD of approximately 25 mg/L. The method was compared with GC-MS and other commercially available amphetamine assays. Other drugs gave erroneous positive identification as 28 with the latter methods, whereas the results of RIA were negative377 . Amino acids accelerate and proteins retard the rate of Cu(II)-catalyzed oxidation of di2-pyridyl ketone hydrazone (173) yielding fluorescent compounds. This has been applied for the analysis of amino acids and proteins378 . 1,4-Dihydropyridines and their N-alkyl derivatives undergo anodic oxidation in basic medium to the corresponding pyridines (reaction 27). The process may be complicated by the presence of other moieties; for example, a nitro group may reductively condense
24. Analytical aspects
N
1107
N NNH2 (173)
N
NOH
O
H NC
Me
NC
NH2
Me
Me
N H
O Me
N (175)
(174)
with nearby cyano or ester functions to yield products such as 174 and 175379
NO2
NO2 H
Me
−2e
CO2 Me
NC
−−
H
+
CO2 Me
NC
Me
Me
N
382 .
N
+
(27)
Me
Me
Me
The fate of dissolved amines during disinfection of water by chlorination was determined by membrane injection MS. Aliphatic amines undergo N-chlorination to exhaustion of the N H atoms by one of the tentatively proposed paths shown in reaction 28. Aromatic amines undergo mainly ring substitution; however, the possible intervention of N Cl intermediates is not excluded. At pH 10.6 aniline chlorination is much slower than that of n-butylamine383 .
RNH2
ClNH2
RNHCl + NH3
ClOH
RNHCl + H2 O
Cl2
+
(28) −
RNHCl + H + Cl
Nonionic surfactants of general structure 176, used in off-shore drilling (e.g. Nonidet AT 85), are toxic and slowly biodegradable. They can be determined in an FIA system by
1108
Jacob Zabicky and Shmuel Bittner
measuring the chemiluminescence produced on oxidation of the tertiary amino group by sodium hypochlorite at ca pH 11, in the presence of rhodamine B (177) as sensitizer. Only tertiary amines, including Me3 N, Et3 N and Pr3 N, show chemiluminescence; however, the simpler amines can be distinguished by their faster kinetics; LOD ca 5 ppm of 176384 .
O N
O
O
O
OH
O
O
OH
(176)
CO2 −
Et2 N
O
N+ Et2
(177)
Primary amino groups covalently attached to the surface of glass were determined by derivatization with 14 C-labelled acetyl chloride and measurement of the radioactivity348 . The interaction of hydrolyzed (3-aminopropyl)triethoxysilane with E-glass results in the formation of a thin coating about 6 nm thick. Investigation of this film by time of flight secondary ion MS (TOF-SIMS)385,386 and by X-ray photoelectron spectroscopy (XPS)387 led to the conclusion that the film consists of three main structures as depicted in 178, where the open bonds on silicon atoms represent oxygen bridges to other silicon atoms. The structure of the two-dimensional molecular aggregates formed at the air water interface of aqueous solutions of amino acids carries precise enantioselective information that influences the direction of growth of glycine crystals at that interface. Thus, solutions of valine, leucine, phenylalanine, norleucine, isoleucine or 2-aminooctanoic N face of glycine crystals at the acid of S-configuration induce fast growth of the (010) air water interface, while that of the 010 phase is induced in the presence of those of R-configuration. Hexafluorovaline, neopentylglycine and t-butylglycyne fail to show this induction388 . Amino acid enantiomers in association with the NaCl H2 O eutectic were investigated by differential scanning calorimetry (DSC) and NMR. Thus, a solution of amino acid in 0.1 M NaCl was heated in the DSC apparatus at a rate of 1 ° C/min, starting at 60 ° C, and the 1 H NMR spectrum was recorded at 20 ° C. The combined DSC and NMR results showed that the L and D forms of the amino acids could be differentiated, based on the singlet and doublet bands389 . The bonding forms of nitrogen in several Australian coals were determined by XPS and predominantly assigned to pyrrolic and pyridinic forms. Amino forms appear to be absent390 .
24. Analytical aspects
O
Si
O
Si
1109
CH2 CH2 CH2 NH2 x
OH O
Si
O
Si
O
NH2
Si
x
CH2 CH2 CH2 NH2 O
Si
O
Si
Si H
x
O
Al
O
OH
O
H n
(178) I. Derivatization
Amines are converted quantitatively to dithiocarbamates (reaction 29), that can be determined by nonaqueous titration with Ce(IV); accuracy 0.8%, RSD 0.7%391 . base
RNH2 C CS2 ! RNHCS2
29
Despite the high sensitivity of the methods for chiral resolution described in Section IV.D.4, more direct methods are afforded by NMR spectroscopy, especially for the products of synthesis. Ephedrine (179), pseudoephedrine (180a) and its Me ether (180b) yield stable epimeric N ! BH3 adducts on treatment with borane. The configuration of the nitrogen moiety was established by NMR, taking into account the conformational analysis of the molecule392 . H
H
HO
NHMe
Ph
Me (179)
RO H Ph
H NHMe
(a) R = H (b) R = Me
Me (180)
Various chiral derivatization reagents containing phosphorus have been proposed for determination of enantiomer excess. Measurement of 31 P NMR has the advantage of large peak separation. Reaction 30 takes place quantitatively with alcohols, thiols and amines in the NMR tube, at room temperature, in C6 D6 or CDCl3 solution. Reagents 181 have C2 symmetry and yield diasteroisomers 182, with excellent 31 P NMR peak separation for accurate integration and determination of enantiomer excess. Other spectra such as 1 H NMR can also be taken, but they may be too complex for enantiomer analysis393 .
1110
Jacob Zabicky and Shmuel Bittner
(CH2 )n
(CH2 )n YH
Ph
Ph N
N H
R
Me
P
Me
1
H
N
Ph
R2
Ph N
N
Y = O, S, NH R1 = alkyl, aryl R2 = alkyl, aryl, CO2 Me
H
P
Me
Me H (30)
Y R1
Me Me n = 2, 3 (181)
R2
(182)
(S)-2H-2-Oxo-5,5-dimethyl-4(R)-phenyl-1,3,2-dioxaphosphorinane (182) and unprotected amino acids are easily combined in aqueous solutions, as illustrated in reaction 31. The resulting phosphamide shows well separated 31 P NMR signals of the diasteroisomers, allowing accurate enantiomer excess determination. Diasteromeric amide derivatives of chiral phosphorinane 183 and unprotected amino acids are similarly useful. The diasteromeric shift depends strongly on pH, pointing to the influence of ionic charge on the diastereomeric shift dispersion394,395 . Also (S,S)-O,O-di-s-butyl phosphonate (184) has been proposed for unprotected amino acids396 .
Me
Me
Me Ph +
O
O
Ph Et 3 N/CCl4 /H2 O/EtOH
R
P O
Me
NH2 O
H CO2 H
O P
O
H (182)
NH R
Me
CH2 NEt2
H
Et
Me O
O
O
P H
Et
O
Me
Me CH2 NEt2
(183)
O
H
O (184)
P H
H CO2 H
(31)
24. Analytical aspects
1111
Additional NMR information may be useful in difficult enantiomer analyses of alcohols, thiols, and primary and secondary amines. Reaction 32 illustrates the process for a chiral primary amine, RŁ NH2 , undergoing N-substitution with chiral reagent 185. Besides the 31 P NMR spectra of the diasteroisomers 186, also 1 H, 13 C and 19 F spectra may be taken. Addition of sulfur or selenium to the NMR tube will afford diasteroisomers 187, for which the corresponding spectra can also be taken397 . Ar
Ar
Ar R ∗ NH
Me
N
N Me P
Ar + Et3 N.HCl
2
Me
Et 3 N
N
N Me P
R∗ NH
Cl Ar = m- C6 H4 CF3
(186)
S8 or Se 8
(185)
(32) Ar
Me
Ar N
N Me
Y P R*NH
Y = S, Se (187)
NMR assignment of configuration served for development of a method claimed to be of great reliability for establishing the absolute configuration of amines with an asymmetric center in the ˛ position, for which no reference compound is needed. The first step consists of derivatizing the amine with a chiral reagent, for example N-[(S)-2methoxy-2-phenylacetoxy]succinimide (188), as shown in reaction 33 for the methyl ester of (R)-tyrosine. The substituents on each one of the asymmetric carbons are designated as follows: If a substituent is an H-bonding donor it is designated as (1); otherwise, the smallest substituent is designated as (1). The largest of the two remaining groups is given designation (2). When drawing the Newman projections with the undesignated groups in anti conformation, the diasteroisomer with both groups of designation (1) on the same side will be the one with the longest retention time when analyzed by HPLC on a silica column. This is the case of derivative 189 of (R)-tyrosine vs 190 of the (S) epimer398 . O
H H
H
O
Ph
+
N
MeO2 C O (188)
O
HN
Ph
CH2
H2 N CH2
MeO
H
MeO2 C
MeO O
C6 H4 OH-p
C6 H4 OH-p
(33)
1112
Jacob Zabicky and Shmuel Bittner
H (1) H
(1) HOC6 H4
H Ph(2)
OMe
(1) H
CO2 Me(2)
Ph(2)
OMe C6 H4 OH(1)
(2)MeO2 C
(189)
(190)
(S)-1,10 -Binaphthyl-2,20 -diol (191) was proposed as a chemical shift reagent for assessing the chiral purity of amino alcohols. It gave a split of about 0.3 ppm for the NCH3 signal of the enantiomer of compound 192 and smaller splits for other configurations399 .
OH OH
OH PhNHCO2 NHCH3
(191)
(192)
CHCONHBu Me (193)
(S)-N-n-Butyl-2-(phenylcarbamoyloxy)propionamide (193) was used as chiral solvating agent in the NMR determination of the enantiomer composition of the N-(3,4dinitrobenzoyl) derivative of amino acid ethyl esters400 . A general approach for the determination of the absolute configuration of a chiral carbon consists of attaching to it a labile chiral unit and a dissymmetric chromophore and measuring the optical rotation at the sodium D line. This has been successfully applied to amino acids401 . Some synthetic polypeptides form lyotropic cholesteric liquid crystals when dissolved in organic solvents. That is the case of poly(-benzyl L-glutamate) in methylene dichloride. This system can be used as a chiral solvent to distinguish enantiomers by 2 H NMR. In such chiral solvents the averaged ordering parameters are different for each enantiomer. The quadrupolar splitting of CD3 signals, Q , is very sensitive to this differential ordering. Determination of enantiomer excess of amino acids requires the scheme shown in reaction 34: The amino acid is esterified with deuterated methanol in the presence of thionyl chloride; the acidity of the reaction mixture is removed with propylene oxide yielding the ˛-amino ester 193 that, in principle, can be dissolved in the liquid crystal submitted to 2 H NMR analysis. However, these esters tend to dimerize and yield the corresponding 2,5-diketopiperazines (194). Hence a Schiff base (195) is produced by treatment of 193 with benzophenoneimine and used for dissolution in the liquid crystal402 .
24. Analytical aspects
CO2 CD3
CO2 H R
1113
CH
R
CH
CD3 OH/SOCl2
NH2
NH2 .HCl
O R
H N
O CO2 CD3 R
O
NH2
R
N H
(34)
CH
(193)
(194)
Ph 2 C =NH/CH2 Cl2
CO2 CD3 R
CH N
CPh2
(195) 2-Amino-5-chlorobenzophenone, an impurity of chlordiazepoxide, can be determined by spectrofluorometry after oxidative cyclization (reaction 35). Chlordiazepoxide does not react403 . O
O
Cl
Cl Ce 4 +/H3 PO4
NH2
N H λ ex 405 nm; λ fl 465 nm
(35) An NMR study on the conformation of glucopyranosylammonium compounds showed that the general tendendency of many electronegative substituents at C1 to adopt an axial conformation was prevalent in this case too, as depicted in equilibrium 36 for R groups of various sizes. These results disclaim the importance of the so-called ‘reverse anomeric effect’404 .
1114
Jacob Zabicky and Shmuel Bittner N+ H2 R
H AcO
AcO +
AcO
O
AcO
N H2 R
AcO
O
AcO
CH2 OAc
H
(36)
CH2 OAc
Enantioselective reagents for ammonium ions include, for example, a mixture containing a host chiral crown ether such as 196, possessing four (R) centers and symbolized as M, a host achiral crown ether of similar functionality, symbolized as R, and a salt of a guest chiral amine, symbolized as A, which is analyzed by fast atom bombardment MS (FAB-MS), and the relative peak intensity of the equilibrium complexes I(MA)/I(RA) is measured and correlated with the chirality of the guest molecule. Many host and guest molecules have been investigated405 . O Ph
O
Ph
O
OMe
O
Ph
O
Ph
OMe (196) V. QUATERNARY AMMONIUM COMPOUNDS
The simultaneous ionic and covalent character of quaternary ammonium compounds (197a) is central to most of their applications. N-Quaternized heteroaromatic compounds possess many of the properties of 197a, and will be mentioned occasionaly in this chapter. In Table 4 are listed some quaternary ammonium compounds that have found industrial application. Many analytical methods make use of this class of compounds both as essential reagents or as accessories; however, in the present chapter quaternary ammonium compounds will appear only as analytes. R4 = alkyl , aryl
4
(a) R1
+
(b) R = C8 H17 to C18 H3 7; R2 = R3 = Me; R4 = PhCH2 ; X = Cl (c) R1 = C16 H3 3 ; R2 , R3 , R4 = Me; X = Br
R
1
3
R
N
R X− 1
2
R
(197)
24. Analytical aspects
1115
TABLE 4. Examples of environmental, occupational and quality control protocols for industrial quaternary ammonium compounds Compound and CAS registry number a
Safetyb
Spectrac
Various protocolsd
Quaternary N attached to four saturated aliphatic carbons Acetylcholine chloride [60-31-1] Benzalkonium chloride [8001-54-5] (197b) Bephenium hydroxynaphthoate [3818-50-6] Betaine hydrochloride [590-46-5] Betanechol chloride [590-63-6] Carbachol [51-83-2] Chlormequat chloride [999-81-5]g Choline chloride [67-48-1] Clidinium bromide [3485-62-9] 1,1-Dimethylpiperidinium chloride [24307-26-4]g Diphemanyl methylsulfate [62-97-5] Echothiophate iodide [513-10-0] Glycopyrrolate [596-51-0] Hexafluorenium bromide [317-52-2]e Isopropamide iodide [71-81-8] Mepenzolate bromide [76-90-4] Methantheline bromide [53-46-3] Methscopolamine bromide [155-41-9] Methylbenzethonium chloride [25155-18-4] Metocurine iodide [7601-55-0]e Piproctanyl bromide [56717-11-4]g Propantheline bromide [50-34-0] (213) Succinylcholine chloride [71-27-2] Tubocurarine chloride pentahydrate [41354-45-4] (205)f
35D 347A
I(1)678C I(1)1322A, N(1)1122D
FZ9800000, USP BO3150000 USP
409A
I(1)588C, N(1)496B
680B
I(1)773D, N(1)649C
BP3136000, USP USP GA0875000, USP
876C
I(1)395D, N(1)347D
KH2975000, USP
TN5075000, USP USP UY4455000, USP BQ8225000, USP USP USP USP YM3675000, USP 2296A
CP1300000, USP USP TN4426000 USP
3556D
GA2360000, USP YO5100000, USP
Quaternary N attached to one aromatic carbon and three saturated aliphatic carbons USP Demecarium bromide [56-94-0]e Dimethylethyl(3-hydroxyphenyl)USP ammonium chloride [116-38-1] Neostigmine bromide [114-80-7] 2528B BR3150000, USP (212) a Nomenclature may vary from source to source. See also Reference 69. b Entry number in Reference 70. c Codes beginning with I and N denote FTIR spectra in Reference 71 and NMR spectra in Reference 72, respectively. d A code of two letters followed by seven digits is a reference to RTECS of NIOSH/OSHA. Standard samples are
commercially available for compounds with reference to USP protocols74 . e The compound has two or more quaternary ammonium groups of the same type. f The compound has several types of quaternary ammonium and amino functional group. g A pesticide, see Reference 75.
1116
Jacob Zabicky and Shmuel Bittner
A. Chromatography
A method for extraction, purification and preconcentration of dialkyldimethylammonium compounds and other detergents before determining their concentration in sewage water and activated sludge was described. It consists of a series of LLE and LC operations, the details of which are dependent of the original matrix, and end analysis was by HPLC-ELCD406 . A general approach to the analysis of aqueous solutions of quaternary ammonium compounds containing large alkyl groups consists of extracting with an organic solvent, applying a separation method and determining the specific components with an adequate sensor. Sometimes an anionic reagent, for example a chromophore, is added to the aqueous medium and the ammonium cation becomes paired to it in the extraction. This approach was used for the determination of quaternary ammonium compounds present in milk, after extraction by the Mojonnier method for fat in milk, RP-LC and detection with diode array at 217 280 nm407 . An interlaboratory study was carried out for the determination of di(hardened tallow)dimethylammonium surfactants in sludges, sediments, soil and aqueous environmental samples, down to ppb concentrations. The method consisted of HPLC-ELCD; LOD in environmental liquids and solids 2.5 mg/L and 0.5 mg/g, respectively, intralaboratory RSD 7% and recovery 90%. The method is highly specific as opposed to the nonspecific colorimetric one based on ion pairing to disulfine blue (198). The method can be extended to other surfactants408 . The various homologues of benzalkonium chloride (197b) in ophthalmic and nasal preparations can be determined by RP-HPLC on a C8 column and UVD with a diode array, measuring at 260 nm409 . The HPLC-UVD procedure is quite simple and adequate for such preparations, and does not suffer from common interferences; recovery of 100.2 š 1.2% n D 10410 412 . A fast FIA-based spectrophotometric method was proposed for determination of benzalkonium chloride (197b) and N-cetylpyridinium chloride, consisting of ion-pair extraction and association of the cations with the anion of tetrabromophenolphthalein ethyl ester (199). The interference caused by ordinary amines on association with 199 disappears on heating to 45 ° C, when the color of these associates fades away413 . The associates of 199 with berberine (200) and benzethonium (201) at pH 11 have a blue color. This was applied to the determination of these quaternary bases, measuring at 610 nm, batchwise or in an FIA system414 . A screening method for the presence of ditallowdimethylammonium ions in environmental waters consists of SPE, normal HPLC and post-column pairing with the fluorescent anion 9,10-dimethoxyanthracene-2-sulfonate (202) (ex 384 nm, fl 452 nm); LOQ 5 mg/L with 21 š 3% recovery415 . A special FIA system was designed for determination of quaternary ammonium compounds, in which segments of solution containing the quaternary ammonium cation paired with a chromophoric anion are alternated with a segment of insoluble solvent. The ion pair becomes adsorbed and preconcentrated on a part of the conduit loaded with immobilized adsorbent, and it is subsequently desorbed by extraction with the organic solvent and measured in a suitable detector. LOD < 107 M for tetrabutyl ammonium paired with bromothymol blue (203)416 . Samples containing quaternary ammonium compounds with a wide range of molecular weights gave unsatisfactory results by HPLC coupled with various detectors (RID, ELCD, UVD). In such cases evaporative light scattering (ELS) may be of advantage. This consists of nebulizing the effluent of the LC column, drying the solvent and carrying the cloud of fine solid particles past a light source. The light scattered by the cloud is detected with a photomultiplier. The method was applied for determination of low levels of alkyltrimethylammonium and methyltrialkylammonium in dialkyldimethylammonium products, using a bonded polyphenol silica gel column with gradient elution417 .
24. Analytical aspects
1117 Br
+
Et2 N
NEt2
SO3
Br −
O
O
Br
Br
−
CO2 Et
HO SO3
−
(198)
(199) O O
+
N
MeO MeO
(200) Me Me
Me
Me +
OCH2 CH2 OCH2 CH2 N CH2 Ph
CCH2 C Me
Me
Me (201)
OMe
Pr-i SO3
−
Br Me
O
OH
Pr-i
Br OMe
(202)
Me
SO3
(203)
−
1118
Jacob Zabicky and Shmuel Bittner
The use of ion pairing agents, such as sodium benzenesulfonate, may be helpful in the analysis of complex mixtures of quaternary ammonium compounds, as they modify their retention times418 . The use of suppressors in ion chromatography of quaternary ammonium compounds can be of advantage. These are ion exchange membranes that introduce hydroxide ions instead of the counterion present in the analyte. This simplifies the mixture and enhances the electrolytic conductivity of the sample. The effluent of the suppressor may be nebulized and subjected to field-assisted evaporation, yielding a cloud of ions suspended in the gas phase, which can be introduced into an MS analyzer designed for work at atmospheric pressure. Both the molecular weight and the structure of the quaternary cations can be determined by this method419 . A TLC method for determination of quaternary ammonium antiseptics was proposed, using silanized silica plates in combination with triiodide ions and UVV densitometry at 400 nm. The method was applied to cetylpyridinium chloride, cetrimide (197c) and the isomers of benzalkonium chloride (197b)420 . The determination of alkyl and alkylbenzyl quaternary ammonium compounds may be complicated by the polarity of the compound, its tendency to form micelles when the alkyl groups have 12 or more carbon atoms and lack of chromophores. Addition of tetrahydrofuran as organic modifier to the solvent precluded micelle formation and allowed the separation of a mixture of alkylbenzyl and alkylbenzylethyl quaternary ammonium compounds by CZE. Indirect determination of these compounds is achieved on addition of cationic chromophores to the buffer, using a standard UVD421 . The indirect methods of detection for CE have been reviewed422 . B. Miscellaneous Methods
Cetylpyridinium chloride, cetrimide (197c) and benzalkonium chloride (197b) were determined at 534 nm by ion-pair formation with eosin Y (204) in the presence of Triton X-100. Standard curves were linear over the ranges 0.2 3.0, 0.3 3.0 and 0.7 15.0 mg/L, respectively423 . The extraction behavior of quaternary ammonium cations (197) paired with bromophenol blue (157a) was studied for various surfactants. Thus, the ion pairs formed with 197 possessing either small or large carbon chains at high concentration of 157a, after addition of one proton, gave yellow chloroform extracts of 1:1 composition. At high concentrations of 157a one ammonium cation became associated with two molecules of the dye and the extract had a more intense color, that could be measured with higher sensitivity424 .
Br O
Br O
OH
Br
Br CO2 −
(204)
24. Analytical aspects
1119
Alternatively, cetrimide (197c) and cetylpyridinium chloride were determined in industrial and consumer products, by indirect adsorptive stripping voltametry on a dropping mercury electrode425 . A rapid method for benzalkonium chloride (197b) in pharmaceutical preparations was based on LLE of the picrate into chloroform in an FIA system and determination of the anion426 . Development of ion selective electrodes for various muscle relaxation drugs was investigated. Thus, tubocurarine (205), pancuronium (206), gallamine (207) and succinylcholine (208), paired with either tetraphenylborate (209) or dipicrylamine (210) anions, were dispersed in a poly(vinyl chloride) membrane adhered to a Ag/AgCl electrode; LOD was ca 106 M at physiological pH values. Electrodes containing the 205 cation or the 210 anion were sensitive to pH, due to the presence of amine moieties capable of attaching or detaching protons, while the others could be used over a wide pH range. The response was linear over 2 3 orders of magnitude. Selectivity varied according to the electrode and the analyte; for example, the electrode containing pancuronium tetraphenylborate (206 paired with 209) had selectivity 100.3 towards 205 and 101.8 towards 207427 . OMe
HO Me
Me N+
O
HN+
HO
Me
O MeO (205) Me
OAc Me
Me
N+
Me
N+
AcO
H (206) +
OCH2 CH2 N Et3 +
+
Et3 N CH2 CH2 O
OCH2 CH2 N Et3
(207)
1120
Jacob Zabicky and Shmuel Bittner CO2 CH2 CH2 N+ Me3
CO2 CH2 CH2 N+ Me3
Ph4 B−
(208)
(209) NO2
NO2 N−
O2 N NO2
NO2
NO2
(210)
A fast and accurate screening test was proposed for nine quaternary ammonium drugs in urine, including pancuronium (206), ambenonium (211), benzethonium (201), neostigmine (212) and propantheline (213). The drugs were extracted as the triodide (I3 ) into dichloromethane and analyzed by direct inlet EI-MS; LOD was 20 150 mg/L for all the analytes428 . Analysis of the neuromuscular blocking agents pancuronium bromide (206) and vecuronium bromide (214) in plasma or urine was performed by CI-MS, placing samples of an extract on the moving belt and monitoring the single metastable transition corresponding to elimination of acetic acid from the m/z 543 ion. The method is sensitive to concentrations below 5 mg/L429 . O
Cl
O
CH2 N+ (Et)2 CH2 CH2 NH
Cl
NHCH2 CH2 N+ (Et)2 CH2
(211) i-Pr
N+ Me3
CO2 CH2 CH2 N+
H
Me
i-Pr Me2 NCO2
O (212)
(213)
The induced circular dichroism and Cotton effect have been investigated for quaternary ammonium ions with N anchored on an asymmetric C, when hosted in calix[n]arene molecules (215, n D 4, 6, 8)430 .
24. Analytical aspects
1121
OAc Me
N
+ −
Me Br
Me
N
AcO (214) Field desorption MS proved to be the most effective MS technique for the detection and determination of bis(quaternary ammonium) molecules, such as the antibiotic drug ethonium (216)431,432 .
OH CH2
n SO3 Na (215)
n-C10 H21O2 CCH2
Me
Me
+
+
Me
Me
N CH2 CH2 N
CH2 CO2 C10 H21 -n
(216)
The critical concentration for micelle formation (CMC) has been determined by various methods, including the use of membrane electrodes that are selective to specific ionic surfactants. Unfortunately, it is difficult to find materials suitable for producing the selective membranes. An alternative method is based on the drastic change in the mobility of the species occurring on micelle formation. This affects the liquid junction potential generated at the interface between two solutions of different concentration. The method was applied for determination of the CMC of alkylammonium nitrates of various chain lengths433 . The structure of the air water interface layer of an aqueous solution of C18 H37 NMe3 Br, at the CMC (3.1 ð 104 M at 33 ° C), was investigated by surface tension and neutron reflectivity. The possible sources of systematic error in the neutron reflectivity measurements were taken into account for the improvement of analysis434 . The effect of various factors on the aggregation number N of alkyltrimethylammonium micells was studied by small-angle neutron scattering. Thus, N was found to increase with concentration and chain length of the alkyl group, and to vary as follows for the various counter ions: 435 OH − Cl < MeSO4 < Br < NO3 . The shape and thickness of the monolayer of cetrimide (197c) formed at the air water interface was determined by neutron reflection. The total thickness of the monolayer was estimated to be 2.1 š 0.2 nm, of which 1.0 nm is immersed in water; six water molecules are associated with each molecule of surfactant436 . Similar studies were performed for various C10 to C18 alkyltrimethylammonium surfactants. Interpretation of the neutron reflection results included an estimate
1122
Jacob Zabicky and Shmuel Bittner
of the molecular cross-section at the air liquid interface, surface roughness, molecular shape and chain orientation437 . The hydration numbers N of the quaternary ammonium alkanesulfonates (217) and alkylidene-˛,ω-disulfonates (218) were determined from the melting points of their saturated aqueous solutions. Both the N values and the melting poins were fairly high (217: N ³ 37, mp 13 19 ° C; 218a: N ³ 52, mp 1 10 ° C; 218b: N ³ 76, mp 13 18 ° C). The water molecules probably assume a clathrate structure438 . [(i-C5 H11 )4 NC ][n-Cx H2xC1 SO3 ] xD1 8 (217)
[R4 NC ]2 [ O3 SCx H2x SO3 ] x D 2 5; (a) R = n-Bu; (b) R = i-C5 H11 (218)
The apparent standard rate constant ks for the transfer of tertiary and quaternary alkylammonium ions between water and nitrobenzene increased slightly when the ionic radius was increased from Me3 HNC to Et4 NC and then it decreased with further increase of the ionic radius until Pr4 NC . The dependence of ks on the ionic radius suggests that with small ions the processes of desolvation and resolvation are involved in the ratedetermining step, while the effect of hydrodynamic drag is the prevalent one with the larger ions439 . The stability of the gel phase and the transitions of coagel and gel phases to liquid crystal in the dioctadecyldimethylammonium bromide water system were determined by differential scanning calorimetry (DSC)440 . VI. NITRO COMPOUNDS A. General
The present section is organized following roughly the nature of the structural frame supporting the nitro groups (arene, hetaryl or alkyl C, N and O atoms) and the presence of other functional groups that may contribute additional analytical methods (phenols, anilines, etc.). Nitro compounds are important intermediates and end products of the chemical industry with a wide range of applications in organic synthesis, manufacturing industries, medicine, agriculture and engineering (civil and military). Table 5 lists nitro TABLE 5. Examples of environmental, occupational and quality control protocols for industrial nitro compounds Compound and CAS registry number a
Safetyb
Spectrac
Nitro group attached to saturated aliphatic carbon 558B I(1)403C, N(1)355A 2-Bromo-2-nitro-propane1,3-diol [52-51-7]g Chloropicrin [76-06-2]g Nitroethane [79-24-3] 2571D I(3)482A, N(1)352C Nitromethane [75-52-5] 2576D I(3)481C, N(1)351D 1-Nitropropane [108-03-2] 2593D I(3)482B Tris(hydroxymethyl)nitro3532C I(1)403A, N(1)354D methane [126-11-4] Nitro group attached to carbon carbon double bond Metronidazole [443-48-1] (268a) Nitrofurantoin [67-20-9] (263)
2467A 2574C
I(2)619B, N(2)490C
Various protocolsd
TY3385000 PB6300000 KI5600000 PA9800000 TZ5075000 TY7350000
NI5600000, USP MU2800000, USP
24. Analytical aspects
1123
TABLE 5. (continued ) Compound and CAS registry number a
Safetyb
Nitrofurazone [59-87-0] (261) Nitromersol [133-58-4]e
2573D
Nitro group attached to aromatic carbon Acifluorfen [50594-66-6]g Aclonifen [74070-46-5]g Benfluralin [1861-40-1]e,g Bifenox [12680-11-4]g Bromethaline [63333-35-7]e,g Bromofenixim [13181-17-4]e,g Butralin [33629-47-9]e,g 2-s-Butyl-4,6-dinitrophenol [88-85-7]e,g Chloramphenicol [56-75-7] 722C Chlomethoxyfen [32861-85-1]g Chlornitrofen [1836-77-7]g 1-Chloro-2,4-dinitrobenzene 769A [97-00-7]e 2-Chloro-4-nitroaniline 815D [121-87-9] 4-Chloro-2-nitroaniline [89-63-4] 816B 1-Chloro-2-nitrobenzene 818D [88-73-3] 2,6-Dichloro-4-nitroaniline [99-30-9]g 1,3-Dimethyl-2-nitrobenzene 2609B [81-20-9] Dinitramine [29091-05-2]e,g 1,2-Dinitrobenzene [528-29-0]e 1430C 1,3-Dinitrobenzene [99-65-0]e 1430D 1431B 1,4-Dinitrobenzene [100-25-4]e 4,6-Dinitro-o-cresol 1436C [534-52-1]e,g e 2,4-Dinitrophenol [51-28-5] 1439D 1442C 2,4-Dinitrotoluene [121-14-2]e (220) 2,6-Dinitrotoluene [606-20-2]e 1442D Dodemorph [1593-77-7]g EPN [2104-64-5]g Ethalfluralin [55283-68-6]e,g Fluazinam [79622-59-6]e,g Fluoroglycofen [77501-60-1]g Isopropalin [33820-53-0]e,g 2-Methyl-5-nitroaniline 2388C [99-55-8] 4-Methyl-2-nitrophenol 2394B [119-33-5] Niclosamide [50-65-7]g Nifedipine [21829-25-4] 5-Nitroacenaphthene [602-87-9] (235)
Spectrac
Various protocolsd LT7700000, USP USP
EPA
SJ9800000 I(2)362D, N(2)340B
AB6825000, USP
I(3)1212D, N(1)1173D
CZ0525000
I(3)1365D, N(1)1168D
BX1400000
I(3)1211A, N(1)1169A I(3)1183D, N(1)1133B
BX1575000 CZ0875000
I(3)1194D, N(1)1146B
ZE4686000, EPA
I(3)1186B, N(1)1135D I(3)1189D, N(1)1139D I(3)1194B, N(1)1146A I(1)1375D, N(1)1182A
CZ7450000, EPA CZ7350000, EPA CZ7525000, EPA GO9625000, EPA
I(1)1370C, N(1)1174C I(3)1211D, N(1)1172B
SL2800000, EPA XT1575000, EPA
I(3)1197D, N(1)1150C
XT1925000, EPA AE0610000Ł TB1925000 XU6200000, EPA
I(1)1364B, N(1)1167C
EPA XU8225000, EPA
I(3)1208A, N(1)1164B
GP2800000 USP AB1060000, MISAf (continued overleaf )
1124
Jacob Zabicky and Shmuel Bittner
TABLE 5. (continued ) Compound and CAS registry number a
Safetyb
2-Nitroaniline [88-74-4] 3-Nitroaniline [99-09-2] 4-Nitroaniline [100-01-6] 2-Nitroanisole [91-23-6] Nitrobenzene [98-95-3] Nitropentachlorobenzene [82-68-8]g 2-Nitrophenol [88-75-5] 4-Nitrophenol [100-02-7] 4-Nitroquinoline N-oxide [56-57-5] 1-Nitro-2,3,5,6-tetrachlorobenzene [117-18-0]g 2-Nitrotoluene [88-72-2] 3-Nitrotoluene [99-08-1] 4-Nitrotoluene [99-99-0] Oryzalin [19044-88-3]e,g Oxamniquine [21738-42-1] Pendimetalin [40487-42-1]e,g Picric acid [88-89-1]e Profluralin [26399-36-0]e,g Tetril [479-45-8]e Trifluralin [1582-09-8]e,g 1,3,5-Trinitrobenzene [99-35-4]e 2,4,6-Trinitrotoluene [118-96-7]e (221) Organic nitrates Erythritol tetranitrate [7297-25-8]e Nitroglycerin [55-63-0] (273)e Pentaerythritol tetranitrate [78-11-5] (274)e Pyroxylin [9004-70-0]e Nitramines HMX [2691-41-0] (275)e RDX [121-82-4] (276)e Tetril [479-45-8]
2549C 2550A 2550C
Spectrac
Various protocolsd
2554A 2695D
I(3)1185C, I(3)1189B, I(3)1193C, I(3)1184C, I(3)1182B, I(1)1382D
N(1)1134D N(1)1139A N(1)1144C N(1)1134C N(1)1131B
BY6650000, EPA BY6825000, EPA BY7000000, EPA BZ8790000 DA6475000, EPA DA6650000, EPA
2581B 2582B 2597B
I(3)1184D, N(1)1134B I(3)1192D, N(1)1144A I(2)919A, N(2)779D
SM2100000, EPA SM2275000, EPA VC2100000, EPA
3248C
I(3)1217D, N(1)1186D
DC1750000
2606B 2606C 2606D
I(3)1182C, N(1)1131C I(3)1186C, N(1)1136A I(3)1190A, N(1)1140A
XT3150000 XT2975000 XT3325000 VC0340000, USP
2836B
I(1)1378D, N(1)1182B
TJ8750000 XU5785000, BY6300000, XU9275000, DC3850000, XU0175000,
EPA EPA EPA EPA EPA
USP QX2100000, USP RZ2620000, USP UX8650000, USP EPA EPA BY6300000, EPA
a Nomenclature may vary from source to source. See also Reference 69. b Entry number in Reference 70. c Codes beginning with I and N denote FTIR spectra in Reference 71, NMR spectra in Reference 72, respectively. d A code of two letters followed by seven digits is a reference to RTECS of NIOSH/OSHA; aŁ denotes a protocol for
a different derivative of the same main compound. Standard samples are commercially available for compounds with reference to protocols of EPA and USP74 . e The compound has two or more nitro groups of the same type. f Included among other pollutants listed by EPA in the Municipal Industrial Strategy for Abatement regulations of the Ontario Ministry of the Environment. g A pesticide, see Reference 75.
24. Analytical aspects
1125
compounds of commercial relevance possessing CNO2 , ONO2 and NNO2 bonds with reference to environmental and occupational protocols. A review appeared on the determination of nitroalkanes, polynitroalkanes, nitroalkenes, aromatic nitro and polynitro compounds, heterocyclic nitro derivatives and inactive compounds after nitration, by polarography, voltammetry and HPLC with electrochemical detection441 . Fluorescent cellulose triacetate membranes were prepared by incorporation of pyrenebutyric acid (219), and were applied to in situ detection of ground water contamination by explosives, based on fluorescence quenching by the nitro groups; LOD 2 mg/L of DNT (220) and TNT (221) and 10 mg/L for RDX (276); the response follows the Stern Volmer law for DNT and TNT442 . CH2 CH2 CH2 CO2 H Me
Me O2 N
(219)
NO2
O2 N
NO2
NO2
(220)
(221)
The nitrogen camera is an instrument based on detection of -rays in the multiscalar mode, after irradiation of a target pixel by a beam from a 50 MeV electron racetrak microtron. An image consisting of 180 2 ð 2 cm2 pixels can be produced in about 7 s. This technique is capable of imaging nitrogen concentrations with surface densities and amounts typical of concealed conventional explosives. The sole interfering signal from 13 C can be disentangled443 . A novel technique for sensing trace vapors of nitro compounds is based on photolysis of the target molecule using a laser operating at 226 nm. The same beam can be used to detect the characteristic NO fragment formed from a rapid predissociation of NO2 , by resonanceenchanced multiphoton ionization and by LIF using the A2 C X2 (0,0) transition. The analytical utility of this technique was demonstrated on a number of compounds, including TNT (221), RDX (276), dimethylnitramine, nitromethane and nitrobenzene, employing molecular beam sampling444 . B. Aromatic Nitro Compounds
1. General
A comparison of active (using pumps) and passive (relying on diffusion) sampling techniques for the determination of nitrobenzene, benzene and aniline in air was mentioned in Section IV.A77 . Several LLE methods for nitroaromatic compounds dissolved in water were evaluated. High recoveries were achieved with discontinuous or continuous extraction with dichloromethane, adsorption on a 1:1:1 mixture of Amberlite XAD-2, -4 and -8 resins and elution with dichloromethane445 . Polynitroaromatic compounds are used as explosives. They are toxic and might cause liver damage, methemoglobinemia and uncoupling of the oxidative phosphorylation process. Trace analyses of polynitroaromatic residues in groundwater, surface water, rainwater
1126
Jacob Zabicky and Shmuel Bittner
runoff, soil and sediments are important because these compounds become absorbed through the skin446 . It is possible to quantify individual nitroaromatic compounds present in commercial nitroglycerine-based explosives without prior separation, by using 500 MHz 1 H NMR. Patterns within the quantitative data provide a good degree of sample batch characterization447 . Mutagenicity tests and gas chromatographic analyses of motor oils exposed to NO2 indicated the presence of many mutagenic nitroaromatic compounds. Comparison of motor oil nitrated with NO2 and used automobile oil show similar behavior448 . A new dual-electrode electrochemical detector for LC was designed utilizing two series of generator/detector electrodes, having a larger electrode area and higher electrolytic efficiency and sensitivity, as compared with the commercial ones. Analytes are reduced at the upstream electrode and the products are then detected by oxidation at the downstream electrode. This eliminates the influence of dissolved oxygen and trace amounts of heavy metals in the mobile phase and sample, and exhaustive removal of dissolved oxygen before injection is not required. The method can be easily automated449 . A semiconductor sensor-based instrument was described for determination of the composition and concentrations of vapors of organic nitro compounds and nitrogen dioxide in the atmosphere. Four organic semiconductor sensors [e.g. aluminum phthalocyanine fluoride (222a)] were tested in conjunction with platinized platinum preconcentrators; sensitivity is to ppm levels of nitrobenzene450 .
N
N
N N
M N
N
N N
(a) M = AlF (b) M = Co (c) M = Fe
N
(222)
LOD and LOQ were measured to assess the sensitivity of the FID, ECD and TSD detectors for GC analysis of various nitroaromatic compounds. A parallel connection of the three detectors at the end of a single narrow-bore capillary column enabled direct comparison of the chromatograms. Structural effects on the response were evaluated and detection mechanisms were discussed. Recommendations were made for identification purposes and for analysis of environmental samples of nitro- and chloro-nitro-benzenes in a wide range of concentrations451 .
24. Analytical aspects
1127
2. Monocyclic arenes
This section also includes nitrated monocyclic arenes with halogen atoms directly attached to the benzene ring. Sampling on Tenax TA followed by thermal desorption and GC affords a simple method for the determination of nitrobenzene in the workplace air. Recoveries were quantitative in the mass range 0.04 10 mg452 . A selective procedure for attomole detection of nitrobenzene and o-nitrotoluene vapors at sub-ppm levels has been developed using resonance-enhanced multiphoton ionization MS. The TOF-MS spectra of these nitroaromatic molecules show a prominent NOC ion signal (m/z 30) together with a characteristic pattern of hydrocarbon fragment ions. In the wavelength range studied, 224 260 nm, generation of NOC is strongly dependent on the laser wavelength, with maximum intensity at 226.3 nm. At this particular wavelength NOC ion signals have been detected with <1 amol (<1018 mol) of nitrobenzene vapor present in the laser beam453 . The same analytes were detected in trace concentrations in gas mixtures at atmospheric pressure in a simple unity-gain ionization chamber. They could be distinguished by observing their different laser-induced MS and the wavelength dependence of their fragmentation454 . Nitrobenzene, 2,4-dinitrotoluene and 2,6-dinitrotoluene were determined in water by GC-EC or GC-CLD thermal energy analyzer (TEA) and by EI-MS, CI-MS and NICIMS455 , after solid-phase microextraction (SPME) with polydimethylsiloxane coated fiber. SPME is a technique to concentrate organic compounds dissolved in an aqueous matrix by adsorption on a solid stationary phase immobilized on a fused silica fiber. The analytes were thermally desorbed directly into the GC injector; LOD was 9 mg/L for nitrobenzene and 15 mg/L for the dinitrotoluenes456 . The recently reviewed EPA method 8330 uses RP-HPLC-UVD for determination of polynitroaromatics and other explosives at ppb concentration levels446 . Very low concentrations of TNT (221), DNT (220) and some nitramines (Section VI.G) in water were determined by isothermal equilibrium adsorption on a porous film, color development with o-toluidine and Griess’ reagent and colorimetric measurements using diffuse reflected light457 . Nitroaromatics and nitramines have been determined in drinking water by GC-ECD, using a DB-1301 wide-bore fused-silica capillary column, at low concentration levels never previously achieved; LOD was 0.003 mg/L for 2,6dinitrotoluene, 0.04 mg/L for DNT and 0.06 mg/L for TNT458 . Mononitrotoluenes, dinitrotoluenes, TNT and nitrotoluidines have been found in concentrations ranging from 0.1 to 20 mg/L in brooks and ponds in former ammunition production areas in Germany. The method consisted of SPE with Amberlite XAD 2/4/8, elution with dichloromethane and RP-HPLC-UVD with a photodiode array at their optimum wavelength; LOD was ca 50 ng/L with 85 105% recoveries, depending on the compound445 . Good separations were achieved with methanol water gradient and a methanol water gradient containing 2% of THF, with different elution orders for nitrated benzenes, nitrated toluenes and nitrated toluidines459 . A method with LOQ at ppt levels was developed based on LLE followed by GC-AFID for the determination of trace concentrations of nitrobenzene, 1-chloro-2-nitrobenzene and synthetic fragrances such as musk xylene (223) and musk ketone (224). The method was applied to study the distribution of these compounds in environmental samples of North Sea waters460 . GC with atomic emission detection (AED) has been successfully applied to the determination of nitro musks in human adipose tissues, at ppb concentration levels. A clean-up procedure for nonpolar substances and element-specific detection with AED enabled for the first time target screening analysis for lipophilic nitro aromatic compounds. The lack of sensitivity of AED was compensated by higher concentrations of the extracts
1128
Jacob Zabicky and Shmuel Bittner Me
Me O2 N
NO2
O2 N
Ac
t-Bu
Me
t-Bu
Me NO2
NO2 (223)
(224)
and injection of larger sample volumes, performed with cold programmed temperature vaporization in the solvent split mode461 . A sensitive ELISA procedure was developed for the determination of TNT (221) and other nitroaromatic compounds. TNT can be detected within the range of 0.02 20 ng/L in water samples462 . A simplified immunofiltration prepacked portable device for field screening tests of TNT in water and soil was also developed. A quantitative color response to concentrations of TNT in the range 1 30 ng/L in water and 50 1000 pg/g in soil was demonstrated463 . A sensitive HPLC method for the determination of 5-(4-nitrophenyl)-2-furoic acid (225), a dantrolene (226) metabolite, in blood plasma and urine was developed464 .
CO2 H
O2 N O (225)
O
NH CH
O2 N
N
N
O O (226)
Adsorptive stripping square-wave polarography and differential-pulse polarography methods were developed for the determination of 4-nitrobiphenyl (227a). The best adsorption conditions on a hanging mercury dropping electrode in aqueous solution with Britton Robinson buffer were pH 3, accumulation potential of 10 mV (vs Ag/AgCl electrode) and accumulation time of 100 s465 . Optimum conditions were found for the determination of 227a by fast scan differential pulse voltammetry at a hanging mercury drop electrode in the concentration range 1 ð 105 to 2 ð 107 M. A further increase in sensitivity was attained by adsorptive accumulation of this substance on the surface of the working electrode466 . The mechanism of the global 4-electron electrochemical reduction of aromatic nitro compounds to hydroxylamines in aqueous medium shown in reaction 37 was investigated by polarography and cyclic voltametry. The nitro group is converted first to a dihydroxylamine, that on dehydration yields a nitroso group; the latter is further reduced to a
24. Analytical aspects
1129
NO2 X (a) X = H; (b) X = 4′-NO2 (227)
hydroxylamino group. The mechanism proposed for the process consists of a 9-membered square scheme involving protonations and electron transfer steps for each one of the equilibria shown in reaction 37467 471 . The electrochemical processes may be complicated to some extent by the presence of other moieties; for example, a nitro group may reductively condense with nearby cyano or ester functions to yield products such as 174 and 175, as discussed in Section IV.H. 2e , 2HC
H2 O
2e , 2HC
ArNO2 ArN(OH)2 ! ArNO ArNHOH
37
3. Polycyclic aromatic hydrocarbons (PAH)
Nitro-substituted PAH have received increased attention as an important class of environmental pollutants. They have been detected in an ample variety of sources, including automobile exhaust fumes, wood and cigarette smoke, kerosene heater flue, emissions of coal-driven power stations and grilled meat. These subjects have been reviewed472,473 . The effect of solvent polarity on the injection conditions for the determination of nitroPAH by capillary GC with splitless injection was investigated; LOD was 129 pg of 2-methyl-1-nitronaphthalene (228), at SNR 2, RSD 1.8 6.7% when measuring by peak area using FID474 . NO2 CH3
(228)
Mutagens in the semivolatile phase of airborne particulate matter of diesel and gasoline engine emissions were investigated using chemical and biological assays. Various modifications of a method for determination of nitro-PAH, such as 1-nitropyrene (229a) and 2-nitrofluorene (230), were described, consisting mainly of a reduction step followed by derivatization and chromatographic end analysis. In one instance the nitro group was reduced to an amino group by Zn or sodium hydrosulfide, derivatized with heptaflourobutyric anhydride and determined by GC-MS. The method was used for air samples collected in workplaces associated with the use of diesel engines, chassis dynamometer studies and others475 . An HPLC-FLD method was developed, including an on-line reduction step for the determination of 229a and its nitroso analog. Chemical reduction on a zinc column was more efficient than electrochemical reduction LOD 20 30 fmol for SNR 3476 . The method was applied to the determination of 229a at low pg levels in a variety of matrices:
1130
Jacob Zabicky and Shmuel Bittner NO2
3
8
X
(a) X = H (b) X = 3-NO2 (c) X = 6-NO2 (d) X = 8-NO2
NO2
6 (229)
(230)
The incubation mixture of a mutagenecity test using Salmonella typhimurium YG1021476 , extracts from diesel particulate emissions477 and leaves of roadside trees478 . Nitropyrenes 229a d found in sooty emissions of diesel and gasoline emissions were determined by HPLC-CLD, after conversion to the corresponding amines 43a d by refluxing samples in the presence of sodium hydrosulfide147 . A sensitive method was developed for determination of nitropyrenes 229a d in airborne particulates and in emission particulates from diesel and gasoline engine vehicles by on-line reduction and RP-HPLC-CLD. Chemiluminescence was according to reaction 24 (Section IV.G) using the oxalate 42. Urban air showed matutine and vespertine peaks; concentrations were higher in autumn and winter than in spring and summer. Mean concentrations of 229a d: 0.70 š 0.28 pmol/m3 ; 2.19 š 0.81 fmol/m3 ; 4.03 š 1.52 fmol/m3 ; 3.63 š 1.40 fmol/m3 , respectively479 481 . Nitro-PAH were determined by capillary GC-MC, after reduction to amines and conversion to pentafluoropropionamides. This made it possible to prove the presence of 229a, 230 and 3-nitrofluoranthene (231a) in most samples of airborne particular matter taken in Upper Silesia482 .
7 X 9
NO2
(a) X = H (b) X = 7-NO2 (c) X = 9-NO2
(231) Nitro-PAH were determined in air particulate matter by RP-HPLC with reductive electrochemical detection; sensitivity of 3 0.3 ng injected483 . 6H-Dibenzo[b,d]pyran-6-one (232a) and its nitro derivatives at positions 2, 3, 4 and 8 (232b e) were characterized by their 1 H-NMR spectra, mass spectra and GC retention indexes, to allow their analysis in ambient samples484 . The 2-nitro isomer (232b) was found to be a significant contributor of ambient air particle and gas-phase mutagenicity, as assayed with a microsuspension modification of the standard Ames Salmonella plate, incorporating test strain Salmonella typhimurium TA98 without activation. Both 232b and 232d were quantified in diesel particulate emissions and in ambient air samples collected in
24. Analytical aspects
1131
2 3 (a) X = Y = H (b) X = 2-Ν Ο2,Y = H (c) X = 3-Ν Ο2,Y = H (d) X = 4-Ν Ο2,Y = H (e) X = H, Y = 8-NO2
X Y O
8 O
(232) southern California and in Washington, DC. It was concluded that nitrodibenzopyranones are formed in the atmosphere485 . A sensitive method for the detection of mutagenic nitroarenes is based on a new strain of Salmonella typhimurium, developed by genetic engineering. Acetyl-CoA:Nhydroxyarylamine O-acetyl transferase is an enzyme involved in the intracellular metabolic activation of arylhydroxylamines derived from mutagenic nitroarenes and aromatic amines. This strain has high O-acetyl transferase activity and was extremely sensitive to the mutagenic action of 229a, 230, 229d, Glu-P-1, 2-aminofluorene (233) and 2-aminoanthracene (105)486 . Biological and chemical assays were recently performed on mutagens in the semivolatile phase of airborne particulate matter of diesel and gasoline engine emission476 . Several new nitroazabenzo[a]pyrenes were detected and found to be mutagenic using Salmonella typhimurium TA98, including 1- and 3-nitro-6-azabenzo[a]pyrenes (234) and their corresponding Noxides. The compounds were detected by HPLC-MS in the semivolatile phase of airborne particulate matter (0.3 1.2 ng/g) and in diesel and gasoline engine emissions (2.2 7.7 ng/g)487 . 1 X 3 NH2
(a) X = 1-NO2 (b) X = 3-NO2
N (233)
(234)
A sensitive umu test system for the detection of mutagenic nitroarenes has been developed, using a new strain of Salmonella typhimurium NM1011 with a high nitroreductase activity. This enables one to monitor the genotoxic activity of various nitroarene compounds by measuring the ˇ-galactosidase activity of the cells. It had nitrofurazone-reductase activity about 3 times higher than the parent strain and was highly sensitive to 1-nitropyrene (229a), 2-nitrofluorene (230), 1-nitronaphthalene, 2nitronaphthalene, m-dinitrobenzene, 4,40 -dinitrobiphenyl (227b), the nitrofluoranthenes 231a c, 5-nitroacenaphthene (235) and 2,4-dinitrotoluene488 . Immunoassay was used for determination of metabolites of nitroarenes and PAH in the urine of occupational patients exposed to diesel exhaust. It was found that the urinary
1132
Jacob Zabicky and Shmuel Bittner
NO2 (235) excretion of metabolites was significantly enhanced in diesel mechanics as compared to that of office clerks489 . The trapping efficiency of solid-phase adsorbents was compared for 4-nitrobiphenyl (227a), 2-nitrofluorene (230) and others. XAD-4 was the best adsorbent for aromatic compounds, followed by supercritical fluid extraction (SFE) with carbon dioxide, resulting in 60 92% recoveries490 . Synthetic hosts with improved binding affinities for nitro substituted PAHs guests were synthesized. The hosts were covalently linked to silica gel (e.g. 236) to produce modified chemically bonded stationary phases. These hosts contain aromatic binding clefts and were used for HPLC analysis of nitro-PAH491 .
N
Me OSi(CH2 )5O
N
Me
N
(236)
The structure of some phenolic metabolites of 3-nitrofluoranthene (231a) and its 2nitro isomer have been analyzed by one-dimensional and two-dimensional 1 H NMR at 500 MHz. Chemical shifts suggest that the nitro group is not strictly coplanar with the aromatic ring system in solution and that metabolism at a distant site can alter the conformation about the CN bond of the nitro group492 .
24. Analytical aspects
1133
4. Phenols
a. HPLC and GC without derivatization. The three mononitrophenols (237) can be determined in distilled and drinking water by HPLC with amperometric detection using a gold electrode493 . p-Nitrophenol (237c) as urinary metabolite was determined by RPHPLC using a C18 column in isocratic mode. The method is rapid, economical and easily automated, and has excellent reproducibility and specificity494 . A similar method was used to analyze 237c and its glucoside conjugates generated in perfused rat liver, bile or blood preparations495 . 237c and its glucurono- or sulfo-conjugates were analyzed by the same technique, using UVD496 . m-Nitrophenol (237b), a metabolite of the anticonvulsant nipecotic acid m-nitrophenyl ester (238) in mouse blood and brain tissue, was determined by HPLC497 . OH
X
CO2
(a) 2-NO2 (b) 3-NO2 (c) 4-NO2
NO2
N H (237)
(238)
p-Nitrophenol, dinitrophenols and nitrocresols in sub-mg/L concentrations were identified in rain water by isocratic HPLC-UVD with photodiode array. The detector allowed identification and determination of individual nitrophenols at their optimum wavelength by comparison with those of reference compounds498 . RP-HPLC and multicomponent UVV spectroscopy were used to analyze mono- and dinitrophenols formed during irradiation of nitrobenzene with 60 Co -rays in aqueous media. Linear multiparametric regression analysis allowed one to calculate the concentrations of nitrobenzene, nitrophenols and dinitrophenols in water, HNO3 and KOH solutions499 . Electrokinetic detection is a technique that uses the charge acquired by a liquid flowing along a solid surface, and is considerably selective towards ionizing solutes. It was applied to determination of nitrophenols eluted from both unmodified and chemically modified silica gel with n-heptane acetone (90:10). The sensitivities are one order of magnitude higher than those attained using photometric detection500 . Nitrophenols in fog and atmospheric particles were determined by GC of the underivatized compounds and their corresponding acetate esters. Four fused-silica columns were used with three alternative detection modes, namely mass-selective detection, nitrogenspecific detection and ECD. GC-ECD of the acetate derivatives gave the best results501 . A capillary GC-UVD method was developed for the determination of small amounts of nitrophenols present in the environment. The method was compared with HPLC-UVD from the point of view of selectivity and sensitivity. LOD for GC were about one-tenth of those for HPLC502 . Nitrocresols in air sample extracts were evaluated by GC using matrix-isolation infrared spectrometry. The IR spectra of the nitrocresols were recorded in argon matrix, xenon matrix, in the vapor phase and in dilute CCl4 . The spectra of the nitrocresols that do not undergo intramolecular hydrogen bonding exhibited split OH stretching bands. Factors that might cause the band splitting are aggregation, solute matrix interactions and isolation of conformers. The presence of the split OH absorption bands did not preclude the use of the same technique to identify several nitrocresols produced by photooxidation of toluene and NOx503 .
1134
Jacob Zabicky and Shmuel Bittner
Nitroxynil (fasciolicide) (239) residues were determined in cow milk by RP-HPLC using dual-electrode coulometric detection; LOD was 0.7 mg/L, average recoveries of 92 97% (n D 5) from milk samples spiked with 0.01 0.1 mg/L of 239504 . 2,6-Di-t-butyl-4-nitrophenol (240), a potentially powerful uncoupler of ATP-generating oxidative phosphorylation, has been physically and spectroscopically characterized using GC-MS, X-ray crystallography (XRD), DSC, TGA, Fourier-transform IR (FTIR) spectrophotometry, UVV spectrophotometry, and 1 H and 13 C FT-NMR505 . A simple and fast method for the growth promoter roxarsone (241) in tissues of swine liver, kidney and muscle involves a microwave assisted LLE followed by HPLC; LOD 0.25 mg/g506 . Another method for 241 is based on LLE followed by RP-HPLC with ICP-MS detection. This was applied to determination of 241 in tissue from chicken fed on a diet supplemented with this compound507 . OH
OH NO2
I
AsO(OH)2 Bu-t
t-Bu
NO2 CN
NO2
OH
(239)
(240)
(241)
b. HPLC and GC with precolumn derivatization. Methylation, acetylation, silylation and dansilation are the commonly used techniques to derivatize nitrophenols. Thus, mononitrophenols and nitrocresols were determined in rain precipitations by GC-NPD and GC-MS, following LLE and methylation with diazomethane508 . A sensitive GC-MS method was developed for the analysis of nitrophenols in polluted waters at 0.1 0.25 mg/L concentration, involving extraction and derivatization509 . Nitrophenolic compounds were analyzed by GC-MS-SIM, after trimethylsilylation by the flash heater derivatization procedure, which is suitable for nitrophenols not easily derivatized by the conventional methods. The method is suitable for identification of complex mixtures and for quantitative analysis in the nanogram range510 . Nitrophenols at sub-ppm levels can be determined after a two-phase dansylation using dansyl chloride (92). LC is carried out with a methanol water gradient followed by photolysis of the eluted derivatives. The strongly quenching electronegative nitrophenol fragments are photochemically removed from the derivatives, while the resulting dansyl hydride and dansyl methoxide products are sensitively detected by peroxy-oxalate chemiluminescence. Chemical excitation is carried out by post-column addition of 2-nitrophenyl oxalate and hydrogen peroxide dissolved in acetonitrile; LOD is ca 0.01 0.1 mg/L511 . c. Miscellaneous methods. Various variables were studied and optimized for the determination of a mixture of nitrophenols 237 by differential pulse voltammetry, using a carbon paste electrode modified with 50% (w/w) of C18 ; LOD was 2 mg/L of 237a, 5 mg/L of 237b and 4.3 mg/L of 237c. The method was applied to samples of a small lake that gathers rain water512 . Simultaneous determination of o- and p-nitrophenol was achieved in a FIA system based on extraction of ion pairs using tetrabutylammonium as counter ion at pH 7.4. Detection was with a diode-array at 260 nm for 237a and 410 nm for 237c; LOD was 0.03 mg/L, RSD 0.15% (n D 8) at 6 mg/L for both isomers; the calibration graphs were
24. Analytical aspects
1135
linear from 0.1 to 12 mg/L513 . An indirect determination of nitrophenols consists of extraction of ionic associates of the analytes with complexes of Cu(II) with bipyridyl (242) or phenanthroline (243), followed by atomic absorption spectroscopy (AAS) determination of Cu. It was possible to determine several tenths to hundredths of ppm of nitrophenols. Extractable associates with these complexes are formed by phenols possessing two substituents or by higher molecular weight phenols such as naphthol or hydroxyquinoline. Monosubstituted phenols fail to form ionic associates of this kind514 .
N
N
N
(242)
N (243)
Analysis of p-nitrophenol in soil can be accomplished by supercritical fluid extraction (SFE) with carbon dioxide, giving recoveries equivalent to LLE with AcOEt. Quantitation of the recovered compounds by ELISA agreed well with the GC analysis. Extraction and analysis by SFE-ELISA results in greater sample throughput allowing for rapid screening of a large number of environmental samples515 . The electrochemical behavior of the components of a commercial plant growth stimulator (Sviton) was studied. This included determination of o-nitrophenol, p-nitrophenol, 2-methoxy-5-nitrophenol and 2,4-dinitrophenol by differential pulse voltammetry at a hanging mercury drop electrode. The optimum conditions were established for their quantitation over the 1 ð 107 to 1 ð 105 M range516 . 5. Aromatic amines
The photometric determination of mixtures of aniline, p-nitroaniline and o-nitroaniline was described. Distribution coefficients and separation efficiency of these compounds by LLE in various solvents were compared517 . Substituted nitroanilines such as 2-chloro-4nitroaniline and 2,4-dinitroaniline are intermediates in the manufacture of the dye D&C Red No. 36 and were identified as impurities by RP-LC518 . A spectrophotometric method was developed for the determination of aniline and m-nitroaniline in a mixture of aniline and nitroaniline isomers by derivatization with 5,7-dichloro-4,6-dinitrobenzofuroxan (244). The relative error of the determination is <5%519 . See also Section IV.D.3.b for similar derivatives. NO2 Cl
N O N
O2 N Cl (244)
Nitrotoluidines and nitrotoluenes, in concentrations ranging from 0.1 to 20 mg/L, have been found in brooks and ponds in former ammunition production areas in Germany, by
1136
Jacob Zabicky and Shmuel Bittner
SPE with Amberlite XAD 2/4/8 mixture, elution with dichloromethane and RP-HPLCUVD with a photodiode-array at their optimum wavelength; LOD is ca 50 ng/L with 85 105% recoveries, depending on the compound445 . 3-Amino-5-nitro-o-toluamide (245) and 5-amino-3-nitro-o-toluamide (246), the principal metabolites in the tissues of chickens fed a diet containing the anticoccidic agent Zoalene (247), were shown to deplete in frozen liver tissues stored up to 1 year at 20 ° C. Both ˛- and ˇ-anomers of the conjugate were observed by LC of tissue extracts520 . CONH2
CONH2 Me
O2 N
NH2 (245)
CONH2 Me
H2 N
NO2
Me
O2 N
(246)
NO2 (247)
p-Nitroaniline has potential application in optical disk coating. Its surface-enhanced Raman scattering properties were recorded and vibrational assignments were made for the molecule in the IR (500 1800 cm1 ) and Raman (200 1800 cm1 ) frequency regions. The Raman enhancement factor was estimated to be of the order of 106 , and the limit of optical detection was estimated to be 30 fg (30 ð 1015 g)521 . The UVV luminescence spectra of p-nitroaniline were analyzed taking into account dipolar interactions and Hbond complexes, conferring on the molecule a twisted conformation in the ground state, due to the rotation of the NH2 group around the CNH2 bond522 . HPLC and GC methods were used for analysis of water-soluble nitro-substituted aromatic sulfonic acids523 . For example, 4-amino-40 -nitrostilbene-2,20 -disulfonic acid (248) HO3 S
H2 N
NO2
SO3 H (248) HO3 S
O2 N
SO3 H (249)
NO2
24. Analytical aspects
1137
4,40 -dinitrostilbene-2,20 -disulfonic
and acid (249) were separated by RP-HPLC on a Bondapak column packed with 10 mm C18 stationary phase. The mobile phase was a 55:45 mixture by volume of 0.15 M aq ammonium sulfate and acetonitrile524 . A general approach to the analysis of multicomponent analytes bearing chromophores was demonstrated with a mixture of nitrophenylhydrazines (250). In a FIA system the mixture was preconcentrated by SPE on C18 bonded silica, followed by desorption with a buffer and detection by UVV on a diode array. The spectrum, resolved for three components, had RSD 1.43% for 11 samples containing 2 ð 105 M of 250c. The method allowed up to 40 samplings per hour527 .
NHNH2 X
(a) X = 2-NO2 (b) X = 4-NO2 (c) X = 2,4-di-NO2
(250)
6. Miscellaneous aromatic compounds
4-Nitrobenzoic acid (251c) was determined in samples containing 2- and 4-nitrotoluene and trinitro-m-cresol (252) as impurities, by peak chromatography on untreated FN-3 paper. The mobile phase was water or water acetone solution. The detection reagent was alizarin Red S (253)525 . An equivalent method was used to determine 3-nitrobenzoic acid (251b) using a lumomagneson solution for the development of the peak526 . OH CO2 H
O2 N X
NO2
(a) 2-NO2 (b) 3-NO2 (c) 4-NO2
Me NO2
(251)
(252) Ο
OH OH
SO3 − Ο (253)
A rapid, sensitive and selective HPLC-UVD method for the determination of the neuroprotectant 1,2,3,4-tetrahydro-2,3-dioxo-6-nitrobenzo[f]quinoxaline-7-sulfonamide (254) in rat plasma has been established528 .
1138
Jacob Zabicky and Shmuel Bittner
O
O
H N
SO2 NH2
N
NO2
N H
N
NMe2
NO2
(254)
(255)
The polarographic behavior of 1-(2-nitrophenyl)-3,3-dimethyltriazene (255) in a mixed aqueous-methanolic solvent was investigated by test polarography, differential pulse polarography and fast scan differential pulse voltammetry at a hanging mercury drop electrode529 . The adsorption behavior of the psychotropic drug flunitrazepam (256) at the hanging mercury drop electrode was studied by staircase voltammetry and by adsorptive stripping differential pulse voltammetry. 256 can be determined down to nanomolar levels by using adsorptive preconcentration prior to the differential pulse voltammetry scan. The method was applied to determination of 256 in human urine530 . Me O
N
Cl O2 N
N
O2 N
N
N
NEt2
F Cl
(256)
NHAc
(257)
Optimal conditions were found for analysis of the azo dye 2,6-dichloro-4-nitro20 -(acetylamino)-40 -(diethylamino)azobenzene (257) by various polarographic reduction methods and a mechanism was proposed for the process531 . A spectrophotometric determination of parathion-methyl (258) in soil and various vegetables is based on reduction of the nitro group to an amino group with zinc/HCl, diazotization and coupling with guaiacol (259) to form a yellow-colored azo dye in alkaline medium532 . OH S
OCH3
NO2
O P
CH3 O
OCH3 (258)
(259)
24. Analytical aspects
1139
C. Nitrofurans
A variety of methods were developed for the identification and determination of the antimicrobial nitrofurans. They include LC, colorimetric and polarographic methods. Nitrofurans could be determined in animal tissues by extraction with acetonitrile, SPE and LC-UVD533 . An LC-UVD method was statistically validated for the determination of nitrofuran drug residues in poultry534 . HPLC methods were modified for the determination of nitrofurans in different tissues535 . A specific and sensitive HPTLC method was developed for the identification and determination of the furazolidone (260), nitrofurazone (261), furaltadone (262) and nitrofurantoin (263) in eggs and milk. The procedure includes extraction of the drug residues with acetonitrile and liquid liquid partitioning for clean-up. The pre-chromatographic photoreaction of the nitrofurans takes place in situ on the HPTLC plate in the presence of pyridine, leading to fluorescent, ionic products536 . See reaction 14 in Section IV.D.3.g for analogous processess of color development. Compounds 260, 261 and 263 were determined in various matrices: In formulations, feed and milk by RP-HPLC-UVD537 or using a high-speed C18 3 ð 3 column538 , and in animal tissues by RP-LC on a ODS Hypersil column539 ; in foods of animal origin by extraction with acetonitrile, followed by TLC or HPLC540 . 260 and 261 were determined in shrimp muscle tissue by LC541 . 263 was determined in plasma of rabbits by RP-HPLC, using acetanilide as internal standard542 . LC was used to determine residues of 261 in chicken raised to maturity on a diet fortified with 0.0055% of this drug543 . A differential pulse polarographic method is described for the determination of 261 in its pharmaceutical formulations using addition of standard544 . Zero-crossing first derivative spectrophotometry was applied to the determination of 263
O2 N
O2 N
CH O
N
N
CH O
O
NNHCONH2
C O (260)
O2 N
(261) N
CH O
N
N
O C O
(262) O O2 N
CH O
N
N
NH C O
(263)
O
1140
Jacob Zabicky and Shmuel Bittner
in tablets545 while for 260, 262 and 263 in formulations and in feeds first and second derivatives of the UVV absorption spectra were used546 . A combination of TLC separation followed by quantitative determination by HPLC of 260 263 and carbadox (264) was developed547 . The simultaneous determination of 260 and nifuroxime (265) in vaginal suppositories by RP-HPLC-UVD was described548 . A simple RP-HPLC-UVD assay has been developed for the determination of 260, 261, 263, 265 and niridazole (266), in pure form and in pharmaceutical preparations, using a Lichrosorb RP-18 column with methanol water buffer pH 3 eluent and detection at 365, 375, 367, 368 and 340 nm, respectively. Recoveries from bulk drugs were quantitative549 . A simple colorimetric method for the determination of nitrazepam (267), 265, 266, 260, 261 and 263 was described, based on the orange to purple discoloration appearing when these nitro compounds react with tetrabutylammonium hydroxide in DMF550 .
O N
O
NH
CH3
N O
O2 N
N
CH
NOH
O
O (264)
(265) H N
O
N O2 N
N
NH O2 N
S O (266)
N Ph (267)
D. Miscellaneous Heterocyclic Compounds
An IR spectrophotometric method (alkali halide matrix) was elaborated for the fast detection and determination of concentration changes of nitroimidazoles, caused by their photolability in the solid state. Even small changes could be directly recognized, based on the appearance of a new band at 1600 1800 cm1 , which is absent in the initial compounds. A decrease in the content of the initial compound could be determined quantitatively by measurement of absorbance at analytical wavelengths, i.e. in the ranges 1665 1430, 1300 1100 and 730 990 cm1 . The method was tested using seven derivatives of 4- and 5-nitroimidazole including compounds applied in therapy, such as metronidazole (268a) and ornidazole (268b)551 . A series of monoclonal antibodies were generated that can bind dimetridazole (269) and other nitroimidazole drugs used in veterinary medicine. An extraction procedure was developed for these nitroimidazoles that is compatible with a competition ELISA method, based on binding of these antibodies to the drugs. As little as 1 ng of 269 could be detected in turkey muscle by this method552 .
24. Analytical aspects
1141
N O2 N
N (a) X = OH (b) X = Cl
Me
N
O2 N
N
CH2 CH2 X
Me
Me
(268)
(269)
An HPLC-UVD method was developed for the determination of the radiosensitizing agent N-(3-nitro-4-quinoline)morpholino-4-carboxamidine (EGIS-4136, 270) in plasma, using an internal standard and measuring at 330 nm. The assay was validated with respect to linearity, sensitivity, accuracy, precision, stability and recovery. The method was applied to pharmacokinetic studies in male rats, monitoring 270 concentrations in the range of 5 10 mg/L553 . NH HN
N
O
NO2 N (270)
3-Nitro-1,2,4-triazole (271) was determined by solvent peak paper chromatography in the presence of impurities554 . The crystallography, morphology, kinetics and mechanism of the thermal decomposition of 3-nitro-1,2,4-triazol-5-one (272) have been studied, applying DTA, DSC, TGA, IR spectroscopy, XRD and hot-stage microscopy. Cleavage of the CNO2 bond with rupture of the adjacent CN bond appears to be the primary step in the thermolysis of 272. The evolved gases were analyzed by IR spectroscopy555 . NO2
NO2 NH
N N NH (271)
O
N NH (272)
E. Aliphatic Compounds
The RP-HPLC retention times of nitroalkanes (e.g. MeNO2 , EtNO2 , n-PrNO2 , i-PrNO2 , c-HexNO2 ), their nitronates and their nitronic acid degradation products (including alkyl oximes, nitrooximes and pseudonitroles) were determined using a Nova-Pak C18 radial column556 . 3-Nitropropanoyl esters of glucose from the roots of Lotus pendunculatus Cav. were determined by analysis of nitrate released on alkaline hydrolysis. This method was validated for quantitation of both total nitro compounds in ethanolic extracts and for individual components from TLC separations557 .
1142
Jacob Zabicky and Shmuel Bittner
Low levels of nitrogen dioxide react with the polyunsaturated fatty acids under anaerobic conditions to give allylic nitro and allylic nitrite derivatives of methyl linoleate and methyl linolenate. These were identified by NICI-MS558 . F. Nitrates
In Table 5 are listed some industrial organic nitrates and protocols containing analytical methods. A method for the spectrophotometric analysis of nitroglycerin (273) in gaseous effluents was developed. The compound is absorbed in an alkaline solution and converted with hydrogen peroxide to nitrite ions. These can be analyzed spectrophotometrically by reacting with a mixture of sulfanylamide (103) and phosphoric acid (diazotization), coupling with N-(1-naphthyl)ethylenediamine (106) and measuring the absorption at 540 nm559 . The determination of nitrite ions is a modification of the Bratton Marshall method (see Section IV.D.3.g). CH2 ONO2 CHONO2 CH2 ONO2 (273)
A rapid and sensitive capillary GC-ECD method was used to evaluate the nitroglycerin (273) content in human blood serum; LOD was 50 ng/L. Significant amounts of the active metabolites 1,2- and 1,3-dinitroglycerine could be demonstrated560 . A major problem in the analysis of 273 and its metabolites is due to adsorption of the nitro compounds on the glassware used during sample preparation or injection. The adsorption problem was overcome by the use of triethylamine, resulting in a simpler sample preparation and accurate results. Coupling this technique to a capillary GC-ECD method gave high precision in the determination of 273 and its metabolites in plasma at low nanomolar level; LOD was ca 0.2 nM in plasma561 . A similar, specific capillary GC-ECD method for the simultaneous determination of 273 and its di- and mononitrate metabolites included an extraction step; LOD was 0.4 mg/L plasma, with recoveries >76% for 273 and the mononitrates and >95% for the dinitrates. The assay was applied to pharmacological studies562 . A combination of FTIR and TGA is very effective for the quantitative and qualitative analysis of gunpowder563 . Four nitrosamines, seven nitramines, three nitroesters and the explosives Semtex 10 and Composition B have been investigated by TGA. Linear dependence was confirmed between the position of the TGA onsets, as defined in the sense of Perkin-Elmer’s TGA7 standard program, and the samples’ weights. The slope of this dependence is closely related to the thermal reactivity and molecular structure. The intercept values of the dependence correlate with the autoignition temperatures and with the critical temperatures of the studied compounds, without any clear influence from molecular structure. Results show that Semtex 10 exhibits approximately the same thermostability as its active component pentaerythrityl tetranitrate (PETN, 274). Results also show that TGA data for Composition B do not correlate with analogous data for pure nitramines564 . G. Nitramines
In Table 5 are listed some industrial nitramines and protocols containing analytical methods. Nitramines are used as explosives and propellants, they are toxic and might cause
24. Analytical aspects
1143
CH2 ONO2 O2 NOCH2
C
CH2 ONO2
CH2 ONO2 (274)
liver damage, methemoglobinemia and uncoupling of the oxidative phosphorylation process. Trace analysis of nitramine residues in groundwater, surface water, rainwater runoff, soil and sediment matrices are important because these compounds become absorbed through the skin446 . Very low concentrations of HMX (275), RDX (276) and some nitroaromatics (see Section VI.A) in water were determined by isothermal equilibrium adsorption, on a porous film, color development with o-toluidine and Griess reagent and colorimetric measurements using diffuse reflected light457 . Nitramines and nitroaromatics have been determined in drinking water, at low concentration levels never previously achieved, by GC-ECD using a DB-1301 wide-bore fused- silica capillary column458 . NO2
O2 N N
N
N
N
O2 N
NO2 N N
NO2
O2 N
N
NO2
(275)
(276)
VI. NITROSO COMPOUNDS A. General
Interest in nitroso compounds as intermediates for organic synthesis has faded due mainly to their potential toxic effects. Table 6, shows that activity in this field is centered mainly on occupational and environmental pollution subjects. An ample review appeared recently on N-nitroso compounds, including chemical, biochemical and analytical aspects566 . B. Nitrosoarenes
A cathodic stripping voltammetric method was developed for the determination of 4nitroso-N,N-diethylaniline (277), using a GCE coated with a cation-exchanger membrane film. The preconcentration step involved a series of electron transfers and dehydration steps by an ECE mechanism, leading to a reduced product that couples with a second molecule of 277 subsequently introduced to the film. This condensation product is reduced at a lower potential than 277. The resulting differential pulse stripping current is directly proportional to the solution concentration over the range 5 810 nM567 .
Et2 N
NO
(277)
1144
Jacob Zabicky and Shmuel Bittner
TABLE 6. Examples of environmental and occupational protocols for nitroso compounds of industrial significance Safetyb
Compound and CAS registry number a N-Nitrosodi-n-butylamine [56375-33-8] N-Nitrosodiethylamine [55-18-5] N-Nitrosodimethylamine [62-75-9] (278a) N-Nitrosodiphenylamine [86-30-6] (278c) N-Nitrosodi-n-propylamine [621-64-7] (278d) N-Nitrosoethylmethylamine [10595-95-6] N-Nitrosomorpholine [59-89-2] N-Nitrosopiperidine [100-75-4] (298) N-Nitrosopyrrolidine [930-55-2] (280)
Spectrac
Various protocolsd EO5730000, EPA IA3500000, EPA IQ0525000, EPA JK0175000, EPA JL9700000, EPA
2599B
2603D
I(3)481B, N(1)355D
KR9200000, EPA QR7525000, EPA TN2100000, EPA UY1575000, EPA
a Nomenclature may vary from source to source. See also Reference 69. b Entry number in Reference 70. c Codes beginning with I and N denote FTIR spectra in Reference 71 and NMR spectra in Reference 72, respectively. d A code of two letters followed by seven digits is a reference to RTECS of NIOSH/OSHA. Standard samples are
commercially available for most compounds with reference to EPA protocols.
The mechanism of electrochemical reduction of nitrosobenzene to phenylhydroxylamine in aqueous medium has been examined in the pH range from 0.4 to 13, by polarographic and cyclic voltametry. The two-electron process has been explained in terms of a nine-membered square scheme involving protonations and electron transfer steps565 . This process is part of the overall reduction of nitrobenzene to phenylhydroxylamine, shown in reaction 37 (Section VI.B.2). Nitrosobenzene undergoes spontaneous reaction at pH > 13, yielding azoxybenzene471 . C. Nitrosamines
A review appeared, discussing the determination of nitrosamines in cosmetics and cosmetic raw materials, including analytical procedures and LOD568 . The nitrosamines connected with tobacco are discussed in Section VI.D below. 1. Gas chromatography
Various gas chromatographic techniques combined with plentiful detection methods were used to separate and quantify volatile N-nitrosamines. Preconcentration methods were usually applied for separating these compounds. Thus, a method was developed for determination of N-nitrosodimethylamine (278a) in minced fish or frankfurters, based on SPE followed by GC-CLD-TEA; RSD was 0.56 to 2.25%569 . This method has been adopted by AOAC. A similar GC method using NPD was described for the determination of 278a in fish products570 . Steam distillation can also be used to isolate volatile R N R
NO
(a) R = Me (b) R = CH2 Ph (c) R = Ph (d) R = Pr (278)
S
S Me2 NC
SS (279)
CNMe2
24. Analytical aspects
1145
components and was applied to separate the 278a found as impurity in thiram (279) formulations, followed by SPE and determination by GC-MS-SIM571 . The nitrosamines on the EPA list (see Table 6) were determined in samples of groundwater and drinking water at the sub-ppb level (0.1 ppb). The method consisted of either LLE with methylene chloride or SPE on a series of two adsorbents (C8 and an activated C cartridge), followed by capillary GC-NPD572 . Of all foods, nitrite-cured meats have been investigated most thoroughly for the presence of nitrosamines, many of which are carcinogens. Thus, varying levels (1 48 ppb) of N-nitrosodimethylamine (278a), Nnitrosopyrrolidine (280) and N-nitroso-N-methylaniline (281) were detected in Icelandic smoked mutton using GC-CI-MS. Low levels of N-nitrosothiazolidine (282, 0.6 2.4 ppb) and N-nitrosothiazolidine-4-carboxylic acid (283, 56 475 ppb) were also present. It was suggested that the formation of all the above nitrosoamines can be minimized by changing or modifying the method of smoking573 . S
S CO2 H
Me N
N
NO (280)
NO (281)
N
N
NO
NO
(282)
(283)
A GC-tandem CI-MS method, using a quadrupole ion storage mass spectrometer, has been developed for the determination of N-nitrosodimethylamine (278a) in complex environmental matrices. No interference from chlorobenzene, ethylbenzene and the xylenes was detected; LOD was in the subpicogram range574 . An alternative method for 278a involves preconcentration by SPE, extraction with CH2 Cl2 and GC-MS, using isotope dilution with hexadeuterated 278a. LOD 1.0 ppt in water, accuracy of 6% at 10 ppt575 . 278a was also determined in drinking water and fruit drinks by GC using both TEA and MS-SIM detection; LOD was 15 pg/g in drinking water and 1 pg/g in fruit drinks576 . Volatile nitroso compounds were determined in hams processed in elastic rubber nettings by SPE and GC-CLD577 . By a similar method N-nitrosodibenzylamine (278b), a semivolatile nitrosamine, was determined in these products by SPE followed by GC interfaced to a nitrosamine-specific TEA-CLD detector; the coefficient of variation was 10.6% at the 2.1 ppb level578 . The nitrosamines detected in ham most likely originate from the amine precursors in rubber and from the nitrite commonly used in the meat curing process. A method involving SPE was developed for the determination of ten N-nitroso amino acids in cured meat products. These compounds were derivatized with diazomethane followed by O-acylation of hydroxyl groups with acetic anhydride-pyridine reagent. The methyl esters and their acylated derivatives were separated by GC on a DB-5 fused silica capillary column and quantified with a TEA-CLD specific for the nitric oxide derived from the thermal denitrosation of nitrosamines; recovery exceeded 75% at the 10 ppb level579 . N-Nitrosodiethanolamine (284), N-nitroso-1,3-oxazolidine (285a) and N-nitroso-5methyl-1,3-oxazolidine (285b) were detected in metalworking fluids in Canada, using GC-ECD. 284 was derivatized with trifluoroacetic acid anhydride, while 285a and 285b were converted to their corresponding nitramine analogs by oxidation with pertrifluoroacetic acid before analysis; LOD was 1.2 5 ng580 . A laboratory-assembled supercritical fluid extractor was designed for the efficient recovery of volatile nitrosamines from frankfurters. The nitrosamines were separated and detected using a GC-TEA-CLD. Recovery of 10 volatile aliphatic and alicylic nitrosamines from frankfurters spiked at the 20 ppb level was 84.3 104.8% with RSD 2.34 6.13%581 .
1146
Jacob Zabicky and Shmuel Bittner R O (a) R = H (b) R = Me
N ON
N(CH2 CH2 OH)2
NO (285)
(284)
2. Liquid chromatograpy
Computer simulation was applied for the development and optimization of a gradient chromatography method for the analysis of nitrosamines582 . Interest in the analysis of nonvolatile N-nitrosamines has recently been renewed due to the development of novel interfaces to TEA or CLD after RP-HPLC. An interface was devised, incorporating a thermospray vaporizer, a counter flow gas diffusion cell to reduce the LC effluent to a dry aerosol and a single-stage momentum separator to form a particle beam of the nonvolatile analyte. This interface was used in the HPLC-TEA analysis of the nonvolatile N-nitrosodiethanolamine (284) and 2-ethylhexyl N-nitroso-N-methyl-paminobenzoate (286). These results are comparable to other LC-TEA interfacing methods; however, several advantages are ease of application, ruggedness and MS compatibility. Full scan EI-MS identification of the N-nitrosamine contaminants in cosmetics was used for confirming the TEA detection data583 . Traces of 284 in triethanolamine, up to 10 mg/L, were determined by HPLC-UVD, using a strongly acidic cation exchanger PRPX200 column and aqueous HClO4 as eluent of high optical transparency, measuring at max 235 nm. The method takes advantage of difference in pKa values of the amine matrix and the nitroso impurity584 . Bu
Me N
CO2 CH2 CH Et
ON (286)
Using TEA-CLD it was possible to determine rapidly total N-nitroso compounds and nitrite in fresh human gastric juice; LOD 1.0 pmol, RSD 1 6%585 . Mixtures of volatile and nonvolatile N-nitroso compounds, including N-nitrosodipeptides, were determined by HPLC-TEA, using a water/acetonitrile gradient mobile phase; RSD was 3.0 and 5.1%, for 80 90 ng injections of N-nitrosoproline (287) and N-nitrosotrimethylurea (288a), respectively586 . NO N
CO2 H
R2
R1
N
N
R2
NO
(a) R1 = R2 = Me (b) R1 = Me, Et, n-Bu; R2 = H
O (287)
(288)
A method for analysis of N-nitroso-N-alkylureas (288b) has been developed by forming fluorescent derivatives with sodium sulfide, taurine (77) and o-phthalaldehyde (73)
24. Analytical aspects
1147
and separating by RP-HPLC. The method was applied to the determination of 288b in blood587 . 2-(Hydroxymethyl)-N-nitrosothiazolidine (289) and 2-(hydroxymethyl)-N-nitrosothiazolidine-4-carboxylic acid methyl ester (290) were determined in cured smoked meats by HPLC-TEA588 . NO
NO N
N CH2 OH
CH2 OH
MeO2 C S (290)
S (289)
Various nonvolatile nitrosamines were analyzed using HPLC-UV photolysis-CLD. This was applied for determination of N-nitrosamides in dried squid589 and Nnitrosodiphenylamine (278c) in treated apples590 . An improved HPLC photohydrolysis colorimetry method was validated for twentyeight reference nitrosamines. These were separated by HPLC and photolytically cleaved by UV radiation. The resulting nitric oxide was oxidized and hydrolyzed to nitrite ions, which were derivatized into an azo dye with Griess’ reagent and measured spectrophotometrically. The method was applied to separate and detect hitherto unknown nonvolatile nitrosamines in biological fluids and food extracts591 . Two conformers of N-nitrosoglyphosate (291) were separated by HPLC. NMR, spectrophotometric and electroanalytical measurements indicate that these conformers are always present in equilibrium, with slow interconversion592 . ON
NCH2 CO2 H CH2 PO3 H2 (291)
Microconcentrations of carcinogenic N-nitrosamines were determined in various rubber articles (tubing, stoppers, hoses, seals, etc.) for medical and food uses by extraction followed by HPLC-FLD593 . N-Nitrosodiphenylamine (278c) present in diphenylamine formulations was determined by LC-TEA on a Zorbax CN column594 . Ce(IV) in acidic medium is a suitable post-column reagent in the LC-amperometric determination of nonvolatile nitrosamines such as nitrosourea, nitrosoguanidine, nitrosourethane and nitrosoamino acids. The behavior of the Ce(IV) Ce(III) couple with a rotating disk electrode approaches the operational conditions of a ‘channel thin layer’ cell with solid electrodes, frequently used as detector for LC. Gold was found to be the most suitable electrode. The reaction between Ce(IV) and NO2 , the product of nitrosamine decomposition in warm acidic solution, was considered595 . An improved LC-amperometric determination of nonvolatile nitrosamines was proposed, using an online detector system based on the Ce(IV) reagent in acidic medium. A two-line flow manifold coupled with a flow-through voltammetric detector equipped with twin gold electrodes, for both mono- and biamperometric detection modes, was evaluated. Monoand biamperometric measurements allowed determination of linear dynamic ranges, sensitivities and LOD of nitrite under different experimental conditions of composition, liquid carrier and temperature of the reactor596 . The use of iodide reagent in acidic medium was introduced for the LC-amperometric determination of nonvolatile nitrosamines. A two-line flow-injection manifold was used, coupled with a voltametric flow-through
1148
Jacob Zabicky and Shmuel Bittner
detector. A peak current signal was obtained for the nitrite iodide reaction. The method has high sensitivity and LOD of about 1 ð 108 M, which is better than with the Ce(IV) reagent597 . Optimized conditions were found for the separation of p-substituted N-nitroso-Nmethylanilines (292), using RP-HPLC with a C18 chemically bonded stationary phase. Four detection techniques were studied: Direct UV photometry, polarography on a hanging Hg electrode, anodic voltammetry on a glassy carbon fiber array electrode and indirect anodic voltammetry after photolytic denitrosation of the analytes. UV photometry is the most universal with LOD around 106 M. Polarography exhibits the poorest sensitivity (LOD ca 105 M) but can be used for selective detection of the p-nitro derivative 292g. Direct voltammetric detection is selective for the oxidizable derivatives, and the LOD attained are lower than those obtained by UV photometry for 292f. When the analytes are photolytically denitrosated to yield oxidizable derivatives, the LOD of voltammetric detection of 292a, 292b, 292d and 292g are an order of magnitude lower than those of UV photometry598 .
Me N
X
ON
(a) (b) (c) (d) (e) (f) (g)
X= H X = Me X = OMe X = Cl X = CN X = OH X = NO2
(292)
The diffusion-limited electrochemical oxidation of N-nitrosamines in an aqueous pH 1.5 buffer was demonstrated at a GCE coated with a film of mixed valence ruthenium oxides, stabilized by cyano crosslinks. This electrode was used in a potentiostatic amperometric detector for FIA and HPLC, to allow the determination of representative Nnitrosamines (278a, 278c and 278d); for 278c, LOD was 10 nM and RSD 2% at 0.80 mM (n D 5)599 . 3. Miscellaneous methods
Hexetidine (293) and hexedine (294), common ‘formaldehyde releasing’ antimicrobial agents and drug constituents, can undergo nitrosation in the pH range 1 4.8. The major nitrosamine product, ‘HEXNO’ (295), can be characterized and analyzed using common spectroscopic methods. Rapid formation of 295 from 293 and 294 supports the hypothesis that tertiary geminal diamines produce nitrosamines rapidly, by a mechanism involving cleavage of a nitrosammonium ion with the assistance of the neighboring nitrogen atom600 . A linear correlation was found between the absorbance and the concentration (12.5 100 mg/L) of sixteen antineoplastic nitrosoureas, belonging to 4 distinct chemical classes, in the presence of ceftizoxime (296) in acidic media ( max 500 nm)601 . Sodium iodide in trifluroacetic anhydride reacts with nitrosamines and releases iodine. This was used for selective detection of nitrosamines after TLC separation602,603 . Denitrosation of N-nitrosamines to yield secondary amines affords an alternative way for detecting N-nitrosamines. Treatment with a hydrogen bromide acetic acid mixture and reacting the resulting amines with 4-(2-phthalimidyl)benzoyl chloride (297) gives fluorescent amides. N-Nitrosodialkylamines such as 278a, 278d, 278e, 280 and N-nitrosopiperidine (298) were used as model compounds604 .
24. Analytical aspects Me
1149 Me
NH2
Bu-n
n-Bu CHCH2 n-Bu
N
Bu-n
N
CHCH2
N
N N
Et
CH2 CH Et
CH2 CH
Et
Et (293)
(294) n-Bu CHCH2 N
Et
N
NO
N
Me
NO
Bu-n CH2 CH Et
(295) S
H2 N
O
N
S HN
N OCH3
N O COOH
(296)
O N
COCl N
O (297)
NO (298)
Quantification of total N-nitroso compounds in urine and gastric juice is achieved by combining photolytic denitrosation with TEA. Nitrite interference is effectively eliminated with sulfamic acid (H2 NSO3 H)605 . S-Nitroso derivatives of the biological thiols glutathione, cysteine (115) and homocysteine have been considered as bioactive intermediates in the metabolism of organic nitrates and the endothelium-derived relaxing factor with properties of nitric oxide. A simple, rapid and reproducible method for separating these thiols from their
1150
Jacob Zabicky and Shmuel Bittner
S-nitrosated and disulfide derivatives using CZE was developed. S-Nitroso thiols were selectively detected at 320 nm606 . D. Tobacco
Tobacco smoke and N-nitrosation are the focus of intense research activity. Workers in the field use the following concepts: Tobacco-specific N-nitrosamines (TSNA); mainstream tobacco smoke (MSTS), smoke inhaled in a puff; sidestream tobacco smoke (SSTS), smoke evolved by smoldering cigarettes between puffs; nitroso organic compounds (NOC), referring especially to N-nitrosamines; volatile NOC (VNOC) and N-nitroso amino acids (NAA). Nicotine and the minor tobacco alkaloids yield TSNA during tobacco processing and smoking607,608 . TSNA increase cancer risk in the upper digestive tract of tobacco chewers and in the lung of smokers, especially pulmonary adenocarcinoma609 . Chemical analysis led to the identification of seven TSNA in smokeless tobacco (25 mg/g) and in MSTS of cigarettes (1.3 mg TSNA/cigarette). Indoor air polluted by tobacco smoke may contain up to 24 pg TSNA/L. The three TSNA N0 -nitrosonornicotine (299), 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (300) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (301) are powerful carcinogens for mice, rats and hamsters. Studies revealed also artifactual formation of VNOC and TSNA during trapping of MSTS and SSTS by the method of Hoffman610 . Comparative analysis of N-nitrosamines in smoke from cigarettes that heat but do not burn (the test cigarette) and in various reference cigarettes was performed. Concentrations of both VNOC and TSNA in both MSTS and SSTS from the test cigarette were substantially lower than in the reference cigarettes611 . An experiment was carried out in which five male nonsmokers were exposed to SSTS generated by a machine smoking reference cigarettes, for 180 minutes, on two occasions six months apart. Twenty-four- hour urine samples were collected before and after exposure. The urine samples were analyzed for 301 and its glucuronide, which are metabolites of the powerful lung carcinogen 300. The urinary excretion of the metabolites increased significantly after exposure to SSTS in all the men. It was concluded that nonsmokers exposed to SSTS take up and metabolize a lung carcinogen, providing experimental support for the contention that environmental tobacco smoke may cause lung cancer612 . N
N NO
NO
N N O (299)
CH3 (300)
N NO N OH
CH3 (301)
24. Analytical aspects
1151
The carcinogenic activity of snuff and other smokeless tobacco products is also attributed to the presence of VNOC and especially to TSNA. The effects of aging and storage on the levels of TSNA, NAA and VNOC in commercial moist snuff was studied. VNOC were analyzed by the method of Brunnemann613,614 , consisting of extraction with citrate buffer containing ascorbic acid, LLE and GC-TEA. NAA and TSNA were similarly separated and derivatized with bis(trimethylsily)trifluoroacetamide (24). The silylated compounds were analyzed by GC-TEA and GC-EI-MS. It was found that none of these compounds increased significantly during storage at 4 ° C. However, at ambient room temperature and at 37 ° C, the levels of NOC and nitrite of the snuff increased significantly after 4 weeks storage. TSNA rose from 6.24 to 18.7 ppm, NAA from 3.13 to 16.3 ppm and VNOC from 0.02 to 0.2 ppm. This study also led to the identification and quantitative determination of 301 in moist snuff614 . A relationship between intragastric N-nitrosation, gastric pH and nitrite was also established. Thus, fasting gastric juice samples were analyzed for total NOC and nitrite concentrations. The results confirmed that both acid-catalyzed and biologically-catalyzed N-nitrosation occur in the human stomach, and that both are markedly affected by factors other than intragastric pH and nitrite concentration615 . A method was developed to assess TSNA in indoor air polluted with tobacco smoke. Collection was followed by enrichment, concentration and desorption, and analysis by capillary GC-TEA. The concentration of N0 -nitrosonornicotine (299) was 0 23 pg/L, that of N0 -nitrosoanatabine (302) was 0 9 pg/L and that of 300 1 29 pg/L. Thus, nonsmokers can be exposed to highly carcinogenic TSNA616 . H
N
N ON (302)
A new approach to the analysis of the carcinogenic TSNA in moist snuff tobacco is based on SFE with methanol-modified carbon dioxide. Extracted TSNA are trapped across a glass cartridge filled with Tenax GR, from which they are subsequently released by thermal desorption and analyzed by capillary GC-TEA; LOD was <2 ng/g. The technique is fast, reproducible, highly selective and sensitive617 . SFE with carbon dioxide was also used in the analysis of TSNA in smokeless tobacco. It revealed the presence of higher levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (300) than had been determined earlier by conventional methods618 . VIII. HYDROXYLAMINES A. Quantitative Analysis
Hydroxylamine and its N-monosubstituted, N,N-disubstituted and O-substituted derivatives were separated by LC using as detector a GCE, modified with a polymeric coating containing cobalt phthalocyanine (222b). The analytes required potentials higher than C1 V for the unmodified GCE vs Ag/AgCl, while the modified electrode gave substantial anodic currents in the C0.25 0.55 V range. Oxidations involved a transfer between 1.2 to 1.6 electrons, depending on the particular hydroxylamine derivative analyzed and the conditions of reaction. The products included oximes, azoxy compounds and dimeric species. The detection could be made selective for hydroxylamine and its N-monosubstituted derivatives by operating at C0.20 V619 .
1152
Jacob Zabicky and Shmuel Bittner
Hydroxylamine, N-methylhydroxylamine and N,N-dimethylhydroxylamine were determined by ion chromatography. Amperometric detection using a GCE showed best sensitivity and selectivity, with injections of nanomole amounts620 . B. Structural Analysis
The conformation energy and inversion barriers around the N(sp3 )O single bond, calculated by ab initio and semiempirical methods, showed a simple twofold character of the conformations, without any appreciable population of the cis conformer. Rotation is generally favored over inversion for hydroxylamine and its methylated derivatives621 . Various authors have conducted calculations on the conformations of hydroxylamine and its N- and O-substituted derivatives. Calicheamicin is a glycosidic antibiotic of very complex structure. Its antitumor activity is due to its capacity of producing an adduct with DNA, followed by breaking-up of the nucleic acid chain and death of the cell. The complexing capacity of calicheamicin is adduced to the shape of the molecule. The contribution of the conformations of the hydroxylamino moiety to the molecular shape was analyzed622 . C. Derivatization
Reaction 38 shows that hydroxylamines can cause amination at allylic positions. Fe(II) phthalocyanine (222c) was the most effective catalyst. Other catalysts and substrates were also investigated623 . Complexes of Mo(VI) were less effective than 222c as catalysts for amination processes of this type624 . PhNH PhNHOH +
Catalyst
Ph
Ph + PhNH2 + PhN (76%)
N(O)Ph
(22%)
(1%)
(38) O-Allylhydroxylamines undergo a selenium-induced cyclization to isoxazolidines, as shown in reaction 39625 . Ph
R R′ NH O
Se+ PhSeSePh, (NH4 )2 S2 O8
R
R′′
R′
NH
R′′
O
(39)
PhSe
R R′ N O
R′′
24. Analytical aspects
1153
IX. AMINO-OXYLS
Bis(trifluoromethyl)amino-oxyl (303) is a relatively stable free radical species that can be scavenged by organic molecules. Due to the reasonable yields of the products, the following reactions may have analytical value, both for tagging organic molecules and for exploring the properties of other amino-oxyls. Reaction 40 illustrates with t-butyl bromide the basic processes undergone by 303 when let to warm up from 196 ° C to room temperature, in the presence of organic compounds. The first step is abstraction of a hydrogen atom yielding the corresponding hydroxylamine (304) and an intermediate free radical (305 for example). The latter may yield an olefin or react with a molecule of the amino-oxyl626 .
(CF3 )2 NO
+
(CH3 )3 CBr
(CF3 )2 NOH
+ [C H2 C(CH3 )2 Br]
(304)
(305)
(303)
(40)
(CF3 )2 NOCH2 CMe2 Br
(CF 3 )2 NO
Me2 C
CH2
(33.5%) In the case of t-butyl acetate, shown in reaction 41, three successive geminal hydrogen abstractions and insertions of 303 take place; a product of reductive dimerization (306) is also formed in small yield626 . (CF3 )2 NOž C CH3 3 COAc ! (CF3 )2 NOH C (CF3 )2 NON(CF3 )2 49%
(303)
(306) 14%
C (CF3 )2 NOCH2 CMe2 OAc C ((CF3 )2 NO)2 CHCMe2 OAc 14% 15%
(41)
C ((CF3 )2 NO)3 CCMe2 OAc 40% The 2:1 adduct 308 obtained from 303 with 2-chloro-2-phenylpropane (reaction 42) is probably derived from the addition of 303 to ˛-methylstyrene (307)626 .
(CF3 )2 NO + (CH3 )2 CCPh (303)
(CF3 )2 NOH + HCl + CH2 (304) 9%
97.5%
(CF3 )2 NO +
MeC
CPhMe
(307) ON(CF3 )2
(42)
CH2
Ph (308) 78% Olefinic compounds such as ˛-pinene (309) and ˇ-pinene (312) undergo hydrogen abstraction followed by rearrangement and amino-oxyl insertion (310, 313) and addition reactions (311, 314, 315), as shown in reactions 43 and 44627 . Other olefinic compounds such as norbornadiene, cyclo-octene and cyclo-octa-1,5-diene gave analogous results628 .
1154
Jacob Zabicky and Shmuel Bittner CH3
CH2 (CF3 )2 NO
(CF3 )2 NO
+
(CF3 )2 NOH +
Me
(304) 37%
Me (309)
(303)
Me Me (310) 66.5% (endo to exo 50:50)
(CF3 )2 NO (CF3 )2 NO
CH3 Me
+
Me (311) 20.5% (various diastereoisomers)
(43) CH2
(CF3 )2 NO
+
CH2ON(CF3 )2
(CF3 )2 NOH +
Me
(304) 21%
Me (312)
(303)
CH2ON(CF3 )2
(CF3 )2 NO +
+
Me Me (313) 48%
CH2ON(CF3 )2
(44)
Me Me
Me
Me
(CF3 )2 NO (314) 10%
(315) 20.5% (two diastereoisomers 59:41)
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Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
25
Environmental aspects of compounds containing nitro, nitroso and amino groups H. K. CHAGGER and A. WILLIAMS Department of Fuel and Energy, University of Leeds, Leeds, LS2 9JT, UK Fax: +44 113 244 0572; e-mail:
[email protected]
I. ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Nitro Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitroso Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Leather and tanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Rubber industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Metal and machining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. ENVIRONMENTAL EXPOSURE TO PREFORMED NITROSAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Sunscreens and Cosmetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Pharmaceutical Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Agricultural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Packing Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Foods and Beverages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Endogenous Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. AMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Hydrazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Azo Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. CONTROL AND LEGISLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I. ABBREVIATIONS
BCG BCNU CCNU
Bacillus Calmette-Guerin bischloroethyl-nitrosourea 1-chloroethyl-3-cyclohexyl-1-nitrosourea
1169
1170 1171 1173 1173 1182 1183 1184 1185 1186 1186 1186 1186 1187 1187 1189 1196 1196 1197 1197 1212
1170 C-PAH DNA EPA HO2 NO2 HNO2 LPS N/C NCO NDBA NDEA NDELA NDMA NDPhA NEMA NHMTCA NHMTHZ NH2 O NHPRO NHPYR Nitro-PAH NMAMBA NMAMPA NMOCA NMOR NMPABOA NMPhA NMPZ NOC NO NO2 NO3 ž NO2 ž N2 O3 NOx N2 O N2 O3 NOCA NPAH NPIP NPRO NPYR NSAR NTCA NTHZ PAH PAC PAN PANH RNO3 VOC
H. K. Chagger and A. Williams C-polyaromatic hydrocarbons deoxyribonucleic acid environmental Protection Agency peroxy nitric acid nitric acid lipopolysaccharide nitrogen/Carbon isocynate radical N-nitrosodibutylamine N-nitrosodiethylamine N-nitrosodiethanolamine N-nitrosodimethylamine N-nitrosodiphenylamine N-nitrosoethylmethylamine N-nitroso-2-hydroxymethylthiazolidine-4-carboxylic acid N-nitroso-2-hydroxymethylthiazolidine oxyamine radical N-nitroso-4-hydroxyproline N-nitroso-3-hydroxypyrrolidine nitro-polyaromatic hydrocarbons N-nitroso-N-(1-methylacetonyl)-3-methylbutylamine N-nitroso-N-(1-methylacetonyl)-2-methylpropylamine N-nitroso-5-methyloxazolidine-carboxylic acid N-nitrosomorpholine 2-ethylhexyl 4-(N,N-dimethylamino) benzoate (Padimate O) N-nitrosomethlyphenylamine N-nitrosomethlyphenylamine N-nitroso compounds nitric oxide nitrogen dioxide nitrate radical nitrite radical nitrogen trioxide mixture of oxides of nitrogen like nitric oxide and nitrogen dioxide nitrous oxide nitrogen pentaoxide N-nitrosooxazolidine-4-carboxylic acid polyaromatic compounds containing nitrogen N-nitrosopiperidine N-nitrosoproline N-nitrosopyrrolidine N-nitrososarcosine N-nitrosothiazolidine-4-carboxylic acid N-nitrosothiazolidine polynuclear aromatic hydrocarbons polynuclear aromatic compounds peroxy acetyl nitrate nitrogen containing polyaromatic hydrocarbons alkyl nitrate volatile organic compounds
25. Environmental aspects of compounds
1171
II. INTRODUCTION
The nitro, amino and nitroso derivatives of organic compounds constitute a large and varied group of compounds which are used widely in industry but can also be formed in the atmosphere by chemical reactions. This series is characterized chemically by substitution of an amino group (NH2 ) or nitro group (NO2 ) for a hydrogen atom of an organic (usually aromatic) compound. Nitroso compounds can be placed into two categories, the N-nitroso and the C-nitroso compounds. The N-nitroso compounds result from typical free radical reactions or by the reaction of secondary amines with nitrous acid. The Cnitroso compounds can be derived from aliphatic compounds by free radical reactions, or from aromatic compounds when, e.g., nitrosation of the aromatic ring of a tertiary amine occurs at either the para or the ortho position. Beside these routes, NOx , which is present in the atmosphere as a result of combustion processes, reacts with volatile organic compounds (VOC) to give rise to various organic NO and NO2 compounds. Ammonia in the atmosphere plays a very minor role, although high levels of ammonia or hydrazine in the work place can produce some very toxic compounds. The nitro compounds which are products of direct nitration can undergo subsequent reduction yielding amines; these amines can be converted into more versatile class of organic compounds as shown in Figure 1. This sequence provides a route to formation of dozens of aromatic compounds. The amino, nitro and nitroso compounds are often used in bulk as intermediates in synthesis of dyes, pharmaceuticals, antioxidants and accelerators for the rubber industry and are also produced during the manufacture of different industrial commodity foods beverages and agricultural products. The nitrosamine production seems to be an unsolved problem, although there has been a reduction in concentration of nitrates in cured meats and other products over the decades. Several new nitrosamines have been identified in tobacco products, while cosmetic and personal care products have been found to be contaminated with nitrosodiethanolamine. Increased use of diesel fuel because of its higher efficiency has led to problems due to emission of high polyaromatic compounds (PAC) which react with either the nitrogen present in the fuel or in the lubricating oil, with NO and NO2 being formed and in term forming nitro-PAH. These nitro-PAH have been found to be even more potent than their parent PAH in terms of mutagenecity and carcinogenecity (Table 1). Legislation and control have been implemented on concentration levels of NOx arising from industries and combustion processes in developed nations (USA, Canada, Europe). Still nitroso compounds are formed invariably as intermediates either during manufacturing cycles or in the atmosphere. Exposure from most compounds occurs during handling of the chemicals, inhalation and ingestion are also becoming prominent routes for exposure. There is sufficient evidence to indicate that the large majority (90%) of these compounds
Sources
Reaction during combustion
Automobiles Combustion processes
Nitro-PAH NPAH C-PAH
Laboratories Industrial processes Atmospheric reactions and transformations
Most of them classified as mutagens and carcinogens Reaction in the atmosphere
FIGURE 1. Formation and reduction of nitro compounds
NOC e.g. NDMA, NDELA, NDEA, NDPA
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H. K. Chagger and A. Williams
TABLE 1. Structure, sources and effects of nitrogen-containing organic compounds1,2 Structure
Sources
Effects
Nitro (NO2 ) Aliphatic (CNO2 ) Examples: Nitromethane, nitroethane, nitropropane etc.
Solvents for cellulose esters, resins, oils, fats, waxes, dyes, vasodilators in medicine, industrial and military explosives
Cause toxic narcosis, liver damage, depressive effect on central nervous system; industrially 30 ppm can cause nausea, vomiting, diarrhea, irritation of the respiratory system, dizziness. Repeated exposure causes cyanosis and may act as potential carcinogens
Nitro-PAH, Nitrophenols
Combustion processes, atmospheric reactions, diesel engines
Mutagenic and carcinogenic
C-nitroso compounds (CNDO)
Combustion products, atmospheric reactions
Mutagenic and carcinogenic
Nitrogen Oxides Nitric oxide (NO)
Fossil flue combustion systems, biomass burning
Cause bronchitis, pneumonia and lung infections, asthma Photochemical smog, acid rain
Amines Hydrazine
Aniline Tobacco plants, polymerization catalysts, pharmaceutical products, corrosion inhibitor in boiler water, propellant fuels
Nitroso (NNDO) (NOC)
Pesticides, industrial waste, drying of foods in combustion gases, e.g. brewing industry, soup mixes, tea, spices, powdered formulations, soy protein isolates, cereal products, dairy products and cured meat products etc. Explosives, dyes, pigments, insecticides, textiles, plastics, resins, elastomers, pharmaceuticals, fuel additives, plant-growth regulators, rubber accelerators and antioxidants Azo dyes, used in textiles, leather, printing, paper making, drugs and food industry
Production of NO2
Some substances were considered to induce cancer of oesophagus, stomach and nasopharynx
Skin irritants, cause cyanosis and methaemoglobinanemia
Mutagenic and carcinogenic
represent a serious health hazard, and are known for their toxic, mutagenic and carcinogenic effects. The simplest of these toxic, compounds are aniline, hydrazine and mononitrobenzene. In most cases the symptoms appear over a period of time usually many years. This causes difficulties in assessing the carcinogenecity of these chemicals and the implication of regulatory activities in order to minimize the exposure to these chemicals. The Occupational Safety and Health Administration in many countries divides these chemicals into three classes, namely potential suspected carcinogens where there is good scientific evidence of human carcinogenesis; suspected carcinogens where there is suggestive evidence of carcinogenecity in man, and experimental carcinogens. Some countries have totally banned the production and use of the first category of these chemicals, and in other cases the production and use are controlled by legislation. A list of some chemical carcinogens is given in Table 2.
25. Environmental aspects of compounds TABLE 2.
Different categories and possible control of chemical
Chemicals
1173 carcinogens3
Control
Human carcinogens 2-Naphthylamine Benzidine 4-Aminobiphenyl 4-Nitrobiphenyl 1-Naphthylamine Acrylonitrile
Suspected human carcinogens 3-Amino-1,2,4-triazole 1,1-Dimethylhydrazine 2-Chloroaniline Methylhydrazine 2-Nitropropane Experimental carcinogens 2-Acetylaminofluorene Diazomethane 4-Dimethylaminoazobenzene Ethyl diazoacetate Ethylenethiourea Ethyl N-nitroso carbamate
Importation and use in manufacture of these are prohibited by legislation, e.g. in the U.K., except if present at less than 1% in another material Use of this is controlled by legislation, e.g. in the U.K. Threshold limit values (TLV) awaiting reassignment when new data becomes available; no exposure permitted Assigned maximum operating levels (TLV) 0.5 ppm (1 mg m3 ) 0.2 ppm (0.35 mg m3 ) 25 ppm (90 mg m3 )
In general carcinogenic activity has also been observed in certain structural classes3 : ž Biological alkylating agents, bis(chloroethyl)amines, ethyleneimines ž Polycyclic hydrocarbons or heterocycles, mono- and di-benzanthracenes, -pyrenes, -acridines ž Aromatic amines, two rings or more, napthylamines, amino- (or nitro-), acetylaminofluoroene ž Nitroso compounds, nitrosoamines, nitrosoamides ž Azo compounds and hydrazines, azo alkanes, azo aromatics, aminoazobenzenes, diazonium salts, diazomethane, hydrazine and its methyl derivatives This review does not deal specifically with all the categories mentioned above, but takes into account compounds which are formed at the work place and result in direct exposure and preformed nitroso compounds. The latter are formed from amines or contain high concentrations of amino compounds. The contamination may arise as a result of contaminated starting material, in particular amines or from the formation of NOC during the manufacturing cycle. III. ENVIRONMENTAL EXPOSURE A. Nitro Compounds
A variety of nitrogen oxides (NOx ) such as nitric oxide (NO) and nitrogen dioxide (NO2 ) as well as nitrous oxide (N2 O) are present in the atmosphere. The sources of these oxides are biological actions and organic decomposition in the soil and in the ocean
1174
H. K. Chagger and A. Williams
(mainly N2 O) or from activities through combustion. The combustion generated NOx mainly consists of NO initially but is rapidly converted into NO2 in the atmosphere. These oxides react with the VOCs in the atmosphere leading to the formation of photochemical oxidants and of smog, when as part of the reaction sequence the hydrocarbon radicals also produce RNO and RNO2 . The major route of formation of these nitro compounds is via the reaction of VOCs with the NOx arising from hot flue gases, such as automobile exhaust gases and gas streams used for drying food stuffs, etc. In these combustion systems the aliphatics can react with nitro compounds or arenes to produce nitro-PAH and nitroarenes. Some of the NOx produced are thus converted into C-nitroso compounds. The interactions and reaction chemistry of these compounds is complex and difficult to interpret. During combustion processes the molecular nitrogen in the combustion air and the fuel nitrogen that may be present in the fuel is converted into nitric oxide and some nitrogen dioxide4 when NO and residual O2 are cooled together. The NO formation is also controlled by (1) thermal NO, (2) prompt NO and (3) N2 O to NO routes5 7 . The amount of prompt NO produced in combustion systems is relatively small compared with the total NOx formation. However, prompt NOx is still formed at low temperatures and is one of the features in producing ultra-low NOx burners. The nitric oxide reacts with other species in the atmosphere to give various other nitrogen oxides, namely NO2 and nitrogen pollutants. Figure 2 shows the nitric oxide cycle resulting in the emission of NOx and pollutants arising from it at atmospheric temperatures8 . Apart from NOx , ammonia also occurs in the atmosphere which is largely formed by the natural ecosystem. In industrial regions it can undergo a series of reactions to produce ammonium sulphate aerosol in presence of sulphuric acid, or alternatively form NH2 , N2 O and NO. These species are responsible for the destruction of ozone in the troposphere9 . NH3 C OH ! NH2 C H2 O NH2 C NO ! N2 O C H2 O NH2 C O3 ! NH2 O C O2 NH2 C NO2 ! N2 O C H2 O NH2 O C NO ! NH2 C NO2 Combustion RNO3
HONO
NO, NO2 HO2NO2
PAN
NO3
Cloud HNO3 VOC
Gas phase reactions Photochemical reactions Gas/surface reactions
FIGURE 2. Nitric oxide cycle and pollutants
Aerosol NO3−
N2O5 Precipitate
25. Environmental aspects of compounds
1175
The NH2 O formed in the series of chain reactions is anticipated to be a short-lived intermediate which could interact with polyaromatic hydrocarbons (PAH) in atmosphere to give nitroarenes or nitro-PAH. A typical fuel combustion process in air produces 50 1000 ppm of NOx in flue gases. The level of NOx occurring during combustion can be reduced considerably by using low or ultra-low NOx burners and such burners have also been produced for food drying. These burners consist of fuel-lean pre-mixed flames burning in a stream of ducted dilutionary air. In such flames, formation of NOx occurs partly via the thermal NOx route and nitrous oxide route. These burners are fuel-lean and hence produce insignificant levels of PAH (0.2 mg/m3 ) and almost no NOx in case of some burners10,11 . Low temperature catalytic combustion of lean natural gas mixtures is another method of eliminating NOx and PAH generated during combustion. Low cost and highly active nickel-cobalt or iron- based catalysts have a great potential in this field12,13 . Application of reburn process, i.e. staging of the fuel to react with NO formed in the flame with hydrocarbon radicals, CHi, and converting it to molecular nitrogen thereby reduce the NOx concentration levels14 . Gas turbines are being used to generate electric power because of their effect on energy conservation and low cost of installation. Gas turbine combustors are now designed to use low NOx burners and typical emissions at full load are around 15 25 ppm only15 . These techniques not only resolve the problem of NOx and PAH, but also that of nitroso compounds which are formed during the combustion process or are formed atmospherically. Besides nitrogen oxides, PAH are also formed due to incomplete combustion or pyrolysis of organic matter in the combustion systems at high temperatures16 19 . Figure 3 0 −1 ammonia log10 p(species containing N)/(atm)
−2 hydrogen cyanide acetonitrile
−3
benzothiazole
−4 propionitrile
−5
CMMO methylamine pyridine benzo(f) quinoline phenanthridine aniline
−6 −7 −8
picoline ethylamine
−9 500
600
700
800
900
T/(K)
FIGURE 3. Variation of nitrogenous species with temperature
1000
1176
H. K. Chagger and A. Williams
illustrates that most nitrogen compounds and nitro-PAH are formed at high temperatures and are produced directly or indirectly during high-temperature combustion processes20 . This raises questions regarding the mode of formation of N-nitroso and C-nitroso compounds, as to whether they are formed in the high combustion region or in the other cooling regions involving reaction products at the same time undergoing a quenching process. Numerous forms of PAH have also been identified in the exhausts from diesel-powered vehicles. Soot generated from combustion processes generally contains about 0.1 mol% of N/C, but the nitrogen content in case of soot deposits in engines is ten times higher than particles found in flames or atmosphere. It was found that the nitrogen-containing PAH (PANH) originated by the reaction of nitrogen oxides (NOx ) with PAH in the hot exhaust gases21 . These PANH can dissociate to give rise to NOx or act as a precursor in the formation of the nitro-PAH which are potent mutagens22 . The unburnt fuel which is between 0.2 1.0% was found to act as a source for the formation of NPAH. Experiments involving the addition of PAH, e.g. pyrene and phenanthrene, to aliphatic fuels was found to increase the emission levels of the PAH and NPAH corresponding to the concentration of its parent PAH. Hence, the variability of PAC components in diesel fuels can significantly affect the PAH concentrations23 . Most commonly found PAH are: naphthalene, fluorene and phenanthrene and their alkyl substituted homologues24 . The PAH are distributed in both the gaseous phase and particle phase in the atmosphere. Some of the two to four ring PAH are present in the gaseous phase depending upon their vapour pressure25,26 . The nitration of the parent aromatic molecule, as a result of either combustion or atmospheric reaction, results in formation of nitro-PAH or nitroarenes27,28 as shown in Figure 4. Combustion emissions from fuel nitrogen and other sources
Low temperature reactions in the atmosphere
Cooling and drying
High temperature chemistry in combustion systems NOx formation
PAH and soot formation C2H2
HCN
NCO
NOx NOx + Food Products Benzene
NHi
NO
NO
NO2
PAH
Atmospheric reactions with PAH in atmosphere
N2O5-NO3-NO2
N2
NOx
PAH + H → PAH∗ + H2
Nitro-PAH
FIGURE 4. Formation of nitro-PAH by association of NOx and PAH compounds
25. Environmental aspects of compounds
1177
Although simpler nitroarenes have been used for decades as industrial chemicals (e.g. nitrobenzene and nitrotolouene) and pharmaceutical chemicals (e.g. nitrofuran), their carcinogenic affects have only come to light in the last two decades. Nitroarenes have also been identified in photocopy toners29,30 , diesel exhaust particles31,32 , kerosene heater emissions33,34 and ambient air. Specific nitroarenes are formed by different mechanisms. Direct combustion appears to emit nitroarenes formed by direct electrophilic nitration (e.g. 1-nitropyrene, 3-nitrofluranthene)35,36 , whereas atmospheric reactions involve multistep reaction of OH radicals in the presence of NOx resulting in different nitroarene isomers. Atmospheric nitroarenes are largely in the vapour phase while the direct nitrated nitroarenes of similar volatility are found in particle extracts distributed between the gas/vapour phase37,38 . Atmospheric reactions
Most of the experimental work on PAH has been conducted on 4 or 6-ring compounds. The PAH undergoes photolysis and reacts with OH and NO3 radicals, N2 O5 and ozone. As the ambient atmosphere contains oxides of nitrogen and OH radicals, it was proposed that the gas-phase reactions of PAH with OH occurred in daytime and with N2 O5 at night. N2 O5 is generated in the atmosphere from the reaction between NO2 with O3 to form NO3 radicals. NO3 then reacts with NO2 to give N2 O5 as shown in reactions 1 and 2. O C NO2 ! NO3
(1)
NO3 C NO2 ! N2 O5
(2)
In the presence of sunlight the NO3 reacts rapidly with NO to yield NO2 and it is photolysed via reactions 3 and 4. NO3 C light ! NO2 C O
(3)
NO3 C light ! NO C O
(4)
Hence, the potential for NO3 and N2 O5 existing in the atmosphere depends upon simultaneous existence of O3 and NO3 in the absence of nitric oxide and sunlight. The reaction mechanism for the formation of a typical PAH is illustrated in Figure 5. The basic steps involve (i) addition of OH at the site of highest electron density, (ii) addition of NO2 to OH-PAH adduct and (iii) loss of water to form nitroarene as shown below in Figure 7. It was suggested that this mechanism could proceed partly or fully in gas phase, followed by condensation of the products, i.e. nitro-PAH on the surface of the particles39 . Nitroarenes were formed under laboratory conditions when PAH reacted with gas-phase OH radical (in presence of NOx ) and N2 O5 40 45 . The atmospheric nitroarene formation rate depends upon the concentration of the individual species N2 O5 NO3 NO2 An analogous reaction sequence occurs when PAH reacts in N2 O5 NO3 NO2 systems46 . Naphthalene reacts with NO3 radical forms NO3 naphthalene adduct, which dissociates or reacts with NO2 to form nitronaphthalene and other products as shown in Figure 6. Table 3 shows the atmospheric lifetime for eleven PAH with respect to gas-phase reaction with OH and NO3 radicals, O3 and N2 O5 . This was calculated from the estimated and calculated rate constants. It is evident that most of the nitroarenes formed under ambient atmospheric conditions were produced by reaction of PAH with OH. The PAH reaction with NO3 radical was also considered as an important step because it resulted in the formation of nitroarenes from the N2 O5 reaction with gas-phase PAH. However, it should be noted that the amount of nitrated (NO2 and NO) compounds in diesel exhaust can be correlated with a number of experimental variables. The key
1178
H. K. Chagger and A. Williams H
OH
H
OH
NO2
H
OH
NO2
H −H2 O
NO2
H OH H OH
NO2
NO2
H
NO2 OH H
−H2 O
FIGURE 5. Gas-phase reactions of PAH with OH radicals and NO2
issue still to be resolved is whether these compounds are formed in the combustion regions (i.e. combustion chambers) or are formed by secondary reaction products in the exhaust soot deposits. Some experimentalist have not found any nitrated products in diesel exhausts48 . However, dinitro compounds like 1,3-dinitropyrene, 1,6-dinitropyrene and 1,8-dinitropyrene have been identified in the diesel exhaust by other authors49 .
25. Environmental aspects of compounds
1179 H
NO3
ONO2
+
H
ONO2 + NO2
(including nitronaphthalenes)
FIGURE 6. Reaction sequence for PAH reaction with N2 O5 NO3 NO2 system TABLE 3. Calculated atmospheric lifetimes of PAH due to gas-phase reactions with OH and NO3 radicals, O3 and N2 O5 47 Lifetime due to reaction with PAH Naphthalene 1-Methylnaphthalene 2-Methylnaphthalene Acenaphthylene Acenapthene Biphenyl Phenanthrene Anthracene Fluoranthene Pyrene Acephenanthrylene
OHa 8.6 3.5 3.6 1.7 1.8 2.1 6.0 1.4 3.7 3.7 1.8
h h h h h days h h h h h
NO3 b
13 min 2.5 h
2.5 h
N2 O5 c
O3 d
83 days 35 days 28 days 21 days >16 yr
>80 days >125 days >40 days ¾43 min >30 days >80 days
64 days 21 days 21 days
>30 days
a For a 12-h daytime OH radical concentration of 1.5 ð 106 molecules cm3 . b For a 12-h nighttime NO radical concentration of 2.4 ð 108 molecules cm3 . 3 c For a 12-h nighttime N O radical concentration of 2.0 ð 1010 molecules cm3 . 2 5 d For a 24-h daytime O radical concentration of 7 ð 1011 molecules cm3 . 3
The soot particles emitted from the diesel and petrol exhaust were found to be very stable over a period of hours. These PAH could undergo nitrosation with nitrogen oxides also produced in the combustion process to give rise to nitroarenes. Diesel particles obtained from a car engine were reacted with N2 O5 and their rate constant was determined. The rate of reaction for the degradation of particulate PAH on atmospheric soot in presence of gas-phase N2 O5 was given by the expression50 : r D kspec [PAH]mass [O] where r is the rate of reaction in moles/unit time and kspec is the specific composite constant unique to the particle size distribution; [PAH]mass denotes the surface coverage and [O] is the concentration (mass/volume) of the gas oxidant (i.e. N2 O5 ). The rate constants for N2 O5 on atmospheric soot particles were found to be in the range from 5 ð 1018 to 3 ð 1018 cm1 molecule1 s1 .
1180
H. K. Chagger and A. Williams
Similarly, the rate constants for gas-phase PAH and N2 O5 were determined from the following expression: rate D kg [N2 O5 ] [PAH] where the rate equals the gas-phase rate constant kg multiplied by the vapour-phase concentrations of [N2 O5 ] and [PAH]. The rate constants reported for N2 O5 with methylnaphthalenes are in the range of 1.4 ð 1017 to 5.7 ð 1017 cm3 molecule1 s1 . It was also estimated that nearly 95% of gaseous PAH would react with N2 O5 to give nitro-PAH. Most PAH are carcinogenic in nature. The biological effects can be put into two categories; effects on health and effects on the ecosystem. Both can be acute or on a long term basis. The different biological responses can be related to each other since the same substance can give rise to several reactions in the organism or in the ecosystem. Nitro-PAH are considered to be even more potent carcinogens than their parent molecules. Hence, nitro-PAH can be classified as possible etiologic agents. Present data do not demonstrate a convincing association between exposure of nitro-PAH found in the petrol and diesel exhaust to that of lung cancer incidence. However, inhalation studies of structures analogous to that of benzo[a]pyrene (1,6-dinitropyrene, 6-nitrochrysene) have shown these to be tumorigenic to rodent lung51 . The structures are shown in Figure 7. However, an epidemilogic study of motor exhaust-related occupation has suggested a possible risk for bladder cancer. Both 2-nitronaphthalene and 4-nitrobiphenyl have been attributed to induce bladder tumours, although bioassay data are limited52 . Application of oxygen enrichers in diesel engines, which are made of an assembly of a large number of hollow fibers, has been shown to emit low levels of soot and NOx . The oxygen enrichers can dissolve oxygen from the atmospheric air and this technique can keep a balance between the air/fuel ratio. The exhaust gas containing the polyaromatics is recycled into the engine and subsequently oxidized into leading to low emissions of soot and NOx . Table 4 gives a list of nitro-PAH arising directly from combustion measured in different cities of the world. This is presented as air concentration and as nitro-PAH levels in soot. Nitrated phenols were identified in fog water in north-eastern Bavaria54 . Phenols are emitted mainly through combustion processes55 or evaporation from the waste water and are very reactive in the atmosphere. The nitrated phenols are formed by atmospheric photochemical reactions of aromatic compounds such as benzene, toluene and cresols with OH-radicals and nitrogen oxides56 59 . Figure 8 shows the structure of nitrophenols identified in the fog. Some of these nitrophenols are included by the Environmental Protection Agency (EPA) list as pollutants, although hardly any data are available regarding their NO2
NO2 1,6-Dinitropyrene
NO2 6-Nitrochrysene
FIGURE 7. Nitroarene structures analogous to that of benzo(a)pyrene
Benzo[a]pyrene
25. Environmental aspects of compounds OH
OH
1181
OH NO2
CH3 NO2 4-Nitrophenol
NO2
NO2
2,4-Dinitrophenol
3-Me-4-NP OH
OH CH3
NO2
H3 C
NO2
NO2 2-Me-4-NP
DNOC
FIGURE 8. Nitrophenols identified in the fog
TABLE 4. Occurrence of nitroarenes53 Chemical (mutagenicity)
Location/Source
3-Nitrotoluene
Ambient air Boise, ID U.S. Diesel particles Ambient air Los Angeles, CA Boise, ID Ambient air Los Angeles, CA Boise, ID Diesel emissions Air particles Tokyo, Japan China Germany
1-Nitronaphthalene
3-Nitrobiphenyl
2-Nitrofluorene
ng/m3 air
mg/g extract from soot 0.1 0.6 0.3 0.7
2 3 0.03 0.4 0.03 0.1 0.6 6.0 71 186 ND 22 0.03 0.7 0.2 5
ND 0.3
9-Nitroanthracene Diesel Ambient air Los Angeles, CA Boise, ID Columbus, OH Outdoors Indoors
5 94 0.05 0.1 0.04 1.5 0.01 0.1 0.04 1.3 (continued overleaf )
1182
H. K. Chagger and A. Williams
TABLE 4. (continued ) Chemical (mutagenicity)
Location/Source
1-Nitropyrene
Diesel particles Gasoline particles Air particles Detroit, MI Tokyo, Japan Boise, ID Los Angeles, CA Columbus, OH Outdoors Indoors Air particles Boise, ID Los Angeles, LA Columbus, OH Outdoors Indoors Air particles Boise, ID Los Angeles, LA Columbus, OH Outdoor Indoors Diesel particles
2-Nitrofluroanthene
3-Nitrofluoranthene
3-Nitrofluoranthene 6-Nitrobenzo(a)pyrene Diesel particles Gasoline particles Air particles Michigan, U.S. 1,3-Dinitropyrene
1,6-Dinitropyrene
1,8-Dinitropyrene
ng/m3 air
mg/g extract from soot 100 200 2.5
0.2 0.6 0.2 1.6 0.06 0.1 0.03 0.04 0.01 0.05 0.005 0.1 0.07 0.2 0.3 0.4 0.03 0.2 0.01 0.2 0.07 0.2 0.3 0.4 0.03 0.2 0.01 0.2 0.9 7.0
ND 50 0.2 33 0.9 2.5 Diesel particles Kerosene heater Air particles Tokyo, Japan Diesel particles Air particles Michigan, U.S.. Tokyo, Japan Diesel particles Air particles Michigan US
0.04 0.3 ND 1.6 0.5 0.005 ND 1.2 0.004 0.05 0.005 0.1
0.1 4.4 0.3 8.7
0.04 3.8
ND 3.4 0.002 0.5
concentrations and fluxes. Nitrophenols have been suggested to be possible contributors to forest decline60 . B. Nitroso Compounds
For the past three decades, active research has been carried out on N-nitroso compounds (NOC) and related compounds. The impact of NOC and nitrogen oxides regarding their effect on human health and safety aspects is well documented in the literature61 63 . Exposure to nitrogenous chemicals, pollutants and their precursors is mainly via ingestion; however, in some cases inhalation is the major route of exposure. The nitroso compounds can be formed by reaction with organic compounds present in the atmosphere and include two categories namely N-nitroso and C-nitroso compounds.
25. Environmental aspects of compounds
1183
The former are formed by the reaction of aromatic amines and NOx in the atmosphere whereas the latter are formed during combustion processes. N-nitroso compounds have been studied extensively and some of them are discussed below. The N-nitroso compounds are substances that have a characteristic linkage of a secondary nitrogen atom to the nitroso group, NDO. These compounds can be formed by interaction of nitrosable substrates with nitrosating agents as illustrated in Figure 9. Nitrosamines, which are the amides of nitrous acid, are more stable and are derived from secondary amines with nitrous acid. N-nitrosamides are substances which have a carbonyl group attached to a nitrogen-bearing NO group, e.g. N-nitrosamides, N-nitrosocarbamates and N-nitrosoureas; see Figure 10. NOC are widely distributed in the human environment and their largest exposures occur in certain work environments. However, very little data are available on the occupational exposure of NOC. The general situation for occupational exposure to NOC is summarized later in Table 5. 1. Leather and tanning
In the leather and tanning industry dimethylamine sulphate is used in depilation processes. Under alkaline conditions, dimethylamine is released into the atmosphere and it reacts with nitrogen oxides produced from exhaust emissions, to give Nitrosable R
Nitrosating agents
R NH
R
NR
HNO2
N2 O3
RONO
M
NO
NOx
O
N
R
Other nitrogen compounds
N
Y
O
N R
R
FIGURE 9. Routes leading to formation of nitrosamines O
O N
R1
N
O N
R2
R1
3
R
N
R1 O
Nitrosamine
N-Nitrosamide
N
R3
N
N O
N-Nitrosourea
R1, R2 = alkyl, aryl; R3 = H, alkyl, aryl
FIGURE 10. Structure of N-nitrosamines and N-nitrosamides
O N R3
R1
N
O O
N-Nitrosocarbamate
R2
1184
H. K. Chagger and A. Williams
N-nitrosodimethylamine (NDMA). N-Nitrosomorpholine (NMOR) is also produced in this process, but the origin of this pollutant is unknown. Samples collected from different tanneries showed airborne nitrosamine contamination ranging from 0.05 47 mg/m3 NDMA (mean 3.4 mg/m3 ) and 0.05 2.0 mg/m3 NMOR (mean 0.2 mg/m3 64 . Studies have indicated the possible risk of nasal cancer to workers exposed to NDMA at a daily exposure level of 440 mg NDMA/person/day and 20 mg NMOR/person/day65 . Animals exposed to long-term inhalation of NDMA were found to have formed malignant tumours of mainly the liver and kidney66 . 2. Rubber industry
The formation of nitroamines occurs due to the use of certain vulcanisation accelerators such as thiurams, dithiocarbamates and sulphenamides. These agents are nitrosated during the vulcanisation process. The origin of the NOC is primarily due to the adsorption of NOx on the large surface of inorganic rubber additives, e.g. zinc oxide and carbon black or nitrosating rubber chemicals. Figure 11 shows the nitrosation reactions of typical accelerators67 . The extent of formation of these NOC depends upon the presence of nitrogen oxides present in the atmosphere during the manufacturing cycle. The major contaminants are NDMA, N-nitrosodiethylamine (NDEA), N-nitrosopyrrolidine (NPYR), NMOR, Nnitrosodiphenylamine (NDPhA), N-nitrosopiperidine (NPIP) and N-nitrosodibutylamine (NDBA)68 . NMOR was found in the hot process areas; NDMA occurred in tube production areas in which NDPhA was being used as retarder and tetramethylthiuram disulphide as an accelerator. Figure 12 shows a proposed reaction scheme of formation of NOC in the rubber industry and subsequent exposure67 . The nitrosamine formation can be controlled by meeting the following regulations69 : ž Block or reduce nitrogen oxide species, have adequate ventilation ž Degrade nitrosamine ž Use amine-free accelerators by changing compounds S
CH3 N
S
C
S
S
CH3
C
N
N
CH3
CH3 S Zn S
CH3 ON
C
NDMA CH3
C4 H9 ON
N
N
NDBA
2
C4 H9
S Zn S
C
ON
N
N
NPIP
2
N S
N
O
ON
N
S
FIGURE 11. Formation of different NOC from their corresponding accelerators
O NMOR
25. Environmental aspects of compounds
1185
Use of amine precursors in industry Process (heat)
Use of NOx -releasing Chemicals
Release of amines
Nitrosamine formation in the product
Nitrosamine formation in the air
Degassing of nitrosamines
Exposure to operators
FIGURE 12. Proposed reaction mechanism of formation and exposure
3. Metal and machining
One of the major pollutants in this industry is N-nitrosodiethanolamine (NDELA) arising from cutting fluids. The simultaneous use of diethanolamine or triethanolamine cutting fluids with nitrite as an anticorrosion (antioxidative) agent in the formulation results in NDELA production. Workers come into direct contact due to inhalation of oil mists as they handle the products directly. The demonstration of dermal penetration of NDELA has been shown in both humans and animals. NDELA in laboratory animals has been shown to induce cancer in different organs like liver, kidneys, nasal cavity and papilloma of trachea70,71 . Workers staying in rooms with 1 mg/m3 revealed two times more DNA damage in mononuclear blood cells than those staying in an environment with less than 50 ng/m3 . However, no significant correlation was obtained between the extent of DNA damage and the extent of skin contact or the concentration of NDELA found in the cutting fluids72 . Table 5 gives the exposure level of different N-nitrosamines analogously arising as pollutants from various chemical industries73 . TABLE 5. Occupational exposure to N-nitroso compounds Industry/occupation Metal working industry Metal foundries (core-making) Leather tanneries Rubber and tyre industry
Chemical industries Rocket fuel industry Dye manufacture Detergents and surfactants Amine and pesticide production Fish processing industry Warehouse and sale rooms (especially for rubber products)
N-Nitrosamine
Exposure levels
N-nitrosodiethanolamine (NDELA) N-nitrosodiethanolamine (NDELA) N-nitrosodimethylamine (NDMA) N-nitrosodiethylamine (NDEA) N-nitrosodimethylamine (NDMA) N-nitrosodimethylamine (NDMA) N-nitrosodiethylamine (NDEA) N-nitrosodibutylamine (NDBA) N-nitrosomorpholine (NMOR) N-nitrosomethlyphenylamine (NMPhA)
>50 >50 >5 >5 >50 >50 >5 >5 >50 >50
N-nitrosodimethylamine (NDMA) N-nitrosodimethylamine (NDMA) N-nitrosodiethylamine (NDEA) N-nitrosodimethylamine (NDMA) N-mononitrosopiperazine (NMPZ) N-nitrosodimethylamine (NDMA) N-nitrosodimethylamine (NDMA) N-nitrosomorpholine (NMOR)
>50 <5 <5 <5 <5 <5 >5 >5
1186
H. K. Chagger and A. Williams IV. ENVIRONMENTAL EXPOSURE TO PREFORMED NITROSAMINES
The presence of non-volatile NOC, i.e. preformed nitrosamines, has been reported in various cosmetics, pharmaceutical products, foods, beverages and dairy products. A. Sunscreens and Cosmetics
Nitrosamine contamination of cosmetic products and toiletries may result through formulation with nitrosamine contaminated amines or via formulation by contact with nitrosating agents or bactericides. Market surveys have detected up to 45 ppm nitrosodiethanolamide and 21 ppm 2-ethylhexyl 4-(N-methyl-N-nitrosamino) benzoate in several sunscreens and cosmetic products. Oxides of nitrogen can also act as potential nitrosating agents in cosmetics. The extent of exposure depends upon the frequency of usage, degree of absorption through the skin and nitrosamine stability on exposure to UV. Products like sunscreens, after being applied to skin, leave a non-aqueous layer as the water from the emulsion evaporates. Oxides of nitrogen can readily be absorbed into a non-polar matrix and nitrosate amines to produce nitrosamines74 . However, the stability of nitrosamine can be questioned as it decomposes in the presence of UV light75 . Hence, more research needs to be carried out where human exposure to NMPABOA and its decomposition in sunlight is concerned, although the carcinogenecity of NMPABOA is uncertain. The products can also undergo nitrosation over a period of time depending on conditions like its storage and temperature. A sunscreen product containing 2-ethylhexyl 4-(N,N-dimethylamino) benzoate (Padimate O) purchased in 1987 was free of nitrosamine contamination. The same product was found to contain 8 ppm nitrosamine derivatives in the year 1990. Hence, seasonal products such as sunscreen, not sold by the end of the summer, may be affected by nitrosamine levels in products depending on their storage conditions. B. Pharmaceutical Products
Several pharmaceutical products undergo nitrosation and form nitrosamines during synthesis and storage in vivo under gastric conditions in human beings. Investigations have reported the development of tumours in test animals when they were exposed to longterm concurrent nitrite and drug feeding76,77 . This in turn has caused some governments to impose legislation for the removal of nitrosamines from these products before the sale. Aminophenazone, a precursor to NDMA, was shown to induce sarcoma in liver and lung and hence has been removed from some pharmaceutical markets. The production of hydrazine and hydrazones by reduction of nitrosamines is another route for NOC production. Piperazine also leads to production of NOC and its use as an antihelminthic has decreased considerably in most developed countries, though not in the case of developing countries due to its low cost. Two N-nitrosoureas, Bischloroethyl-nitrosourea (BCNU) and 1-chloroethyl-3cyclohexyl-1-nitrosourea (CCNU), have been used as anticancer agents in clinics but their mechanism and their toxicities have yet to be determined78 . C. Agricultural Products
There are several routes for nitrosamine contamination in pesticides: use of contaminated chemicals during synthesis, side reactions, use of nitrite as a preservative and corrosion inhibitor of metal containers and by reactions with environmental nitrosating agents. Over 300 formulations were shown to be contaminated with nitrosamines; however, the main contamination was confined to 2,6-dinitroaniline herbicides, dimethylamino salts of phenoxyalkanoic acid herbicide, diethanolamine and triethanolamine salts of acid
25. Environmental aspects of compounds
1187
pesticide, quaternary ammonium compounds and morpholine derivatives79 . Presence of NDPA in herbicide trifluralin was reported due to nitrosation of the respective amine used during synthesis. Accumulation of agricultural chemicals in soils may lead to formation of nitrosamines. The herbicides atrazine and butralin were found to form nitrosamines only in the presence of high levels of nitrite. Active uptake of NDMA and NDEA by wheat and barley has been published; however, no conclusive evidence has been reported80 . D. Packing materials
Migration of nitrosamines into consumer products can occur via direct contact of materials such as waxed containers, elastic and rubber etc.81 . Morpholine is used extensively as an industrial solvent for wax formulations. The wax formulations are used for coating fruits and vegetables to prevent moisture loss and increase shelf-life of the products. Paper and cardboard packed with morpholine was also found to give rise to NDMA, as these packaging materials were found to be contaminated with NDMA as well. Besides this, rubber products also provided a migratory source for both nitrosamines and nitrosable amine precursors, as trace levels of NDEA and N-nitrosodibutylamine (NDBA) have been reported in cured meats with amine-based accelerators in the rubber nettings82 . E. Foods and beverages
NOC constitute a large category of genotoxic chemical carcinogens occurring in human diet and are known to induce cancer in experimental animals. Nitrosamines are generally found in foods since they are more stable than nitrosamides. Some NOC precursors do not act directly but must be converted to other nitrosation species. Human exposure to nitrates is via exposure to food and drinking water. The nitrates in food may be present naturally or as an additive introduced for various technological reasons. Nitrite is added to foods for preservation, but is reactive in foods, whereas nitrate is quite unreactive. Vegetables are also a prime source of nitrate, and variations in their nitrate levels occur due to conditions employed during the cultivation and storage processes. The nitrate concentration in surface water has increased due to increased use of artificial fertilizers, changes in land use and disposal of waste from intensive farming. Nitrate is readily converted in mammalian systems through bacterial and mammalian enzymes to nitrite which can react with amines, amides and amino acids to form NOC. Critical analysis has shown that most dietary components contaminated with NOC can be classified into different categories as follows83 : ž In foodstuff preserved by addition of nitrate/nitrite (namely cured meat produce and cheeses) both methods of preservation introduce nitrosating species into the food matrix. ž In foodstuffs preserved by smoking (such as fish and meat products) oxides of nitrogen present in the smoke act as nitrosating agents. ž Nitrosated amino acids during cooking yield corresponding volatile nitrosamines: Nnitrosoproline (NPRO), N-nitroso-4-hydroxyproline (NHPRO) and N-nitrososarcosine (NSAR), respectively. ž Concentration of different N-nitrosamines in nitrite-cured meat products is further increased following smoking processes. ž Foodstuffs subject to drying by combustion gases (containing oxides of nitrogen) such as malt for production of beer and whiskey, low-fat dried milk products and spices.
1188
H. K. Chagger and A. Williams
ž Pickled and salt-preserved foods, in particular plant-based products (pickled vegetables) in which microbial reduction of nitrate to nitrite occurs. Foodstuffs stored under humid conditions favouring fungal contamination, particularly the growth of Fusarium moniliforme. ž Migration and formation of nitrosamines from food contact materials. The last source of NOC that has been a major source for health concern of infants is usage of rubber pacifiers and baby feeding bottles fitted with rubber nipples. NOC present in the rubber formulations can migrate into baby foods and drinks and into meat packed in rubber nettings. Various NOC can be found in food processing operations. The most commonly known contributors to dietary volatile and non-volatile N-nitrosamines are nitrite cured meats, particularly fried bacon and beer. Several reviews cover the occurrence and formation of NOC in foods and beverages84 86 . The contamination in beer with NOC was first reported in Germany in 197987 . The contamination of beer occurs during the kilning (drying) process of malt88 and fermentation89 , which leads to the occurrence of NDMS and NPYR. The nitrogen oxides were identified as a source of nitrosamine formation in the beer, formed by nitrosation of the alkaloids present in the malt90 . Since NDMA is a potent carcinogen it could pose serious health implications, as beer is widely used in Western Europe. A recent study which involved 14 German beers could detect only two compounds, NDMA (0.17 š 0.18 mg/kg) and NPYR (1.5 š 1.01 mg/kg), in very low concentrations. Continuous efforts by the brewing industry and change in brewing technology has resulted in a significant reduction in the NDMA contamination by 1 5% over the years. See Table 6 for details. Hence it can be concluded that for moderate beer drinkers, current levels of NDMA are unlikely to represent a significant health risk, and NPYR was shown to be non-carcinogenic92 . TABLE 6. Reduction of N-nitrosodimethylamine (NDMA) in beer and some representative current data91,85 NDMA (mg/kg) Country FRG
USA Canada USA & Canada Netherlands Italy Sweden Poland China Japan UK
Year
mean
range
1977/78 1980 1981 1989 1990 1980 1988 1978 1982 1989 1979 1980 1982 1986 1988 1989 1981 1987
2.7 0.28 0.44 0.16 0.17 5.9 0.26 1.4 0.31 0.07 2.0 0.2 0.4 0.3 0.2 0.2 2.1 0.5
0 68 0 9.2 0 7.0 0 1.7 0 0.6 0 14 0.03 0.99 0.60 4.9 0 1.9 0 0.58 0 7.4 0 1.2 0 0.79 0 0.71 0 6.5 0 0.3 0 6.5 0 6 0 <5 0.9 23
25. Environmental aspects of compounds
1189
Over the last two decades there has been a net decrease in both nitrate and nitrite in cured meats and foods. In cured meat products it is generally accepted that the formaldehyde present in the wood smoke is involved in the formation of N-Nitrosothiazolidine (NTHZ) and N-Nitrosothiazolidine-4 carboxylic acid (NTCA). Bacon represents a unique case as uncooked bacon is generally free of nitrosamines, but high levels of nitrosamines are formed during cooking. The conditions leading to formation of nitrosamines in bacon have been widely studied and the presence of NTCA in raw and fried bacon has been reported93 97 . It has been suggested that the thermal process results in transformation of NTCA into NTHZ during the frying process98 . Over 300 NOC have been shown to be carcinogenic to more than one animal species. Table 7 shows some compounds present in the diet, their occurrence and their carcinogenecity99 . F. Endogenous Formation
There is sufficient evidence to indicate that the NOC compounds represent a serious potential health hazard, although the magnitude of this hazard remains to be established. Exposure to nitroso compounds and their precursors is mainly via ingestion. However, in some cases inhalation may become the major route of exposure. Figure 13 illustrates the total exposure of NOC compounds on humans occurring via both exogenous and endogeneous routes100 . Nitric oxide is formed endogenously in the body by many types of cells for the purpose of intercellular communication (brain, cardiovascular system), or as a part of the immune or inflammatory response (macrophages, endothelial cells). The chemistry of nitric oxide formation in the body is very complex both in terms of chemical species and in the number of parallel and consecutive reactions. Damage to DNA in mammalian cells is caused by at least two major pathways: one arising from the reaction of NO with molecular oxygen and the other by reaction of NO with superoxides. The first route gives N2 O3 , which can either (1) nitrosate secondary amines to form carcinogenic or mutagenic N-nitrosamines or (2) nitrosate primary amines on DNA bases. The latter reaction results in deaminated bases from adenine, cytosine, 5-methylcytosine and guanine. NOC have been shown to produce cancer in humans, particularly when exposure starts early in life and persists over a long period101 . Figure 14 shows endogeneous NOC synthesis in the human body102 . The NOC production is brought about by bacterial enzymes which catalyse nitrosation from
Total exposure
Exogenous exposure
Endogenous exposure
Life style
Occupational
Uptake of precursors
Formation of precursors
Tobacco +tobacco smoke Food Cosmetic products Household commodities Indoor air Drugs
Rubber industry Leather industry Chemical industry Mining Pesticide production
Nitrite Nitrous gases NOx Nitrosatable amino compounds
nitrite from nitrate
FIGURE 13. NOC and total exposure
Et
Et
N-Nitrosodiethylamine (NDEA) Et ON N Hamster
Mouse
Rat
Hamster
Liver, nasal cavity, (oesophagus) Liver, nasal cavity, trachea
Rat
Liver, kidney, (oesophagus) Liver, lung, oesophagus, forestomach Trachea, lung, nasal cavity, (oesophagus, forestomach, liver
lung
N-Nitrosoethylmethylamine (NEMA) Me ON N
Me
kidney, (lung) kidney, lung (glandular stomach)
Liver, Liver, Liver, Liver Liver, Liver
Organotropy
Rat Mouse Hamster Guinea pig Rabbit Mink
Species
N-Nitrosodimethylamine (NDMA) Me ON N
N-Nitroso compound
Carcinogenicity (following oral administration)
TABLE 7. N-Nitroso compounds in the diet, carcinogenicity and occurrence99
Millet flour and grain products (China)
Cured meats (packed in rubber nettings) Salami
Cured meats Fried bacon Marine products: Dried fish (Japan) Dried fish (Greenland) Dried shrimps (China) Broiled squid (China) Millet flour and grain products (China) Dairy and cheese products Dried milk products Edible oils and fats Pickled/fermented vegetables Beer Alcoholic beverages (whisky) Pickled/fermented vegetables (China)
Foodstuff
<3.9 0.1 0.5
<2.4
0.1 1.3 1 6 <7.0 <1.0 <5.0 <0.5 <2.0 <5.0
3.0 39 8.6 38 5.4 132 <300
1.0 5.0 <23
Range
Concentration
Major dietary source (mg/kg)
0.6 0.22
0.2 1.0
0.5
43.9
8.6
4.0
Mean
1190
NO
N
N-Nitrosopiperidine (NPIP)
NO
N
N-Nitroso-3-hydroxypyrrolidine (NHPYR) OH
NO
N
N-Nitrosopyrrolidine (NPYR)
N-Nitrosodibutylamine (NDBA) Bu ON N Bu
Mouse Hamster
Rat
Rat
Mouse
Rat
Guinea pig
Hamster
Mouse
Rabbit, cat Guinea pig, dog, monkey Rat
Liver, oesophagus, upper respiratory and digestive tracts, nasal cavity Forestomach, liver, lung Liver, upper respiratory and digestive tracts
Liver
Liver, nasal cavity, (vagina, testis) Lung
Liver, urinary bladder, (oesophagus, pharynx) Forestomach, liver, oesophagus, urinary bladder, (lung) Respiratory tract, lung, urinary bladder Liver, urinary bladder
Liver, oesophagus Liver
<30 <300 0.6 3.5 <14
Peppered salami Pepper Mixed spices Pickled vegetables
5.8
2.2
3.1
1.8 17
10.2
1.4
(continued overleaf )
<20 <9.2
<7.0 0.4 3.9
1.0 5.0 <130 <96 <10 <6.0 2.4 13
<3.1
<5.3
1 56
<4.5
Cured meats Fried bacon
Cured meats Fried bacon
Cured meats Fried bacon Pickled vegetables Mixed spices Dried chillies Broiled squid
Cured meats (packed in rubber nettings) Smoked chicken Dried fish (Japan)
Dried cuttlefish
1191
NO
N
N-Nitrososarcosine (NSAR) Me ON N CH2 COOH
NO
N
N-Nitrosomorpholine (NMOR) O
HOCH2
N-Nitroso-2-hydroxymethylthiazolidine (NHMTHZ) S
NO
N
N-Nitrosothiazolidine (NTHZ) S
N-Nitroso compound
TABLE 7. (continued )
Rat Mouse
Rat Mouse Hamster
Rat
Species
Oesophagus Lung, nasal cavity, (small intestine)
Liver, (kidney, ovary) Liver, lung Liver, upper respiratory tract, colon
No data available
Non-carcinogenic
Organotropy
Carcinogenicity (following oral administration)
Cured meats Pickled vegetables Brewing malt
Packaging contamination of: Fats/margarine Dairy products
Cured meats Smoked ham
Cured meats Fried bacon Smoked fish Smoked oyster
Foodstuff
<410 <36 Occasionally
1.7 3.8 <3.2
Occasionally <2.8
<32 <30 <6 <109
Range
Concentration
Major dietary source (mg/kg)
8.9
Mean
1192
COOH
COOH
Me
NO
N
COOH
N-Nitroso-2-methylthiazolidine-4-carboxylic acid (NMTCA) S
NO
N
COOH
N-Nitrosothiazolidine4-carboxylic acid (NTCA) S
NO
N
N-Nitroso-4-hydroxyproline (NHPRO) HO
NO
N
N-Nitrosoproline (NPRO)
Rat Mouse
Rat Mouse
Cured meats Fried bacon Smoked poultry Smoked fish Smoked oyster Smoked cheese Cured meats Smoked poultry
No data available
Cured meats
Cured meats Preserved fish Broiled squid Dried vegetables Dried chillies Brewing malt Beer
No data available
Non-carcinogenic Non-carcinogenic
Non-carcinogenic Non-carcinogenic
<28 <98
67
85
1.7
140
(continued overleaf )
<1620 <14,000 <1240 <1600 <167 5 24
10 560
20 580 <89 <94 <24 <132 <113 1 6
1193
NO
N
COOH
COOH
Me
NO
N
COOH
N-Nitroso-5-methyloxazolidine-4-carboxylic acid (NMOCA) O
NO
N
N-Nitrosooxazolidine-4carboxylic acid (NOCA) O
HOCH2
N-Nitroso-2-hydroxymethylthiazolidine-4-carboxylic acid (NHMTCA) S
N-Nitroso compound
TABLE 7. (continued )
Species
No data available
No data available
No data available
Organotropy
Carcinogenicity (following oral administration)
Cured meats
Cured meats
Cured meats Smoked cheese Smoked poultry
Foodstuff
30 120
40 70
<2100 <1628 <462
Range
Concentration
Major dietary source (mg/kg)
Mean
1194
Mice
Reproduced with permission from Reference 83.
NO
N
N-Nitroso-N-(1-methylacetonyl)-3-methylbutylamine (NMAMBA) O
NO
N
N-Nitroso-N(1-methylacetonyl)2-methylpropylamine (NMAMPA) O
No data available
Forestomach (tested by feeding with amine C nitrite)
Millet flour and grain products (China)
Moldy millet and wheat flour
0.1 1.3
<1.2
0.2
1195
1196
H. K. Chagger and A. Williams Bacteria (30-90%strains from human sources)
NO3 , NO2
Macrophages
Endothelial cells
(activated by LPS, BCG)
(bradykinin)
Arginine
Arginine
Nitric oxide
Nitrosating agent
NOC FIGURE 14. Proposed scheme of formation of NOC by bacterial activated macrophages and endothelial cells through intermediate nitric oxide
nitrates or nitrites, probably through formation of nitric oxide at natural pH. Activated macrophages use arginine as a source to produce nitric oxide. Once generated, nitric oxide can be oxidized to nitrosating agents that form NOC readily in the presence of amines. A similar reaction is thought to occur also in endothelial cells. V. AMINES
Several amino compounds are being used extensively in industrial processes. Most of these compounds are manufactured, except hydrazine. Azo dyes are produced by diazotization of aromatic amines and currently there are at least 3000 azo dyes in use. These dyes are used widely in textiles, leather, printing, paper making, drug and food industries. In the past three decades many food, drug and cosmetic colours have been banned from commercial use as food colourants. This section gives a brief account of adverse affects caused by the use of various amino compounds. A. Hydrazine
The only known natural source of hydrazine is found in tobacco plants and it may also occur as an intermediate in biological nitrogen fixation. Alkaline solutions of hydrazine in water can be subject to autooxidation by dissolved oxygen, leading to increased hardness and high pH. Decomposition of hydrazine and the increase of pH just below 7 have adverse effects on the marine life ecology. Frog spawn showed teratogenic effects, the embryos of fathead minnows showed deformities and the rainbow trout had poor fitting jaws, pronounced mouth gap and absence of body movement. In air, hydrazine can be oxidized by ozone and hydroxyl radicals. Hydrazine can also be co-metabolised to nitrogen gas by the nitrifying bacterium Nitrosomonas. Germination of seeds of brush squash, peanut and
25. Environmental aspects of compounds
1197
corn was inhibited upon exposure to hydrazine and led to wilting and subsequently death of the plant2 . NOC might be generated by aerial oxidation of the hydrazines. Experimental studies on oxidation of 1,1-dimethylhydrazine which is not a mutagen and N-aminopiperidine which is a mutagen indicated that the oxides of both hydrazide samples were mutagenic103 . B. Azo Dyes
These dyes are used extensively and can be divided into four different categories: azo dyes containing a nitro group, azo dyes containing benzeneamines and related chemicals, azo dyes containing a benzidine group and miscellaneous azo dyes. This section will not lay too much emphasis on the subject of azo dyes as several reviews exist on this topic104,105 . Some of the dyes are not mutagenic but become mutagenic through intestinal microflora mechanism for mammalian azo reduction and chemical reduction. It is also possible that the carcinogenesis occurs due to formation of aromatic amines, formed by enzymatic cleavage of azo bonds with subsequent N-ring hydroxylation and N-acetylation of aromatic amines. Table 8 gives a list of dyes which were shown to be carcinogenic and mutagenic to animals and humans106 . The C sign indicates that metabolic activation was required and the sign shows cases where no activation was required, i.e. which are direct mutagens. VI. CONTROL AND LEGISLATION
Most of the pollution of nitroso and other nitrogen related compounds occurs mainly through anthropogenic sources, the largest contributor being combustion. Hence, legislation and control is basically oriented around controlling the amount of dry NOx input into the atmosphere. The estimated global NOx arising from anthropogenic sources is of the order 100 ð 106 t/a, and it is increasing every year. By the year 2020 the expected NOx level is calculated to go up by a factor of 15%. In developed countries like Canada, USA, Europe and Japan limits and guidelines have been specified for the NO/NO2 concentration levels. Amongst the developing countries China is one of the biggest NOx contributors; the total emission is around 6.77 Tg nitrogen per year107 . The NOx level is in the developing countries are quite high due to lack of legislative and strategic policies. In order to control the increasing levels of NOx these countries need to implement specified levels of NOx concentrations that should be emitted into the atmosphere. To date, several reviews exist on the control technologies of NOx 6 , the issue is to reduce the formation of nitroso and nitro compounds which are formed inadvertently in industrial processes or in the atmosphere. In case of the rubber industry, new accelerators are being tested which are relatively safe as they do not form carcinogenic nitrosamines108 . Some of the straight-chain accelerators do not produce detectable amounts of environmentally undesirable N-nitrosoamines. The main source of NDMA and other nitrosamines occurs in food and beverages when direct fire is employed. This has been controlled by reducing the nitrate concentration in the foods and by employing ultra-low NOx burners. The formation of nitroso compounds in cosmetic products can be reduced by elimination of secondary amines as cosmetic ingradients, reduction of the levels of secondary amines and nitrite in the raw products, and avoiding contamination of cosmetics and raw materials with oxides of nitrogen. The federal government in the USA is imposing and amending regulations to reduce the discharge of nitroso compounds into the atmosphere. Besides this, smoking contributes to a high level of indoor pollution, hence most offices and work places are being designated as non-smoking zones in order to cut down the nitroso levels.
O2 N
Chrysoidin (C.I. Index 11270)
Azo Dyes Containing Benzeneamines and Related Compounds
Orasol Navy Blue 2RB
Red GTL (C.J. Basic Red 18)
Acid Alizarin Yellow R
Alizarin Yellow G G
Azo Dyes Containing Nitro Groups
Common name
O2 N
O2 N
O2 N
N N
NH
N N
OH
OH
+
−
NH2
Cl
Cl
2
CO
C2 H4 H (CH3 )3 X
N
OH
O
OH
O
C2 H2
HO
N2 O
N N
N N
N N
Chemical structure
TABLE 8. Mutagenic azo dyes: chemical structures and requirements for metabolic activation106
C
š
š
Metabolic activationa
1198
2-Methyl-N,N dimethyl-4aminoazobenzene
4-Aminoazobenzene
N N
H3 C
N N
N N
CH3
CH3
N(OH2 )2
CH3
CH3
NH3
NHCH3
H
N
N(CH3 )2
N N NaO3 S
OH
OH
N N
CH3
OCH2
N N
N N
O
N-Methyl-4aminoazobenzene
N2 O2 S
HO
H3 C
N N
N N
H2 N
N N
N,N-Dimethyl-4aminoazobenzene
Methyl Orange
Methyl Red
Guiba Black D (C.I. Direct Black 17)
Sudan IV
CH3
NH3
(continued overleaf )
C
C
C
C
C
C
š
C
1199
40 -Methoxycarbonyl-Nmethoxycarbonyl N-methyl-4aminoazobenzene
40 -Methoxycarbonyl-Nhydroxy N-methyl-4aminoazobenzene
N-BenzoyloxyN-methyl-4aminoazobenzene
N-Acetoxy-N-methyl4-aminoazobenzene
N-Hydroxy-4aminoazobenzene
3-Methoxy-4aminoazobenzene
O-Aminoazotoluene
Common name
TABLE 8. (continued )
CH3
CH3
O C
O
O O C
N N
N N
N N
CH3 N O O C
CH3 H O O C CH3
H OH CH3
OCOCH2
CH3
N(CH) N
N N
N N
NH2
N
OCH2
NH3
CH3
N N
N N
CH3
Chemical structure
š
š
C
C
C
Metabolic activationa
1200
O
methyl-N-acetyl-4aminoazobenzene
30 -Methyl-N-
30 -Methyl-4aminoazobenzene
30 -Methyl-N-methyl-4aminoazobenzene
30 -Methyl-N,N dimethyl-4aminoazobenzene
CH3
H3 C
H3 C
N N
N N
N N
N N
N N
N N
N-Methyl-N-hydroxy4-aminoazobenzene
H3 C
O C
N N
CH3
N-Hydroxyl-N-methyl4-aminoazobenzene
benzoyloxyN-methyl-4aminoazobenzene
40 -Methoxycarbonyl-N-
NCH3 COCH3
NH2
H
H CH3
N(CH3 )2
OH
H CH3
OH
H CH3
CH3 H O O C
(continued overleaf )
C
C
C
C
š
š
š
1201
N,N-dimethyl-4aminoazobenzene
30 -Carboxylic
30 -Formyl-N,Ndimethyl-4aminoazobenzene
30 -Hydroxylmethyl-4aminoazobenzene
N-methyl-4aminoazobenzene
30 -Hydroxylmethyl-
30 -HydroxylmethylN,N-dimethyl-4aminoazobenzene
30 -Methyl-N-acetyl-4aminoazobenzene
Common name
TABLE 8. (continued )
O HOC
O HC
HOH2 C
HOH2 C
HOH2 C
CH2
N N
N N
N N
N N
N N
N N
Chemical structure
N(CH3 )2
N(CH3 )2
NH2
N CH3 H
N(CH3 )2
NHCOCH3
C
C
C
C
C
C
Metabolic activationa
1202
40 -Methyl-N,Ndimethyl-4aminoazobenzene
20 ,3-HydroxylmethylN,N-dimethyl-4aminoazobenzene
20 -Methyl-N,Ndimethyl-4aminoazobenzene
30 -AcetoxymethaneN,N-dimethyl-4aminoazobenzene
3,30 -Bischloromethyl-4aminoazobenzene
30 -Methyl-40 -hydroxylN,N-dimethyl-4 -aminoazobenzene
30 -CarboxylicN-methyl-4aminoazobenzene
H3 C
N N
N N
N N
N N
N N
N N
CH2 OH
N N
CH3
CH2 OAc
CH2 Cl
HO
CH2
O HOC
N(CH3 )2
N(CH3 )2
CH2 OH
N(CH3 )2
N(CH3 )2
NH2
CNCH3
N(CH3 )2
HHCH3
(continued overleaf )
C
C
C
C
C
C
1203
4,40 -Diaminoazobenzene
Bismark Brown R (C.I. Index 21010)
Bismark Brown Y (C.I. Index 21000)
Chrysoidin Y (C.I. Index 11325)
5-Dimethylaminophenylazoindoline (5I)
6-Dimethylaminophenylazobenzthiazole (6BT)
40 -HydroxymethylN,N-dimethyl-4aminoazobenzene
Common name
TABLE 8. (continued )
CH3
H2 N
H2 N
S
H2 N
HN N
HN
HOH2 C
N N
NH2
N N
NH2
N2 H
N N
N N
CH3
N N
N N
N N
N
N
H2 N
CH3
H2 N N N
NH2
CH2
CH2
CH3
CH3
NH2
NH2
CH3
N(CH3 )2
NH2
N N
CH3
Chemical structure
C
C
C
C
C
C
C
Metabolic activationa
1204
Direct Black 19 Analogue
Direct Black 19 Analogue
Direct Black GB NB
Direct Black 38 (Direct Deep Black EX)
Direct Black 19
4,40 -(B-Hydroxyethylamino)Azobenzine
H1N
HO
OH
HO2 S
H1N
H1N
N2 H
N N
OH
N N
NH2
N N
OH
N N
NH2
N N
NH2
N N
N N SO2 H
HO2 S
SO2 H
HO2 S
N N
N N
SO2 H
HO2 S
OH
N N
HO
N N
H2 N
N N
NH2 OH
SO2 Na
N N
N N
N N
NH2 OH
NH2 OH
N2 H N N
NHCH2 CH2 OH
NH2 OH
N N SO2 N
N N NaO2 S
NH2 OH
C NH O
N N NO2 S
HOH2 CH2 CHN
OH
SO2 H
NH2
NH2
(continued overleaf )
C
C
C
C
C
C
1205
HO
HO
HO
Evan’s Blue
Trypan Blue (Direct Blue 14)
Brown 5 R (C.I. Acid Orange 45)
O S O O
NH2 OH
NH2 OH
N N
OH
N N
OH
NaO2 S
NaO2 S
NaO2 S
H3 C
HOOC
Azo Dyes Containing the Benzidine Group
Direct Black 19 Analogue
Direct Black 19 Analogue
Common name
TABLE 8. (continued )
H3 C
N N
CH3
N N
CH3
N N
N N H3 C
NaO2 S
N N
SO2 H
N N
SO2 Na
N N
SO2 H
HO2 S
OH
N N
N N
OH
NH2 OH
Chemical structure
NH2
OH
SO3 Na
SO2 Na
SO2 Na
HO
COOH
SO2 Na
SO3 Na
NH2 OH
N N
H2 N
N N
OH
N N
OH OH
C
C
š
C
C
Metabolic activationa
1206
Direct Blue 6
Direct Brown 95
Pentacyl Sky Blue 4 B X
Direct Blue I
Benzopurpurin 4 B (Deltapurpurin)
Congo Red
NaO2 S
HO
NaOOC
NaO2 S
NaO3 S
NH2 OH
N N
NH2 OH
SO3 Na
NH2 OH
SO3 Na
N N
SO2 Na
N N
H3 CO
N N
H3 CO
N N
SO3 Na
NH2
H3 C
N N
SO3 Na
NH2
HO
N N
NaO3 S
N N
O
NaO3 S
N N
OCH3
N N
OCH3
N N
CH3
N N
OH
N N
O
OH
OH
NH2
NH2
O
SO3 Na
SO3 Na
SO2 Na
SO2 Na
SO3 Na
NH2
SO3 Na
NH2
SO3 Na
NH2
(continued overleaf )
C
C
C
C
C
C
1207
Direct Blue 53
Direct Red 2
Acid Red 85
Direct Brown 31
Direct Brown 1:2
Common name
HO
NaOOC
TABLE 8. (continued )
N
N
H3 C
N N
H3 C
N N SO2 Na
NH2
S O O N N
NaO2 S
N2 H
O
N N
OH2
NH2 N N
N N
NH2 OH
NaO2 S
NaO2 S
H3 C
HO
NaOOC
N N
HO
OH
SO2 Na
SO2 Na
SO2 Na
SO2 Na
SO2 Na
OH
SO2 Na
NH2
NaO2 S
N N
SO2 Na
N N
OH2
N N
N N
OH2
NH2
HO
OH2
N2 H
N N
Chemical structure
C
C
C
C
C
Metabolic activationa
1208
Direct Blue 10
Direct Blue 8
Direct Violet 32
Direct Blue 15
Acid Red 114
NaO2 S
NaO2 S
H3 C
OH N N
SO2 Na
OH
CH3 O
N N
CH3 O
N N
CH3 O
SO2 Na
SO2 Na
OH
H3 CO N N
SO2 Na
NH2
NH2 OH
S O O
O N N
H3 C
NaO2 S
N N
OCH3
N N
OCH3
N N
OCH3
NaO2 S
N N
OCH3
HO
OH
OH
SO2 Na
OH
SO2 Na
OH
NH2 OH
NaO2 S
N N
OH2
SO2 Na
SO2 Na
SO2 Na
(continued overleaf )
C
C
C
C
C
1209
Sudan 2
Miscellaneous Azo Dyes
Direct Red 46
Direct Red 39
Direct Orange 6
Direct Blue 25
Common name
TABLE 8. (continued )
NaO2 S
H3 C
NaO2 S
NaO2 S
C3 H2 O
NaO2 S
OH
SO2 Na
N N
OH2
OH2
H3 C
N N
O
N N
NH2
NH2
N N
NH2 H3 C
OH
O
HO
N N
NH2
NaO2 S
N N
OH2
N N
CH3
SO2 Na
N N
OH2
HO N N
CH3
Chemical structure OH
SO2 Na
SO2 Na
SO2 Na
SO2 Na
OH
COOH2
OH
C
C
C
C
C
Metabolic activationa
1210
COOH
HO
N N
NaO2 S
H3 C
H3 C
NaO2 S
Reproduced with permission from Reference 106.
HO
S
N N
OH
N N
CH3
HO
N N
OH
N N
O HO
a C, metabolic activation required; , no metabolic activation is required, i.e. a direct mutagen.
Thiodiphenyl-4,40 diazo-bis-salicyclic Acid
Eriochrome Blue Black B
Ponceau 3R (Acid Dye, C.I.16155)
Acid Alizarin Violet N
Acid Alizarin Red B
N O
OH
N N
SO2 Na
SO2 Na
SO2 Na
SO2 Na
COOH
OH
š
C
C
C
C
1211
1212
H. K. Chagger and A. Williams VII. REFERENCES
1. Luigi Parmeggiani, Encyclopedia of Occupational Health and Safety, Vol. 2, Geneva, 1983 p. 1449. 2. Hydrazine, Envt. Health Criteria 68, WHO, Geneva, 1987. 3. L. Bretherilk (Ed.), Hazards in Chemical Laboratory, Royal Society of Chemistry, London, 1981. 4. J. A. Miller, M. C. Branch, W. J. McLean, D. W. Chandler, M. D. Smooke and R. J. Kee, 20th Int. Symp.Combustion, The Combustion Institute, 1984, p. 673. 5. J. A. Miller and C. T. Bowman, Prog. Energy Combust. Sci., 15, 287 (1989). 6. A. Clarke and A. Williams, Energy and Environ., 3, 280 (1992). 7. A. Williams, M. Pourkashanian, P. Bysh and J. Norman, Fuel, 73, 1006 (1994). 8. Private communication. 9. F. J. Dentener and P. J. Crutzen, J. Atmos. Chem., 19, 3 (1994). 10. V. Dupont, M. Porkashanian and A. Williams, J. Inst. Energy, 66, 20 (1993). 11. P. O’Nions and M. M. Vahadati, 3rd International Conf. on Combustion Technologies for a Clean Environment, Centro cultural de Belem, Lisbon, Portugal, 1995. 12. D. Klvana, J. Chaouki, C. Guy and J. Kirchnerova, 3rd International Conf. on Combustion Technologies for a Clean Environment, Centro cultural de Belem, Lisbon, Portugal, 1995. 13. V. A. Self, P. A. Sermon, P. Kumaraswamy and M. S. Vong, 3rd International Conf. on Combustion Technologies for a Clean Environment, Centro cultural de Belem, Lisbon, Portugal, 1995. 14. J. O. L. Wendt, Proceedings of the 2nd International Conf. on Combustion Technologies for a Clean Environment, Portugal, 1993. 15. H. Maghon, A. Kreutzer and H. Termuehlen, Proc. Am. Power Conf., 60 (1988). 16. A. Ciajolo, R. Barbella, M. Mattiello and A. D’Alessio, 19th Int. Symp. Comb. Technion Israel Institute of Technology, Haifa, Israel, The Combustion Institute, Pittsburgh, PA, 1982, p. 1369. 17. G. Prado, A. Garo, A. Ko and A. Sarofim, 20th Int. Symp. Combustion, University of Michigan, Ann Arbor, MI, The Combustion Institute, Pittsburgh, PA, 1985, p. 989. 18. M. Toqan, W. F. Farmayan, J. M. Beer, J. B. Howard and J. D. Teare, 20th Int. Symp. Combustion, University of Michigan, Ann Arbor, MI, The Combustion Institute, Pittsburgh PA, 1984, p. 1075. 19. K. Nikolaou, P. Masclet and G. Mouviar, Sci. Total Environ., 32, 103 (1984). 20. D. Thompson, 3rd International Conf. on Combustion Technologies for a Clean Environment, Centro cultural de Belem, Lisbon, Portugal, 1995, p. 20. 21. D. Schuetzle, Environ. Health Perspectives, 47, 65 (1983). 22. T. C. Pederson and J. S. Siak, J. Appl. Toxicol., 1, 54 (1981). 23. P. T. Williams, K. D. Bartle and G. E. Andrews, Fuel, 65, 1150 (1986). 24. R. Atkinson, and S. M. Aschmann, Int. J. Chem. Kinet., 20, 513 (1988). 25. R. W. Coutant, L. Brown, J. C. Chuang, R. M. Riggin and R. G. Lewis, Atmos. Environ., 22, 403 (1988). 26. M. P. Ligocki and J. F. Pankow, Environ. Sci. Technol., 23, 75 (1989). 27. J. N. Pitts Jr., K. A. Van Cauwenberghe, D. Grosjean, J. P. Schmid, D. R. Fitz, W. L. Belser, Jr., G. B. Knudson and P. M. Hynds, Science, 202, 515 (1978). 28. J. N. Pitts, Jr., Phil. Trans. R. Soc. London A, A290, 551 (1979). 29. G. Lofroth, E. Hefner, I. Alfheim and M. Moller, Science, 209, 1037 (1980). 30. H. S. Rosenkranz, E. C. McCoy, D. R. Sanders, M. Butler, D. K. Kiriazides and R. Mermelstein, Science, 209, 1039 (1980). 31. D. Schuetzle, F. S. C. Lee, T. J. Prater and S. B. Tejada, Int. J. Environ. Anal. Chem., 9, 93 (1981). 32. J. Lewtas, Fundamentals and Applied Toxicol, 10, 571 (1988). 33. T. Tokiwa, R. Nakagawa and K. Horikawa, Mutation Res., 157, 39 (1985). 34. G. W. Traynor, M. G. Apte, H. A. Sokol, J. C. Chang and J. L. Mumford, Proc. of the 79th Air Pollution Control Association Annual Meeting, Minneapolis, 1986. 35. J. Arey, B. Zielinska, R. Atkinson and A. M. Winer, Atmos. Environ., 21, 1437 (1987). 36. M. C. Paputa-Peck, R. S. Marano, D. Scheutzle, T. L. Riley, C. V. Hampton, T. J. Prater, L. M. Skewes, T. E. Jensen, P. H. Reuhle, L. C. Bosch and W. P. Duncan, Anal. Chem., 55, 1946 (1983). 37. H. Tokiwa and Y. Ohnishi, CRC Crit. Rev. Toxicol., 17, 23 (1986). 38. M. G. Nishioka and J. Lewtas, Atmos. Environ., 26, 2077 (1992). 39. J. N. Pitts Jr., Atmos. Environ., 21, 2531 (1987).
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1213
J. Arey, B. Zielinska, R. Atkinson, A. M. Winer, T. Ramdahl and J. N. Pitts Jr., Atmos. Environ., 20, 2339 (1986). R. Atkinson, J. Arey, B. Zielinska and S. M. Aschmann, Environ. Sci. Technol., 21, 1014 (1987). B. Zielinska, J. Arey, R. Atkinson and P. A. McElroy, Environ. Sci. Technol., 22, 1044 (1988). B. Zielinska, J. Arey, R. Atkinson and P. A. McElroy, Environ. Sci. Technol., 23, 723 (1989). E. S. C. Kwok, R. Atkinson and J. Arey, Int. J. Chem. Kinet., 26, 511 (1994). R. Atkinson, E. C. Tuazon, I. Bridier and J. Arey, Int. J. Chem. Kinet., 26, 605 (1994). R. Atkinson, J. Arey, B. Zielinska and S. M. Aschmann, Int. J. Chem. Kinet., 22, 999 (1990). B. Zielinska, J. Arey and R. Atkinson, Env. Sci. Res., 40, 73 (1990). P. T. Williams, Private communication, 1995. R. Crebelli, L. Conti, B. Crochi, A. Carere, C. Bertoli and N. D. Giacomo, Mutat. Res., 346, 167 (1995). R. C. Kamens, J. Guo, Z. Guo and S. R. McDow, Atmos. Environ., 24A(5), 1161 (1990). T. Maeda, K. Izumi, H. Otsuka, Y. Manabe, T. Kinouchi and Y. Ohnishi, J. Natl. Cancer Inst., 76, 693 (1986). D. T. Silverman, R. N. Hoover, T. J. Manson and G. M. Swanson, Cancer Res., 46, 2113 (1986). J. Lewtas and M. Nishioka, Environ. Sci. Res., 40, 61 (1989). H. Richartz, A. Reischi, F. Traunter, and O. Hutzinger, Atmos. Environ., 24, 3067 (1990). P. Romeliotis, W. Liebald and K. K. Unger, Int. J. Environ. Anal. Chem., 9, 27 (1981). D. Grosjean, Environ. Sci. Technol., 19, 968 (1985). K. Nojima and S. Kanno, Chemosphere, 6, 371 (1977). J. A. Leone and J. H. Seinfeld, Int. J. Environ. Anal. Chem. Kinet., 16, 159 (1984). J. A. Leone, R. C. Flagan, D. Grosjean and J. H. Seinfeld, Int. J. Chem. Kinet., 17, 177 (1983). F. Trautner, A. Reischl and O. Hutzinger, Umweltchem. Okotox., 3, 10 (1989). S. Preston-Martin and P. Correa, Cancer Res., 8, 459 (1989). I. K. O’Neill, J. Chen and H. Bartsch, IARC Scientific Publication No. 105, International Agency for Research on Cancer (WHO), Lyon, (1991). M. J. Hill (Ed.), Nitrosamine, Toxicology and Microbiology, Ellis Horwood, Chichester, (1988). J. M. Fajen, D. P. Rounbehler and D. H. Fine, ‘N-Nitroso compounds: occurrence and biological effects’, IARC Scientific Publications No. 41, International Agency for Research on Cancer, Lyon, 1982, p. 223. D. H. Fine, Oncology, 37, 199 (1980). G. E. Moiseev and V. V. Benemansky, Voprosy Onkologii, 26, 107 (1975). B. Spiegelhalder and C. D. Wacker, in ACS Symp. Ser., 553, (Eds. R. N. Loeppky and C. J. Michejda, Washington, DC, (1994), p. 43. D. P. Rounbehler and J. M. Fajen, ‘N-nitroso compounds in factory environment’, Report, NIOSH Contract No. 210-77-0100, National Institute for Occupational Safety and Health, Cincinnati, OH, 1982. D. G. Lloyd and G. Monsanto, Rubber World, 210, 25 (1994). R. Preussmann, H. Habs and D. Schmahl, Cancer Res., 42, 5167 (1982). H. Zerban, R. Preussmann and P. Bannasch, Carcinogenesis, 9, 607 (1988). J. Fuchs, J. Burg, J. G. Hengstler, U. Bolm-Audorff and F. Oesch, Mutat. Res. 342, 95 (1995). A. R. Tricker, B. Spiegelhalder and R. Preussmann, Cancer Survey, 8, 251 (1989). J. B. Powell, J. Soc. Cosmet. Chem., 38, 29 (1987). R. C. Doerr and W. J. Fiddler, Chromatography, 140, 284 (1977). W. Lijinsky and H. W. Taylor, Food Cosmet. Toxicol., 15, 269 (1977). W. Lijinky, Drug Dev. Eval., 93 (1990). R. N. Loeppky, Nitrosamines and Related N-nitroso Compounds, (Eds. R. N. Loeppy and C. J. Michejda, ACS Symp. Series 553, American Chemical Society, Washington, DC, 1994, p. 1. G. Zweig, S. Selim, R. Hummel, A. Mittelman, D. P. Wright, C. Law and E. Regezman, ‘Nnitroso compounds: Analysis, Formation and Occurrence’, IARC Publication No. 31, International Agency for Research on Cancer, Lyon, 1980, p. 555. J. Dressel, Z. Lebensm.-Unter. Forsch., 163, 11 (1976). N. P. Sen, in ACS Symp. Ser., 365, (Ed. J. H. Hotchkiss), American Chemical Society, Washington, DC, 1988, p. 146. N. P. Sen, P. A. Baddoo, D. Weber and S. W. Seaman, J. Food Sci., 53, 731 (1988). A. R. Tricker and R. Preussmann, Mutat. Res., 259, 277 (1991). J. H. Hotchkiss, Cancer Surveys, 8(2), 295 (1989).
1214 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108.
H. K. Chagger and A. Williams A. R. Tricker and S. J. Kubacki, Food Additives and Contaminants, 9(1), 39 (1992). A. D. Gangolli, P. A. Brandt van den, V. J. Feron, C. Janzowsky, J. H. Koeman, G. J. A. Speijers B. Spiegelhalder, R. Walker and J. S. Wishnok, Eur. J. Pharmacol. Environ. Toxicol., Pharmacol. Section, 292, 1 (1994). B. Spiegelhalder, G. Eisenbrand and R. Preussmann, Food Chem. Toxicol., 17, 29 (1979). B. Spiegelhalder, G. Eisenbrand and R. Preussmann, Oncology, 37, 211 (1980). J. Calderbank, and J. R. M. Hammond, J. Inst. Brew., 95, 277 (1989). M. M. Mangino and R. A. Scalan, J. Agric. Food Chem., 33, 699 (1985). A. R. Tricker and R. Preussmann, J. Cancer Res. Clin. Oncol., 117, 130 (1991). R. Preussmann and B. Steward, ‘N-Nitroso carcinogens’, in Chemical Carcinogenesis (Ed. C. D. Searle), American Chemical Society, Washington, DC, 1984, p. 643. H. C. Grice, D. J. Clegg, D. C. Eargle, M. Tein-Lo, E. J. Middleton, E. Sandi, P. M. Scott, N. P. Sen, B. L. Smith and J. R. Withey, in Carcinogenesis in Industry and Environment (Ed. Sontag), J. M. Marcel Dekker, New York, 1981. J. W. Pensabene, and W. Fidler, J. Food Sci., 48, 1870 (1983). A. K. Mandagere, J. I. Gray, D. J. Skrypec, A. M. Booren and A. M. Pearson, J. Food Sci., 49, 658 (1984). N. P. Sen, L. Tessier, S. W. Seaman and P. A. Baddoo, J. Agric. Food Chem., 33, 264 (1985). J. W. Pensabene and W. Fiddler, J. Assoc. Off. Anal. Chem., 68, 1077 (1985). N. P. Sen, P. A. Baddoo and S. W. Seaman, J. Food Sci., 51, 821 (1986). A. R. Tricker and R. Preussmann, Mutat. Res., 259, 277 (1991). D. H. Fine, D. Lieb and F. Rufeh, J. Chromatography, 107, 351 (1975). S. R. Tannenbaum, S. Tamir, T. de. Rojas-Walker and J. S. Wishnok, in ‘Nitrosamines and Related N-nitroso Compounds (Eds. R. N. Loeppy and C. J. Michejda), ACS Symp. Ser., 553, American Chemical Society, Washington, DC, (1994), p. 120. H. Bartsch, International Agency for Research on Cancer, IARC Scientific Publication No. 105, Lyon, (1991). G. Lynn, E. B. Sansone and A. W. Andrews, Environ. Molecular Mutagenesis, 17, 59 (1991). ‘The Evaluation of the Carcinogenic Risk of Chemicals to Humans’, IARC Scientific Publication No. 29, International Agency for Research on Cancer (WHO), Lyon, 1982. C. P. Hartman, G. E. Fulk and A. W. Andrews, Mutat. Res., 44, 9 (1978). K. T. Chung, and C. E. Cerniglia, Mutat. Res., 277, 201 (1992). J. Dignon, Atmos. Environ., 26A, 1157 (1992). R. W. Layer and D. W. Chasar, Eur. Pat. Appl. (Patent No. 591632 A2 940413).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
CHAPTER
26
SN Ar reactions of amines in aprotic solvents NORMA S. NUDELMAN Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, 1428 Buenos Aires, Argentina Fax: 541-782 0529; e-mail:
[email protected]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. SYSTEMS SHOWING CLASSICAL KINETICS . . . . . . . . . . . . . . . . . A. The Specific Base General Acid (SB GA) Mechanism . . . . . . . . . . . B. Medium Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Mono-solvent parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Hydrogen-bonding scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Mixed solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. The Influence of the Nucleophile . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Basicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Nucleophilicity and polarizability . . . . . . . . . . . . . . . . . . . . . . . 3. Steric effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Gas-phase basicity scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Solvation effects on relative basicities . . . . . . . . . . . . . . . . . . . . D. The Influence of the Substrate . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Steric and conformational effects . . . . . . . . . . . . . . . . . . . . . . . . 2. o- vs p-Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. The field effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. The nitro nucleofuge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Molecular Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Electrophilic Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Aromatic Nucleophilic Substitution with Amines in which the Nucleofuge is a Sulphur Derivative . . . . . . . . . . . . . . . . . . . . . . . . H. Aromatic Nucleophilic Substitution with Amines under High Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. SYSTEMS SHOWING ‘ANOMALOUS’ KINETICS . . . . . . . . . . . . . . . A. Fourth-order Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. The Eight-membered Cyclic Transition state . . . . . . . . . . . . . . . . . . C. Aggregation of the Nucleophile . . . . . . . . . . . . . . . . . . . . . . . . . . . D. The ‘Dimer Nucleophile’ Mechanism . . . . . . . . . . . . . . . . . . . . . . .
1215
1216 1218 1218 1220 1220 1222 1225 1228 1228 1232 1235 1237 1238 1240 1240 1241 1243 1244 1245 1250 1253 1256 1261 1261 1264 1265 1267
1216
Norma S. Nudelman
E. F. G. H. I. J. K. L. M.
Specific Solvent Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catalysis by Methanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catalysis by Hydrogen-bond Acceptor (HBA) Additives . . . . . . . . . . The Homo- and Hetero-conjugate Mechanisms . . . . . . . . . . . . . . . . The Substrate Catalyst Molecular Complex . . . . . . . . . . . . . . . . . . The ‘Desolvative Encounter Mechanism’ . . . . . . . . . . . . . . . . . . . . Conformational Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Isotope Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Further Treatment of Kinetic Results . . . . . . . . . . . . . . . . . . . . . . . 1. ‘Inversion Plots’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Evaluation of the equilibrium constants . . . . . . . . . . . . . . . . . . . 3. The dichotomy of amine effects in aromatic nucleophilic substitution (ANS) in aprotic solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. CONCLUDING REMARKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1272 1273 1275 1276 1278 1281 1282 1285 1286 1286 1289 1290 1294 1294 1295
I. INTRODUCTION
For neutral nucleophiles (e.g. amines, alcohols, water) there is much evidence that the addition elimination mechanism depicted in equation 1 fits very well most of the intermolecular and intramolecular nucleophilic displacements involving nitro-activated aromatic substrates1 . L
+
L
Nu
NuH k 3 B [B]
+ :NuH
k1
EWG
+
(1) k2
EWG
EWG = electron-withdrawing group
−
+ L + H
−
k-1
EWG
(1)
Some of the most important evidence for the two-step mechanism comes from studies of base catalysis, in this regard, reactions involving primary and secondary amines have played a central role1 5 . The initially formed -adduct, 1, is zwitterionic and contains an acidic proton, which can be removed by a base which may be the nucleophile itself. Conversion of 1 to products can then occur via the uncatalysed k2 pathway or via the base-catalysed k3 B pathway. The influence of Brønsted base catalysis, the experimental observation of 1,1- and 1,3--adducts, the sensitivity of the system to medium effects, are some experimental evidence of the mechanism depicted in equation 1. Assuming for simplicity that only a particular base B is an effective catalyst in equation 1, application of the steady-state approximation derives in equation 2 the expression of the second-order rate constant, kA , at a given concentration of B. rate k1 k2 C k1 k3 B [B] D kA D 1 2 k1 C k2 C k3 B [B] [Ar-L] [R R NH]
2
Three main situations of interest with respect to the reaction shown in equation 1 were earlier considered in equation 22b . (a) k2 C k3 B [B] × k1 . In this case, no base catalysis is possible: equation 2 simplifies to kA D k1 and the formation of the intermediate is rate-limiting.
26. SN Ar reactions of amines in aprotic solvents
1217
(b) k2 C k3 B [B] − k1 . This situation corresponds to a rapid formation of the intermediate 1 followed by its rate-determining decomposition. In this case, equation 2 reduces to equation 3, which predicts base catalysis with a linear dependence of kA on [B]: kA D
k1 k2 k1 k3 B [B] C k1 k1
3
(c) k2 C k3 B [B] ³ k1 . In this intermediate situation, equation 2 indicates that base catalysis should be observed with a curvilinear dependence of kA on [B]. At low [B], the plot of kA vs [B] should be a straight line which will change to a plateau at high [B], where formation of the intermediate becomes rate-limiting. A downward curvature is expected on these grounds. Numerous kinetic studies devoted to the reactions shown in equation 1 have demonstrated the validity of equations 2 and 32 10 . The isolation and/or NMR spectroscopic characterization of -complexes, as that shown by 1, have received considerable attention over the past two decades, because of the relationship between the formation of such adducts and that of the metastable cyclohexadienyl intermediates postulated in the SN Ar mechanism. The detailed structures of these adducts are now well known, and their reactions, the kinetics and thermodynamics of their formation and decomposition, as well as their spectral properties have been investigated in detail5,11,12 . Although these studies constitute an important contribution to the understanding of the intermediates involved in SN Ar, they will not be discussed in this chapter since they have been recently reviewed; furthermore, most of the -adducts were formed by the addition of anionic nucleophiles1a,5,11 . Many recent investigations have been also carried out in the field of heterocyclic compounds. As a result of the replacement of a ring carbon atom in an arene system by a more electronegative atom, the greater electron density on that atom and the concomitant reduction in electron density on the remaining carbon atoms make these substrates prone to suffer nucleophilic attack. A 1 H and 13 C NMR study of substituted nitropyridines and nitrobenzenes, and of their SN Ar products obtained with amines, demonstrated that the electronic aza and nitro group effects are comparable if conjugation of the nitro group is not hindered12 . Many SN Ar reactions with nitro-activated heterocyclic compounds have been reported; however, a peculiar feature of aza-aromatic systems is that nucleophilic displacements of common leaving groups, as well as of hydrogen, can occur through multistep sequences involving ring opening reclosure (RORC) of the heterocyclic system13 . These reactions are commonly referred to as SN (ANRORC) because they are promoted by initial addition of the nucleophile (AN) at an activated unsubstituted carbon1a,13 . Evidence has been provided that this mechanism can operate to a large extent in the substitution of halonitropyridines by strong nucleophiles like OH in water/DMSO mixtures rich in DMSO, or with amide ions in ammonia14 16 . The identification of the open intermediates16 constitutes a strong indication to suggest that the conversion of 2-halo-5-nitropyridines into the corresponding 2-hydroxypyridines occurs via the SN (ANRORC)-type process rather than via the anticipated SN Ar mechanism. The feasibility of nucleophilic substitutions at the 4- or 7-position in condensed heterocycles such as nitrobenzofurazans has been also recently proved, and the finding of -adducts of the type found in trinitrobenzene analogues gives strong support to the operation of similar mechanisms17 . Nevertheless, the observation of by-products indicates that nucleophilic attack also occurs at the annelated moiety with destruction of the heterocyclic system. Numerous kinetic studies devoted to SN Ar reactions with amines indicate that the occurrence and efficiency of base catalysis depend on the identity of the amine, the nucleofugue, the base and the solvent. In general, base catalysis is more often observed with secondary than with primary amines, with poor leaving groups and in the less polar solvents; one
1218
Norma S. Nudelman
of the three described kinetic situations is observed. Nevertheless, it will be shown in the forthcoming discussion that a new situation has been recently discovered: for several systems an upward curvature has been found in the plot of kA vs [B], which corresponds to a parabolic dependence of kA on [B], and a fourth-order kinetic law. Several alternative mechanisms have been proposed to account for this new kinetic finding. Most of the more relevant findings related to SN Ar reactions in the last decade have been observed in aprotic solvents, and the factors that have been studied with amines in aprotic solvents will be discussed. The first part will deal with works where some of the three kinetic situations described above have been found. In the second part, the systems where ‘anomalous’ kinetics have been observed will be discussed. II. SYSTEMS SHOWING CLASSICAL KINETICS A. The Specific Base General Acid (SB GA) Mechanism
For reactions in which the decomposition of the zwitterionic intermediate, ZH, is, at least partially, rate-limiting, two major mechanisms are now widely accepted. These are known as the specific base general acid (SB GA) and the rate-limiting proton transfer (RLPT) mechanisms and are shown in Scheme 11a . In the rate-limiting proton transfer mechanism, the initially formed ZH undergoes ratelimiting, base-induced deprotonation followed by rapid uncatalysed or acid-catalysed leaving-group departure from the anionic intermediate, Z . This mechanism was initially proposed by Bunnett and Randall2d and then thoroughly studied by Bernasconi and coworkers3,18 who demonstrate that diffusion-controlled proton transfer steps can be overall rate-determining in multistep processes where the species undergoing deprotonation is present in a highly unfavourable equilibrium, or where reversion of this species is extremely rapid. This situation is clearly found for SN Ar in protic solvents and this mechanism has been well established in those cases. On the contrary, for aprotic solvents the situation is still unclear. The SB GA mechanism consists of a rapid equilibrium deprotonation of the ZH intermediate, followed by rate-limiting, general acid-catalysed leaving-group departure from the anionic -complex Z via the concerted transition state, 2. The derived expression for this mechanism is equation 4, where k4 BH is the rate coefficient for acid-catalyzed expulsion of L from Z and K3 is the equilibrium constant for the reaction ZH!Z C BH. k1 k2 C k1 k4 BH K3 [B] kA D 4 k1 C k2 C k4 BH [B] The SB GA mechanism was earlier established by Orvick and Bunnett19 for the reaction of 2,4-dinitro-1-naphthyl ethyl ether with n-butylamine and t-butylamine in DMSO, and it has been recently reported for the reactions of 2,4,6-trinitroanisole, 2,4,6trinitrophenetole and methyl-4-methoxy-3,5-dinitrobenzoate with n-butylamine, and for the reactions of 2,4-dinitro-1-ethylnaphthyl ether with piperidine and pyrrolidine20 24 . While the rate constants (k1 for formation of the zwitterionic intermediates) are consistent with the expected trend, i.e. pyrrolidine is more reactive than piperidine by a factor of 2.5, the results obtained for the decomposition of the intermediates were rather amazing. The rate constant k4 for the decomposition of the pyrrolidine adduct, Z , is about 11,000 times greater than that for the piperidine analogue20 24 . Similarly, the general acid-catalysed decomposition of the pyrrolidine intermediate, ZH, is considerably faster than that of the piperidine analogue. Sekiguchi and coworkers21a have recently produced evidence that base catalysis in the substitution reaction of n-butylamine with
26. SN Ar reactions of amines in aprotic solvents
1219
L NO2 + R1R2 NH
NO2
k −1
k1
+ NR1R2
L
NO2 −
NR1R2
L
NO2
k 3 B [B] −
k 3 BH[BH]
NO2
NO2
ZH
Z
−
k 4 BH[BH]
k2
+
NR1R2
B
H
NR1R2
L
NO2
NO2 −
NO2
NO2
(2)
SCHEME 1
1-pyrrolidino-2,4-dinitronaphthalene also involves rate-limiting deprotonation of the zwitterionic intermediate. All the available information indicates that the most plausible interpretation of these huge differences between systems apparently so similar, is in terms of stereoelectronic or conformational factors that result in destabilization of the transition states for general acid-catalysed expulsion of the leaving group in the piperidine system relative to pyrrolidine20,21 . Interestingly, the sensitivity of the efficiency of the acid catalysis of the leaving-group departure to structural factors is in itself a criterion for the validity of the SB GA mechanism1 . This mechanism has been also observed in other dipolar aprotic solvents like acetone or acetonitrile25,26 ; in the latter, catalysis by Cl has been observed26 . In non-polar aprotic solvents, however, the SB GA mechanism is more difficult to accept because of the known inability of these solvents to stabilize ionic species. The following discussion will consider the different proposals as well as several aspects that have been recently studied.
1220
Norma S. Nudelman
B. Medium Effects
Changes in reactivity due to transfer from protic to dipolar aprotic solvents were early recognized in SN Ar reactions and some novel aspects have been recently studied11,27 . Reactions carried out in the presence of crown ethers28,29 , micellar surfactants and related modified micelles30 32 , or under conditions of phase transfer cataysis (PTC)29,33 35 , have been recently reported, as well as the effect of molten dodecyltributylphosphonium salts on SN Ar reactions by halide ions36 . Since most of these studies refer to anionic nucleophiles, they will not be discussed in this chapter. 1. Mono-solvent parameters
Many different approaches have been reported in the last decade toward a better understanding of the medium factors that influence reaction rates. Fundamental studies have been devoted to probe the reaction at a microscopic level in order to obtain information on the nature of several specific solvent solute interactions on SN Ar and to attempt a description of these effects quantitatively. Recent works have shown the wide applicability of a single parameter scale such as the ET (30) Dimroth and Reichardt37 , as well as other multi-parameter equations. In this respect, the solvatochromic approach developed by Kamlet, Taft and coworkers38 which defines four parameters: Ł , ˛, ˇ and υ (with the addition of others when the need arose), to evaluate the different solvent effects, was highly successful in describing the solvent effects on the rates of reactions, as well as in NMR chemical shifts, IR, UV and fluorescence spectra, solvent water partition coefficients etc.38 . In addition to the polarity/polarizability of the solvent, measured by the solvatochromic parameter Ł , the aptitude to donate a hydrogen atom to form a hydrogen bond, measured by ˛, or its tendency to provide a pair of electrons to such a bond, ˇ, and the cavity effect (or Hildebrand solubility parameter), υ, are integrated in a multi-parametric equation to rationalize the solvent effects. The number of terms in the equation used to correlate the studied property (XYZ) depends on the significance of the solute solvent interactions. When the property studied refers to a single solute in multiple solvents, the general equation is usually expressed as equation 539 : 5 XYZ D XYZ0 C sŁ C a˛ C bˇ C dυ This solvatochromic solvent effect equation has been probably the most widely used one in the analysis of solvent effects40 and it has been applied to literally hundreds of processes in solution and for the correlation of all kinds of solvents effects39 43 . Application of these single- and multi-parameter analyses in SN Ar will be referred to in many aspects discussed below. The importance of the hydrogen bond interactions has been also considered in other approaches which attempted to explain the solvent effects in these reactions43,44 . Thus, two solvatochromic indicators for hydrogen bond donation and acceptance have been recently reintroduced, and the respective scales have been determined for 17 solvents45 . H-bonding scales will be discussed in the next section. In some cases, the solvent hydrogen-bond basicity, ˇ, has been identified with the solvent nucleophilicity, but Bentley46 has recently pointed out that it is only an assumption. Nevertheless, there is a reasonable connection between the nucleophilic solvent parameter YC of Kevill and Anderson47 and the solvent ˇ values38a . In SN Ar involving amines as the nucleophiles, abundant recent studies afford evidence of the importance of the nature of the solvent in determining whether the formation or the decomposition of the zwitterionic intermediate will be the rate-determining step1,3b,20 .
26. SN Ar reactions of amines in aprotic solvents
1221
Furthermore, in many cases, changes in the mechanism have also been observed and they will be discussed in a later section. Nevertheless, by selecting a system that exhibited the same rate-determining step in a variety of solvents it would be possible to assess how the rate of a given process may be affected by a solvent transfer. Such is the case of the reaction of 1-chloro-2,4-dinitrobenzene with piperidine, where the rate dependence with amine concentration has been studied in 12 aprotic solvents48a as well as in 10 protic solvents48b . It was found that the reaction does not exhibit base catalysis in any of the solvents studied; that is, addition of piperidine is rate-limiting in all the cases48 . It is shown in Table 1 that for aprotic solvents, the rates increase with increasing solvent polarity, as a result of increased stabilization of the transition state leading to the zwitterionic intermediate. Many solvent parameters were tested and the best correlation was observed with the Dimroth Reichardt ET (30) values37 . The observation of a satisfactory correlation between reactivity and the ET parameter in hydrogen bond acceptor aprotic solvents suggests that strong intramolecular hydrogen bonding between the ammonio proton and the ortho-nitro group is responsible for the stabilization of the ZH and of the corresponding transition state in these solvents48a . On the other hand, and in spite of increased polarity, the reactivity in hydroxylic solvents (Table 2) is slower than in any of the aprotic solvents studied and no correlation exists with ET values48b . In this instance, the reactivity is inversely proportional to the hydrogen bond donating ability of the solvent as measured by the ˛-hydrogen bond donor solvent parameter38 . The fact that the rates are correlated by the hydrogen bond donicity of the hydroxylic solvent supports the view that the relatively low rates of substitution are the result of a strong solvation of the amine molecules48b . A similar effect will be also found in reactions discussed in Section III. When the decomposition of the zwitterionic intermediate is rate-determining, the effect of the solvent is crucial since it may produce changes in the mechanisms and in the rate-determining step. A recent study of the kinetics of the reactions of 1-chloro-, 1fluoro- and 1-phenoxy-2,4-dinitrobenzene with piperidine, n-butylamine and benzylamine in ethyl acetate and THF indicated that these reactions resemble those in dipolar aprotic solvents when primary amines are the nucleophiles (i.e. that shown in equation 1, with
TABLE 1. Reaction of 1-fluoro-2,4-dinitrobenzene (DNFB) with piperidine in aprotic solvents at 15 ° C48a second-order overall rate coefficientsa 103 [Piperidine] (M) Solvent Toluene Benzene Dioxane Trichloroethane Tetrahydrofuran Chlorobenzene Ethyl acetate Chloroform Dichloromethane Acetone Acetonitrile Nitromethane
ET (30) 33.9 34.5 36.0 36.2 37.4 37.5 38.1 39.1 41.1 42.2 46.0 46.3
0.625
1.25
2.06 3.28 4.59 5.22 6.34 18.9
2.48 2.94 4.23 3.48 24.8
31.6 87.9 163
a [DNFB] D 5 ð 105 M; k in 1 mmol1 s1 . A
2.50
5.00
7.50
1.38 2.34 2.57 5.35 7.83 8.42 9.55 19.5 39.7 44.3 99.4 172
2.55 3.70 3.42 8.48 13.3 13.7 15.6 20.0 42.4 64.9 110 192
3.58 5.09 4.11 11.7 18.0 18.4 20.3 20.2 45.3 79.5 114
10.0 4.48 6.45 5.05 15.0 22.3 22.4 25.0 20.4 47.4 116
12.5
15.0
5.41
6.19
5.83 17.5 26.5 24.7 28.7 20.6
6.67 20.7 30.6 28.0 32.3
1222
Norma S. Nudelman
TABLE 2. Second-order reaction rate coefficients, kA , at 15, 25 and 40 ° C, and activation parameters for the reactions 104 M of 1-chloro-2,4-dinitrobenzene with piperidine in hydroxylic solvents48b 102 kA (mol1 s1 )
Solvent Methanol Ethanol 2-Methylpropan-1-ol Propan-1-ol Propan-2-ol Butan-2-ol Benzyl alcohol 2-Phenoxyethanol 2-Methoxyethanol Diethylene glycol
H† S† 15 ° C 25 ° C 40 ° C (kJ mol1 ) (JK1 mol1 ) ET (30)a 0.801 1.05 1.03 1.40 1.48 0.494 0.836 2.34 3.00
1.41 1.80 1.90 1.92 2.51 2.57 1.02 1.68 4.01 5.50
2.80
39.0
151.7
4.61 4.76 6.25 6.04 2.84 4.53 9.09 13.0
41.9 43.5 42.7 39.9 49.8 48.1 38.4 41.5
145.3 140.3 141.1 150.3 123.5 125.6 151.6 138.2
55.5 51.9 49.0 50.7 48.6 47.1 50.8 52.0 52.3 53.8
˛b
υSA c
ˇd
0.98 0.83
3.0 2.1
0.62 0.77
0.77 0.70
1.8 1.5
0.92
0.60
0.56
a Reference 37. b Reference 38a c Reference 38b d Reference 39
˛ D H-bond acidity; ˇ D H-bond basicity; υ D cavity effect.
a molecule of the solvent replacing that of base) and those in aprotic solvents when the nucleophile is a secondary amine. SN Ar reactions of nitroaromatics such as 1-chloro-2,4-dinitrobenzene and 2,4,6trinitroanisole with amines are accelerated in micelles or microemulsions49 . As with anionic nucleophiles, the rate enhancement is mainly the effect of a high local concentration of both reactants1a,31 . 2. Hydrogen-bonding scales
One of the most comprehensive hydrogen-bonding scales is due to Abraham and his coworkers50 , who have derived the general solvation equation 651 H
log SP D c C rR2 C s2 Ł C a˛2 H C bˇ2 H C Vx
6
where SP is some solvent property of a series of solutes in a given system and the explanatory variables, or descriptors, are solute properties as follows: R2 is an excess H molar refraction, 2 Ł is the solute dipolarity/polarizability, and ˛2 H and ˇ2 H represent the solute overall hydrogen-bond acidity and basicity, respectively. Thus, water octanol partition coefficients (log Poct ) were shown to follow equation 7: H
log Poct D 0.088 C 0.562R2 1.0542 Ł C 0.034˛2 H 3.460ˇ2 H C 3.814Vx
7
Table 3 presents the parameters for an extensive set of solutes. The treatment has been successfully applied to the correlation of the reversed-phase HPLC capacity factors52,53 . For a molecule with multiple hydrogen bonding sites, it has been found that additivity can be applied54 56 . This additivity assumption has been successfully used in quantitative structure activity relationships (QSAR), in many reactions and particularly in drug design57 59 . Some abnormalities observed by Abraham54 with pyridines and alkylpyridines in tetrachloromethane have been recently revisited, and the treatment has also been applied to other heterocycles employing 1,1,1-trichloroethane as solvent60 .
26. SN Ar reactions of amines in aprotic solvents equations72 .
TABLE 3. Solutes and their descriptors used in the regression from Reference 72. Copyright (1994) American Chemical Society Solute Benzene Toluene Ethylbenzene o-Xylene m-Xylene p-Xylene n-Propylbenzene Isopropylbenzene n-Butylbenzene Isobutylbenzene s-Butylbenzene t-Butylbenzene trans-ˇ-Methylstyrene Allylbenzene Biphenyl 2-Methylbiphenyl 3-Methylbiphenyl 4-Methylbiphenyl Naphthalene Fluorobenzene Chlorobenzene 2-Chlorotoluene 3-Chlorotoluene 4-Chlorotoluene Benzyl chloride 2-Chloroethylbenzene 1-Chloro-3-phenylpropane Bromobenzene 2-Bromotoluene 3-Bromotoluene 4-Bromotoluene Benzyl bromide 2-Bromo-1-phenylethane 1-Bromo-3-phenylpropane Methyl phenyl ether 2-Methylanisole 3-Methylanisole Benzaldehyde 2-Methylbenzaldehyde 3-Methylbenzaldehyde 4-Methylbenzaldehyde Acetophenone 3-Methylacetophenone 4-Methylacetophenone Ethylphenylketone n-Propyl phenyl ketone n-Butyl phenyl ketone n-Pentyl phenyl ketone n-Hexyl phenyl ketone Methyl benzoate Ethyl benzoate
1223
Reprinted with permission
R2
2 H
˛2 H
ˇ2 H
ˇ2 0
Vx
0.610 0.601 0.613 0.663 0.623 0.613 0.604 0.602 0.600 0.580 0.603 0.619 0.913 0.717 1.360 1.331 1.371 1.380 1.340 0.477 0.718 0.762 0.736 0.705 0.821 0.801 0.794 0.882 0.923 0.896 0.879 1.014 0.974 1.078 0.708 0.725 0.709 0.820 0.870 0.840 0.862 0.818 0.806 0.842 0.804 0.797 0.795 0.719 0.720 0.733 0.689
0.52 0.52 0.51 0.56 0.52 0.52 0.50 0.49 0.51 0.47 0.48 0.49 0.72 0.60 0.99 0.88 0.95 0.98 0.92 0.57 0.65 0.65 0.67 0.67 0.82 0.90 0.90 0.73 0.72 0.75 0.74 0.98 0.94 1.00 0.75 0.75 0.78 1.00 0.96 0.97 1.00 1.01 1.00 1.00 0.95 0.95 0.95 0.95 0.95 0.85 0.85
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
0.14 0.14 0.15 0.16 0.16 0.16 0.15 0.16 0.15 0.15 0.16 0.16 0.18 0.22 0.22 0.23 0.23 0.23 0.20 0.10 0.07 0.07 0.07 0.07 0.33 0.25 0.24 0.09 0.09 0.09 0.09 0.20 0.30 0.27 0.29 0.30 0.30 0.39 0.40 0.42 0.42 0.48 0.49 0.51 0.51 0.50 0.50 0.50 0.50 0.46 0.46
0.14 0.14 0.15 0.16 0.16 0.16 0.15 0.16 0.15 0.15 0.16 0.16 0.18 0.22 0.22 0.23 0.23 0.23 0.20 0.10 0.07 0.07 0.07 0.07 0.33 0.25 0.24 0.09 0.09 0.09 0.09 0.20 0.30 0.27 0.29 0.30 0.30 0.39 0.40 0.42 0.42 0.48 0.49 0.51 0.51 0.50 0.50 0.50 0.50 0.46 0.46
0.7164 0.8573 0.9982 0.9982 0.9982 0.9982 1.1391 1.1391 1.2800 1.2800 1.2800 1.2800 1.0961 1.0961 1.3242 1.4650 1.4650 1.4650 1.0854 0.7341 0.8388 0.9797 0.9797 0.9797 0.9797 1.1206 1.2615 0.8914 1.0320 1.0320 1.0320 1.0320 1.1732 1.3030 0.9160 1.0569 1.0569 0.8730 1.0140 1.0140 1.0140 1.0139 1.1550 1.1550 1.1550 1.2960 1.4370 1.5780 1.7190 1.0726 1.2135
(continued overleaf )
1224
Norma S. Nudelman
TABLE 3. (continued ) Solute Methyl 2-methylbenzoate Methyl 3-methylbenzoate Methyl 4-methylbenzoate Phenyl acetate Benzyl acetate Methyl phenylacetate Ethyl phenylacetate Methyl 3-phenylpropanoate Ethyl 3-phenylpropanoate Methyl 4-phenylbutanoate Dimethyl phthalate Benzonitrile 2-Methylbenzonitrile 3-Methylbenzonitrile 4-Methylbenzonitrile Phenylacetonitrile 3-Phenylpropanonitrile 4-Phenylbutanonitrile Aniline o-Toludine m-Toludine p-Toludine 2-Bromoaniline 3-Bromoaniline 2-Nitroaniline 3-Nitroaniline 4-Nitroaniline N-Ethylaniline Nitrobenzene 2-Nitrotoluene 3-Nitrotoluene 4-Nitrotoluene Benzamide 3-Methylbenzamide N-Methylbenzamide N,N-Dimethylbenzamide Phenylacetamide 3-Phenylpropanamide Acetanilide Phenol o-Cresol m-Cresol p-Cresol 2,4-Dimethylphenol 2,5-Dimethylphenol 4-t-Butylphenol 2-Isopropyl-5-methylphenol 2-Phenylphenol 3-Phenylphenol 4-Phenylphenol 2-Chlorophenol 3-Chlorophenol 4-Chlorophenol 2-Bromophenol
R2
2 H
˛2 H
ˇ2 H
ˇ2 0
Vx
0.772 0.754 0.730 0.661 0.798 0.703 0.660 0.687 0.654 0.693 0.780 0.742 0.780 0.762 0.740 0.751 0.771 0.759 0.955 0.966 0.946 0.923 1.070 1.128 1.180 1.200 1.220 0.945 0.871 0.866 0.874 0.870 0.990 0.990 0.950 0.950 0.950 0.940 0.870 0.805 0.840 0.822 0.820 0.843 0.840 0.810 0.822 1.550 1.560 1.560 0.853 0.909 0.915 1.037
0.87 0.88 0.88 1.13 1.06 1.13 1.01 1.21 1.20 1.29 1.41 1.11 1.06 1.08 1.10 1.15 1.35 1.38 0.96 0.92 0.95 0.95 0.98 1.19 1.37 1.71 1.91 0.85 1.11 1.11 1.10 1.11 1.50 1.50 1.44 1.40 1.60 1.65 1.40 0.89 0.86 0.88 0.87 0.80 0.79 0.89 0.79 1.40 1.41 1.41 0.88 1.06 1.08 0.90
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.26 0.23 0.23 0.23 0.31 0.31 0.30 0.40 0.42 0.17 0.00 0.00 0.00 0.00 0.49 0.49 0.35 0.00 0.52 0.52 0.50 0.60 0.52 0.57 0.57 0.53 0.54 0.56 0.52 0.56 0.59 0.59 0.32 0.69 0.67 0.35
0.43 0.47 0.47 0.54 0.65 0.58 0.57 0.59 0.62 0.59 0.88 0.33 0.31 0.34 0.34 0.45 0.51 0.51 0.41 0.45 0.45 0.45 0.31 0.30 0.36 0.35 0.38 0.43 0.28 0.27 0.25 0.28 0.67 0.63 0.73 0.98 0.79 0.80 0.67 0.30 0.30 0.34 0.31 0.39 0.37 0.41 0.44 0.49 0.45 0.45 0.31 0.15 0.20 0.31
0.43 0.47 0.47 0.54 0.65 0.58 0.57 0.59 0.62 0.59 0.88 0.33 0.31 0.34 0.34 0.45 0.51 0.51 0.50 0.59 0.55 0.52 0.39 0.34 0.36 0.35 0.38 0.51 0.28 0.27 0.25 0.28 0.67 0.63 0.73 0.98 0.79 0.80 0.67 0.30 0.30 0.34 0.31 0.39 0.37 0.41 0.44 0.49 0.45 0.45 0.31 0.15 0.20 0.31
1.2135 1.2135 1.2135 1.0730 1.2135 1.2135 1.3544 1.3544 1.4953 1.4953 1.4288 0.8711 1.0120 1.0120 1.0120 1.0120 1.1529 1.2938 0.8162 0.9570 0.9570 0.9570 0.9910 0.9910 0.9910 0.9910 0.9910 1.0980 0.8910 1.0320 1.0320 1.0320 0.9728 1.1137 1.1137 1.2546 1.1137 1.2546 1.1133 0.7751 0.9160 0.9160 0.9160 1.0569 1.0569 1.3387 1.3387 1.3829 1.3829 1.3829 0.8975 0.8975 0.8975 0.9501
26. SN Ar reactions of amines in aprotic solvents
1225
TABLE 3. (continued ) Solute 3-Bromophenol 4-Bromophenol 2-Bromo-4-methylphenol 2-Methoxyphenol 3-Methoxyphenol 4-Methoxyphenol 2-Hydroxybenzaldehyde 3–Hydroxybenzaldehyde 4-Hydroxybenzaldehyde 2-Cyanophenol 3-Cyanophenol 4-Cyanophenol 2-Aminophenol 3-Aminophenol 4-Aminophenol 2-Nitrophenol 3-Nitrophenol 4-Nitrophenol Catechol Resorcinol Hydroquinone Methylparaben n-Propylparaben Methyl 3-hydroxybenzoate 2-Hydroxybenzamide Benzyl alcohol 3-Nitrobenzyl alcohol 4-Nitrobenzyl alcohol 2-Phenylethanol 3-Phenylpropanol 2-Phenylpropan-2-ol 4-Phenylbutanol 5-Phenylpentanol 1-Phenylpropan-1-ol 2-Phenylpropan-1-ol 1-Phenlpropan-2-ol Benzenesulphonamide
R2
2 H
˛2 H
ˇ2 H
ˇ2 0
Vx
1.060 1.080 1.040 0.837 0.879 0.900 0.962 0.990 1.010 0.920 0.930 0.940 1.110 1.130 1.150 1.015 1.050 1.070 0.970 0.980 1.000 0.900 0.860 0.905 1.140 0.803 1.064 1.064 0.811 0.821 0.848 0.811 0.804 0.775 0.810 0.787 1.130
1.15 1.17 0.90 0.91 1.17 1.17 1.15 1.38 1.01 1.33 1.55 1.63 1.10 1.15 1.20 1.05 1.57 1.72 1.07 1.00 1.00 1.37 1.35 1.40 1.50 0.87 1.35 1.39 0.91 0.90 0.85 0.90 0.90 0.83 0.90 0.90 1.55
0.70 0.67 0.35 0.22 0.59 0.57 0.11 0.74 0.77 0.74 0.77 0.79 0.60 0.65 0.65 0.05 0.79 0.82 0.85 1.10 1.16 0.69 0.69 0.66 0.59 0.33 0.44 0.44 0.30 0.30 0.32 0.33 0.33 0.30 0.30 0.30 0.55
0.16 0.20 0.31 0.52 0.39 0.48 0.31 0.40 0.44 0.33 0.28 0.29 0.66 0.79 0.83 0.37 0.23 0.26 0.52 0.58 0.60 0.45 0.45 0.45 0.52 0.56 0.64 0.62 0.64 0.67 0.65 0.70 0.72 0.66 0.64 0.72 0.80
0.16 0.20 0.31 0.52 0.39 0.48 0.31 0.40 0.44 0.33 0.28 0.29 0.66 0.79 0.83 0.37 0.23 0.26 0.52 0.58 0.60 0.45 0.45 0.45 0.52 0.56 0.64 0.62 0.64 0.67 0.65 0.70 0.72 0.66 0.64 0.72 0.80
0.9501 0.9501 1.0910 0.9747 0.9747 0.9747 0.9317 0.9317 0.9317 0.9298 0.9298 0.9298 0.8749 0.8749 0.8749 0.9493 0.9493 0.9493 0.8340 0.8340 0.8340 1.1313 1.4131 1.1313 1.0315 0.9160 1.0902 1.0902 1.0569 1.1978 1.1978 1.3387 1.4796 1.1978 1.1978 1.1978 1.0971
3. Mixed solvents
The study of solute solvent and solvent solvent interactions in mixed solvents has been gaining significance in recent years61 64 , because of the increasing application of these solvents. Casassas and collaborators67 have used the Kamlet Taft multiparametric equation for the correlation of dissociation constants of acids in 1, 4-dioxane water mixtures. They found that when the main solvent is retained the property does not involve significant changes in the cavity volumes and, in those cases, the pK in binary solvents can be described by equation 8: pK D pK0 C sŁ C dυ C a˛ C bˇ
8
Bosch, Roses and coworkers62,65,66 have used the dissociation of electrolytes in binary solvents of low permittivity using 2-methylpropanol or propan-2-ol as the main solvent
1226
Norma S. Nudelman
to evaluate the parameter(s) describing the preferential solvation. The authors observed that equation 8 is applicable and could evaluate the variations in parameters as a function of the mole fraction (x) of the cosolvent. They found that for a non-polarizable main solvent polarizability effects can be considered to be proportional to the mole fraction of polarizable cosolvent (equation 9): υmixture D xmain solvent υmain solvent C xcosolvent υcosolvent D xcosolvent υcosolvent
9
The results are given in Table 4. By statistical treatment of the coefficients, it was found that the b coefficient is not significant in most cases and equation 8 can be further simplified to equation 10: 10 pK D sŁ C dυ C a˛ The applicability of the equation to predict pK values was confirmed by the good fits obtained for experimental and predicted values. A graphical example is given in Figure 1 for the dissociation constants of picric acid in binary mixtures62 . Recently68,69 Abraham and coworkers have applied equation 6 to the correlation of several physico-chemical and biological phenomena in binary systems. These include solvent water partition coefficients70,71 , HPLC capacity factors53,72 and the distribution 2.0
1.5
1.0
∆pK calculated
0.5
0.0
−0.5
−1.0
−1.5
−2.0 −2.0
−1.0
0.0
1.0
2.0
∆pK experimental FIGURE 1. Dissociation constants of picric acid in binary mixtures62 . Reprinted with permission from Reference 62. Copyright (1994) American Chemical Society
26. SN Ar reactions of amines in aprotic solvents
1227
Ł ,
TABLE 4. Variation in ˛ and ˇ solvatochromic parameters in 2-methylpropan-2-ol by addition of cosolvents62 . Reprinted with permission from Reference 62. Copyright (1994) American Chemical Society Cosolvent
a
xa
n-Hexane
0.00200 0.00398 0.00794 0.01961 0.03846 0.05660 0.09091 0.12281 0.13793 0.16667 0.00200 0.00398 0.00794 0.01961 0.03846 0.05660 0.09091 0.12281 0.13793 0.16667 0.00200 0.00398 0.00794 0.01961 0.03846 0.05660 0.09091 0.12281 0.13793 0.16667 0.00200 0.00398 0.00794 0.01961 0.03846 0.05660 0.09091 0.12281 0.13793 0.16667
0.00146 0.00292 0.00581 0.01441 0.02841 0.04202 0.06812 0.09284 0.10472 0.12755 0.00214 0.00427 0.00851 0.02100 0.04113 0.06046 0.09686 0.13054 0.14646 0.17661 0.00249 0.00496 0.00987 0.02432 0.04748 0.06957 0.11081 0.14854 0.16624 0.19950 0.00326 0.00649 0.01290 0.03164 0.06133 0.08926 0.14041 0.18612 0.20720 0.24625
0.000 0.000 0.005 0.009 0.014 0.023 0.037 0.051 0.060 0.074 0.000 0.000 0.000 0.005 0.005 0.009 0.009 0.014 0.019 0.023 0.000 0.000 0.000 0.005 0.005 0.005 0.005 0.009 0.009 0.009 0.000 0.000 0.000 0.000 0.005 0.005 0.005 0.005 0.009 0.009
0.001 0.001 0.001 0.000 0.003 0.002 0.003 0.002 0.000 0.003 0.000 0.000 0.000 0.004 0.005 0.009 0.012 0.018 0.023 0.030 0.002 0.004 0.007 0.014 0.029 0.042 0.065 0.080 0.088 0.103 0.007 0.012 0.023 0.050 0.084 0.115 0.163 0.200 0.211 0.236
0.003 0.003 0.000 0.002 0.007 0.007 0.012 0.014 0.014 0.019 0.003 0.005 0.010 0.031 0.051 0.077 0.110 0.144 0.162 0.190 0.000 0.000 0.000 0.003 0.000 0.002 0.005 0.002 0.005 0.007 0.013 0.015 0.020 0.023 0.028 0.028 0.028 0.031 0.036 0.036
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.002 0.004 0.009 0.021 0.041 0.060 0.097 0.131 0.146 0.177 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
0.00200 0.00398 0.00794 0.01961 0.03846 0.05660 0.09091 0.12281 0.13793 0.16667
0.00469 0.00933 0.01849 0.04498 0.08609 0.12381 0.19061 0.24795 0.27368 0.32019
0.000 0.000 0.000 0.000 0.000 0.005 0.005 0.009 0.009 0.009
0.020 0.036 0.063 0.120 0.183 0.225 0.292 0.337 0.358 0.393
0.000 0.003 0.003 0.008 0.015 0.028 0.041 0.059 0.064 0.074
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
Benzene
Propan-2-ol
Ethanol
Methanol
Ł
a D Volume fraction of cosolvent; x D mole fraction of cosolvent.
˛
ˇ
υ
1228
Norma S. Nudelman
of solutes between blood and brain73 . It was shown in a recent publication74 that for a series of alcohols, the a coefficient is effectively zero, so that all the alcohol phases have the same basicity as bulk water, no matter what their water content is. This would indicate that the alcohols have similar hydrogen-bond basicity to water, contrary to results of solvatochromic measurements; the anomaly is assumed to be due to the strong dependence of the ˇ values on the indicator used in the solvatochromic determinations75 . It is suggested that the partition equations are more useful to represent the real interactions with the solvatochromic method74 . C. The Influence of the Nucleophile
The basicity, nucleophilicity, polarizability and steric requirements of the nucleophile have been recently shown to affect the SN Ar reactions with amines. 1. Basicity
The effect of basicity is clearly shown by the dependence of the rates of reactions of structurally related nucleophiles76,77 . Bordwell76 has pointed out that Brønsted plots reported in the literature for reactions in which bond formation to the nucleophile is rate-limiting have slopes ˇNu that range for the most part between 0.5 0.7, as shown in Table 5; ˇNu measures the sensitivity of the rates to changes in the basicity of the nucleophile. Its size appears to be associated with the extent of charge transfer in the transition state for the rate-limiting step, and it can be used to describe the position of the transition state along the reaction coordinate. In single-electron-transfer reactions from carbanions where charge transfer is essentially complete, ˇNu is near-unity, while for SN 2 reactions ˇNu ranges from 0.2 to 0.5. In SN Ar processes, where the size of ˇNu is determined by the bonding between the TABLE 5. Brønsted ˇNu values for SN Ar reactions with thianion, amine, and oxanion families in hydroxylic solvents76 . Reprinted with permission from Reference 76. Copyright (1986) American Chemical Society Nu family
Substrate
Solvent
ˇNu
Reference
MeOH, 50 ° C
0.52
a
ArS
F
ArS
Cl
NO2
MeOH, 50 ° C
0.48
a
ArS
Br
NO2
MeOH, 50 ° C
0.55
a
ArS
l
MeOH, 50 ° C
0.55
a
MeOH
0.91
b
NO2
NO2 NO2
ArO
Cl
NO2
26. SN Ar reactions of amines in aprotic solvents
1229
TABLE 5. (continued ) Nu family
Substrate
Solvent
ˇNu
Reference
water
0.42
c
water
0.52
c
water
0.45
c
NO2
water
0.64
c
NO2
80% MeOH/water
0.56
d
NO2
75% EtOH/water
0.67
e
NO2 Amines
r
NO2 NO2
Amines
Cl
NO2
NO2 Amines
l
NO2 NO2
Amines
Cl O2 N NO2
2-NpCOO
Br NO2 NO2
ArO
Cl NO2
a G. Bartoli, L. DiNunno, L. Forlani, and P. E. Todesco, Int. J. Sulphur Chem., Part C 6 77 (1971). b G. D. Leahy, M. Liveris, J. Miller and A.J. Parker, Aust. J. Chem., 9, 382 (1956). c J. E. Dixon and T.C. Bruice, J. Am. Chem. Soc., 94, 2052 (1972). d P. A. Nadar and C. Gnanasekaran, J. Chem. Soc., Perkin Trans. 2, 671 (1978). e J. J. Ryan and A. A. Hummfray, J. Chem. Soc. (B), 1300 (1967).
nucleophile and a partially positively charged sp2 carbon atom, ˇNu is large but not near-unity. The observation that it increases when more nitro groups are added to the electrophile (e.g. ˇNu for amines reacting with picryl chloride is 0.12 unit larger than for 1-chloro-2,4-dinitrobenzene) is consistent with the expected extent of charge transfer in the transition state. Connected with the determination of Brønsted plots, some mathematical treatments have been recently developed attempting to yield structural information on the transition state.
1230
Norma S. Nudelman
These treatments have been also applied to SN Ar. For example, for a neutral nucleophile, all the classical pathways identified at present are represented by the general reaction mechanism shown by Scheme 2. A concerted mechanism, indicated by the diagonal path in Scheme 2, had not been discussed until lately, but was observed, among other systems, in the hydrolysis of 1-chloro-2,4,6-trinitrobenzene and 1-picrylimidazole. The study was then extended to other related substrates and structure reactivity relationships could be obtained78 . X
X
NuH
k1
+ NuH
−
k- 1
k2
A
A
Nu
kc [B] [BH] [B]
k − 3 [BH]
k 3 [B]
k4
X
A
Nu
X
(5) + Nu
−
k′1
−
k′−1
A (3)
A (4) SCHEME 2
The Brønsted ˇ values for substituted phenyl ethers, 0.39 to 0.52, are in the range expected for concerted reactions, but indicate a transition state with less proton transfer than in the case of 3-methylimidazolium chloride derivatives, (ˇ D 0.60 0.65). The structure reactivity parameters were interpreted on the basis of the mathematical method developed by Jencks and More O’Ferral. The tridimensional energy maps are shown in Figure 2, where proton transfer is represented along the x-axis and CO bond formation along the y-axis. The position of the transition state along the reaction coordinate is shown in Figure 3 (the third dimension is omitted for clarity). The reaction coordinate shows more degree of proton transfer than CO bond formation. The change in the nucleofugue from imidazole to OPh produces some stabilization in state II and a greater decrease in the energy of state IV. This produces a shift along the reaction coordinate toward I (arrow 1) and a little shift to II (arrow 2) by a perpendicular Thornton effect. The result of the two changes (arrow 3) indicates a lower degree of proton transfer and a small increase in the CO bond formation78 . Recently, the same group79 have reported the kinetic study of the reaction of 1-pyrrolidino-2,4-dinitrobenzene, 1-piperidino-2,4-dinitrobenzene and 1-morpholino-2,4dinitrobenzene with NaOH in the presence of the amine leaving group and proposed the formation of -complexes, which were found to react faster than the original substrates.
26. SN Ar reactions of amines in aprotic solvents
O2N
+ H O H NO2
X
B
1231
X
7t
Z 2
OH NO2′
O2N 4
+
BH
Z 3 C X O2N
NO2
H2O B
O
1 B
X
H O2N
NO2
Z
+
BH OH Z FIGURE 2. Tridimensional reaction coordinate diagram for the hydrolysis of 1-X-4-Z-2,6dinitrobenzene. The x-axis represents the proton transfer reaction and the y-axis, the CO bond formation78 . Reproduced by permission of the Indian Journal of Technology
H X
+
H X
O
O2N
B
B NO2
OH NO2
O2N
NO2 H
BH
ΙΙ
ΙV
NO2
4
C
6
b Ι
a 3
5 2
O 1
ΙΙΙ X
X O2N H2O
NO2
O2N
NO2
B
BH NO2
+
HO
−
NO2
FIGURE 3. Structure reactivity Jencks More O’Ferral diagram for the hydrolysis of 1-X-2,4,6-trinitrobenzenes: (a) vertical level line as a consequence of ∂ˇ/∂pKBH D px D 0; (b) level line clockwise rotated from the horizontal as a consequence of ∂ˇXH / ∂pKXH D py D negative; (c) reaction coordinate with an angle higher than 45 degrees with the vertical as the line that bisects the two level lines. Effect of change in the X substituent by better withdrawing groups, arrows 1, 2 and 3. Effect of change in the base (B) by other with lower pKBH , arrows 4, 5 and 678 . Reproduced by permission of the Indian Journal of Technology
1232
Norma S. Nudelman
2. Nucleophilicity and polarizability
The nucleophilicity of the amine is another factor affecting reactivity, and changes in it have been sometimes responsible for the observed scattering in the Brønsted plots. The Ritchie equation80 (equation 11) has been applied to a variety of reactions in which nucleophilic addition to, or combination with, an electrophilic center is rate-limiting. log k D log k0 C NC
11
Here k is the rate constant for reaction of an electrophile with a given nucleophile in a given solvent, k0 corresponds to the reaction of the same electrophile with water (in water) and NC is a parameter characteristic of the given nucleophile in the given solvent, but independent of the electrophile80 . Ritchie’s ideas imply that the transition states are characterized by rather large separations of the nucleophile and electrophile moieties. For SN Ar reactions involving rate-determining nucleophilic addition, this would mean that bond formation and charge transfer have made little progress in the transition states. These conclusions are in disagreement with those reached on the basis of the ˇNu values obtained from Brønsted plots76 . A possible explanation of this conflicting situation is in terms of imbalanced transition states, with desolvation of the nucleophile being ahead of bond formation and charge transfer in the transition state1a . A recent study of the reactions of 2,4-dinitrochlorobenzene and of picryl chloride with a series of nucleophiles that are presented in Table 6 shows that a plot (not shown) of log k against the pKa values of all the nucleophiles is badly scattered77 . Differences of up to 108 are observed for bases with similar pKa values. Part of this scatter is due to deviations that result because different families of nucleophiles (with different nucleophilic atoms) give rise to different Brønsted correlation lines. Thus, for the reactions of picryl chloride good correlations are observed for a family of oxyanions (ˇ D 0.38, plot not shown), primary and secondary amines (Figure 4, ˇ D 0.52) and quinuclidines (Figure 4, ˇ D 0.66). On the other hand, the correlation with the NC parameter shown in Figure 4 for the same reaction is a good one, with a slope of 0.79 š 0.11. The rate constants in this correlation span a range of almost 105 in reactivities. For the reaction of 2,4-dinitrochlorobenzene a slope of 0.95 š 0.13 is observed in Figure 5. The correlation spans a reactivity range of almost 107 . Despite these overall good correlations, there are significant changes in relative nucleophilic reactivities, which the authors attributed mainly to steric effects77 . For example, secondary amines such as piperidine and morpholine are relatively more reactive than less hindered primary amines in reactions with 2,4-dinitrochlorobenzene. Notwithstanding, it will be shown below that other effects have been also found to be responsible for these changes. Steric effects cannot account for the slope of less than one observed for the reactions of picryl chloride, because the slope is not significantly different (0.82 š 0.11) when the points for the more hindered secondary amines are omitted from the plot77 . The slopes less than one observed for these reactions (Figure 5) mean that picryl chloride shows a lower selectivity toward nucleophilic attack than does 2,4-dinitrochlorobenzene, in accordance with the reactivity selectivity principle and with relative nucleophilic reactivities that are substrate-dependent77 . Nevertheless, in other cases, it has been found that nucleophilic additions to halonitroarenes do not follow the reactivity selectivity principle7 . The nitro group is highly polarizable and electrostatic repulsion between this group and the incoming nucleophile should decrease the rate when the nitro group is located in the ortho-position. Nevertheless, polarizability effects of the nucleophile may be rateenhancing because of the operation of London forces, as shown earlier with the reactions with thiophenoxide ions81 . Although no studies of these effects have been conducted in
26. SN Ar reactions of amines in aprotic solvents
1233
TABLE 6. Second-order rate constants for nucleophilic aromatic substitution 77 reactions of 2,4-dinitrochlorobenzene and picryl chlorided . Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society Nucleophile (NC)b 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 21 22 23 24 25 26 27
NH2 CH2 CH2 NH2 (5.37) NH2 CH2 CH2 NH3 4 (3.91) CF3 CH2 NH2 (2.89) NH2 NHCONH2 (3.17) Morpholine (5.25) Piperidine (6.11) HO (4.75) Morpholine2 (5.8)h Piperidineg (6.6)h CH3 ONH2 (3.88) Phenoxide (5.6) HOO (8.08) SCH CO (8.7)l 2 2 CH3 O (7.68) Thiophenoxideg (10.51) NH2 CH2 CONHCH2 CO2 (4.48) NH2 CH2 CO2 (5.22) NH2 NH2 (5.66) Quinuclidinol (5.50) 3-Quinuclidinol DABCO (5.30) 3-Quinuclidine CH3 COO (>2.95) H2 O (0) CO3 2 HCO3 PO4 3 Borate
log h M1 81 PCe 0.412 0.821 1.91 1.10 0.23 1.05 0.155l 0.131 1.06 1.06 3.00h 0.194l 0.959t 1.31 3.22 4.01j 4.96 4.41 7.19l,m 2.62l 3.84l 2.06l 4.70l
DNCBd
5.58 5.15 2.48e 1.39 3.91e 2.59e 2.00e 5.35e 3.00e 0.64e 0.57e 1.50e 1.30e 4.20e 3.40e 2.80e
a At 25 ° C in aqueous solution. b From C. D. Ritchie, J. Am. Chem. Soc. 97, 1170 (1975) unless noted otherwise. c PC is picryl chloride. d DNCB is 2,4-dinitrochlorobenzene. e Data from Reference 80c. f R. H. Rossi and E. B. Vargas, J. Org. Chem., 44, 4100 (1979). g In methanol at 25 ° C. h Data from M. R. Crampton and J. A. Stevens, J. Chem. Soc., Perkin Trans. 2, 1097 (1990). i Data from J. E. Dixon and T. C. Bruice, J. Am. Chem. Soc., 94, 2052 (1972). Rate constants corrected from 30 to 25 ° C using the Arrhenius equation, assuming an activation energy of 10 kcal mol1 . j log k D 4.01 from work reported in R. H. Rossi and E. B. Vargas, J. Org. Chem., 44, 4100 (1979). k Values of NC for morpholine and piperidine in methanol solution were obtained by taking the average value of NC determined by fitting the rate constants for the reactions of these nucleophiles with 2,4-dinitrofluorobenzene, 2,4-dinitrochlorobenzene, 2,4dinitrobromobenzene and 2,4-dinitroiodobenzene, to plots of log k against NC (using the data reported in Reference 80c). Data for the reactions of these substrates with azide ion were excluded from the correlation lines for the purpose of calculating these NC values. l Based on data from Reference 80c. m In units of S1 .
1234
Norma S. Nudelman
1
6
5
1
−1 −1
0 log k M
s
16
−1
−2
2
3 6
9
12
pKa −1
s
−4
−1 −1
−3
log k M
−2
−5
−6
6
8
10
12
pKa FIGURE 4. (Top) plot of log k for the reactions of primary and secondary amine nucleophiles with picryl chloride against their pKa values in aqueous solution at 25 ° C. (Bottom) plot of log k for the reactions of a series of substituted quinuclidine ions with picryl chloride against the pKa values of the nucleophiles. In aqueous solution at 25 ° C77 . Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society
26. SN Ar reactions of amines in aprotic solvents
1235
4 13 2
log k M−1 s−1
0
16 4
−2
7
2
7 16
4
−8 −2
3
0
2
12 14
5 8
−4
15
13
6
10 3
−6
18 6 9 1 5 8
9
18 11 17
10
4
6
8
10
12
N+ FIGURE 5. Plot of log k for the reactions of nucleophiles with 2,4-dinitrochlorobenzene and picryl chloride against the NC parameter. In aqueous or methanol solutions at 25 ° C77 . Numbers 1 18 are defined in Table 6. Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society
the reactions with amines, it is expected that highly polarizable amines would react faster than other amines of similar basicity, since the polarizability effect has been considered in SN Ar reactions76,81 . 3. Steric effects
Steric effects in the nucleophile have been long known to affect the reactivity in SN Ar reactions, mainly due to the steric hindrance to the entrance of the nucleophile in the formation of the zwitterionic intermediate1 . In the case of amines, branching in the nucleophile was shown to decrease the rate of reaction with nitrohalobenzenes and the result was interpreted as due to a decrease in the rate of formation of the zwitterionic intermediate4 , and a similar result was observed in the reaction of 1,2-dinitrobenzene9 . Table 7 shows the SN Ar of several substrates with n- and s-butylamine. It can be observed that s-BuNH2 exerts an important decrease in reactivity with respect to n-BuNH2 for every substrate. The ˛-branching of the amines decreases the k2 /k1 values, probably by increasing k1 via steric hindrance, and retardation is present despite the electronic effect of the methyl group. On the other hand, it will be shown that ˛-branching of the amines reduces k3 /k1 by reducing the rate of proton transfer (k3 ). It has been recently reported that, contrary to previous assumptions, primary steric effects due to a branching in the amine do not produce a large decrease in the reaction rate when the first step is rate-determining82 . In SN Ar reactions of amines with fluoronitrobenzene, it is generally accepted that the second step of the mechanism depicted in Scheme 1 is rate-determining; base catalysis is frequently found and the observed rate constants obey equation 2. Nevertheless, the reaction of o-fluoronitrobenzene with n- and iso-propylamine in toluene and in DMSO are only slightly sensitive to the nucleophile concentration. The
0.54 ð 104 3.09 ð 105 0.16 5.47 ð 105 5.13 ð 105 1.20 ð 102
Hexanea Benzeneb Benzenec Benzenec
Benzenec
Benzenec
1,2-DNB 1,2-DNB 1-F-2,4-DNB 6-NO2 -2-Clbenzothiazole 6-NO2 -2-Brbenzothiazole 6-NO2 -2-Fbenzothiazole
a T 37 ° C. b T 27 ° C. c T 25 ° C.
k0 (dm3 mol1 s1 )
Solvent
Substrate
2.98
1.04 ð 103
6.10 ð 104 3.76 ð 104 35.8 1.11 ð 103
k 0 (dm3 mol1 s1 )
Bun NH2
3.41 ð 103
1.0 ð 106
0.31 ð 104 0.28 ð 105 0.023 3.0 ð 106
k0 (dm3 mol1 s1 )
1.90 ð 101
5.02 ð 105
0.23 ð 104 0.41 ð 105 1.36 5.28 ð 105
k 0 (dm3 mol1 s1 )
Bus NH2
3.5
51
17 11 6.9 18.2
2
2
0 kBu s NH
0 kBu n NH
TABLE 7. Experimental and literature kinetic constants for SN Ar reactions of Bun NH2 and But NH2 with several substrates9
15.7
20.7
26.5 21.4 26.3 21.0
00 kBu s NH
2 2
00 kBu n NH
159
160
107 9 111 160
Reference
1236
26. SN Ar reactions of amines in aprotic solvents
1237 k0
mild acceleration observed conforms to the mathematical form of equation 12; and k 00 become the terms k1 k2 /k1 and k1 k3 /k1 , respectively, when the effect is due to authentic base catalysis, as is the case of the reactions with p-fluoronitrobenzene. kA D k 0 C k 00 [B]
12
Examining the results of the reactions of o- and p-fluoronitrobenzene with npropylamine and isopropylamine in toluene and in DMSO, the observed very low k 00 :k 0 ratio for the reactions of o-fluoronitrobenzene clearly shows that decomposition of the intermediate -complex is not a slow step. Efficient activation in this reaction requires coplanarity of the o-nitro group (the nitro-oxygen atoms support a strong negative charge as shown by theoretical calculations)83a,b and the result is interpreted as due to the strong hydrogen bond formed between the ammonium hydrogen and the oxygen atoms, which loosens the NH bond (calculations show that a real hydrogen transfer occurs in the vacuum)83a . It was observed that branching in the amine does not produce a highly significant decrease in the rate (see also Table 28). The reaction of p-fluoronitrobenzene with n-propylamine, on the contrary, proceeds almost exclusively by the base-catalysed step. Very interestingly, this reaction exhibits a 100-fold decrease in rate when compared with the reaction with n-propylamine in toluene. It is obvious that primary steric effects cannot be greater than those in ofluoronitrobenzene: interestingly, it was found that the large diminution in the rate is due to the great slowness of the base-catalysed step82 . Therefore, when comparing reactivities in reactions with fluorine substrates, steric effects of the nucleophile must be examined at different amine concentrations; it is almost certain that primary steric effects should be low, but stereoelectronic effects on the hydrogen abstraction in the intermediate complex are expected to be important: the o:p ratio for isopropylamine in toluene is ca 104 . Although it may be argued that branching in the amine reduces the k3 /k1 values not only by reducing the rate of proton transfer (k3 ) but also by increasing the rate of decomposition of the zwitterionic intermediate to reactants (k1 ) because of steric congestion, this effect was shown to be not very important with the reactions of o-fluoronitrobenzene (see Table 28) and also with the reactions of p-fluoronitrobenzene in DMSO82 . It was observed that knpropylamine /kisopropylamine changes from 100 in toluene to almost 1 in DMSO where the first step is rate-determining. Consistently with these arguments, analysis of the data in Table 7 indicates that stronger influence of steric effects is exerted on k 00 (related to k3 ) than on k 0 (related to k2 ). It is also observed that the ratios of k 0 seem to depend on the substrate, while the ratios of k 00 for the same reactions are higher (stronger retardation effects) and similar, despite the nucleofuge9 . There is evidence21 for unfavourable stereoelectronic conformational effects when the transition step contains piperidine groups and it has been also recently reported that a change from primary amines to piperidine results in a reduction in the rate of proton transfer24 . Section III will show the importance of amine aggregates in SN Ar reactions in aprotic solvents when the second step is rate-determining: it is obvious that branching of the amine will diminish the formation of the aggregates that help the proton transfer and the nucleofuge departure from the -complex. 4. Gas-phase basicity scales
The advent of techniques that enable the study of fast reactions in the gas phase, such as ion cyclotron resonance (ICR) spectrometry, Fourier-transform ion cyclotron resonance spectrometry (FT-ICR) and high pressure mass spectrometry (HPMS), allowed the measurement of the gas-phase proton affinities for strong bases84 86 as well as for
1238
Norma S. Nudelman
low-basicity compounds87 91 . These data are useful as a reference for further estimations of the specific solute solvent interactions when the compounds are used in solution, especially in solvents of low permittivity (i.e. low dielectric constant). Recent measurements for the following gas-phase proton transfer equilibria: B i HC C B 0
! Bi C B0 HC , υG° D RT ln K
where B0 is the reference base, have been made by ICR, FT-ICR87,88 and HPMS91,92 , 87 covering a wide interval between 41 kcal mol1 and 318.2 kcal mol1 . Superbases. Measurements of the basicity of very strong bases have been carried out in the gas phase, extending the gas-phase basicity scale for organic compounds 84 86 up to PA D 1050 kJ mol1 , and a basicity scale for these superbases has been 86,87,93 . Raczynska and coworkers, studied a series of amidines84,85 and recently proposed guanidines86 using the gas-phase values for Pr3 n N and Bu3 n N85 as the starting points in the basicity scale. A quantitative comparison based on the Taft and Topsom analysis94 was conducted for alkyl substituents, for which the relative basicities (υR GB) obey equation 13: υR GB D a a C c
13
where a is the reaction constant for the polarizability effect and a is the directional polarizability parameter of Taft and coworkers94,95 . An interesting intramolecular stabilization has been observed with the amidinium and guanidinium ions, that will be discussed in Section III. M, because of its connection with the ‘dimer’ mechanism. Weak bases. Several basicity scales have been suggested, such as the HPMS91 and the FT-ICR87,88 basicity scales. Most of the investigations have been centred on compounds which are usually more basic than water, but Table 8 shows the recently measured relative basicities υG0 and the basicity relative to ammonia, υG0 (NH3 ) of very low-basicity compounds, determined by FT-ICR87 . The FT-ICR gas-phase basicity scale for the weak bases87,93 can be compared with the results obtained by McMahon and coworkers91,92 using ICR and HPMS spectrometric techniques. Satisfactory agreement was found with the existing ICR data, but some variances were observed with the HMPS results. 5. Solvation effects on relative basicities
The overall importance of the medium on the reaction rates has been shown previously, but the nature and extent of solute solvent interactions can alter tremendously various properties of the nucleophile; the variations are usually satisfactorily correlated by some of the several quantitative structure activity relationships (QSAR) that have been discussed37,38,51,96 . The term quantitative structure property relationship (QSPR) has been recently proposed for cases where a specific property, such as the basicity, is examined97 . The QSAR technique, widely developed by Kamlet, Taft and coworkers38,98 for the prediction of specific solute solvent interactions, has been used to predict the different solute solvent contributions to property variations of compounds. The influence of solvent on the relative basicity of dipolar trimethylamines has been recently studied: a descriptor was developed to describe a unique solute solvent interaction involving dipolar amines99 .
26. SN Ar reactions of amines in aprotic solvents
1239
Directly measured relative basicities υG° and the basicity relative to ammonia,
TABLE 8. 87a υG° (NH3 )a,b, . Reprinted with permission from Reference 87a. Copyright (1994) American Chemical Society Directly measured d∆G°
d∆G°(NH3) 33.4
(CF3)2CHOCH3 H2 S
33.9°
0.9
33.8°
CF3COOH
0.3
CF3SSCF3 CF3COOCH2CF3
34.2
0.7
(CF3CH2)2O
3.7
1.2
0.6
CF3CH2OH
35.4° 36.1
2.0 2.1
(CN)2C=C(CN)2
CF3CN
CF3CHO C 2 H4
37.4
1.7
H2 O
CF3COCl
34.8
0.7
(F2CH2)CO
(CF3)2CHOH
34.1
2.0
1.5
37.5° 39.1
0.8 1.0
39.9
0.2
1.2
40.1
0.2 1.8
0.2
2.4
40.3 1.3 1.3
0.2
(CN)2
1.7
FCN
41.2 >1.3
(CF3)3COH
41.7 0.5
CF3C≡CH
(CF3)2O SO2F2
43.0
0.7 43.4
0.5
43.7
1.3 1.5
0.2 0.9
0.8
43.0° 0.4
(CF3)2CO
1.1
1.2
1.2
COS
42.5 1.9
1.2
F2NH
F2CO
42.2 1.0
FSO2Cl
SO2
40.5° 40.5°
1.5
1.0
45.0 45.2 46.0
a All quantities are given in kcal mol1 . b υG° NH D G° NH G (base). 3 3 c See also S. G. Lias, J. E. Bartmess, J. F. Liebman, J. L. Holmes, R. D. Levin and G. W. Mallard, J. Phys. Chem.
Ref. Data, 17, Suppl. 1 (1988).
It was found that a better representation of non-specific interactions between solvents and the monosubstituted dipolar trimethylammonium ions is gained from the product of Ł and the solvent dipole moment ( ). The obtained results were compared with the gas-phase basicity and the solvent attenuation factors (SAF) were calculated99 . The multiparametric equation 14 has been also applied to estimate solvent effects on the relative basicities υG of propylamines97 : υG D sŁ C a˛ C bˇ C υG0
14
where the intercept, i.e. υG0 , represents the relative basicity in the absence of solvents.
1240
Norma S. Nudelman
TABLE 9. Solvent solvatochromic parametersa and the relative basicities (υG) of propylamines in the gas phase and various solvents (values are in kcal mol1 at 298 K and relative to diethylamine)97 . Reprinted with permission from Reference 97. Copyright (1995) American Chemical Society Solventb (Gas)c AQ MeOH EtOH 2-PrOH EG DMSO AN NB NM
Ł 1.1 1.09 0.60 0.54 0.46 0.92 1.00 0.76 1.01 0.85
˛
ˇ
PrNH2
1.17 0.98 0.86 0.78 0.92 0.00 0.15 0.00 0.23
0.18 0.62 0.77 0.90 0.52 0.76 0.31 0.39 0.37
6.8 0.61 0.47 0.38 0.56 0.48 0.30 1.24 0.75 1.00
Pr2 NH 2.3 0.03 0.29 0.23 0.31 0.40 1.02 0.00 0.29 0.00
Pr3 N 8.7 0.44 1.39 1.56 1.11 2.11 2.61 0.83 1.11 0.88
a From Reference 101. b (Gas), gas phase; AQ, water; MeOH, methanol; EtOH, ethanol; 2-PrOH, propan-2-ol; EG, ethylene glycol; DMSO,
dimethyl sulphoxide; AN, acetonitrile; NB, nitrobenzene; NM, nitromethane.
c Gas-phase basicity values are taken from D. H. Aue and M. T. Bowers, in Gas Phase Ion Chemistry (Ed.
M. T. Bowers), Vol. 2, Academic Press, London, 1979.
Table 9 shows the basicity variations of propylamines in the gas phase and in different solvents, relative to diethylamine; the equilibrium is given by equation 15. C ! Prn NHC 4n C Et2 NH Prn NH3n C Et2 NH2
15
Propylamines with positive basicity values are less basic than diethylamines, and propylamines with negative values are more basic than diethylamines. The expected order Pr3 N > Pr2 NH > PrNH2 is observed in the gas phase, while in solution the basicity trend shown in Table 9 indicates that dipropylamine is the most basic amine in all the solvents used, except in DMSO, where propylamine is the most basic amine. Analysis of the different solute solvent interactions carried out by the correlation coefficients found for equation 14 shows that the dipolarity polarizability term (Ł ) has an important contribution (the coefficient changes from 2.4 for PrNH2 to C3.9 for Pr3 N), possibly due to the different interactions in the ammonium ions. It has been shown that alkyl substituents which are polarizable98 do contribute to the reduction of the positive character of the ammonium ions, although this contribution is highly attenuated in solution100 . The solvent basicity (ˇ) is also important because the number of acidic sites differs for the different types of ammonium ions. Propylammonium ion has three acidic hydrogens at which individual specific solute solvent interactions take place. On the other hand, tripropylammonium ions depend strongly on this specific interaction for the dispersal of the charge into the solvent. This is shown by the b values, that change from 2.3 to C4.3. Thus, for the basicity of propylamines in solution, solute solvent interactions of the ammonium ions with the dipolar basic solvents seem to play the greatest role in the determination of the relative basicities. This observation is consistent with that made for the basicity of substituted ethylamines, in which it was shown that their basicities are very sensitive to the polar, acidic and basic nature of the medium101 . D. The Influence of the Substrate
1. Steric and conformational effects
The relative importance of steric effects in the substrate on the rates of SN Ar reactions with amines in aprotic solvents was studied earlier and it was shown that the rates
26. SN Ar reactions of amines in aprotic solvents
1241
of reaction of 2-nitro-6-alkyl chlorobenzenes with piperidine in benzene could be satisfactorily correlated with the -Hammett substituents102 . Correlations including steric parameters did not significantly improve the linear regression coefficient. This means that substitution in both sites of the reaction centre does not produce severe steric congestion that would affect the rates unless very bulky substituents were present. Thus, in the case of the reactions of 2-nitro-6-alkyl chlorobenzenes with piperidine in benzene only the bulkiest substituent, the 6-methyl group, was out of the straight line102 . Similar results were then found for piperidino-debromination of various nitro-activated five-membered ring heterocycles103 . The existence of such linear Hammett plots for ortho-substituted substrates was interpreted as a peculiar feature of five-membered ring heterocycles, where steric effects of substituents ortho to the site of the nucleophilic attack are minimized1a . It was recently shown that also the reactions of 2-nitro-6-alkyl anisoles with amines in aprotic solvents are not strongly influenced by steric effects104 . On the contrary, it was observed that even the 6-methyl-2-nitroanisole reacts with cyclohexylamine about 15-fold faster than the 4-methyl-2-nitroanisole. The absence of primary steric effects and even the increase in rate can be understood by considering some substrate conformational features. When one of the ortho positions is not substituted, the methoxy group may be coplanar with the ring, but when both ortho positions are substituted, rotation of the methoxy group was predicted. The loss of coplanarity would result in a decrease of resonance stabilization, as can be seen in Figure 6; this was proposed as the reason that makes the 6-substituted compound more reactive104 . Further crystallographic studies of related anisoles and phenetoles confirmed that the alkoxide group is almost perpendicular to the aromatic ring105 . Thus, an X-ray determination of the structures of both 2,6- and 2,4-dinitroanisole revealed that when methoxy is ortho-substituted on one side alone, the methoxy group makes only a very small angle (5° ) with the ring, whereas when there are two nitro groups adjacent to methoxy, the methoxy group makes a large angle with the ring (79° ), as shown in Figure 7105 . Taft and coworkers106a , have recently reviewed the substituent and structural effects in a comprehensive analysis of substituents constants106a , followed by a survey of structural effects in organic chemistry106b . 2. o- vs p-Activation
; ;; ; ; ;;
For SN Ar reactions with amines, the presence of a nitro group in a position ortho to the nucleofuge plays an important role. In spite of the steric effects which will tend to decrease the reactivity of o-nitroaromatics, and the fact that the rate-enhancing effect of the resonance stabilization of the transition state will be more important from the para position, a k o /k p ratio greater than unity is usually found in the reactions of nitroaromatics
H
R
Me
R
O
O
Me
N
O
O FIGURE 6. Orbital interactions in 4-R- and 6-R-2-nitroanisoles104
N
O
O
1242
Norma S. Nudelman C7 O22
O21
N2
N2
C3
C1
O22
C2
C2
C7
B
C3
C4 A C1 O1 C6
C5 N6
O62
O1
O21
N6 C6 C5
O61
C4
O62
O61 A FIGURE 7. ORTEP plot of of Crystallography
B
2,6-dinitroanisole105 .
Reproduced by permission of the International Union
with amines. This ratio is always greater for reactions carried out in aprotic solvents than those in protic solvents1b,2c,107 . This inversion in reactivity has received considerable attention, and recent studies have contributed to a better understanding of the transition states and intermediates in the SN Ar reactions with amines. Several explanations have been proposed for the greater reactivity of the o-nitro derivatives with amines. The first, which is applicable to most of the systems, is an enhanced stabilization of the zwitterionic intermediate through intramolecular hydrogen bonding between the ammonio proton and the ortho-nitro group (a phenomenum visualized in structure 6a and earlier called ‘built-in solvation’)2c . Although this proposal has been criticized, independent evidence that such intramolecular hydrogen bonding indeed occurs has been obtained from a proton transfer study, that suggests a hydrogen bond of about 9.6 kJ mol1 for a 2,4,6-trinitrobenzene derivative in aqueous solution108 . No doubt that in a less polar solvent, and with a smaller number of nitro groups sharing the negative charge, this hydrogen bond will be appreciable stronger. O
R′ R H N N+
O
H O N
−
(6a)
O
H3 C O2 N
+
O
NC5H10 NO2
−
(7)
Besides the increased reactivity, formation of species like 6a may also produce a change in the rate-determing step in substitutions of ortho-derivatives when compared with the para-isomers. For example, it has been recently demonstrated that the formation of 1 L D F; R1 D n-C3 H7 , i-C3 H7 ; R2 D H is rate-limiting in the reaction of n-propylamine and isopropylamine with o-fluoronitrobenzene in toluene, while it is the decomposition of the corresponding zwitterionic intermediate that is rate-determining in the same reactions
26. SN Ar reactions of amines in aprotic solvents
1243
with p-fluoronitrobenzene82 . Such differences in the mechanisms of the reactions must be kept in mind in the analysis of the activation of SN Ar reactions with ortho- and para-nitro groups1a . 3. The field effect
For dinitro-substituted substrates, it has been recently shown that activation in 2,4dinitrophenyl substrates is mainly due to the mesomeric effect of the 4-nitro group, thus reducing the electron density at the reaction site83 . However, another important feature of highly polarizable groups, such as a nitro group in the ortho position, has been considered to be the field effect107 . This effect has been reported in the reactions of 2,4- and 2,6-dinitroanisole (DNA) with cyclohexylamine in benzene107 . Both substrates have an ortho-nitro group and the stabilization of the zwitterionic intermediate through hydrogen bonding with the ammonio proton will be similar in both cases. Nevertheless, in spite of increased steric hindrance in the di-ortho-derivative and of the expected greater resonance stabilization of the intermediate by a para- than by an ortho-nitro group, and hence an overall higher energy of the transition states of the substitution of 2,6-DNA when compared with its 2,4-isomer, the inverse effect is observed. The accepted mechanism for the uncatalysed step involves a transfer from an ammonium proton to the nucleofuge in concert with the departure of the leaving group, as shown by complex 7. When there are two o-nitro groups, the quaternary ammonium proton can be hydrogen-bonded to one or the other; formation of this intermediate is favoured by the twisting of the methoxy group, giving a more favourable ‘looser’ transition state. In the reactions of the same substrates with piperidine, SN 2 reactions are observed together with SN Ar. The SN Ar reaction of 2,6- is 10 times faster than that of the 2,4-, while the SN 2 reaction is 103 times faster107 . The spectacular inversion in reactivity was interpreted as due to a favourable field effect by the ortho-nitro group. It was proposed that the methoxy group in 2,6-DNA would adopt a conformation perpendicular to the ring plane and the greater reactivity of 2,6- over 2,4-DNA would be due to a favourable field effect, as in the previous reaction with cyclohexylamine107 . To confirm this assumption, the SN 2 reaction with N-methylpiperidine in benzene was also studied. As expected on the grounds of the favourable field effect, the 2,6-DNA was nearly 300 faster than the 2,4-DNA107 . SN Ar with other 6-R-2-nitroanisoles R D alkyl were also studied and the results compared with the 4-R-2-nitroanisoles83a . It was found in all cases that 6-R reacted faster than the 4-R consistent with the absence of primary steric effects due to the proposed twisting of the di-ortho-substituted anisoles. However, the more striking result was the spectacular reactivity of the 6-bromo- and the 6-nitro-isomer, in spite of the electronic and steric effects; e.g. in the reaction with cyclohexylamine in benzene 6-Br is almost 104 more reactive than the 4-R83a . It was proposed that the methoxy group in the diortho-substituted anisoles is twisted out of the plane of the aromatic ring by the presence of substituents on each side, which facilitates the replacement of methoxy by an amine group. When both substituents are electron-withdrawing groups, the favourable field effect exerted through the space is superimposed on the twisting of the nucleofuge, and both are responsible for the spectacular increase in rate of the 2,6-dinitroanisole when compared with the 2,4-dinitro isomer. Thus, in the case of the DNA with piperidine, the SN Ar reaction with 6-NO2 is nearly 10 times that of the 4-, while the SN 2 is nearly 104 times faster than the 4-NO2 83a . A similar twisting was expected to occur with the phenoxy ether to explain the greater reactivity of the 2,6-isomer in recent studies of the reactions of 2,4-dinitro and 2,6dinitrophenyl phenyl ethers with n-butylamine109 . Nevertheless, in this case, the authors
1244
Norma S. Nudelman
assume that the twisting of the phenyl moiety in the 2,6-substrate will increase the electron density on the oxygen atoms of ‘at least one of the nitro groups in the -complex, leading to stronger ortho-nitro hydrogen bonding of the ammonio hydrogen atoms and to a greater propensity to a reaction third order in nucleophile concentration’109 . When a methyl group is introduced at the 6-position of the 2,4-dinitrophenyl ether, the curvilinear upward kinetic form which is observed was also attributed to the increase in basicity of the ethereal oxygen atom. Notwithstanding, the unexpected increased reactivity of the 6-position in all these systems is well explained in terms of the field effect in all the cases. On the contrary, the changes in the kinetic law, giving rise to a third-order dependence on the nucleophile concentration, require a more comprehensive mechanistic explanation, as will be discussed in Section III. 4. The nitro nucleofuge
When the leaving group is the nitro group, the reactions with amines in aprotic solvents show a behaviour different from SN Ar reactions with other nucleofuges, such as halogens or alkoxy groups, since an intramolecular hydrogen bond may be expected between the leaving nitro group and the ammonium H of the nucleophiles. This effect was observed in the reactions of 1,2-dinitrobenzene with butylamine and piperidine, in several aprotic solvents110 . In solvents such as ethyl acetate, THF, acetonitrile, DMF and DMSO (called solvent set A), neither reaction is base-catalysed and the formation of the intermediate is rate-determining kA D k1 . The sequence and range of reactivity for butylamine and piperidine are similar in these solvents. This is unexpected, considering that from the overall rate constants observed in SN Ar reactions, in which the formation of the adduct is rate-determining, butylamine is usually an order of magnitude less reactive than piperidine1 . Besides the intramolecular hydrogen bond with the o-nitro group, similar to that depicted in complex 6a, another intramolecular hydrogen bond was postulated for 1,2-dinitrobenzene (DNB) (or other substrates where nitro is the nucleofuge) such as that depicted in the intermediate 6b.
H
O N
R
R′
N+
O
O
N −
O
(6b) If this structure makes a major contribution to the stability of the transition state, the usual reactivity and solvent effects found for other nucleofuges with these amines will not be the same in these cases. A structure such as 6b was earlier proposed for rationalizing the unexpected fast expulsion of the nitro group in the reactions of 1,2DNB and 1,2,4-trinitrobenzene with piperidine in benzene111 . This proposal was fully confirmed by the study of the reactions in several aprotic solvents. The reactions of 1,2DNB with butylamine (BA) (Table 10) and piperidine in the set of solvents A could be correlated with the Kamlet Taft38 solvatochromic equation, when the ˇ parameter, which measures the solvent hydrogen-bond acceptor capability, was included in the correlations. The calculated equations as well as the whole F and partial F1 , F2 confidence levels showed the weight of the ˇ parameter110 .
26. SN Ar reactions of amines in aprotic solvents
1245
TABLE 10. Rate constants of reactions between 1,2-DNB and BA in aprotic solvents at various temperaturesa,110 . Reprinted with permission from Reference 110. Copyright (1989) American Chemical Society Solvent
Parameter
Values
Chloroformb
[BA] (M) 0.10 0.20 104 kA (mol1 dm3 s1 ) 0.11 0.15
Ethyl acetatec
[BA] (M) 0.20 0.28d 0.28e 0.30 0.40 0.49 0.50 0.60 104 k (s1 ) 0.32 0.29 0.92 0.52 0.86 1.01 0.95 1.19 104 kA (mol1 dm3 s1 ) 1.97 (r = 0.9979)
THFc
[BA] (M) 0.10 0.11 0.20 0.30 0.40 0.50 0.60 0.30d 0.30e 104 k (s1 ) 0.31 0.34 0.67 1.07 1.28 1.73 1.89 0.61 1.56 104 kA (mol1 dm3 s1 ) 3.29 (r = 0.9989)
ACNc
[BA] (M) 0.10 0.20 0.30 0.40 0.46 0.50 0.55 0.40f 0.40g 104 k (s1 ) 0.23 0.45 0.63 0.81 0.91 1.12 1.29 0.52 1.56 104 ka (mol1 dm3 s1 ) 0.22 (r = 0.9979)
DMFc
[BA] (M) 0.20 0.30 0.40 0.50 0.60 0.40d 0.40e 104 k (s1 ) 0.16 0.24 0.34 0.39 0.52 0.29 0.55 104 kA (mol1 dm3 s1 ) 0.83 (r = 0.9990)
DMSOc
[BA] (M) 0.10 0.20 0.30 0.40 0.50 0.30h 0.30i 104 k (s1 ) 0.24 0.35 0.64 0.77 0.90 0.84 1.16 104 kA (mol1 dm3 s1 ) 18.89 (r = 0.9972)
Diisopropyl etherb
[BA] (M) 0.20 0.30 104 kA (mol1 dm3 s1 ) 0.43 0.52
0.40 0.73
0.50 0.60 0.86 0.91
Tolueneb
[BA] (M) 0.10 0.20 104 kA (mol1 dm3 s1 ) 0.38 0.51
0.30 0.63
0.40 0.50 0.70 0.71 0.81 1.00
Chlorobenzeneb
[BA] (M) 0.26 0.38 104 kA (mol1 dm3 s1 ) 0.73 0.93
0.51 1.10
0.64 0.77 1.00 1.02 1.31 1.47 1.51 1.90
0.30 0.18
0.40 0.50 0.60 0.70 0.18 0.20 0.22 0.23
a [1,2-DNB] ³ 104 M. b Reactions at 27.0 š 0.1 ° C unless stated otherwise. c Reactions at 27.5 š 0.1 ° C unless stated otherwise. d 17.0 š 0.1 ° C. e 37.0 š 0.1 ° C. f 16.3 š 0.1 ° C. g 36.3 š 0.1 ° C. h 34.5 š 0.1 ° C. i 42.0 š 0.1 ° C.
In non-polar solvents such as benzene, toluene, chlorobenzene and diisopropyl ether (called solvent set B), a mild acceleration is observed, and the reactions are slower than in hexane. A molecular complex (see below) is proposed to explain the results for the reactions in solvent set B. E. Molecular Complexes
It is now well established that molecular complexes may play a catalytic role in chemical transformations112,113 , and their influence in the SN Ar reactions with amines is the subject of intense research activity at present8,10,110,113 117 . Although there is no total acceptance that these complexes are real intermediates on the reaction path, increasing evidence is being accumulated regarding their role in the substitution reactions. The curve-crossing (configuration mixing) model118 120 has proved very useful in providing a
1246
Norma S. Nudelman
qualitative insight into the origin of activation barriers in reactions between nucleophiles and electrophiles, and of the contribution of donor acceptor pairs in the reaction pathway. It has been recently shown that the differences between charge-transfer transition energies calculated for donor acceptor pairs at infinite separation and values determined experimentally for the charge-transfer complex geometry vary according to the charge type of the pairs and within a group of fixed charge type121 . Intramolecular charge-transfer (ICT) interactions in aromatic amines are considered and have been recently studied in hydroxylic solvents in their connections with hydrogen-bond-induced rehybridization of trivalent nitrogen atoms. Most of the experimental studies concerning the formation of electron donor acceptor (EDA) complexes between nitroaromatics and amines have been reported by Silber and coworkers9,115 117 . On the basis that 1,2-DNB forms stronger EDA complexes with aliphatic amines in hexane than 1,3- or 1,4-DNB116a the authors proposed the catalytic effect of EDA complexes in the reactions with aliphatic primary116b and secondary117 amines, as shown in Scheme 3. Although the kinetic behaviour would be also consistent with a classical base-catalysed decomposition of the -complex as in Scheme 1, preference is given to Scheme 3 based on the observation of absorbances attributed to EDA complexes between substrate and reactants at zero reaction time. In the case of secondary amines, such as, e.g. piperidine, the behaviour of the rate coefficients with the amine (Am) concentration could be best explained in terms of the formation of the [1,2-dinitrobenzene piperidine] complex. Application of the stationary-state hypothesis to the mechanism of Scheme 3 given equation 16, where kA is the observed second-order rate constant. kA D
k1 k2 C k1 Ks k3 B [Am] k1 C k2 C k3 B [Am]1 C Ks [Am]
(16)
kA D
k1 k2 Ks k1 Ks k3 B [Am] C k1 k1
(17)
NO2
NO2 NO2
NO2 k5
+ RNH2
RNH2
1,2- DNB k′1
k′− 1
R HNR
O2 N NO2
H
+
H NO2
k2 −
RNH2
k3
N
[RNH2 ]
SCHEME 3
26. SN Ar reactions of amines in aprotic solvents
1247
For Ks [Am] × 1 and k2 Ck3 [Am] − k1 , a linear response to the nucleophile concentration, such as that depicted in equation 8, is obtained. This behaviour is characteristic of most base-catalysed reactions. On the other hand, whereas all the studied reactions were base-catalysed in n-hexane, only mild acceleration was observed in benzene9 . Also, the reactions seem to be inhibited in benzene and other electron-donor solvents, and Silber and coworkers attributed this effect to a preferential solvation exerted through EDA complex formation with the aromatic substrate, as shown in Scheme 49 . 1, 2- DNB
+
PIP
Ks
[1,2- DNB.PIP] ku
+
D
Products
KD kc
[1,2- DNB.D]
PIP
SCHEME 4
These studies have been recently extended to the reaction of n-butylamine (n-BA) and piperidine (PIP) with other aromatic substrates, such as 1-chloro-2,4-dinitrobenzene (CDNB) and 4-chloro-3-nitrotrifluoromethylbenzene (CNTFB) in hexane, benzene, mesitylene and binary mixtures of hexane with the aromatic solvents, and the results are consistent with Scheme 4 which includes the proposal of a preferential solvation with the donor solvent, D115 . As expected, a decrease in rate was observed in the reactions with butylamine with increasing amounts of the donor solvent, which was attributed to the formation of the EDA complex with the solvent. The result is expressed by equation 18 which, in the limiting case where Ks − KD , reduces to equation 19. k D
Ks ku C kc KD [D][Am] 1 C Ks [Am] C KD [D]
(18)
k D
Ks ku C kc KD [D] [Am] 1 C KD [D]
(19)
By fitting equation 19 with the experimental data, the values of KD were obtained for the following systems: CDNB benzene D 0.76 š 0.02, CNTFB benzene D 0.26 š 0.02, CDNB mesitylene D 0.96 š 0.02 and CNTFB mesitylene D 0.48 š 0.02 mol1 . It can be observed that KD increases with increasing donor strength of the aromatic solvents115 . For the reactions with piperidine, on the contrary, an increase in rate was observed with increased molar fractions of the donor solvent. This result was interpreted as a conventional solvent effect since, in this case, KS ¾ D KD . The SN Ar reactions with amines in chloroform show a peculiar behaviour and the rates cannot usually be correlated with reactions in other solvents. It has been observed in the reaction of 2,4-dinitrochlorobenzene with piperidine48c and in the reaction of 1,2DNB with butylamine115 that chloroform exerts a special solvent effect due to its known hydrogen-bond donor ability. Thus, an association between the solvent and the nucleophile can be postulated as a side-reaction to the SN Ar115 . Associations of chloroform with amines are known122 and the assumption of a partial association between piperidine or butylamine and chloroform as the cause of the downward curvature in the plots of kA vs [amine] seems plausible. Forlani and coworkers123 studied the reactions of 1-halogeno-2,4,6-trinitrobenzene with 2-hydroxypiridine in aprotic solvents: the reaction provides two isomeric products as
1248
Norma S. Nudelman
shown in Scheme 5. For X D Cl, in THF at 45 ° C the reaction afforded compound 8a in 68% relative yield, and 32% of compound 8b. In the presence of 2-hydroxypyridine compound 7 is quantitatively converted into compound 8b. The authors studied the kinetics of the reaction of 2,4-dinitrofluorobenzene in THF, toluene and chlorobenzene in excess of 2-hydroxypyridine, and the data are gathered in Table 11, which also includes data of the reaction of 2,4-dinitrochlorobenzene in chlorobenzene.
N H +
O
Hal
N NO2
O2 N
O2 N
O
+
N
O NO2
NO2 O2 N
NO2
NO2
NO2 (8b)
(8a) SCHEME 5
It can be observed that kobs increases with increasing initial concentration of 2hydroxypyridine. The authors interpret the increase in rate as due to the formation of a molecular complex as shown in Scheme 6; the equilibrium constant K for the formation of the complex was estimated in each case and the values are shown in Table 12. Some observations on these results are discussed in Section III. FTNB
K (+Py)
Pathway 0
(+Py)
(+Py) k 10
Molecular complex Pathway C
k −10
k1
k −1
Zwitterionic intermediate
Zwitterionic intermediate
k2
k2 0
Product SCHEME 6
Other interesting data in these reactions concern the H/D isotopic effect of the nucleophile/catalyst, for example when [2-hydroxypyridine] D [2 O2 H] D 0.08, kobs H /kobs D D 1.5. Since a very poor H/D effect is usual in SN Ar reactions with neutral nucleophiles (amines) in apolar solvents1c , the authors conclude that the unusually high H/D effect should be due to a difference in the KH /KD D 1.75 of the molecular complex. Nevertheless, the same effect could be explained on the basis of an autoassociation of
26. SN Ar reactions of amines in aprotic solvents
1249
TABLE 11. Kinetic data for reactions between FTNB (2,4,6-fluorotrinitrobenzene) and Py in chlorobenzene (unless otherwise indicated)123 T D 45 ° C; [FTNB]0 D 6.5 ð 104 mol dm3 102 [Py]0 (mol dm3 ) 3.09 102 kobs (dm3 mol1 s1 ) 3.50
4.63 4.94
6.18 6.52
7.72 7.56
T D 35 ° C; [FTNB]0 D 6.5 ð 104 mol dm3 102 [Py]0 (mol dm3 ) 3.10 102 kobs (dm3 mol1 s1 ) 2.80
4.65 4.04
5.27 4.52
6.20 5.01
T D 25 ° C; [FTNB]0 D 5.5 ð 104 mol dm3 102 [Py]0 (mol dm3 ) 1.41 102 kobs (dm3 mol1 s1 ) 0.944 102 [Py]0 (mol dm3 ) 6.30 102 kobs (dm3 mol1 s1 ) 3.43
1.88 1.27 7.96 4.51
2.35 1.45 9.02 5.08
3.15 2.05 10.6 5.75
4.73 2.68
T D 25 ° C; [FTNB]0 D 2.9 ð 104 mol dm3 102 [2 H-Py]0 (mol dm3 ) 3.64 102 kobs (dm3 mol1 s1 ) 1.46
4.86 1.96
6.07 2.30
8.03 2.94
9.45 3.50
2.24 4.54
3.14 5.77
3.85 6.29
4.71 7.66
3.61 4.71 9.09 12.0
5.40 6.66
6.05 8.44
7.20 9.88
2.05 1.78
3.11 2.25
3.22 2.30
T D 25 ° C; [FTNB]0 D 2.9 ð 104 mol dm3 102 [Py]0 (mol dm3 ) 1.57 102 kobs (dm3 mol1 s1 ) 3.50
a
T D 25 ° C; [FTNB]0 D 3.7 ð 104 mol dm3 102 [Py]0 (mol dm3 ) 1.80 103 kobs (dm3 mol1 s1 ) 2.44 102 [Py]0 (mol dm3 ) 8.23 103 kobs (dm3 mol1 s1 ) 11.1
b
T D 45 ° C; [CTNB]0 D 3.5 ð 104 mol dm3 10[Py]0 (mol dm3 ) 1.73 105 kobs (dm3 mol1 s1 ) 1.59
c
a In THF. b In toluene. c In chlorobenzene.
TABLE 12. kc and K valuesa (see text) for reactions between FTNB (2,4,6fluorotrinitrobenzene) and Py123 T (° C)
kc (dm3 mol1 s1 )
K (dm3 mol1 )
nb
Rc
25d 35d 45d 25d,e 25f 25g 45d,h
0.21 š 0.05 0.29 š 0.06 0.48 š 0.2 0.23 š 0.06 0.17 š 0.02 0.4i 4.7 š 0.1 ð 105
3.5 š 0.9 3.6 š 0.8 3.0 š 1 2.0 š 0.06 17 š 2 0.34j 2.9 š 0.1
9 4 4 5 5 7 4
0.9982 0.9991 0.9976 0.9986 0.9976 0.9994 0.9999
a Errors are calculated from standard deviations. b Number of points. c Correlation coefficient. d In chlorobenzene. e Monodeuteropyridone. f In THF. g In toluene. h 1-Chloro-2,4,6-trinitrobenzene. i Indicative value: error is higher than value. j Indicative value: 1/k K D 7.4 š 0.2. c
1250
Norma S. Nudelman TABLE 13. Apparent stability constants of molecular complexes between 2-hydroxypyridine and some aromatic nitro derivatives in benzene-d6 at 25 ° C125 . Reproduced by permission of societ`a chimica Italiana from Reference 125 Nitro derivative
K (mol1 )a
nb
Rc
DNBd CNBe CDNBf CTNBg OFNBh PFNBi FDNBl PFNBi,m FDNBl,m
0.12 š 0.01 0.36 š 0.02 0.22 š 0.03 0.31 š 0.02 0.19 š 0.01 0.51 š 0.04 0.42 š 0.03 0.15 š 0.01 0.25 š 0.02
4 5 5 5 6 5 5 5 5
0.996 0.999 0.979 0.992 0.995 0.993 0.992 0.994 0.991
a Errors are standard deviations. b Number of points. c Correlation coefficient. d 1,3-Dinitrobenzene. e 1-Chloro-4-nitro-benzene. f 1-Chloro-2,4-dinitrobenzene. g 1-Chloro-2,4,6-trinitrobenzene. h 1-Fluoro-2-nitrobenzene. i 1-Fluoro-4-nitrobenzene. l 1-Fluoro-2,4-dinitrobenzene. m Monodeutero-2-hydroxypyridine.
the nucleophile, since the tendency of 2-hydroxypyridine to form dimeric species is very well known124 . The study of molecular complexation was then extended to other aromatic nitro derivatives125 . Although, as was described before, one of the more frequent methods of studying the formation of molecular complexes is by UV-visible spectrophotometry, the author did not observe detectable differences in the UV-visible absorbance spectra between the 2-hydroxypyridine 1-fluoro-2,4-dinitrobenzene (FDNB) mixtures and the sum of their separate components. The author observed that the signals of the 1 H NMR spectra of FDNB in apolar solvents were shifted downward by the addition of 2-hydroxypyridine: from solutions where [2-hydroxypyridine] − [FDNB] he calculated the apparent stability constants, which are shown in Table 13. F. Electrophilic Catalysis
When expulsion of the nucleofuge is rate-determining, stabilization of the transition state for the leaving group departure is important especially in solvents of low permittivity. Because of the anionic nature of the nucleofuge in the zwitterionic intermediate, acid catalysis has been sought since early times but the results were rather controversial1 . Capon and Rees126 suggested that in aprotic solvents the catalysed reaction proceeded via a cyclic intermediate such as shown by 9. On the other hand, Orvick and Bunnett19 were able to measure separately the rates of formation and decomposition to products of the intermediate (the conjugate base corresponding to 2 in Scheme 1) formed in the reaction of 2,4-dinitro-1-naphthyl ethyl ether with butylamine in DMSO. The decomposition of the intermediate was found to be first-order in n-butylammonium ion, but independent of the free amine concentration, and this was an important piece of evidence of the SB-GA.
26. SN Ar reactions of amines in aprotic solvents
1251
R2
R1 N H L
+
H NR1R2 NO2
−
NO2 (9)
Recently, Hirst and collaborators127 have carried out a more comprehensive search for electrophilic catalysis in SN Ar reactions with primary and secondary amines in dipolar aprotic solvents. Thus, the effects of lithium, trialkylammonium and tetraalkylammonium ions on the reactions of piperidine with 2,4-dinitroanisole and of morpholine with 2,4dinitrophenyl phenyl ether were investigated in DMSO. Although the reaction between 1-fluoro-4-nitrobenzene and trimethylamine in DMSO had been previously found to be catalysed by trimethylammonium and lithium ions127 , no evidence for electrophilic catalysis was found in the present systems. In the case of lithium ions, expulsion of the methoxy or phenoxy groups was not catalysed by this ion. When the putative catalysts are trialkylammonium ions, the lack of catalysis could be due to an unfavourable equilibrium between the ions and piperidine in the case of the methoxide expulsion, as was observed by Nudelman and Palleros104 for the reactions of piperidine with 2,4- and 2,6dinitroanisole in benzene. But in the phenyl ether morpholine system, this is not the case, and although catalysis of the ejection of the phenoxy group has never been demonstrated experimentally, the premise that it does occur is the basis of the SB-GA mechanism19 . The lack of catalysis could be due to steric effects. Crampton and Routledge24 have shown that steric effects operate in the ejection of the leaving group when the nucleophile is piperidine and the catalyst is its conjugate acid. Similarly, reductions in the rate constants for proton transfers from the zwitterionic intermediates to amines to less than expected for diffusion-controlled reactions have been attributed to steric effects. Additionally, Hirst and coworkers128 have tentatively proposed a contribution of ‘proximity’ effects. In the system studied by Orvick and Bunnett19 the conjugate acid of the base that removes the proton from the intermediate is generated in the immediate vicinity of the nucleofuge and hence has an advantage over other catalysts in solution. Nevertheless, the effect of HBA additives was investigated with regard to the homo heteroconjugate mechanism (see below) and electrophilic catalysis was found. Recently, Forlani129 studied the reactions of fluoro dinitrobenzene (FDNB) with several amines in the presence of some compounds that have been found to catalyse the reaction. The plots of kobs vs [catalyst] show a linear dependence at low catalyst concentration and then a downward curvature. This behaviour has been previously observed in several related cases: the usual interpretation is that the kobs increases on increasing the [catalyst] value until it reaches a maximum when k1 D k1 C k2 [catalyst]. The deviation from linearity was explained by including a third term due to the catalyst in the rate law equation (equation 20) and the results are given in Table 14. kobs D A C B [catalyst] C C [catalyst]2
20
1252
Norma S. Nudelman
TABLE 14. A, B and C values (see text) for reactions between FDNB and amines in the presence of various catalysts at 25 ° C (errors are standard deviations)129 . Reproduced by permission of Societ`a Chimica italiana from Reference 129 Aminea
Sb
Catalystc
Ad
Be
Cf
ng
rh
Pip Pip Pip Pip Pip Pip Pip Bu Bu Bu Bu t-Bu
Bz Bz Bz Bz D Ch Ch Bz Bz Bz Bz Bz
1 2 5 6 1 1 8 1 9 10 11 1
1.29 š 0.1 1.40 š 0.3 1.90 š 0.5 1.28 š 0.3 2.29 š 0.2 23.5 š 0.6 23.0 š 0.3 0.21 š 0.01 0.26 š 0.05 0.23 š 0.04 0.22 š 0.2 1.89 š 0.04 ð103
960 š 30 460 š 100 1070 š 200 730 š 100 320 š 20 900 š 300 250 š 40 5.8 š 0.7 13 š 2 13 š 2 9š1 6.5 š 0.6 ð102
1.9 š 0.1 ð 104 1.9 š 1 ð 104 3.6 š 1 ð 104 2.6 š 1 ð 104 1.6 š 0.1 ð 103 5.7 š 2 ð 104 6.3 š 0.9 ð 104 20 š 7 39 š 13 49 š 14 26 š 8 1.1 š 0.1
6 5 9 6 9 5 4 8 7 6 6 6
0.999 0.978 0.979 0.989 0.989 0.949 0.992 0.992 0.993 0.995 0.997 0.995
a Pip D piperidine; Bu D n-butylamine; t-Bu D t-butylamine. b Solvent: Bz D benzene; Ch D chloroform; D D p-dioxan. c Numbers refer to the original publication. d In s1 M1 . e In s1 M2 . f In s1 M3 . g Number of points. h Correlation coefficient.
TABLE 15. Dissection of experimental data (k2 and K values, see text) for reactions between FDNB and amines in the presence of various catalysts at 25 ° C129 . Reproduced by permission of Societ`a Chimica Italiana from Reference 129 Aminea
Sb
Catalystc
k2 d
Ke
rf
Pip Pip Pip Pip Pip Pip Pip Pip Bu Bu Bu Bu t-Bu
Bz Bz Bz Bz Bz D Ch Ch Bz Bz Bz Bz Bz
1 2 5 6 7 1 1 8 1 9 10 11 1
12 4.2 14 9.0 8.0 35 27 27 0.80 2.0 1.2 1.1 4.1 ð 103
141 515 153 145 183 13 1120 362 16 13 31 19 26
0.999 0.978 0.992 0.996 0.998 0.998 0.999 0.949 0.995 0.998 0.986 0.994 0.983
a Pip D piperidine (pK D 11.06); Bu D n-butylamine (pK D 10.59); t-Bu D t-butylamine (pK D 10.8). a a a b Solvent: Bz D benzene; Ch D chloroform; D D p-dioxan. c Numbers refer to the original publication. d In s1 M1 . e In M1 . f Correlation coefficient.
Nevertheless, it can be observed that the significant values are in B, and these show a strong influence of the amine used. The author129 interpreted the results through a mechanism involving a molecular complex substrate, and calculated the values of k2 and of the equilibrium constant K, shown in Table 15. Again, the significant values depend on the nucleophilic power of the amine. If such a molecular complex between
26. SN Ar reactions of amines in aprotic solvents
1253
the substrate and the catalyst would exist (the author suggests an interaction between the amido group and the fluorine atom or the nitro group), it should be possible to detect it since, in this case, it would not react as it occurs with other previously studied catalysts. Nevertheless, the author was unable to detect any interaction between the catalyst and FDNB. The downward curvature observed in this and other systems could be easily explained in terms of a ‘mixed aggregate’ between the catalyst and the nucleophile. A hydrogen-bond donation to the amide catalyst would render the amine a better nucleophile, up to a value of ‘saturation’, after which increasing amounts of catalysts should have no further effect. The results in Table 15 can be easily explained in the same terms, where K measures the equilibrium of the association between the amine and the catalyst. G. Aromatic Nucleophilic Substitution with Amines in which the Nucleofuge is a Sulphur Derivative
Ethyl 2,4,6-trinitrophenyl sulphide. Crampton’s group130,131 has recently studied the reaction of amines with activated substrates where the nucleofuge has a sulphur atom attached to the reaction centre. Thus, in the reactions of ethyl 2,4,6-trinitrophenyl sulphide with butylamine and with pyrrolidine in DMSO, substitution occurs without the accumulation of intermediates on the reaction pathway130 . With n-butylamine a firstorder dependence on amine was observed indicating that nucleophilic attack, k1 , was rate-determining, whereas with pyrrolidine a squared dependence on amine was observed. The authors argued that base catalysis in this reaction was likely to involve rate-limiting proton transfer from the zwitterionic intermediate, based on the failure to observe an intermediate on the lower kinetic barrier expected for loss of an alkylthio relative to an alkoxy group132 , and on the unlikelihood of general acid catalysis involving proton transfer to a sulphur atom. 40 -Substituted Phenyl 2,4,6-trinitrophenyl sulphides. By UV-VIS measurements of the reactions of 40 -substituted phenyl 2,4,6-trinitrophenyl sulphides with amines in DMSO, Crampton’s group131 showed the presence of two well-separated processes which were interpreted by Scheme 7129 . In each case a rapid reversible equilibrium was established leading to the 3-adduct (10). They also observed a second, much slower process resulting in formation of the N-substituted picramide derivatives, 13. The final spectra were identical to those of the independently prepared products, 13. Chamberlain and Crampton133 showed that the reaction products are in rapid equilibrium with anions derived from them by amine addition at the 3-position and/or loss of a side-chain proton, but they did not find evidence for the accumulation of spectroscopically observable concentrations of intermediates such as 12. By application of the steady-state treatment to Scheme 7, the authors calculate the general rate expression for reaction at the 3-position to produce adducts 10 kfast , and the rate expression for product formation kslow , respectively (equations 21 and 22). k3 kAm [Am]2 C k3 kAmH C [AmHC ] k3 C kAm [Am] k1 kAm [Am]2 [Am]2 1 C 1 C Kc,3 D k1 C kAm [Am] [AmHC ]
kfast D kslow
Am D R1 R2 NH; AmHC D protonated R1 R2 NH2 C
(21)
(22)
O2 N
(a) R = H (b) R = Me (c) R = Br (d) R = NO2
NO2
S
R
k3 k -3
NO2
−
NO2
+ 2R1R2 NH
O2 N
S
R
k- 1
k1
H
+ NHR1R2
NO2
R
O2 N
+ R1R2 NH
S
kA m
O2 N
S
O2 N
SCHEME 7
(11)
NO2 (13)
k4
R
SH (13)
(12)
NO2
+ + NH2 R1R2
+ NHR1R2
NR1R2
NO2
O2 N
NO2
+
R
+ + NH2 R1R2
−
NO2
k A m H+
kA m +
NR1R2
NO2
H
NR1R2
+ R1R2 NH
(10)
NO2
−
S
−
NO2
+ NHR1R2
k A m H++
R
1254
26. SN Ar reactions of amines in aprotic solvents
1255
The above equations could be further simplified by limiting conditions and the authors found that, in the reactions with pyrrolidine, the values for kfast showed that in the formation of the 3-adduct 10, the proton transfer is partially rate-limiting, whereas the kslow relating to the displacement of the phenylthio group showed a squared dependence on the pyrrolidine concentration: this is compatible with the proton transfer being the ratedetermining step in the substitution. On the other hand, the values of kfast and kslow increase linearly with the amine concentration for the reactions with butylamine, indicating that nucleophilic attack is rate-determining. A Hammett plot of the values of Kc,3 for these reactions has a slope, , of 1.2: the authors133 recognize that in view of the remoteness of the substituents from the reaction centre, this value is surprisingly large and indicates that the phenylthio groups play a significant role in delocalizing the negative charge in the adduct. For comparison, Crampton and coworkers134 have previously determined the for the related process of hydroxide addition at the 3-position and found a value of 0.98 Phenyl 2,4-dinitronaphthyl sulphide, 14. Chamberlain and Crampton130 showed by UVVIS determinations of the reactions of phenyl 2,4-dinitronaphthyl sulphide 14 with amines in DMSO that the reactions proceed through the formation of a single intermediate (Scheme 8) resulting in the quantitative formation of the product, 15. In the reactions with SPh
NHR1R2
PhS NO2
NO2 k1
+ 2R1R2 NH
_
k-1
NO2
NO2
kA m k A m H+
(14) NR1R2
PhS
NO2 _
+ + NH2 R1R2 k2
NO2 k4
NR1R2 NO2 PhSH + NHR1R2 +
NO2 (15)
SCHEME 8
+ R1R2 NH
1256
Norma S. Nudelman
n-butylamine kobs increases linearly with [butylamine], whereas in the reactions with pyrrolidine the plot of kobs /[pyrrolidine] versus [pyrrolidine] passes through the origin, and curves with decreasing slope as [pyrrolidine] is increased. That the plot passes through the origin indicates that the uncatalysed pathway, k2 , is unimportant, while the curvature indicates that the proton transfer step, kAm , is partially rate-limiting. Phenyl 2,6-dinitro-4-trifluoromethylphenyl sulphide. Chamberlain and Crampton130 studied also the reaction of phenyl 2,6-dinitro-4-trifluoromethylphenyl sulphide with amines in DMSO. They observed a single rate process with butylamine giving the expected substituted product; again, the observed rate constant increased with [butylamine]. In the reaction with pyrrolidine a rapid reaction giving the 3-pyrrolidino adduct was observed, which could be suppressed by addition of pyrrolidinium perchlorate. Under these conditions the expected 1-substituted product was formed. It can be concluded that in the reactions of amines with activated substrates derived from substituted arylthio-derivatives in DMSO, the reactions with pyrrolidine are faster than with butylamine. The rate-determining step in the formation of 3-adducts changes from nucleophilic attack with n-butylamine to proton transfer, partially rate-limiting with pyrrolidine and fully rate-determining with piperidine. Crampton and coworkers found that the major factor is the change in kAm with the changing nature of the amine. Although the proton transfer step leading to adducts 10 is thermodynamically favoured, values of the rate constants are very much lower than those expected for diffussion-controlled reactions. This reflects steric hindrance to the approach of the reagents, which becomes increasingly severe as the amine is changed from n-butylamine to pyrrolidine to piperidine. For reactions at the 1-position, with butylamine as the nucleophile, nucleophilic attack is rate-determining, whereas when pyrrolidine is the nucleophile the reactions are basecatalysed, and the values of K1 kAm show a small dependence on the nature of the 40 -substituent. The relatively small decrease on changing the 1-substituent from SPh to SEt is compatible with the interpretation that, in the reactions with pyrrolidine, proton transfer from the zwitterionic intermediate to amine is rate-limiting. The authors also discussed why the alternative explanation of base catalysis in terms of the SB-GA mechanism is less preferred; a greater sensitivity on the nature of the leaving group should be expected if this mechanism were operating. Acid-catalysed expulsion of the nucleofuge is also unlikely in view of the pKa values of the group involved. H. Aromatic Nucleophilic Substitution with Amines under High Pressure
Several studies have recently appeared on the acceleration of SN Ar reactions by high pressure135 139 . Ibata and coworkers135,136 studied the SN Ar reaction of mono-, di-, triand pentachloronitrobenzenes with various amines under high pressure. In particular, when pentachloronitrobenzene (16) is heated at 50 ° C for 20 h with 6.0 molar equivalent of morpholine at 0.60 GPa in tetrahydrofuran (THF) solution in the presence of 5.0 molar equivalent of triethylamine, several products were isolated and are shown in Scheme 9. Table 16 shows the results of the same reaction under different pressures between atmospheric pressure (104 GPa) to 0.78 GPa. At atmospheric pressure, nitro-groupsubstitution product, 18a, and o-mono- and p-monosubstitution products 19a and 20a were obtained in a total yield of 7.4% recovering 92% of the starting pentachloride 16. When the pressure was raised, the yields of these monosubstitution products increased; at higher pressures di- and trisubstitution products appeared and this trend continued in the reactions under pressures above 0.60 GPa, affording higher yields of the trisubstitution product 23a. These results indicate that the second substitution occurred at the pressure
26. SN Ar reactions of amines in aprotic solvents Cl
Cl
NO2
Cl
Cl
+ R2 NH
0.6 GPa
1257
Cl
R2 N
50°C, 20 h
Cl
THF/NEt 3
Cl
Cl
Cl
(16)
(17)
R2 N
(18)
Cl
+ NO2
Cl
(b) R2N =
R2 N
Cl
Cl
Cl
Cl
R2 N
(20) R2 N
−
Cl
NR2 + NO2
+
(19) (a) R2N = O
Cl
Cl + NO2
Cl
Cl
Cl (21)
Cl
R2 N
Cl
N
+ NO2
−
N
(c) R2N = (C2H5)2N
−
NR2 + NO2
Cl
Cl
NR2
R2 N
(22)
Cl (23)
SCHEME 9 TABLE 16. Pressure effect of the SN AR reaction of pentachloronitrobenzene with morpholinen Reprinted by permission of The Chemical Society of Japan
Run
18
19
20
21
22
1 2 3 4 5 6 7 8
1/10000 0.10 0.20 0.30 0.40 0.50 0.60 0.78
0.6 1.0 1.7 2.6 2.6 2.9 2.6 3.2
6.0 18.6 40.0 65.4 63.5 50.0 19.3 3.0
0.9 4.0 9.0 14.2 14.9 7.9 1.2 0.6
0 0 0.4 4.4 6.0 18.6 40.2 52.9
0 0 0.4 3.4 4.4 14.6 25.8 24.0
.
23
Total yield (%)
18/Total yield
Recovered 16(%)
0 0 0 0 0 0 3.7 12.1
7.5 23.6 51.5 90.0 91.4 94.0 92.6 95.8
0.080 0.042 0.038 0.029 0.028 0.030 0.028 0.033
92.2 75.8 47.1 8.3 4.6 0 0 0
Yield (%)b
Pressure (GPa)
136
a The reactions were carried out under the following conditions using 1.0 mmol of 16 and 6.0 mmol of 17; 50 ° C, 20 h, in THF. b Determined by HPLC.
over 0.20 GPa and that the third substitution does not proceed below 0.60 GPa, according to what is expected on the basis of the reduced activation of the corresponding reaction centre. By comparing the results observed on changing the amount of morpholine from 1.0 to 15.0 molar equivalent relative to 16, it is again confirmed that the di- and trisubstitution reactions are slower than the mono substitution.
1258
Norma S. Nudelman
The reactions of 16 with pyrrolidine and diethylamine were studied at 0.60 GPa in a similar way described above, with or without triethylamine, as shown in Table 17. It can be observed that even with 10.0 molar equivalent of diethylamine only mono-substitution products 18c, 19c and 20c were obtained, whereas pyrrolidine yielded the trisubstitution product 23b in higher yield than did morpholine. The authors explained these results on the basis of the bulkiness of the amines135 . The effect of steric hindrance was further studied by comparing the reactivity of primary and secondary amines of different steric requirements with 2,3,5,6-tetrachloronitrobenzene, 24 (Scheme 10)140 . It is shown in Table 18 that open-chain amines give higher yield of the nitro-substitution products. Cl
Cl
Cl 0.6 GPa
+ R1R2 N H
NO2
Cl
Cl
R1R2 N
50 °C, 20 h THF/Et 3 N
Cl
Cl
Cl
(24)
(25) 1 2
RR N
NR1R2
Cl
Cl
+
+
+ NO2
NO2
Cl
Cl
Cl (26)
R1R2 N +
(27) R1R2 N
Cl +
NO2
R1R2 N
Cl
Cl (28)
Cl
NO2
NR1R2
Cl (29)
SCHEME 10
The reactivity and regioselectivity in the first and second substitutions steps were studied by Ibata’s group141 in the reactions of 24 with 6.0 molar equivalent of morpholine and pyrrolidine, monitoring the kinetics of formation of the reaction products by 1 H NMR measurements. In the reactions with morpholine (Figure 8), the yields of 25a, 26a and 27a increased monotonously during the initial 20 h, while 1 decreases monotonously to zero recovery. The amount of 26a decreases slowly after 20 h: this indicates that the second attack of morpholine proceeds slowly to give 28a and 29a, in contrast to no attack on 27a. The reaction of pyrrolidine is faster than that of morpholine142 and almost all 16 was consumed in the first 10 h (Figure 9). An interesting feature in this reaction is that the
1.0 2.0 3.0 4.0 5.0 6.0 10.0 15.0 1.0 2.0 3.0 4.0 5.0 6.0 10.0 15.0 6.0 10.0 1.0 6.0 10.0 1.0 6.0 10.0
5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 0 0 5.0 0 0 5.0 0 0
Amount of NEt3 (mmol) 0.60 0.60 0.60 0.60 0.60 0.60 0.60 0.60 0.78 0.78 0.78 0.78 0.78 0.78 0.78 0.78 0.60 0.60 0.60 0.60 0.60 0.60 0.60 0.60
Pressure (GPa) 2.4 2.5 2.4 2.4 2.5 2.6 2.4 3.0 2.3 2.4 2.9 3.3 3.2 3.2 3.2 3.0 3.1 3.6 18.2 34.1 40.7 0 1.9 3.7
18 57.2 62.8 50.3 35.7 28.4 19.3 11.9 2.5 53.7 42.0 24.2 10.5 4.1 3.0 0.5 0 26.6 0 48.8 1.5 0 40.4 62.5 73.8
19
135
15.6 15.6 10.0 5.3 3.6 1.2 0.5 0.2 15.7 9.3 3.1 1.4 0.6 0.6 0.2 0 3.5 0 17.0 0 0 11.8 8.5 12.4
20 1.2 6.8 16.2 26.4 32.7 40.2 44.4 46.0 3.8 20.1 34.6 45.2 50.9 52.9 50.9 46.0 34.0 50.0 2.4 20.0 8.5 0 0 0
21
Yield (%)b
a The reactions were carried out under the following conditions using 1.0 mmol of 17; 50 ° C, 20 h, in THF. b Determined by HPLC for Run 1 16. Isolated by column chromatography for Run 17 24.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Run
Amount of HNR2 (mmol)
Reaction of pentachloronitrobenzene with secondary amines under high pressurea
Amine 17
TABLE 17.
2.5 6.1 12.7 19.7 22.8 25.8 25.2 23.1 3.0 14.8 23.5 24.7 24.8 24.0 16.1 11.7 21.4 20.4 3.0 3.2 0 0 0 0
22 0 0 0.4 1.5 2.4 3.7 6.1 14.3 0 0.8 2.5 6.4 10.2 12.1 23.8 30.4 4.0 24.1 0 29.8 40.6 0 0 0
23 78.9 93.8 92.0 91.0 92.4 92.8 90.5 89.4 78.0 89.4 90.8 91.5 93.8 95.8 94.7 91.1 92.6 94.5 89.4 88.6 89.8 52.2 72.9 89.9
Total yield (%) 0.030 0.027 0.026 0.026 0.027 0.028 0.027 0.033 0.029 0.027 0.032 0.036 0.034 0.033 0.034 0.033 0.033 0.038 0.200 0.380 0.450 0.000 0.026 0.041
18/Total yield 19.3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 38.5 19.3 2.4
Recovered (%)
1259
1260 TABLE 18.
Norma S. Nudelman Yields of the reaction of 2,3,5,6-tetrachloronitrobenzene (24) with amines140 Yield (%)
Amine Morpholine Piperidine Pyrrolidine Diethylamine Aniline Benzylamine Butylamine iso-Butylamine sec-Butylamine t-Butylamine
25
26
27
28
Total yield (%)
Recovered 24 (%)
Ratio 25/total yield
1.6 5.3 38.0 0 0 64.7 82.8 48.2 40.3 7.3
30.2 72.2 42.1 7.1 0 14.3 15.7 17.7 19.1 12.4
6.7 10.4 8.6 0 0 0 0 3.4 6.6 0
0 0 0.6 0 0 0 0 0.9 1.7 0
38.5 87.9 89.3 7.1 0 79.0 98.5 70.2 67.7 19.7
58.6 8.1 1.9 87.1 100 8.0 1.1 14.4 16.1 74.2
0.042 0.060 0.426 0 0.819 0.841 0.687 0.595 0.371
100
80
Yield (%)
27a 60
40
25a
20
28a 29a
26a
24a
0 0
10
20 Time (h)
30
40
FIGURE 8. Monitoring of products in the reaction of 16 with morpholine141
high yield (45%) of the nitro group substitution product 25c was observed at the early stage of the reaction (5 h), and it remained constant within experimental error after 10 h. The yields of ortho-mono-26c became maximum at 5 h and, after that, 26c decreased gradually with the increase of disubstitution products 28c and 29c until all 26c was consumed completely in 20 h. This means that the second attack of pyrrolidine onto 26c gives disubstitution products 28c and 7c. On the contrary, the decrease in the yield of 27c is found to be slower than that of 26c. Taking into account that the nucleophilicities of morpholine and pyrrolidine do not show a big difference, the authors explained the difference of the regioselectivity between these amines by the bulkiness of the amine, since similar effects of bulkiness on the regioselectivity were observed in the reactions of 24 with several butylamines (Table 18). By comparing CPK models of the Meisenheimer intermediates which should be formed in each case, steric hindrance for substitution of the nitro group (intermediate 30) should be larger than for substitution of any of the chlorine atoms (intermediates 31, 32). This is in accordance with the observed results where bulkiness of the butylamine leads to a diminution of the corresponding nitro-substitution product. Nevertheless, as we have
26. SN Ar reactions of amines in aprotic solvents
1261
50 26a 40
Yield/%
27a 30
20 25a 28a
10
29a 0
0
10
20
30
40
Time/h FIGURE 9. Monitoring of products in the reaction of 16 with pyrrolidine141
explained before, pyrrolidine exhibits an unusual high SN Ar reactivity and it seems that this will also be the effect here, since the steric requirements between both cyclic amines are not extremely different. Cl O −
Cl
Cl
+ N
O + H N R1 2 R
O −
Cl
+ N
−
+ H N R1 R2
Cl
O + N − O
−
O
Cl
Cl
(30)
(31)
Cl
Cl
Cl −
Cl
H
Cl + N R2 R1
(32)
III. SYSTEMS SHOWING ‘ANOMALOUS’ KINETICS A. Fourth-order Kinetics
The classical two-step base-catalysed SN Ar reaction with amines, B, follows the thirdorder kinetic law given by equation 2. As noted in Section II, this equation predicts a straight line in the plot of kA vs [B] or a downward curvature. But several SN Ar reactions with amines in aprotic solvents studied in the last decade exhibit an upward curvature, as is shown in Figure 10 for the reactions of 2,4-dinitroanisole with n-butylamine and the SN Ar reaction of 2,6-dinitroanisole with n-butylamine in benzene143 . In these systems, if kA /[B] is plotted vs [B], straight lines are obtained and a downward curvature may be observed in some cases (as shown in Figure 11 for the reaction of 2,4-dinitroanisole with butylamine in benzene at 60 ° C), which demonstrates that a new kinetic law is obeyed
1262
Norma S. Nudelman
6
(A) 104 kA (s−1 M−1) (B) 104 kSNAr (s−1 M−1) A
B 5
4
3
2
1
(A) 102 [B] (M) (B) 102 [B] (M)
4
8
12
16
20
24
28
FIGURE 10. (A) Reaction of 2,4-dinitroanisole with n-butylamine at 100 ° C. (B) Reaction of 2,6dinitroanisole with n-butylamine at 45 ° C144 . Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society
showing third-order dependence on the amine (equation 23). kA D k[B]2 C k 0 [B]3
23
To the best of our knowledge, the first report of this fourth-order kinetics was published in 1980, for the reactions of 2,4- and 2,6-dinitroanisole with butylamine in benzene143b , and afterwards several other systems were studied in the same laboratory, some of which are shown in Table 19144 . An early observation in these systems was that they frequently exhibited negative energies of activation; it can be observed in Figure 11 that for low [B], the rates at 60 ° C are higher than those at 80 and 100 ° C. Both results, the thirdorder dependence on [B] added to the observation of negative enthalpies of activation (characteristic of the existence of pre-equilibrium in the reaction coordinate), were considered evidence of the aggregation of the nucleophile, and that the reaction could proceed by attack of a dimer of the amine (B:B) superimposed on the classical mechanism by the monomer144 . Amine aggregations are known to be affected by temperature145,146 , inversely so that very low and even overall negative enthalpies of activation are observed where a pre-equilibrium, such as 2B!B:B, exists144 . Although these peculiar kinetics had never been observed before, a careful search in the literature revealed that some ‘anomalous’ results ambiguously ascribed by the authors to ‘unspecific solvent effects’103,147 , were indeed due to the fact that these SN Ar reactions exhibit a fourth-order kinetic law144 . Some of them are shown in Table 20. Shortly afterwards, some other authors reported third-order dependence in amine in SN Ar reactions in aprotic solvents148 152 . Several alternative mechanisms have been suggested to rationalize this kinetic finding and many studies in the last years have attempted to
26. SN Ar reactions of amines in aprotic solvents
1263
TABLE 19. Aromatic nucleophilic substitution in non-polar aprotic solvents. Third-order in amine kinetic law144 . Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society Substrate, S 2,4-Dinitroanisole 2,6-Dinitroanisole
Amine, B cyclohexylamine
p-Fluoronitrobenzene 3,5-Dinitro-2methoxy-pyridine 3,5-Dinitro-2methoxy-piridine
80; 80; 80; 35; 45;
Reference
0.01 0.82 0.10 0.82 0.00 0.06
benzene
35; 50; 60
benzene
60
n-propylamine
0.1 1.5
toluene
60; 80; 100
82
cyclohexylamine
0.01 0.10
toluene
35
12
benzylamine
0.02 0.12
toluene
35
12
o-anisidine o-anisidine-pyridine
0.51 0.61 0.34 0.46 1.25 0.50 0.70 0.70 0.17
100c
60; 60; 60; 27; 35; 45 35 35 27;
n-butylamine cyclohexylamine
0.06 0.05 0.05 0.03 0.03 0.10 0.30 0.10 0.01
Temp. ( ° C)
Solvent cyclohexane benzene benzene benzene cyclohexane benzene:MeOHa toluene toluene-DMSOb benzene
n-butylamine 2,4-Dinitrofluorobenzene
[B]
100c 100c 45 55
35; 45
144a 144a 144b 144a 144a 175 180 180 174 172
a Up to 30% MeOH, b Up to 2% DMSO, c Overall negative activation energies were observed.
103kA (S−1 M−2) [B]
100 °C 80 °C
2
60 °C
1
[B] (M) 0.1
0.2
0.3
FIGURE 11. Reaction of 2,4-dinitroanisole with butylamine in benzene144 . Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society
1264
Norma S. Nudelman
TABLE 20. Reported ‘anomalous’ aromatic nucleophilic substitutionsn from Reference 144. Copyright (1983) American Chemical Society Substrate, S 2,4-Dinitrofluorobenzene 2,3-Dinitronaphtalene 2-Methoxy-3-nitrotiophene 2-Phenoxy-1,3,5-triazine 1-Fluoro-4-nitronaphtalene 1-Fluoro-4,5-dinitronaphtalene 2-Nitrophenyl 2,4,6-trinitrophenyl ether 3-Nitrophenylether 4-Nitrophenylether bis-2,4-Dinitrophenyl ether phenyl 2,4,6-Trinitrophenyl ether
144
. Reprinted with permission Temp. ( ° C)
Amine, B
[B]
Solvent
p-anisidine aniline morpholine piperidine piperidine piperidine n-butylamine n-butylamine
0.05 0.29 0.05 0.30 0.002 0.20 0.02 3.0 0.10 2.04 0.03 0.330 0.03 0.30 0.01 0.24
benzene toluene benzene benzene benzene iso-octane benzene benzene
25 40 25 22; 50; 60 20 23; 71 25 25
Reference 147c 147b 147c 160 103 147a 18 103
aniline aniline aniline morpholine
0.02 0.18 0.18 0.10
0.08 0.25 0.25 0.60
benzene benzene benzene benzene
5, 15, 25, 35 5, 15, 25, 35 5, 15, 25, 35 30
151 151 151 148
aniline
0.03 0.06
benzene
15; 25; 30
150
n Treatment of the reported data shows third-order in amine kinetic laws.
elucidate the factors involved in these reactions. Hirst153 has recently reviewed some of the evidence of the mechanisms proposed in this controversial subject. B. The Eight-membered Cyclic Transition State
In the reactions of anilines with picryl phenyl ethers in benzene, Banjoko’s group150,154,155 observed that the second-order rate constant, kA , exhibits a linear dependence on the square of the nucleophile concentration (equation 24). kA D k0 C k 0 [amine]2
24
Banjoko has interpreted the third-order term in the amine concentration as due to a reaction proceeding through an eight-membered ring formed through a network of the inter-hydrogen bonding between two aniline molecules and the zwitterionic intermediate as shown in Scheme 11. In these reactions, the authors found that kA showed little change with temperature in the range 5 35 ° C, k0 is almost invariant with temperature, and k 0 has negative activation energy for anilines containing electron-releasing substituents. The kinetic form also depends on the substitution in the nucleofuge. Thus, for unsubstituted or nitro-substituted leaving groups a third-order dependence is observed, whereas for leaving groups containing 2,4-, 3,4- and 2,5-dinitro groups in amine a second-order, and for the 2,6-dinitrophenoxy groups a first-order, kinetic law was obtained. The results were explained as a change in the transition state: from eight- to six- to four-membered rings, containing three, two or one molecules of aniline, respectively. Why an eight-membered transition state would be more effective in removing the nucleofuge than a six-membered one was not explained. Considering that formation of the cyclic intermediate requires the encounter of intermediate 33 with two amine molecules (aggregates are not considered) to form the highly ordered transition state 35, a highly negative entropy of activation would be expected, but the observed values are within the usual ranges. Addition of methanol to the reaction of aniline with picryl ether in benzene resulted in a continuous curvilinear increase of kA over the entire range of solvent composition from pure benzene to pure methanol155 . The order in aniline changes from three in benzene to
26. SN Ar reactions of amines in aprotic solvents
1265
H +
C6 H5O
NHR
O2 N
NO2 _
NO2
k2
k4
(34) H NRH
+
C6 H5O
NRH
O2 N
NO2 _
O2 N + 2RNH2
NO2
+ C6 H5OH
2NHRH2 +
k3
k5
(33)
NO2
H
k1
HRN C6 H5
NRH
H
O O2 N
NO2
H +
C6 H5O NO2
NRH
O2 N
NO2 _
+ RNH2
NO2
NO2
(35) SCHEME 11
two in pure methanol. The expression in equation 25, where B D amine, holds over the range 0 0.6% methanol. kA D k0 C k B [B]2 C k MeOH [MeOH]
25
The authors presume that the observed effect is due to acid catalysis by methanol, but no catalysis by phenol was observed. Pietra and Vitali111 have shown earlier that phenol catalyses the reaction of 1-fluoro-2,4-dinitrobenzene with piperidine in benzene. C. Aggregation of the Nucleophile
The mechanisms of chemical reactions are concerned largely with the sequence in which reactants are assembled and dispersed in relation to the bond-making and bondbreaking steps156 . This is specially important for reactions in aprotic solvents in which
1266
Norma S. Nudelman
solvation is not as clear as in the network encountered in protic solvents. It is well known112,114,145,146,157 that amines may undergo auto-association in aprotic media giving rise to aggregates of various stoichiometry. The dominating aggregate is a dimer with typical formation constant K ¾ D 0.1 M1 (the value for cyclohexylamine in cyclohexane)145 . The structure of the aggregates has been studied in some cases and found to be non-cyclic oligomers146 . Amine aggregates are known145,157 to be affected inversely by temperature, hence in SN Ar rates, then, overall negative energies of activation can be observed in reactions where K B:B, exists. It has been proved in many reactions in a pre-equilibrium, such as 2B ! solution that aggregates can react without previous dissociation. One of the earlier reports is on the butylaminolysis of p-nitrophenyl acetate in chlorobenzene158 , more recent ones are about the butylaminolysis of 2-hydroxy-5-nitro-˛-toluene sulphonic acid sultone in acetonitrile and toluene159 , the butylaminolysis of several nitro-substituted 4-nitrophenyl benzoates and cinamates114 and on the rearrangement of the Z-p-nitrophenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into 4-benzoylamino-2-p-nitrophenyl-5-phenyl1,2,3-triazole in benzene152 . Curiously, in this last reaction, the authors ‘have excluded the possibility that the amine behaves as a dimer because in other reactions catalysed by aliphatic secondary amines (e.g. SN Ar) this kind of dependence on amine concentration is not usually observed’152,160 . They described the effect as ‘catalysis of catalysis’, a term that was also used in the observed effect by two molecules of piperidine in the reaction of 1,2-dinitrobenzene in n-hexane115 . Notwithstanding, it has been recently shown that for SN Ar reactions in non-polar solvents, auto-association of amines is very important because of the low permittivity of the media and the consequent range of electrostatic forces and the importance of hydrogen bonding. These types of interactions form the basis of the so-called ‘dimer nucleophile’ mechanism10,143,144 . It had been previously suggested114a,163,164 that amine dimers should be more nucleophilic than the free amine, since the formation of the hydrogen bond would increase the electronic density on the nitrogen atom which partially donates its hydrogen. In fact, theoretical calculations by the PCILO method165 showed that the dimers of aliphatic amines are linear, stabilized with respect to the monomer Eca, 4 5 kcal mol1 and the examination of the electron density shows a 0.022 electron transfer. Ab initio theoretical calculations166 carried out on ammonia dimers indicate a 0.0136 electron density increase. NMR studies169 of butylamine in benzene show also that aggregation increases the amine nitrogen electron density167,168 . Besides self-association, the nucleophile can also aggregate to any other hydrogenbond acceptor present in the media, forming mixed aggregate; this effect is particularly important in solvents of low permittivity10 . Tertiary non-nucleophilic amines added as catalysts are prone to form these mixed aggregates, and various authors have recently shown their formation in SN Ar reactions with amines in non-polar solvents. Thus, Hirst and coworkers162 have recognized the importance of these interactions to stabilize the protonated amine in the reactions of 1-chloro- and 1-fluoro-2,4-dinitrobenzenes with morpholine in benzene, forming what they called the hetero-conjugates of the conjugate acid of the nucleophile. (See Section III.I.) Frena and coworkers152,160 described as ‘catalysis of catalysis’ the effect that requires association of a pair of amines, and this term was also used in the observed effect of pyridine in the reaction of piperidine with 1,2dinitrobenzene in n-hexane115 . In this reaction, taking into account that there are no significant changes of kA with [Py] when the constant concentration of piperidine is high, the authors concluded that piperidine is a better catalyst than the mixed aggregate [piperidine-pyridine].
26. SN Ar reactions of amines in aprotic solvents
1267
Aggregation with the co-solvent may also be very important in SN Ar reactions with amines in binary solvents, when the non-polar solvent is mixed with small amounts of a co-solvent that has hydrogen-bond donor or hydrogen-bond acceptor capabilities. Thus, aggregation of amines with protic solvents is very well known, and aggregation with DMSO144,161 and with other hydrogen-bond acceptor additives162 has also been shown. Ab initio theoretical calculations show a three times stronger interaction for the solvated nucleophile CH3 OH Ð Ð Ð NH3 than for the ammonia dimer167 . Ab initio calculations168 on the hydrogen-bonding ability of pyridine bases with water showed a 0.03 charge transfer from the pyridine to the water molecule and the dimers are again linear, the stabilization energy being 4.7 kcal mol1 . The operation of all these mixed aggregates will be discussed below in connection with the ‘dimer nucleophile’ mechanism169 . D. The ‘Dimer Nucleophile’ Mechanism
Taking into account the self-aggregation of the amine that prevails in non-polar aprotic solvents, Nudelman and Palleros144 proposed that the observed third-order in amine could be due to a mechanism involving attack of the dimer of the nucleophile superimposed on the classical reaction with the monomer, as shown in Scheme 12 A cyclic intermediate, 36, similar to 9 proposed by Capon and Rees126 , is formed straightforwardly in the addition step through the dimer of the amine. The proposed mechanism does not preclude attack by the monomer which directly would form intermediate 37, as reported for the two-step mechanism shown by equation 1. The intermediate 36 formed in the first step is in mobile equilibrium with the second classical intermediate 37, and either of them can react to form ultimate products, by spontaneous or base-catalysed decomposition. The whole reacting system is depicted in Scheme 12. A cyclic transition state was also proposed by Banjoko and Otiono170 but for the second step (decomposition of the intermediate complex, 37). Application of the steady-state treatment to the whole mechanism gives an expression involving the seven specific rate constants for each step, the association equilibrium constant for the nucleophile, K1 , and the constant for the equilibrium between intermediates 36 and 37, K2 . The complete expression and the different limit situations that were evaluated are derived in Reference 144. A simplified reacting scheme, where only attack for the dimer is considered, is shown by equations 26 and 27. The dimer of the nucleophile (B:B), equation 26, attacks the substrate, S, forming the intermediate, SB2 , and a third molecule of amine assists the decomposition step (equation 27). Both transition states in Scheme 12 are highly zwitterionic and the extra amine molecule should help to stabilize the developing charges in these non-polar solvents and to assist the departure of the nucleofuge (probably as suggested by Hirst, see below). The derived expression for kA in this simplified reacting scheme is equation 28. 2B
K
(26)
B:B k2
S + B:B
k1 k −1
[SB2 ]
Products
(27)
k3 , B
kA D
k1 k2 K[B] C k1 k3 K[B]2 k1 C k2 C k3 [B]
(28)
Here K D [B:B]/[B]0 2 stands for the amine auto-association constant. Usually, in the reactions with amines with poor nucleofuges the second step is rate-determining, the inequality
1268
Norma S. Nudelman R
H N H
H X
+
X
NHR NO2
NO2 H + RN H
H
k1
NR
_
k −1
B: B
k2
NO2
NO2 (36)
k3
k1 B
B k2 B
X
+ NH2 R
X NO2
NHR NO2
+R
NH2 B
k4
_
NO2 k5
+ XH
k-4
NO2
NO2
NO2
(37) SCHEME 12
k1 × k2 C k3 [B] holds and equation 28 can be further simplified to equation 29, which predicts a linear dependence of kA /[B] vs [B]. k1 k2 K k1 k3 K[B] kA D C [B] k1 k1 kA /[B] D k1 K
(29) (30)
If k1 ¾ D k2 C k3 [B], at high [B], equation 28 may be transformed into equation 30, which is responsible for the plateau observed in some cases in the plot of kA /[B] vs [B] (e.g. the reaction of 2,4-dinitroanisole with butylamine in benzene at 60 ° C, Figure 11)143a . The first report of this mechanism was published in 1980143b for the reactions of 2,4and 2,6-dinitroanisole with butylamine in benzene, and afterwards several other systems were studied some of which are shown in Table 19. That association of the nucleophile, at relatively high [B], in SN Ar reactions should increase its nucleophilicity was suggested earlier163a,171 ; the original proposal here is the operation of the dimer of the amine as an entity, according to the experimental evidence. The reactions shown in Table 19 exhibit a very small overall energy of activation, and in some cases [e.g. the reaction of 2,4-dinitroanisole with butylamine in benzene (Figure 11), and with cyclohexylamine in cyclohexane and in benzene (not shown)144 ] negative activation energies are observed. Since the equilibrium association constant, K1 ,
26. SN Ar reactions of amines in aprotic solvents
1269
diminishes with increasing temperature, this is a reasonable explanation for the apparently surprising ‘inverse’ temperature effect. The rate-determining step is preceded by a fast equilibrium, whereby the expected increase in rate for the slow step with increasing temperature would be compensated by a shift of the preceding equilibrium towards the monomer. Similar small or even negative overall energies of activation were observed by Banjoko and Ezeani150 for the reactions of dinitrophenyl phenyl ethers with aniline and substituted anilines in benzene. In the cyclic intermediate proposed in Scheme 12, the second molecule of amine acts as a proton donor to the leaving group as well as a proton acceptor from the positively charged nitrogen of the zwitterion, thus stabilizing the dipolar transition state that otherwise should be quite unstable in benzene. The third molecule of amine would assist the decomposition of the zwitterionic intermediate to the products, forming the acid conjugate of the dimer through concerted detachment of the proton from the intermediate. This ‘protonated dimer’ catalyses the nucleofuge departure in the non-polar solvents10 . If this interpretation is correct, catalysis by mixed aggregates should be also observed since, as was mentioned above, amines form such aggregates in non-polar aprotic media. Overwhelming evidence of the participation of these aggregates in the kinetic law has been accumulated in recent years. One of the first systems where this effect was considered is the reaction of 2,4-dinitrofluorobenzene with o-anisidine in benzene172 . A quadratic dependence of kA with [B] was observed and interpreted as due to a hydrogen-bonded dimer operating as the main nucleophile in a mechanism similar to that shown in Scheme 12. When the reaction is run in the presence of a hydrogen-bond acceptor (HBA) such as pyridine, a new mixed associated nucleophile, B:P, is present in the system as depicted in Scheme 13. Three competing nucleophilic reactions are shown: attack by the dimer (measured by k1 ), by the monomer (determined by k4 ) and by the B:P complex (measured by k7 ). An equilibrium between the three possible tetrahedral intermediates (36,37,38) is established (measured by the equilibrium constants K2 , K3 and K4 ), k4 being greater 0 0 than k1 and k7 as discussed earlier. The whole kinetic expression for kA as well as the simplification that can apply to limit situations are fully discussed in Reference 172; the general expression for kA can be reduced to equation 31, which can be written in the condensed form of equation 32. kA D k3 k4 C k1 k5 K1 [B] C k1 k3 K1 [B]2 C k1 k8 K1 C k7 k3 K3 [B][P] C k5 k7 K3 C k4 k8 [P]/k4 2
kA D k˛ [B] C kˇ [B] C k [B][P] C kυ [P]
(31) (32)
Several experiments were carried out to test equation 32 and the four constants could be evaluated; the determined values are shown in equation 33172 . It can be observed that catalysis by a HBA-nucleophile complex is more important than for the nucleophile itself, as expected on the basis of the ‘dimer nucleophile’. kA D 104 0.152 [B] C 0.780 [B]2 C 9.22[B][P] C 13.5[P]
33
Experiments carried out in the range [B] D 0.025 0.1 M, in the presence of pyridine, [P] D 0.037 and 0.062 M, showed that equation 31 holds in the whole range of [B] studied, i.e. 0.02 0.8 M. At low [B] the points for kA vs [B] approach a straight line of slope 5.0 ð 105 s1 M2 and intercept 3.8 ð 105 s1 M1 (for [P] D 0.037 M). If equation 32 holds, the slope of kA vs [B] at the origin is a measure of k˛ C k [P]. This term was measured and found to be 4.4 ð 105 s1 M1 , which agrees fairly well with the value of 5.9 ð 105 s1 M1 found for the runs at low [B], showing that equation 32 holds in the whole range of [B] studied172 .
1270
Norma S. Nudelman R
H N
H X
H + NHR
X
NO2
NO2 H + RN H
H
k1
NR H
−
k −1
B:B NO2
NO2 k2
(36)
K1
B k3
B
K2 B
X
+
NHR
NH2 R
X
NO2
NO2 k4
+ RNH2
−
k −4
B NO2
NO2 k5
k6
NO2
+ XH
B
NO2
(37) K3
H + NHR
X
NO2
NO2 + R3 N P:B NO2
k8 k9
R3 N X
P
p
k4
p
H
Η NR
k7 k −7
−
NO2 (38)
SCHEME 13
From the magnitude of the calculated constants it is possible to estimate a higher limit for the value of the uncatalysed term in equation 31; since k [P] is between 2 and 8ð105 s1 M1 , the uncatalysed term should be <6ð107 s1 M1 . For measurements of this term it would be necessary to work at very low [B] and also at very low [P], but then the reactions would become too slow to be measured. In terms of the ‘dimer mechanism’ a term in [P]2 would also be expected in special systems according to the reacting scheme shown in Scheme 13. Actually, one molecule of pyridine would act forming the mixed associate nucleophile, and the second molecule
26. SN Ar reactions of amines in aprotic solvents
1271
could operate in the base-catalysed decomposition of the intermediate 38. In the reactions of 2,4-dinitrofluorobenzene with o-anisidine in benzene, the [P] was relatively low ([P] < 0.07 M) and the term [P]2 becomes negligible when compared with the catalytic terms [B]:[P] and [P] and a linear dependence of kA on [P] is observed. Nevertheless, with a less basic nucleophile such as morpholine, M, it was found in the reaction with 2,4dinitrofluorobenzene (DNF) in benzene that the dependence of kA on [P] departs from the line (upward curvature), and this was considered to be a medium effect due to the relatively high [P] used (up to 0.5 M)147c . Nevertheless, if the data are treated as if a 1:1 complex between morpholine and pyridine is formed, the empirical equation 34 can be formulated for the overall-rate second-order rate coefficient which shows a quadratic dependence of kA on [P]. kA D k0 C kM [M] C kP [P] C kP:M [P]2
34
If the terms independent of [P] are divided by [P] and the quotient plotted against [P], a straight line is obtained, which demonstrates the validity of equation 34 and the existence of a non-negligible term in [P]2 for this case. Further studies of the reactions of DNF with aniline in toluene also showed a quadratic dependence of the rate with [pyridine] (Figure 12). In other systems, similar kinetic laws were observed when studying the effect of added pyridine, although differentiation with the ‘dimer nucleophile’ mechanism is made in the interpretation of the experimental results (see below). Rationalizations of the involved phenomena are based on the strong hydrogen-bond interactions between the nucleophile and the pyridine, and on the catalytic effect of a third amine molecule in the decomposition of the zwitterionic intermediate in non-polar solvents.
4
k A (dm3 mol−1 s−1)
3
2
1
0
0.2
0.4 [B] (mol dm−3)
0.6
FIGURE 12. Reaction rates, kA (f), of DNF (2,4-dinitrofluorobenzene) with aniline in acetonitrile (ð104 ); ethyl acetate (ð104 ); chloroform (ð107 ) and toluene (ð107 ) as a function of [aniline]; in toluene (5 ð 104 ) as a function of [pyridine]190
°
1272
Norma S. Nudelman
E. Specific Solvent Effects
The quadratic dependence of kA on [B] is a peculiar phenomenon observed in aprotic solvents. The mechanisms proposed to explain the results should consider the strong hydrogen-bond interactions that are expected to stabilize the highly ionic intermediates in the poorly solvating media. Thus changes in the reaction media will have a strong influence on the rates and on the kinetics. Interactions between alcohols and amines are known to be stronger than among amines themselves, and it has been demonstrated that nitro-tonitrogen proton transfers are intrinsically slower than nitro-to-oxygen proton transfers173 . It is therefore of critical importance to determine the effect of adding defined amounts of a protic solvent to the reaction media to test the validity of the ‘dimer nucleophile’ mechanism. A special system where classical solvent effects should be negligible is, e.g., the reaction of 2,6-dinitroanisole with cyclohexylamine. Indeed, at 45 ° C and [B] D 0.4 M, the kA has almost the same values in benzene and in methanol (5.27 and 5.82 ð 104 M1 s1 , respectively)174 . If no special effects were operating, the reaction rate should increase slightly and steadily on addition of methanol to benzene in the reaction media; this should be expected since the zwitterionic transition states should be stabilized by the more polar solvent. However, a spectacular effect was observed, namely the reaction rate decreases abruptly on small additions of methanol to benzene, reaches a minimum at nearly 25% of methanol and then begins to increase up to the given value in pure methanol (Figure 13a)175 . The huge decrease in rate was interpreted as the result of competition between the auto-association of the amine and the amine-methanol aggregates, where the hydroxylic solvent acts as proton donor: ROHÐ Ð ÐNH2 R, thereby decreasing the nucleophilicity of the amine. Higher oligomers with more than one ROH molecule are also possible176 . In spite of the rate decrease, the third order in amine rate dependence is observed up to 25% methanol:75% benzene, i.e. the binary mixture where the minimum region is observed. 7
kA (10−4 dm3 mol−1 s−1)
6
a
5 4
∗
∗
∗
b
3
∗ 2
∗
∗
30
40 50 60 % ROH
1 0
0
10
20
70
80
90 100
FIGURE 13. Overall second-order rate coefficients, kA , for the reaction of 2,6-dinitroanisole with cyclohexylamine in binary solvents: , benzene methanol; Ł, toluene octanol175 .
26. SN Ar reactions of amines in aprotic solvents
1273
Linearization of the amine profiles (kA /[B] vs [B]) shows decreasing slopes for 0 25% methanol, consistently what would be expected on the basis of the mechanism depicted in Scheme 12. The continuous diminution of the slope with increasing methanol percentage shows the continuous diminution in the auto-association constant of the amine, K, to be practically nil at 25% methanol175 . For higher methanol content in the mixed solvent, the classical mechanism is observed. F. Catalysis by Methanol
The above interpretation of specific solvent effects on the ‘dimer nucleophile mechanism’ has been recently criticised, however, by Banjoko and Bayeroju155 in a paper which they called “strong evidence against the ‘dimer’ mechanism”. Their contention was that the observed decrease in rate is due to a special feature in the reaction of 2,6-dinitroanisole (2,6-DNA) with cyclohexylamine in benzene175 . Since they did not observe similar behaviour in the reaction of phenyl 2,4,6-trinitrophenyl ether with aniline in benzene-methanol155 they proposed that the retarding effect observed in the reaction of 2,6-DNA with cyclohexylamine is the result of the reaction being reversible. According to their suggestions, since methanol is formed as a product arising from the nucleofuge departure, additions of small amounts of methanol to the solvent would result in a decrease in rate as expected by Le Chatelier’s principle. This argument, obviously, does not take into account the rising portion of the curve, and the fact that the reaction produces quantitatively N-(2,6-dinitrophenyl) cyclohexylamine even in pure methanol. Moreover, the authours even suggest that all reactions of amines with substrates having methoxy nucleofuges are likely to be reversible. Although this argument could be refuted by the observation of the ‘dimer nucleophile’ in other systems10 , it was of interest to examine the effect of addition of a hydrogenbond donor(HBD) co-solvent different from methanol, to the reaction of a substrate where the nucleofuge is methoxide, such as the reaction of 2,6-DNA with cyclohexylamine in toluene octanol binary mixtures177 . As regards octanol: (a) it would not compete with the product (methanol) in case of a reversible reaction; (b) its dipolarity Ł D 0.37 is between that of toluene and methanol178 ; (c) its hydrogen-bond donor ability (˛ D 0.30179 is greater than that of toluene or cyclohexylamine (˛ D 0 for both) but smaller than that of methanol (˛ D 0.69179 . In the reactions of 2,6-DNA with cyclohexylamine [B] D 0.264 M in toluene and in octanol at 35, 45 and 60 ° C, it was observed that at 35 ° C the reaction is slightly faster in toluene than in octanol, whereas at 45 and 60 ° C the inverse is observed177 . These results show, once more, the difficulties of studying related reaction rates at a single temperature. A very low enthalpy of activation is observed for the reactions in toluene consistently with the operation of the ‘dimer’ nucleophile mechanism. The reaction in octanol shows a higher enthalpy of activation and also a slightly higher entropy of activation177 . To add new experimental evidence to the argument of competition between self- and mixed aggregates, the reaction was studied in toluene octanol mixtures at the same base concentration that was used in studies in toluene methanol, i.e. [B] D 0.4 M. A continuous increase in rate on addition of increasing amounts of octanol to toluene would be expected on the basis of Banjoko and Bayeroju’s arguments155 . On the contrary, a decrease in rate is observed on small additions of octanol (Figure 13b), up to nearly 30% of octanol where the valley of the curve is reached; then it begins to increase up to the value in pure octanol. As expected, on the basis of a special effect of a medium hydrogen-bond donor co-solvent that competes with the amine itself for aggregation, the reaction in the toluene octanol system exhibits a similar, albeit smaller, dependence on the protic solvent content than that observed in the toluene methanol system104 .
1274
Norma S. Nudelman
It was observed that in pure toluene kA exhibits a curvilinear dependence with [B]. A similar response is found in the binary solvents, the curvature being smaller on increasing the octanol content. The plot of kA /[B] versus [B] (Figure 14) in pure toluene is a straight line (equation 30), which indicates the parabolic dependence of kA on [B], consistent with equation 29. Similar behaviour is observed in the plot of kA /[B] versus [B] for the reactions carried out in 5, 20, 30 and 50% octanol toluene binary solvents. It can be observed in Figure 14 that the slope decreases sharply on passing from pure toluene to 5% octanol; then the decrease is smaller. A small decrease is also observed in the intercepts of the plots up to 30% octanol (Table 21) and then the intercepts increase in pure octanol. In fact, the intercept is greater than the slope in pure octanol, since in this solvent k3 is almost negligible, consistently with the entire concept of the ‘dimer’ mechanism. In their paper against this mechanism, Banjoko and Bayeroju155 argued that the intercepts should decrease on adding increasing amounts of methanol to toluene, and the fact that the figure in Reference 144 did not show significant changes from 4 30% methanol, in their opinion: ‘casts serious doubt on the validity of equation 31 and hence on the dimer mechanism on which it is based’. It can be observed in Table 21 that the values of the intercepts change slightly in the present study, and also in the reactions in benzene methanol mixtures: they decrease from 6.06 to 1.04 ð 104 Lmol1 s1 on going from pure benzene to 4% methanol benzene. Furthermore, although the intercepts k1 k2 K/k1 and the slope k1 k3 K/k1 are equally influenced by the dimerization constant K in equation 28, this does not imply that they should show the same effect on changing the solvent. According to the ‘dimer mechanism’, it could be expected that the ‘base catalysed’ decomposition of the transition state SB2 , measured by k3 , should be more depressed by small additions of protic solvents than the ‘spontaneous’ decomposition measured by k2 . Indeed, the overwhelming evidence on the classical base catalysis by amines shows that usually k3 is more important in aprotic than in protic solvents1 .
k A[CHA] (10−4 dm6 mol−2 s−1)
20
15
10 ∗
∗ 5
∗
∗
0 0
0.2 0.4 [CHA] (mol dm−3)
0.6
FIGURE 14. Overall second-order rate coefficients over cyclohexylamine (CHA) concentration, kA /[B], for the reaction of 2,6-dinitroanisole with cyclohexylamine in: , toluene; and , 5; Ł, 20; , 30; x, 100% octanol toluene binary solvents, as a function of [B]177
°
26. SN Ar reactions of amines in aprotic solvents
1275
TABLE 21. Reaction of 2,6-dinitroanisole (DNA) with cyclohexylamine (CHA) in toluene octanol 177 binary solvents, at 35 ° Ca % Octanol 0
5
10 15 20
30
50
100
[CHA] (mol dm3 )
kA 104 dm3 mol1 s1
kA /[CHA] 104 dm6 mol2 s1
0.109 0.188 0.264 0.376 0.470 0.096 0.223 0.260 0.415 0.518 0.264 0.264
0.67 1.27 2.53 4.39 6.76 0.38 1.28 1.77 3.93 5.28 1.29 1.08
6.14 6.84 9.58 11.78 14.51 3.98 5.76 6.81 9.48 10.19 4.89 4.10
0.109 0.218 0.393 0.492 0.096 0.223 0.415 0.518
0.45 1.13 2.46 3.66 0.30 0.85 2.13 3.28
4.17 5.19 6.26 7.44 3.07 3.79 5.13 6.34
0.264 0.415 0.518 0.109 0.194 0.260 0.388 0.485 0.530
1.05 2.05 3.35 0.92 1.61 2.37 3.76 5.36 5.90
3.98 4.94 6.45 9.20 8.30 9.11 9.69 11.05 11.13
k1 k3 K/k1 104 dm9 mol3 s1
k1 k2 K/k1 104 dm6 mol2 s1
24 š 2
3.1 š 0.5
15 š 1
2.6 š 0.4
8š1
3.3 š 0.2
8š1
2.2 š 0.2
9š1
1.3 š 0.2
8š1
6.8 š 0.2
a [DNA] D 20 ð 104 mol dm3 .
G. Catalysis by Hydrogen-bond Acceptor (HBA) Additives
If the ‘dimer mechanism’ interpretation is correct, addition of a HBA co-solvent, e.g. dimethyl sulphoxide (DMSO) ˇ value D 0.76178 , in catalytic amounts should increase the reaction rate by forming a mixed aggregate RNH2 Ð Ð Ð OS(CH3 )2 (B:DMSO), equation 35, where the amine acts now as a HBD, and therefore this mixed aggregation should increase its nucleophilicity. DMSO has been shown to increase the nitrogen electron density of primary and secondary amines161 . S
+
[B:DMSO]
P
[SB:DMSO]
(35)
B
The reaction rate of 2,6-dinitroanisole with cyclohexylamine in toluene increases rapidly with small additions of DMSO up to 0.5%; then the increase with [DMSO] is slower108 .
1276
Norma S. Nudelman
Studies of the amine concentration rate dependence show that the reactions are strictly third-order in amine for DMSO <2%. For DMSO constants >10% the reactions show the classical behaviour usually found in base-catalysed SN Ar180 . The specific solvent effects observed for small additions of the HBD co-solvent are consistent with the formation of the mixed aggregate, and a linear correlation was found between kA and [DMSO], shown by equation 36, which expresses that the third-order term is more affected by the small additions of DMSO than the fourth-order term. Equation 36 is valid for [DMSO] <2% (0.282 M). 36 kA D k0 k˛ C kˇ [DMSO] [B] C kD [B]2 Although the catalytic effect of the aggregation of the nucleophile with DMSO could also operate in the second step, the above interpretation is preferred since it also explains the early reported ‘anomalous’ catalytic effect of small additions of DMSO (<0.2 M) observed when the first step is rate-determining (i.e. reaction of 2,4-dinitrochlorobenzene with piperidine in benzene)181 . Similar rate accelerations due to the addition of small amounts of DMSO were found in the reactions of 1,2-dinitrobenzene with butylamine in benzene. While the reaction is almost insensitive to other additives, the accelerations observed upon addition of DMSO to benzene exceed expectations based only on considerations of the polarity of the medium9 . Catalysis by other HBA additives was recently studied by Hirst and coworkers162 in connection with the ‘homo-/hetero-conjugate mechanism’. H. The Homo- and Hetero-conjugate Mechanisms
Hirst and coworkers proposed in 1977182 that in the reactions of 2,4,6-trinitrophenyl phenyl ether with aniline in benzene, aggregates can be formed between the nucleophile and its conjugate acid, which can be formulated as NuHNuC , and the reaction would take place within aggregates by SB-GA. They explained148 the upward curving plots as being due to electrophilic catalysis of the expulsion of the leaving group by homo- and hetero-conjugates of the conjugate acid, as shown in Scheme 14, where I and II refer to the intermediates in equation 1 and Scheme 1, and Nu is the nucleophile. C
I C Nu II C NuH C
NuHC C Nu NuH Nu
II C NuHC Nu products SCHEME 14
Accelerations of the rates due to an additive P are explained as electrophilic catalysis by the heteroconjugate NuHC P, while a second-order term in the concentration of P can be obtained if the relative basicities of Nu and P are such that P can compete with Nu for removal of the proton from I followed by electrophilic catalysis by the homoconjugate PHC P. Support for this mechanism has been obtained from the study of the effect of twelve hydrogen-bond acceptors on the reactions of 1-chloro- and 1-fluoro-2,4-dinitrobenzenes with morpholine in benzene162 . The reaction of 1-chloro-2,4-dinitrobenzene is not catalysed by either morpholine or DABCO, i.e. kA D k1 ; the first stage of the reaction is rate-determining and the various additives have no effect on the rate constant. On the other hand, Table 22 shows that the reaction of the fluoro-substrate is highly sensitive to the presence of the various additives and it is base-catalysed while for ten additives there was a linear dependence of kA on either their concentration, [P], or on the square
1.26a 2.1e 7.58
2.94 ð 102
THF 1.32b 6.8 18.3g
6.69 ð 102
Cyclohexanone 0.73a 11.26 34.8
1.07 ð 101
Nitrobenzene 1.88a 5.22 12.4h
1.87 ð 101
Pyridine 5.61 2.03a 6.00
ð 101
4-Mepy 3.26 2.20b 8.60
DABCO
3.89 2.53a 0e 46.7
Me2 SO
6.94 2.76a 0.79
pyNO
30.0g
25.1 3.56a
HMPA
f Dielectric constant; see ‘Organic Solvents’, in Techniques of Organic Chemistry (Eds. J. A. Riddich and W. B. Bunger), Vol. II, 3rd edn., Wiley-Interscience, New York, 1970. g At 20 ° C. h At 21 ° C.
a Reference162 . b L. Jores, J. Mitsky and R. W. Taft, J. Am. Chem. Soc., 94, 3438 (1972). c D.D. Perrin, Dissociation Constants of Organic Bases in Aqueous Solution, I.U.P.A.C.-Butterworths, London, 1965. d M. M. Fickling, A. Fischer, B. R. Munn, J. Packer and J. Vaughan, J. Am. Chem. Soc., 81, 4226 (1959). e E. M. Arnett, Prog. Phys. Org. Chem., 1, 223 (1963).
0.90b 10.13e 37.5
0.45b 5.07d
MeCN
pkHB 0.02a pka 25 (H2 O)c 6.51 E25 f 4.33
DMA 3.09 ð 102
Anisole
k 00
P
TABLE 22. Effect of some additives P on the reaction of 1-fluoro-2,4-dinitrobenzene with morpholine in benzene at 30 ° C. Values of k 00 (mol2 l2 s1 in the equation kA D k 0 C k 00 [P] and other relevant data162
1277
1278
Norma S. Nudelman
of their concentration, [P]2 . An approximately linear correlation was found between the logarithms of the factors which measure the dependence on [P] and the hydrogen-bonding parameter, ˇ179 . The authors correlate the slopes with the former pKHB ‘Taft parameter’, which is now called the hydrogen-bonding parameter, ˇ179 . The acceptors, P, consisted of a variety of substances ranging from acetonitrile through nitrobenzene and pyridine N-oxide to hexamethylphosphoric triamide, and covered a range of pKHB values from 0.90 to 3.56. Anisole and dimethylaniline with very low pKHB values of 0.02 and 0.45 did not produce accelerations. The effect is interpreted as evidence of the operation of the homo-/hetero-conjugate mechanism. The authors presume that for the mechanism given by equation 1, for additives P which are much less basic than the nucleophile N, electrophilic catalysis also occurs both with the hetero-conjugate NC HP formed between the conjugate acid of the nucleophile, N, and P, as well as with the homo-conjugate NuC HNu. For more basic additives, electrophilic catalysis is possible by the species PHC and its homo-conjugate 153,162,182 PHPC . The interpretation of formation of homo- (or hetero-) conjugated acid BHC B by proton transfer from the intermediate and the electrophilically catalysed departure of the nucleofuge due to this aggregate is common to this and to the ‘dimer mechanism’ and they can be formulated as essentially the same, and as reflecting different parts of a spectrum of methods for the formation of the second intermediate153 . For a given nucleophile, dimer formation increases with increase of concentration, hence the relative importance that reaction via a dimer should increase with increasing nucleophile concentration. I. The Substrate Catalyst Molecular Complex
That the formation of molecular complexes (especially EDA complexes) can catalyse the decomposition of the -adduct has been discussed in Section II.E. Another possibility is that the substrate and catalyst (nucleophile or added base) form a complex which is then attacked by a new molecule of the nucleophile: in this context catalysis need no longer be associated with proton removal. Thus, Ryzhakov and collaborators183 have recently shown that the N-oxides of 4-chloropyridine and 4-chloroquinoline act as donors toward tetracyanoethylene and that the reactions of these substrates with pyridine and quinoline are strongly catalysed by the -acceptor. Similarly, the formation of a Meisenheimer complex between 1,3,5-trinitrobenzene and 1,8-diazabicyclo[5,4,0]undec7-ene in toluene has been assumed to take place via an association complex to explain the observed second-order in tertiary amine184 . A new assumption to be discussed in this section is that the fourth-order kinetics in SN Ar by amines in aprotic solvents is due to the formation of the substrate-catalyst molecular complex. Since 1982, Forlani and coworkers149 have advocated a model in which the third order in amine is an effect of the substrate nucleophile interaction on a rapidly established equilibrium preceding the substitution process, as is shown in Scheme 15 for the reaction of 4-fluoro-2,4-dinitrobenzene (FDNB) with aniline (An), where K measures the equilibrium constant for: K
! FDNB C An FDNB Ð An If, for the sake of simplicity, it is assumed that the reaction proceeds only via the molecular complex, according to Scheme 15 the relation between kA and [An] is shown by equation 37. 0 0 Kk200 C k10 /k1 Kk300 [An] kA /[An]1 C K[An] D k10 /k1
37
26. SN Ar reactions of amines in aprotic solvents FDNB
+
ArNH2
K
1279
[FDNB . ArNH2 ] + ArNH2 k ′−1
Products
k ′′2 k ′′3 (A rNH2 )
k ′1
(I) . ArNH2
SCHEME 15
Scheme 15 could be a reaction pathway parallel to the classical reaction (equation 1), and it was postulated to explain the third order in amine observed in the reactions of FDNB and aromatic amines in benzene and in chloroform184 . The K values were calculated from the absorbances of the reaction mixture extrapolated to zero reaction time, in a wavelength range in which the starting materials do not show an appreciable absorbance value. Good agreement was observed between the values of K for the FDNB/aniline complex in chloroform by U.V. and 1 H-NMR spectroscopy, as well as for the K obtained kinetically (based on Scheme 15) and spectroscopically. Catalysis by DABCO in the reactions of FDNB with piperidine, t-butylamine, aniline, p-anisidine and m-anisidine (usually interpreted as base catalysis as in Section II) was also assumed to occur by the formation of a complex between DABCO and the substrate149b . The high (negative) -value of 4.88 was deemed inappropriate for the usually accepted mechanism of the base-catalysed step (reaction 1). For the reactions with p-chloroaniline, m- and p-anisidines and toluidines in benzene in the presence of DABCO a -value of 2.86 was found for the observed catalysis by DABCO (k3 DABCO ). The results were taken to imply that the transition state of the step catalysed by DABCO and that of the step catalysed by the nucleophile have similar requirements, and in both the nucleophilic (or basicity) power of the nucleophile is involved. This conclusion is in disagreement with the usual interpretation of the base-catalysed step. The reaction of FDNB with aniline, first studied in toluene and in chloroform, was then extended to other solvents: in the reactions with aromatic amines, the order changes from two in solvents of considerably donicity (THF, dioxane) to three in solvents of low donicity (benzene, carbon tetrachloride), and is explained as arising from competition between the solvent and amine for complex formation with the substrate185 . (Molecular complexes formed within benzene and 1,2-DNB were discussed in Section II.E.) In the presence of a constant initial concentration of triethylamine (TEA) approximately of the same magnitude as that of the nucleophile, the reactions of FDNB with both aniline and p-chloroaniline in benzene are no longer catalysed by the nucleophile, while catalysis is observed when the reagent is p-anisidine185 . This is interpreted as evidence of the substrate-catalyst association. Considering that the K value for FDNB-TEA 0.47š0.17 is higher than that between FDNB and aniline (0.062) and p-chloroaniline (0.02) the insensitivity to catalysis by the nucleophile is assumed to be due to a ‘saturation’ phenomenon (complete formation of the molecular complex FDNB-TEA) that precedes the attack of the nucleophile. Since the association constant of TEA and p-anisidine (0.67) is of the same order of magnitude than FDNB-TEA, catalysis of the reaction by the nucleophile still takes place in the presence of TEA. Nevertheless, when other solvents were studied, no total consistency is observed between the magnitude of the equilibrium constants and the experimental order in
1280
Norma S. Nudelman
amine. Thus, while the reactions in chloroform K D 0.37 š 0.9 and in chlorobenzene K D 0.27 š 0.1 are third-order in amine, the reaction in 1,4-dioxane K D 0.81 š 0.7 is second-order in amine186 . These peculiarities were not explained. The reactions of FDBN with substituted 2-aminothiazoles in benzene are not catalysed by the nucleophile (they do not form molecular complexes), however the reactions are catalysed by DABCO, 2-hydroxypyridine and ˛-valerolactam. Forlani has shown that ˛-valerolactam forms a hydrogen-bonded complex with the substrate and similar complexes are formed between 2-hydroxypyridine and aromatic nitro derivatives187 . The reaction of 1,3,5-trinitrobenzene (TNB) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene184 was also proposed to proceed by the mechanism shown in Scheme 16. The visible spectrum, recorded immediately after mixing appropriate solutions of TNB and DBU in toluene, shows a feeble absorbance maximum at 505 nm, which changes to a stable maximum at 468 nm, after variable reaction times. The first maximum was attributed to a molecular complex between TNB and DBU, and the second maximum at the Meisenheimer complex, 39, although NMR structural determinations were not possible, because of the low solubility of the complex in toluene. TNB
molecular complex (MC) (+ DBU) k1
+
( DBU) k −1 ° k1°
k −1
zwitterionic complex I SCHEME 16
N
(CH2 )5
+ N
H O2 N
NO2 −
NO2 (39)
Under the experimental conditions [TNT] × [DBU]0 , the rate of formation of the second maximum (468 nm) is slow and the authors could make a quantitative evaluation of the first interaction attributed to the formation of a molecular complex (MC). The low reactivity under these conditions was interpreted as due to the fact that the MC has very little tendency to rearrange to the zwitterionic complex, since the amount of DBU complexed by TNB would be unavailable for the nucleophilic attack. Since in this system the basecatalysed step for departure of HL does not exist, the small increase in kobs values with the [DBU] was interpreted as evidence of the mechanism shown in Scheme 16. Similarly, the increase in kA with [amine] observed in the reactions of FDNB with butylamine in
26. SN Ar reactions of amines in aprotic solvents
1281
toluene, usually considered base-catalysed, was recently reinvestigated188 and interpreted as produced by the formation of a substrate-amine molecular complex, which with another amine molecule rearranges to the Meisenheimer complex as shown in Scheme 16. Nevertheless, several conceptual problems are associated with this alternative interpretation. One of the major conflicts between this mechanism and that described in Section II.E is the requirement of an additional molecule of amine, associated with the assumption that the molecular complex cannot evolve to the intermediate. J. The ‘Desolvative Encounter Mechanism’
Hayami and Sugiyama189 have recently found that picryl fluoride in acetonitrile follows second-order kinetics with saturation behaviour, while essentially no Brønsted base catalysis was observed, as would be suspected from the ‘rate-limiting nucleophilic’ addition of the nucleophilic amines. Interestingly, picryl chloride was more reactive than picryl fluoride in the presence of a low concentration of the amine nucleophile 2,4dimethoxyaniline (DMA). The diminished reactivity of picryl fluoride is proposed to stem from the unfavourable encounter complex formation and also from the unfavourable first-order reaction in the complex. The reaction shown in Scheme 17 is proposed as the ‘desolvative encounter mechanism’. It is suggested that in acetonitrile, strongly solvated picryl fluoride, [Pic (Sol)n ], is only slightly desolvated on encounter with the first molecule of the nucleophile, so that the solvation is still tight, preventing it from nucleophilic attack by the nucleophilic partner in the complex. However, the participation of a second molecule of the nucleophile would result in a more profound desolvation allowing a productive attack, and would allow the faster reaction in the k2 step for the picryl fluoride (3150, at 298 ° C) than picryl chloride (5.2), thus showing a reactivity order parallel to the intrinsic reactivity of these substrates. PicX. (Sol)n + DMA k1 K
Products
PicX. (Sol)m . DMA k 2 , DM A
SCHEME 17
The calculated equilibrium constants for the ‘encounter complex’ are given in Table 23189 . The K value for the complex between 2,4-dimethoxyaniline and picryl chloride is higher than that for picryl fluoride, and this is proposed to be responsible for the higher rate observed for the chloro-substituted compound. The calculated equilibrium constants for the ‘encounter complex’ are different from those for the ‘charge-transfer (or EDA) complex formation’, as shown in Table 23. If the charge-transfer complex were formed through the ‘encounter or association complex’, the equilibrium constant for the charge-transfer complex formation should be larger than that of the encounter complex. Since this is not the case, the authors proposed that the desolvation for the encounter should be much lighter than that required for the charge-transfer peripheral desolvation in the former interaction against the double facile desolvation in the latter (m < n, in complexes 40 and 41). The authors propose that the two interactions constitute different association (reaction) channels and that the charge-transfer complex would not lead to any action of the nucleophile on the substrate189 .
1282
Norma S. Nudelman TABLE 23. Encounter and charge transfer associations (in Acetonitrile at 298 K)189 Acceptor PicF PicF PicF PicCl TNB TNB TNB TNB
KCT
Donor N,N-dimethylaniline N,N-dimethyl-p-toluidine 2,4-dimethylaniline 2,4-dimethylaniline N,N-dimethylaniline N,N-dimethyl-p-toluidine 2,4-dimethylaniline N,N-dimethyl dimethylaniline
ca 0.5 ca 0.7
KEncounter 80 14.4 77.7
0.42 0.43 0.59 0.67
K. Conformational Effects
Most of the novel mechanisms hitherto presented were based on the observation of overall fourth-order kinetics (third-order in amine). Nevertheless, this result gives an account only of how many molecules are involved in the rate-determining step. It cannot distinguish, e.g., between three mechanisms that could be depicted as equations 38 40. B
! S C 2B SB2 ! Products
(38)
2B
! S C B (SB) ! Products B
(39) B
! S C B (SB) ! SB2 ! SB3 ! Products
(40)
To strengthen the point that a dimer nucleophile mechanism could be responsible for the observed third-order dependence on amine and some other peculiar features, some of them already described, a nucleophile was chosen in which intramolecular NHÐ Ð ÐN hydrogen bonding could exist. With such a nucleophile, the reaction with the intramolecularly H-bonded nucleophile should be faster than with the non-H-bonded molecule; and, furthermore, a third-order rate dependence in amine should not be observed for systems (substrate and solvent) where this kinetic behaviour has been found in SN Ar reactions with related amines143,144 . The plot of the rate of reaction of FDNB with cyclohexylamine in toluene against [B] exhibits a slight upward curvature, typical of a third-order dependence on [B]190 . On the contrary, the reactions of trans-1,2-diaminocyclohexane, 42, shows a linear dependence of kA on [B]: it is known that diaxial interactions in this type of amines prevent self-association190 and the kinetic behaviour is that usually found in the classical base-catalysed rate-determining decomposition of the zwitterionic intermediate. However, a more interesting result, expected within the dimer nucleophile mechanism, is the more
26. SN Ar reactions of amines in aprotic solvents
1283
TABLE 24. Reaction of 1-fluoro-2,4-dinitrobenzene (FDNB) with cyclohexylamine, and with 1,2190 diaminocyclohexane (DACH) in toluene at 5 ° Ca 1,2-DACH kA (dm3 mol1 s1 )
Cyclohexylamine
cis- and trans-1,2-DACH
[B] (mol dm3 )
kA (dm3 mol1 s1 )
[B] (mol dm3 )
trans
cis
[B] (mol dm3 )
kA (dm3 mol1 s1 )
0.0234 0.127 0.236 0.365 0.539
0.044 0.067 0.102 0.142 0.239
0.000218 0.00733 0.0118 0.0719 0.107
0.181 0.206 0.223 0.342 0.451
0.399 0.440 0.466 0.810 1.01
0.00756 0.0407 0.0535 0.0774 0.111
0.338 0.425 0.516 0.590 0.749
a [FDNB] 2.05 ð 106 mol dm3 ; error in k < 2%. A
than twofold increase in rate with the cis-isomer, in spite of enhanced steric hindrance. Intramolecular hydrogen bonding between both amine groups in the cis-configuration, 43, increases the nucleophilicity of the hydrogen-bonded donor amine, thereby increasing the rate190 (Table 24). NH2
NH2 NH2
N H
H (42)
(43)
Consistent with this interpretation is the effect of addition of small amounts of a hydrogen-bond donor solvent. The rate behaviour is compared with that found before in the reaction of the same substrate with piperidine in benzene ethanol mixtures. It is shown that the reaction with piperidine is base-catalysed k3 /k2 D 1230, no selfassociation of the nucleophile in benzene is observed and when small amounts of ethanol are added an important increase in rate is observed. On the other hand, an important decrease in the rate of reaction with the cis- and trans-1,2-diaminocyclohexane mixture was observed on addition of small amounts of methanol. The rate decreases up to 50% toluene 50% methanol and then a two-fold increase in rate takes place on going to pure methanol. The sharp decrease in rate is interpreted as partially due to the rupture of the intramolecular hydrogen bonding between both cis-amino groups, by competition with external hydrogen bonding with the good HBD methanol ˛ D 0.93178 . The data allowed calculation of the rate ratio shown in Table 25190 . The k3 /k2 quotients for both nucleophiles are almost equal; the more than two-fold increase in rate observed for the cis-isomer should then be due to a similar increase in k1 or a decrease in k1 . It is reasonable to expect that k1 would be similar for the two amines (or even bigger for the cis-isomer due to the greater steric effects); thus the increase in rate observed with the cis-1,2-diaminocyclohexane should be due to an increase in k1 . The k1 values were calculated in both cases by standard procedures and it was found that the value is five times greater for the cis-isomer (Table 25). This enhanced rate in the first step is
1284
Norma S. Nudelman TABLE 25. Reaction of 1-fluoro-2,4-dinitrobenzene with 1,2diaminocyclohexanes in toluene at 5 ° C, with rate coefficients quotient190 .
k1 k3 /k1 k1 k2 /k1 k3 /k2 k1
1,2-DACH
cis-1,2-DACH
cis/trans
2.4 0.19 12.9 0.413
5.7 0.40 14.3 2.08
65 2.1 1.1 5.0
fully consistent with the proposal of an ‘intramolecularly self-associated nucleophile’ in solvents of low permittivity190 . This proposal finds good support in the gas-phase basicities (GB)68 of various polyfunctionalized amines recently determined. An intramolecular stabilization of protonated polyfunctional groups, also called ‘internal solvation’, has been observed in the gas phase with the amidinium and guanidinium cations86,191,192 . This effect is due to cyclization by internal hydrogen bonding between the protonated functional group (Y) and a hydrogenbond donor group (X), 44. Studies of substituent effects on the basicity of amidines and guanidines in solution193 have shown that the amino nitrogen is the preferred site of protonation in solution, similarly as in the gas phase. Thus, the pKa values can be directly compared with the GB values: good regression values are obtained for the plots of pKa vs GB; in the alkyl systems the polarizability P effect seems to be the most important parameter, whereas for aromatic systems other terms are also contributing. H +Y
X (CH2 )n (44)
The bicyclic amidines 1,5-diazabicylo[4,3,0]non-5-ene (DBN, 45), 1,5-diazabicylo[4,4,0]dec-6-ene (DBD, 46) and 1,5-diazabicylo[5,4,0]undec-7-ene (DBU, 47) are widely used in ANS as base catalysts, because they exhibit high basicity and low nucleophilicity; the GB values are 993.9, 999.6 and 1002.9, respectively86 . It is interesting that the proton affinity (PA) of DBN (1025.7)86 derived from the experimental GB measurements is very similar to the recently reported PA of arginine (1025.9)194 . Raczynska and coworkers86 suggested that the strong GB of arginine may be due to the ‘internal solvation’ of the guanidinium cation, 48. In histamine, 49, an important biogenic molecule, Raczynska and coworkers86 have demonstrated the existence of
N N
N N
DBN (45)
N N
DBD (46)
DBU (47)
26. SN Ar reactions of amines in aprotic solvents
1285
H NH2 H (H2 N)2 C
Ν+
CH (CH2 )3 (48)
+
NH2 + COOH
N
N H (49)
‘internal solvation’, favoured by the alkylamino chain separated by three carbon atoms from the imidazole nitrogen. In the gas phase, the imidazole ‘sp2’ nitrogen atom is the preferred site of protonation. (GB for histamine is 949 kJ mol1 , for 4-methylimidazole 915 kJ mol1 and for PhCH2 CH2 NH2 895 kJ mol1 .) In aqueous solution PhCH2 CH2 NH2 is more basic than 4-methylimidazole by 2.3 pKa units (13 kJ mol1 ). This reversal is due to a better solvation of NH3 C compared with DNHC , but in the gas phase, and likely in aprotic solvents, the energetically preferred imidazole nitrogen protonation is further favoured by ‘internal solvation’. This change in histamine cation structure on going from aqueous media to gas phase has recently been considered in theoretical calculations195,196 . Similarly for the case of the ˛-amino acid histidine, a recent semi-empirical calculation197 gives the structure with an intramolecular H-bond CDOÐ Ð ÐHN(Im) as the most stable conformation of protonated histidine. Arginine is another example of an ˛-amino acid in which guanidine and amine functions are separated by a chain of four carbon atoms. Raczynska and coworkers86 suggested that the strong gas-phase basicity of arginine (comparable to the GB of DBN) may be due to the ‘internal solvation’ of the guanidinium cation, 48. These authors conclude that ‘the problem of internal solvation is still an experimental and theoretical challenge’; GB measurements for this type of molecules of low volatility are not always in good agreement194 . Molecular orbital calculations may help to solve the difficult experimental problems, but they have to take into account conformational isomerisms and the prototropic tautomerisms of the amidine and guanidine moieties. In light of the above discussion, the proton affinities deduced from the experimental GB values should be based on accurate estimations of the ‘entropy of cyclization’86 . The accurate determination of gas-phase basicities and gas-phase acidities opened the way to analyses of the effect of solvation on proton acidities, and on hydrogen-bond acidities and basicities, as well as on substituents effects. L. Isotope Effects
Forlani and coworkers184 determined that the magnitude of kA was found to increase linearly with nucleophile concentration for the reaction of picryl fluoride with 2-hydroxypyridine in chlorobenzene, and kA H /kA D D 1.5 for mono-deutero-2hydroxypiridine was observed184 . Since isotope effects are usually small in SN Ar in apolar solvents1 the authors attributed the isotope effect to the formation of a substratecatalyst molecular complex. They obtained a value of kA H /kA D D 1.75 for the ratio of the association constants, kH /kD . When the substrate was picryl chloride, the slight increase of kA with nucleophile concentration was interpreted in terms of Scheme 6 giving a value of K D 2.9 š 1 identical with that for the fluoro-substrate 3.0 š 1. Taking into account, for instance, the slight differences in K observed for 1-fluoro-2,4,6trinitrobenzene and 1-chloro-2,4,6-trinitrobenzene in Table 13, it is difficult to explain such a difference in KH /KD . Nevertheless, a H/D isotopic effect of 1.5 could be easily explained
1286
Norma S. Nudelman
on the basis of the auto-association of 2-hydroxypyridine, involving hydrogen bonding, since the tendency of 2-hydroxypyridine to form dimeric species is very well known124 . Another alternative explanation for the observed H/D isotopic effect is the ability of 2-hydroxypyridine to act as a ‘bifunctional’ catalyst: as mentioned in Section II.F, 2hydroxypyridine is able to both base-catalyse proton abstraction and acid-catalyse the nucleofuge departure. Either of these two explanations seems to be more satisfactory to account for the observed H/D isotopic effect than the weak rationale based on the molecular complexes. Clearly, these isotope effects could also be explained on the basis of the ‘dimer nucleophile’ or ‘homo/heteroconjugate’ mechanisms. M. Further Treatment of Kinetic Results
1. ‘Inversion Plots’
Several alternative mechanisms have been described here that have been reported to explain the ‘anomalous’ kinetic results, such as the observed fourth-order kinetics. Further treatment of the different equations may help to understand the scope of the different proposals. In a simplified form for the dimer mechanism, only attack by the dimer nucleophile can be considered, as shown by equation 41. k2
S + B:B
k1 k −1
[SB2 ]
P
(41)
k3 B
It was shown that the derived expression for kA is equation 28. (Section III.D). If k1 ¾ D k2 Ck3 [B], at high [B] equation 28 may be transformed into equation 30, which is responsible for the plateau observed in some cases [e.g. the reactions of 2,4-dinitroanisole with cyclohexylamine in benzene (Figure 11) and in cyclohexane (not shown)]143,144 and it was also observed in the reactions with n-butylamine in benzene at 60 ° C (the reactions at 80 ° C show a slight curvature, tending to a farther asymptotic behaviour). In all the SN Ar systems studied by other authors, in which fourth-order kinetics were found, the observation of a similar plateau in the plots of kA /[B] vs [B] was not reported. Inversion of equation 28 (Section III.D) gives expression 42, which allows some estimation of the different k values involved: k1 1 [B] C D kA k1 K k1 k2 K C k1 k3 K[B]
42
Taking into account that the uncatalysed decomposition is slower than the base-catalysed one, equation 42 can be simplified to equation 43: k1 1 [B] C D kA k1 K k1 k3 K[B]
43
A plot of [B]/kA vs [B]1 should be linear, except where the conditions that allow the simplification to equation 43 are not fulfilled. Such a plot is presented as line A in Figure 15 for the reaction of 2,4-dinitroanisole (DNA) with cyclohexylamine (CHA) in cyclohexane, and as line B in Figure 15 for the reactions with n-butylamine (BA) in benzene, both at 80 ° C. Each is satisfactorily linear, and they allow evaluation of the different k values. Estimations of the k1 k3 K/k1 values for this and other reactions are given in Table 26144 . The reactions at 80 ° C exhibit useful behaviour for evaluation of the
26. SN Ar reactions of amines in aprotic solvents 5 5
10
B
10−2[n
10−3[CHA] / kA(nH2)
1287
[n − BA]−1 (H−1) − BA]−1 / kA(nH−2)
10
4 Β 3 A
B
Α
5
2
1 −1
2
4
A
6
[CHA] 8
(H−1)
ž
FIGURE 15. Inversion plot: A, reaction of 2,4-dinitroanisole with cyclohexylamine at 80 ° C ( ); B, reaction of 2,4-dinitroanisole with n-butylamine (n-BA) in benzene in 80 ° C ( , data from Reference 143a)144 . Reprinted with permission from Reference 144. Copyright (1983) American Chemical Society
°
TABLE 26. Amine
Rate coefficient relationships for SN Ar reactions of dinitroanisole (DNA)199 Substrate
Cyclohexylamine 2,4-DNA
Solvent benzene cyclohexanee
2,6-DNA
n-Butylamine
benzene
2,4-DNAf benzene 2,6-DNAf benzene
Temp 104 k3 k4 / 103 k1 k3 K1 / 103 k1 k2 K1 / ( ° C) k4 K2 a k4 K2 a k4 K2 b k1 K1 /k4 100 80 60 100 80 60 45 35 27 100 80 60 45 35 27
0.602 <0.34 <0.13 0 0 0 6.06 4.57 3.78 3.61 <3.2 <4.0 19.0 15.0 13.0
0.781 >0.86 >1.0 1.73 1.81 >2.65 1.78 2.00 2.04 5.78 >6.8 >6.6 9.5 10.9 12.3
1.26 1.81 1.89 4.0
12.9 22.7
a From Equation 28. b From the inverted slope of Equation 43. c From the quotient between the slope and the intercept of Equation 28. d From the quotient between the inverted slope of Equation 43 and the intercept of Equation 28. e Cyclohexane/benzene ratio of 99:1. f Data from Reference 144.
13c >37d >140d 1 1 1 2.9c 4.4c 5.4c 16c >40d >57d 5.0c 7.3c 9.5c
1288
Norma S. Nudelman
same expression from the plot of kA /[B] vs [B]. Indeed, at low [B] equation 28 can be simplified to equation 29, and the slope of the plot of kA /[B] vs [B] agrees satisfactorily with the values obtained from the inversion plot. These results can be interpreted as evidence that equation 28 holds and that the simplification to equation 29 is justified10 . The intercepts allow an estimation of the order of magnitude of k1 k2 K/k1 and, from both quotients, the ratio k3 /k2 can be reckoned (Table 26). The quotients increase with decreasing temperature in accord with the increased association constant. In the reaction of DNA with CHA and with BA in benzene, the slopes of the curves at the origin are not zero. For the last case, the rate of the reaction allows several kinetic measurements at low [B] and exact evaluation of the slope at the origin of kA vs [B] for a range of [B] D 0 0.03 M. At 45 ° C a value of 2.2 ð 103 M2 s1 is obtained which agrees satisfactorily with the value k1 k2 K/k1 D 1.9 ð 103 M2 s1 obtained from the intercept of the plot of kA /[B] vs [B] constructed with the data obtained at higher [B]. The values for the reaction at 35 and 27 ° C are 1.6ð103 and 1.4ð103 s1 M2 , respectively, which agree satisfactorily with the data obtained at higher [B]. Similar agreement was found for the other systems gathered in Table 16. The satisfactory agreement between the quotients obtained from both sets of data obtained under different conditions indicates that the assumptions made are correct and the whole treatment justified. Hirst’s proposal for the fourth-order kinetics implies an electrophilic catalysis of the second step by the homoconjugate acid of the nucleophile, BHC B (where B stands for the nucleophile). The simplified equation would be k3 B k1
S +B
k −1
[SB]
P
(44)
+
k 4 BH B
which requires that the catalyst acts in the second step, and the derived expression is given by equation 45: kA D
k1 k2 C k1 k3 K[B] C k1 k4 K[B]2 k1 C k2 C k3 [B] C k4 K[B]2
45
On the other hand, the eight-membered cyclic transition state mechanism proposes that two molecules of the nucleophile intervene in the decomposition of the zwitterionic intermediate. It can be described in condensed form by equation 46, and the derived kinetic expression is equation 47. k2
S + B
k1 k −1
[SB]
P
(46)
k 3 2B
kA D
k1 k2 C k1 k3 [B]2 k1 C k2 C k3 [B]
(47)
Equation 45 and 47 as well as equation 28 account for the quadratic dependence of kA with [B], with a zero intercept if the uncatalysed decomposition is assumed to be negligible. However, the peculiar kinetic behaviour observed in some systems (which has just been described) can only be explained by equation 28. Hirst148 and Banjoko170
26. SN Ar reactions of amines in aprotic solvents
1289
have not reported the observation of a plateau in the plots of kA /[B] vs [B] in the reactions studied, therefore their respective mechanisms can account satisfactorily for their results. However, only the dimer nucleophile mechanism can account for the observation of the ‘inversion plots’, i.e. a linear plot of [B]/kA vs [B]1 , agreement between the several k values evaluated under different reaction conditions and a rather large range of [B]. The other alternative mechanisms discussed here, which are based on the formation of different types of complexes with the substrate, failed to accommodate additional observations, such as the conformational effects. Indeed, if any difference would be expected between the cis- and trans-1,2-diaminocyclohexane in forming complexes with the substrate, that would be in favour of an increase in rate for the reaction with the trans-isomer, contrarily to the experimental observation. 2. Evaluation of the equilibrium constants
One of the major difficulties in Forlani’s proposal of the molecular complex substratecatalyst mechanism, to explain the fourth-order kinetics, is the assumption that this complex needs an additional molecule of amine to decompose to products. The formation of molecular complexes between dinitrohalobenzenes and certain amines (especially aromatic amines) has been widely studied, and their involvement in SN Ar reaction has been discussed in Section II.E. The equilibrium constants for the formation of those complexes were calculated in several cases, and they were included in the kinetic expressions when pertinent. But in all cases, the complex was assumed to be in the reaction pathway, and no need of an additional amine molecule was invoked by the several authors who studied those reactions. In some of Forlani’s works, such as the reactions of 1-halogeno-2,4,6-trinitrobenzene with 2-hydroxypyridine123,125 , a substrate-catalyst molecular complex was assumed, but the kinetic law showed the regular second order in amine. Rather interestingly in this scheme, the authors assume that the molecular complex can lead to the formation of products following a second order in nucleophile kinetics, while in the reactions with amines it was presumed that the complex was not on the reaction coordinate, and that an additional molecule of amine was required (the authors needed to include this additional molecule to account for the third order in amine rate law). In the mechanisms involving molecular complexes discussed in Section II.E, several authors were able to calculate the equilibrium association constants, in reactions showing classical kinetics. On the other hand, Forlani and coworkers, in the reactions discussed in Section III.I, assume that the complexes intervene in determining the third order in amine kinetic law, and make calculations of some K; some results were presented in Table 13. Several features arise from this Table: (a) The effect of adding a nitro group at the ortho-position diminishes the association constant when compared with p-chloronitrobenzene, but adding another nitro group at the other ortho-position increases K, comparatively to CDNB. The author concludes that this probably arises from a balance of the interaction of the additional nitro group and the steric hindrance of the nitro group in the ortho-position to the halogen atom, but the steric hindrance should be more noticeable in CTNB and the observed effect is the inverse. (b) The data for the monodeutero-2-hydroxypyridine (KH /KD D 1.7 for FDNB and 3.4 for 1-fluoro-4-nitrobenzene) is interpreted as a clear indication that a major interaction is the hydrogen bond involving the halogen atom (or the nitro group), but it is not so clear, then, why the KH /KD for the 1-fluoro-4-nitrobenzene is twice the value for FDNB. (c) The large differences between K values for FDNB in THF (17 dm3 mol1 ) and in chlorobenzene (3.5 dm3 mol1 ) or toluene (0.34), shown in Table 12, are also unexplained.
1290
Norma S. Nudelman
Taking into account these apparent inconsistencies between the values, which are rather higher than the stated errors given as standard deviations, results in suspicions us regarding the whole way of calculating of the stability constants. 3. The dichotomy of amine effects in aromatic nucleophilic substitution (ANS) in aprotic solvents
In the preceding sections throughout this chapter, several aspects of the influence of the nucleophile on the rates of the different reaction steps and/or mechanisms involved in ANS with amines have been discussed. One of the most outstanding features and most widely studied phenomena is the observation or the absence of base catalysis and, somewhat related with this subject, is the occurrence of a first, second or third order in amine kinetic law. Hirst and coworkers198 have recently examined the dichotomy of primary and secondary amine effects in ANS in the reactions of 2-trifluoromethyl- and 2-cyano4-nitrofluorobenzenes with piperidine, n-butylamine, morpholine and benzylamine in acetonitrile and benzene (see Table 27). The substituents in the 2-position were chosen on the basis of their different steric requirements: the cyano group is linear and much smaller than either the nitro or the trifluoromethyl groups. For the reaction of 2-cyano-4nitro-fluorobenzene with benzylamine the k3 /k2 value is 1.9, and for the trifluoromethyl substrate the values of the ratio are: 6.0 (n-butylamine), 14.9 (piperidine) and 1.2 (benzylamine)198 , According to Bunnett’s criteria these low values do not represent true base catalysis, and the authors take the measured kA values as being those for the formation Pip Bu of the intermediate. The ratio of the rate constants for piperidine and butylamine kA /kA are 15.5 and 4.5 for the ortho-nitro and -cyano substrates, respectively, whereas when the ortho group is the trifluoromethyl the ratio is 0.2, i.e. the secondary amine is less reactive than the primary one. This is interpreted as evidence of the operation of a primary steric effect: as we have demonstrated in an early study on the effect of 2-R substituents in ANS reactions with piperidine in benzene102 , this kind of effect should only be observed with an ortho-substituent of steric requirements similar to or greater than a methyl group. The reactions of the three substrates with morpholine showed base catalysis, and when the nucleophile is benzylamine, plots of the second-order rate constants against the nucleophile concentration have an upward curvature197 . Similar behaviour exhibits the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in acetonitrile182 while the corresponding reaction with n-butylamine is not catalysed182 , thus providing further examples of the dichotomy of amine effects198,199 . Taking into account that the dichotomy is also observed when the ortho-group is cyano, for which it has been demonstrated that there is little or no hydrogen bonding between it and the ammonio group of the -complex, the authors conclude that the effects must be steric, although these would not arise from differential steric compressions between primary and secondary amines, but from stereoelectronic effects198 . The existence of stereoelectronic effects in ANS have been previously proposed by Bunnett20b,c and Hasegawa22 for reactions involving ortho-nitro groups. Bunnett and Cartano20a ascribed the very large difference in rates between piperidine and pyrrolidine to stereoelectronic inhibition of the detachment of the nucleofuge when piperidine is the nucleophile. Since morpholine and piperidine are stereochemically similar but exhibit different pKa values, the difference between their rates in the reactions of the fluoro-substrates in acetonitrile could be also due to a change in mechanism, whereby proton transfer from the intermediate 1 in equation 1 becomes rate-limiting when the reagent is morpholine. The change from an uncatalysed to a base-catalysed reaction with decrease in basicity of the nucleophile is well known in ANS for both primary and secondary amines1,200 .
26. SN Ar reactions of amines in aprotic solvents
1291
(dm3 mol1 s1 )
TABLE 27. Rate constants for the reactions of 2-cyano- and 2-trifluoromethyl-4nitrofluorobenzenes and 2-cyano-4-nitrophenylphenyl ether with some amines in aprotic solvents at 30 ° C198 Solvent Acetonitrile
Substrate 2-Trifluoromethyl-4nitrofluorobenzene
2-Cyano-4nitrofluorobenzene
Nucleophile
c(mol dm3
kA
k 00 /k 0a
Piperidine
5.0 ð 102 6.0 ð 102 8.0 ð 102 10 ð 102
1.48 ð 103 1.60 ð 103 1.85 ð 103 2.11 ð 103
14.9
n-Butylamine
1.0 ð 102 1.5 ð 102 1.6 ð 102 2.0 ð 102 2.5 ð 102
4.29 ð 103 4.41 ð 103 4.58 ð 103 4.53 ð 102 4.68 ð 103
6.0
Morpholine
5.0 ð 102 10 ð 102 15 ð 102 20 ð 102 25 ð 102 30 ð 102 40 ð 102 50 ð 102
2.06 ð 105 3.61 ð 105 4.86 ð 105 5.85 ð 105 6.84 ð 105 7.77 ð 105 9.53 ð 105 10.8 ð 105
Benzylamine
4.0 ð 102 6.0 ð 102 8.0 ð 102 10 ð 102 15 ð 102 20 ð 102
3.95 ð 104 3.88 ð 104 3.98 ð 104 4.04 ð 104 4.45 ð 104 4.54 ð 104
Piperidine
8.0 ð 104 10.0 ð 104 12.0 ð 104 14.0 ð 104 100 ð 104
4.55 ð 101 4.60 ð 101 4.60 ð 101 4.70 ð 101 4.30 ð 101
n-Butylamine
4.0 ð 103 6.0 ð 103 8.0 ð 103 10.0 ð 103 20.0 ð 103
9.95 ð 102 10.9 ð 102 10.4 ð 102 9.53 ð 102 10.0 ð 102
Morpholine
8.0 ð 103 10.0 ð 103 20.0 ð 103 40.0 ð 103 60.0 ð 103 80.0 ð 103 100 ð 103 150 ð 103
3.46 ð 103 3.88 ð 103 4.87 ð 103 7.03 ð 103 9.45 ð 103 11.8 ð 103 13.3 ð 103 17.7 ð 103
Benzylamine
4.0 ð 102 6.0 ð 102 8.0 ð 102 10.0 ð 102
1.72 ð 102 1.73 ð 102 1.83 ð 102 1.90 ð 102
1.2
1.9
(continued overleaf )
1292 TABLE 27.
Norma S. Nudelman (continued )
Solvent
Substrate
Dimethylsulphoxideb
Benzene
2-Cyano-4nitrophenyl phenyl ether
Nucleophile
c(mol dm3
k 00 /k 0a
Morpholine
4.0 ð 104 6.0 ð 104 8.0 ð 104 10.0 ð 104 12.0 ð 104 14.0 ð 104 20.0 ð 104
1.47 1.56 1.50 1.54 1.31 1.46 1.52
Benzylamine
1.0 ð 103 2.0 ð 103 2.5 ð 103 5.0 ð 103 10.0 ð 103
3.40 ð 101 3.25 ð 101 3.30 ð 101 3.36 ð 101 3.47 ð 101
Piperidine
6.0 ð 103 8.0 ð 103 10.0 ð 103 20.0 ð 103 30.0 ð 103
0.867 ð 102 1.05 ð 103 1.12 ð 102 1.30 ð 102 2.57 ð 102 3.80 ð 102
n-Butylamine 4.0 ð 102 6.0 ð 102 8.0 ð 102 10.0 ð 102 20.0 ð 102
0.86 ð 103 1.26 ð 103 1.70 ð 103 2.06 ð 103 4.11 ð 103
408
Morpholine
5.0 ð 102 6.0 ð 102 8.0 ð 102 10.0 ð 102 12.0 ð 102
1.57 ð 103 1.90 ð 103 2.45 ð 103 3.01 ð 103 3.64 ð 103
233
Benzylamine
1.0 ð 101 2.0 ð 101 3.0 ð 101 4.0 ð 101 5.0 ð 101
3.09 ð 104 6.50 ð 104 10.3 ð 104 14.1 ð 104 19.1 ð 104
Piperidine
3.0 ð 101 4.0 ð 101 5.0 ð 101 6.0 ð 101 7.0 ð 101 8.0 ð 101
2.11 ð 105 3.25 ð 105 4.36 ð 105 5.55 ð 105 5.97 ð 105 7.06 ð 105
n-Butylamine 2.0 ð 101 3.0 ð 101 4.0 ð 101 5.0 ð 101 6.0 ð 101 Acetonitrile
kA
Piperidine
5.0 ð 102 7.5 ð 102 10.0 ð 102 20.0 ð 102 25.0 ð 102 30.0 ð 102
0.835 ð 106 1.24 ð 106 1.44 ð 106 2.14 ð 106 2.57 ð 106 3.00 ð 105 3.88 ð 105 5.50 ð 105 11.2 ð 105 13.1 ð 105 15.1 ð 105
1
123
26. SN Ar reactions of amines in aprotic solvents TABLE 27. Solvent
1293
(continued ) Substrate
Nucleophile n-Butylamine
c(mol dm3 1.0 ð 101 2.0 ð 101 3.0 ð 101 4.0 ð 101 5.0 ð 101 6.0 ð 101
k 00 /k 0a
kA 0.975 ð 105 1.42 ð 105 1.72 ð 105 2.03 ð 105 2.46 ð 105 2.77 ð 105
5.4
a See the text. b At 29 ° C.
TABLE 28. Calculated values for reactions of o- and p-fluoronitrobenzenea n-C3 H7 NH2
o-Fluoronitrobenzene 106 kA (l mol1 s1 ) 106 k 00 106 k 0 k 00 /k 0 Ht (kcal mol1 ) St (cal K1 mol1 ) p-Fluoronitrobenzene 106 kA (l mol1 s1 ) 106 k3 k1 /k1 106 k2 k1 /k1 k3 /k2 Ht (kcal mol1 ) St (cal Kt mol1 )
82
iso-C3 H7 NH2
Toluene
DMSO
Toluene
24 12.9 22.6 0.57 10.6 46
3130
5.4 6.04 4.77 1.27 11.1 48
643
0.0005 0.06c 0.01c 5c 9 65
400b
0.054 0.75 1 7.4 69
9.5 55 205b
DMSO
10 42
a At 45 ° C, [Amine] 0.1M. b Data at 50 ° C from Reference 181. c Only the order of magnitude is accurate. See text.
Other clear-cut evidence that the dichotomy between primary and secondary amines cannot be due to differential steric compression in the -complexes formed in these reactions has been afforded by Nudelman and Cerdeira82 in their study of the reactions of o-and p-fluoronitrobenzenes with two primary amines: n- and iso-propylamine in toluene (Table 28). For the reactions with o-fluoronitrobenzene the ratio kA n-Pr /kA i-Pr is 4.4, whereas for the reactions with p-fluoronitrobenzene kA n-Pr /kA i-Pr is 108. The high decrease in the rate of reaction of i-propylamine with p-fluoronitrobenzene cannot be obviously due to primary steric effects of the isopropylamine, since they should be more noticeable with the o-substrate. We have examined the effect of the amine on the concentration reaction rates and demonstrated that for the o-substrate only a slight effect is observed, whereas the reactions of p-fluoronitrobenzene with n-propylamine proceed only through the catalysed pathway k3 /k2 D 1 with the branched amine k3 and k2 are of the same order of magnitude. This clearly demonstrates that the huge decrease in rate on passing from n-to iso-propylamine is due to a retarding effect in the base-catalysed decomposition of the -complex. Crampton24 has also demonstrated that for Meisenheimer complex formation, increased crowding at the reaction site caused by change from primary amines to piperidine results in rate reduction of proton transfer from the complex to the amine catalyst, and Hirst199
1294
Norma S. Nudelman
has interpreted similar results as due to steric inhibition to the electrophilic catalysis of the expulsion of the nucleofuge; the authors expect that the k3 /k2 values should be lower for secondary than for the corresponding primary amines, except where hydrogen bonding can take place between a group ortho to the reaction site and the ammonio hydrogen of the intermediate. Nevertheless, the results observed for the reactions of o- and p-fluoronitrobenzenes with propylamines demonstrate that: (a) the dichotomy is not only observed when comparing primary with secondary amines; (b) the origin is not due to primary steric effects; (c) when there is no ortho-nitro group the decrease in rate for the bulky amine is greater; (d) the diminution in rate is due to an inhibition effect in the base-catalysed decomposition. All these observations, together with the finding that in the reactions of pfluoronitrobenzene with n-propylamine in toluene the plot of kA against n-propylamine exhibits a negative intercept, typical of a third order in amine kinetic law, are consistent with the operation of amine aggregates (‘dimers’ or ‘mixed aggregates’) in solvents of low permittivity. In the absence of an ortho-nitro group that could assist the reaction through H-bonding, and it being clear that fluorocarbon compounds are very poor hydrogenbond acceptors201 , the only effective way for stabilizing the -complex is through hydrogen bonding with the amine, as observed in the intermediate formed with the ‘dimer’ nucleophile, followed by the amine catalysed decomposition. Branching in the amine hinders aggregation in the nucleophile as well as in the intermediate: this interpretation is confirmed by the solvent effects. As discussed in Section DMSO is a good hydrogenbond acceptor, forms ‘mixed aggregates’ with the amines and consistently with the whole mechanism, the reactions in DMSO are very much faster: the reaction rates with npropylamine and iso-propylamine are of the same order of magnitude, the reaction rate with this amine being almost twice the value of n-propylamine, as expected for a better nucleophile in the absence of steric effects. IV. CONCLUDING REMARKS
The SN Ar reactions with amines in aprotic solvents pose various difficulties, related to the inability of those solvents to stabilize ionic species, as has been discussed. Several alternative mechanisms have been proposed for these reactions, specially connected with the finding of ‘anomalous’ kinetics, some of them controversial. Although we believe the case is not closed, certain features of the reactions in aprotic solvents can be considered well settled. Those are: the existence of aggregates of the nucleophile and their influence on the kinetic expressions, the formation of complexes between the nucleophile and the substrate (although their participation in the kinetic law is not completely clear); the accelerating effect of HBA additives; the formation of ‘mixed aggregates’; and the homo- and hetero-conjugate acid complexes. In this respect, we agree with Hirst and coworkers109,162 that the interpretation of formation of homo- (or hetero-) conjugated acid BHC B by proton transfer from the intermediate and the electrophilically catalysed departure of the nucleofuge due to this aggregate is common to this and to the ‘dimer mechanism’ and they can be formulated as essentially the same, and as reflecting different parts of a spectrum of methods for the formation of the second intermediate, the relative importance of which depends not only on the entities employed, but on their concentrations as well. Nevertheless, there are some experimental findings such as the conformational effects and the ‘inversion plots’, that are only explained by the ‘dimer nucleophile’ mechanisms. V. ACKNOWLEDGEMENTS
The author is deeply indebted to her coworkers in this area, whose names appear in the references. Enlightening discussions with Prof. J. F. Bunnett on many occasions
26. SN Ar reactions of amines in aprotic solvents
1295
throughout almost two decades devoted to the study of SN Ar reactions are heartily acknowledged. VI. REFERENCES 1. For recent reviews see: (a) F. Terrier, ‘Nucleophilic aromatic displacement: The influence of the nitro group’, in Organic Nitro Chemistry Series (Ed. H. Ferrer), VCH Publishers, New York, 1991. (b) N. S. Nudelman, An. Acad. Nac. Ciencias Exactas (Buenos Aires), 32, 109, (1980). (c) C. F. Bernasconi, MTP Int. Rev. Sci., Org. Chem. Ser. 1, 3, 33, (1973). (d) J. F. Bunnett and J. J. Randall, J. Am. Chem. Soc., 80, 6020 (1958). 2. (a) J. F. Bunnett and R. J. Garst, J. Am. Chem. Soc., 87, 3875 (1965). (b) J. F. Bunnett and R. J. Garst, J. Am. Chem. Soc., 87, 3879 (1965). (c) J. F. Bunnett and R. J. Morath, J. Am. Chem. Soc., 77, 5051 (1955). 3. (a) C. F. Bernasconi, Acc. Chem. Res., 11, 147 (1978). (b) C. F. Bernasconi, Chimia, 324, 1 (1980). 4. (a) N. S. Nudelman and J. A. Brieux An. Asoc. Quim. Arg., 207 (1978). (b) N. S. Nudelman and J. A. Brieux, An. Asoc. Quim. Arg., 217 (1978). 5. F. Terrier, Chem. Rev., 82, 77 (1982). 6. (a) R. Bacaloglu, A. Blasko, C. A. Bunton, E. Dorwin, F. Ortega and C. Zucco, J. Am. Chem. Soc., 113, 238 (1991) and references cited therein. (b) R. Bacaloglu, C. A. Bunton and F. Ortega, J. Am. Chem. Soc., 111, 1041 (1989). (c) R. Bacaloglu, C. A. Bunton and F. Ortega, J. Am. Chem. Soc., 110, 3503 (1988). 7. J. I. Hayami, S. Otani, F. Yamaguchi and Y. Nishikawa, Chem. Lett., 739 (1987). 8. L. Forlani, M. Sintoni and P. E. Todesco, J. Chem. Res. (S), 66, 344 (1986). 9. S. M. Chiacchiera, J. O. Singh, J. D. Anunziata and J. J. Silber, J. Chem. Soc., Perkin Trans. 2, 1585 (1988). 10. N. S. Nudelman, J. Phys. Org. Chem., 2, 1 (1989) and references cited therein. 11. (a) E. Buncel, M. R. Crampton, M. J. Strauss and F. Terrier. In Electron-Deficient Aromatic and Heteroaromatic Base Interactions, Elsevier, Amsterdam, 1984. (b) G. A. Artamkina, M. P. Egorov and I. P. Beletskaya, Chem. Rev., 82, 427 (1982). 12. N. S. Nudelman and S. B. Cerdeira, Magn. Reson. Chem., 24, 1098 (1986). 13. (a) D. A. De Bie, B. Geurtsen, I. E. Berg and H. C. Van der Plas, J. Org. Chem., 51, 3209 (1986). (b) H. C. Van der Plas, M. Wozniak and H. J. Van der Haak, Adv. Heterocycl. Chem., 33, 96 (1983). 14. K. Bowden, S. Prasannan and R. J. Ranson, J. Chem. Soc., Perkin Trans. 2, 181 (1987). 15. (a) F. Bazzani, P. Mencarelli and F. Stegel, J. Org. Chem., 49, 2375 (1984). (b) A. Annulli, P. Mencarelli and F. Stegel, J. Org. Chem., 49, 4065 (1984). 16. J. D. Reinheimer, N. Sourbais, R. L. Lavallee and D. Goodwin and G. L. Gould, Can. J. Chem., 62, 1120 (1984). 17. F. Terrier, A. P. Chatrouse, P. Soudais and M. Hlaibi, J. Org. Chem., 49, 4176 (1984). 18. C. F. Bernasconi and R. H. de Rossi, J. Org. Chem., 41, 44 (1976). 19. J. A. Orvick and J. F. Bunnett, J. Am. Chem. Soc., 92, 2417 (1970). 20. (a) J. F. Bunnett and A. V. Carta˜no, J. Am. Chem. Soc., 103, 4861 (1981). (b) J. F. Bunnett, S. Sekiguchi and L. A. Smith, J. Am. Chem. Soc., 103, 4865 (1981). (c) S. Sekiguchi and J. F. Bunnett, J. Am. Chem. Soc., 103, 4871 (1981). 21. (a) S. Sekiguchi, M. Hosokawa, T. Suzuki and M. Sato, J. Chem. Soc., Perkin Trans. 2, 1111 (1993). (b) H. Fujinuma, M. Hosokawa, T. Suzuki, M. Sato and S. Sekiguchi, Bull. Chem. Soc. Jpn., 62, 1969 (1989). 22. (a) Y. Hasegawa, Bull. Chem. Soc. Jpn., 56, 1314 (1983). (b) Y. Hasegawa, J. Org. Chem., 50, 649 (1985). 23. Y. Hasegawa, J. Chem. Soc., Perkin Trans. 2, 547 (1984). 24. M. R. Crampton and P. J. Routledge, J. Chem. Soc., Perkin Trans. 2, 573 (1984). 25. R. H. de Rossi and R. A. Rossi, J. Org. Chem., 39, 3486 (1974). 26. T. O. Bamkole, J. Hirst and G. Hussain, J. Chem. Soc., Perkin Trans. 2, 681 (1984). 27. E. R. de Vargas and R. H. de Rossi, J. Org. Chem., 49, 3978 (1984). 28. F. Del Cima, G. Biggi and F. Pietra, J. Chem. Soc., Perkin Trans. 2, 559 (1983).
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116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138.
Norma S. Nudelman (a). G. Consiglio, R. Notto and D. Spinelli J. Chem. Soc., Perkin Trans. 2, 222 (1979). (b) D. M. Brewis, N. B. Chapman, J. S. Paine, J. Shorter and D. J. Wright, J. Chem. Soc. Perkin Trans. 2, 1787 (1974). (c) G. Becker, C. F. Bernasconi and H. Zollinger, Helv. Chim. Acta, 49, 10 (1966). (a) N. S. Nudelman and D. Palleros, J. Chem. Soc., Perkin Trans 2, 805 (1985). (b) D. Palleros and N. S. Nudelman An. Soc. Cient. Arg., 43, 3 (1986). (a) S. C. Nyburg, C. H. Faerman, L. Prasad, D. Palleros and N. S. Nudelman Acta Crystallogr., C43, 686 (1987). (b) N. S. Nudelman and D. Garrido, J. Chem. Soc., Perkin Trans. 2, 1256 (1976). (a) C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 91, 165 (1991). (b) R. W. Taft, J. Chim. Phys., 89, 1557 (1992). N. S. Nudelman and D. Palleros J. Chem. Soc., Perkin Trans. 2, 995 (1981). C. F. Bernasconi, J. Phys. Chem. 75, 3636 (1971). T. A. Emokpae, P. U. Uwakwe and J. Hirst, J. Chem. Soc., Perkin Trans. 2, 509 (1991). S. M. Chiacchiera, R. I. Cattana, J. O. Singh, J. D. Anunziata and J. J. Silber, J. Phys. Org. Chem., 2, 631 (1989). F. Pietra and D. Vitali, J. Chem. Soc., Perkin Trans. 2, 385 (1972). G. A. Jeffrey and W. Saenger, Hydrogen Bonding in Biological Molecules, Springer-Verlag, Berlin Heidelberg, 1991. K. Tamaru and M. Ichikama, Catalysis by Electron-Donor-Acceptor Complexes, Wiley, New York, 1975. (a) O. B. Nagy, Bull. Soc. Chim. Belg., 94, 11 (1985). (b) O. B. Nagy, M. Wa Muanda and J. B. Nagy, J. Chem. Phys., 83, 1961 (1979). (a) E. Durantini, L. Zingaretti, J. D. Anunziata, and J. J. Silber, J. Phys. Org. Chem., 5, 557 (1992). (b) L. Giacomelli, R. Cattana, J. D. Anunziata, J. J. Silber, M. Hedrera, S. Salerno and I. Perillo, J. Phys. Org. Chem., 7, 162 (1994). (a) J. O. Singh, J. D. Anunziata and J. J. Silber, Can J. Chem., 63, 903 (1985). (b) S. M. Chiacchiera, J. O. Singh, J. D. Anunziata and J. J. Silber, J. Chem. Soc., Perkin Trans. 2, 987 (1987). R. I. Cattana, J. O. Singh, J. D. Anunziata and J. J. Silber, J. Chem. Soc., Perkin Trans. 2, 79 (1987). (a) S. S. Shaik Pure Appl. Chem., 63, 195 (1991). (b) S. S. Shaik J. Org. Chem., 52, 1563 (1987). A. Pross, Acc. Chem. Res., 18, 212 (1985). (a) S. S. Shaik, in New Theoretical Concepts for Understanding Organic Reactions (Eds. J. Bertran and J. G. Csizmadia), ed. p. 165. Kluwer, Dordrecht, 1989. (b) S. S. Shaik J. Am. Chem. Soc., 106, 1227 (1984). D. Bethell and V. D. Parker, J. Phys. Org. Chem., 5, 317 (1992). E. Sinsheimer and A. M. Keuhnelian, Anal. Chem., 44, 89 (1974). L. Forlani, G. Guastadisegni and L. Raffellini, J. Chem. Res. (S), 392 (1989). M. H. Krackov, C. M. Lee and H. G. Mautner, J. Am. Chem. Soc., 99, 4090 (1977). L. Forlani, Gazz. Chim. Ital., 121, 475 (1991). B. Capon and C. W. Rees, An. Rep. Prog. Chem., 60, 279 (1963). J. Hirst, G. Hussain and I. Onyido, J. Chem. Soc., Perkin Trans. 2, 397 (1986). D. Ayediran, T. O. Bamkole and J. Hirst, J. Chem. Soc., Perkin Trans. 2, 1013 (1974). L. Forlani, Gazz. Chim. Ital., 122, 349 (1992). R. Chamberlain and M. R. Crampton, J. Chem. Soc., Perkin Trans. 2, 75 (1993). R. Chamberlain and M. R. Crampton, J. Chem. Soc., Perkin Trans. 2, 425 (1994). M. R. Crampton and J. A. Stevens, J. Chem. Soc., Perkin Trans. 2, 925 (1989). R. Chamberlain and M. R. Crampton, J. Chem. Res. (S), 106; (M), 811 (1993). R. Chamberlain, M. R. Crampton and R. L. Knight, J. Chem. Res. (S), 444; (M), 2986 (1993). T. Ibata and X. Zou, High Pressure Research, 11, 81 (1992). T. Ibata, Y. Isogami and J. Toyoda, Chem. Lett., 1187 (1987); T. Ibata, Y. Isogami and J. Toyoda, Bull Chem. Soc. Jpn., 64, 42 (1991). K. Matsumoto, T. Uchida, T. Okamoto and S. Hashimoto, Chem. Express. 2, 551 (1987). S. Hashimoto, S. Otani, T. Okamoto and K. Matsumoto, Heterocycles, 27, 319 (1988); K. Matsumoto, T. Uryu and M. Munakata, Chem. Express, 3, 739 (1988).
26. SN Ar reactions of amines in aprotic solvents 139. 140. 141. 142. 143. 144. 145. 146. 147.
148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. 172. 173. 174. 175. 176. 177. 178. 179. 180. 181.
1299
K. Matsumoto, S. Hashimoto, H. Minatogawa, M. Munakata and S. Otani, Chem. Express, 5, 473 (1990). T. Ibata, X. Zou and T. Demura, Tetrahedron Lett., 34, 5613 (1993). T. Ibata, X. Zou and T. Demura, Bull Chem. Soc. Jpn., 67, 196 (1994). T. Ibata, Y. Isogami and J. Toyoda, Chem. Lett., 1187 (1987); Bull Chem. Soc. Jpn., 64, 42 (1991). ´ 1, 125 (1981). (a) N. S. Nudelman and D. Palleros, Acta Sud. Am. Quim., (b) D. Palleros and N. S. Nudelman, Proceedings IInd Phys. Org. Chem. Symposium, Cordoba, 1980; p. 33. N. S. Nudelman and D. Palleros, J. Org. Chem., 48, 1607 (1983). L. Abello, M. Kern, C. Caseres and G. Pannetier, Bull Soc. Chim. France, 94 (1970). J. C. Shug and W. M. Chang J. Phys. Chem., 75, 938 (1971). (a) G. Illuminati, F. La Torre, G. Liggieri, G. Sleiter and F. Stegal J. Am. Chem. Soc., 97, 1851 (1975). (b) D. M. Brein, J. Chem. Soc., Perkin Trans. 2, 1787 (1974). (c) G. Becker, C. F. Bernasconi and H. Zollinger, Helv. Chim. Acta, 49, 10 (1966). (a) T. O. Bamkole, J. Hirst and J. Onyido, J. Chem. Soc., Perkin Trans. 2, 889 (1982). (b) E. T. Akinyele, I. Onyido and J. Hirst, J. Phys. Org. Chem., 3, 41 (1990). (a) L. Forlani and C. Cimarelli, J. Chem. Res. (S), 62 (1982). (b) L. Forlani and C. Cimarelli, J. Chem. Res. (S), 258 (1982). (c) L. Forlani, Gazz. Chim. Ital., 112, 205 (1982). O. Banjoko and C. Ezeani, J. Chem. Soc., Perkin Trans. 2, 1357 (1982). G. Guanti, G. Petrillo and S. Thea, Tetrahedron, 38, 505 (1982). V. Frenna, N. Vivona, A. Caronia, G. Consiglio and D. Spinelli., J. Chem. Soc., Perkin Trans. 2, 1203 (1983). J. Hirst, J. Phys. Org. Chem., 7, 68 (1994). O. Banjoko and C. Ezeani, J. Chem. Soc., Perkin Trans 2, 531 (1986). O. Banjoko and I. A. Bayeroju, J. Chem. Soc., Perkin Trans. 2, 1853 (1988). W. P. Jencks, Chem. Soc. Rev., 10, 345 (1981). A. Wolff and G. Gamer, J. Phys. Chem., 76, 871 (1972). J. M. Menger and J. H. Smith, J. Am. Chem. Soc., 91, 4211 (1969). F. Ciuffarin, M. Isola and P. Leoni, J. Org. Chem., 46, 3064 (1981). V. Frena, N. Vivona, G. Consiglio and D. Spinelli, J. Chem. Soc. Perkin Trans. 2, 1865 (1985). A. Reyes and R. M. Scott, J. Phys. Chem., 84, 3600 (1980). J. Hirst, G. N. Onuoha and I. Onyido J. Chem. Soc. Perkin Trans. 2, 971 (1988). (a) C. F. Bernasconi and H. Zollinger, Helv. Chim. Acta, 49, 2570 (1966). (b) C. F. Bernasconi, M. Kaufmann and H. Zollinger, Helv. Chim. Acta, 49, 2563 (1966). S. D. Ross, Tetrahedron, 25, 4427 (1969). ´ 10, 50 (1979). R. Cetina, M. Rubio and M. A. Mora Rev. Latinoam. Quim., (a) P. A. Kollman and L. C. Allen, J. Am. Chem. Soc., 93, 4991 (1971). (b) J. E. del Bene, J. Am. Chem. Soc., 95, 5460 (1973). a) F. Ratkonis and T. Salamon, Acta Chim. Acad. Sci. Hung., 94, 93 (1977). (b) M. K. D. Choudhury and H. B. Mathur, Indian J. Chem., A, 14, 735 (1976). J. del Bene, J. Am. Chem. Soc., 102, 5191 (1980). L. Farah, G. Giles, D. Wilson, A. Ohno and R. M. Scott, J. Phys. Chem., 83, 2455 (1979). O. Banjoko and P. Otiono, J. Chem. Soc., Perkin Trans. 2, 399 (1981). J. F. Bunnett and R. H. Garst, J. Org. Chem., 33, 2320 (1968). N. S. Nudelman and D. Palleros, J. Org. Chem., 48, 1612 (1983). A. J. Kresge and M. F. Powell, J. Am. Chem. Soc., 103, 972 (1981). D. Palleros and N. S. Nudelman Acta Sud Am. Quim., 3, 49 (1984). N. S. Nudelman and D. Palleros J. Chem. Soc. Perkin Trans. 2, 1277 (1984). G. Visandul, V. S. Kutz and V. D. Pokhodenko, Zh. Obshch. Khim., 43, 180 (1972). N. S. Nudelman, M. Marder and A. Gurevich, J. Chem. Soc., Perkin Trans. 2, 229 (1993). J. M. Harris, S. P. McManus, M. R. Sedaghat-herati, N. Neamati-Mazraey, R. M. Doherty, R. W. Taft and M. H. Abraham, Am. Chem. Soc. Ser., 215, 247 (1987). R. W. Taft, T. Gramstad and M. J. Kamlet, J. Org. Chem., 47, 4557 (1982). D. Palleros and N. S. Nudelman, J. Chem. Soc., Perkin Trans. 2, 479 (1985). H. Suhr, Ber. Bunsenges. Phys. Chem., 67, 893 (1963).
1300 182. 183.
Norma S. Nudelman
D. Ayediran, T. O. Bamkole, J. Hirst and I. Onyido, J. Chem. Soc., Perkin Trans. 2, 597 (1977). A. V. Ryzhakov, V. V. Vapirov and L. L. Rodina, J. Org. Chem. USSR. (Engl. Transl.), 27, 825 (1991). 184. (a) L. Forlani and C. Cimarelli, J. Phys. Org. Chem., 2, 653 (1989). (b) L. Forlani, G. Guastadisegni and L. Raffellini, J. Chem. Res. (S), 392 (1989). 185. L. Forlani, J. Chem. Res. (S), 260 (1984). 186. L. Forlani and M. Sintoni, J. Chem. Soc., Perkin Trans. 2, 1959 (1988). 187. L. Forlani, Gazz. Chim. Ital., 121, 475 (1991). 188. L. Forlani and M. Bosi, J. Phys. Org. Chem., 5, 429 (1992). 189. J. Hayami and N. Sugiyama, Proceedings Vth. KISPOC, Japan, 1993, p. 031. 190. N. S. Nudelman and J. Montserrat, J. Chem. Soc., Perkin Trans. 2, 1990, 1073 (1990). 191. H. E. Audier, G. Bouchoux, D. Thilmann, Analysis, 20, 20s (1992). 192. G. Bouchoux, S. Jezequel and F. Penaud Berruyer, Org. Mass. Spectrom, 28, 421 (1993). 193. J. Oszczapowicz, in The Chemistry of Amidines and Imidates (Eds. S. Patai and Z. Rappoport), Vol. 2, Chap. 12, Wiley, Chichester, 1991 and references cited therein. 194. (a) Z. Wu and C. Fenselau, Rapid Commun. Mass Spectrom., 4, 403 (1992). (b) G. S. Gorman, J. P. Speir, C. A. Turner and I. J. Amster, J. Am. Chem. Soc., 114, 3986 (1992). 195. O. Tapia, R. Cardenas, Y. G. Smeyers, A. Hernandez.Laguna and F. J. Randez, Int. J. Quantum Chem., 38, 727 (1990). 196. A. Hernandez.Laguna, J. L. M. Abboud, R. Notario, H. Homan and Y. G. Smeyers, J. Am. Chem. Soc., 115, 1450 (1993). 197. A. A. Bliznyuk, H. F. Schaefer III and I. J. Amster, J. Am. Chem. Soc., 115, 5149 (1993). 198. R. E. Akpojivi, T. A. Emokpae and J. Hirst, J. Chem. Soc., Perkin Trans. 2, 443 (1994). 199. T. A. Emokpae, P. U. Uwakwe and J. Hirst, J. Chem. Soc., Perkin Trans. 2, 125 (1993). 200. T. A. Emokpae, J. Hirst and P. U. Uwakwe, J. Chem. Soc., Perkin Trans. 2, 2191 (1990). 201. F. Hibbert and J. Emsley, Adv. Phys. Org. Chem., 26, 255 (1990).
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
Author index This author index is designed to enable the reader to locate an author’s name and work with the aid of the reference numbers appearing in the text. The page numbers are printed in normal type in ascending numerical order, followed by the reference numbers in parentheses. The numbers in italics refer to the pages on which the references are actually listed.
Abraham, M.H. 381 (16a c, 17a e, 19, 20a c), 386 (45a, 45b), 387 (53), 395 (81), 417 419, 427 (26), 428 (40 42), 429 (26), 433 (80), 471, 472, 1220 (41a, 41b, 42), 1222 (50 52, 54 56, 59), 1223 (72), 1226 (68 72), 1228 (73, 74), 1238 (51), 1273, 1275, 1283 (178), 1296, 1297, 1299 Abraham, R.J. 301, 302 (16), 332 Abramovitch, R.A. 640 (67), 660 Abrigo, C. 1074 (179), 1158 Abu-Dagga, F. 1067 (130), 1157 Abuirjeie, M.A. 1140 (545), 1166 Abu-Namous, A.M.A. 877 (71), 890 Abu-Soud, H.M. 989 (105), 990 (110), 991 (113), 996 Ace, L.N. 1139 (542), 1166 Achari, B. 598 (377), 624 Achiba, Y. 161, 163, 171 173, 193, 197 (21), 202 Achilli, G. 1078 (198), 1159 Ackworth, I.N. 1071 (153), 1158 Acree, W.E.Jr. 338 (5), 357 (67), 358 (71 73), 372, 376 Adachi, H. 787 (101), 820 Adachi, K. 1086 (272), 1160 Adachi, T. 551 (89a, 89b, 90, 91), 618 Adamo, N.C. 1135 (518), 1165 Adams, J.E. 163 (29), 202 Addadi, L. 1108 (388), 1163 Adeloju, S.B. 1119 (425), 1163 Adewiyu, G.O. 1080 (224), 1159 Agafonov, V. 453 (206), 475 Agarrabeitia, A.R. 716 (136), 743 Agren, H. 171 (76), 203
Aakermark, B. 568 (188), 620 Aaker¨oy, C.B. 428 (29), 471 Abbotto, A. 398 (109a, 110, 111), 420, 509 (195), 530 Abboud, J.L. 433 (80), 439 (129), 443 (158), 472 474, 1220 1222, 1238, 1244 (38a, 38b), 1296 Abboud, J.-L.M. 381 (16a c, 17d, 18, 20b), 387 (53), 408 (165b, 168), 417, 418, 421, 428 (42), 471, 524 (253, 254), 531, 1220 (41a, 41b, 42), 1222, 1238 (51), 1285 (196), 1296, 1300 Abdel-Latif, F.F. 722 (153d), 743 Abdel-Magid, A. 113, 114 (43), 154 Abdel-Magid, A.F. 563 (156), 620 Abdel-Malik, M.M. 722 (153h), 743 Abdil-Rashid, M.K. 1064 (104), 1157 Abdulla, R.F. 442 (147), 473 Abdul-Majid, Q. 715 (130a, 130b), 742 Abe, E. 1078 (206), 1159 Abe, H. 1089 (287), 1161 Abe, M. 654 (151), 662 Abello, L. 434 (85, 91), 472, 1262, 1266 (145), 1299 Abernathy, C.L. 348 (30a), 373 Abernethy, C.L. 361, 362, 367, 371 (84), 377 Abeywickerema, A.N. 655 (160), 662 Abia, L. 644 (96), 661 Abini, A. 684 (5), 740, 758 (29), 818 Abou-Khalil, S. 1025 (135, 138), 1038 Abou-Khalil, W.H. 1025 (135, 136, 138), 1038 Abowitz, G. 435 (99), 472 Abraham, M. 1220 (38a, 40), 1221, 1222, 1238, 1244 (38a), 1296
1301
1302
Author index
Ahlbrecht, H. 603 (392), 624 Ahuja, S. 106 (14), 153 Aiello, E. 630 (15), 633 (27), 659 Aimi, H. 866 (34), 889 Ainscow, T.A. 97 (66), 103 Akabori, S. 536 (21), 537 (22), 617 Akagi, M. 432, 443 (72), 472, 1220 (44), 1296 Akerkar, S. 1150 (612), 1167 Akermark, B. 542 (54), 617 Akhtar, M.H. 1134 (506), 1165 Akihiro Yoshino (88), 334 Akikusa, N. 592 (332), 623 Akino, T. 1089 (290), 1161 Akinyele, E.T. 1262, 1264, 1276, 1288 (148b), 1299 Akio Kuwae 320 (84), 334 Akiyama, F. 654 (151), 662 Akiyama, I. 188 (115 117), 204 Akiyama, K. 750 (6), 817 Akiyama, S. 1091 (304), 1161 Akkok, S. 216 (63c), 245 Akopyan, Z.A. 363 (89), 377 Akpojivi, R.E. 1290, 1291 (198), 1300 Akritopoulou, I. 566 (181), 620 Akutsu, Y. 77 (127 129), 78 (128, 129), 79 (129), 84 Alagona, G. 3 (2a), 81 Alanzo, V. 398 (110), 420 Albanese, D. 616 (462, 463), 626 Albelda, C. 1048 (55), 1156 Albert, A. 381 (3), 416 Albery, W.J. 409 (176), 421 Albinati, A. 94 (36), 102 Albini, A. 773 (62), 819 Albuquerque, L.M.P.C. 1228 (75), 1297 Aldegunde, M. 1078 (204, 205), 1159 Alder, A. 733 (184), 744 Alder, R.W. 66 (111, 112), 67 (111), 84, 166, 168 (52), 176 (88), 179 (52, 88, 93), 181 (96), 184 (52, 98, 105), 185 (52), 202, 203, 435 (102), 472 Aleman, R. 216, 218 (65), 245 Alessi, D.M. 124 (74), 155, 427 (22), 471 Alewood, P. 1029 (167), 1038 Alex, A. 956 (44), 971 Alexakis, A. 126, 127 (80), 155, 546 (73), 618, 1111 (397), 1163 Alexander, J. 1012, 1033 (84), 1036 Alexander, R.W. 977 (53), 995 Alfanio, J.C. 694 (67), 741 Alfassi, Z.B. 826 (26), 827 (29, 33), 828 (42), 835 Alfheim, I. 1177 (29), 1212 Alfonso, E.F.S. 1067 (133), 1157 Algrim, D. 415 (205), 422 Algrim, D.J. 400 (127), 420 Ali, M. 954 (23), 970
Ali, M.H.H. 679 (86), 682 Ali, S.F. 896 (15), 940, 944 (60), 947, 948 Aliev, A.E. 322 (102), 334 Alison, C.E. 220 (95), 246 Al-Kaabi, S.S. 448 (190), 474, 672 (32), 680 Al-Khalil, S.I. 611 (445), 612 (449), 626 Allan, J. 485 (47), 526 Allen, A.D. 510 (203), 530 Allen, F.H. 37 (56), 82 Allen, L.C. 1266 (166a), 1299 Allen, R.L.M. 628, 629, 636 (5), 659 Allenmark, S.G. 1089 (283), 1160 Alley, E.W. 991 (125), 997 Allinger, N.L. 3 (1a, 3a d, 4a), 4 (1a, 4a, 5, 6, 43, 44), 5 (1a, 3a d, 8), 6 (5), 7 (5, 6), 8 (5), 9 (5, 6), 10, 11 (5), 12 (5, 6), 15 (26a), 16 (5, 8, 26a), 20 (4a), 21 (4a, 6, 30b, 31), 22 (8, 31), 23 (5, 6, 30b), 24 (6, 30b, 34, 35), 25 (6), 26 (6, 30b), 27 (3a d, 4a, 6, 30a, 30b), 28 (30b), 29 (1a, 30b, 42, 43), 30, 31 (43), 32 (31, 43), 33, 35 (44), 38 (6), 41 (5), 57 (30a, 86), 59 (98, 102), 61 (5, 6), 62, 64, 65 (108), 68 (114), 81 84 Allison, W.S. 1012 (75), 1036 Al-Mallah, K. 674 (53), 675 (54), 677 (53), 681 Almas, M. 1089 (288), 1161 Almerico, A.M. 630 (15), 633 (27), 659 Almond, H.R.Jr. 73 (124), 84 Al-Omran, F. 880 (83), 890, 952 (17), 970 Alonso, M.L. 1085 (266), 1160 Alonso, R.M. 1074 (183), 1158 Alonso Triana, J.L. 873 (62), 890 Alper, H. 595 (357), 624 Altenbach, H.-J. 165, 166, 182 (47), 202 Alti, G.de 192 (131), 204 Altona, C. 3 5 (1d), 15, 17 (25a, 25b), 29 (1d), 57 (92), 81, 83 Alty, A.C. 636 (34), 659 Alvarez, A.I. 1085 (266), 1160 Alvi, S.N. 1137 (524), 1165 Alwehaid, A.M. 1101 (353), 1162 Aly, M.M. 722 (153d), 743 Al Zamil, Z. 1106 (376), 1162 Amaglio, C. 1133 (496), 1165 Amano, M. 776 (66), 819 Amaral, L.do 1009 (59), 1036 Amatatsu, Y. 34 (46), 82 Amatore, C.M. 840, 848 (9), 855 Ambroseti, R. 443 (155), 474 Ambs, S. 1022 (111), 1037 Amin, M. 509 (191), 530 Amin, M.R. 883 (91), 891, 968 (63), 971 Amino, U. 1087 (276), 1160 Ammon, H.L. 80 (135), 84, 91 (24), 93 (22 24), 99 (23, 24), 100 (95), 102, 103, 730 (181d), 733 (183a), 744
Author index Ammon, H.P.T. 1001 (32), 1035 Amri, H. 597 (371), 624 Amrollah-Madjdabadi, A. 607 (416), 625 Amster, I.J. 390 (71), 419, 1284 (194b), 1285 (194b, 197), 1290 (197), 1300 An, X.-W. 346 (19), 373 Anadon, A. 1025 (139), 1038 Ananthan, S. 605 (410), 625 Anantharamaiah, G.M. 119 (60), 154 Anantharaman, P.N. 845 (32a, 32b), 846 (37), 855, 856 Anda, T. 735 (190c), 745 Anders, E. 398 (108), 420 Andersen, K.K. 491, 503, 504, 515, 517 (96, 97), 527 Anderson, M.P. 1142 (561), 1166 Anderson, B.A. 119, 120 (59), 154 Anderson, D.A. 610 (437), 615 (460), 625, 626 Anderson, D.G. 710 (112), 742 Anderson, D.R. 807 (149b, 150), 808 (151), 821 Anderson, J.E. 43 (66), 50 (66, 74), 52 (74), 83 Anderson, K.E. 993 (145), 997 Anderson, L. 447 (180), 474 Anderson, L.O. 315 (63), 333 Anderson, M. 594 (347, 348), 623 Anderson, R.F. 329 (117), 334 Anderson, R.J. 1047 (44), 1155 Anderson, S.W. 1220 (47), 1296 Anderson, W.D. 60 (103d), 84 Andersson, P.G. 120 (61), 154 Ando, I. 322, 323 (96), 334 Ando, M. 1081, 1091 (234), 1159 Ando, T. 933 (47), 934 (50), 935 (53), 947, 948 Andose, J.D. 3 5, 29 (1c), 81, 356 (60), 375 Andraos, J. 658 (175), 663 Andreae, S. 553 (105), 618 Andreevskaya, O.I. 866 (36), 889 Andreoli, P. 549 (81), 618 Andresen, B.D. 1033 (199), 1039 Andrews, A.W. 1197 (103, 105), 1214 Andrews, G.E. 1176 (23), 1212 Andries, S.W. 1142 (560), 1166 Andrieux, C.P. 846 (35), 855 Andrussow, K. 491, 500 (107a), 527 Anet, F.A.L. 74 (125), 84, 353 (49), 375 Anghoni, L. 57 (89), 83 Aniello, A.d’ 1089 (281), 1160 Annese, M. 426 (14), 470 Annulli, A. 1217 (15b), 1295 Anoniou, H. 978 (71), 995 Antipova, I.V. 347 (25), 373 Antoni, G. 932 (45), 947 Anulewicz, R. 454 (210), 475 Anumula, K.R. 1085 (258), 1160
1303
Anunziata, J. 433 (81), 472 Anunziata, J.D. 440 (139 141), 463 (254), 464 (255), 467 (271), 473, 476, 1217, 1235 1237 (9), 1244 (110), 1245 (110, 115a, 115b, 116a, 116b, 117), 1246 (9, 115a, 115b, 116a, 116b, 117), 1247 (9, 115a, 115b), 1266 (115a, 115b), 1276 (9), 1295, 1298 Anvia, F. 308, 309 (42), 333, 384 (29), 407 (161b), 408 (167b), 417, 421, 524 (254), 531, 1238 (87a, 87b, 93), 1239 (87a), 1297 Ao, M.S. 737 (197), 745 Aoe, K. 730 (182b), 734 (188a), 744 Aoki, E. 587 (297), 622 Aoki, I. 1101 (352), 1162 Aoki, S. 537 (22), 617 Aoyama, H. 686 (29), 722 (159a), 740, 743 Aoyama, I. 432, 443 (72), 472, 1220 (44), 1296 Aoyama, T. 538 (34), 617 Aparicio, D. 573 (203), 620 Apasov, E.T. 609 (432), 625 Aped, P. 14 (22a, 22b), 15, 16 (22a, 22b, 26b, 26c), 17 (22a, 22b), 18 (22b), 19 (22a, 22b), 20 (22a, 27 29), 21 (22a), 43, 54 (67), 81 83 Apeloig, Y. 15, 16 (26b), 82, 161, 173 (19), 202, 208 (10), 244 Apoita, M. 718 (148), 743 Apte, M.G. 1177 (34), 1212 Arai, S. 718 (147), 743 Arai, T. 438 (125, 126), 473, 778 (74), 819 Arakawa, R. 260 (53), 292 Araki, T. 733 (183b), 744 Arata, Y. 396 (93), 419, 686 (29), 740 Arbus, A.M. 978 (71), 995 Arca, V. 1220 (29b), 1296 Archibald, T.G. 97 (60, 61), 101 (61), 103, 537 (25), 606 (414), 617, 625 Archinal, A.E. 130 (91), 155 Arcoria, A. 434 (88), 472 Arey, J. 1130 (484), 1131 (485), 1165, 1177 (35, 40 46), 1179 (47), 1212, 1213 Arfsten-Romberg, U. 763 (41), 818 Argay, G.Y. 94 (34), 102 Arimura, G.K. 1024 (129), 1025 (136), 1037, 1038 Arinch, A.K. 884 (96), 891 Armesto, D. 710 (118), 715 (129, 132), 716 (132 139), 717 (144), 718 (146, 148), 742, 743 Armstrong, D.R. 396 (92), 419 Armstrong, D.W. 1089 (284), 1090 (295), 1095 (326), 1160, 1161 Armstrong, H.E. 481 (12, 15), 484 (37), 525, 526 Armstrong, K.B. 1113 (404), 1163
1304
Author index
Arnal, J.F. 979 (75), 995 Arnaut, L.G. 409 (179), 422 Arnelle, D. 673 (44), 681 Arnelle, D.R. 674 (49), 681 Arnett, E.M. 381 (7), 397 (102), 400 (125), 410 (7), 411 (185), 416, 420, 422, 436 (116, 117), 473 Arnold, D.R. 704 (108), 742 Arnold, M.A. 1104 (365), 1162 Arnold, U. 1082 (239), 1160 Arnold, W. 975 (17, 18), 994 Arnold, W.P. 975 (6), 994 Arnould, J.C. 737 (195b, 195c), 745 Arp, J.A. 1119 (426), 1163 Arrigoni-Martelli, E. 1068 (136), 1157 Arrowsmith, R.J. 66, 67 (111), 84, 166, 168 (52), 179 (52, 93), 181 (96), 184, 185 (52), 202, 203 Artamkina, G.A. 457 (230), 475, 1217, 1220 (11b), 1295 Arthur, L.O. 1024 (126), 1037 Artonioletti, R. 777 (68), 819 Arumugasamy, N. 441 (143), 473 Arvanaghi, M. 510 (204), 530 Asada, H. 735 (190b), 745 Asada, K. 535 (11), 616 Asakuno, K. 1072 (159), 1158 Asano, Y. 1072 (162), 1158 Ascherl, M. 1003, 1005, 1007, 1009, 1011, 1020, 1022 (40), 1025 (133), 1029 (40), 1032 (189), 1035, 1038, 1039 Aschmann, S.M. 1176 (24), 1177 (41, 46), 1212, 1213 Asenjo, R.A. 1100 (350), 1162 Asensio, G. 568 (189), 620 Asfari, Z. 969 (64), 971 Ashfaquzzaman, S. 93 (14), 102 Ashman, W.P. 6 (10), 81 Ashton, D.S. 976 (39), 977 (47), 978 (39, 47), 980 (39), 994, 995 Askew, S.C. 669 (26), 670 (26, 27), 680 Aslam, M.H. 501 (143, 144), 502 (143, 144, 146), 503, 520 (143, 144), 529 Asmus, K.-D. 828 (44), 830 (50, 52), 832 (55, 56), 835, 836 Aso, Y. 583 (276), 622 Asowata, C. 1127, 1143 (458), 1164 Ast, T. 250 (1), 291 Astephen, N. 1085 (265), 1160 Astier, A. 1133 (494), 1165 Astor, M.B. 1031 (182), 1039 Astorga, C. 592 (337), 623 Athalye, V.V. 1049 (66), 1156 Athanassakis, V. 1220 (30b), 1296 Atherton, S.J. 783 (91, 92), 820 Atkins, R.K. 544 (66), 617 Atkins, R.L. 877 (69), 890
Atkinson, E.R. 653 (143, 144), 662 Atkinson, R. 1131 (485), 1165, 1176 (24), 1177 (35, 40 46), 1179 (47), 1212, 1213 Attina, M. 232 (141), 247 Attolini, L. 1061 (91), 1156 Atwell, G.J. 329, 330 (111), 334 Aubeck, R. 1119 (427), 1163 Audier, H.E. 212 (43, 46 50), 216 (48 50, 58, 60, 61), 218 (85), 222 (43, 46 50, 58), 228 (130), 233 (145), 238 (130), 244 247, 1284 (191), 1300 Aue, D.H. 164 (33, 34), 165 (44), 166 (44, 50), 178 (34), 202, 232 (140), 236 (167, 168), 247, 386 (48a, 48b), 418 Aue, W.A. 1047 (31), 1155 Auman, B.C. 863 (24), 889 Aurrocoechea, J.M. 546 (76), 554 (115a), 618, 619 Ausloos, P. 211 (37), 244 Auzou, G. 589 (308), 623 Avakyan, V.G. 413 (199), 422 Awen, B.Z.E. 611 (441), 625 Axelsson, B.S. 932 (44), 933 (46), 947 Axenrod, T. 281 (93), 293, 317 (67, 69), 318 (78), 333, 334 Ay, M. 552, 553 (103), 618 Ayediran, D. 1251 (128), 1276, 1278, 1290 (182), 1298, 1300 Ayesh, R. 1064 (103), 1157 Azam, F. 1048 (61), 1156 Azami, T. 262 (58), 292 Azazdoi, K.M. 993 (146), 997 Aziz, A. 1067 (130), 1157 Aziz, E. 1090 (294), 1161 Azoulay, M. 447 (178), 474, 806 (146), 821 Azzaro, M. 381 (13), 416 Baader, H. 1029 (159), 1038 Baar, B.L.M.van 215 (56), 216 (63c), 245 Baba, A. 543 (64), 617 Baba, K. 1122 (438), 1164 Babbage, C.A. 785 (95), 820 Babbitt, D. 1087 (277), 1160 Bacaloglu, R. 1217 (6a c), 1295 Baccant, M. 1046 (9), 1155 Bachman, B.J. 767 (50b), 819 Bachman, G.B. 639 (61), 660 Bachovchin, W.W. 322 (103), 334 Bachrach, S.M. 80 (136b), 84 Backaert, J. 991 (124), 996 Backstr¨om, M. 171 (76), 203 Baddoo, P.A. 1145 (573, 576), 1147 (588), 1166, 1167, 1187 (82), 1189 (96, 98), 1214 Bader, R.F.W. 648 (115), 661 Badet, B. 592 (335), 623 Badger, G.M. 717 (143b), 743 Badr, M.Z.A. 722 (153d), 743
Author index Bae, J.Y. 1148 (600), 1167 Baek, K.J. 987 (98), 996 Baer, H.H. 482, 483, 507 (22), 525 Baer, T. 234 (152), 247, 259 (42), 262 (57), 292 Bagno, A. 381 (5b), 405 (153), 416, 421, 657 (169), 662, 1012 (78), 1036 Bahsas, A. 570 (195), 620 Baig, T. 588 (303), 623 Baigent, D.R. 1067 (129), 1157 Baik, W. 534 (5), 616 Bailey, G.F. 151, 152 (160), 157 Baitz, E.G. 851 (55), 856 Bak, T. 286 (103), 293, 775 (64), 819 Baker, A.D. 160 (1, 2, 5, 15), 161, 163 (1), 171, 175 (70), 201, 203 Baker, C. 160, 161, 163 (1), 201 Baker, G.B. 1065 (105), 1157 Baker, J.W. 485 (51), 526 Baker, R.J. 433 (79), 472 Baker, R.W. 143 (131), 156 Baker, T.R. 1119 (429), 1163 Baker, V.J. 57 (89), 83 Bakker, N.A.C. 694 (65), 741 Bakshi, R.K. 111 (37), 154 Balaban, A.T. 968 (61), 971 Balakrichnan, P. 313, 314 (58), 333 Balakrishnan, P. 325, 326, 329 (110), 334, 722 (158b), 743 Balasubramanian, K.K. 270 (82), 293 Balasubramanian, T. 270 (82), 293 Balasubramanian, T.K. 1049 (66), 1156 Balasubramanian, T.M. 590 (322), 623 Baldeschwieler, J.D. 235 (162), 247 Baldwin, J. 442 (148), 473 Baldwin, M.A. 266 (70 72), 267 (71), 293 Baldwin, R.P. 1073 (172, 173), 1093 (319), 1151 (619), 1158, 1161, 1167 Ballard, R.E. 160 (6), 188 (120), 201, 204 Ballesteros, E. 408 (168), 421 Balligand, J.L. 992 (127, 133), 997 Ballini, R. 607 (415), 608 (423), 610 (436), 625 Ballot, B.A. 975 (22), 994 Bally, T. 833, 834 (66), 836 Balon, M. 409 (169a, 169b), 421 Bamberger, E. 639 (55), 660, 867 (38), 889, 1000, 1019 (4), 1035 Bamkole, T.O. 1219 (26), 1251 (128), 1262, 1264 (148a), 1276 (148a, 182), 1278 (182), 1288 (148a), 1290 (182), 1295, 1298 1300 Ban, Y. 736 (194c), 745 Banbury, F.A. 396 (92), 419 Banerjee, A. 96, 97 (57), 103 Banica, F.-G. 846 (38), 856 Banjoko, O. 467 (272, 273), 476, 1262 (150), 1264 (150, 154, 155), 1267 (170), 1269
1305
(150), 1273, 1274 (155), 1288 (170), 1299 Banks, R.E. 303, 308 (37), 333, 636 (34), 659 Banks, T.C. 992 (130), 997 Bannasch, P. 1185 (71), 1213 Banthorpe, D.V. 859 (4, 7, 11), 888, 889, 897 (20), 905 (32), 947 Bao, W. 557 (125), 619 Bapat, G.S. 880 (82), 890, 950 (6), 970 Baracchi, A. 780 (82), 819 Bar-Adon, R. 1001, 1007, 1008 (20), 1035 Barancyk, S.V. 729 (176a), 744 Baranne-Lafont, J. 580 (252b), 621 Baranski, A. 561 (142), 619 Barany, G. 564 (167), 620 Barbella, R. 1175 (16), 1212 Barber, C.M. 977 (51), 995 Barber, M. 234 (157), 247 Barbetti, J.F. 563 (164), 620 Barboni, L. 608 (426b), 625 Barbour, R.K. 1133 (503), 1165 Barbucci, R. 389 (60), 390 (62), 418 Barcel´o, D. 1047 (52), 1068 (139), 1078, 1079 (195), 1156, 1158, 1159 Barchiesi, E. 398 (106, 112), 420 Barcza, L. 431 (61, 62), 471 Barczynski, P. 430 (54), 471 Bard, A.J. 838 (5), 855 Bardin, V.V. 1137 (525), 1165 Bardoli, R.S. 234 (157), 247 Barek, J. 1125 (441), 1128 (466), 1135 (516), 1138 (529, 531), 1148 (598), 1164 1167 Bares, J.E. 398 (115), 410 (182), 420, 422 Bargar, T.M. 577 (219), 621 Bar-Haim, A. 607 (417), 625 Baricos, W.H. 673 (42), 681, 975 (25, 27), 994 Barker, J. 348 (30b), 373 Barkley, R.M. 1047 (51), 1155 Barltrop, J.A. 685 (9, 11), 740 Barluenga, J. 396 (88), 419, 568 (189), 576 (213), 620, 621 Barnes, C.E. 950 (13), 965 (52), 970, 971 Barnes, D. 536 (16), 617 Barnes, D.M. 119, 120 (59), 154 Barnett, D.J. 669, 670 (26), 672 (37), 680 Barney, C.L. 563 (157), 577 (219), 620, 621 Baron, V. 494, 507 (121), 528 Barone, V. 389 (60), 390 (62), 418 Barra, D. 1083 (250), 1160 Barra, M. 658 (175), 663 Barrett, A.G.M. 604 (399), 625 Barrett, J. 669 (18, 23), 680 Barrio, J.R. 652 (139, 140), 653 (140), 656 (165), 662 Barron, D. 152 (161), 157 Barron, L.D. 150 (157), 151 (158), 152 (163 166), 153 (165, 166, 168), 157
1306
Author index
Barrow, P. 879 (77), 890 Barrow, R.P. 240 (186), 248 Barry, B.K. 975 (20, 26, 27), 994 Barry, J.E. 430 (55), 440 (55, 137), 471, 473 Bartell, L.S. 3 5, 29 (1e), 81 Barth, T. 436 (113), 473 Bartle, K.D. 1176 (23), 1212 Bartmess, J.E. 235, 236 (166), 247, 255 (24), 292, 382, 385 (22), 398 (115), 410 (182), 411 (193), 417, 420, 422 Bartoli, G. 608 (425, 426a, 426b), 625 Barton, D. 414 (200), 422 Barton, D.H.R. 538 (36, 37), 548 (80), 584 (278, 279), 615 (461), 617, 618, 622, 626, 735 (191), 745 Bartoszak, E. 436 (114), 473 Bartsch, H. 1066 (115), 1147 (591), 1157, 1167, 1182 (62), 1189 (102), 1213, 1214 Baruah, J.B. 569 (190), 620 Basil, A. 133 (97), 155 Bass, V.-M. 175 (82), 203 Bassani, D.M. 686 (24, 27, 28, 30, 31), 687 (31), 699 (24, 28), 700 (24, 100), 701 (28, 100), 706 (24, 28), 740, 742 Bates, F.N. 673 (42), 681 Bates, J.N. 673 (46), 681 Bates, W.W. 426 (16), 470 Batlle, A. 846 (35), 855 Batt, L. 339, 340 (8), 357 (8, 68), 360 (8), 372, 376 Battaglia, L.P. 445 (164), 474 Battioni, P. 572 (202), 620 Battiste, D.R. 192 (133), 204 Batts, R.D. 310 (45), 333 Baudy-Floc’h, M. 544 (69), 618 Bauer, J.A. 673 (47), 681 Bauer, L. 405, 407 (149), 421 Bauer, P.I. 1024 (124), 1037 Bauld, N.L. 727 (167), 744 Baum, K. 97 (60, 61), 101 (61), 103, 537 (25), 606 (414), 617, 625 Baum, M. 992 (131), 997 Baumann, K. 582 (269), 622 Baumann, R.A. 1116 (415), 1163 Baumann, V. 603 (392), 624 Baumgaertel, H. 164, 166, 168 (32), 202 Baumstark, A.L. 71 (120), 84, 313, 314 (58), 333 Bausch, M.J. 400 (129), 420 Bayeroju, I.A. 1264, 1273, 1274 (155), 1299 Bayfield, R.F. 735 (190a), 745, 1012 (80), 1036 Baylis, S.A. 992 (132, 134, 135), 997 Bayliss, N.S. 641 (71, 75), 655 (71), 660 Bazin, M. 781 (83), 819 Bazzani, F. 1217 (15a), 1295 Beagley, B. 7 (12), 81
Bean, G.P. 408 (167a), 421 Beaten, A. 388 (58), 418 Beauchamp, A.L. 100 (88), 103 Beauchamp, J.L. 178, 188 (92), 192 (132), 203, 204, 235, 236 (165), 247, 353 (46), 375 Beaulie, B.B. 1032 (196), 1039 Beck, K. 186 (110), 204 Becker, A.R. 871 (51), 890 Becker, E.D. 302 (20), 317 (67), 332, 333 Becker, G. 396 (91b), 419, 1241 (103c), 1262, 1264 (103c, 147c), 1298, 1299 Becker, H.-D. 779 (75), 819 Becker, H.G.O. 649 (119), 661 Beckhaus, H.-D. 184, 186 (106), 204 Beckwith, A.L.J. 655 (160 163), 662 Beckwith, K.R.Jr. 579 (229), 621 Bedford, C.D. 606 (412), 625 Bedi, G. 572 (202), 620 Beecroft, R.A. 693 (56), 741 Beer, J.M. 1175 (18), 1212 Begley, D.J. 1079 (207), 1159 Behnert, S. 1116 (406), 1163 Beinert, W.D. 1082 (235, 236), 1159, 1160 Bekki, K. 165, 166 (23), 202 Bekkum, H.van 489, 490 (83), 527 B´elaadi, S. 357 (69), 376 Beland, F.A. 1012 (85), 1031 (180), 1033 (85), 1036, 1039 Belanger, J.M.R. 1134 (506), 1165 BelBruno, J.J. 226 (117), 246 Belder, A.J.de 673 (40, 41), 681 Beletskaya, I.P. 457 (230), 475, 1217, 1220 (11b), 1295 Belevsky, V.N. 824 (2, 3), 835 Belhassen, L. 992 (133), 997 Bell, H.M. 638 (49), 660 Bell, R.A. 88, 90 (8), 102 Bell, R.P. 508 (186), 529 Bellanato, J. 453 (204), 475 Bellard, S. 37 (56), 82 Bellas, M. 698 (92), 742 Bello, J.M. 1101 (354, 355), 1162 Bellobono, I.R. 447 (187), 448 (188), 474 Bellucci, G. 443 (155), 474 Bellus, D. 733 (184), 744 Belmont, M.R. 97 (66), 103 Belopushkin, S.I. 824 (2, 3), 835 Belostotskii, A.M. 43, 54 (67), 55, 56 (79), 83 Belot, G. 845 (29), 855 Belser, W.L.Jr. 1176 (27), 1212 Beltrame, P.L. 448 (188), 474 Belyaev, E.Y. 636 (35), 659, 1000, 1009, 1019 (7), 1035 Belyaev, E.Yu. 515 (231), 530 Benali, B. 1136 (522), 1165 Benati, L. 1012, 1013 (79), 1036
Author index Ben Ayed, T. 597 (371), 624 Benbrook, C.H. 648 (110), 661 Bencini, A. 391 (64 66), 396 (101), 418 420 Bencivenni, L. 435 (100), 472 Bender, C. 29 (42), 82 Bene, J.E.del 1266 (166b, 168), 1267 (168), 1299 Ben-Efraim, D.A. 589 (313), 623 Benemansky, V.V. 1184 (66), 1213 Benesch, R. 1003 (46), 1036 Benesch, R.E. 1003 (46), 1036 Benet, L.Z. 1142 (562), 1166 Benito, C.G. 1088 (279), 1160 Benko, S. 1141 (553), 1166 Bennani, Y.L. 125 (77), 155 Benneche, T. 579 (234), 621 Bennet, R.A. 257 (36), 292 Benson, R.L. 1045 (5), 1155 Benson, S.C. 130 (89), 155 Benson, S.W. 221 (108), 246, 343 (16), 354 (53), 372, 375 Benson, W.R. 240 (186), 248 Bente, P.F.III 209 (27), 244 Benthem, R.A.T.M.van 568 (187), 620 Bentley, T.W. 1220 (46), 1296 Beranova, S. 240 242 (189), 248 Beresford, K.J.M. 569 (192), 620 Berestovitskaya, V.M. 604 (401), 625 Berg, I.E. 1217 (13a), 1295 Berg, U. 432 (71), 472, 938 (55), 948 Bergander, K. 396 (87), 419 Berger, S. 1004 (42), 1035 Bergmann, H. 188, 189 (125, 127), 191, 192 (125), 204 Berkowitz, J. 160 (7), 201, 360 (78), 376, 382 (23), 417 Berliner, L.J. 1022 (116, 117), 1037 Bermejo, E. 1138 (530), 1166 Bernasconi, C.F. 409 (176, 178), 410 (184), 415 (204), 416 (211), 421, 422, 465, 466 (263), 476, 508 (187), 529, 1216 (1c, 3a, 3b), 1217 (3a, 3b), 1218 (3a, 3b, 18), 1219 (1c), 1220 (1c, 3b), 1235 (1c), 1241 (103c), 1242 (108), 1244, 1248, 1250 (1c), 1262 (103c, 147c), 1264 (18, 103c, 147c), 1266 (163a, 163b), 1268 (163a), 1274 (1c), 1275 (108), 1290 (1c), 1295, 1298, 1299 Bernauer, K. 717 (141), 743 Berndt, A. 291 (119), 294 Berne, F.D. 1079 (208), 1159 Bernheim, M. 552 (104), 618 Bernstein, M.A. 550 (86a), 574 (206), 618, 621 Bernstein, M.D. 563 (154), 619 Bernstein, M.P. 396 (91e, 94), 419 Berova, N. 139 (116, 117), 141 (116, 117, 119), 142 (121), 143 (126 130), 156
1307
Berr, S. 1119 (435), 1164 Berrier, C. 609 (433), 625 Bersier, P. 634 (29), 659 Berthelot, M. 381 (17d, 17e), 395 (82 84), 417, 419, 451 (195), 474, 505 (158), 524 (254), 529, 531, 1222 (51), 1238 (51, 87b), 1296, 1297 Berthod, A. 1089 (284), 1160 Bertolasi, V. 96 (51), 103, 426 (15), 435 (103), 470, 472 Bertoli, C. 1178 (49), 1213 Bertolo, P.L. 1074 (177, 178, 180), 1158 Bertonello, R. 175 (83), 203 Bertran, J. 754 (14, 15), 758 (31), 817, 818 Bertrand, G. 592 (334, 338), 623 Bertrand, M. 252, 253, 262 (11), 291 Berube, L.R. 1032 (194), 1039 Bess, J.W. 1024 (126), 1037 Besse, J. 650 (124), 661 Bestmann, H.J. 553 (108a, 108b), 618 Bethell, D. 1246 (121), 1298 Betner, I. 1082 (237), 1160 Betschart, C. 564 (169), 620 Betteridge, D. 160 (2), 192 (134), 201, 204 Bettinetti, G.F. 708 (110), 742, 758 (29), 818 Beugelmans, R. 607 (416), 625 Beutler, E. 1022 (118), 1037 Beveridge, K.A. 784 (94), 820 Bey, P. 576 (218), 621 Beyerman, H.C. 130, 131 (92), 155 Beyersbergen van Henegouwen, G.M.J. 1026 (141), 1038 Beynon, J.H. 206, 207 (2a, 2f), 217 (77), 233 (2a, 2f, 146), 243, 245, 247, 250 (1), 251 (4), 252 (11), 253 (10, 11), 262 (11), 264 (63), 265 (67, 69), 266 (73), 267 (76), 291, 293 Bhaskar, K.R. 1044 (3), 1154 Bhattacharjee, S.K. 93 (22, 23), 99 (23), 102 Bhattacharyya, K. 694 (66), 738 (199), 741, 745 Bhattacharyya, S. 562 (151), 563 (161), 619, 620 Bhattacharyya, S.N. 833 (68), 836 Bhongle, R.K. 876 (68), 890 Bhuyan, P.J. 569 (193), 620 Biaglow, J.E. 1031 (182), 1039 Bianchi, A. 391 (63 66), 396 (101), 418 420 Bianchini, R. 443 (155), 474 Biase, D.de 1083 (250), 1160 Biasutti, M.A. 440 (141), 473 Bickley, A.N. 1108 (390), 1163 Bida, G.T. 652, 653 (140), 656 (165), 662 Biedrzycka, Z. 310, 311 (50), 333 Biekofsky, R.R. 438 (127), 473 Bielski, B.H.J. 829 (47), 836 Biemann, K. 206, 207, 233 (2b), 243
1308
Author index
Bieniek, A. 560 (136), 619 Bieri, G. 166, 169 (51), 202 Bieri, J.H. 717 (142), 743 Bigeleisen, J. 894 (6 8), 946, 947 Bigelow, S.S. 97, 101 (61), 103, 606 (414), 625 Bigg, D.C.H. 592 (334, 338), 623 Biggi, G. 1220 (28), 1295 Biles, C. 584 (287), 622 Billar, T.R. 979 (78), 995 Billedeau, S.M. 1146 (583), 1167 Billeter, M. 60 (103b), 83 Billiar, T.R. 979 (76), 995 Billii, L. 549 (81), 618 Billington, A.P. 769 (56), 819 Billups, W.E. 589 (312), 623 Bilodeau, M.T. 119, 120 (59), 154 Binkley, J.S. 407 (163), 421 Binkley, R. 764 (42), 818 Binsch, G. 317 (70), 333 Biradha, K. 452 (199), 475 Birch, D. 739 (202, 203), 745 Bird, I.A. 1027, 1028 (154), 1038 Birkall, T. 400 (124a), 420 Birks, J.W. 1047 (42), 1155 Birnbaum, G.I. 453 (205), 475, 866 (35), 889 Birnbaum, S.M. 107 (26), 154 Birner, G. 1026 (147), 1038 Bischof, P. 184 (102), 203 Bischoff, L. 566 (178), 620 Bishop, S.W. 650 (128), 661 Biswas, G.K. 738 (200b), 745 Biswas, S.S. 578 (225), 621 Bitsch, A. 1022 (111), 1037 Bjerrum, N. 483 (30), 526 Bjornholm, T. 212 (41, 42), 213 (42), 214, 216 (41, 42), 225 (42), 244 Blaauboer, B. 1097 (335), 1162 Black, T.M. 148 (147), 152 (147, 164), 157 Blackburn, E.V. 710 (113), 742 Blackstock, S.C. 440 (142), 473, 854 (66), 856 Blair, L.K. 442 (148, 150), 473 Blaive, B. 4, 13 (16), 81 Blanchet, D. 765 (46), 818 Blanco-Gomis, D.D. 1081 (227), 1159 Blangey, L. 628, 634 (4), 658 Blank, D.H. 595 (354), 624 Blank, H.U. 870 (48), 890 Blankespoor, R.L. 675 (62), 681 Blasig, I.E. 1080 (225), 1159 Blasko, A. 1217 (6a), 1295 Bliznyuk, A.A. 1285, 1290 (197), 1300 Bloch, D.B. 977, 979 (50), 995 Bloch, K.D. 977, 979 (50), 995 Bloomfield, C. 880 (84), 890, 958 (48, 49), 971 Blough, N.V. 810 (156), 821
Blount, H.N. 843, 844 (23), 855 Blum, L. 902 (25), 947 Blum, W. 268, 269 (79), 293 Blundell, N.J. 1045 (5), 1155 Blunt, J.W. 954, 963 (31), 971 Boaretto, A. 1147 (592), 1167 Bobbit, D.R. 1069 (145), 1158 Bobrowski, K. 832 (54 56), 836 Bobylev, V.A. 1240 (101), 1297 Bocelli, G. 100 (91), 103 Boche, G. 396 (99, 100), 413, 414 (197), 420, 422, 551 (95), 552 (104), 618 Bochu, C. 724 (161), 727 (168), 743, 744 Bock, C.W. 452 (201), 475 Bock, H. 160 (11), 163 (27), 164 (27, 32, 35, 38, 43), 165 (27, 38), 166 (27, 32, 38, 43), 167 (35), 168 (27, 32, 38), 188, 189 (127), 201, 202, 204 Bockman, M. 790 (111d), 820 Bockman, T.M. 455 (216), 475 Bodenhausen, G. 297 (11), 332 Bodor, N. 170 (65), 203 Boduszek, B. 865 (27), 889, 930 (42), 947 Boegesoe, K.P. 62, 63 (109), 84 Boehm, K.A. 1047 (28), 1155 Boens, N. 695 (71), 741 Boer, Th.J.de 262, 263 (59), 292, 484 (34), 526 Boese, M. 992 (140), 997 Boese, R. 165, 166 (49), 168 (61), 202, 398 (108), 420 Boeyens, J.C.A. 58 (96, 97), 83, 453 (207, 208), 475 Boga, C. 564 (168), 620 Bogaard, M.P. 151 (158), 157 Boggs, J.E. 25 (39, 40), 82 Bohlmann, F. 425 (6), 470 Bohm, H.B. 1133 (498), 1165 B¨ohm, S. 348 (28), 373 Bohme, D.K. 178 (91), 203, 235 (160), 247, 380, 383, 390 (2), 416 B¨ohme, E. 977 (45, 48), 983 (86), 984 (45), 995, 996 Bohme, H. 443 (154), 474 B¨ohn, K.H. 413, 414 (197), 422 Boichinova, E.S. 1137 (526), 1141 (554), 1166 Boivin, J. 613 (451), 626 Boje, K.M. 977 (55), 995 Bojensen, G. 390 (69, 72), 419 Boji´c, V.D. 563 (160), 620 Bokii, N.G. 636 (39), 659 Bolin, G. 573 (204), 620 Bollyky, L.J. 1105 (368), 1162 Bolm-Audorff, U. 1185 (72), 1213 Bologa, U.L. 968 (61), 971 Bolton, J.L. 1032 (187), 1039 Bolton, J.R. 739 (206), 745
Author index Bolz, W. 763 (41), 818 Bon, E. 592 (334, 338), 623 Bonamartini, A.C. 426 (14), 470 Bond, A.M. 851 (53), 856 Bondi, A. 78 (132), 84 Bonham, G.A. 405 (151a), 421 Bonilha, J.B.S. 753, 757 (13, 27), 817, 818 Bonincontro, A. 1126 (451), 1164 Bonnat, M. 536 (19), 617 Bonneau, P.R. 46, 47 (71), 83 Bonneau, R. 688 (35, 36), 695 (74), 740, 741 Bonnet, J.J. 654 (149), 662 Bonnett, R. 317 (65), 333, 672 (32), 680 Booms, R.E. 1009 (65), 1036 Boone, C.D.G. 90, 93 (19), 102 Booren, A.M. 1189 (95), 1214 Boothby, C.St.J. 181 (96), 203 Boppana, V.K. 1079 (210), 1159 Borah, H.N. 608 (427), 625 Borch, R.F. 563 (154), 619 Borchers, F. 240 (184), 248 Bordwell, F.G. 308 (41), 333, 381 (6a, 6b), 387 (52b), 398 (115), 400 (127, 129), 401 (133), 402 (131 133, 139), 403 (137, 140, 141), 404 (143, 144), 407 (159), 409 (6b), 410 (182, 183), 413 (198), 415 (205), 416, 418, 420 422, 436 (116, 117), 473, 505 (163), 508 (183), 529, 1228, 1232, 1235 (76), 1297 Bories, G. 1024 (128), 1037 Borisenko, K.B. 452 (201, 202), 475 Borkent, J.H. 695 (70), 741 Bornhop, D.J. 1093 (316), 1161 Borossay, J. 164 (37), 202 Borrull, F. 1083 (246), 1160 Bors, D.A. 399 (117, 118), 420 Borsa, F. 1083 (250), 1160 Boryak, O.A. 1119 (432), 1164 Bos, H.J.T. 718 (145), 734 (185a), 743, 744 Bos, R.P. 1129 (475), 1132 (489), 1164, 1165 Bosch, E. 792 (115), 820, 1225 (62, 65, 66), 1226, 1227 (62), 1228 (75), 1297 Bosch, L.C. 1177 (36), 1212 Bosch, T. 803 (143), 821 Bosco, M. 608 (426a), 625 Bosi, M. 464, 467, 468 (259), 476, 1281 (188), 1300 Bosma, N.L. 234, 238, 240 243 (158), 247 Bosnich, B. 151 (159), 157 Bostick, J.M. 1080 (220), 1159 Boszczyk, W. 775 (64), 819 Bothelo, L.H. 1005 (51), 1036 Bott, K. 639 (63), 660 Bottaro, J.C. 605 (405), 606 (412), 625 Botting, H.G. 1085 (262), 1160
1309
Boubaker, T. 416 (212), 422, 509 (188), 529 Boucetta, A. 1136 (522), 1165 Bouchoux, G. 216 (61), 231 (134), 232 (142), 245, 247, 260 (47, 48), 292, 1284 (191, 192), 1300 Boudrant, J. 1069 (142), 1158 Bougeard, D. 457 (227), 475 Bouhedir, K.H. 1071 (152), 1158 Bouma, W. 208 (8), 244 Bouma, W.J. 208 (12, 13, 19), 209 (22, 25), 210 (19), 211 (13, 19), 214 (12, 52), 215 (55), 235 (19), 244, 245 Bouquant, J. 590 (315), 623 Bourasseau, S. 78, 79 (133), 84 Bourie, J.R. 457 (227), 475 Bourn, A.J.R. 319 (81), 334 Bourrel, M. 844 (25b), 855 Boutha, J.R. 845 (31), 855 Bovill, M.J. 60 (103c), 84 Bowden, K. 509 (192), 530, 1217 (14), 1295 Bowen, D. 217 (74, 75), 218, 221 (75), 245 Bowen, R.D. 216 (63e, 66, 67), 218 (87, 88), 220, 221 (99), 223 (113), 224 (88), 225 (116), 226 (118, 121), 227 (118, 126, 127, 129), 228, 229 (118, 127, 129), 230 (127, 132), 231 (136, 138, 139), 232 (138, 144), 236, 237 (174), 238 (118, 174, 178), 239 (178), 241 (118, 132), 245 248, 284, 285 (101), 293 Bowers, M.T. 164 (33, 34), 165 (44), 166 (44, 50), 178 (34), 202, 232 (140), 236 (167, 168), 247, 386 (48a, 48b), 418 Bowley, H.J. 266 (72), 293 Bowman, C.T. 1174 (5), 1212 Bowman, W.R. 601 (384a, 384b), 611 (444, 445), 612 (446 450), 624 626, 1019 (93), 1037 Bowyer, W.J. 850 (52b), 856 Boyd, A.A. 360 (80), 377 Boyd, D.B. 3 5, 29 (1b), 81, 442 (147), 473 Boyd, M. 329 (111, 117), 330 (111), 334 Boyd, P.D.W. 329, 330 (111), 334 Boyd, R.J. 411 (190, 191), 422 Boyd, R.K. 253 (10), 291 Boyd, S.R. 1049 (64), 1156 Boyer, J.H. 606 (413), 625, 1000, 1007, 1009, 1011 (2), 1035 Boykin, D.W. 71 (120), 84, 297 (8), 313, 314 (58), 315 (64), 325, 326, 329 (110), 332 334 Boyland, E. 1000 (8), 1035 Boyle, M. 1145 (576), 1167 Boyle, P.H. 412, 413 (196), 422 Bozhkova, N. 139, 141 (116, 117), 143 (126), 156 Bracken, C. 712 (122), 742 Bracuti, A.J. 87, 88 (7), 102
1310
Author index
Bradamante, S. 397 (104, 105), 398 (106, 109a, 109b, 110 112), 400 (105), 420 Bradamente, S. 509 (193 195), 530 Bradfield, A.E. 486 (61, 62, 64), 526 Bradley, R.B. 317 (67), 333 Bradley, S.J. 1047 (41), 1155 Bradshaw, T.P. 1019 (94), 1026 (142), 1037, 1038 Braga, M. 184 (100), 203 Braghetti, M. 99 (79), 103 Brahmi, R. 609 (433), 625 Brammer, R. 171 (76), 203 Bramwell, M.R. 330 (126), 335 Branca, J.C. 410 (183), 413 (198), 422 Branch, G.E.K. 499 (139), 515 (229), 520 (139), 528, 530 Branch, M.C. 1174 (4), 1212 Branchflower, R.V. 1025 (132), 1038 Brandsen, J. 99 (86), 103 Brandt, P.A.van den 1188 (86), 1214 Bratton, A.C. 1087 (277), 1160 Brauchle, C. 1119 (427), 1163 Brauman, J.I. 220 (105), 246, 385 (34a, 34b), 398 (113a), 401 (136), 417, 420 Braun, S. 1004 (42), 1035 Braverman, S. 1012, 1015 (82), 1036 Bravo, C. 644 (92), 660 Bray, D.D. 94 (35), 102 Brechbiel, M. 897 (22), 904 (26), 905 (29), 947 Breckenridge, A.M. 1028 (156), 1038 Brede, O. 649 (119), 661 Bredig, G. 483 (29), 526 Bredt, D.S. 976 (42 44), 977 (44), 978 (43, 69), 983 (43), 984 (90), 992 (42, 43, 143), 995 997 Brega, A. 1133 (496), 1165 Breganza, J.M. 1097 (334), 1162 Breichbiel, M. 860 (17), 861 (17, 19), 863 (23), 889 Breindhal, T. 390 (72), 419 Breitmaier, E. 302, 303 (22), 332 Brel, V.K. 607 (419), 625 Bremser, W. 310 (47), 333 Brennan, J.G. 43 (68), 83 Brent, D.A. 290 (118), 294 Bresse, M. 398 (116), 420 Breuer, E. 552 (100a), 565 (172), 618, 620 Breuer, M. 1069 (143), 1158 Brevis, D.M. 1262, 1264 (147b), 1299 Brewis, D.M. 434 (85), 472, 511 (211, 212), 530, 1241, 1262, 1264 (103b), 1298 Brewster, J.H. 106 (9), 137 (108), 153, 156 Brezden, C.B. 1032 (191), 1039 Brice, M.D. 37 (56), 82 Bridier, I. 1177 (45), 1213 Brien, D.J. 166 (53), 202
Brieux, J.A. 1216, 1217, 1235 (4a, 4b), 1295 Brieva, R. 592 (336), 623 Briggs, A.J. 99 (84), 103 Briggs, J.M. 320 (91), 331 (128), 334, 335 Brinck, T. 408, 409 (170), 421 Bringas, P. 1025 (139), 1038 Brink, C.P. 407 (158b, 158c), 421 Brinkman, U.A.T. 1105 (369), 1134 (511), 1162, 1165 Brintzinger, H.H. 115 (49), 154 Brito-Palma, F.M.S. 57 (89), 83 Britton, D. 98 (73), 103 Brizgys, M.W. 1100 (348), 1162 Brock, C.P. 442 (150), 473 Brock, L.v.den 1012 (77), 1036 Brodalla, D. 86, 88 (4), 102 Broitman, F. 827 (40), 835 Bromidge, S.M. 589 (310), 623 Bromilow, J. 303 (26, 27), 310, 311 (44), 332, 333, 504, 505 (155), 529 Brooke, D.N. 416 (213), 422 Brooke, G.M. 635 (30), 659 Brorson, T. 1063 (97), 1157 Brourcier, S. 106 (6), 153 Brouwer, A.M. 446 (171, 173), 474 Brown, A.S. 392 (73), 419, 673 (40), 681 Brown, B.E. 88, 90 (8), 102 Brown, C.J. 90, 93 (18), 96, 97 (57), 102, 103 Brown, D.S. 612 (448, 450), 626 Brown, H.C. 114 (46), 117 (54), 118, 119 (55), 154, 488, 489 (82), 527, 552 (100a, 100b), 565 (172, 176), 618, 620 Brown, J.H. 48 (72), 49 (73), 83 Brown, L. 1176 (25), 1212 Brown, P.S. 590 (322), 623 Brown, R.S. 171, 174, 184, 188 (67), 203 Brownawell, M.L. 861, 863 (21), 877 (72), 889, 890, 911 (34), 915 (36), 918, 920 (37), 947 Browne, S. 1068 (140), 1158 Brownell, R.M. 497 (133), 528 Brownlee, R.T.C. 303 (26, 27), 310, 311 (44), 312 (56), 313 (56, 57), 314, 315 (57), 332, 333, 490 (92), 491, 503 (99), 504 (92, 154, 155), 505 (155), 515, 518 (154), 521, 522 (92), 527, 529, 642 (83), 660 Brownson, D.M. 1066 (120), 1157 Brownstein, S. 877 (73), 890 Broxton, T.J. 1220, 1222 (31a, 31b), 1296 Bruckner, H. 1090 (291), 1161 Bruckner, S. 53 (77), 83 Brudel, M. 1080 (225), 1159 Brugger, E. 762 (38a, 38b), 818 Bruguerolle, B. 1061 (91), 1156 Bruhlmann, U. 810, 811 (159), 821 Bruice, T.C. 535 (12), 616 Bruins, A.P. 1012, 1033 (85), 1036
Author index Brundle, C.R. 160 (1, 5), 161, 163 (1), 201 Bruneau, C. 591 (327), 598 (374), 623, 624 Brunet, J.-J. 587 (299), 588 (302a, 302b), 622, 623 Bruni, P. 441 (146), 473 Brunmark, P. 1081 (230), 1159 Brunnemann, K.D. 1150 (607 610, 612), 1151 (613, 614, 616, 617), 1167 Bruno, A.E. 1093 (315, 316), 1161 Brunton, G. 955 (40), 971 Bryant, G.L.Jr. 590 (317), 623 Bryant, L.R.B. 730 (181e), 744 Bryant, M.S. 1021, 1030 (103), 1037 Bryant, T. 677 (74), 678 (79), 679 (86), 681, 682 Bryce, M.R. 456 (222), 475, 594 (347, 348), 623 Bryce-Smith, D. 685, 686 (7), 698 (92), 740, 742 Brycki, B.E. 560 (136), 619 Bryker, W.J. 640 (68), 660 Brynmor Jones 486 (61 63), 526 Brzezinski, B. 435 (108 112), 472, 473 Brzezinski, J. 593 (343), 623 Bu, M. 1024 (125), 1037 Buchachenko, A.L. 649 (118), 661 Buchanan, M.V. 1047 (49), 1155 Buchel, T. 717 (142), 743 Buchko, G.W. 833 (70), 836 Buchler, N. 733 (184), 744 Buchner, E. 654 (146), 662 Buchwald, S.L. 115 (47, 48, 51), 116 (51, 52), 117 (48, 52), 154, 546 (74a, 74b), 577 (220), 584 (282), 618, 621, 622 Buck, H.M. 648 (112), 661 Buckee, G.K. 1047 (27), 1155 Buckingham, A.D. 6 (9), 81, 150 (157), 151 (158), 157 Buckingham, J. 106, 113 (5), 153 Buckley, T.J. 211 (38), 244 B¨uckmann, A.F. 1103 (363), 1162 Budˇesˇ¨insk¨y, M. 522 (240, 241), 531 Budzikiewicz, H. 206, 207, 233 (2c, 2e), 243 Buechele, B. 1146 (584), 1167 Bug, R. 767 (53), 819 Buga, G. 976 (32), 994 Buga, G.M. 974 (2), 993 (144), 994, 997 Bugaj, A. 1140 (551), 1166 Buglass, J. 405 (150a), 421 Buijten, J.C. 1063 (101), 1157 Buist, G.J. 381 (20b), 417, 428 (42), 471 Buki, K.G. 1024 (123, 124), 1037 Bullen, J.V. 879 (77 80), 890, 967 (57), 971 Bult, A. 1119 (426), 1163 Bulusu, S. 281 (92, 93), 293, 317 (69), 318 (78), 333, 334 Bunce, N.J. 685 (11), 740, 755 (19), 818
1311
Buncel, E. 411 (189), 414 (202), 422, 457 (231, 235), 475, 476, 512 (215, 216), 530, 859 (5), 865 (29, 30), 866 (35), 888, 889, 1217, 1220 (11a), 1295 Bunes, L. 582 (263), 622 Bunker, C.E. 441 (145), 473 Bunnell, R.D. 410 (184), 422 Bunnett, J.F. 457 (233), 466 (266, 268), 475, 476, 611 (443), 625, 1216 (1d, 2a c), 1217 (2a c), 1218 (19, 20a c), 1219, 1220 (1d, 20a c), 1232 (81), 1235 (1d, 81), 1242 (2c), 1244 (1d), 1250 (1d, 19), 1251 (19), 1268 (171), 1274 (1d), 1278 (2a c), 1290 (1d, 20a c), 1295, 1297, 1299 Bunt, R.C. 590 (316), 623 Bunton, C.A. 510 (196), 530, 877 (73), 890, 1217 (6a c), 1220 (30a, 30b, 32a, 32b), 1295, 1296 Burch, E.L. 686, 699, 700, 706 (24), 729 (176a, 176b), 740, 744 Burdash, N. 1148 (601), 1167 Burden, A.G. 501 503, 520 (143), 529 Burg, J. 1185 (72), 1213 Burgar, M.I. 312 (53), 333 B¨urger, H. 164 166, 168 (38), 202 Burgers, P.C. 208 (7, 11), 209 (11), 214 (11, 51), 215 (7, 56), 233 (148, 149), 234 (148), 244, 245, 247, 254 (23), 255 (23, 27), 292 Burgess, E.M. 737 (197), 745 Burgot, J.L. 1107 (380), 1162 Burguera, J.L. 1074 (174), 1158 Burguera, M. 1074 (174), 1158 Burke, P.O. 405 (147, 148), 421 Burke, T.R. 1025 (132), 1038 Burkert, U. 3 5 (1a), 24 (35), 29 (1a), 81, 82 Burkle, W. 121 (68), 122, 123 (69), 155 Burns, C.A. 612 (450), 626 Burns, D.T. 1126 (447), 1164 Burri, P. 648 (110), 661 Burrow, P.D. 173 (77), 203 Burrows, E.P. 137 (109, 112), 138 (109), 156 Burton, T.C. 748 (1), 817 Busch, K.L. 251, 253, 254 (5), 291 Buschek, J.M. 184, 187 (104), 203 Busconi, L. 977 (56), 979 (74), 995 Bush, L.P. 1151 (614), 1167 Bush, P.A. 993 (144), 997 Bushweller, C.H. 46 (70, 71), 47 (71), 48 (72), 49 (73), 83 Buss, V. 139 (113), 141 (120), 156 Busse, R. 992 (140), 997 Bussolari, J. 576 (216), 621 Busto, O. 1083 (246), 1160 Butcher, A.R. 264, 266 (64), 293 Butcher, M. 268 (78), 293 Butin, K.P. 444 (161), 474
1312
Author index
Butler, A.R. 628, 640, 644 (1), 658, 669 (20), 670 (27), 680, 985 (96), 996 Butler, J. 827 (35), 835 Butler, L.J. 795 (122), 820 Butler, M. 1047 (32), 1155, 1177 (30), 1212 Butler, R.N. 630 (14), 632 (21), 636 (14), 646 (102), 659, 661 Butoh, M. 1069 (147), 1130 (147, 479, 481), 1158, 1165 Butts, C.P. 456 (220), 475, 954 (39), 971 Buv´ari, A. 431 (62), 471 Buxaderas, S. 1085 (264), 1160 Buys, H.R. 15, 17 (25b), 81 Buzby, J.H. 579 (237), 621 Buzzaccarini, F.de 1220 (30b), 1296 Buzzigoli, G. 1085 (261), 1160 Byrn, S.R. 91, 93 (21), 102 Byrns, R.E. 974 (2), 976 (32), 994 Bysh, P. 1174 (7), 1212 Cabeza, A.S. 1097 (339), 1162 Cacace, F. 232 (141), 247 Cadogan, J.I.G. 647 (105), 650 (127), 661 Cady, H.H. 329 (112), 334 Cai, G. 139, 141 (116), 143 (126), 156 Cai, P. 130 (89), 155 Caia, V. 99 (79), 103 Cainelli, G. 549 (81), 618 Calabrese, J.C. 90, 93 (13), 102, 587 (301), 623 Calatayud, J.M. 1088 (279), 1099 (344), 1160, 1162 Calaycay, J. 978 (63, 65), 995 Calcasi, M. 991 (124), 996 Calder, I. 1029 (167), 1038 Calderbank, J. 1188 (89), 1214 Caldin, E. 894 (3), 946 Caldwell, W.S. 1150 (611), 1167 Callaghan, P.T. 330 (119), 335 Callahan, C.M. 1063 (98), 1157 Calvert, J.L. 883 (92), 891, 954 (33, 35, 36), 969 (36), 971 Calvin, M. 515 (229), 530 Camanas, R.M.V. 1067 (133), 1086 (273), 1157, 1160 Cambon, A. 540 (45), 617 Camerman, A. 96 (48), 102 Camerman, N. 96 (48), 102 Cameron, D. 390 (70), 419 Cameron, J.F. 767 (52b), 819 Cameron, M. 447 (180), 474 Caminati, W. 25 (39), 71 (121), 82, 84 Campbell, A.L. 724 (160), 743 Campbell, D. 785 (97b), 820 Campbell, G.A. 875 (66, 67), 890 Campbell, S. 178, 188 (92), 203, 673 (41), 681 Campos, K.J. 985 (97), 996
Campos, K.L. 983 (84), 996 Campos, P.J. 576 (213), 621 Canal, G. 576 (213), 621 Canas, M. 545 (70), 618 Cancela, G.D. 1048 (58), 1156 Canet, I. 1112 (402), 1163 Canet, J.I. 1112 (402), 1163 Canevari, L. 1078 (204, 205), 1159 Cantos, A. 754 (15, 17a, 17b), 756 (23), 758 (30), 817, 818 Cao, J.A. 231 (137), 247 Capdevielle, P. 580 (241, 252a, 252b), 590 (321), 621, 623 Capon, B. 1250, 1267 (126), 1298 Caporusso, A.M. 575 (211), 621 Capozzi, G. 1012, 1015 (73), 1036 Capriogu, M.T. 968 (61), 971 Caprioli, R.M. 233 (146), 247, 251 (4), 291 Caranoni, C. 94 (37), 102 Carballeira, L. 15, 16 (26e), 55 57 (82), 82, 83 Carboni, B. 566 (177), 620 Carchon, H.A. 1078 (201), 1159 Cardenas, R. 1285 (195), 1300 Carere, A. 1178 (49), 1213 Carey, J. 107 (20), 153 Carfagna, C. 398 (112), 420 Carlsen, L. 251 (6), 253, 254 (15), 255 (15, 29), 259 (44 46), 260 (15, 50), 262 (55), 263, 264 (61), 290 (45), 291, 292 Carlson, R. 563 (165), 583 (272), 620, 622 Carlson, R.G. 1080 (222, 223), 1159 Carlson, T.A. 160 (3), 201 Carlsson, A. 62 (107), 84 Carlsson, D.J. 825 (24), 835 Carlstrom, D. 89, 90 (9), 102 Carmella, S.G. 1150 (612), 1167 Carmona, C. 409 (169a, 169b), 421 Carnahan, G.E. 668 670, 672 (14), 680 Carney, T.E. 234 (152), 247 Carnovale, F. 166 (60), 202 Caronia, A. 1262, 1266 (152), 1299 Carpenter, A.J. 595 (351), 624 Carpenter, B.K. 769 (56), 819 Carpenter, J.G.D. 57 (86), 83 Carper, W.R. 281 (94), 293 Carpino, P.A. 575 (209), 621 Carr, P.W. 381 (21), 417, 428 (43), 471 Carraro, F. 1059 (83), 1156 Carrasco, R. 584 (283), 622 Carreira, L.A. 8 (13), 81 Carreiro, J.C. 753 (13), 757 (27), 817, 818 Carrell, H.L. 452 (199), 475 Carreyre, H. 609 (433), 625 Carri, M. 1085 (261), 1160 Carroll, R.T. 1133 (497), 1165 Carson, K.G. 563 (156), 620 Carta˜no, A.V. 1218 1220, 1290 (20a), 1295
Author index Cartano, V. 457 (233), 475 Carter, D.M. 266, 267 (71), 293 Carter, M.A. 871 (55), 890 Carter, R.E. 408, 409 (170), 421 Cartwright, B.A. 37 (56), 82 Carunchio, V. 1091 (298), 1161 Carvalho, E. 606 (411), 625, 882 (86), 890 Carver, D.R. 575 (210), 621 Casado, J. 643, 645 (88), 660 Casalnuovo, H.L. 587 (301), 623 Casara, P. 576 (218), 621 Casarini, A. 551 (93), 618 Casarini, D. 43 (66), 50 (66, 74), 52 (74), 83 Casassas, E. 1225 (67), 1297 Casciano, D.A. 1033 (203), 1039 Case, D.A. 3 (2a, 2b), 81 Casella, L. 137 (111), 156 Caseres, C. 1262, 1266 (145), 1299 Casewit, C.J. 38 40 (58, 59), 82 Casey, H. 1045 (5), 1155 Caspar, J.V. 441 (144), 473 Casselberry, R.L. 843, 844 (23), 855 Cassman, K.G. 1047 (25), 1155 Casson, A. 66, 67 (111), 84, 166, 168, 179, 184, 185 (52), 202 Castellato, F. 456 (225), 475 Castellino, F.J. 564 (167), 620 Castello, G. 1126 (451), 1164 Castelnovo, P. 1092 (308), 1161 Castenmiller, W.A.M. 648 (112), 661 Castleman, A.W.Jr. 262 (54), 292, 385 (41), 418 Castro, A. 643 (88), 644 (92, 96), 645 (88, 98), 660, 661, 677 (72), 681, 886 (101 103), 888 (106), 891 Castro, L. 992 (139), 997 Castro, M.D.L.de 1137 (527), 1166 Catalan, J. 407 (161b), 408 (165a, 165b, 166, 167b), 421, 524 (253), 531, 780 (81), 819 Cataliotti, R.S. 99 (79), 103 Cater, S.R. 755 (19), 818 Cattana, R. 433 (81), 472, 1245 1247, 1266 (115b), 1298 Cattana, R.I. 1244 (110), 1245 (110, 117), 1246 (117), 1298 Cauchi, B. 1079 (208), 1159 Caufield, C. 41 (63), 82 Cauletti, C. 165 167 (24), 202 Cava, M.P. 717 (143a), 743 Cavoli, P. 94 (36), 102 Cayon, E. 756 (23), 788 (102), 818, 820 Cazabeil, J.M. 1078 (199), 1159 Cazeau du Broca, C. 1136 (522), 1165 Ceasar, G.P. 175 (84), 203 Cecil, R. 1012 (74), 1036 Celander, D.W. 756 (22), 818
1313
Cellerino, G.P. 1078 (198), 1159 Cellota, R.J. 257 (36), 292 Cense, J.M. 453 (206), 475 Ceolin, R. 453 (206), 475 Cerdeira, S. 1235, 1237, 1243, 1263, 1293 (82), 1297 Cerdeira, S.B. 1217, 1263 (12), 1295 Cerioni, G. 53 (77), 70 (119), 83, 84, 315 (62), 333 Cerniglia, C.E. 1197, 1198 (106), 1214 Cernigliaro, G.J. 658 (175), 663 Cerny, A. 633 (26), 659 Cerny, R.L. 208 (16), 211 (36), 244 Cerrello, J. 754 (14), 817 Cerreta, F. 591 (325), 623 Cert, A. 283, 284 (100), 293 Cervello, J. 758 (31), 818 Cerveny, L. 870 (49), 890 Cervinka, O. 112, 113 (41), 154 Cetina, R. 434 (90), 472, 1266 (165), 1299 Chaabouni, R. 566 (180), 567 (183), 620 Chabinyc, M.L. 1134 (505), 1165 Chadha, H.S. 1222 (56, 59), 1226 (71), 1228 (73, 74), 1296, 1297 Chadikun, F. 254, 288 (22), 292 Chadwick, D.J. 60 (103c), 84 Chadwick, I. 456 (223), 475 Chaffin, J.D.E. 612 (448), 626 Chakrabarti, A. 738 (200b), 745 Chakrabarty, T. 694 (66), 741 Chakrabotry, D.P. 738 (200b), 745 Challis, B.C. 593 (344), 623, 628, 640, 644 (1), 658, 1047 (41), 1155 Chaloner, C. 1097 (334), 1162 Chamberlain, R. 1253 (130, 131, 133), 1255 (130, 133, 134), 1256 (130), 1298 Chamberlin, R.A. 457 (234), 476 Chambers, R.D. 435 (107), 472, 651 (134), 662 Chamchaang, W. 545 (71), 618 Champagne, M.H. 830 (51), 836 Chan, K.C. 1094 (322), 1096 (327), 1161 Chan, T.H. 1066 (121), 1157 Chan, W.H. 1097 (337), 1162 Chan, Y.M. 110 (34), 154 Chandler, D.W. 1174 (4), 1212 Chandra, H. 834 (74), 836 Chandrakumar, N. 396 (87), 419 Chandramouly, T. 148 (144), 156 Chandrasekaran, K. 693 (54), 741 Chandrasekaran, S. 608 (421), 625 Chandrasekhar, J. 386 (46), 418, 956 (44), 971 Chandross, E.A. 695 (72), 741, 767 (49), 819 Chanet-Ray, J. 598 (373), 624 Chang, C.J. 581 (259), 622 Chang, D.W.L. 812 814 (165), 821 Chang, G. 41 (63), 82
1314
Author index
Chang, H. 596 (369), 624 Chang, J.C. 1177 (34), 1212 Chang, K.-C. 100 (94), 103 Chang, K.Y. 1020 (95), 1037 Chang, M. 1072 (154), 1158 Chang, W.B. 1076 (185), 1158 Chang, W.M. 434 (86), 472, 1262, 1266 (146), 1299 Chantal, P.D. 1067 (125), 1157 Chantry, D. 96 (50), 103 Chao, J. 431 (67), 472 Chao, O. 434 (90), 472 Chaouki, J. 1175 (12), 1212 Chapel, H.L. 807 (149b), 821 Chapleo, C.B. 584 (284), 622 Chaplinski, V. 164, 165 (36), 168 (61), 202 Chapman, N.B. 434 (85), 472, 501 (143, 144), 502 (143, 144, 148), 503 (143, 144, 149), 511 (208, 210 212), 520 (143, 144), 529, 530, 1241, 1262, 1264 (103b), 1298 Chapman, O.L. 353 (49), 375, 724 (162a), 743 Chapman, R. 828 (44), 835 Chardhuri, G. 974 (2), 994 Chardin, A. 395 (84), 419 Charles, I.A. 992 (134), 997 Charles, I.E. 992 (132), 997 Charles, I.G. 979 (77), 992 (135), 995, 997 Charles, S.J. 976 (40), 994 Charlton, J.L. 778 (70b), 819 Charton, B. 524 (256), 531 Charton, B.I. 499 (140), 528 Charton, M. 490 (95), 492 (109 111), 493 (109, 112, 113), 498 (95), 499 (140 142), 501 (95, 143, 144), 502, 503 (143, 144), 504, 512 (109), 514 (109, 112), 517, 518 (109), 520 (109, 143, 144), 521 (95), 522 (249), 524 (109, 255, 256), 525 (257), 527 529, 531, 642 (85), 660 Chartrain, N. 993 (147), 997 Chartrain, N.A. 979 (78), 995 Chasar, D.W. 1197 (108), 1214 Chastel, R. 349 (32), 374 Chateauneuf, J. 809 (152), 821 Chatgilialoglu, C. 806 (147), 821 Chatrouse, A.P. 1217 (17), 1295 Chatrousse, A.P. 415 (207, 209, 210), 422 Chatterjee, A. 562 (151), 619 Chatterjee, S.K. 536 (20), 617 Chaudhury, D.K. 511 (210), 530 Chauhan, S.M.S. 675 (64), 677 (71), 681 Chauvin, R. 564 (166), 620 Chawla, H.M. 1100 (351), 1162 Che, R. 77 79 (129), 84 Chechik, V.O. 1240 (101), 1297 Chee, C. 673 (44), 681 Cheetham, A.K. 86 (3), 102 Cheikh, R.B. 567 (183), 620
Chekhuta, V.G. 348 (31), 373 Chen, C. 1116 (410 412), 1163, 1228, 1232 1235, 1239 (77), 1297 Chen, C.-K. 560 (137), 619 Chen, F.-M. 137 (109, 112), 138 (109), 156 Chen, H. 993 (147), 997 Chen, H.G. 580 (244), 621 Chen, H.S. 979 (72), 995 Chen, J. 1182 (62), 1213 Chen, J.G. 1074 (182), 1158 Chen, J.S. 427 (19), 470 Chen, K. 4 (44), 21, 22, 32 (31), 33, 35 (44), 82 Chen, K.-L. 605 (410), 625 Chen, P.-F. 989 (103), 996 Chen, S.-F. 714 (124, 125), 742 Chen, S.-H. 567 (182), 620 Chen, S.-J. 592 (330), 623 Chen, S.-T. 592 (330), 623 Chen, S.-Y. 592 (330), 623 Chen, Y.J. 609 (430), 625 Chen, Z. 433 (79), 472 Chenevert, R. 722 (153g), 743 Cheng, C.H. 447 (185), 474 Cheng, J.-F. 120, 142 (62), 154 Cheng, J.-P. 401, 402 (133, 139), 420 Cheng, M.Y. 96 (45), 102 Cherkasov, A.R. 506 (175), 529 Cherkasov, R.A. 506 (175), 529 Chernov, A.N. 592 (339), 623 Chernovitz, A.C. 150 (154), 157 Chesick, J.P. 90 (10), 102 Chesney, A. 594 (347), 623 Chess-William, R. 976 (40), 994 Chesta, C.A. 727 (169), 744 Cheung, A.V. 978 (71), 995 Cheung, E.T. 1238, 1240 (97), 1297 Chiacchera, S.M. 467 (271), 476 Chiacchiera, S.M. 1217 (9), 1220 (33), 1235 1237 (9), 1244 (110), 1245 (110, 116b), 1246 (9, 116b), 1247, 1276 (9), 1295, 1296, 1298 Chiang, Y. 658 (175), 663 Chiappardi, D.M. 843, 844 (23), 855 Chiara, J.L. 453 (204), 475 Chiavari, G. 563 (162), 620 Chiba, M. 749 (3a, 3b), 817 Chickos, J.S. 338 (4, 6), 346 (21), 347 (24), 352 (41, 44), 355 (57), 356 (59), 372 375 Childers, J.W. 1133 (503), 1165 Chimichi, S. 780 (82), 819 Chin, D. 430 (50), 471 Chin, T. 767 (51), 819 Chin, W.S. 193, 194 (143, 144), 195, 196 (143), 197 (143, 144), 198, 199 (144), 200 (150, 151), 204
Author index Chini, M. 544 (65, 68), 617 Chio, C. 3 (2a), 81 Chipko, B.R. 1024 (131), 1038 Chirico, R.D. 346 (20), 350, (35, 37), 373, 374 Chir´on, S. 1068 (139), 1078, 1079 (195), 1158, 1159 Chiu, F.T. 714 (124), 742 Cho, B.T. 114 (46), 154 Cho, H. 992 (131), 997 Cho, H.J. 978 (58, 63, 65), 995 Cho, I.S. 692 (50), 714 (126), 741, 742 Choi, C. 563 (155), 620 Choi, C.S. 86, 88 (5), 102 Choi, H. 108 (27), 154 Choi, J. 534 (2), 537 (30), 616, 617 Chokshi, H.P. 1080 (222, 223), 1159 Choudary, B.M. 596 (360), 624 Choudhury, M.K.D. 1266, 1267 (167b), 1299 Chow, Y.L. 684 (1), (41), 740, 810 (174), 811 (163, 174), 812 (165 168, 174), 813 (165, 166, 168, 169), 814, (165, 170), 815 (171), 816 (169, 172), 817 (173), 821 Chowdary, A. 357 (67), 376 Chowdhury, S. 256 (34, 35), 258 (38), 292, 385 (37a, 40), 418 Choy, G.S.-C. 648 (113), 661 Choy, N. 108 (27), 154 Chracek, J. 1077 (192), 1159 Christ, H.A. 312 (51), 316, 317 (66), 333 Christensen, J.B. 212, 222 225 (44), 244 Christie, J.R. 219 (91), 220 (104), 236 (171), 246, 248, 1220, 1222 (31a, 31b), 1296 Chronister, C.W. 445 (166), 474 Chrystal, E.J.T. 1032 (196), 1039 Chu, S.C. 992 (130), 997 Chuang, J.C. 1176 (25), 1212 Chuang, T.H. 581 (259), 622 Chuchani, G. 483 (32), 526 Chuche, J. 590 (315), 623 Chudek, J.A. 456 (224), 475 Chumachenko, T.A. 1119 (432), 1164 Chung, K.T. 1197, 1198 (106), 1214 Chupka, W.A. 217 (76), 245 Ci, Y.X. 1076 (185), 1158 Ciajolo, A. 1175 (16), 1212 Cicatiello, L. 992 (126), 997 Cimarelli, C. 459, 464, 468 (245), 476, 1262 (149a, 149b), 1278 (149a, 149b, 184a), 1279 (149b, 184a), 1280, 1285 (184a), 1299, 1300 Cimiraglia, R. 803 (138), 821 Cini, R. 57 (93), 83 Ciociaro, D. 1085 (261), 1160 Ciommer, B. 208 (9, 10), 244 Cioslowski, J. 411 (194, 195), 412 (194), 422 Cipciani, A. 1220 (32a, 32b), 1296 Cirrincione, G. 630 (15), 633 (27), 659
1315
Citra, M. 150 (152), 157 Citro, M.L. 1149 (605), 1167 Citterio, A. 655 (157), 662 Ciuffarin, E. 398 (113a, 113b), 420 Ciuffarin, F. 1236, 1266 (159), 1299 Ciureanu, M. 846 (36b), 856 Civisova, D. 1138 (531), 1166 Claramunt, R.M. 407 (161b), 421 Clark, A. 1127 (453, 454), 1164 Clark, C.R. 1063 (99), 1071 (152), 1157, 1158 Clark, D.N. 601 (384a, 384b), 624 Clark, D.T. 310 (48), 333 Clark, E.P. 1031 (182), 1039 Clark, G.D. 1063 (98), 1157 Clark, J.E. 984 (90), 996 Clark, M. 36 38, 42 (52), 82 Clark, M.T. 685, 686 (7), 740 Clark, P. 989 (107), 991 (113), 996 Clark, T. 956 (44), 971 Clarke, A. 1174 (6), 1212 Clarke, C.T. 542 (52), 617 Clarke, R.A. 1105 (368), 1162 Claus, P.K. 1015, 1018 (86), 1036 Clavijo, E. 431 (66), 472 Clay, R.M. 355, 356 (58), 375 Cleary, P.D. 975 (13), 994 Clegg, D.J. 1189 (93), 1214 Clegg, W. 396 (90), 419 Cleghorn, S.J.C. 844 (28), 855 Cleland, W.W. 894 (4), 946 Clemens, A.H. 967 (60), 971 Clennan, E.L. 56 (80c), 83 Cleveland, P.G. 724 (162a), 743 Clewley, R.G. 950 (12), 970 Clifford, P. 220, 221 (99), 246 Closset, J.L. 100 (90), 103 Clovis, J.S. 905 (30), 947 Cnubben, N.H.P. 1097 (335), 1162 Coade, M.E. 674 (52), 681 Cobbledick, R.E. 329 (116), 334, 950 (4), 970 Coburn, M.D. 370 (100 102), 378 Cockerill, A.F. 509 (192), 530 Cocksey, B.J. 168 (62), 202 Coello, A. 677 (73), 681, 888 (107), 891 Cohen, B.E. 686 (24), 696 (81), 699, 700, 706 (24), 707 (109), 740 742 Cohen, H. 829 (48), 836 Cohen, K.A. 1071 (151), 1158 Cohen, L.A. 497, 516 (134), 528 Cohen, M.D. 436 (119, 120), 473, 750 (5), 817 Cohen, M.P. 537 (25), 617 Cohen, N. 345 (17), 372 Cohen, S.A. 1084 (254, 256), 1085 (267), 1160 Cohen, S.G. 687 (39), 740 Cohen, T. 653 (145), 656 (164), 662 Coitino, E.L. 453 (206), 475
1316
Author index
Colbourne, D. 166 (56), 202 Colburn, A.W. 227 229 (129), 231 (136), 246, 247 Coldani, R. 1085 (261), 1160 Cole, E.R. 735 (190a), 745, 1012 (80), 1036 Cole, N.W. 219 (91), 246 Cole, S. 1126, 1127, 1143 (446), 1164 Cole, T.E. 118, 119 (55), 154 Coleman, M.D. 1027 (148, 152), 1028 (156), 1038 Coleman, R.S. 595 (351), 624 Coles, B. 672 (36), 680 Colina, C.de la 1048 (58), 1156 Coll, J.C. 347 (27), 373 Collet, A. 106 (12), 153, 553 (106), 618 Collie, J.N. 485 (48), 526 Collina, G. 459 (241), 476 Collings, P. 674 (53), 675 (54, 63), 677 (53), 681 Collins, C. 899 (23), 947 Collins, P.M. 771 (59), 772 (60, 61), 819 Collins, S. 115 (50), 154 Collos, Y. 1046 (17), 1155 Collum, D.B. 396 (85, 86a, 86b, 89, 91a, 91e, 94, 97), 419 Collyer, S.M. 384 (30c), 417 Colombo, B. 1046 (9), 1155 Colomina, M. 357 (70), 376 Colon, C.J. 812 814 (165), 821 Colon, D.F. 137 (107), 155 Colon, M. 130 (89), 155 Colonna, F.P. 165, 166, 178 (46), 191, 199 (130), 202, 204 Colonna, M. 191, 199 (130), 204, 969 (66), 970 (67), 971 Colpitts, T.L. 564 (167), 620 Colson, A.O. 830 (51), 836 Colton, R.J. 191 (129), 192, 193, 200, 201 (136), 204 Colucci, W.J. 70 (117a, 117b), 84 Colwell, K.S. 38 40 (58, 59), 82 Commenges, G. 588 (302b), 623 Compton, D.A.C. 1142 (563), 1166 Comuzzi, C. 405 (153), 421 Conboy, J.J. 1118 (419), 1163 Connell, R.D. 542 (54), 568 (188), 617, 620 Connelli, G.D. 1153 (626 628), 1168 Conner, J.M. 1150 (611), 1167 Conser, K.R. 119 (58), 154 Consiglio, G. 100 (92), 103, 388 (56), 418, 1236 (160), 1241 (103a), 1262 (103a, 152), 1264 (103a), 1266 (152, 160), 1298, 1299 Constant, D. 165, 166, 182 (47), 202 Conti, C. 441 (146), 473 Conti, F. 390 (62), 418 Conti, L. 1178 (49), 1213 Contineanu, I. 353 (50), 375
Continetti, R.E. 795 (125), 820 Contreras, R. 1109 (392), 1163 Contreras, R.H. 319, 320 (82), 334, 438 (127), 473 Convery, M.A. 412, 413 (196), 422 Cook, C.D. 956 (43), 971 Cook, K.S. 933, 935, 938 (48), 947 Cook, P.M. 728 (170), 744 Cook, W.S. 895, 896, 936 (11), 947 Cooke, J.M. 825 (24), 835 Cooke, P.W. 461 (252), 476 Cooks, R.G. 209 (29), 217 (77), 233 (146), 234 (156), 238 (176, 179, 181), 244, 245, 247, 248, 251 (4), 252, 253, 262 (11), 291, 390 (70), 419, 1107 (383), 1163 Cookson, R.C. 686 (25), 688 (32), 698, 700 (25), 740 Cooley, J.H. 581 (260), 622 Coombes, R.G. 953 (20), 955 (41, 42), 956 (42), 965, 967 (20), 970, 971 Coon, C.L. 362 (90), 363 (90, 91), 377 Cooper, A.B. 550 (84), 618 Cooper, B.R. 1079, 1080 (218), 1159 Cooper, J.C. 1103 (359), 1162 Cooper, S.F. 1145 (580), 1167 Copin, A. 100 (90), 103 Corbett, M.D. 1024 (129, 131), 1037, 1038 Corey, D.E. 124 (74), 155, 427 (22), 471 Corey, E.J. 111 (37), 154, 539 (42), 617 Cornelisse, J. 753 (12), 754 (18), 788 (103), 817, 818, 820 Cornforth, F.J. 398 (115), 410 (182), 420, 422 Corradi, A.B. 445 (164), 474 Corradini, R. 1091 (300), 1161 Correa, P. 1182 (61), 1213 Correa, P.E. 698 (95, 96), 742 Corriou, R.J.P. 573 (204), 620 Cossy, J. 590 (318), 591 (328), 623, 737 (195a c), 745 Costa, S.M.de B. 686, 698, 700 (25), 740 Cotsaris, E. 445 (169), 474 Coughlin, E.B. 757 (26), 818 Coulter, D.R. 444 (162), 474 Courthaudon, L.O. 1047 (50), 1155 Courtieu, J. 1112 (402), 1163 Courtois, G. 576 (214), 621 Courtot-Coupez, J. 400 (126), 420 Coustard, J.M. 609 (433), 625 Coutant, R.W. 1176 (25), 1212 Coutts, R.T. 1065 (105), 1157 Couture, A. 724 (161, 164), 727 (168), 743, 744 Couture, Y. 450 (193), 474 Covert, R. 1068 (140), 1158 Covington, K. 992 (132), 997 Cowie, G.L. 1067 (131), 1157 Cowling, S.A. 171, 174 (72), 203
Author index Cowperthwaite, M. 369 (96), 378 Cox, A.J. 1031 (178), 1039 Cox, J.A. 1073 (169, 170), 1143 (567), 1148 (599), 1158, 1166, 1167 Cox, J.D. 218, 225 (82), 245, 339 (10), 372 Cox, J.E. 1151 (616 618), 1167 Cox, K.A. 1070 (149), 1158 Cox, R.A. 381 (5a), 400 (123), 416, 420, 641 (76), 660, 859 (5), 888 Cox, R.H. 302 (21), 332 Cox, R.L. 1081 (229), 1159 Coyle, J.D. 722 (156a, 156b), 730 (177a, 179, 181e), 734 (185a, 185b, 189), 739 (202, 203, 205), 743 745 Coynev, E.C. 655 (156), 662 Crabb, T.A. 15, 17 (24a), 81 Cradock, S. 164 (39), 202 Cragghine, I. 396 (92, 96), 419 Craig, B.B. 782 (90), 783 (90 92), 820 Craig, J.C. 130 (92), 131 (92 94), 132 (93 95), 155 Craik, D.J. 303 (27), 310, 311 (44), 312 (56), 313 (56, 57), 314, 315 (57), 332, 333, 491, 503 (99), 527 Craine, L. 1012, 1015 (83), 1036 Cram, D.J. 508 (185), 529, 1009 (65), 1036 Cramer, J.W. 1031 (179), 1039 Cramer, R.D.III 36 38, 42 (52), 82 Cramer, R.E. 96 (45), 102 Crampton, M.R. 416 (213), 422, 457 (231, 234), 475, 476, 1003, 1005 (49), 1036, 1217 (11a), 1218 (24), 1220 (11a), 1237, 1251 (24), 1253 (130 133), 1255 (130, 133, 134), 1256 (130), 1293 (24), 1295, 1298 Crandall, J.K. 579 (235), 621 Crank, G. 729 (173), 744 Craswell, E.T. 1048 (59), 1156 Cravedi, J.-P. 1024 (128), 1037 Craven, P.A. 975 (19), 994 Crawford, K.S.K. 338, 339, 342 346 (1), 371 Crawford, M.C. 446 (174), 474 Crawford, M.K. 694 (75), 741 Crawford, P.C. 370 (104), 378 Crebelli, R. 1178 (49), 1213 Cremer, D. 24 (37), 82 Crestini, C. 560 (135), 619 Crews, H.M. 1134 (507), 1165 Cribb, A.E. 1001, 1007, 1009, 1011 (28), 1027 (28, 155), 1035, 1038 Crider, A.M. 1133 (497), 1165 Crisma, M. 142 (124), 156 Crochi, B. 1178 (49), 1213 Crombie, R.A. 288, 289 (108), 293 Cronin, J.R. 1060 (87, 88), 1156 Crookes, M.J. 675 (56), 681 Crosby, D. 612 (450), 626 Cross, G.G. 950 (7), 970
1317
Crossley, M.L. 648 (110), 661 Croteau, L.G. 1134 (506), 1165 Crotti, P. 544 (65, 68), 545 (72), 617, 618 Crouch, R.K. 1019 (94), 1037 Crouuzet, C. 825 (19 22), 835 Crow, F.W. 281 (94), 293 Crowfoot Hodgkin, D. 96 (50), 103 Crowley, T.O. 1136 (523), 1165 Cruickshank, F.R. 354 (53), 375 Crumbliss, A.L. 407 (158a c), 421 Crum Brown, A. 484 (38), 526 Cruse, H.W. 955 (40), 971 Crutzen, P.J. 1174 (8, 9), 1212 Csapo, J. 1093 (309), 1161 Csapokiss, Z. 1093 (309), 1161 Csizmadia, I.G. 236, 238 (173), 248 Csoregi, E. 1103 (357), 1162 Cu, A. 899 (24), 947 Cuevas, G. 15, 17 (23e), 81 Cullimore, P.A. 348 (30b), 373 Cum, G. 226 (120), 246 Cunkle, G.T. 56 (80b), 83 Cunnigham, A.J. 235 (159), 247 Cunningham, J.M. 978 (68), 995 Currell, L.J. 783 (93), 820 Curry, G.B. 1093 (311), 1161 Curtis, D.Y. 447 (179), 474 Curtiss, L.A. 208 (4), 244, 355 (55), 375, 384 (28a, 28b), 417 Curzon, E. 297 (9), 332 Cuscela, M. 578 (224), 621 Cygler, M. 53, 54 (78), 83, 866 (35), 889 Cyr, A. 845 (30), 855 Cyr, D.R. 795 (125), 820 Czapski, G. 829 (48), 836 Czerlinski, G.H. 670 (28), 680 Czeschka, K. 697 (87), 741 Dabek-Zlotorzynska, E. 1073 (169, 170), 1158 Daelemans, F.F. 1142 (560), 1166 Dagani, F. 1078 (204, 205), 1159 Dahlgren, R.A. 1046 (15), 1155 Dahn, H. 315 (61), 316 (61, 66), 317 (66), 333 Dai, M. 431 (67), 472 Dai, S. 232 (143), 247 Dai, W. 547 (77), 618 Dai-Ho, G. 714 (128), 742 Dais, P. 510 (199), 530 Dakabu, M. 234 (151), 247 Dale, J.A. 124 (76), 125 (76, 78), 155, 1089 (285, 286), 1160, 1161 Dalene, M. 1063 (97), 1081 (230, 231), 1157, 1159 Dale Pace, M. 782, 783 (90), 820 D’Alessio, A. 1175 (16), 1212 Dalinger, I.L. 550 (85), 618 Dalla Croce, P. 539 (39), 617
1318
Author index
Dallenbach-Toelke, K. 1086 (274), 1160 Dalpozzo, R. 608 (425, 426a, 426b), 625 Daly, J.J. 780 (80), 819 Damato, G. 1126 (451), 1164 Damewood, J.R. 60 (103d), 84 Dammel, R. 164 (32, 38), 165 (38), 166, 168 (32, 38), 202 Damoser, J. 1139 (535), 1166 Damour, D. 576 (217), 621 Danby, C.J. 168 (62), 202 Danehey, C.T.Jr. 46, 47 (71), 83 Danen, W.C. 684 (1), 740 D’Angelo, D.D. 977 (51), 995 Daniels, M.W. 933, 935, 938 (48), 947 Danielson, N.D. 1070 (149), 1158 Danis, P.O. 208, 210 212, 215 (17), 244 Dannenberg, J.J. 435 (97), 439 (130), 472, 473 Danovich, D. 161, 173 (19), 202 Danzer, M.H. 1118 (421), 1163 Dapporto, P. 396 (101), 420 Darbre, A. 1047 (32), 1155 Darbyshire, J.F. 669 (25), 680 Darchen, A. 447 (182, 184), 474, 838 (7a), 843 (18, 19), 848 (7a), 855 Darchen, S. 1011, 1019 (71), 1036 Darcy, M.G. 579 (237, 238), 621 Das, K.G. 289 (115), 294 Das, P.K. 738 (199), 745 Das, P.R. 259, 262 (43), 292 Das, S. 824 (6, 7), 835 Dasgupta, P.K. 1116 (416), 1163 Dashevskii, V.G. 363 (89), 377 Dassbjerg, K. 651 (136), 662 Daszkiewicz, Z. 593 (346), 623, 878 (76), 890 Date, M. 649 (120), 661 Date, T. 396 (93), 419 Datta, M. 1046 (13), 1155 Datta, M.H. 1118 (421), 1163 Dattolo, G. 630 (15), 633 (27), 659 Daugaard-Jenson, M. 1033 (202), 1039 Daun, J.K. 1046 (11), 1155 D’Auria, M. 777 (67 69), 781 (85), 819 Davalli, S. 50, 52, 53 (75), 83 Davey, J.F. 1067 (127), 1084 (257), 1157, 1160 David, J.Y. 1107 (379), 1162 Davidoff, A.J. 992 (127), 997 Davidson, E.R. 173 (79), 203 Davidson, M.G. 396 (92, 96), 419 Davidson, R.S. 684 (3), 685 (10), 693 (56), 695 (73, 74), 740, 741 Davidson, W.R. 165, 166 (44), 202, 232 (140), 247 Davies, C.J. 859 (3), 888 Davies, I.W. 598 (376), 624 Davies, J.S. 106 (2), 153, 1090 (294), 1161 Davies, J.W. 56 (80e), 83
Davies, K.J.A. 832 (59 62), 836 Davies, M. 426 (16), 470 Davies, M.M. 430 (56), 471 Davies, R.L. 1067 (129), 1157 Davies, S.R. 456 (222), 475 Davis, A.P. 412, 413 (196), 422 Davis, B. 239 (183), 248 Davis, F.J. 670 (29), 680 Davis, G.T. 491, 503, 504, 515, 517 (96, 97), 527 Davis, L.P. 192 (133), 204 Dawes, J.M. 209 (25), 244 Dawson, T.M. 992 (142, 143), 997 Dawson, V.L. 992 (142), 997 Day, R.J. 238 (176), 248 Deadwyler, G.H. 71 (120), 84 Deady, L.W. 878 (74), 890 Deakyne, C.A. 385 (43b, 43c), 418 Dean, J.R. 1134 (507), 1165 Deas, R.M. 1127 (454), 1164 Debenham, D.F. 669 (18), 680 De Bie, D.A. 1217 (13a), 1295 Debies, T. 171, 174 (71), 203 Debies, T.P. 188 (121), 204 Debnath, J. 1111 (398), 1163 DeBoer, J.E. 639 (60), 660 De Boer, Th.J. 695 (70), 741 De Bruyn, V.H. 759 (35b), 818 Deccouzon, M. 407 (160), 421 Dechat, T. 582 (269), 622 Deck, J. 1132 (492), 1165 Declemy, A. 697 (89), 741 Declercq, D. 697 (86), 741 DeClercq, D.R. 1046 (11), 1155 Decloitre, F. 1025 (137), 1038 Decouzon, M. 348 (28), 373, 406 (154), 421, 459 (244), 476, 499, 522 (138), 528, 1237, 1238 (84 86), 1284, 1285 (86), 1297 Dedeva, P. 192 (131), 204 Deeb, T.M. 599 (381), 624 Deeba, M. 538 (38), 617 DeEds, F. 1031 (178), 1039 Defelippis, M.R. 827 (37 40), 835 Defrees, D.D. 384 (27), 417 Dega-Szafran, Z. 430 (54), 431 (59), 436 (114), 471, 473 Degen, G.H. 1034 (205), 1039 De Jong, A.W.J. 695 (70), 741 De Jong, G.J. 1134 (511), 1165 Dekaban, G.A. 1027, 1028 (154), 1038 DeKimpe, N. 569 (191), 586 (296), 620, 622 Dekker, L. 883 (91), 891, 968 (63), 971 Delair, P. 845 (30), 855 Delbressine, L. 1012 (77), 1036 Del Cima, F. 1220 (28), 1295 De Leenheer, A.P. 1061 (92), 1156 De Leeuw, F.A.A.M. 57 (92), 83
Author index Delfini, M. 390 (62), 418 Delgado-Cobos, P. 283, 284 (100), 293 Delhalle, J. 218 (81), 245 Delker, G. 1116 (411), 1163 Dellaria, J.F. 650 (128), 654 (148), 657 (168), 661, 662 Dellaria, J.F.Jr. 574 (208), 621 Dell’Erba, C. 100 (93), 103 Delmas, D. 1098 (342), 1162 Delpeyroux, D. 4, 13 (16), 81 Delsignoret, M.E. 832 (59, 61), 836 De Marchis, M. 1078 (200), 1159 Dembech, P. 551 (93), 618 De Mendoza, J. 537 (23), 617 Demers, J.P. 595 (353), 624 Demko, D.M. 595 (353), 624 Demmelmair, H. 1059 (81), 1156 Dempsey, B. 381 (4b), 416, 491, 500 (107b), 527 Demura, T. 601 (385), 624, 1258, 1260 (140, 141), 1261 (141), 1299 Demuth, R. 188, 189, 191, 192 (125), 204 Dem’yanovich, V.M. 139 (115, 115), 156 Deng, Z. 153 (167), 157 Denhez, J.-P. 212 (43, 46, 48 50), 216 (48 50), 222 (43, 46, 48 50), 233 (145), 244, 245, 247 De Nicola, A. 583 (274), 622 Denison, P. 1108 (385, 386), 1163 Denisov, E.T. 401 (135), 420 Denner, L. 453 (207, 208), 475 Denny, W.A. 329 (111, 117), 330 (111), 334 Dent, A. 879 (77), 890 Dentener, F.J. 1174 (8, 9), 1212 Depaemelaere, S. 697 (86), 741 De Paz, J.L.G. 407 (161b), 408 (166, 167b), 421 De Pietro, S. 455 (212), 475 Depke, G. 268 (77, 79), 269 (79), 293 De Proft, W. 388 (58), 418 DePuy, C.H. 408 (167a), 421 De Queiroz, M.E.L.R. 1145 (572), 1166 Derguini, F. 141 (119), 142 (121), 156 Deril, G.M. 1078 (198), 1159 Derissen, J.L. 90, 93 (19), 102 De Roos, F.L. 217 (78), 245 De Rosa, M. 873 (62), 874 (63, 64), 890 Derrick, P.J. 208 (14), 212 (44), 214, 215 (14), 217 (79), 218 (84), 219 (89 91), 220 (90, 93 95, 104), 221 (84), 222 (44), 223 (44, 93), 224, 225 (44, 115), 227 229 (93, 129), 231 (136), 236 (171), 244 248 DeRubertis, F.R. 975 (19), 994 Deruiter, J. 1063 (99), 1071 (152), 1157, 1158 De Schryver, F.C. 694 (58, 59), 695 (71, 77), 697 (86), 741 Desclaux, R. 360 (80), 377
1319
Deselaers, K. 646 (101), 661 Deshpande, S.R. 285 (102), 293 Desilva, K. 1079 (216), 1159 De Sio, F. 780 (82), 819 Desiraju, G.R. 427 (28), 452 (197 200), 471, 475, 792 (117), 820 Desjardins, S. 845 (29), 855 Deslongchamps, P. 15, 17 (23c), 81 DesMarteau, D.D. 602 (389), 624, 1238 (93), 1297 Detter, L.D. 234 (156), 247 Deutsch, J. 592 (329), 623 Deutz, N.E.P. 1078 (196), 1159 De Vos, M.-J. 535 (12), 616 Dewar, M.J. 943 (69), 948 Dewar, M.J.S. 161 (18), 170 (65), 173 (18), 202, 203, 859 (8, 10), 889, 897 (21), 905 (31), 947 Dhaneshwar, N.N. 93, 96, 98 (25, 56), 102, 103 D’Hondt, L. 586 (296), 622 Diamantino, M.T.R.S. 753 (13), 817 D´ıas, T.G. 1139 (538), 1166 Diaz, M.J. 1025 (139), 1038 D´ıaz, T.G. 1140 (546), 1166 Di Bugno, C. 143 (125), 156 Dickel, B.de 1076 (186), 1159 Dickinson, C. 97 (65), 103, 329 (114), 334 Diehl, P. 312 (51), 316, 317 (66), 321 (94), 333, 334 Diem, M. 150 (153), 157 Diener, H. 631 (18), 644 (93), 659, 660 Diepold, C. 1003, 1005 1007, 1009, 1011, 1012, 1014, 1019, 1027, 1029, 1030 (36), 1035 Diestad, A.M.L. 236 (172), 248 Diestad, E.L. 236 (172), 248 Dieterich, D.A. 447 (179), 474 Dietrich, B. 390 (67), 419 Dietrich, C.O. 572 (200), 620 Dietz, A.G. 656 (164), 662 Dietze, P.E. 873 (61), 890 DiFuria, F. 405 (150b), 421 Diggle, A.W. 955 (41, 42), 956 (42), 971 Dignon, J. 1197 (107), 1214 Di Grazia, M. 286, 287 (105), 293 Dijkstra, G. 208 (6), 244 Dillard, J.G. 208, 210, 217, 237 (18), 244 Dillow, G.W. 257 (37), 258 (37, 38), 292, 385 (37b), 418 Dilts, R.V. 668 670, 672 (14), 680 Dimroth, K. 425 (6), 470 Ding, A. 978 (63), 995 Dinges, W. 571 (199), 620 Dingle, R. 641 (75), 660 Dinning, P.G. 1129 1131 (476), 1164 Diomede, L. 1085 (269), 1160
1320
Author index
Di Palo, V. 1081 (232), 1159 Dippy, J.F.J. 493 (115), 528 Di Renzo, F. 98 (77), 103 Dirkx, I.P. 484 (34), 526 Di Sanzo, F.P. 1046 (14), 1155 DiSilvio, M. 979 (76), 995 Distefano, G. 164 (37), 165, 166 (46), 173 (78), 175 (83), 178 (46), 191, 199 (130), 202 204 Dittmar, G. 657 (171), 662 Dittrich, K. 1094 (323), 1161 Divers, E. 679 (87), 682 Dix, L.R. 666 (2), 676 (67), 680, 681 Dixit, A.S. 871 (51), 890 Dixneuf, P.H. 591 (327), 595 (359a, 359b), 598 (374), 623, 624 Dixon, D.A. 90, 93 (13), 102, 384 (26), 417 Dixon, J.P. 1228 (74), 1297 Dixon, R. 1097 (336), 1162 Djerassi, C. 106 (7), 153, 227 (124), 246, 267 (75), 293 Djerassi, K. 206, 207, 233 (2c, 2e), 243 Djordjevic, M.V. 1150 (607, 609), 1151 (614, 617), 1167 Dobler, C. 130 (90), 155, 1112 (399), 1163 Dobratz, P.M. 370 (104), 378 Dobson, C.M. 322 (103), 334 Dockery, S.P. 977 (53), 995 Dodd, J.A. 385 (34a), 417 Dodsworth, D.J. 874 (64), 890 Doerr, R.C. 1186 (75), 1213 Doh, C.H. 543 (61), 617 Doherty, R.M. 381 (16b, 16c, 17d, 20b), 387 (53), 417, 418, 428 (42), 471, 1220 (42), 1222, 1238 (51), 1273, 1275, 1283 (178), 1296, 1299 Doi, E. 724 (165), 744 Doiron, C.E. 384 (30a), 417 Dole, A.J. 1220, 1222 (31a), 1296 Dolle, A. 98 (74), 103 D¨olle, B. 1003, 1007 1009, 1011, 1012 (33), 1035 Domalski, E.S. 338 (2d, 3, 5), 361 (2d), 372 Domanski, A. 593 (346), 623 Dombrovskii, A.V. 654 (147), 662 Domelsmith, L.N. 163, 164, 166, 179, 180 (28), 202 Domenicano, A. 98 (77), 103, 435 (100), 472 Domingue, R.P. 43 (68), 83 Donati, D. 780 (82), 819 Donchi, K.F. 212 (44), 218 (84), 219 (90), 220 (90, 104), 221 (84), 222 225 (44), 236 (171), 244 246, 248 Donnelly, D.M.X. 584 (279), 622 D’Onofrio, F. 777 (68), 781 (85), 819 Dopp, D. 693 (55), 741, 759 (36), 762 (38a, 38b, 39, 40), 763 (41), 818
Doraiswamy, S. 753 (10), 817 Dorey, R.C. 281 (94), 923 Dorff, P. 576 (216), 621 Dorie, J. 300 (15), 317 (77), 332, 334 D¨orler, G. 639 (54), 660 Dorminy, M. 1024 (123), 1037 Dorofeeva, O.V. 8 (14a, 14b), 24 (14a, 14b, 37), 81, 82 Dorr, F. 685 (19), 740 D¨orre, R. 273, 274 (84), 293 Dorwin, E. 1217 (6a), 1295 Dosch, H.-M. 1027 (155), 1038 Dossena, A. 1091 (300), 1161 Dou, L. 1067, 1076 (126), 1157 Doubleday, A. 37 (56), 82 Dougherty, D. 188 (114), 204 Dougherty, R.C. 943 (69), 948 Doughty, E. 1126, 1127, 1143 (446), 1164 Douglas, J.E. 165, 166 (44), 202 Doussot, J. 537 (31), 617 Dovichi, N.J. 1096 (330, 331), 1161 Dowd, W. 945 (70), 948 Doyle, M.P. 639 (60), 640 (68), 650 (128), 654 (148), 657 (168), 660 662, 667 (8), 675 (62), 680, 681 Drago, R.S. 445 (166, 167), 474 Draxl, K. 208, 210, 217, 237 (18), 244 Drazen, J.M. 673 (44), 681 Dressel, J. 1187 (80), 1213 Dressler, M. 1047 (29), 1155 Drevinkova, D. 1138 (529), 1166 Drew, M.G.B. 59 (100, 101), 60 (101), 83, 453 (209), 475 Drewello, T. 211 (40), 244, 251 (6), 253 255, 260 (15), 291, 292 Drewlies, R. 547 (79), 618 Drewniak, M. 546 (76), 618 Drnevich, D. 1083 (252), 1160 Drolet, D. 1145 (580), 1167 Drucker, G.E. 398 (115), 410 (182), 420, 422 Drummond, D.F. 384 (30b), 417 Drushel, H.V. 1047 (39), 1155 Du, S. 557 (124, 125), 619 Du, Z. 80 (135), 84 Duarte, M. 88, 90 (8), 102 Duce, P.P. 381 (17a c), 417, 428 (41), 471 Duckworth, C.A. 590 (322), 623 Dudek, V. 112, 113 (41), 154 Duffy, C. 991 (117), 996 Duinker, J.C. 1079 (209), 1159 Duisenberg, A.J.M. 91, 93 (20), 102 Dull, D.L. 124, 125 (76), 155, 1089 (285), 1160 Dumanovic, D. 447 (183), 474, 838 (4b), 855 Duncan, W.P. 1177 (36), 1212 Dungthai, S. 318 (78), 334 Dunham, R.C. 35 (50), 82
Author index Dunitz, J.D. 60 (104), 84, 90 (11), 96 (49), 102 Dunkin, D.B. 235 (161), 247 Dunn, D.A. 688 (35, 36), 740 Dunn, T.J. 570 (196), 620 Duong, K.D. 1081 (227, 228), 1159 Dupas, S. 1068 (139), 1158 Dupont, V. 1175 (10), 1212 Durant, F. 100 (90), 103 Durantini, E. 463 (254), 476, 1245 1247, 1266 (115a), 1298 Durantini, E.N. 1220 (33), 1296 Durie, A. 969 (64), 971 Durieux, M.E. 977 (51), 995 Durr, H. 738 (200a), 745 Durst, H.D. 563 (154), 619 Durst, R.A. 1100 (348), 1162 Durst, T. 411 (189), 414 (202), 422, 737 (198), 745 Dusick, A. 1068 (140), 1158 Dutra, A. 673 (39), 681 Duttachowdhury, S.K. 562 (151), 619 Dutuit, O. 262 (57), 292 Dzharimova, E.S. 353 (50), 375 Dziembowska, T. 436 (120), 473
Eargle, D.C. 1189 (93), 1214 Earle, C.W. 1096 (331), 1161 Eastland, G.W. 824 (5), 835 Eastwood, G.B.M. 290 (117), 294 Eaton, P.E. 604, 605 (404), 625 Ebdon, L. 1134 (507), 1165 Eberson, L. 455 (218), 456 (220), 475, 790 (108, 109b, 111b, 111c, 112 114), 820, 883 (92), 891, 954 (34 39), 969 (36), 970 (37, 38), 971 Ebertova, H. 1135 (516), 1165 Ebsworth, E.A.V. 164 (39), 202 Echavarren, A. 392 (77), 419 Echavarren, A.M. 537 (23), 617 Echterhoff, A.M. 1139 (536), 1166 Eder, H. 772 (61), 819 Edge, G.J. 797 (131), 820 Edgecombe, K.E. 411 (190, 191), 422 Edgell, K.W. 1061 (90), 1156 Edwards, D.I. 1032 (195), 1039 Edwards, J.C. 673 (42), 681, 975 (25 27), 994 Edwards, J.O. 466 (265), 476, 678 (84), 682 Edwards, M.L. 543 (58), 617 Efremov, D.A. 604 (401), 625 Egawa, T. 616 (465), 626 Egberink, R.J.M. 969 (64), 971 Egdell, R. 188, 191 (128), 204 Egger, N. 588 (306), 623 Eggermont, E. 1078 (201), 1159 Eggimann, T. 148, 149, 152 (149, 150), 157
1321
Eggimann, W. 457 (235), 476 Egolf, R.A. 834 (73), 836 Egorov, M.P. 457 (230), 475, 1217, 1220 (11b), 1295 Egsgaard, H. 212, 222 225 (44), 244, 251 (6), 253, 254 (15), 255 (15, 29), 259 (44 46), 260 (15, 50), 262 (55), 263, 264 (61), 290 (45), 291, 292 Eguchi, M. 543 (57), 617 Ehlhardt, W.J. 1032 (197), 1039 Ehrenberg, M. 90, 93 (18), 102 Ehrenson, S. 490 (90 92), 491 (90), 498 (91), 503 (90), 504 (92), 521 (91, 92), 522 (92), 527, 642 (83), 660 Ehrlich, S.H. 1100 (347), 1162 Eigen, M. 435 (105), 472 Einhorn, C. 594 (349), 624 Einhorn, J. 583 (274), 594 (349), 622, 624 Einstein, F.W.B. 329 (116), 334, 950 (4), 970 Eisch, J.J. 554 (111), 618 Eisenbrand, G. 1188 (87, 88), 1214 Eisenthal, K.B. 446 (174), 474, 694 (75), 741 Eissa, N.T. 992 (130), 997 Eizawa, H. 978 (59, 66), 995 Elad, D. 722 (153f), 743 ELAmin, B. 119 (60), 154 Eland, J.H.D. 160 (9), 168 (62), 201, 202 Elbel, S. 188, 189, 191, 192 (125), 204, 260 (50), 292 Elbert, J.E. 729 (174), 744 El-Brashy, A.M. 1099 (343), 1140 (545, 550), 1162, 1166 El-Din, M.S. 1140 (545, 549), 1166 El´egant, L. 381 (13), 416 Elferink, V.H.M. 718 (145), 743 El Gaied, M.M. 597 (371), 624 Elguero, J. 407 (161b), 408 (165a, 165b, 166, 167b, 168), 421, 435 (106), 472, 524 (253), 531, 780 (81), 819 Elias, A.J. 584 (289), 622 Eliel, E.L. 1009 (66), 1036 Eliet, E.L. 297 (10), 332 Elisei, F. 778 (71), 819 El Kaaim, L. 613 (451), 626 El-Kholy, A.E. 439 (134), 473 Ellaithy, M.M. 846 (36c), 856 Ellencweig, A. 15, 16 (26b), 82 Ellerbrock, R. 192 (138), 204 Elliott, J.D. 542 (52), 617 Elliott, R.C. 654 (148), 662 Ellis, A.F. 57 (90a), 83 Ellis, M.K. 1001, 1003, 1007, 1009, 1011, 1012 (29), 1028 (29, 157), 1029 (157), 1035, 1038 Ellis, R. 1140 (552), 1166 Ellison, G.B. 360 (78), 376, 382 (23), 417
1322
Author index
Elliston, K. 992 (131), 997 Ellsworth, T.R. 1045 (4), 1154 Elofson, R.M. 653 (141), 662 Elquero, J. 426 (13), 470, 631 (17), 659 Emmrich, M. 1116 (406), 1127 (459), 1163, 1164 Emokpae, T.A. 1243, 1244 (109), 1287 (199), 1290 (198 200), 1291 (198), 1293 (199), 1294 (109), 1298, 1300 Emsley, J. 428 (36), 471, 1294 (201), 1300 Emsley, J.W. 320 (89), 321 (92), 334 Emson, P. 978 (70), 979 (77), 995 Emson, P.C. 992 (135), 997 Emster, K.van 654 (146), 662 Enders, D. 586 (295), 622 Endo, Y. 872 (56), 873 (57), 890 Engel, A. 628 (6), 659 Engel, M.H. 1049 (68), 1060 (86), 1156 Engel, P.S. 649 (119), 655 (159), 661, 662 Engleman, J.A. 686, 699, 700, 706 (24), 740 Engler, E.M. 3 5, 29 (1c), 81, 356 (60), 375 Enholm, E.J. 550 (83), 618 Enikolopyan, N.S. 352 (43), 374 Entrena, A. 60, 62 (105), 84 Entwistle, D.A. 589 (310), 623 Eon-Burgot, G. 1107 (380), 1162 Epp, E.R. 1031 (182), 1039 Eppers, O. 396 (87), 419 Epstein, S. 1060 (87, 88), 1156 Erdik, E. 552, 553 (103), 618 Erickson, B.W. 739 (207), 745 Ermisch, A. 1079 (207), 1159 Ernst, R.R. 297 (11), 332 Ernst, T.D. 551 (88), 618 Ernsting, N.P. 188 191 (126), 204, 803 (137, 139), 821 Errser, R.S. 1084 (257), 1160 Ershov, V.V. 637, 639 (44), 660 Ersser, R.S. 1067 (127), 1157 Ertl, P. 499, 522 (138), 528 Eschenmoser, A. 427 (20), 470 Eskew, D.L. 1048 (59), 1156 Eslami, M. 1074 (181), 1158 Esp´ın, M. 846 (35), 855 Espinosa, A. 60, 62 (105), 84 Espy, H.H. 1016 (88), 1037 Essefar, M. 408 (168), 421 Esteve-Romero, J.S. 1088 (278), 1160 Estler, C.J. 1001 (32), 1035 Esumi, H. 992 (126), 997 Etter, M.C. 98 (68, 73), 103, 428 (39), 433 (78), 471, 472 Eustace, S.J. 1012 (78), 1036 Evain, E.J. 581 (260), 622 Evangelatos, G.P. 1099 (345, 346), 1162 Evans, D.A. 119 (56, 59), 120 (59), 154 Evans, D.H. 832 (63, 64), 836, 839 (8a, 8b),
850 (8b, 52a, 52b), 851 (8a, 8b, 56 58), 852 (59, 60), 855, 856 Evans, F.E. 1003, 1004, 1009, 1011, 1012, 1031 (35), 1035, 1132 (492), 1165 Evans, J.C. 35 (49), 82 Evans, P.D. 1063 (96), 1157 Evans, W.H. 338 (3, 5), 372 Even, U. 426 (11), 470 Evrard, G. 100 (90), 103 Ewbank, J.D. 24 (36), 56 (85), 82, 83 Ewing, D.F. 302 (23), 303 (23, 24), 332, 491, 503, 504 (98), 527 Exner, O. 348 (28), 373, 405 (149), 406 (154), 407 (149, 160), 421, 487 (69, 74, 77), 488 (74, 78), 490 (77, 94), 494 (122, 123), 495 (77), 496 (78, 128), 499 (138), 514, 515, 517, 518 (78), 519 (78, 237), 521 (78, 94), 522 (77, 138, 240 243), 526 528, 531 Eyer, P. 1001 (18, 19, 22 27, 31), 1003 (18, 22 25, 34, 36, 39, 40), 1004 (24, 26, 45), 1005 (25, 27, 36, 40), 1006 (18, 22, 36), 1007 (18, 22, 24, 25, 36, 39, 40), 1008 (18, 25), 1009 (18, 22, 24, 26, 27, 36, 40, 63), 1010 (18, 22, 24 26, 63, 68), 1011 (18, 22, 24 26, 36, 40), 1012 (24 26, 36, 39), 1013 (24), 1014 (24, 26, 36, 45, 68), 1015 (26, 45, 68), 1016 1018 (68), 1019 (36, 45, 68, 92), 1020 (19, 27, 34, 40, 92, 100), 1022 (34, 40, 92, 100, 113, 114), 1023 (19), 1025 (22, 23, 133), 1026 (25), 1027 (19, 25, 36), 1029 (25, 36, 39, 40, 68, 163 165, 169, 170), 1030 (25, 36, 174), 1032 (189), 1035 1039 Eyring, H. 894 (9), 947 Ezeani, C. 467 (272, 273), 476, 1262 (150), 1264 (150, 154), 1269 (150), 1299 Faber, D.H. 3 5, 29 (1d), 81 Fabiano, E. 538 (35), 617 Fabrizio, E.C.R.de 643 (86), 660 Fackler, J. 673 (44), 681 Fadlallah, S. 1145 (580), 1167 Faerman, C.H. 1241, 1242 (105a), 1298 Fahey, R.C. 896 (14), 947 Fail, J. 96 (46), 102 Fajen, J.M. 1184 (64, 68), 1213 Falco, P.C. 1097 (339), 1162 Falicki, S. 825 (24), 835 Fan, E. 428, 430 (35), 471 Fan, J. 1151 (614), 1167 Fan, J.G. 1150 (607), 1167 Fananas, F.J. 396 (88), 419 Fang, J.M. 581 (259), 622 Faraggi, M. 827 (37 40), 828 (41), 835 Farah, L. 1267 (169), 1299 Farah, S. 1032 (194), 1039 Farah, S.F. 1007, 1015, 1032 (57), 1036
Author index Farina, D.A. 1148 (601), 1167 Farkas, E. 406 (155), 421 Farmayan, W.F. 1175 (18), 1212 Farmer, M.L. 589 (312), 623 Farmer, P.B. 1021 (104), 1037 Farnell, L.F. 331 (128), 335 Farrel, P.G. 416 (212), 422, 456 (225), 475 Farrell, N. 329 (116), 334 Farrell, P.G. 415 (203, 207 210), 422, 509 (188, 189), 529, 530 Farwell, S.O. 1047 (46), 1155 Fasani, E. 773 (62), 819 Fateyev, O.V. 413 (199), 422 Faul, M.M. 119 (56, 59), 120 (59), 154 Faulkner, T.R. 147 (139), 156 Favaro, G. 1147 (596), 1148 (597), 1167 Favero, L. 544 (68), 545 (72), 617, 618 Fawcett, F.S. 515, 519 (230), 530 Fazio, M.J. 738 (201), 745 Federici, F. 1091 (299), 1161 Fedotov, M.A. 306, 311, 313 (38), 315 (59), 333 Fehsenfeld, F.C. 235 (161), 247 Feier, U. 1058 (78), 1156 Feiring, A.E. 863 (24), 889 Feldman, K.S. 950 (13), 970 Feldman, P.L. 669 (21), 680, 985 (91, 95), 991 (113), 996 Feldman, V.I. 824 (2, 3), 835 Feltes, J. 1125 (445), 1127 (445, 455), 1133 (498), 1136 (445), 1164, 1165 Feltkamp, H. 37, 38, 41 (55), 82 Felton, J.S. 1033 (199, 200), 1039 Feng, L.B. 810 (154, 155), 821 Feng, R. 208, 210 212, 215 (17), 244 Feng, X. 1060 (88), 1156 Fenselau, C. 227 (124), 246, 1024 (127), 1037, 1284, 1285 (194a), 1300 Ferguson, D.M. 59 (102), 83 Ferguson, E.E. 262 (54), 292 Ferguson, I.J. 57 (89), 83 Feringa, B.L. 125 (79), 127 (81), 128 (85), 155, 585 (291), 622, 1110 (393 396), 1163 Fermo, I. 1085 (269), 1160 Fern´andez, B. 15, 16 (26e), 82 Fernandez, I. 615 (461), 626 Fernandez, S. 592 (333), 623 Fern´andez-Alba, A. 1078, 1079 (195), 1159 Fern´andez-Band, B. 1137 (527), 1166 Feron, V.J. 1188 (86), 1214 Ferraccioli, R. 398 (112), 420 Ferrannini, E. 1085 (261), 1160 Ferrao, M.L.C.C.H. 349 (32, 33), 374 Ferretti, V. 426 (15), 435 (103), 470, 472 Ferrige, A.G. 975, 976 (11), 994 Ferris, D.C. 445 (166), 474 Ferruti, R. 390 (62), 418
1323
Fesen, M.P. 1024 (125), 1037 Fetterolf, D.D. 238 (180), 248 Fetzer, S. 188 (119), 204 Feuer, H. 534 (1b, 1c), 604 (400), 616, 625 Fiat, D. 312 (53), 333 Fickling, M.M. 516 (233), 530 Fiddler, W. 1144 (569), 1145 (577 579, 581), 1166, 1167, 1189 (94, 97), 1214 Fiddler, W.J. 1186 (75), 1213 Field, F.H. 208, 210, 217 (18), 234 (154), 237 (18), 244, 247 Field, K.W. 552 (102), 618 Field, L. 668 670, 672 (14), 680 Fields, E.K. 265 (68), 293 Fierz-David, H.E. 628, 634 (4), 658 Figueredo, M. 754 (14), 817 Figuredo, M. 758 (30, 31), 818 Fijalek, Z. 447 (183, 186), 474, 838 (4b), 855, 1005 (50), 1036 Fiksdahl, A. 109 (32), 154 Filippini, G. 433 (73), 472 Filippo, J.S. 877 (72), 890 Finch, A. 366, 369, 370 (98), 378 Finch, A.F. 1019 (90), 1037 Fine, D.H. 1047 (41), 1155, 1184 (64, 65), 1189 (100), 1213, 1214 Finet, J.P. 538 (36), 584 (278, 279), 617, 622 Fingas, M. 255 (25), 292 Fink, M. 767 (53), 819 Finkam, M. 586 (295), 622 Finkelstein, M. 430 (55), 440 (55, 137), 471, 473 Finley, K.T. 358 (76), 376 Fiorani, G.F.M. 1147 (595, 596), 1148 (597), 1167 Fischbach, T. 1029 (161), 1038 Fischer, A. 510 (205), 516 (233), 530, 792 (116), 820, 880 (82), 890, 950 (3 12), 951 (10, 11), 958 (9, 46, 50), 964 (5), 967 (58), 970, 971 Fischer, B. 717 (140), 743 Fischer, E. 447 (178), 474, 778 (73), 806 (146), 819, 821 Fischer, H. 95 (43), 102 Fischer, M. 240 (185), 248, 722 (153a), 743 Fischer, V. 1019 (91), 1037 Fischer, W. 512 (219), 530 Fish, L.L. 407 (158c), 421 Fishbein, J. 645 (100), 661 Fishbein, J.C. 868 (41), 889 Fisher, A.A. 977 (53), 995 Fisher, G. 1089 (281), 1160 Fisher, G.B. 536 (18), 617 Fisher, R.D. 945 (70), 948 Fisher, T.A. 658 (175), 663 Fishman, M.C. 992 (143), 997 Fishwick, B.R. 636 (34), 659
1324
Author index
Fityygibbones, L.J. 669 (23), 680 Fitz, D.R. 1176 (27), 1212 Fitzner, J.N. 575 (209), 621 Fitzpatrick, J. 629 (12), 659 Fitzpatrick, P.A. 108 (29), 154 Fitzsimons, M.F. 1064 (104), 1157 Flad, D. 722 (154a, 154b), 743 Flagan, R.C. 1180 (59), 1213 Flament, J.P. 232 (142), 247 Flammang, R. 232 (142), 247, 274, 275 (85), 293 Flammang-Barbieux, M. 274, 275 (85), 293 Flavian, S. 436 (119), 473 Flechtner, T.W. 764 (42), 765 (43), 818 Fleischman, S.H. 46 (70), 83 Fleischmann, E.D. 411, 412 (194), 422 Fleming, I. 220, 232 (101), 246, 642 (81), 660 Fleming Mattox, T. 444 (163), 474 Fletcher, D.S. 993 (147), 997 Flippen-Anderson, J.L. 97 (60, 61), 101 (61), 103, 606 (414), 625 Floegel, R. 315, 316 (61), 333 Flˆorencio, H. 251 (6), 253 255, 260 (15), 291, 292 Flowers, M. 979 (72), 995 Fl¨urscheim, B. 484, 485 (41), 526 Foces-Foces, C. 435 (106), 472 Fogel, P. 415 (209), 422 Fokkens, R.H. 220 (94), 231 (135), 246, 247, 260, 263 (51), 292 Folestad, S. 1077 (193), 1093 (309), 1159, 1161 Foley, S.A. 100 (94), 103 Fonrodona, G. 1225 (67), 1297 Font, G. 1048 (55), 1156 Fontana, L.P. 133 (102, 105), 134 136 (105), 148 (144, 146), 155 157 Fontecave, M. 669 (16, 22), 680 Foote, C.S. 781 (84), 819 Forbes, D.C. 550 (83), 618 Forbes, E.J. 635 (30), 659 Ford, G.P. 491, 503 (101), 527 Ford, M.E. 538 (38), 617 Ford, P.C. 669 (25), 680 Forlani, L. 426 (14), 445 (164), 454 (211), 455 (211, 212), 459 (240, 241, 245), 462 (253), 463 (253, 257, 258), 464 (245, 258 262), 465 (264), 466 (253, 260), 467 (259, 270), 468 (245, 259), 470, 474 476, 1217, 1245 (8), 1247, 1249 (123), 1250 (125), 1251 1253 (129), 1262 (149a c), 1278 (149a c, 184a, 184b), 1279 (149b, 184a, 184b, 185), 1280 (184a, 184b, 186, 187), 1281 (188), 1285 (184a, 184b), 1289 (123, 125), 1295, 1298 1300 Formaggio, F. 142 (124), 156 Formosinho, S.J. 409 (180, 181), 422
Fornarini, S. 232 (141), 247 Forrest, D. 803 (141), 821 Forsberg, J.H. 590 (322), 623 Forst, W. 221 (106), 246 F¨orstermann, U. 977 (46), 995 Foss, O. 675 (61), 681 Foster, D. 1001, 1003, 1007, 1009, 1011, 1012, 1028 (29), 1035 Foster, P.M.D. 1028, 1029 (157), 1038 Foster, R. 456 (224), 475 Foster, R.F. 220 (105), 246, 439 441, 460, 462 (132), 473 F¨ostermann, U. 977, 978 (49), 995 Fouad, F.M. 415 (210), 422 Foubelo, F. 396 (88), 419 Foulds, G.J. 456 (220), 475, 954 (39), 971 Foulkes, M.E. 1134 (507), 1165 Fournier, J. 598 (374), 624 Fournier, M. 1145 (580), 1167 Fowler, M. 991 (116), 996 Fox, D. 384 (28a), 417 Fox, I.R. 491, 503, 504, 515, 517 (96, 97), 527 Fox, S.D. 1149 (605), 1167 Fracasini, M.C. 1220 (32b), 1296 Fraefel, A. 251 (9), 291 Fraisse, D. 289 (115), 294 Francis, J.T. 220, 221 (99), 246 Francis, P.L. 976, 978, 980 (39), 994 Francis, S.A. 673 (45), 681 Francke, J.P. 1048 (57), 1156 Francotte, E. 106 (15), 153 Frandsen, H. 1012, 1033 (84), 1036 Franke, S. 1127 (460), 1164 Frankenbach, G.M. 98 (73), 103 Frankenberger, W.T. 1073 (167, 168), 1158 Frankhauser, J.E. 575 (209), 621 Frank-Kamenetskaya, O.V. 94, 100 (32), 102 Franklin, J.L. 208, 210, 217, 237 (18), 244 Franklin, N.C. 37, 38, 41 (55), 82 Frascerra, S. 1085 (261), 1160 Fraser, R.R. 128 (84), 155, 312 (55), 333, 398 (116), 399 (121), 420 Fr¨ater, G. 860 (18), 889 Fratinden, A.V. 1134 (505), 1165 Frayssinet, C. 1025 (137), 1038 Frazier, J. 544 (66), 617 Frechet, J.M.J. 584 (280), 622, 767 (52b), 819 Frederick, R.C. 875 (66), 890 Freedman, H.H. 580 (242), 621 Freedman, T.B. 148 (146), 150 (152, 154 156), 153 (167), 157 Freeman, H.S. 1073 (164), 1158 Freeman, R. 297 (13), 332 Freemantle, M. 107 (23), 154 Frena, V. 1236, 1266 (160), 1299 Frenking, G. 208 (10), 234 (150), 244, 247, 396 (100), 420
Author index Frenna, V. 388 (56), 418, 1262, 1266 (152), 1299 Frensham, A.B. 1067 (129), 1157 Frey, H. 788 (104), 820 Frey-Forgues, S. 697 (88), 741 Fridovich, I. 992 (138), 997 Fried, B. 1069 (141), 1158 Fried, H.E. 403 (140), 407 (159), 421 Friedrich, I.E. 402 (130), 420 Frierson, M.R. 5, 16, 22 (8), 81 Friesen, M.D. 1066 (115), 1157 Friess, H.A. 670 (28), 680 Frigo, T.B. 56 (80a), 83 Frikha, M.G. 1098 (342), 1162 Fripiat, J.C. 100 (90), 103 Fritz, G. 733 (183d), 744 Fritzsche, C.J. 481 (10), 525 Frolow, F. 1108 (388), 1163 Fronza, G. 321 (93), 334 Fronzoni, G. 192 (131), 204 Frost, D.C. 166 (56), 202, 290 (116), 294 Frost, D.I. 1059 (82), 1156 Frund, R. 321 (95), 334 Frutos, J.C. 126, 127 (80), 155, 1111 (397), 1163 Fruttero, R. 324 (104), 334 Fry, A. 895, 896, 936 (11), 947 Fry, A.J. 838 (1, 2), 840 (1, 13), 844 (24), 848 (45), 850 (51), 854 856 Fry, S.E. 1220 (36), 1296 Fu, C. 1148 (604), 1167 Fu, P.P. 1129 (472), 1164 Fu, S.-C.J. 107 (26), 154 Fuchigami, T. 1095 (325), 1161 Fuchs, B. 14 (22a, 22b), 15, 16 (22a, 22b, 26b-d), 17 (22a, 22b), 18 (22b), 19 (22a, 22b), 20 (22a, 27 29), 21 (22a), 81, 82 Fuchs, J. 1185 (72), 1213 Fugassa, E. 1078 (200), 1159 Fujie, S. 736 (192b), 745 Fujii, H. 452 (196), 475, 824 (12), 835, 1022 (116, 117), 1037 Fujii, M. 650 (126), 661 Fujii, S. 552 (101), 618 Fujimori, K. 866 (33), 889 Fujinari, E.M. 1047 (50), 1048 (56), 1070 (150), 1155, 1156, 1158 Fujinuma, H. 1218, 1219, 1237 (21b), 1295 Fujinuma, K. 1083 (245), 1160 Fujio, M. 387 (52a), 418, 496, 505 (131), 524 (254), 528, 531 Fujisawa, H. 983 (81), 996 Fujita, H. 598 (375), 624 Fujita, K. 848 (45), 856 Fujita, T. 306 (34), 333, 506 (173), 529 Fujita, Y. 1104 (364), 1162 Fujitaki, J.M. 1097 (336), 1162
1325
Fujiwara, H. 1090 (297), 1161 Fujiwara, K. 880 (83), 890, 952 (17), 970 Fujiwara, M. 543 (64), 617 Fujiwara, S. 1108 (389), 1163 Fujiwara, Y. 654 (151), 662 Fujiyama, Y. 604 (395), 624 Fukase, K. 852 (61), 856 Fukoto, J.M. 993 (144), 997 Fukuda, E.K. 436 (117), 473 Fukuhara, G. 1097 (338), 1162 Fukuhara, K. 1131 (487), 1165 Fukuhara, T. 651 (132, 133), 656 (166), 657 (132), 661, 662 Fukui, K. 220, 232 (100), 246 Fukumoto, T. 868 (42), 889 Fukushima, D. 666, 667, 670 (6), 672 (6, 34), 680 Fukushima, K. 57 (88), 83 Fukushima, T. 1081 (233), 1091 (301 303), 1159, 1161 Fukuto, J.M. 990 (108, 111), 991 (114), 996 Fukuyo, M. 502 (147), 529 Fukuzumi, S. 749 (2, 3a, 3b), 817 Fulco, A.J. 984 (88), 996 Fulisch, M. 992 (141), 997 Fulk, G.E. 1197 (105), 1214 Fuller, D.J. 396 (86b, 89, 91e), 419 Fuller, J.C. 536 (18), 617 Fulton, K.L. 456 (220), 475, 954 (39), 971 Fultz, E. 1033 (201), 1039 Fung, H. 673 (48), 681 Fung, H.-L. 673 (47), 681, 977 (55), 995 Furchgott, R.F. 974 (1), 975 (5, 13 16), 993, 994 Furfine, E.S. 991 (116, 117), 996 Furguson, E.E. 235 (161), 247 Furin, G.G. 306, 311, 313 (38), 315 (59), (86), 333, 334, 866 (36), 889 Furlanetto, S. 1116 (409), 1163 Furlong, J.J.P. 396 (98), 419 Furst, P. 1076 (188), 1159 Furukawa, J. 358 (73), 376 Furukawa, M. 551 (94), 618 Furuya, Y. 1000 (1), 1035 Fuß, W. 164, 166 (43), 202 Futrell, J.H. 220 (103), 246 Fyles, D.L. 950, 951 (10, 11), 970
Gabe, E.J. 93, 100 (26), 102, 453 (205), 475 Gaboriaud, R. 1222 (49a, 49b), 1296 Gadallah, F.F. 653 (141), 662 Gaffield, W. 144 (132), 156 Gage, D.A. 1066 (119), 1157 Gage, D.R. 1047 (46), 1155 Gagjee, P. 1097 (334), 1162
1326
Author index
Gahr, M. 686 (24, 31), 687 (31), 697 (83), 699 (24), 700 (24, 99), 701, 704 (99), 706 (24), 740 742 Gaillard, Y. 1063 (100), 1157 Gaind, V.S. 1065 (107 109), 1157 Gainza, A.H. 1100 (350), 1162 Gaitonde, C.D. 1074 (184), 1158 Gal, J.-F. 348 (28), 373, 381 (13, 19, 20b), 384 (33b), 387 (51, 55), 406 (154), 407 (160), 416 418, 421, 499 (138), 505 (158), 522 (138), 524 (254), 528, 529, 531 Gal, J.F. 428 (42), 459 (244), 471, 476, 1237, 1238 (85, 86), 1284, 1285 (86), 1297 Gal´an, A. 392 (77), 419, 537 (23), 584 (284), 617, 622 Gal´an-Estella, F. 1128 (465), 1164 Galasso, V. 186, 187 (109), 204 Galaverna, G. 1091 (300), 1161 Galaverna, N.S. 440 (140), 473 Galceran, M.T. 1129 (474), 1130 (483), 1164, 1165 Gal’chenko, G.L. 347 (25), 373 Galera, M.M. 1139 (538), 1166 Galezowski, W. 460 (249), 476 Galianoroth, A.S. 396 (86b), 419 Galiazzo, G. 778 (71), 819 Galkin, V.I. 506 (175), 529 Gallagher, T. 598 (376), 624 Gallardo, I. 756 (23), 818, 846 (35), 855 Gallas, J.K. 556 (121), 619 Galle, J.E. 587 (300), 622 Gallego, M.G. 716 (136 138), 717 (144), 718 (146, 148), 743 Gallemann, D. 1004 (45), 1007 (56), 1009 (63), 1010 (63, 68), 1014, 1015 (45, 56, 68), 1016 (56, 68), 1017 (68), 1018 (56, 68), 1019 (45, 56, 68), 1029 (56, 68, 163 165, 170), 1036, 1038 Galli, C. 165 167 (24), 202, 649, 651 (116, 117), 653 (117), 661 Gallo, M.A. 60, 62 (105), 84 Gallo, R. 4, 13 (16), 81 Gallon, A.A. 1142 (558), 1166 Galloway, W.J. 510 (205), 530 Galoux, M. 1076 (186), 1159 Gamache, P. 1071 (153), 1158 Gamba, A. 398 (107), 420 Gamer, G. 434 (92), 472, 1266 (157), 1299 Gan, T.-H. 166 (60), 202 Gandler, J.R. 508 (187), 529, 1228, 1232 1235, 1239 (77), 1297 Gandour, R.D. 70 (117a, 117b), 84 Ganem, B. 604 (397), 625 Gange, D. 1152 (622), 1168 Gangolli, A.D. 1188 (86), 1214 Ganguly, S. 543 (60), 617
Gannett, P.M. 56 (80b), 83 Gao, C.X. 1083 (243, 244), 1160 Garbow, J.R. 322 (99), 334 Garcia, E. 94 (33), 102 Garcia, F.V. 1047 (25), 1155 Garcia, J. 573 (203), 620 ´ Garc´ıa-Alvarez-Coque, M.C. 1088 (278), 1160 Garc´ıa-B´aez, E. 1109 (392), 1163 Garcia-Espa˜na, E. 391 396, (64 66, 101), 418, 419, 420 Gard, J.-C. 450 (193), 474 Gardiner, T.M. 217 (79), 245 Gardner, C. 1089 (281), 1160 Gardner, P.J. 366, 369, 370 (98), 378 Gardner, W.S. 1060 (85), 1079 (211), 1156, 1159 Gargano, P. 165 167 (24), 202 Gargaro, A.R. 152 (165, 166), 153 (165, 166, 168), 157 Gargiulo, D. 139 (116, 117), 141 (116, 117, 119), 142 (121), 156 Gariepy, K.C. 1071 (153), 1158 Garito, A.F. 94 (30), 102 Garley, M. 675 (63), 681 Garley, M.S. 678 (85), 682 Garner, W.E. 348 (30a), 361, 362, 367, 371 (84), 373, 377 Garo, A. 1175 (17), 1212 Garren, L. 1066 (115), 1157 Garrido, D. 1241, 1242 (105b), 1298 Garrido Fern´andez, A. 1083 (248), 1160 Garst, R.H. 1268 (171), 1299 Garst, R.J. 1216, 1217, 1278 (2a, 2b), 1295 Garthwaite, J. 976 (40), 994 Garvey, E.P. 991 (116, 117), 992 (132), 996, 997 Gasco, A. 324 (104), 334 Gascon, J. 1047 (52), 1156 Gase, M.B. 587 (298), 622 Gassman, P.G. 510 (200, 201), 530, 875 (65 67), 890 Gaston, B. 673 (44), 681 Gatermann, R. 1127 (460), 1164 Gates, R.A. 1145 (577), 1167 Gatten, R.A. 1047 (35), 1155 Gatti, C. 398 (107), 420 Gauthier, S. 584 (280), 622 Gautier-Luneau, I. 437 (122), 473 Gavezzotti, A. 433 (73), 472 Gawinecki, R. 454 (210), 475, 775 (64), 819 Gawinecky, R. 286 (103), 293 Gay-Montchamp, J.P. 1063 (100), 1157 Gebicki, J. 770 (57), 819, 833, 834 (66), 836 Gebicki, J.M. 832 (57), 836 Gebicki, S. 832 (57), 836 Gebreyesus, T. 267 (75), 293
Author index Gedanken, A. 133 (97, 101), 149 (151), 155, 157 Gedeck, P. 686, 699, 700, 706 (24), 740 Gee, K.R. 537 (33), 617 Geels, E.J. 1020 (95), 1037 Geerlings, P. 388 (58), 418 Geib, S.J. 428, 430 (35), 471 Geiduschek, E.P. 1048 (60), 1156 Geiger, G. 810, 811 (159, 160), 821 Geissler, A. 1134 (509), 1165 Gelan, J. 697 (86), 741 Gella, I.M. 132, 133 (96), 155 Geller, D.A. 979 (76, 78), 995 Gelperin, A. 993 (149), 997 Genet, J.P. 551 (92), 566 (178), 618, 620 Genin, M.J. 584 (287), 622 Gennaro, M.C. 1074 (177 180), 1158 Genoud, F. 807 (149a), 821 Gentric, E. 381 (18), 417 George, C. 97 (60, 61), 101 (61), 103, 606 (414), 625 George, M. 231 (137), 247, 276, 279 (86, 87), 280 (90), 293 George, M.V. 738 (199), 745, 771 (58), 819 Geppert, J.T. 957 (45), 971 Geraci, G. 1003 (47), 1036 Gerald, R.III 698 (98), 742 Gerba, S. 655 (162), 662 Gerger, W. 426 (9), 470 Gerhardt, K.O. 1047 (31), 1155 Geri, R. 575 (211), 621 G´eribaldi, S. 387 (51), 418 Gerike, P. 1116 (408), 1163 Gerlack, J. 977 (48), 995 Germain, P. 1069 (142), 1158 Germani, R. 1220 (32a, 32b), 1296 Gernstein, J. 407 (157b), 421 Gerth, D.B. 649 (119), 661 Gescher, A. 1141 (556), 1166 Geseke, D.H. 184 (101), 203 Geske, D.H. 843 (22), 847 (39, 40b), 855, 856 Geurtsen, B. 1217 (13a), 1295 Gevers, A.C.M. 1026 (141), 1038 Ghai, S.S. 873 (60), 890 Ghailane, F. 1136 (522), 1165 Ghosh, A. 1138 (531), 1166 Ghosh, A.C. 608 (427), 625 Ghosh, D.K. 987 (99), 996 Ghosh, K.K. 405 (151b), 421 Ghosh, P.K. 160 (8), 201 Giacomelli, L. 433 (81), 472, 1245 1247, 1266 (115b), 1298 Giacomellio, P. 232 (141), 247 Giacomo, N.D. 1178 (49), 1213 Giammaruco, M. 570 (194), 620 Giasson, R. 765 (44 46), 818 Gibbs, D.E. 536 (16), 617
1327
Gibbs, H.W. 958 (47), 971 Gibson, B. 457 (234), 476 Gibson, H.H. 640 (67), 660 Gibson, H.W. 584 (286), 622 Gibson, J. 484 (38), 526 Gierlich, H.H. 240 (184), 248 Gies, H. 628 (10), 659 Giffney, J.C. 880 (83), 890, 952 (17, 18), 970 Gil, V.M.S. 320 (83), 334 Gilabert, D.M. 580 (245), 621 Gilabert, E. 697 (87), 741 Gilardi, R. 97 (60, 61), 101 (61), 103, 606 (414), 625 Gilbert, A. 685, 686 (7), 692 (53), 694 (59), 698 (92), 702, 709 (53), 740 742 Gilbert, B.C. 670 (29), 680 Gilbert, J.R. 509 (192), 530 Gilchrist, A.B. 329 (116), 334 Gilchrist, J.H. 396 (86b, 89, 91e), 419 Giles, G. 1267 (169), 1299 Gilkar, F. 976, 978 (38), 994 Gillaspy, M.L. 168 (61), 202 Gilli, G. 96 (51), 103, 426 (15), 435 (103), 470, 472 Gilli, P. 426 (15), 435 (103), 470, 472 Gillies, D.G. 297 (4), 332 Gillis, R.G. 289 (112), 293 Gilman, J.P. 255 (30), 262 (30, 56), 292 Gilmore, J. 266, 267 (71), 293 Ginsberg, A. 636 (33), 646 (101), 659, 661 Giorgi, G. 57 (93), 83 Giorgi, R. 143 (125), 156 Giorgini, E. 441 (146), 473 Giovanelli, J. 983 (84), 985 (97), 996 Gipp, J.J. 1032 (192, 193), 1039 Girelli, A. 456 (225), 475 Girelli, A.M. 1091 (298, 299), 1161 Girgis, S. 1029 (159), 1038 Gisler, M. 1220 (34), 1296 Gittins, V.M. 57 (87), 83 Giumanini, A.G. 53 (77), 71 (121), 83, 84, 173 (78), 203, 563 (162, 163), 583 (270a, 270b), 620, 622 Giuo, J. 1179 (50), 1213 Giuo, Z. 1179 (50), 1213 Giusti, M. 391 (64, 65), 418, 419 Givens, R.S. 1080 (222, 223), 1159 Giziewicz, J. 453 (205), 475 Glader, B.E. 1027 (151), 1038 Glaeske, K.W. 578 (222), 621 Glasby, J.S. 106 (3), 153 Glaser, R. 648 (113, 114), 661 Glasstone, S. 487 (68), 526, 894 (9), 947 Glatt, C.E. 976, 977 (44), 993 (151), 995, 997 Glatt, C.S. 978 (69), 995 Glauser, J. 669 (18, 23), 680 Gledhill, A.P. 650 (129), 661
1328
Author index
Gleich, A. 393, 394 (78), 419 Gleiter, R. 174, 175 (81), 184, 185 (108), 199 (148), 203, 204 Glenn, R. 99 (80), 103 Glick, R.E. 490, 491, 503 (90), 527 Glish, G.L. 238 (179), 248, 251, 253, 254 (5), 264, 269, 270 (66), 291, 293 Glover, S.A. 667 (8), 680 Glowka, M.L. 98 (75), 103 G¨obel, I. 164, 167 (35), 202 G¨obl, M. 830 (52), 836 Goddard, W.A.III 37 (55), 38 (55, 58), 39, 40 (58), 41 (55), 82 Godel, H. 1076 (188), 1090 (291), 1159, 1161 Godfrey, A.G. 604 (397), 625 Godovikova, T.I. 628 (8), 659 Goedeweeck, R. 695 (77), 741 Goerdeler, J. 636 (32, 33), 646 (101), 659, 661 Goetsch, P.H. 1058 (78), 1156 Goez, M. 692 (52), 741 Gokel, G.W. 902 (25), 947 Gold, V. 894 (3), 946 Goldberg, I. 15, 16 (26b, 26c), 82 Goldberg, L.S. 795 (120), 820 Golden, D.M. 354 (53), 375, 401 (134), 420, 883 (88), 890 Golden, J.T. 877 (70), 890 Golderer, G. 993 (148), 997 Golding, B.T. 297 (9), 332, 538 (35), 617 Golding, J.G. 953, 965, 967 (20), 970 Goldman, E.N. 1033 (201), 1039 Goldman, P. 1032 (196, 197), 1039 Gol’dshtein, I.P. 381 (9), 416 Goldstein, I. 993 (146), 997 Goldstein, J. 589 (310), 623 Goldstein, P. 435 (99), 472 Goldstein, S. 829 (48), 836 Goldwhite, H. 165, 166 (44), 202 Golly, I. 1026 (145), 1038 Gomes, A. 505 (156), 529 Gomez, J.A. 60, 62 (105), 84 G´omez Hens, A. 1077, 1098 (194), 1159 Gomez-Sanchez, A. 453 (204), 475 Goncalves, R.M.C. 1228 (75), 1297 Gonzales, M. 886 (102), 891 Gonz´alez, G. 431 (66), 456 (223), 472, 475 Gonzalez, R. 396 (88), 419 Gonzalez-Lafont, A. 754 (15), 817 Goodall, C.M. 1030 (171), 1038 Gooden, R. 767 (50a), 819 Goodfriend, G.A. 1060 (86), 1093 (310, 312, 313), 1156, 1161 Goodwin, D. 693 (56), 741, 1217 (16), 1295 Goosen, A. 667 (8), 680 Gopidas, K.R. 738 (199), 745
Gopinathan, C. 832 (58), 836 Goralski, C.T. 536 (18), 617 Gorczynska, A. 1096 (333), 1161 Gorden, R. 211 (37), 244 Gordge, M.P. 674 (50), 681 Gordillo, B. 297 (10), 332 Gordon, D.M. 430 (50), 471 Gorelik, M.V. 631 (19, 20), 659, 884 (96), 891 Gorman, G.S. 390 (71), 419, 1284, 1285 (194b), 1300 Gorman, P. 979 (77), 995 Gorner, H. 750 (7), 778 (70a, 70c, 71 73), 783 (93), 817, 819, 820 Gornostaev, L.M. 1000, 1009, 1019 (7), 1035 Gors, B. 141 (120), 156 Gorski, W. 1143 (567), 1148 (599), 1166, 1167 Gorsky, L.D. 977 (46), 995 Gort, S.M. 1116 (415), 1163 Gorton, L. 1103 (357), 1162 Gosciniak, D.J. 825 (24), 835 Goss, F.R. 486 (57), 526 Gotchiguian, P. 234 (153), 247 Goti, A. 580 (249), 621 Gotor, V. 592 (333, 336, 337), 623 Gottardi, W. 581 (256), 622 Gottlieb, H.E. 43, 54 (67), 55, 56 (79), 83 G¨otz, R. 434 (84, 89), 472 Gouali, M. 358 (75), 376 Goudgaon, N.M. 565 (171), 620 Gouesnard, J.P. 297 (6), 300 (15), 332 Gougoutas, J.Z. 651 (137), 652 (138), 662 Gould, G.L. 1217 (16), 1295 Goulding, B.T. 208 (5), 244 Govoni, P. 447 (187), 474 Gowenlock, B.G. 188, 191 (128), 204, 354 (53), 375, 447 (176, 180), 474, 803 (141), 821, 1007 (52), 1036 Graaf, B.van de 519 (236), 531 Graboski, G.G. 604 (399), 625 Grabowski, S.J. 99 (85), 103 Grabowski, Z.R. 693 (57), 694 (60), 741 Grady, G.L. 46 (70, 71), 47 (71), 83 Graham, L. 1024 (125), 1037 Graham, M. 444 (162), 474 Graham, W.R. 1027 (149), 1038 Grambal, F. 392 (75), 419 Gramstad, T. 431 (63 65), 471, 472, 1273, 1278 (179), 1299 Grandclaudon, P. 698 (93), 724 (161, 164), 727 (168), 742, 743, 744 Grandinetti, F. 165 167 (24), 202 Granozzi, G. 175 (83), 203 Grant, R.D. 793 (118), 820 Grant, T.M. 1063 (98), 1157 Graser, T.A. 1076 (188), 1159 Gratteri, P. 1116 (409), 1163
Author index Gravel, D. 765 (44 46), 769 (55), 818, 819 Gray, D.O. 1088 (280), 1160 Gray, E.J. 633 (23), 659 Gray, J.I. 1189 (95), 1214 Gray, M.J. 954 (25, 29), 970, 971 Graziano, K.A. 767 (52a), 819 Grech, E. 322, 323 (96), 334, 435 (108 112), 436 (120), 472, 473 Greci, L. 191, 199 (130), 204, 969 (66), 970 (67), 971 Greck, C. 551 (92), 566 (178), 618, 620 Greef, J.van der 218 (86), 246 Green, F.J. 1053, 1054, 1058, 1115, 1124, 1144 (73), 1156 Green, J.C. 164, 165, 175 (31), 188 (126, 128), 189, 190 (126), 191 (126, 128), 202, 204, 803 (139), 821 Green, L.C. 1021, 1030 (103), 1037 Green, M.M. 209 (23), 244 Green, S.A. 810 (156), 821 Greenberg, A. 345 (18), 361 (86), 373, 377 Greenblatt, G.D. 795 (124), 820 Greenblatt, J. 1007 (53), 1036 Greene, E.F. 466 (265), 476 Greenhalgh, C. 457 (234), 476 Greenlee, R.B. 589 (312), 623 Greenstein, J.P. 107 (25, 26), 154 Greenstock, C.L. 823 (1), 835 Greenwood, D.R. 1141 (557), 1166 Greer, M.L. 854 (66), 856 Grefenstein, L. 400 (128), 420 Grehn, L. 540 (46), 541 (46, 51), 542 (53), 617, 854 (63), 856 Greig, C.C. 958 (50), 971 Grelier, P.L. 1220 (42), 1222 (50, 51), 1238 (51), 1296 Grellier, P.L. 381 (17b-e, 19, 20b, 20c), 395 (81), 417, 419, 428 (41, 42), 471 Griben, B.J. 991 (119, 120), 996 Grice, H.C. 1189 (93), 1214 Grieco, P.A. 570 (195), 620 Grierson, L. 579 (239), 621 Griffin, R.G. 322 (103), 325, 326 (108), 334 Griffith, O.W. 669 (21), 680, 976, 978 (38), 985 (91, 95), 991 (118), 994, 996 Griffiths, H. 1059 (80), 1156 Grigg, R. 1100 (349), 1162 Grillot, G.F. 554 (110), 618 Grimaldi, J. 598 (378), 624 Grimmett, M.R. 100 (94), 103 Grimsrud, E.P. 385 (37a), 418 Griscavage, J.M. 990 (108), 996 Grivas, S. 1004, 1007, 1009 (43), 1012 (43, 84), 1019 (43), 1033 (84), 1035 (43), 1036 Grob, C.A. 179 (94), 203, 512 (217 222), 530 Grob, R. 1145 (572), 1166 Gr¨obner, P. 993 (148), 997
1329
Groen, M.B. 757 (25), 818 Gronchi, G. 854 (67), 856 Gronert, S. 399 (119), 420 Groombridge, C.J. 324 (104), 334 Gros, C. 106 (6), 153 Grosjean, D. 1176 (27), 1180 (56, 59), 1212, 1213 Grosjean, F. 546 (73), 618 Grosjean, M. 106 (8), 153 Gross, A.W. 539 (42), 617 Gross, B.L. 1025 (132), 1038 Gross, J.H. 227 229 (128), 230, 231 (133), 246, 247 Gross, M.L. 208 (16), 211 (35, 36, 39), 217 (78), 222, 223 (112), 244 246, 595 (354), 624 Gross, S.S. 976 (35), 994 Grosvenor, P.W. 1088 (280), 1160 Grover, P.L. 1000 (8), 1035 Gruen, H. 778 (70), 819 Gruetter, C.A. 673 (42), 681, 975 (20, 25 28), 992 (28), 994 Gruetter, D.Y. 975 (26, 27), 994 Grunwald, E. 409 (175), 421, 424 (2, 4), 470 Gruszecka, E. 861, 863 (21), 867 (37), 889, 918, 920 (37), 947 Grutzmacher, H.-F. 216 (63f), 245 Grywacz, C.M. 1082 (241), 1160 Gu, J. 535 (9), 616 Guan, Y. 562 (153), 619 Guanti, G. 100 (93), 103, 1262, 1264 (151), 1299 Guardado, P. 409 (169a, 169b), 421 Guardia, M.de la 1074 (174), 1158 Guasch, J. 1083 (246), 1160 Guastadisegni, G. 1247, 1249 (123), 1278 1280, 1285 (184b), 1289 (123), 1298, 1300 Gudmundsdottir, A.D. 710 (111), 742 Gudriniece, E. 437 (124), 473 Guennouni, F. 540 (45), 617 Guerra, M. 50, 53 (76), 83 Guerra, R. 673 (46), 681 Guerrieri, A. 1078 (197), 1159 Guerro, S.A. 175 (83), 203 Guida, W.C. 41 (63), 82 Guih´eneuf, G. 381 (17d, 18), 417, 1222, 1238 (51), 1296 Guilhem, J. 592 (335), 623 Guillaumet, G. 596 (366), 624 Guindi, L.H.M. 616 (464), 626 Guiry, P.J. 584 (279), 622 Guissani, A. 834 (71, 72), 836 G¨ulbaran, E. 1000, 1009 (6), 1035 G¨ulec, B. 644 (93), 660 Gullberg, P. 932 (45), 947 Gullion, T. 322 (97, 98), 334
1330
Author index
Gullotti, M. 137 (111), 156 Gumbleton, M. 1142 (562), 1166 Gundertofte, K. 41, 42 (60), 82 Gunn, V.E. 886 (98), 891 Gunther, H. 25, 38 (38), 82, 396 (87), 419 Guo, Q. 232 (143), 247 Gupta, O.D. 593 (345), 623 Gupta, S. 1238 (96), 1297 Gupta, V. 1152 (622), 1168 Gupta, V.K. 1138 (532), 1166 Guram, A.S. 584 (282), 622 Gurd, F.R.N. 1005 (51), 1036 Gurevich, A. 1273 1275 (177), 1299 Gurka, D. 381, 395 (14a, 14b), 416 Gur’yanova, E.N. 381 (9), 416 Gustavsson, B. 1082 (237), 1160 G¨usten, H. 176 (87), 199 (147), 203, 204 Guthrie, J.P. 348 (30b), 373 Guti´errez, E. 1046 (16), 1155 Gutman, D. 360 (78), 376, 382 (23), 417 Gutmann, V. 381 (12a c), 416, 424 (3), 425 (3, 8), 426 (9), 431 (3), 470 Gutsche, C.D. 843 (20a), 855 Gutshke, D. 871 (54), 890 Guy, A. 537 (31), 563 (164), 617, 620 Guy, C. 1175 (12), 1212 Guy, L. 553 (106), 618 Haammerum, S. 224, 225 (115), 246 Haas, J.W. 1047 (49), 1155 Haas, Y. 795 (124), 820 Haase, A. 330 (122), 335 Haasmann, S. 1090 (291), 1161 Habdas, J. 905 (29), 947 Haber, F. 838 (3), 854 Hable, M. 1127, 1143 (458), 1164 Habraken, C.L. 878 (75), 890 Habs, H. 1185 (70), 1213 Hachisuka, C. 565 (175), 620 Hacksell, U. 62 (107), 84 Hada, W.A. 168 (61), 202 Hadayatullah, M. 578 (226), 621 Haddad-Fahed, O. 1222 (49a, 49b), 1296 Hadfi, S. 1089 (288), 1161 Hadjigeorgiou, P. 953, 965, 967 (20), 970 Hadrick, G.R. 369, 370 (99), 378 Hadzi, D.D. 62 (106), 84 Haga, N. 872 (56), 873 (57), 890 Haga, T. 679 (87), 682 Hagashijima, T. 1095 (325), 1161 Hageman, H.J. 722 (153e), 743 Hague, D.N. 390 (61), 418 Hahn, J.-T. 534 (5), 616 Hai, P.T. 1148 (598), 1167 Haink, H.J. 163 (29), 202 Haisa, M. 93 (15, 16), 98 (16), 102 Haiza, M.A. 130 (89), 155
Hajicek, J. 566 (178), 620 Hakam, A. 1024 (123, 124), 1037 Haken, J.K. 434 (95), 472 Hale, P.D. 729 (174), 744 Halim, H. 208 (9), 220, 221, 232 (97), 244, 246 Hall, A.V. 978 (71), 995 Hall, E.J. 1031 (182), 1039 Hall, J.L. 257 (36), 292 Hall, L.D. 330 (118), 335 Hall, R.C. 1047 (44), 1155 Hall, W.E. 175 (84), 203 Halldin, C. 932 (45), 947 Halle, J.-C. 512 (216), 530 Hallett, G. 448 (190), 474, 677 (75), 681 Halsall, H.B. 1103 (362), 1162 Halvax, J.J. 1119 (426), 1163 Halverson, A.M. 759 (35a, 35b), 818 Hamada, K. 34 (46), 82 Hamada, T. 736 (194a, 194b), 745 Hamada, Y. 24 (32), 82 Hamaguchi, M. 457 (235), 476 Hamamoto, I. 605 (409b), 614 (452 454, 456, 457), 615 (458), 625, 626 Hamamoto, K. 870 (47), 890 Hamanoue, K. 776 (66), 819 Hamasuna, S. 562 (150), 619 Hamazone, I. 308, 309 (39), 333 Hambley, T.W. 58 (94), 83, 97, 98, 101 (67), 103 Hamelin, J. 589 (311), 623 Hamer, G.K. 505 (156), 529 Hamilton, A.D. 428, 430 (35), 471 Hamilton, I.C. 1046 (18), 1155 Hammel, P. 736 (192a), 745 Hammerich, O. 839, 851 (8c), 855 Hammerle, M. 1103 (359), 1162 Hammerum, S. 208 (14, 15), 209 (26), 212 (26, 41, 42, 44, 45), 213 (15, 26, 42), 214 (14, 15, 41, 42), 215 (14), 216 (41, 42, 59, 63d), 218 (45, 84, 85), 219 (89, 92), 220 (93 95), 221 (26, 84, 107), 222 (44, 45, 59), 223 (44, 93), 224 (44), 225 (42, 44), 227 229 (93), 244 246 Hammes, P.W. 1079 (213), 1159 Hammett, L.P. 483 (28), 487 (72, 73), 493 (28, 116), 525, 527, 528, 644, 647 (95), 660 Hammick, D.Ll. 484 (40), 526 Hammock, B.D. 1135 (515), 1165 Hammond, G.S. 905 (30), 947 Hammond, J.R.M. 1188 (89), 1214 Hammons, J.H. 398 (113a, 113b), 420 Hampel, F. 397 (103), 420 Hampp, N. 1119 (427), 1163 Hampson, N.A. 581 (255), 622 Hampton, C.V. 1177 (36), 1212 Han, B.H. 534 (3), 616
Author index Han, C. 1142 (562), 1166 Han, C.-C. 385 (34a, 34b), 417 Han, J.L. 534 (5), 616 Han, S.H. 886 (99), 891 Han, X. 992 (133), 997 Han, Y. 540 (47), 617 Hanada, Y. 1065 (113), 1157 Hanafusa, T. 962 (51), 971 Hanaki, K. 1083 (253), 1160 Hanato, H. 685 (14), 740 Hanaue, K. 1047 (22), 1155 Hanazaki, Y. 534 (7), 616 Hancock, D.K. 1092 (305), 1161 Hancock, R.D. 58 (95 97), 83 Hand, O.W. 234 (156), 247 Handrick, G.R. 338, 361, 362, 364 (2b), 372 Haney, W.A. 455 (215), 475, 790 (109a), 820 Hanioka, N. 1081, 1091 (234), 1159 Hannigan, T.J. 404 (145), 405 (148), 421 Hansch, C. 303 (29), 332, 494 (118), 504 (150), 514 (118, 150), 515, 517, 518 (150), 522 (150, 251), 528, 529, 531, 1006, 1024, 1026 1028, 1030 1032 (55), 1036, 1241 (106a), 1298 Hansch, C.G. 522 (245), 531 Hansel, S.B. 1133 (495), 1165 Hansen, H.-J. 152 (162), 157 Hansen, I. 603 (393), 624 Hansen, S.H. 1142 (561), 1166 Hansh, C. 1238 (95), 1297 Hansson, L. 583 (272), 622 Hantzsch, A.R. 482 (24), 525 Hapiot, P. 832 (63), 836, 839, 851 (8a), 855 Happe, J. 1033 (199), 1039 Happer, D.A.R. 505 (157), 529 Hara, K. 693, 694 (62), 741 Harada, K. 650 (124a), 651 (133), 661 Harada, N. 140 (118), 141 (118, 119), 142 (121, 122), 156 Harada, Y. 193, 194, 197 199 (144), 204 Harasek, M. 582 (269), 622 Harbison, G.S. 325, 326 (108), 334 Hard, K. 722 (155), 743 Hardemare, A.du M.d’ 669 (16), 680 Harden, A. 120 (61), 154 Hardy, J.K. 1059 (82), 1156 Harger, W.P. 1131 (485), 1165 Hargittai, I. 8, 24 (14a), 81, 452 (201), 475 Hargittai, K.B. 452 (202), 475 Hariharan, M. 1085 (260), 1160 Harirchian, B. 727 (167), 744 Harke, H.R. 1096 (331), 1161 Harlow, R.L. 543 (63), 617 Harmon, M.F. 991 (116, 117), 996 Harms, K. 396 (99, 100), 420 Harper, E.M. 676 (69), 681 Harper, T. 96 (50), 103
1331
Harrelson, J.A. 403 (141), 421 Harriman, A. 827 (36), 835 Harrington, G.W. 94 (41), 102 Harris, F.M. 266 (73), 293 Harris, J.M. 933, 935, 936 (51), 947, 1273, 1275, 1283 (178), 1299 Harris, K.D.M. 322 (102), 334 Harris, P.A. 556 (119), 557 (126, 127), 619 Harris, R.K. 57 (90b), 83, 297 (14), 332 Harrison, A.G. 216 (62), 226 (121), 234 (155, 158), 236 (173, 174), 237 (174), 238 (158, 173, 174, 178), 239 (178), 240 243 (158), 245 248, 254 (22), 287 (106), 288 (22, 106, 108), 289 (108, 113), 292 294 Harrison, A.T. 396 (86b, 89, 91e), 419 Harrison, D. 673 (42), 681 Harrison, D.G. 673 (46), 681, 977 (53), 979 (75), 995 Harrison, J. 536 (18), 617 Harrison, J.H. 1022 (112), 1037 Harrison, J.K. 977 (51), 995 Harrold, M.P. 1093 (318), 1161 Hart, B.T. 1046 (18), 1155 Hart, T.W. 668 (15), 680 Hart, W.J.van der 289 (114), 294 Harten, B. 1024 (123, 126), 1037 Hartman, C.P. 1197 (105), 1214 Hartneck, C. 991 (122), 996 Hartree, E.F. 975 (7), 994 Hartshorn, M.P. 455 (218), 456 (220), 475, 790 (108, 109b, 111b, 111c, 112 114), 820, 883 (89, 90, 92), 890, 891, 954 (24 39), 956 (28), 961 (24), 962 (30), 963 (31), 968 (26), 969 (36), 970 (37, 38), 970, 971 Hartshorn, S.R. 896 (16), 945 (70), 947, 948 Hartstock, F.W. 595 (357), 624 Harvey, D. 1025 (134), 1038 Harvey, T.M. 289 (109), 293 Harwood, L.M. 858 (2), 888 Hasanuddin, S.K. 192 (134), 204 Hasegawa, E. 688 (43), 690 (45), (44), 740 Hasegawa, T. 722 (159a), 743 Hasegawa, Y. 596 (361a, 361b), 624, 1218 (22a, 22b, 23), 1290 (22a, 22b), 1295 Hashemi, P. 1074 (181), 1158 Hashida, Y. 648 (107), 661 Hashimoto, A. 1090 (292), 1161 Hashimoto, C. 724 (166b), 744 Hashimoto, K. 824 (12), 835 Hashimoto, M. 165, 166 (23), 202 Hashimoto, S. 736 (192b), 745, 1256 (137 139), 1298, 1299 Hashmall, J.A. 184 (102), 203 Hass, H.J. 738 (200a), 745 Hass, M.P.de 696 (78), 741 Hassan, S.M. 1140 (548, 549), 1166 Hassan, Y.A. 1106 (376), 1162
1332
Author index
Hassel, O. 442 (149, 152), 473 Hassner, A. 43, 54 (67), 55, 56 (79), 83, 717 (140), 743 Hassnoot, C.A.G. 57 (92), 83 Hatanaka, Y. 730 (181c, 182b), 744 Hatano, H. 739 (204), 745 Hatano, Y. 695 (68), 741 Hatch, F.T. 1033 (199), 1039 Hatem, J. 598 (378), 624 Hathaway, B.J. 329 (113), 334 Hathaway, C. 877 (70), 890 Hathout, Y. 1024 (127), 1037 Hattori, M. 776 (65), 819 Hattori, R. 978 (59, 66), 995 Haugen, G.R. 354 (53), 375 Haumann, T. 168 (61), 202 Hauske, J.R. 576 (216), 621 Hausladen, A. 992 (138), 997 Hautefeuille, A. 1147 (591), 1167 Havery, D.C. 1146 (586), 1167 Havinga, E. 15, 17 (25b), 81, 753 (11, 12), 757 (25), 817, 818 Havingna, E. 754 (18), 788 (103), 818, 820 Havlas, Z. 164, 167 (35), 202 Haw, J.F. 414 (201), 422 Hawkes, G.E. 324 (104), 334 Hawkins, C.J. 58 (94), 83 Hawkins, J.M. 72 (123), 84 Hayakawa, K. 1069 (147), 1079, 1083 (217), 1129 (476), 1130 (147, 476, 479, 481), 1131 (476), 1158, 1159, 1164, 1165 Hayakawa, S. 551 (91), 618 Hayami, J. 467, 468 (274), 476, 1281, 1282 (189), 1300 Hayami, J.I. 1217 (7), 1295 Hayashi, J. 1085 (270, 271), 1160 Hayashi, K. 614 (455), 615 (459), 626, 1097 (338), 1162 Hayashi, M. 602 (390), 624 Hayashi, T. 1087 (276), 1090 (292), 1160, 1161 Hayes, J.M. 1059 (79), 1156 Hays, J.T. 1016 (88), 1037 Hayward, M.A. 991 (118), 996 Hayward, M.J. 1107 (383), 1163 Hazard, R. 1107 (380), 1162 Hazelwood, R. 991 (117), 996 Hazlett, J.S. 1118 (421), 1163 He, G.Z. 795 (121), 820 He, H. 437 (121), 473 He, L. 1070 (149), 1158 He, R.X. 396 (87), 419 Head, A.J. 366, 369, 370 (98), 378 Head-Gordon, M. 384 (28a), 417 Headley, A.D. 388 (57), 389 (59), 418, 523 (252), 524 (254), 531, 1238 (97, 99), 1239 (99), 1240 (97, 100), 1297
Healy, H.F. 161, 173 (18), 202 Heany, H. 585 (290), 622 Hearing, E.D. 338 (2d, 3, 5), 361 (2d), 372 Heaton, B.T. 859 (3), 888 Heaton, J.N. 594 (347, 348), 623 Hecht, L. 152 (164 166), 153 (165, 166, 168), 157 Hecht, S.S. 1150 (612), 1167 Hecker, M. 992 (140), 997 Hedberg, K. 436 (118), 473 Hedberg, L. 436 (118), 473 Hedges, J.I. 1067 (131), 1157 Hedlund, H. 993 (145), 997 Hedrera, M. 433 (81), 472, 1245 1247, 1266 (115b), 1298 Hedstrand, D.M. 675 (62), 681 Heema, W. 208 (6), 244 Heesing, A. 871 (54), 890, 904 (27, 28), 947 Heffron, P.J. 117 (53), 154 Hefnawy, M.M. 1140 (548, 549), 1166 Hefner, E. 1177 (29), 1212 Hegarty, A.F. 329 (113), 334, 642 (78), 660 Hegedus, L.S. 605, 614 (409a), 625 Hegyes, P. 564 (167), 620 Hehre, W.J. 34 (48), 82, 208 (4), 244, 303 (25), 332, 510 (207), 523 (252), 530, 531 Heilbronner, E. 66, 67 (111), 84, 160 (12), 166 (51, 52), 168 (52), 169 (51), 170 (12), 179 (52, 94), 181 (96), 184 (52, 102, 103, 105), 185 (52), 201 203 Heilmair, R. 1030 (177), 1039 Heim, F. 1001 (32), 1035 Heimbach, H. 238 (177), 248 Heimgartner, H. 717 (142), 743 Heindel, N.D. 834 (73), 836 Heineman, W.R. 1023 (121), 1037, 1103 (362), 1162 Heinis, T. 256 (35), 292, 385 (34d), 417 Heinrich, G. 199 (147), 204 Heinrich, N. 211 (40), 216 (63c), 244, 245 Heinze, J. 164, 165 (36), 202 Heinze, T.M. 1146 (583), 1167 Heinzel, B. 983 (86), 996 Helbert, M. 395 (83), 419, 505 (158), 529, 1238 (87b), 1297 Helgaker, T. 236 (172), 248 Helgason, T. 1145 (573), 1166 Heller, H.E. 868 (40), 889 Helmig, D. 1130 (484), 1131 (485), 1165 Helquist, P. 542 (54), 568 (188), 617, 620 Helsberg, I. 1139 (535), 1166 Helsby, P. 953 (19), 970 Hemalatha, J. 269 (80), 293 Hemelaar, P.J. 1026 (141), 1038 Hemsworth, R.S. 235 (160), 247 Henderson, D. 1126, 1127, 1143 (446), 1164 Henderson, D.A. 565 (170), 620
Author index Henderson, D.O. 148 (146), 157 Henderson, E. 1024 (126, 127), 1037 Henderson, G.N. 880 (82), 890, 899 (24), 947, 950 (4 12), 951 (10, 11), 958 (9), 964 (5), 967 (58), 970, 971 Henderson, K.W. 396 (90), 419 Henderson, W.G. 524 (254), 531 Hendricks, L. 217 (77), 245 Hendrickson, A.R. 1087 (277), 1160 Hendrickson, T. 41 (63), 82 Hengstler, J.G. 1185 (72), 1213 Henion, J.D. 1118 (419), 1163 Hennion, B. 457 (227), 475 Henriet-Bernard, C. 598 (378), 624 Henry, L. 482 (26), 525 Henry, Y. 834 (71, 72), 836 Henschler, D. 1021 (104), 1037 Henshall, J.L. 97 (66), 103 Heppener, M. 445 (169), 474 Hepworth, P.A. 1102 (356), 1162 Heras, A.P. 1048 (58), 1156 Herbert, C.G. 265 (67), 293 Herbert, J. 769 (55), 819 Herbstein, F.H. 98, 101 (76), 103 Herche, L.R. 1060 (85), 1156 Hercouet, A. 536 (19), 617 Hermans, E. 697 (86), 741 Hermant, R.M. 694 (65), 696 (79), 741 Hern´andez, L. 1128 (465), 1134 (512), 1138 (530), 1164 1166 Hern´andez, P. 1128 (465), 1134 (512), 1164, 1165 Hern´andez-Cassou, S. 96 (46), 102, 1097 (340), 1162 Hernandez-Laguna, A. 1285 (195, 196), 1300 Herron, J.T. 208, 210, 217, 237 (18), 244 Hershey, N.D. 938 (57), 948 Hertel, M. 639 (65), 660 Herterich, R. 1133 (501), 1165 Hertle, H. 1020, 1022 (100), 1037 Herzfeld, J. 322 (103), 325, 326 (108), 334 Herzshuh, R. 273, 274 (84), 293 Hess, B.A.Jr. 148 (145, 146), 157 Hess, G.P. 769 (56), 819 Hesse, D.G. 338 (4), 347 (24), 355 (57), 356 (59), 372, 373, 375 Heufer, J. 693 (55), 741 Heuser, N. 139 (113), 156 Hevel, J.M. 978 (67), 983 (85), 995, 996 Hevesi, L. 218 (81), 245 Heydkamp, W.R. 552 (100a), 565 (172), 618, 620 Heyrovsky, M. 869 (45), 889 Heywood, P.J. 57 (87), 83 Hibbert, D.B. 883 (91), 891, 968 (63), 971 Hibbert, F. 381 (8), 416, 435 (104), 472, 1294 (201), 1300
1333
Hibbs, J.B.Jr. 975 (29, 30), 976 (30, 34), 978 (29, 61), 980, 983 (34), 994, 995 Hiberty, C. 443 (159), 474 Hickel, B. 834 (71, 72), 836 Hida, M. 718 (147), 743 Hida, S. 686 (26), 740 Hidaka, Y. 1114 (405), 1163 Hidalgo, J. 409 (169a, 169b), 421 Hiemstra, H. 568 (187), 620 Higgs, E.A. 669 (19), 680, 975 (4), 978 (62), 994, 995 Higgs, H. 37 (56), 82 Higuchi, D. 551 (90, 91), 618 Higuchi, J. 789 (106), 820 Hikasa, M. 561 (148), 619 Hiki, K. 978 (66), 995 Hilinski, E.F. 455 (213), 475 Hill, H.H. 1047 (30), 1155 Hill, J. 1001, 1007, 1009, 1011, 1027 (28), 1035 Hill, M.J. 1182 (63), 1213 Hill, R.A. 106, 113 (5), 153 Hill, R.R. 739 (202, 203, 205), 745 Hill, S. 1001, 1003, 1007, 1009, 1011, 1012, 1028 (29), 1035 Hiller, K.-O. 830 (50, 52), 836 Hillyer, C.D. 1024 (123), 1037 Hiltunen, R. 1083 (251), 1160 Hindawey, A.M. 439 (134), 473 Hindawi, S.K. 260, 263 (51), 292 Hinko, C.N. 1133 (497), 1165 Hinman, M.M. 119 (56), 154 Hino, T. 565 (174), 620 Hinson, J.A. 1011, 1012 (72), 1026 (142, 143), 1029 (72, 168), 1036, 1038 Hintz, P.J. 187 (112), 204 Hiramatsu, M. 751 (8), 759 (36a), 817, 818 Hirao, A. 111 (36), 154 Hirashima, T. 596 (365), 624 Hirata, S. 1106 (378), 1162 Hirata, Y. 724 (166c), 744 Hirayama, S. 1030 (176), 1039 Hirokawa, S. 96, 97 (59), 103 Hirosawa, Y. 458 (238), 476 Hirose, K. 1114 (405), 1163 Hirota, K. 722 (158a), 743 Hirsch, D.J. 984 (90), 993 (151), 996, 997 Hirsch, M.S. 445 (166), 474 Hirshberg, Y. 436 (120), 473 Hirshfeld, F.L. 87, 88 (6), 102 Hirst, J. 1219 (26), 1243, 1244 (109), 1251 (127, 128), 1262 (148a, 148b), 1264 (148a, 148b, 153), 1266, 1267 (162), 1276 (148a, 148b, 162, 182), 1277 (162), 1278 (153, 162, 182), 1287 (199), 1288 (148a, 148b), 1290 (182, 198 200), 1291 (198), 1293 (199), 1294 (109, 162), 1295, 1298 1300
1334
Author index
Hishikura, H. 458 (238), 476 Hiskey, M.A. 370 (100, 101), 378 Hitchings, G.J. 604 (394), 624 Hladonikova, R. 1077 (192), 1159 Hlaibi, M. 1217 (17), 1295 Hlavica, P. 1026 (145), 1038 Ho, J. 645 (100), 661 Ho, K.B. 1139 (534), 1166 Ho, L.Y. 447 (185), 474 Ho, M.F. 1097 (337), 1162 Ho, P.S. 810 (156), 821 Ho, T.I. 685 (8, 14, 15, 20 23), 698 (8, 22), 704 (8), (41), 740 Hobbs, A.J. 990 (111), 996 Hobbs, M.E. 426 (16), 470 Hobo, T. 1085 (270, 271), 1160 Hobson, J.D. 581 (261), 622 Hobza, P. 426 (10, 12), 428 (30), 431 (12), 434 (83), 470 472 Hochstrasser, R.M. 441 (144), 473 Hoefnagel, A.J. 494, 495 (117, 124, 125), 498 (125), 519 (124, 125, 236), 520 (239), 522 (248), 528, 531 Hoefnagel, M.A. 520 (239), 531 Hoeve, W.ten 539 (40), 617 Hoffman, E.P. 979 (78), 995 Hoffman, M.K. 217 (78), 245 Hoffman, R.V. 580 (250), 621, 634 (28), 659 Hoffmann, D. 1150 (607 610, 612), 1151 (613, 614, 616 618), 1167 Hoffmann, H.M.R. 229 (131), 247 Hoffmann, R. 184 (99), 203 Hofman, H.J. 262, 263 (59), 292 Hofmann, L. 1146 (584), 1167 Hog, J.H. 171 (68), 203 Hogendoorn, E.A. 1116 (415), 1163 Hohi Lee 320 (84), 334 Hojo, M. 498 (137), 528 Holbrook, K.A. 505 (161), 529 Holcman, J. 832 (54 56), 836 Holden, J.R. 80 (135), 84, 93 (22), 97 (65), 102, 103, 329 (114), 334 Holleck, L. 869 (45), 889 Holleman, A.F. 484 (42), 526 Holleyhead, R. 317 (65), 333 Holmes, E.L. 485 (54, 55), 526 Holmes, J.L. 208 (7, 11), 209 (11, 33), 214 (11, 51), 215 (7, 56), 217 (72), 231 (137), 233 (148, 149), 234 (148, 151), 235, 236 (166), 237 (175), 244, 245, 247, 248, 251 (8), 254 (19), 255 (24 28), 260 262 (52), 291, 292 Holmes, L.S. 992 (135), 997 Holmquist, F. 993 (145), 997 Holt, A. 1065 (105), 1157 Holt, D.E. 1025 (134), 1038
Holub, D.P. 550 (83), 618 Holzapfel, W.H. 1069 (144), 1158 Holzwarth, G. 147 (139), 156 Hom, G. 993 (147), 997 Homan, H. 1285 (196), 1300 Homero M´endez, D. 1083 (248), 1160 Hon, Y.-S. 539 (41), 617 Honegger, E. 179 (94), 184 (105), 203 Hong, J. 1134 (510), 1165 Hong, Y. 115 (50), 154 Hooft, R. 99 (86), 103 Hoogmartens, J. 1118 (420), 1163 Hooper, R.M. 97 (66), 103 Hoover, D.J. 168 (61), 202 Hoover, R.N. 1180 (52), 1213 Hop, C.E.C.A. 234 (151), 247, 260 262 (52), 292 Hope, H. 87, 88 (6), 102, 442 (152), 473 Hopfel, D. 330 (122), 335 Hopfinger, A.J. 13 (19), 81 Hopkins, P.B. 575 (209), 621 Hopkins, T.E. 583 (273), 622 Hoppilliard, Y. 216 (61), 232 (142), 245, 247 Horan, C.J. 648 (113, 114), 661 Horeld, G. 639 (56), 660 Horgan, A.G. 860 (17), 861 (17, 19), 863 (23), 889, 897 (22), 899 (23), 904 (26), 905 (29), 947 Hori, K. 722 (159c), 743 Hori, T. 572 (200, 201), 620 Hori, Y. 597 (370), 624 Horie, K. 1106 (378), 1162 Horie, T. 458 (236), 476 Horikawa, K. 1177 (33), 1212 Horiuchi, T. 843 (21), 855 Horng, J.Y. 1127 (456), 1164 Horniak, I. 1113 (403), 1163 Hornung, V. 184 (102), 203 Horsman-van den Dool, L.E.W. 696 (78), 741 Horspool, W. 710 (118), 742 Horspool, W.H. 715 (129), 742 Horspool, W.M. 715 (132), 716 (132 139), 717 (144), 718 (146, 148), 742, 743 Horsthius, P. 1048 (57), 1156 Hortmann, A.G. 560 (137), 619 Horton, D. 15, 17 (23b), 81, 106 (4), 153 Hoshino, N. 437 (122), 473 Hoshino-Miyajima, N. 437 (123), 473 Hosken, G.D. 412, 413 (196), 422 Hosokawa, M. 458 (236), 476, 1218, 1219, 1237 (21a, 21b), 1295 Hosomi, A. 541 (50), 617 Hosseini, M.W. 390 (67), 419 Hosseini, S. 352 (41), 374 Hotchkiss, J.H. 1147 (589, 590), 1167, 1188 (84), 1214 Hothersall, J. 674 (50), 681
Author index Houdijk, A. 1078 (203), 1159 Houk, K.N. 72 (122a, 122b, 123), 84, 163, 164, 166 (28), 169 (63), 179, 180 (28), 199 (145), 202 204, 655 (161), 662 Houle, F.A. 192 (132), 204 Houlihan, F.M. 767 (50a, 50b, 51), 819 Houriet, R. 179 (94), 203, 218 (81), 245 Hovey, J.K. 385 (34d), 417 Hovinen, J. 645 (100), 661 Howard, A.E. 60 (103b), 83 Howard, J.B. 1175 (18), 1212 Howard, K.H. 710 (114), 742 Howard, P.C. 1132 (492), 1165 Howard-Lock, H.E. 88, 90 (8), 102 Howe, G.P. 569 (192), 620 Howe, I. 209 (27), 221 (109), 227 (122), 244, 246 Hrabie, J.A. 448 (189), 474 Hrnciar, P. 313, 314 (58), 333 Hromadova, M. 1119 (436), 1164 Hsieh, C.L. 1081 (226), 1159 Hsieh, D.P.H. 1132 (490), 1165 Hsieh, T. 255 (30), 262 (30, 56), 292 Hsieh, Y.Z. 1093 (320), 1161 Hsu, E.C. 147 (139), 156 Hsu, V.L. 1048 (60), 1156 Hsu, W.N. 1073 (164), 1158 Hu, H. 540 (47), 580 (243), 617, 621 Hu, J. 346 (19), 373 Hu, L.Q. 1238 (93), 1297 Hu, N.X. 583 (276), 622 Hu, R. 346 (19), 373 Hu, X. 535 (9, 10), 616 Hu, Y. 580 (243), 621 Hua, S.-T. 100 (94), 103 Huang, C.-G. 658 (175), 663 Huang, H.H. 97 (64, 67), 98, 101 (67), 103, 193, 194 (143, 144), 195, 196 (143), 197 (143, 144), 198, 199 (144), 200 (150, 151), 204 Huang, P.L. 992 (143), 997 Huang, S.D. 1127 (456), 1164 Huang, X. 583 (277), 622 Huang, Y. 450 (193), 474, 589 (309), 623 Huang, Z.H. 1066 (116, 119), 1157 Hub, W. 685 (19), 740, 803 (143), 821 H¨ubel, M. 547 (79), 618 Huber, C.P. 329 (115), 334 Huber, E.W. 563 (157), 620 Huber, H. 66, 67 (111), 84, 166, 168, 179, 184, 185 (52), 202 Huber, J.E. 108 (29), 154 Huber, J.R. 163 (29), 202, 810 (157, 159 162), 811 (159, 160), 816 (162), 821 Hubler, K. 396 (91b), 419 H¨ubner, H. 484 (35), 526 Huch, V. 396 (91d), 419
1335
Hudec, J. 686 (25), 688 (32), 698, 700 (25), 740 Hudlicky, M. 638 (49), 660 Hudson, C.E. 216 (64, 65), 217 (80), 218 (65), 245 Hudson, K. 405 (150a), 421 Huehnerfuss, H. 1127 (460), 1164 Huerta, A. 1138 (530), 1166 Huffmann, K.R. 710 (115), 742 Hug, W. 151 (160), 152 (160, 162), 157 Hugel, H.M. 303 (27), 332 Hughes, D.L. 403 (140), 407 (159), 410 (183), 413 (198), 421, 422, 1228, 1232, 1235 (76), 1297 Hughes, E.D. 645 (97), 661, 859 (11), 868 (40), 877 (73), 889, 890, 897 (20), 947 Huh, K.T. 543 (61), 617 Huie, R.E. 824 (9), 827 (27 30, 32, 33), 828 (42), 835 Huisgen, R. 426 (16), 470, 639 (56), 660 Huizer, A.H. 754 (16), 818 Hulett, L. 329 (113), 334 Hull, K. 1071 (153), 1158 Hulst, R. 125 (79), 128 (85), 155, 1110 (393 396), 1163 Hummel, R. 1187 (79), 1213 Hummelink, T. 37 (56), 82 Hummelink-Peters, B.G. 37 (56), 82 Humski, H. 896 (17), 947 H¨unig, S. 186 (110), 204 Hunt, D.F. 289 (109), 293 Hunt, S. 512 (216), 530 Hunter, C.A. 430 (46), 471 Hunter, J. 59 (100), 83 Huo, J.Z. 1061 (92), 1156 Hurley, R. 1025 (134), 1038 Hurshman, A.C. 989 (106), 996 Hurst, W.J. 1067 (128), 1157 Hursthouse, M.B. 97 (66), 103, 456 (222), 475 Hurtaud, D. 544 (69), 618 Hurvois, J.P. 1107 (379 382), 1162, 1163 Husain, P.A. 1111 (398), 1163 Husain, S. 1137 (524), 1165 Husain, S.M. 859 (13), 889 Huse, G. 461 (252), 476 Husek, P. 1066 (116 118), 1068 (135), 1157 Hush, N.S. 445 (169), 474 Husinec, S. 585 (294), 622 Hussain, F. 1028 (156), 1038 Hussain, G. 1219 (26), 1251 (127), 1295, 1298 Hussey, C.G. 1046 (10), 1155 Hutchings, G.J. 556 (122), 619 Hutchins, R.O. 113, 114 (43), 154, 541 (49), 617 Hutchinson, N. 993 (147), 997 Hutchinson, N.I. 979 (78), 995 Hutchinson, P.J.A. 975 (12), 994
1336
Author index
Hutchinson, R.E.J. 504, 515, 518 (154), 529 Hutta, M. 1133 (499), 1165 Hutte, R.S. 1047 (42), 1155 Huttner, G. 115 (49), 154 Hutzinger, O. 1180 (54), 1182 (60), 1213 Hvistendahl, G. 226 (121), 227 (123), 236 (123, 169, 170), 239 (182), 246, 248 Hvoslef, J. 95, 96 (44), 102 Hwang, P.M. 976, 977 (44), 995 Hwang, Y. 1083 (253), 1160 Hwu, J.R. 534 (6), 605 (410), 610 (437), 615 (460), 616, 625, 626 Hyman, A. 975 (21, 22), 994 Hyman, A.L. 673 (42), 681, 975 (25), 994 Hynds, P.M. 1176 (27), 1212
Iannotta, A.V. 1105 (368), 1162 Ibata, T. 601 (385), 624, 1256 (135, 136), 1257 (136), 1258 (135, 140 142), 1259 (135), 1260 (140, 141), 1261 (141), 1298, 1299 Ibe, A. 1083 (245), 1160 Ibers, J. 24 (33), 82 Ibers, J.A. 654 (149), 662 Ibrahim, F.A. 1140 (548, 549), 1166 Ibrahim, P.N. 792 (116), 820 Ichikama, M. 1245 (113), 1298 Ichikawa, N. 767 (54), 819 Ichinose, N. 1086 (272), 1160 Ide, H. 833 (69), 836 Ideomoto, T. 657 (172), 662 Idowu, O.R. 1080 (224), 1159 Iffland, D.C. 628 (9), 659 Iglesias, A. 453 (206), 475 Iglesias, E. 643 (88), 644 (92, 96), 645 (88, 98), 660, 661, 677 (72), 681, 886 (101, 103), 887 (104), 888 (106), 891 Ignarro, L.J. 673 (42), 681, 974 (2), 975 (20 22, 25 28), 976 (32), 978 (60), 990 (108, 111), 992 (28), 993 (144), 994 997 Ignat’ev, N.V. 1238 (93), 1297 Ignatov, S.M. 553 (107), 618 Ihara, M. 580 (251), 621 Iizuki, H. 736 (192c, 192d), 745 Ikeda, M. 552 (98, 101), 618 Ikeda, S. 161, 163, 164 (22), 202 Ikeda-Saito, M. 984 (89), 989 (107), 996 Ikedo-Saito, M. 987 (100), 996 Ikegami, Y. 750 (6), 817 Ikemoto, N. 139, 141 (116, 117), 156 Ikenaga, K. 655 (154), 662 Ikenoue, T. 750 (6), 817 Ilczyszyn, M. 430 (57), 471 Ilett, K.F. 1033 (202), 1039 Iley, J. 606 (411), 625, 882 (86), 890
Il’ina, I.G. 444 (161), 474 Illingworth, W.S. 484 (40), 526 Illuminati, G. 1262, 1264 (147a), 1299 Imada, M. 543 (64), 617 Imada, Y. 535 (8), 576 (212), 593 (341), 616, 621, 623 Imafuku, K. 863 (25), 889 Imai, K. 1081 (233), 1091 (301 304), 1159, 1161 Imai, T. 112 (40), 154 Imai, Y. 590 (320), 623 Imam, M.R. 5, 16, 22 (8), 81 Iman, M.R. 27, 57 (30a), 82 Iman, S.H. 797 (131), 820 Imanaka, T. 534 (4), 616 Imasaka, T. 1095 (325), 1161 Imazumi, N. 1069, 1130 (147), 1158 Inaba, M. 541 (50), 617 Inabe, T. 437 (122, 123), 473 Inagaki, T. 563 (159), 620 Ing, H.R. 486 (56), 526 Ing, H.T. 883 (90), 890, 954 (24, 26), 961 (24), 968 (26), 970, 971 Ingemann, S. 216 (59), 219 (92), 220 (93 95), 222 (59), 223, 227 229 (93), 245, 246, 354 (54), 375 Ingold, C.K. 485 (50 52, 54, 55), 486 (57 60), 515 (50), 526, 859 (11), 868 (40), 889, 897 (20), 947 Ingold, E.H. 485 (52), 526 Ingold, K.U. 806 (147), 809 (152), 821 Ingold, K.V. 985 (96), 996 Inoue, A. 962 (51), 971 Inoue, H. 703 (101), 742 Inoue, M. 1119 (433), 1164 Inoue, N. 552 (100b), 618 Inoue, T. 596 (368), 624 Inoue, Y. 650, 652 (130), 661 In Quan, O. 824 (2), 835 Insogna, A.M. 688 (37), 740 Ioffe, S.L. 448 (192), 474, 608 (424), 625 Ion-Carastoian, A. 846 (38), 856 Ippoliti, J.T. 56 (80a), 83 Irgum, K. 1105 (370), 1162 Irion, M.P. 262 (54), 292 Irle, S. 848 (43), 856 Irsch, G. 165, 166, 192 (45), 202 Irving, K. 453 (206), 475 Isami, T. 561 (147), 619, 704 (105), 742 Ishibashi, N. 1095 (325), 1161 Ishida, A. 824 (11, 12), 835 Ishida, H. 843 (21), 855 Ishida, T. 647 (104), 661 Ishidate, M.J. 1131 (486), 1165 Ishidate, M.J.R. 1131 (488), 1165 Ishii, K. 123 (72), 155, 561 (148), 619 Ishii, S. 595 (355, 358), 624
Author index Ishii, Y. 654 (149), 662, 751 (9), 817 Ishikawa, M. 718 (147), 743 Ishimoto, M. 596 (361b), 624 Isildar, M. 1025 (136, 138), 1038 Isogami, Y. 1256, 1257 (136), 1258 (142), 1298, 1299 Isola, M. 1236, 1266 (159), 1299 Issa, R.M. 439 (134), 473 Issaq, H.J. 1094 (322), 1096 (327), 1149 (605), 1161, 1167 Ithakissios, D.S. 1099 (345, 346), 1162 Ito, K. 111 (36), 154, 536 (14), 565 (175), 617, 620 Ito, T. 654 (149), 662 Ito, Y. 602 (390), 624 Itoh, M. 565 (176), 620 Itoh, T. 1078 (206), 1159 Itoho, K. 1000 (1), 1035 Itou, K. 551 (89b), 618 Itsuno, S. 111 (36), 154, 536 (14), 565 (175), 617, 620 Ivanov, P.M. 57 (91), 83 Ivanova, E.V. 444 (161), 474 Ivanovi´c, M.D. 563 (160), 620 Iwamoto, H. 635 (31), 659 Iwamura, H. 312 (52), 333, 407 (156), 421 Iwanaga, H. 1092 (307), 1161 Iwanicka, I. 98 (75), 103 Iwasaki, M. 1080 (221), 1159 Iwasaki, T. 438 (125), 473 Iwashita, T. 139, 141 (117), 156 Iwata, J. 442 (151), 473 Iwata, S. 161, 163, 171 173 (21), 193, 197 (21, 142), 202, 204 Iyengar, R. 976 (31, 33), 978, 980 (31), 994 Iyer, L.M. 950 (8), 970 Izquierdo, P. 1077, 1098 (194), 1159 Izquierdo-Pulido, M.L. 1079 (214), 1159 Izumi, K. 1180 (51), 1213 Izumikawa, S. 1072 (159), 1158 Izumiya, N. 107 (26), 154 Jachak, M. 588 (307), 623 Jackson, R.A. 655 (163), 662 Jackson, S.W. 612 (448), 626 Jackson, W.A. 1069 (145), 1158 Jacob, C. 859 (3), 888 Jacob, E. 1046 (12), 1155 Jacob, G.S. 325 (109), 334 Jacobs, P.A. 580 (240), 621 Jacobsen, E.N. 119 (57, 58), 154 Jacobson, I. 1077 (193), 1159 Jacobus, D.P. 1027 (152), 1038 Jacox, M.E. 795 (126), 820 Jacques, J. 106 (6, 12), 153 Jacquesy, J.C. 609 (433), 625 Jaeger, R. 547 (79), 618
1337
Jaeger, W. 686, 699, 700, 706 (24), 740 Jaeken, J. 1078 (201), 1159 Jaff´e, H.H. 488 (80), 527, 811 (164), 821 Jagow, R.H. 896 (14), 947 Jaime, C. 5 (7), 81 Jakobson, G.G. (86), 334 Jakschik, B. 975 (24), 994 Janarthanan, N. 596 (367), 624 Jandera, P. 1077 (192), 1159 Jang, D.G. 534 (3), 616 Janini, G.M. 1094 (322), 1096 (327), 1149 (605), 1161, 1167 Janousek, Z. 403 (138a, 138b), 420 Jansen, E. 1078 (201), 1159 Janssen, M.G.A. 1128 (464), 1164 Janssens, J.J. 1142 (560), 1166 Janssens, S.P. 977, 979 (50), 995 Janzen, E.G. 807 (148), 821 Janzowsky, C. 1188 (86), 1214 Jaraki, O. 673 (43, 45), 681 Jarczewski, A. 435 (112), 460 (248, 249), 473, 476, 509 (190), 530 Jarema, M.A. 130 (91), 155 Jask´olski, M. 436 (114), 473 Jason, M.E. 68 (113), 84 Jaszberenyi, J.C. 548 (80), 618 Jatoe, S.D. 1030 (173), 1038 Jaunin, A. 63 (110b), 84 Javoy, M. 1049 (64), 1156 Jedrzejczak, K. 1065 (107 109), 1157 Jeffrey, G.A. 427 (27), 471, 1245, 1266 (112), 1298 Jeffs, G.E. 739 (202, 203, 205), 745 Jegorov, A. 1090 (293), 1161 Jenck, J. 588 (303), 623 Jencks, W.P. 431 (68), 432 (71), 466 (267), 472, 476, 943 (67), 948, 1265 (156), 1299 Jenkins, D.C. 992 (135), 997 Jenkins, E.L. 1061 (90), 1156 Jenkins, S.D.W. 1145 (575), 1167 Jenks, W.P. 407 (157b), 409 (177), 421, 422 Jennings, K.R. 284, 285 (101), 293 Jennings, W.B. 170 (65), 203 Jensen, B.S. 838 (6), 855 Jensen, C.B. 1029 (162), 1038 Jensen, R.G. 954, 963 (31), 971 Jensen, R.K. 57 (90a), 83 Jensen, T.E. 1177 (36), 1212 Jensen, W.B. 381 (10), 416 Jeon, Y.T. 690 (45), 691 (48), 740, 741 Jespersen, N.D. 1126 (448), 1164 Jeyaraman, R. 579 (228a), 621 Jezequel, S. 1284 (192), 1300 Ji, G.-Z. 404 (143, 144), 421 Ji, G.-Z.J. 401, 402 (133), 420 Jia, X. 1048 (60), 1156
1338
Author index
Jian, C. 1125 (442), 1164 Jiang, J. 557 (127), 559 (133, 134), 619 Jiang, W. 941, 943, 944 (64), 948 Jiang, X. 608 (422), 625 Jiang, Z. 846 (35), 855 Jimenez, J.J. 1025 (138), 1038 Jim´enez, P. 357 (70), 376 Jim´enez, R.M. 1074 (183), 1158 Jiminez, J.J. 1025 (136), 1038 Jiminez, P. 408 (168), 421 Jinfeng Cai 506 (168, 169), 529 Jino, H. 1081, 1091 (234), 1159 Jochims, H.W. 164, 166, 168 (32), 202 Johannsen, M. 571 (198), 620 Johannson, M. 1152 (623), 1168 Johansen, C. 109 (32), 154 Johansson, A.M. 62 (107), 84 Johansson, K. 1103 (357), 1162 Johansson, L. 1012 (78), 1036 John, M. 977 (45), 983 (86), 984 (45), 995, 996 Johns, A. 673 (42), 681 Johnsen, J. 675 (61), 681 Johnson, B.L. 317 (65), 333 Johnson, C.A.F. 803 (140), 821 Johnson, C.D. 510 (206), 530, 1006 (54), 1036 Johnson, D.C. 698 (98), 742, 1073 (166), 1074 (176), 1085 (268), 1158, 1160 Johnson, D.E. 785 (97b), 820 Johnson, D.J. 1142 (563), 1166 Johnson, E.M. 975 (24), 994 Johnson, J. 651 (137), 662 Johnson, J.S. 1119 (435), 1164 Johnson, K.G. 1065 (106), 1157 Johnson, L.F. 96 (53), 103 Johnson, M.R. 738 (201), 745 Johnson, M.W. 950 (13), 957 (45), 970, 971 Johnson, R. 98 (68), 103, 433 (78), 472 Johnson, R.L. 290 (118), 294 Johnson, R.S. 677 (77), 681 Johnson, T.A. 538 (38), 617 Johnson, W.C.Jr. 133 (102), 155 Johnson, W.H. 339 (9, 12), 341, 342 (12), 372 Johnston, D. 411 (185), 422 Johnston, L.J. 755 (19), 818 Johnstone, R.A.W. 171, 174 (72), 203, 206, 207, 233 (2g), 243 Johson, D.F. 1077 (190), 1159 Jollow, D.J. 1019 (94), 1022 (112), 1026 (142), 1029 (162), 1037, 1038 Jolly, W.L. 400 (124a), 420 Jones, C. 384 (28b), 417 Jones, D.S. 1118 (423), 1163 Jones, F.R. 1108 (385 387), 1163 Jones, H.O. 666, 668 (4), 680 Jones, J. 188 (120), 204 Jones, J.B. 1046 (10), 1155
Jones, J.H. 542 (52), 617 Jones, J.R. 508, 509 (184), 512 (216), 529, 530 Jones, N.D. 442 (147), 473 Jones, P.G. 98 (74), 99 (80, 84), 103 Jones, R.R.M. 1119 (435), 1164 Jones, W. 437 (121), 473 Jones, W.M. 497, 516 (134), 528 Jong, B.de 696 (78), 741 Jonge, C.R.H.I.de 637, 639 (44), 660 Jonge, L.H.de 1069 (143), 1158 Jonker, S.A. 697 (85), 741 Jonsson-Pettersson, G. 1103 (357), 1162 Jordan, K.D. 173 (77), 203 Jorgensen, F.S. 171, 174, 184, 188 (67), 203 Jørgensen, K.A. 571 (198), 620, 642 (79), 660, 675 (64), 678 (83), 681, 682 Jorgensen, M. 1142 (561), 1166 Jorgensen, W.L. 386 (46), 418 Jorgenson, J.W. 1079, 1080 (218, 219), 1159 Jørgenson, K. 1152 (623), 1168 Joris, L. 381, 395 (14b), 416 Jortner, J. 426 (11), 470 Joshua, C.P. 717 (143b), 743 Joswiak, A. 554 (115b), 619 Jothionandan, D. 975 (13 16), 994 Joussot-Dubien, J. 688 (35), 695 (74), 740, 741 Jovanovic, S.V. 827 (36), 835 Joyeux, M. 456 (226), 475 Juan, A.de 1225 (67), 1297 Juaristi, E. 15, 17 (23e), 81, 398 (113c), 420, 583 (275), 622 Judd, M.C. 954 (32), 971 Juffermans, J.P.H. 878 (75), 890 Julin, S. 576 (216), 621 Jumeau, E.J. 1049 (68), 1156 Jund, K. 576 (218), 621 Junek, H. 588 (307), 623 Jung, M. 121 (66), 155 Jung, M.E. 604 (396), 625 Jungk, S.J. 70 (117a), 84 Juranic, I. 585 (294), 622 Jurˇsi´c, B. 581 (253), 622 Juyn, S. 1097 (335), 1162
Kabachnik, M.I. 519 (238), 531 Kabalka, G.W. 565 (170, 171, 173), 566 (179a, 179b), 616 (464), 620, 626 Kacaniklic, V. 1103 (357), 1162 Kachanov, A.V. 133 (99, 100), 146 (136), 155, 156 Kachurin, O.I. 348 (31), 373 Kaddachi, M.T. 581 (258), 622 Kadeˇra´ bek, V. 438 (128), 473 Kaderlik, K. 1066 (115), 1157
Author index Kaderlik, K.R. 1033 (202, 203), 1039 Kadiri, A. 1136 (522), 1165 Kadlubar, F.F. 1003, 1004, 1009 (35), 1011, 1012 (35, 72), 1021 (109), 1029 (72), 1031 (35, 180), 1033 (202, 203), 1035 1037, 1039, 1066 (115), 1157 Kado, N.Y. 1132 (490), 1165 Kadorkina, G.K. 133 (98, 99), 146 (136), 155, 156 Kadota, H. 561 (148), 619 Kadowitz, P.J. 673 (42), 681, 975 (20 22, 25), 994 Kagel, R.A. 1047 (46), 1155 Kagiya, T. 833 (69), 836 Kahne, D. 1152 (622), 1168 Kai, M. 1080 (221), 1159 Kai, Y. 96 (49), 102, 614 (455), 615 (459), 626 Kaim, W. 163 166, 168 (27), 202 Kaise, M. 854 (64), 856 Kaiser, M. 1127 (459), 1164 Kaji, A. 605 (409b), 609 (435), 610 (439), 611 (440), 614 (452 454, 456, 457), 615 (458), 625, 626 Kajiwara, Y. 776 (66), 819 Kakabakos, S.E. 1099 (345, 346), 1162 Kakechi, H. 730 (181a), 744 Kakihana, M. 614 (452, 455), 626 Kakikawa, T. 565 (174), 620 Kakimoto, M. 590 (320), 623 Kakinuma, K. 1022 (117), 1037 Kakitani, N. 694 (58), 741 Kakiuchi, T. 1122 (439), 1164 Kalatzis, E. 633 (24, 25), 643 (86, 87), 644 (25, 90, 91), 659, 660 Kalbalka, G.W. 284, 285 (101), 293 Kalck, P. 588 (303), 623 Kalhern, T.F. 785 (97b), 820 Kalinin, A.V. 609 (432), 625 Kalinowski, H.O. 96 (49), 102, 1004 (42), 1035 Kalligas, G. 1139 (537), 1140 (547), 1166 Kallury, R.K.M.R. 269 (80), 287, 288 (106), 293 K´alm´an, A. 93 (27), 94 (34), 98 (27), 100 (27, 89), 102, 103 Kaltenbach, M.S. 1104 (365), 1162 Kamal, A. 108 (30), 154 Kamataki, T. 1004, 1007, 1009, 1034 (41), 1035 Kamath, H.V. 271, 273 (83), 293 Kambe, N. 563 (159), 596 (368), 620, 624 Kamens, R.C. 1179 (50), 1213 Kametani, T. 580 (251), 621 Kameyama, H. 1067 (124), 1157 Kamiga, S. 886 (100), 891 Kamigata, N. 736 (192b d), 745
1339
Kamimura, A. 605 (409b), 610 (438), 611 (440), 625 Kamimura, H. 848 (45), 856, 969 (65), 971 Kamlet, J. 381 (18), 417 Kamlet, M.J. 308 (39), 309 (39, 43), 333, 381 (15a, 15b, 16a d, 17d, 20b), 387 (53), 416 418, 428 (42), 433 (80), 439 (129), 443 (157, 158), 471 474, 1220 (38a, 38b, 39, 41a, 41b), 1221 (38a, 38b), 1222 (38a, 38b, 39, 51), 1238 (38a, 38b, 51), 1244 (38a, 38b), 1273, 1278 (179), 1296, 1299 Kamlett, M.J. 453 (203), 475 Kammerer, C. 652, 653 (140), 662 Kamminga, D.A. 1134 (511), 1165 Kamoonpuri, S.I.M. 461 (251), 476 Kampar, V.E. 636 (43), 659 Kampe, K.-D. 588 (306), 623 Kampffmeyer, H. 1003 (34, 36), 1005 1007, 1009, 1011, 1012, 1014, 1019 (36), 1020, 1022 (34), 1025 (133), 1027 (36), 1029 (36, 169), 1030 (36), 1035, 1038 Kamphuis, J. 142 (124), 156, 734 (185a), 744 Kanagasabapathy, V.M. 510 (203), 530 Kanai, Y. 1072 (155, 158, 159), 1158 Kanaoka, Y. 728 (172), 730 (178, 180a, 181a c, 181f, 182a, 182b), 733 (183c), 734 (186, 187, 188a, 188b), 744 Kanaoko, Y. 730 (177b), 744 Kanazawa, Y. 551 (94), 618 Kaneda, K. 534 (4), 616, 654 (151), 662 Kaneda, T. 1114 (405), 1163 Kanekiyo, T. 795 (128), 820 Kaneko, Y. 585 (293), 622 Kaniou, I. 1139 (537), 1140 (547), 1166 Kanjia, D.M. 303, 308 (37), 333 Kanno, S. 758 (33a, 33b, 34d), 818, 1180 (57), 1213 Kanters, J.A. 4, 14 (20), 81, 99 (86), 103 Kanth, J.V.B. 536 (17), 582 (266), 584 (281), 617, 622 Kao, J. 13 (18), 81 Kaplan, J. 599 (380), 624 Kaplan, L. 221 (110), 246 Kaplan, S. 637 (45), 660 Kapon, M. 98, 101 (76), 103 Kapoor, S.K. 832 (58), 836 Kaptein, R. 953 (22), 970 Kapturczuk, M. 992 (127), 997 Karaki, I. 698 (94), 742 Karaktov, S.D. 884 (95), 891 Karakus, C. 854 (65), 856 Kargin, Y. 848 (41a), 856 Karkowski, F.M. 57 (86), 83 Karlen, A. 62 (107), 84 Karni, M. 15, 16 (26b), 82, 208 (10), 244 Karrer, P. 483 (31), 526
1340
Author index
Karreth, S. 1026 (146), 1030 (146, 175, 177), 1038, 1039 Karube, I. 1103 (358), 1162 Karyakin, N.V. 353 (50), 375 Kashara, I. 715 (131), 742 Kashihira, N. 1047 (40), 1155 Kashino, S. 93 (15, 16), 98 (16), 102 Kashiwabara, Y. 992 (129, 131), 997 Kass, S.R. 408 (167a), 421 Kastening, B. 840 (10a d, 12c), 855 Kasukhin, L.F. 649 (118), 661 Kataoka, H. 1065 (110 112), 1157 Kataoka, K. 872 (56), 873 (57), 890 Kataoka, N. 722 (157b), 743 Kataoka, Y. 571 (197), 620 Katayama, A. 657 (172), 662 Katayama, M. 1069 (146), 1158 Katening, B. 869 (45), 889 Kato, M. 616 (465), 626, 1091 (303), 1161 Kato, R. 1003 (37), 1004, 1007 (41), 1009 (37, 41), 1012, 1013, 1019 (37), 1034 (41, 204), 1035 (37, 204), 1035, 1039 Kato, S. 193, 194, 197 199 (144), 204, 546 (75), 574 (205), 618, 620 Katoh, M. 312 (52), 333 Katritzky, A.R. 15, 17 (24a), 57 (89), 81, 83, 426 (13), 470, 491, 503 (100, 101), 504, 515, 518 (154), 527, 529, 546 (76), 554 (112 114, 115a c), 555 (115c, 116, 117), 556 (118 123), 557 (126, 127), 558 (128 132), 559 (133, 134), 560 (136), 593 (343), 604 (394), 607 (418), 618, 619, 623 625 Katriztky, A.R. 409 (171), 421 Katrusiak, A. 4, 13, 69 (17), 81, 145 (135), 156 Katsu, T. 1104 (364), 1162 Katsudi, S. 975 (6, 17, 18), 994 Katsuhara, Y. 722 (155), 743 Katsumata, S. 161, 163, 171 173 (21), 193, 197 (21, 142), 202, 204 Katsumi, M. 142 (123), 156 Katzenellenbogen, J.A. 547 (77), 618 Kau, C.-L. 978 (71), 995 Kaufman, M.J. 399 (117, 118), 420 Kaufman, S. 983 (80, 84), 985 (97), 996 Kaufmann, F. 717 (141), 743 Kaufmann, G. 657 (171), 662 Kaufmann, M. 1266 (163b), 1299 Kaupp, G. 1020 (95), 1037 Kavarnos, G.J. 446 (170), 474 Kawada, Y. 312 (52), 333 Kawaguchi, H. 873 (59), 890 Kawai, C. 978 (59, 66), 995 Kawai, M. 142 (123), 156, 695 (69), 741 Kawanisi, M. 698 (91), 741 Kawano, C. 650 (126), 661
Kawasaki, H. 396 (93), 419 Kawase, M. 592 (331), 623 Kawashima, T. 93, 98 (16), 102 Kawate, T. 565 (174), 620 Kawazura, H. 654 (149), 662 Kawenoki, I. 692 (51), 741 Kayamoto, T. 1104 (364), 1162 Kaye, D.M. 992 (133), 997 Kazanis, S. 1001, 1003, 1005 1008, 1010, 1011, 1014, 1031, 1032 (30), 1035 Kazerouni, M.R. 436 (118), 473 Kazitsyna, L.A. 636 (40), 638 (48), 659, 660 Kazuhisa Iwasawa (88), 334 Keana, J.F.W. 537 (33), 617 Keaney, J. 673 (43), 681 Keaney, J.F. 673 (45), 681 Kearns, D.R. 1048 (60), 1156 Kebarle, P. 235 (159), 247, 256 (34, 35), 257 (37), 258 (37, 38), 288 (107), 292, 293, 384 (32), 385 (34c, 34d, 37a, 37b, 40), 392 (73), 417 419 Kedderis, G.L. 1031 (183), 1039 Kee, R.J. 1174 (4), 1212 Keeble, D.J. 834 (74), 836 Keefer, L.K. 448 (189), 474 Keenan, G. 355, 356 (58), 375 Keesee, R.G. 385 (41), 418 Keever, J.T. 1066 (123), 1073 (164), 1157, 1158 Keffer, L.K. 144 (132), 156 Keiderling, T.A. 147, 148 (140, 141), 156 Keilin, D. 975 (7), 994 Keinan, E. 568 (186), 620 Keire, D.A. 1004 (44), 1036 Keita, B. 692 (51), 741 Kellogg, R.M. 127 (81), 155 Kelly, D.P. 303 (27), 332 Kelly, F.W. 505 (160), 529 Kelly, R.A. 992 (127, 133), 997 Kemp, T.J. 780 (76, 78, 79), 819 Kempsell, S.P. 955 (41, 42), 956 (42), 971 Kemula, W. 840 (12b), 847 (40a), 855, 856 Kende, A.S. 609 (434), 625 Kennard, O. 37 (56), 82, 433 (74 77), 453 (205), 472, 475 Kenne, L. 62 (107), 84 Kennedy, R.M. 112 (40), 154 Kensuke Takashi (88), 334 Kenyon, G.L. 165, 166 (44), 202 Keough, T. 234 (156), 247 Kern, M. 434 (91), 472, 1262, 1266 (145), 1299 Kerr, S.W. 673 (38), 681 Kervagoret, J. 613 (451), 626 Kessar, S.V. 721 (152), 722 (152, 158b), 743 Kessel, C.R. 166 (53), 202 Kessik, M.A. 945 (70), 948
Author index Ketterer, B. 672 (36), 680, 1003, 1004, 1009, 1011 (35), 1012 (35, 85), 1031 (35), 1033 (85), 1035, 1036 Keuchel, C. 1128 (462, 463), 1164 Keuhnelian, A.M. 434 (96), 472, 1247 (122), 1298 Keumi, T. 650, 652 (130), 661 Keute, J.K. 807 (149b), 808 (151), 821 Kevill, D.N. 1220 (47), 1296 Khamsi, J. 538 (36), 584 (278), 617, 622 Khan, S.H. 1069 (141), 1158 Kharasch, M.S. 338 (2a), 354 (51), 358 (74), 359, 361 (2a), 372, 375, 376 Kheir, A.A. 414 (201), 422 Khetrapal, C.L. 317, 320, 321 (90), 334 Khmel’nitzki, L.I. 628 (8), 659 Kicherer, M. 1079 (213), 1159 Kido, A. 1065 (113), 1157 Kienle, R.H. 648 (110), 661 Kiese, M. 1000 (10, 13 17), 1009 (10), 1020 (16, 17, 100), 1021 (17, 101), 1022 (14, 16, 100, 101), 1023 (10), 1027 (16, 17), 1028 (16, 101), 1029 (159), 1035, 1037, 1038 Kiff, R.J. 991 (117), 996 Kiguchi, T. 724 (162b, 166b), 743, 744 Kikuchi, T. 651, 657 (132), 661, 1144 (570), 1166 Kikuchi, Y. 778 (74), 819, 1083 (245), 1160 Kikugawa, Y. 592 (331, 332), 623, 871 (53), 890 Kikukawa, K. 654 (150, 152), 655 (153 155), 657 (170, 172), 662 Kilbourn, R.G. 991 (118), 996 Kim, B.H. 534 (5), 616 Kim, C.-K. 896, 935, 941 (18), 947 Kim, E.G. 563 (155), 620 Kim, E.K. 455 (216), 475, 790 (111d), 820 Kim, J.C. 886 (99), 891 Kim, J.H. 1066 (120), 1157 Kim, J.M. 692 (50), 741 Kim, J.U. 688 (43), (44), 740 Kim, K. 1134 (510), 1165 Kim, K.H. 506 (174), 522 (245), 529, 531 Kim, K.R. 1066 (120), 1157 Kim, K.-W. 118, 119 (55), 154 Kim, N. 993 (146), 997 Kim, S. 596 (369), 602 (386), 624 Kim, S.C. 108 (27), 154 Kim, S.H. 1147 (589), 1167 Kim, T. 1134 (510), 1165 Kim, Y.H. 654 (148), 662, 666, 667, 670 (6), 672 (6, 34), 677 (76), 678 (78), 680 682 Kim, Y.J. 396 (86b), 419 Kimoto, M. 776 (66), 819 Kimura, E. 390, 391 (68), 419 Kimura, H. 765 (47), 818, 975 (6), 994 Kimura, K. 161, 163, 171 173 (21), 193, 197
1341
(21, 142), 202, 204, 722 (157b), 743 Kimura, M. 585 (292), 622 Kimura, T. 933 (47), 947 Kinchesh, P. 330 (123, 124, 127), 331 (127), 332 (130, 131), 335 King, C.R. 730 (181d), 744 King, J.A.Jr. 590 (317), 623 King, J.F. 737 (198), 745 King, M.M. 318 (78), 334 Kingston, D.H. 722 (156a), 743 Kingston, E.E. 266 (73), 293 Kinoshita, M. 735 (190b), 745 Kinouchi, T. 1180 (51), 1213 Kinsley, S.A. 590 (322), 623 Kint, S. 151, 152 (160), 157 Kira, M. 163 166, 168 (27), 202 Kirby, A.J. 15, 17 (23a), 81, 98 (74), 99 (80, 84), 103, 351 (38), 374 Kirby, S.P. 218 (83), 245, 338, 361 (2), 371, 410 (188), 422 Kirchmeier, R.L. 593 (345), 623 Kirchnerova, J. 1175 (12), 1212 Kiriazides, D.K. 1177 (30), 1212 Kirichenko, V.E. 1062 (94), 1156 Kirilenko, A.G. 547 (78), 618 Kirita, K. 1047 (40), 1155 Kirschbaum, J. 1082 (235, 236), 1159, 1160 Kirst, H.A. 535 (13), 616 Kirsten, E. 1024 (123), 1037 Kiseki, Y. 655 (153), 662 Kishi, H. 258 (38), 292 Kishikawa, K. 796 (130), 820 Kishimoto, J. 978 (70), 995 Kiss, A. 431 (61), 471 Kiss, T. 406 (155), 421 Kitaguchi, H. 108 (29), 154 Kitajima, H. 650, 652 (130), 661 Kitamura, F. 1096 (328), 1161 Kitamura, R. 1069, 1130 (147), 1158 Kjellerup, V. 1047 (26), 1155 Klabunde, K.J. 591 (324), 623 Klapper, M.H. 827 (37 40), 828 (41), 835 Klar, G. 96 (58), 103 Klasinc, L. 176 (87), 180 (95), 188 (122, 123), 199 (147), 200 (149), 203, 204 Klatt, P. 985 (92), 990 (109), 991 (122), 992 (136, 137), 996, 997 Klausener, A. 870 (48), 890 Klebe, G. 413, 414 (197), 422 Kleemiss, W. 551 (95), 618 Klehr, H. 1001 (24, 26), 1003 (24, 38, 39), 1004 (24, 26, 38), 1005 (38), 1007 (24, 38, 39), 1008 (38), 1009 1011 (24, 26, 38), 1012 (24, 26, 38, 39), 1013 (24, 38), 1014 (24, 26, 38), 1015 (26), 1029 (39), 1035 Klein, G. 1020, 1022 (100), 1037 Klein, M. 139 (113), 156
1342
Author index
Klein, N.M. 977 (48), 995 Klemchuk, P.P. 825 (23), 835 Klessinger, M. 171, 174, 184, 188 (66), 203 Klibanov, A.M. 108 (29), 154 Kliner, D.A.V. 416 (211), 422 Klingebiel, U. 396 (91f), 419 Klink, J.R. 877 (70), 890 Klinowski, J. 437 (121), 473 Klopman, G. 642 (80), 660 Klose, W. 268 (77, 79), 269 (79), 293 Klotz, H. 1116 (408), 1163 Klotz, I.M. 670 (28), 680 Kl¨otzer, W. 639 (54), 660 Kluft, E. 220 (95), 246 Klunkin, G. 685, 686 (7), 740 Klvana, D. 1175 (12), 1212 Klyne, W. 106, 113 (5), 153 Knicker, H. 321 (95), 334 Knight, R.L. 1255 (134), 1298 Knipe, A.C. 507, 512 (181), 529 Knipmeyer, S.E. 346 (20), 350 (35), 373, 374 Knize, M.G. 1033 (199, 200), 1039 Knochel, P. 96 (49), 102, 580 (244), 621 Kn¨opfel, N. 160 (13), 201 Knowles, R.G. 976 (39, 41), 978, 980 (39), 991 (117), 992 (134), 994, 996, 997 Knudson, G.B. 1176 (27), 1212 Ko, A. 1175 (17), 1212 Kobayashi, A. 551 (91), 618 Kobayashi, H. 635 (31), 659 Kobayashi, K. 169 (64), 203, 758 (33a, 33b, 34b, 34d, 34e), 818, 1079 (212), 1159 Kobayashi, M. 184, 185 (108), 204, 736 (192b d), 745 Kobayashi, T. 169 (64), 171 (73), 192 (135), 193, 197 (140), 203, 204 Kobayashi, T.K. 715 (131), 742 Kobzik, L. 992 (133), 997 Koch, R.L. 1032 (196), 1039 Koch, T.H. 710 (114), 742, 807 (149b, 150), 808 (151), 821 Koch, W. 209 (31), 234 (150), 244, 247 Kochi, J.K. 439 (133), 440 (142), 455 (213 216), 456 (221), 473, 475, 789 (107), 790 (107, 109a, 110, 111a, 111d), 792 (115), 820 Kocian, , O. 396 (96), 419 Kocjan, D. 62 (106), 84 Kocovsky, P. 574 (207), 621 Kodama, M. 390, 391 (68), 419, 1122 (440), 1147 (587), 1164, 1167 Kodera, Y. 535 (8), 616 Koeman, J.H. 1188 (86), 1214 Koen de Vries, N. 125 (79), 128 (85), 155, 1110 (393 396), 1163 Koestler, C.J. 1145 (574), 1167 Koetzle, T.F. 94 (39), 102
Koga, K. 396 (93), 419 Koga, Y. 34, 35 (45), 82 Koge, M. 962 (51), 971 Koh, H.J. 936 (54), 948 Koh, J.S. 108 (27), 154 Koh, L.L. 97 (64), 103 Kohnstam, G. 448 (191), 474, 869 (44), 889 Kohra, S. 541 (50), 585 (292), 617, 622 Kohzuki, T. 824 (11), 835 Koike, A. 649 (120), 661 Kojima, E. 1080 (221), 1159 Kojima, N. 724 (163), 743 Kojima, S. 459 (244), 476 Kojima, T. 7 (11), 81 Kok, R.A. 27, 57 (30a), 82 Kokars, V.R. 636 (43), 659 Kokkinidis, G. 844 (26, 27), 855 Kol, M. 579 (230, 231), 621 Kolbe, H. 482 (20), 525 Koller, S. 636 (42), 659 Kollman, P.A. 3 (2a, 2b), 60 (103a, 103b), 81, 83, 165, 166 (44), 202, 1266 (166a), 1299 Kolodziejczyk, H. 1081 (227, 228), 1159 Kolster, K. 141 (120), 156 Koltypin, Y. 133 (101), 155 Koltypin, Yu. 149 (151), 157 Komaki, T. 308, 309 (42), 333 Komaromi, I. 1152 (621), 1168 Komatsu, K. 767 (54), 819 Kometani, J.M. 767 (50b, 51), 819 Komissarov, V.N. 576 (215), 621 Komiya, Y. 591 (326), 623 Komori, Y. 990 (108), 991 (114), 996 Kondo, S. 34, 35 (45), 82 Kondratenko, N.V. 1238 (93), 1297 Konior, R.J. 968 (61), 971 K¨onnecke, A. 273, 274 (84), 293 Konno, R. 1089 (290), 1161 Kono, K. 657 (172), 662 Konyeaso, R.I. 1100 (350), 1162 Kooijman, H. 4, 14 (20), 81 Kooijman, J.G.A. 1116 (408), 1163 Koopmans, T. 160, 163, 190 (17), 201 Kopf, J. 96 (58), 103, 396 (95), 419 Koppang, M.D. 1081 (229), 1159 Koppel, A. 384 (29), 417 Koppel, I. 235, 236 (165), 247, 524 (254), 531 Koppel, I.A. 1238 (87a, 89, 93), 1239 (87a), 1297 Koppen, B. 1072 (161), 1158 Korenman, Y.I. 1135 (517), 1165 Korn, S.R. 435 (107), 472 Kornblum, N. 611 (442), 625, 628 (9), 650 (125), 659, 661 Korneev, V.A. 133 (100), 155 Kornfield, R. 209 (27), 244 Kort, W. 677 (77), 681
Author index Korth, H.G. 985 (96), 996 Kort¨um, G. 491, 500 (107a), 527 Korytsky, O.L. 878 (74), 890 Korzeniowski, S.H. 902 (25), 947 Koscielniak, J. 1022 (116, 117), 1037 Kosevich, M.V. 1119 (431, 432), 1164 Kosfeld, H. 763 (41), 818 Koshy, K.M. 945 (71), 948 Kosmidis, C. 1127 (454), 1164 Kosower, E.N. 424 (5), 470 Kossanyi, J. 692 (51), 741 Kosse, P. 396 (91d), 419 Kossowski, T. 1146 (582), 1167 Kost, D. 1009 (67), 1036 Kostyanovskii, R.G. 553 (107), 618 Kostyanovsky, R.G. 132 (96), 133 (96, 98 100), 146 (136), 155, 156 Kostyukovskii, Ya.L. 1147 (593), 1167 Kosuga, K. 978 (59, 66), 995 Kotake, M. 123 (71), 155 Kotani, M. 1122 (439), 1164 Kotera, K. 730 (182b), 744 Kothandaraman, H. 441 (143), 473 Kotiaho, T. 1107 (383), 1163 Koty, P.P. 979 (78), 995 Kotynek, O. 112, 113 (41), 154 Kotynski, A. 1148 (602, 603), 1167 Kovac, B. 66, 67 (111), 84, 166, 168 (52), 176 (87), 179, 184, 185 (52), 202, 203 Kovacic, P. 552 (102), 618 Kowaluk, E.A. 673 (48), 681 Kowski, K. 163 (26), 164, 165 (26, 36), 166, 170, 172, 175, 189, 192, 195, 201 (26), 202 Koyama, K. 551 (89b), 618, 730 (178), 744 Kozak, A. 1139 (540), 1166 Kozak, M. 977 (54), 995 Koziara, A. 537 (32), 540 (44), 542 (55), 617 Kozina, M.P. 347 (25), 373 Koziol, A.E. 554 (115a), 619 Koziol, B. 459 (242), 476 Koziol, J. 439 (135), 440 (136), 473 Krabbenhoft, H.O. 224 (114), 246 Krackov, M.H. 1250 (124), 1298 Kracov, M.H. 426 (17), 470 Krajnovich, D. 795 (122), 820 Kralicek, P. 1073 (163), 1158 Kramer, H. 672 (36), 680 Kramer, M.P. 591 (324), 623 Kramer, P.A. 1027 (151), 1038 Krane, J. 74 (125), 84 Krattiger, B. 1093 (315), 1161 Krauklish, I.V. 1137 (526), 1141 (554), 1166 Krause, R. 1027, 1028 (154), 1038 Krause, W. 443 (154), 474 Krecz, I. 1089 (288), 1161 Krenmayr, P. 642 (77), 660 Krepelka, J. 633 (26), 659
1343
Kresge, A.J. 409 (176), 421, 658 (175), 663, 1272 (173), 1299 Krestonosich, S. 692, 702, 709 (53), 741 Kresze, G. 668 (13), 677 (77), 680, 681, 803 (143), 821 Kreutzer, A. 1175 (15), 1212 Kricheldorf, H.R. 324 (107), 325 (106), 334 Krieger, C. 95 (43), 102, 436 (113), 473 Kriessmann, U. 588 (307), 623 Krijnen, B. 694 (65), 741 Krishnamohan Sharma, C.V. 452 (197, 198), 475 Krishnamurthy, R.V. 1060 (87), 1156 Krishnamurthy, V.V. 510 (204), 530 Krishnan, A.M. 606 (413), 625 Krishnan, R. 407 (163), 421 Krishnan, V. 753 (10), 817 Krishnani, K.K. 405 (151b), 421 Kristjansen, O. 1047 (26), 1155 Krist´of, E. 386 (45a), 418 Krizsan, K. 1089 (288), 1161 Krogh Andersen, E. 93 (29), 98 (70), 102, 103 Kroh, J. 824 (14, 15), 835 Krok, K.A. 1077 (191), 1159 Krolikiewicz, K. 603 (391), 624 Krom, J.A. 399 (120), 420 Kroon, J. 4, 14 (20), 81, 99 (86), 103 Kroschwitz, J.I. 310 (47), 333 Krueger, W.E. 886 (98), 891 Kruger, C. 139 (113), 156 Kruger, G.J. 97 (62), 103 Krull, I.S. 1067, 1076 (126), 1083 (243, 244), 1157, 1160 Kruse, C.G. 539 (40), 617 Kruzik, P. 1139 (535), 1166 Krygowski, T.M. 98 (69), 99 (85), 103, 444 (160), 454 (210), 474, 475, 522 (243), 531, 840 (12b), 848 (43), 855, 856 Krzeminski, J. 1150 (607), 1167 Ku, H. 652 (139, 140), 653 (140), 662 Kuang, J. 4, 29 32 (43), 82 Kubacki, S.J. 1188 (85), 1214 Kubena, L.F. 1139 (543), 1166 Kuberski, S. 770 (57), 819 Kubo, J. 704 (103, 105), 742 Kubo, Y. 730 (180a, 180b), 733 (183b), 744 Kubota, M. 94 (31), 99 (83), 102, 103 Kuchitsu, K. 24 (32), 56 (84a, 84b), 82, 83 Kuck, D. 208 (14), 212 (41, 42), 213 (42), 214 (14, 41, 42), 215 (14), 216 (41, 42), 225 (42), 244 Kuckowski, R.L. 431 (69), 472 Kudo, K. 596 (362), 624 Kudo, T. 608 (428, 429), 625 Kudzin, Z.H. 1148 (602, 603), 1167 Kuem, S.R. 866 (35), 889 Kuhn, H.J. 783 (93), 820
1344
Author index
Kuhn, R. 1082 (239), 1160 Kuhn, S.J. 448 (191), 474 Kuhnle, W. 697 (84, 85), 741 Kuhr, W.G. 1118 (422), 1163 Kukhar, V.P. 547 (78), 618 Kukhtenko, I.I. 869 (46), 890 Kulh´anek, J. 507 (178, 179), 529 Kulkarni, P.S. 271, 273 (83), 293 Kulkarni, S.N. 271, 273 (83), 293 Kumakura, S. 98 (72), 103 Kumar, A. 580 (250), 621 Kumar, A.C. 317, 320, 321 (90), 334 Kumar, B.S.A. 322 (101), 334 Kumar, C.V. 738 (199), 745 Kumar, L. 1139 (534), 1166 Kumar, M. 824, 826, 827 (4), 828 (4, 42), 835 Kumar, M.U. 600 (382), 624 Kumar, N. 143 (130), 156 Kumaraswamy, P. 1175 (13), 1212 Kumi´nska, M. 392 (76), 419 Kun, E. 1024 (123 127), 1037 Kunitake, T. 1122 (440), 1164 Kunst, A.G.M. 696 (79), 741 Kuntz, B.A. 115 (50), 154 Kuntz, I. 463, 465, 466 (256), 476 Kunz, D. 992 (128), 997 Kuokkanen, T. 648 (111), 649 (123), 661 Kupezyk-Subotkowska, L. 860, 861 (17), 863 (22), 889 Kupletskaya, N.B. 638 (48), 660 Kurahashi, M. 502 (147), 529 Kurian, E.M. 1141 (555), 1166 Kuroishi, Y. 98 (72), 103 Kurokawa, Y. 798 (133), 799 (133, 134), 800 (134), 801 (135), 802 (136), 821 Kurono, S. 647 (104), 661 Kurtz, A.N. 589 (312), 623 Kuruc, J. 833 (67), 836, 1133 (499), 1165 Kurz, J.L. 933 (48, 49), 934 (49), 935, 938 (48, 49), 947 Kurzweil, P.R. 68 (113), 84 Kusaba, M. 824 (11, 12), 835 Kusano, E. 1072 (162), 1158 Kusters, E. 1090 (296), 1161 Kusumoto, S. 852 (61), 856 Kuthan, J. 184, 185 (108), 204 Kutz, V.S. 1272 (176), 1299 Kuvihara, T. 870 (50), 890 Kuwahara, H. 534 (4), 616 Kuwana, T. 1079 (216), 1080 (220, 223), 1096 (328), 1159, 1161 Kuwata, S. 1090 (297), 1092 (307), 1161 Kuzmenko, V.V. 552 (97), 618 Kuzmic, P. 756 (21), 757 (24), 789 (105), 818, 820 Kuzmicky, P.A. 1132 (490), 1165
Kuzmierkiewicz, W. 554 (115a), 619 Kuz’min, V.A. 684 (6), 740 Kuznetsova, O.P. 352 (43), 374 Kwackman, P.J.M. 1105 (369), 1162 Kwakman, P.J.M. 1134 (511), 1165 Kwart, H. 859 (15), 860 (17), 861 (17, 19), 863 (23), 889, 897 (22), 899 (23), 904 (26), 905 (29), 947 Kwiatkowski, S. 96 (49), 102 Kwok, E.S.C. 1177 (44), 1213 Kwok, H.S. 795 (121), 820 Kwon, N.S. 976 (37, 38), 978 (37, 38, 58), 980, 983 (37), 985 (91), 994 996 Kydd, R.A. 35 (50), 82 Kyziol, J.B. 593 (346), 623, 878 (76), 890
Labanowski, J.K. 29 (42), 82 Lablache-Combier, A. 684 (4, 5), 698 (93), 724 (161), 727 (168), 740, 742, 743, 744 Labudzinska, A. 1096 (333), 1161 Lacasse, R. 843 (17), 845 (33), 846 (34), 855, 1129 (468 470), 1164 Lacey, M.J. 267 (74), 293 Lacey, M.P. 234 (156), 247 Lachkar, A. 395 (83), 419 Lackey, D.A. 1024 (123), 1037 Lacourse, W.W. 1073 (166), 1158 Lacroix, M.D. 1145 (571), 1166 Lacy, N. 1134 (505), 1165 Ladell, J. 435 (99), 472 Laderoute, K. 216 (62), 245 Ladure, P. 453 (206), 475 Lady, J.H. 434 (89, 93, 94), 472 Lafarge-Frayssinet, C. 1025 (137), 1038 Laffitte, M. 349 (32), 374 Lafon-Cazal, M. 991 (124), 996 Lagowski, L.L. 400 (124b), 420 Lahav, M. 1108 (388), 1163 Lahbabi, N. 598 (373), 624 Lahmani, F. 810 (158), 821 Lai, Z.G. 941 (62, 63), 948 Laidig, K.E. 403 (142), 421 Laidler, K.J. 78 (131), 84, 894 (9), 947 Laikhter, A.L. 852 (59), 856 Lakom´y, J. 519 (237), 531 Lalonde, M. 1066 (121), 1157 Lam, J.N. 593 (343), 623 Lam, S. 1078 (202), 1159 Lam, Y.L. 97 (64, 67), 98, 101 (67), 103 Lam, Y.-T. 217 (70), 245 Lamas, S. 977 (52), 979 (72), 995 Lambe, T.M. 646 (102), 661 Lambert, C. 397 (103), 420 Lambert, J.B. 317 (70), 333 Lambert, W.E. 1061 (92), 1156 Lamont, R.B. 598 (376), 624
Author index Lancaster, J.S. 1108 (384), 1163 Lancaster, M. 737 (196), 745 Land, E.J. 827 (35), 835 Landeck, H. 434 (84, 89), 472 Landells, R.G.M. 648 (107), 661 Landini, D. 616 (462, 463), 626 Landor, S.R. 109 (33), 110 (33 35), 113 (33, 42), 154 Landsheidt, H. 870 (48), 890 Lang, H. 558 (129), 619 Lang, J. 1146 (584), 1167 Lang, N.P. 1066 (115), 1157 Langa, F. 715 (132), 716 (132, 134, 135), 742 Langenaeker, W. 388 (58), 418 Langer, M. 1090 (291), 1161 Langford, E.J. 673 (40), 681 Langlotz, I. 396 (99, 100), 420 Langstrom, B. 932 (44, 45), 933 (46), 947 Lank, W. 1030 (177), 1039 Lanzone, L. 1085 (261), 1160 Lapat, A. 1113 (403), 1163 Lapidus, A.L. 596 (360), 624 Lapierre, J.C. 639 (59), 660 Lapouyade, R. 446 (172), 474, 697 (87), 741 Lapworth, A. 483, 507 (27), 525 Lardeux, C. 810 (158), 821 Lardicci, L. 575 (211), 621 Larka, E.A. 265 (67), 267 (76), 293 Larock, R.C. 657 (173), 663 La Rosa, C. 539 (39), 617 Larsen, E. 212, 222 225 (44), 244 Larsen, I.K. 100 (87), 103 Larsen, N.W. 171 (68), 203 Larson, J.R. 698 (98), 742 Larson, J.W. 385 (35a e, 38a c, 39a, 39b), 418 Larson, R.A. 1136 (523), 1165 Larsson, S. 184 (100), 203 Larsson, U. 583 (272), 622 Laschever, M. 289 (111), 293 Lasia, A. 450 (193), 474 Latajka, Z. 27 (41), 82 Lathan, W.A. 208 (4), 244 Latif, M. 558 (130), 619 La Torre, F. 1262, 1264 (147a), 1299 Lattes, A. 587 (298), 622 Lau, D.T.W. 1142 (562), 1166 Lau, M.P. 811 (163), 821 Lau, W.M. 290 (116), 294 Lau, Y.H. 288 (107), 293 Lau, Y.K. 392 (73), 419 Lauderdale, W.J. 77 (130), 84 Lauransan, J. 381 (18), 417 Laurence, C. 381 (17d, 17e), 395 (82 84), 417, 419, 451 (195), 474, 505 (158, 159), 529, 1222 (51), 1238 (51, 87b), 1296, 1297 Laurent, A. 566 (180), 567 (183), 620
1345
Lauterbur, P.C. 317 (75), 334 Lavagnini, I. 1147 (592), 1167 Lavallee, R.L. 1217 (16), 1295 Lavigne, A. 580 (252a, 252b), 621 Laviron, E. 841 (14, 15), 843 (16, 17), 845 (33), 854 (69), 855, 856, 1129 (467 471), 1143 (565), 1144 (471), 1164, 1166 Law, C. 1187 (79), 1213 Law, K.Y. 637 (45), 639 (53), 660 Lawesson, S.O. 642 (79), 660, 675 (64), 678 (83), 681, 682 Lawler, H.J. 653 (144), 662 Lawrance, G.A. 851 (53), 856 Lawson, J.P. 575 (210), 621 Lay, P.A. 851 (53, 54), 854 (54), 856 Layer, R.W. 1197 (108), 1214 Layne, W.S. 811 (164), 821 Laza, M.R.C. 1047 (25), 1155 L´azaro, F. 1137 (527), 1166 Lazdins, D. 877 (70), 890 Lazzari, D. 551 (93), 618 Leaf, C.D. 976 (33), 994 Leahy, D.E. 1222 (57, 58), 1296 Leahy, D.J. 795 (125), 820 Leardini, R. 655 (158), 662 Leathy, D.E. 1222 (60), 1297 Lebedev, Y.A. 352 (43), 374 Leblanc, J.-P. 584 (286), 622 Leblanc, Y. 550 (86a, 86b), 574 (206), 618, 621 Leboutet, L. 576 (214), 621 LeBreton, P.R. 188 (113, 115 119), 204 Le Bris, M.T. 697 (88), 741 Lecher, H. 666 (3), 680 Lechevallier, A. 607 (416), 625 LeClouerec, E. 563 (165), 620 L´ecolier, S. 591 (327), 595 (359a), 623, 624 LeCorr´e, M. 536 (19), 617 Lecoultre, J. 179 (94), 203 LeDemenez, M. 400 (126), 420 Ledingham, K.W.D. 1127 (453, 454), 1164 Lee, A.W.M. 1097 (337), 1162 Lee, B.C. 936 (54), 948 Lee, B.-S. 936 (54), 948 Lee, C. 1058 (76), 1156 Lee, C.K. 749 (4), 817 Lee, C.M. 426 (17), 470, 1250 (124), 1298 Lee, C.P. 691 (48), 741 Lee, C.S. 108 (27), 154, 604 (403), 625 Lee, C.-W. 844 (24), 855 Lee, F.S.C. 1177 (31), 1212 Lee, G.A. 580 (242), 621 Lee, H.C. (41), 740 Lee, H.H. 329 (117), 334 Lee, H.J. 534 (2), 616 Lee, H.W. 534 (2), 616, 950 (13), 970 Lee, I. 936 (54), 948
1346
Author index
Lee, J. 446 (175), 474 Lee, J.B. 581 (255), 622 Lee, J.R. 502 (148), 503 (149), 529 Lee, K.C. 534 (5), 616 Lee, K.-Y. 94 (33), 102, 369 (99), 370 (99 102), 378 Lee, L.K. 188 (116, 117), 204 Lee, M.L. 1047 (37), 1155 Lee, N.E. 577 (220), 621 Lee, N.H. 534 (5), 616 Lee, S.H. 1085 (259), 1160 Lee, S.J. 1103 (363), 1162 Lee, S.Y. 97 (64), 103 Lee, S.-Y.C. 130, 131 (92), 155 Lee, T.A. 1059 (82), 1156 Lee, T.D. 978 (63, 65), 995 Lee, T.H. 192, 193, 200, 201 (136), 204 Lee, T.V. 584 (284), 622 Lee, W.Y. 1083 (249), 1160 Lee, Y.H. 1093 (317), 1161 Lee, Y.T. 795 (121, 122), 820 Leeder, J.S. 1001, 1007, 1009, 1011 (28), 1027 (28, 155), 1035, 1038 Leeds, J.P. 535 (13), 616 Lees, C. 673 (41), 681 Lees, D.E. 1025 (132), 1038 Leeuwen, P.A.M.van 1078 (203), 1159 Lefebvre, R.A. 1062 (93), 1156 Leffek, K.T. 509 (190), 530 Leffler, J.E. 424 (2), 470 Lefker, B.A. 168 (61), 202 Lefkowitz, S.M. 824 (10), 835 Legon, A.C. 428 (37, 38), 471 Legrand, M. 106 (8), 153 LeGrel, P. 544 (69), 618 Legua, C.M. 1097 (339), 1162 Legube, B. 1079 (208), 1159 Lehn, J.-M. 390 (67), 392 (77), 419, 428 (32, 33), 471 Lehtonen, P. 1083 (251), 1160 Leinhos, U. 697 (84, 85), 741 Leis, J.R. 644 (96), 661, 675 (57, 60), 677 (72), 681, 886 (101, 103), 888 (106), 891 Leiserowitz, L. 1108 (388), 1163 Leister, D. 13 (18), 81 Lejon, T. 563 (165), 620 Lelievre, J. 415 (203, 207, 209), 416 (212), 422, 1222 (49a, 49b), 1296 Lelj, F. 321 (93), 334 Lemaire, M. 537 (31), 617 Lembach, L.A. 1097 (336), 1162 LeMelle, J. 303, 305 (31), 333 Lemieux, L. 1104 (366, 367), 1162 Lemire, G.W. 1125 (444), 1164 Lemire, W.G. 1135 (519), 1165 Lemor, A. 537 (31), 617 Lenga, R.E. 1053, 1054, 1058, 1115, 1124,
1144 (70), 1156 Lengyel, J. 1141 (553), 1166 Lenhert, P.G. 668 670, 672 (14), 680 Lenk, W. 1026 (144, 146), 1029 (144, 161), 1030 (146, 175), 1038, 1039 Le Noble, W.J. 938 (56), 948 Lenz, G.R. 724 (160, 162c), 743 Leo, A. 303 (29), 332, 504, 514, 515, 517, 518 (150), 522 (150, 245), 529, 531, 1006, 1024, 1026 1028, 1030 1032 (55), 1036, 1238 (95), 1241 (106a), 1297, 1298 Leo, A.J. 494, 514 (118), 528, 1228 (74), 1297 Leonard, D.R.A. 950 (3), 970 Leonard, J.M. 6 (10), 81 Leonard, N.J. 347 (27), 373 Leone, A. 711 (120), 742 Leone, A.M. 976, 978, 980 (39), 994 Leone, J.A. 1180 (58, 59), 1213 Leone-Bay, A. 712 (122), 742 Leonetti, J. 840 (13), 855 Leon-Gonz´ales, M.E. 1135 (513), 1165 Leoni, M.A. 708 (110), 742, 758 (29), 818 Leoni, P. 1236, 1266 (159), 1299 Leont’eva, L.B. 1137 (525, 526), 1141 (554), 1165, 1166 Le Page, Y. 93, 100 (26), 102 LePoire, D.M. 667 (8), 680 Lepom, P. 273, 274 (84), 293 Le Questel, J.-Y. 395 (83), 419, 1238 (87b), 1297 Leriverend, C. 591 (325), 623 Lerner, R.D. 216, 218 (65), 245 Leroy, G. 410 (187a, 187b), 422 Leska, B. 459 (243), 460 (248), 476 Lessard, J. 450 (193), 474, 845 (29, 30), 855 Lessen, T.A. 595 (353), 624 Lester, G.R. 233 (146), 247, 251 (4), 264 (63), 291, 293 L´etard, J.-F. 446 (172), 474 Lett, R.G. 57 (90a), 83 Leutwyler, S. 426 (11), 470 Lever, O.W.Jr. 290 (118), 294 Levi, R. 976 (35), 994 Levin, I. 251, 254, 262 (7), 291 Levin, R.D. 235, 236 (166), 247, 255 (24), 258 (39), 292, 383, 384 (24a), 407 (161a), 417, 421 Levine, H.B. 369 (95), 378 Levitt, M.S. 1067 (129), 1157 Levsen, K. 206 (1), 209 (28), 226 (119), 233 (147), 238 (177), 240 (184), 243, 244, 246 248, 250 (2), 251 (3), 253 (3, 12), 259, 261 (3), 291, 1068 (138), 1116 (406), 1125 (445), 1127 (445, 455), 1133 (498), 1136 (445), 1158, 1163 1165 Levy, A.B. 565 (176), 620 Levy, D.H. 694 (67), 741
Author index Levy, G.C. 297, 300, 301 (2), 302 (19), 303 (30), 308 (35), 310 (46), 312, 313 (56), 318 (80), 332 334 Levy, N. 482, 483 (23), 525, 750 (5), 817 Lewarchik, R.J. 653 (145), 662 Lewin, R.O. 436 (115), 473 Lewis, D.W. 128 (82, 83), 129 (82), 155 Lewis, E.S. 409 (172), 421 Lewis, F.D. 684 (2, 5), 685 (2, 8, 13, 17 19, 21 23), 686 (24, 27, 28, 30, 31), 687 (31), 696 (81), 698 (8, 22, 95, 96), 699 (24, 28, 97), 700 (24, 99, 100), 701 (28, 99, 100), 704 (8, 99, 107), 706 (24, 28), 707 (109), 729 (174, 175a, 175b, 176a, 176b), 740 742, 744 Lewis, G.E. 648 (107), 661, 717 (143b), 743 Lewis, I.C. 489 (87, 88), 490 (90), 491 (90, 96, 97), 493 (87), 503 (90, 96, 97), 504 (87, 96, 97), 515 (96, 97), 517 (87, 96, 97), 527 Lewis, J.F. 96, 97 (57), 103 Lewis, P.R. 1033 (199), 1039 Lewis, R.G. 1176 (25), 1212 Lewis, R.J. 1126 (447), 1164 Lewkowicz, E. 396 (98), 419 Lewtas, J. 1177 (32, 38), 1181 (53), 1212, 1213 Leyden, D.E. 302 (21), 332 Leyrer, U. 123 (70), 155 Li, C.N. 609 (430), 625 Li, G. 562 (152), 619 Li, H. 431 (67), 472, 1130 (480), 1165 Li, J. 381 (21), 417, 428 (43), 471, 562 (152), 619 Li, K. 188 (116, 117), 204 Li, L. 1048 (62), 1156 Li, Q.X. 1135 (515), 1165 Li, S. 68 (114), 84 Li, S.-S. 4, 14 (21), 81 Li, T.-K. 1027 (151), 1038 Li, W.-K. 411 (192), 422 Li, Y.S. 1136 (521), 1165 Li, Z. 119 (57, 58), 154 Liang, Y. 565 (171), 620 Liao, M. 978 (70), 995 Lias, S.G. 211 (38), 235, 236 (166), 244, 247, 255 (24), 258 (39), 292, 383 (24a, 24b), 384 (24a, 24b, 26), 407 (161a), 417, 421, 436 (115), 473 Libby, P.S. 1047 (21), 1155 Libman, J.F. 407 (161a), 421 Lichtenberger, D.L. 178, 188 (92), 203 Lichter, R.L. 297, 300, 301 (2), 302 (19), 303 (30, 31), 305 (31, 32), 308 (35, 36), 310 (46), 317 (76), 318 (80), 332 334 Lide, D.R.Jr. 45 (69), 83 Lieb, D. 1189 (100), 1214 Liebald, W. 1180 (55), 1213
1347
Lieberman, S.H. 1098 (341), 1162 Liebig, J. 482 (17), 525 Liebman, J.F. 235, 236 (166), 247, 255 (24), 258 (39), 292, 338 (1, 4), 339 (1, 7), 342 (1, 14), 343 (1, 15), 344 346 (1), 347 (24), 348 (29), 354 (54), 355 (57), 356 (59, 61, 62), 357 (70), 360 (14), 361 (83, 86), 365 (92), 371 373, 375 378, 383, 384 (24a), 417, 436 (115), 473 Liedle, S. 164, 167 (35), 202 Liembeck, A. 1089 (288), 1161 Lien, E.J. 522 (245), 531 Liepmann, E. 273, 274 (84), 293 Lierheimer, E. 1001 (19, 23), 1003 (23), 1020, 1023 (19), 1025 (23), 1027 (19), 1035 Lifshitz, C. 234 (153), 247, 251, 254, 262 (7), 291 Liggieri, G. 1262, 1264 (147a), 1299 Ligocki, M.P. 1176 (26), 1212 Lii, J.-H. 3, 4, 20 (4a), 21 (4a, 30b), 23, 24, 26 (30b), 27 (4a, 30b), 28, 29 (30b), 62, 64, 65 (108), 81, 82, 84 Lijinsky, W. 1186 (76, 77), 1213 Liljefors, T. 62, 63 (109), 84 Lillard, T.J. 1147 (590), 1167 Lillocci, C. 165 167 (24), 202 Lilse, J.B. 208 (4), 244 Lilzefors, T. 41, 42 (60), 82 Lin, C.R. 685 (15), 740 Lin, C.-T. 91, 93 (21), 102 Lin, D.X. 1066 (115), 1157 Lin, J. 188 (115 117), 204 Lin, S.K. 809 (153), 810 (154, 155), 821 Lin, S.W. 832 (59, 60), 836 Lin, T.I. 1093 (317), 1161 Lin, T.S. 453 (205), 475 Lin, Y. 1126 (449), 1164 Lin, Y.C. 685 (20), 740 Lin, Y.H. 1105 (371), 1162 Lind, J. 827 (34), 835 Linda, P. 426 (13), 470 Lindeke, B. 1029 (158), 1038 Lindgren, C.C. 1116 (416), 1163 Lindner, W. 1130 (477), 1164 Lindon, J.C. 320 (89), 334 Lindqvist, T. 1029 (158), 1038 Lindsey, J.S. 428 (34), 471 Lingafelter, E.C. 636 (38), 659 Linkerhaegner, M. 1128 (461), 1164 Linley, E.A.S. 1098 (342), 1162 Lin-Zhi Chen 274, 275 (85), 293 Lipczynnska-Kochany, E. 407 (156), 421 Lipina, E.S. 604 (401), 625 Lipkowitz, K.B. 3 5, 29 (1b), 81, 312 (54), 333 Lippton, H. 673 (42), 681, 975 (25), 994 Lipschultz, F. 1049 (67), 1156
1348
Author index
Lipscomb, G.F. 94 (30), 102 Lipton, M. 41 (63), 82 Lisini, A. 192 (131), 204 Liˇska, J. 507 (180), 529 Liskamp, R. 41 (63), 82 Lister, D.G. 171 (68), 203 Liszi, J. 386 (45a, 45b), 418 Little, R.D. 840 (13), 850 (50), 855, 856 Littler, J.S. 646 (103), 661 Liu, A. 1073 (171), 1158 Liu, G.K. 590 (322), 623 Liu, H. 1082 (242), 1160 Liu, H.J. 1084 (255), 1160 Liu, J. 978 (57), 995 Liu, J.P. 1093 (320, 321), 1161 Liu, J.-Y. 739 (206), 745 Liu, L. 979 (77), 995 Liu, Y.-C. (68), 971 Liu, Y.M. 1081, 1091 (234), 1159 Livant, P. 164, 165, 168 (40), 202 Livett, M.K. 166 (55), 202 Lizasoain, I. 992 (134), 997 Lizhi, L. 978 (70), 995 Llamas-Saiz, A.L. 435 (106), 472 Lledos, A. 453 (206), 475 Llewellyn, G. 1090 (294), 1161 Llobera, A. 585 (294), 622 Lloyd, D.G. 1184 (69), 1213 Lluch, J.M. 754 (14, 15), 758 (31), 788 (102), 817, 818, 820 Lo, L.-C. 143 (128), 156 Lobanov, D.I. 519 (238), 531 Lobell, M. 1092 (306), 1161 Lobley, R.W. 1097 (334), 1162 Locaj, J. 1133 (499), 1165 Locascio-Brown, L. 1100 (348), 1162 Lock, C.J. 88, 90 (8), 102 Locke, M.J. 386 (44), 418 Lockhart, R.L. 812 814 (165), 821 Lockhart, R.W. 812, 813 (168), 821 Lodder, G. 753 (11), 817 Loeppky, R.N. 107 (24), 154, 886 (97), 891, 1143 (566), 1148 (600), 1166, 1167, 1186 (78), 1213 Loewenthal, E. 427 (20), 470 Lofroth, G. 1177 (29), 1212 Loftus, P. 301, 302 (16), 332 Lomzakova, V.I. 631 (19), 659 Loncharich, R.J. 72 (123), 84 Long, A.R. 1139 (539, 541), 1166 Long, Q.-H. 554 (115b), 558 (132), 619 Longevialle, P. 216 (63g), 245 Longmore, R.W. 655 (163), 662 Lonkar, S.T. 1058 (77), 1127 (452), 1156, 1164 Look, G.van 1066 (122), 1157 Lopes, A.J.M. 349 (32, 33), 374
Lopez, C. 407 (161b), 421 Lopez, V.O. 303 (26), 332, 504, 505 (155), 529 ´ L´opez-Avila, V. 1061 (90), 1156 Lopez Cancio, J. 1131 (485), 1165 Lorand, J.P. 440 (142), 473 Lorch, E. 717 (141), 743 Lord, R.C. 8 (13), 81 Lorec, A.M. 1061 (91), 1156 Lorentzen, R.J. 137 (108), 156 Lorenzen, N.P. 396 (95), 419 Lorr, S. 355, 356 (58), 375 Lory, J.A. 1049 (65), 1156 Loscalzo, J. 673 (39, 43 45), 681, 1150 (606), 1167 Lossing, F.P. 208 (7, 11), 209, 214 (11), 215 (7), 217 (70 72), 237 (175), 244, 245, 248, 255 (25 28), 292 Lothrop, W.C. 338, 361, 362, 364 (2b), 372 Lotlikar, P.D. 1000, 1009, 1031 (9), 1035 Lou, J. 607 (420), 625 Lou, W. 607 (420), 625 Loudon, A.G. 217 (79), 245 Loudon, G.M. 552 (99), 618, 843 (20b), 855 Lougmani, N. 834 (71, 72), 836 Lovey, R.G. 550 (84), 618 Lowe, J.P. 36, 38, 41 (54), 82 Lowe, P. 96 (54), 103 Lowe-Ma, C.K. 96 (53), 103 Lowenstein, C. 976, 977 (44), 995 Lowenstein, C.J. 979 (76), 991 (125), 992 (127), 995, 997 Lowenstein, C.R. 978 (69), 995 Lown, J.W. 675 (64), 677 (71), 681 Lowry, M.K. 552 (102), 618 Lowry, T.M. 146 (138), 156 Loy, M. 710 (115), 742, 1105 (368), 1162 Lu, G.K. 977 (52), 995 Lu, J. 348 (30b), 373 Lu, J.R. 1119 (434, 436), 1122 (437), 1164 Lu, L. 539 (41), 617 Lu, S.M. 583 (277), 622 Lu, W.C. 978 (71), 995 Lu, Y. 1151 (613), 1167 Lubben, M. 585 (291), 622 Lubberts, P.T. 639 (53), 660 Lubeskie, A. 991 (121), 996 Lucas, S. 987 (98), 996 Luche, J.-L. 583 (274), 594 (349), 622, 624 Lucht, B.L. 396 (86a, 91a), 419 Luckas, B. 1079 (213), 1082 (235, 236), 1159, 1160 Lu¸con, M. 451 (195), 474, 505 (158), 529 Ludemann, H.D. 321 (95), 334 Ludwig, E. 1082 (239), 1160
Author index Ludwig, M. 494 (120, 121), 507 (120, 121, 178, 179), 522 (242), 528, 529, 531 Lue, P. 554 (115b), 555 (117), 558 (132), 562 (152), 619 Luijten, W.C.M.M. 282 (96 99), 283 (98, 99), 289 (114), 293, 294 Lumme, P. 640 (69), 660 Lunazzi, L. 43 (66), 50 (66, 74 76), 52 (74, 75), 53 (75, 76), 83 Lund, E.D. 1048 (54), 1156 Lund, H. 651 (136), 662, 840 (12a), 855 Lundin, R.E. 144 (132), 156 Lundstedt, T. 563 (165), 620 Luneau, I. 437 (123), 473 Lunn, G. 1197 (103), 1214 Lunte, C.E. 1023 (121), 1037 Lunte, S.M. 1080 (222, 223), 1159 Luo, P.F. 1073 (172, 173), 1158 Lupton, E.C. 522 (244), 531 Lusztyk, J. 809 (152), 821 Luteyn, J.M. 539 (40), 617 L¨uttke, W. 188 (124), 204, 1007 (52), 1036 Lyapkaio, I.M. 448 (192), 474 Lyapkalo, I.M. 608 (424), 625 Lyle, R.E. 886 (98), 891 Lynch, B.M. 199 (145), 204 Lynch, K.R. 977 (51), 995 Lynch, R.D. 137 (112), 156 Lynch, T.-Y. 403 (137, 140, 141), 407 (159), 420, 421 Lynes, A. 1108 (384), 1163 Lyons, C.R. 978 (68), 995 Lyttle, D.J. 1122 (437), 1164 Ma, B. 441 (145), 473 Ma, Y. 571 (199), 620 Maas, W.P. 211 (40), 244 Maas, Y.E.M. 1045 (7), 1155 Maat, L. 130, 131 (92), 155 Mabry, T.J. 1066 (120), 1157 Macbeth, A.K. 676 (69), 681 Maccarone, E. 434 (88), 472 Macchia, F. 544 (65, 68), 545 (72), 617, 618 Macciantelli, D. 50 (75, 76), 52 (75), 53 (75, 76), 83 Maccoll, A. 210 (34), 216 (66), 217 (70, 74, 75), 218 (75, 88), 221 (75), 223 (113), 224 (88), 244 246, 940 (59), 948 MacCormack, P. 1237 (83a, 83b), 1243 (83a), 1297 Macdonald, C.G. 267 (74), 293 MacDonald, K.I. 581 (255), 622 MacDougall, G.S. 804 (145), 821 MacFarlane, R.G. 1063 (95, 96), 1157 Mach´acˇ kov´a, O. 638 (52), 660 Macheleid, J. 640 (66), 660 Machida, M. 609 (431), 625, 728 (172), 730
1349
(180a, 181a, 181f, 182a), 733 (183c), 734 (186, 187, 188a, 188b), 744, 798 (132), 820 Maciel, G.E. 330 (121), 335 MacIntyre, D.W. 505 (156), 510 (199), 529, 530 Macko, S.A. 1049 (68), 1060 (86), 1156 Maclagan, R.G.A.R. 954 (35), 971 MacLeod, S.C. 1063 (95), 1157 MacMicking, J.D. 993 (147), 997 Macys, D.A. 1134 (505), 1165 Mader, C.L. 369 (95), 378 Maeda, K. 593 (342), 623 Maeda, T. 1180 (51), 1213 Maemura, K. 655 (153), 662 Maeno, N. 758 (32a, 32b), 818 Magagnoli, C. 50, 53 (76), 83 Maghon, H. 1175 (15), 1212 Magno, F. 1147 (592), 1167 Mahalakshmi, P. 286 (104), 293 Mahdavi, F. 748 (1), 817 Mahe, R. 595 (359a), 624 Maher, T. 1071 (153), 1158 Mahler, G.S. 124 (74), 155, 427 (22), 471 Mahling, S. 830 (52), 836 Mahmood, S. 848 (44), 856 Mahy, J.P. 572 (202), 620 Mai, J.C. 685 (20), 740 Mai, K. 584 (285a, 285b), 622 Maia, L.S. 854 (63), 856 Maier, J.P. 164, 165, 171, 174 (42), 175 (42, 85), 176, 178 (86), 202, 203 Maier, N. 603 (393), 624 Maier, U. 426 (9), 470 Mair, F.S. 396 (92, 96), 419 Maister, H. 1003, 1020, 1022 (34), 1035 Maiti, S.N. 537 (26, 28), 617 Maity, D.K. 825 (17), 835 Maiya, B.G. 753 (10), 817 Majdi, H.S. 366, 369, 370 (98), 378 Majeed, N.N. 804 (144, 145), 821 Majenz, W. 694 (63), 697 (87), 741 Majer, J. 438 (128), 473 Mak, M. 851 (55), 856 Makarski, V.V. 94, 100 (32), 102 Makhamatkhanov, M.M. 519 (238), 531 Maki, A.H. 843 (22), 847 (39, 40b), 855, 856 Maki, Y. 722 (158a), 743 Makik, G. 1128 (466), 1164 Makino, K. 739 (204), 745, 803 (142), 821, 1047 (40), 1155 Makita, M. 1065 (110 112), 1157 Malamidou-Xenikaki, E. 721 (150), 743 Malaraski, Z. 435 (108 111), 472 Mal´endez, E. 631 (17), 659 Malfroot, T. 582 (264), 622 Malik, A.A. 537 (25), 617 Malikova, J. 1068 (135), 1157
1350
Author index
Malinski, T.A. 992 (127), 997 Malkin, A.N. 684 (6), 740 Mallard, G.W. 338, 339, 342 346 (1), 371 Mallard, W.G. 235, 236 (166), 247, 255 (24), 292, 348 (29), 361 (83), 373, 377 Mallart, S. 551 (92), 618 Mallols, J.M.S. 1067 (133), 1086 (273), 1157, 1160 Malmborg, P. 932 (45), 947 Malmer, M.F. 1082 (238), 1160 Malone, P.L. 1238, 1240 (97), 1297 Malpass, J.R. 56 (80e), 83 Malpezzi, L. 53 (77), 83 Mamaveille, C. 1147 (591), 1167 Mammen, M. 430 (50), 471 Manabe, O. 448 (191), 474, 869 (43), 870 (47), 889, 890 Manabe, S. 1072 (155 160, 162), 1158 Manabe, Y. 1180 (51), 1213 Mancheno, M.J. 716 (139), 743 Mancini, P.M.E. 1221 (48a c), 1222 (48b), 1247 (48c), 1296 Mandagere, A.K. 1189 (95), 1214 Mandal, P.C. 833 (68), 836 Mandal, S.B. 598 (377), 624 Mandal, T.K. 1139 (542), 1166 Mandel, M. 96 (45), 102 Mandelbaum, A. 208 (10), 244 Mandell, G.L. 1027 (153), 1038 Manderville, R.A. 512 (215), 530 Manes, J. 1048 (55), 1156 Manes, J.D. 1070 (150), 1158 Manescalchi, F. 564 (168), 620 Mangani, S. 391 (65), 419 Mangeney, P. 126, 127 (80), 155, 546 (73), 618, 1111 (397), 1163 Mangino, M.M. 1188 (90), 1214 Manglik, A.K. 880 (84), 890 Mann, B.E. 297 (14), 332 Mann, B.R. 516 (233), 530 Mann, D.E. 45 (69), 83 Manning, C. 685, 686 (7), 740 Manousek, O. 848 (41a, 41b), 856 Manoussaridou, E. 1048 (53), 1156 Mansfield, P. 330 (120), 335 Manson, D. 1000 (8, 12), 1015 (12), 1035 Manson, T.J. 1180 (52), 1213 Mansour, T.S. 398 (116), 399 (121), 420 Mansuy, D. 572 (202), 620 Mao, J. 1076 (187), 1159 Maples, K.R. 1019, 1020, 1022 (92), 1037 Maquestiau, A. 232 (142), 247, 274, 275 (85), 293 Maquin, F. 209 (31), 244 Marano, R.S. 1177 (36), 1212 Marcantoni, E. 608 (425, 426a, 426b), 625 Marcantonio, R.P. 43 (68), 83
March, J. 653 (142), 662, 1009, 1013, 1015 (58), 1036 March, R.E. 254, 288 (22), 292, 1145 (574), 1167 Marchal, J. 825 (19 21), 835, 1069 (142), 1158 Marchand, A. 897 (21), 947 Marchand, A.P. 604 (402), 625 Marchelli, R. 1091 (300), 1161 Marchesini, A. 397 (104), 420 Marchetti, F. 143 (125), 156 Marchidan, D.I. 353 (50), 375 Marciniec, B. 1140 (551), 1166 Marcon, M.G. 94 (36), 102 Marcucci, J.L. 540 (43), 617 Marcus, Y. 1220 (45a, 45b), 1225 (61, 63, 64), 1296, 1297 Marder, M. 1273 1275 (177), 1299 Marengo, E. 1074 (177), 1158 Margaretha, P. 720 (149), 743 Margolin, A. 410 (182), 422 Margolin, Z. 398 (115), 420, 436 (116), 473 Margreth, A. 1000, 1009, 1031 (9), 1035 Maria, P.-C. 348 (28), 373, 381 (13, 19, 20b), 387 (51, 55), 406 (154), 416 418, 421, 499, 522 (138), 528 Maria, P.C. 407 (160), 421, 428 (42), 459 (244), 471, 476, 1237 (84 86), 1238 (84 86, 93), 1284, 1285 (86), 1297 Maria, P.de 1012 (81), 1036 Mariano, P.S. 684 (5), 685 (16), 688 (42, 43), 690 (45 47), 691 (48), 692 (50), 710 (117a, 117b, 119), 711 (120, 121), 712 (122, 123), 714 (124 128), (44), 740 742 Marianucci, E. 465 (264), 476 Mar¨in, J. 1046 (19), 1155 Marine-Font, A. 1079 (214), 1159 Marini, E. 551 (93), 618 Markov, V.I. 132, 133 (96), 155 Marko-Varga, G. 1103 (357), 1162 Markovits, G.Y. 641 (70), 660 Markowicz, T. 53, 54 (78), 83 Marks, H.M. 1047 (24), 1155 Marks, M.J. 137 (112), 156 Marletta, M.A. 976 (31, 33, 36), 978 (31, 36, 67), 980 (31), 983 (36, 82, 83, 85, 87), 984 (87), 985 (82, 94), 989 (104, 106), 990 (112), 991 (115), 994 996 Marmon, R.J. 601 (384a, 384b), 624 Maron, A. 505 (156), 529 Maroulis, A.J. 704 (108), 742 Marples, B.A. 797 (131), 820 Marquardt, D.J. 599 (380), 624 Marquet, B. 566 (180), 620 Marquet, J. 754 (14 16, 17a, 17b), 755 (20), 756 (23), 758 (30, 31), 788 (102), 817, 818, 820, 846 (35), 855
Author index M´arquez, C.D. 1066 (114), 1157 Marr, H.E.III 97 (62), 103 Marriott, S. 506 (164 167), 510 (167, 199), 529, 530 Marrone, M.J. 795 (120), 820 Marrosu, G. 191, 199 (130), 204 Marrs, D. 59 (100), 83 Marsch, G.A. 1033 (201), 1039 Marsch, M. 396 (99, 100), 413, 414 (197), 420, 422 Marschner, F. 171, 174 (74), 203 Marsden, P.A. 977 (52), 978 (71), 979 (72), 995 Marsden, R.J.B. 487 (67), 526 Marsella, J.A. 543 (62), 617 Marsh, R.E. 444 (162), 474 Marshall, A. 1127 (453, 454), 1164 Marshall, A.G. 235 (164), 247 Marshall, E.K.Jr. 1087 (277), 1160 Marshall, S. 991 (116), 996 Marstokk, K.M. 56 (83), 83 Martelli, G. 549 (81), 618 Martens, D.A. 1073 (167, 168), 1158 Martens, M.H.J. 1129 (475), 1132 (489), 1164, 1165 Martin, G. 317 (77), 334 Martin, G.J. 297 (6), 303 (28), 332 Martin, H.-D. 165, 166 (47), 178 (90), 182 (47), 202, 203 Martin, H.D. 184 (107), 204 Martin, J. 673 (41), 681, 1046 (13), 1155 Martin, J.A.F. 715 (129, 132), 716 (132, 133), 742 Martin, J.A.J. 1119 (429), 1163 Martin, J.F. 673 (40), 681 Martin, M.L. 297 (6), 303 (28), 332 Martin, M.W. 1118 (419), 1163 Martin, T.G. 1093 (309), 1161 Martin, W. 975 (14 16), 994 Martin, X. 788 (102), 820 Martin, Y.C. 506 (174), 529 Martinelli, G. 576 (216), 621 Martinez, A. 408 (167b), 421 Mart´ınez, L.L. 1139 (538), 1140 (546), 1166 Martinez, R.D. 1221 (48a c), 1222 (48b), 1247 (48c), 1296 Martinez-Carrera, S. 435 (98), 472 Martinez-Fresneda, P. 566 (177), 620 Martinez-Larranaga, M.R. 1025 (139), 1038 Martinho Sim˜oes, J.A. 342 (14), 343 (15), 360 (14), 372 Martins, L.J.A. 780 (76 79), 819 Martins Costa, M.T.C. 456 (226), 475 Martyn, R.J. 954 (27), 971 Martynov, I.V. 607 (419), 625 Martz, J.T. 582 (264), 622 Maruha, J. 94 (38), 102
1351
Maruthamuthu, P. 827 (27, 28), 835 Maruyama, K. 730 (180a, 180b), 733 (183b), 744 Maruyama, R. 597 (370), 624 Maruyama, Y. 437 (122, 123), 473 Marvel, C.S. 677 (77), 681 Maryanoff, B.E. 73 (124), 84 Maryanoff, C.A. 563 (156), 620 Marzabadi, M.R. 560 (137), 619 Marzin, C. 426 (13), 470 Marzluff, E.M. 178, 188 (92), 203 Marzo, A. 1068 (136), 1157 Masamune, S. 112 (40), 154 Mascal, M. 427 (18), 470 Maschmeier, C.P. 603 (393), 624 Masclet, P. 1175 (19), 1212 Mashima, M. 505 (163), 529 Masi, D. 57 (93), 83 Maskill, H. 648 (111), 661 Maslen, E.N. 95 (42), 102 Masnovi, J. 433 (79), 472 Masnovi, J.M. 455 (213 215), 456 (221), 475, 790 (110), 820 Mason, J. 297 (3), 303, 308 (37), 315 (63), 332, 333, 666, 669 (7), 680 Mason, R.P. 1019 (91, 92), 1020, 1022 (92), 1037 Massey, R.C. 1134 (507), 1165 Masters, B.S.S. 984 (90), 985 (93), 989 (101, 102), 991 (118), 996 Mastrokalos, C. 633, 644 (25), 659 Mastryukov, V.S. 8 (14a, 14b), 24 (14a, 14b, 37), 81, 82 Masuda, H. 111 (36), 154 Masuda, S. 193, 194, 197 199 (144), 204, 649 (120), 661 Masuda, Y. 866 (34), 889, 1078 (206), 1159 Masui, M. 676 (68), 681 Mataga, N. 694 (58), 695 (69), 741 Matage, M. 698 (94), 742 Matcham, G.W. 108, 109 (31), 154 Mateos, J.L. 434 (90), 472 Mathews, R.J. 268 (78), 293 Mathews, W.R. 673 (38), 681 Mathhews, W.S. 410 (182), 422 Mathias, J.P. 430 (50 53), 471 Mathieu, J. 1145 (572), 1166 Mathur, H.B. 1266, 1267 (167b), 1299 Mathur, H.M. 285 (102), 293 Matiskella, J.D. 582 (262), 622 Matiushin, Y.N. 362, 363 (90), 377 Matschiner, H. 603 (393), 624 Matsson, O. 932 (44), 933 (46), 938 (55), 947, 948 Matsubara, S. 597 (372), 624 Matsuda, H. 543 (64), 590 (319), 596 (361a, 361b), 617, 623, 624
1352
Author index
Matsuda, T. 654 (150, 152), 655 (153 155), 657 (170, 172), 662 Matsui, A. 164, 170 (30), 202, 638 (50), 660 Matsui, K. 758 (32a, 32b), 818 Matsui, T. 565 (174), 620 Matsumiya, T. 1073 (165), 1158 Matsumoto, K. 787 (101), 820, 1106 (372), 1162, 1256 (137 139), 1298, 1299 Matsumoto, M. 1134 (504), 1165 Matsumoto, Y. 736 (194b), 745 Matsumura, G. 96 (47), 102 Matsumura, S. 866 (32), 889 Matsunaga, K. 698 (91), 741 Matsuo, T. 1083 (253), 1160 Matsuoka, A. 989 (107), 996 Matsuoka, S. 824 (11, 12), 835 Matsushima, H.K.Y. 1079, 1083 (217), 1159 Matsushita, A. 651 (133), 661 Matsushita, T. 215 (54), 245 Matsuyoshi, H. 596 (362), 624 Matteoli, E. 386 (45b), 418 Matthew, D.E. 976, 978 (38), 994 Matthew, P. 1001, 1003, 1007, 1009, 1011, 1012, 1028 (29), 1035 Matthews, D.P. 577 (219), 621 Matthews, W.S. 398 (115), 420 Matthiesen, U. 1060 (84), 1156 Matthijs, E. 1116 (408), 1163 Mattiello, M. 1175 (16), 1212 Mattusch, J. 1094 (323), 1161 Matuura, T. 866 (34), 889 Matvienko, N.M. 348 (31), 373 Matyska, M. 1146 (582), 1167 Maumy, M. 580 (241, 252a, 252b), 590 (321), 621, 623 Maurer, J. 648 (109), 661 Maurin, J. 98 (69), 103, 444 (160), 474 Maurin, R. 598 (378), 624 Mautner, H.G. 426 (17), 470, 1250 (124), 1298 Maverick, D. 60 (104), 84 Mawson, S.D. 675 (60), 681 Maxwell, B.E. 899 (23), 947 Maxwell, R.J. 1145 (581), 1167 May, D.P. 171, 175 (70), 203 May, S.W. 1111 (398), 1163 Mayence, A. 556 (120), 558 (131), 619 Mayer, B. 165, 166 (47), 178 (90), 182 (47), 184 (107), 202 204, 977 (45), 983 (86), 984 (45), 985 (92), 990 (109), 991 (122), 992 (136, 137), 995 997 Mayer, N. 552 (104), 618 Mayo, E.C. 497 (133), 528 Mayo, P.de 722 (153h), 728 (171a, 171b), 743, 744 Mayo, S.L. 37, 38, 40 (57), 82 Mays, J.B. 1011, 1012 (72), 1029 (72, 168), 1036, 1038
Maystre, F. 1093 (315), 1161 Mazurek, R. 1046 (16), 1155 Mazzocchi, H.P. 730 (177c), 744 Mazzochi, P.H. 733 (183a, 183d, 183e), 744 Mazzucato, U. 778 (71), 819 McAdoo, D.J. 216 (63b, 63h, 64, 65), 217 (80), 218 (65), 245 McAlduff, E.J. 199 (145), 204 McAninly, J. 669 (26), 670 (26, 27), 680 McAuley, I. 785 (95), 820 McCafferty, D.G. 739 (207), 745 McCallum, G.J. 410 (182), 422 McCallum, R.J. 398 (115), 410 (182), 420, 422 McCarthy, J.R. 543 (58), 563 (157), 577 (219), 617, 620, 621 McClellan, A.L. 427 (24), 471 McClelland, C.W. 667 (8), 680 McClelland, R.A. 868 (41), 889, 1001, 1003, 1005 1008, 1010, 1011, 1014, 1031 (30), 1032 (30, 186, 187, 190 194), 1035, 1039 McCluskey, J.G. 581 (261), 622 McCollum, G.J. 398 (115), 420 McCollum, G.W. 565 (173), 620 McCombie, J. 1102 (356), 1162 McCormack, M.T. 329 (113), 334 McCoy, E.C. 1177 (30), 1212 McCreary, M.D. 128 (83), 155 McCrudden, K. 648 (111), 661 McCullough, K. 447 (176), 474 McDermott, S.D. 405 (147, 148), 421 McDougal, J.S. 1024 (125, 126), 1037 McDougall, G.J. 58 (95 97), 83 McDow, S.R. 1179 (50), 1213 McDowell, C.A. 166 (56), 202, 290 (116), 294 McElroy, P.A. 1177 (42, 43), 1213 McEwen, A.B. 184 (105), 203 McEwen, I.J. 447 (180), 474 McEwen, W.K. 400 (122), 420 McFarlane, H.C.E. 297 (7), 332 McFarlane, W. 297 (7), 332 McGhee, W.D. 595 (356), 596 (364), 624 Mcgill, C.K. 560 (138), 619 McGill, R.A. 381 (20b), 417, 428 (42), 471 McGlynn, S.P. 188 (114), 200 (149), 204 McIntire, G.L. 843, 844 (23), 855 McIntyre, J.S. 448 (191), 474 McIver, R.T. 308 (41), 333, 496 (131), 505 (131, 163), 528, 529 McIver, R.T.Jr. 235, 236 (165), 247, 382 (22), 384 (33b), 385 (22), 386 (44), 387 (52a, 52b), 411 (193), 417, 418, 422, 436 (117), 473 McKee, M.L. 164, 165, 168 (40), 202, 255 (32, 33), 292, 410 (186), 422 McKelvey, G.N. 594 (347), 623 McKelvie, I.D. 1045 (5), 1046 (18), 1155 McKenna, J. 859 (13), 889
Author index McKenna, J.M. 859 (13), 889 McKenzie, H.A. 1047 (23), 1155 Mckeown, C. 1140 (552), 1166 McKimmey, J.E. 688 (33), 740 McKinney, T.M. 184 (101), 203 McLafferty, F.W. 206, 207 (3), 208 (17), 209 (27, 30), 210 (17), 211 (17, 35), 212, 215 (17), 217 (68), 219 (3, 68), 226 (3, 68, 119), 229, 233 (3), 243 246, 253 (13, 14), 254 (16, 20), 292 McLafferty, M.A. 1032 (196), 1039 McLean, A.D. 384 (27), 417 McLean, W.J. 1174 (4), 1212 McLenaghan, C.C. 1147 (594), 1167 McLeod, J.K. 208 (8), 244 McLuckey, S. 251, 253, 254 (5), 291 McLuckey, S.A. 264, 269, 270 (66), 293, 390 (70), 419 McLuckley, S.A. 238 (179, 181), 248 McMahon, A.W. 254, 288 (22), 292 McMahon, T.B. 384 (25b, 25c, 30a c), 385 (34c, 34d, 35a e, 38a c, 39a, 39b), 417, 418, 1238 (91, 92), 1297 McManus, S.P. 1273, 1275, 1283 (178), 1299 McMillan, D.C. 1019 (94), 1026 (142, 143), 1037, 1038 McMillan, K. 984 (90), 985 (93), 989 (101, 102), 991 (118), 996 McMillen, D.F. 401 (134), 420, 883 (88), 890 McMinn, D.G. 1047 (30), 1155 McMurray, M.E. 1238, 1239 (99), 1297 McMurry, M.E. 389 (59), 418 McNally, A.J. 1106 (377), 1162 McNamara, D.B. 975 (20), 994 McNulty, J.F. 554 (111), 618 McPhail, A.T. 397 (102), 420 McPhee, J.R. 1012 (74), 1036 McRae, T.A. 1026 (143), 1038 McWherter, C.A. 322 (99), 334 Mead, D.A.Jr. 1073 (166), 1158 Mead, P.T. 220 (104), 246 Means, G.E. 119 (60), 154 Mechin, B. 317 (77), 334 Mecklenburg, S.L. 739 (207), 745 Meddour, A. 1112 (402), 1163 Mederer, K. 553 (108b), 618 Medica, A. 1116 (409), 1163 Medina, H.L.de 1046 (16, 19), 1155 Medwid, A.R. 7 (12), 81 Meeks, J. 188 (114), 204 Meerman, J.H.N. 1012, 1033 (85), 1036 Meerwein, H. 654 (146), 657 (171), 662 Meeus, F. 695 (77), 741 Meguro, S.-I. 1030 (176), 1039 Mehdi, S. 98 (71), 103 Mehnert, R. 649 (119), 661 Meier, B. 1086 (274), 1160
1353
Meier, C. 551 (95), 618 Meijere, A.de 164, 165 (36), 168 (61), 202 Meijide, F. 677 (72, 73), 681, 886 (102), 888 (106, 107), 891 Meijs, G.F. 655 (160), 662 Meisels, G.G. 255 (30), 259 (43), 262 (30, 43, 56), 292 Meites, L. 840 (11), 855 Mejstrik, V. 1135 (516), 1165 Melamed, D.B. 1147 (593), 1167 Melander, L. 859 (12), 889, 894 (2, 5), 895 (2), 946 Melhorn, A. 722 (153c), 743 Mellion, B.T. 975 (21, 22), 994 Mellor, N. 1047 (33), 1155 Mel’nikov, E.B. 636 (35), 659 Memory, J.D. 302 (18), 332 Mencarelli, P. 1217 (15a, 15b), 1295 Mende, P. 1148 (600), 1167 Mendeleyev, J. 1024 (123 127), 1037 Mendicino, M.E. 854 (66), 856 Mendoza, J.de 392 (77), 419 Mendoza, J.S. 609 (434), 625 Menendez, E. 592 (333), 623 Menendez, M. 408 (165a), 421 Menger, J.M. 1266 (158), 1299 Menzel, H. 1029 (159), 1038 Meot-Ner, M. 384 (25a), 385 (36, 42, 43a c), 417, 418, 429 (44), 471, 833 (65), 836, 1238 (90), 1297 Merchan, M. 455 (218), 475, 790 (114), 820 Mer´enyi, G. 827 (34), 835 Merenyi, R. 403 (138a, 138b), 420 Merlet, N. 1079 (208), 1159 Merlino, S. 93 (28), 102 Mermelstein, R. 1177 (30), 1212 Merrill, B.M. 992 (132), 997 Merritt, D.A. 1059 (79), 1156 Merwe, M.J.van der 1061 (89), 1156 Mes, G.F. 696 (78), 741 Messina, A. 1091 (298, 299), 1093 (314), 1161 Messinger, J. 139 (113), 156 Mestdagh, H. 240 (188), 248 Metcalf, T. 1080 (220), 1096 (328), 1159, 1161 Metzler, M. 1000, 1003, 1009 (11), 1035 Metzner, P. 591 (325), 623 Meunier-Prest, R. 843 (17), 845 (33), 846 (34), 854 (69), 855, 856, 1129 (467 471), 1144 (471), 1164 Meurs, F.van 100 (89), 103 Meyer, D.J. 672 (36), 674 (50), 680, 681 Meyer, G.-J. 649 (122), 661 Meyer, M. 407 (162), 421 Meyer, R. 35 (51), 82 Meyer, T.A. 448 (190), 474, 629 (12), 659, 676 (66, 70), 677 (66), 681, 888 (105), 891
1354
Author index
Meyer, T.J. 739 (207), 745 Meyer, V. 482 (18, 19), 525 Meyer, V.R. 1093 (313), 1161 Meyers, A.I. 575 (210), 621 Meyers, C.B. 975 (22), 994 Meyers, E.F. 710 (119), 742 Meyerson, S. 265 (68), 293 Meyerstein, D. 829 (48), 836 Mezzina, E. 464 (262), 476 Mhala, M. 1220 (32a), 1296 Mialocq, J.C. 697 (88), 741 Micetich, R.G. 537 (26), 617 Michael, J.P. 453 (207, 208), 475 Michaelsen, S. 1096 (329), 1161 Michalak, J. 833, 834 (66), 836 Michalik, M. 130 (90), 155, 1112 (399), 1163 Michalowicz, W. 639 (61), 660 Michalska, D.F. 148 (142), 156 Michaud, D.P. 1084 (254), 1160 Michejda, C.J. 107 (24), 154, 1143 (566), 1166 Michejda, J.A. 173 (77), 203 Michel, A. 100 (90), 103 Michel, T. 977 (52, 56), 979 (72, 74), 992 (127, 133), 995, 997 Micheloni, M. 389 (60), 391 (63 66), 396 (101), 418 420 Michels, J.J. 568 (187), 620 Michurin, A.A. 592 (339), 623 Mi´covi´c, I.V. 563 (160), 620 Middelburg, J.J. 1045 (7), 1155 Middleton, E.J. 1189 (93), 1214 Midgley, J.M. 1063 (95, 96), 1157 Midland, M.M. 565 (176), 620 Midleton, S. 268 (78), 293 Miginiac, L. 576 (214, 217), 621 Migita, M. 695 (69), 741 Migita, Y. 730 (178), 744 Migliorese, K.G. 1144 (568), 1166 Migron, Y. 1220 (45a, 45b), 1225 (64), 1296, 1297 Mikulcik, P. 393, 394 (78), 419 Milakofsky, L. 945 (70), 948 Milewska, M.J. 4, 13 (17), 69 (17, 116), 81, 84, 145 (135), 156 Millar, K.G. 1222, 1226 (53), 1296 Millefiori, A. 199 (146), 204 Millefiori, S. 199 (146), 204 Millen, D.J. 428 (38), 471 Miller, A. 75 (126), 84 Miller, A.M. 1024 (129), 1037 Miller, A.R. 938 (56), 948 Miller, B. 865 (26), 889, 930 (43), 947 Miller, B.J. 110 (35), 154 Miller, D.L. 222, 223 (112), 246 Miller, E.C. 871 (52), 890, 1000, 1009 (9), 1031 (9, 179), 1035, 1039 Miller, E.J. 1082 (240), 1160
Miller, J. 510 (197), 511 (209, 213, 214), 515 (213), 516 (197, 213, 232), 530 Miller, J.A. 1000, 1009 (9), 1020 (99), 1031 (9, 179), 1035, 1037, 1039, 1174 (4, 5), 1212 Miller, J.L. 590 (322), 623 Miller, J.S. 90, 93 (13), 102 Miller, M. 1001, 1007, 1009, 1011, 1027 (28), 1035 Miller, M.J. 552 (99), 618 Miller, R.B. 1116 (410 412), 1163 Millerstein, C. 1079 (210), 1159 Milliet, A. 212 (46 50), 216 (48 50, 61), 222 (46 50), 233 (145), 244, 245, 247 Mills, H.A. 1046 (10), 1155 Mills, J.E. 590 (323), 623 Milne, G.A. 317 (67), 333 Milner, D.J. 651 (131), 661 Milstein, D. 587 (301), 623 Min, W. 979 (73), 995 Minamikawa, J. 552 (98, 101), 618 Minamikawa, S. 733 (183e), 744 Minatogawa, H. 1256 (139), 1299 Minchin, R.F. 1033 (202), 1039 Ming Miao, F. 96 (54), 103 Ming Miao, F. 96 (46, 50), 102, 103 Minkwitz, J. 164, 166, 168 (32), 202 Minoli, G. 708 (110), 742, 758 (29), 818 Minor, R.L. 673 (46), 681 Minsek, D.W. 445 (168), 474, 698 (98), 742 Mintrop, L. 1079 (209), 1159 Miralles-Roch, F. 849 (48), 856 Miroshnichenko, E.A. 352 (43), 374 Miser, J.R. 656 (164), 662 Mishani, E. 607 (417), 625 Mishima, M. 308 (39, 41), 309 (39), 333, 387 (52b), 418, 524 (254), 531 Mishra, A.K. 873 (60), 890 Mishra, A.S. 873 (60), 890 Mishra, P. 594 (350), 624 Miskowski, V.M. 444 (162), 474 Mison, P. 567 (183), 620 Missavage, R.J. 347 (27), 373 Misumi, S. 695 (69), 741, 1114 (405), 1163 Mitani, K. 193, 197 (142), 204 Mitani, T. 437 (122, 123), 473 Mitchell, D. 284, 285 (101), 293 Mitchell, D.J. 15, 17 (24b), 81 Mitchell, H. 550 (86b), 618 Mitchell, J.A. 977, 978 (49), 995 Mitchell, R. 1096 (328), 1161 Mitchell, R.C. 1222 (56, 59), 1226 (71), 1228 (73), 1296, 1297 Mitchell, S.C. 1064 (103), 1157 Mito, T. 1119 (433), 1164 Mitri, M. 1046 (18), 1155 Mitrovic, M. 1127, 1143 (457), 1164
Author index Mitscherlich, E. 481 (7), 525 Mitsui, H. 579 (232), 621 Mitsui, K. 592 (331, 332), 623, 871 (53), 890 Mitsunobu, O. 543 (56, 57), 602 (388), 617, 624 Mittal, C. 975 (6, 17, 18), 994 Mittal, J.P. 441 (144), 473, 825 (17), 827 (27), 835 Mittelbach, M. 588 (307), 623 Mittelman, A. 1187 (79), 1213 Mitza, N.A. 688 (32), 740 Miura, K. 870 (50), 890 Miura, M. 582 (268), 622, 692 (49), 741 Miura, Y. 735 (190b), 745 Miwa, G.T. 1031 (183), 1039 Miyaguchi, N. 582 (267), 622 Miyaki, K. 685 (12), 740 Miyamoto, H. 722 (159d), 743 Miyamoto, Y. 1065 (110 112), 1157 Miyashi, T. 452 (196), 475 Miyashita, M. 593 (340), 611 (441), 623, 625 Miyata, N. 96 (47), 102, 1131 (487), 1165 Miyata, O. 724 (163, 165, 166c), 743, 744 Miyazaki, H. 654 (151), 662 Miyazaki, K. 111 (36), 154 Miyazaki, M. 1069 (147), 1079, 1083 (217), 1129 (476), 1130 (147, 476, 479, 481), 1131 (476), 1158, 1159, 1164, 1165 Miyazawa, T. 1090 (297), 1092 (307), 1161 Miyoshi, N. 563 (159), 620 Miyoshi, Y. 1079, 1083 (217), 1159 Mizoguchi, T. 730 (178, 181b, 181c), 744 Mizokami, T. 656 (166), 662 Mizukami, H. 593 (342), 623 Mizuno, M. 721 (151), 743 Mizuno, T. 596 (365), 624 Mizutani, M. 704 (105), 742 Mlekuz, M. 595 (357), 624 Mlynarik, V. (87), 334 Mochizuki, A. 590 (320), 623 Modelli, A. 173 (78), 203 Modena, G. 405 (150b), 421, 1012, 1015 (73), 1036 Moens, L. 586 (296), 622 Moffatt, J.R. 1220 (30a, 32a), 1296 Mogami, T. 596 (368), 624 Moghe, P.P. 578 (225), 621 Mohamadi, F. 41 (63), 82 Mohammad, A. 461 (250), 476 Mohan, H. 825 (17), 835 Mohan, L. 579 (228a, 228b), 621 Mohnke, M. 1063 (101), 1157 Moinet, C. 447 (182, 184), 474, 838 (7a), 843 (18, 19), 848 (7a), 855, 1011, 1019 (71), 1036, 1107 (380, 382), 1162, 1163 Moiseev, G.E. 1184 (66), 1213 Moiseeva, A.A. 444 (161), 474
1355
Mok, C.Y. 193, 194 (143, 144), 195, 196 (143), 197 (143, 144), 198, 199 (144), 200 (150, 151), 204 Mokhov, A.A. 1137 (525), 1165 Molder, U.H. 1238 (89), 1297 Mold¨eus, P. 1029 (158), 1038 Molenaar-Langeveld, T.A. 231 (135), 247 Moleva, V.I. 1119 (432), 1164 Molher, L.K. 405 (151a), 421 Molina, G.A. 650 (127), 661 Mollah, Y. 1067 (129), 1157 Mollendal, H. 56 (83), 83 Moller, M. 1177 (29), 1212 Moller, P. 1096 (329), 1161 Moltzen, E.K. 591 (324), 623 Momchilova, T.G. 57 (91), 83 Mommers, A.A. 233 (148, 149), 234 (148), 247 Moncada, S. 669 (19), 673 (39 41), 680, 681, 975 (4, 8 12), 976 (11, 39, 41), 977 (47), 978 (39, 47, 62), 979 (77), 980 (39, 79), 992 (134, 135), 994, 995, 997 Mondelli, R. 321 (93), 334 Mongkolaussvaratana, T. 1100 (349), 1162 M¨onig, J. 828 (44), 830 (52), 835, 836 Monsanto, G. 1184 (69), 1213 Monshouwer, J.C. 494, 495, 519 (124), 528 Monte, M.J.S. 357 (67), 376 Monteiro, L.S. 854 (63), 856 Montenegro, M.I. 854 (63), 856 Montevecchi, P.C. 1012, 1013 (79), 1036 Montgomery, R.L. 342 (13), 372 Monti, N. 1068 (136), 1157 Montserrat, J. 1271, 1282 1284 (190), 1300 Montserrat, J.M. 469 (279), 477 Montzka, T.A. 582 (262), 622 Monzyk, B. 407 (158a), 421 Mooberry, E.A. 70 (117b), 84 Moodie, R.B. 880 (84), 890, 958 (47 49), 968 (62), 971 Moor, H. 666 (5), 680 Moore, C. 1068 (140), 1158 Moore, C.M. 1030 (171), 1038 Moore, D.W. 96 (53), 103 Moore, L.L. 544 (66), 617 Moormann, A.E. 563 (158), 579 (229), 620, 621 Mootz, D. 86, 88 (4), 102 Mora, M.A. 1266 (165), 1299 Morales, E.Q. 143 (128), 156 Moraru, M. 846 (38), 856 Morath, R.J. 1216, 1217, 1242, 1278 (2c), 1295 Moreau, J.J.E. 573 (204), 620 Moreland, W.T. 491 (102), 527 Moreno-Manas, M. 754 (14, 15, 17a, 17b), 756 (23), 758 (30, 31), 817, 818
1356
Author index
More O’Ferrall, R.A. 381 (5b), 416, 895 (13), 943 (66), 947, 948 Moreton, A.D. 390 (61), 418 Morgan, K.M. 355 (56), 375 Morgan, T.G. 266 (73), 293 Mori, A. 649 (120), 661 Mori, H. 1106 (378), 1162 Mori, M. 578 (223), 621 Mori, S. 538 (34), 596 (362), 617, 624 Moriarty, R.M. 583 (273), 622, 1009 (64), 1036 Moriarty, T.C. 400 (125), 420 Morimoto, T. 553 (109), 618 Morin, N. 240 (188), 248 Morishima, I. 165, 166 (23), 202 Morita, M. 1103 (360, 361), 1162 Morita, O. 1030 (176), 1039 Morita, T. 704 (102), 742 Moriya, F. 739 (204), 745 Moriyama, M. 438 (126), 473 Mornet, F. 1046 (17), 1155 Morosin, B. 636 (38), 659 Morozumi, T. 1119 (430), 1163 Morris, D.G. 395 (84), 419, 451 (195), 474, 505 (158), 529 Morris, G.E. 595 (357), 624 Morris, J.J. 381 (17a e, 19, 20b, 20c), 395 (81), 417, 419, 428 (41, 42), 471, 1222 (50, 51, 57, 58, 60), 1238 (51), 1296, 1297 Morris, M.E. 1133 (495), 1165 Morris, M.L. 588 (305), 623 Morris, P.A. 666 (2), 680 Morris, P.G. 330 (120), 335 Morrison, J.D. 121 (63, 64), 154, 155 Morse, M.D. 90 (10), 102 Morton, A.G. 216 (63a), 245 Morton, T.H. 228, 238 (130), 246 Morton, T.ZH. 216 (63h), 245 Moschwitzer, U. 1082 (239), 1160 Moscowitz, A. 147 (139), 156 Mosher, H.S. 114 (45), 121 (63), 124 (76), 125 (76, 78), 147 (139), 154 156, 1089 (285, 286), 1160, 1161 Moskovits, M. 151 (159), 157 Moskowitz, D. 509 (189), 530 Mosquera, M. 886 (102), 891 Mosquera, R.A. 55 57 (82), 83 Moss, D.W. 992 (135), 997 Moss, J. 992 (130), 997 Moss, R.E. 56 (80e), 83, 184 (105), 203 Mosseri, S. 826 (26), 827 (27), 835 Mostad, A. 636 (41), 659 Motevalli, M. 456 (222), 475 Motherwell, W.D.S. 37 (56), 82 Motoc, I. 29 (42), 82 Motokawa, H. 597 (370), 624 Mott, F. 669 (24), 672 (33), 680
Moulin, C. 1112 (401), 1163 Moussounga, J. 590 (315), 623 Mouviar, G. 1175 (19), 1212 Mower, H.F. 96 (45), 102 Moyano, A. 545 (70), 618 Moyano, E. 1129 (474), 1130 (483), 1164, 1165 Moyes, W. 171, 172, 174, 175 (75), 193, 197 199 (141), 203, 204 Moynihan, H.A. 669, 673 (17), 680 Muanda, M.wa 468 (275), 476 Muck, S. 1068 (136), 1157 Mudgett, J.S. 979 (78), 993 (147), 995, 997 Mueller, R. 297 (5), 332 Mugnier, Y. 450 (193), 474 Mugnoli, A. 100 (92, 93), 103 Muhl, H. 992 (128), 997 Mukai, T. 757 (28), 818 Mukaiyama, T. 593 (340), 602 (387), 623, 624 Mukherjiee, T. 441 (144), 473 Mulcahy, R.T. 1032 (192, 193), 1039 Mulder, G.J. 1003, 1004, 1009 (35), 1011 (35, 72), 1012 (35, 72, 85), 1029 (72), 1031 (35), 1033 (85, 202, 203), 1035, 1036, 1039 Muller, D. 324 (107), 325 (106), 334 M¨uller, G. 393, 394 (78), 419 M¨uller, M. 165, 166, 182 (47), 202 M¨uller, P. 580 (245), 621 Muller, R.P. 810 (157, 161, 162), 816 (162), 821 Mullin, A.S. 416 (211), 422 Mullins, M.E. 673 (44), 681 Mullins, M.W. 830 (51), 836 M¨ulsch, A. 992 (140), 997 Mulvaney, R.L. 1045 (4), 1048 (61, 62), 1154, 1156 Mulvey, R.E. 396 (90), 419 Mumford, J.L. 1177 (34), 1212 Mumford, R. 992 (131), 997 Mumford, R.A. 978 (63, 65), 995 Munakata, M. 1256 (138, 139), 1298, 1299 Munasinghe, V.R.N. 771 (59), 772 (60), 819 Munchausen, L.L. 163, 164, 166, 179, 180 (28), 202 Mungwari, F.P. 1048 (61), 1156 Munns, R.K. 1139 (539, 541), 1166 Munowitz, M. 322 (103), 334 Munowitz, M.G. 325, 326 (108), 334 Munoz, M.A. 409 (169a, 169b), 421 Munson, M.S.B. 234 (154), 247 Murad, F. 975 (6, 17, 18), 977 (46, 49), 978 (49), 991 (123), 994 996 Muradov, N.Z. 1142 (559), 1166 Murahashi, S. 579 (232, 236), 582 (265, 267), 593 (341), 621 623 Murahashi, S.-I. 535 (8), 576 (212), 580 (246), 616, 621
Author index Murahashi, T. 1130 (481), 1165 Murai, S. 1078 (206), 1159 Murai, T. 574 (205), 620 Murai, Y. 587 (297), 622 Murakami, M. 602 (390), 624 Murakami, T. 1064 (102), 1157 Muralidharan, S. 782 (86 89), 783 (88, 89), 784 (94), 785 (95), 819, 820 Murata, S. 358 (73), 376, 582 (268), 622, 692 (49), 741, 810 (161), 821 Murata, Y. 506 (173), 529 Murer, P. 583 (275), 622 Murphy, D.M. 653 (143), 662 Murphy, S.E. 1150 (612), 1167 Murphy, T. 879 (77), 890 Murphy, T.J. 977 (53), 995 Murphy, W.J. 991 (125), 997 Murphy, W.S. 552 (100a), 565 (172), 618, 620 Murray, A.W. 858 (1), 888 Murray, B.A. 412, 413 (196), 422 Murray, J.S. 408, 409 (170), 421 Murray, R.W. 579 (228a, 228b, 233a, 233b), 621 Mursyidi, A. 729 (173), 744 Murthy, C.P. 827 (39, 40), 835 Murthy, J.T. 879 (81), 890 Muschik, G.M. 1094 (322), 1096 (327), 1149 (605), 1161, 1167 Musiani, M. 563 (162), 620 Mussche, P. 1063 (101), 1157 Musso, H. 3 5, 29 (1g), 81 Musumarra, G. 434 (88), 472 Muszkat, K.A. 184 (103), 203 Mutai, K. 169 (64), 203, 751 (8, 9), 758 (33a, 33b, 34a e), 759 (36a c), 817, 818 Mutti, S. 126, 127 (80), 155, 1111 (397), 1163 Myers, P.R. 673 (46), 681 Myhre, P.C. 950 (13), 951 (15), 957 (45), 965 (52), 966 (54), 970, 971
Naal, R.M.Z.G. 757 (27), 818 Nabeshima, T. 605 (406), 625 Nabi, S.A. 461 (250), 476 Nadjo, L. 692 (51), 741 Nafie, L.A. 147 (140), 148 (140, 146), 150 (152, 154 156), 153 (167), 156, 157 Nafti, A. 567 (183), 620 Nag, A. 694 (66), 741 Naga, S. 1085 (260), 1160 Nagai, U. 142 (123), 156 Nagakura, S. 171 (73), 193, 197 (140), 203, 204, 751 (8), 758 (34a, 34c), 759 (36a, 36b), 817, 818 Nagao, M. 1029 (166), 1038 Nagase, S. 409 (174), 421 Nagashima, U. 437 (122), 473
1357
Nagata, Y. 1089 (289, 290), 1161 Nagayoshi, A. 950 (14), 970 Nagira, K. 654 (152), 657 (170), 662 Nago, M. 677 (71), 681 Nagren, K. 932 (45), 947 Nagy, A. 164, 165, 175 (31), 202 Nagy, J.B. 468 (275), 476, 1245, 1266 (114b), 1298 Nagy, O.B. 468 (275), 476, 1245, 1266 (114a, 114b), 1298 Nagy-Felsobuki, E. 166 (55, 57 59), 202, 510 199, 530 Nagy-Tur´ak, A. 1086 (275), 1160 Naidu, B.N. 578 (222), 621 Naidu, S.R. 1141 (555), 1166 Naik, S.N. 96 (56), 103 Naito, A. 685 (14), 740 Naito, T. 724 (162b, 162d, 162e, 163, 165, 166a d), 743, 744 Nakagaki, R. 432, 443 (72), 472, 751 (8, 9), 759 (36a c), 817, 818, 1220 (44), 1296 Nakagawa, M. 565 (174), 620 Nakagawa, R. 1177 (33), 1212 Nakagome, S. 1067 (124), 1157 Nakahama, S. 111 (36), 154 Nakai, H. 324 (105), 334, 730 (178, 181b, 181c, 182b), 744 Nakaitani, D. 522 (245), 531 Nakaji, D.Y. 355 (56), 375 Nakajima, D. 1130 (478), 1164 Nakamoto, A. 1096 (328), 1161 Nakamura, E. 1047 (22), 1155 Nakamura, I. 576 (212), 621 Nakamura, J. 758 (34a, 34c), 818 Nakamura, M. 704 (102), 742 Nakamura, N. 123 (71), 155 Nakamura, T. 614 (455), 626 Nakane, M. 977 (46, 49), 978 (49), 995 Nakanishi, K. 139 (116, 117), 140 (118), 141 (116 119), 142 (121, 122), 143 (126), 156 Nakano, M. 111 (36), 154 Nakano, S. 561 (147), 619 Nakano, T. 590 (319), 623, 735 (191), 745 Nakashima, K. 1091 (304), 1161 Nakashima, N. 824 (12), 835 Nakato, T. 582 (267), 622 Nakausa, R. 649 (120), 661 Nakayama, D.K. 979 (76), 995 Nakayama, H. 595 (358), 624, 1122 (438), 1164 Nakayama, T. 776 (66), 819 Nakazato, M. 1083 (245), 1160 Nakazawa, H. 1134 (504), 1165 Nakazono, Y. 1106 (372), 1162 Nalamasu, O. 767 (51), 819 Nallaiah, C. 578 (227a, 227b), 621 Namiki, H. 1047 (22), 1155
1358
Author index
Nanni, D. 655 (158), 662 Naota, T. 580 (246), 582 (265, 267), 621, 622 Narang, R.S. 94 (30), 102 Narang, S.C. 510 (204), 530 Narayanan, K. 991 (118), 996 Narayanan, V.A. 1101 (354, 355), 1162 Nardi, L.O. 984 (88), 996 Narkates, A.J. 1082 (240), 1160 Narsimha, R. 1137 (524), 1165 Naruchi, K. 795 (128, 129), 820 Naruto, S. 722 (157b), 743 Nasr, M.M. 933 (48, 49), 934 (49), 935, 938 (48, 49), 947 Nass, R. 164, 166, 168 (32), 202 Nassereddine-Sebaei, M. 1133 (497), 1165 Nathan, C. 978 (63, 65), 992 (129, 131), 993 (147, 150), 995, 997 Nathan, C.F. 976 (35, 37, 38), 978 (37, 38, 58, 61, 64), 980, 983 (37), 985 (91), 994 996 Nau, H. 977 (48), 995 Naughton, A.B.J. 1126 (448), 1164 Nauman, R.V. 192 (133), 204 Naumann, W. 649 (119), 661 Naumova, I.I. 884 (95), 891 Navas, J.P. 977 (53), 995 Naylor, R.D. 218 (83), 245, 338, 361 (2), 371, 410 (188), 422 Neamati-Mazraey, N. 1273, 1275, 1283 (178), 1299 Nebenzhal, L.L. 398 (113c), 420 Neca, J. 1133 (500), 1165 Needleman, P. 975 (24), 994 Neenan, T.X. 767 (50b, 51), 819 Neergaard, J.R. 137, 138 (109), 148 (142), 156 Neeter, R. 220 (102), 246 Nefedov, V.I. 160 (10), 201 Negoita, N. 968 (61), 971 Negrebetsky, V. 437 (124), 473 Negrusz, A. 1068 (140), 1158 Neibecker, D. 587 (299), 588 (302a, 302b), 622, 623 Neiland, O.Y. 636 (43), 659 Neild, G.H. 674 (50), 681 Nelsen, S.F. 56 (80a d), 83, 164 (41), 166 (53), 169 (41), 184 (104), 187 (104, 112), 202 204, 684 (1), 740 Nelson, G.L. 302 (19), 332 Nelson, J. 59 (100), 83 Nemeryuk, M.P. 633 (26), 659 Nemethy, S. 1093 (309), 1161 Nerem, R.M. 977 (53), 995 Neset, S.M. 579 (234), 621 Nesi, R. 780 (82), 819 Nesmeyanov, A.N. 657 (173), 663 Nesterova, Y.M. 636 (40), 659 Neta, P. 824 (4, 9), 826 (4, 26), 827 (4, 27 33), 828 (4, 42), 832 (63, 64), 833 (65),
835, 836, 839 (8a, 8b), 850 (8b), 851 (8a, 8b), 855 Netherton, L.T. 895, 896, 936 (11), 947 Neuenschwander, K. 143 (130), 156 Neugebauer, F.A. 95 (43), 102, 436 (113), 473 Neumann, H.-G. 1000 (11), 1003 (11, 33), 1007, 1008 (33), 1009 (11, 33), 1011, 1012 33, 1021 (102 105), 1022 (110, 111), 1026 (147), 1030 (103), 1035, 1037, 1038 Neumann, W.L. 570 (196), 620 Neumark, D.M. 795 (125), 820 Neveux, M. 591 (327), 623 Newcomb, M. 599 (380, 381), 600 (382, 383), 624 Newman, L. 641 (70), 660 Newman, P. 106 (13), 153 Nguyen, A. 346 (20), 350 (35), 373, 374 Nguyen, D.T. 3 (2b), 81 Nguyen, K.C. 580 (252b), 621 Nguyen, M.T. 642 (78), 660 Nguyen, N.V. 97, 101 (61), 103, 606 (414), 625 Nguyen, T. 640 (67), 660 Nguyen Quy Dao 456 (226), 457 (227), 475 Ni, J.X. 416 (211), 422 Nibbering, N.M.M. 211 (40), 216 (59), 218 (86), 220 (94, 95, 102), 222 (59), 231 (135), 244 247, 260 (51), 262 (58, 59), 263 (51, 59), 292, 354 (54), 375 Nicholas, K.M. 567 (184), 571 (199), 620, 1152 (624), 1168 Nichols, M.A. 396 (91c), 397 (102), 419, 420 Nick, K. 1134 (508), 1165 Niclas, H.J. 592 (329), 623 Nicol, G. 385 (34d), 417 Nicolaides, D.N. 721 (150), 743 Nicolet, P. 381 (20b), 417, 428 (42), 471 Nicoletti, I. 1093 (314), 1161 Nicoletti, R. 560 (135), 619 Niedercorn, F. 587 (299), 622 Niedzielska, J. 1139 (533), 1166 Nielsen, A.T. 604 (400), 625 Nieman, T.A. 1083 (249), 1160 Niemann, M.A. 1082 (240), 1160 Niemczyk, M.P. 445 (168), 474 Niessner, R. 1128 (462, 463), 1164 Nieuwenhuize, J. 1045 (7), 1155 Nigenda, E.S. 883 (88), 890 Niketic, S.R. 3 5, 29 (1f), 81 Nikiforov, G.A. 637, 639 (44), 660 Nikitenkova, L.P. 884 (95), 891 Nikolaou, K. 1175 (19), 1212 Nilsson, J.L.G. 62 (107), 84 Nims, R.W. 669 (25), 680 Ning, H.S. 1132 (490), 1165 Ninomiya, I. 724 (162b, 162d, 162e, 163, 165, 166a d), 743, 744
Author index Niroomand, F. 977 (48), 995 Nishida, A. 736 (194a, 194b), 745 Nishida, K. 977 (53), 995 Nishiguchi, H. 551 (89a, 89b), 618 Nishiguchi, I. 596 (365), 624 Nishiguchi, Y. 724 (166a), 744 Nishihara, C. 854 (64), 856 Nishijima, Y. 695 (68), 741 Nishikata, Y. 734 (188a), 744 Nishikawa, T. 1090 (292), 1161 Nishikawa, Y. 467, 468 (274), 476, 1217 (7), 1295 Nishima, T. 1083 (245), 1160 Nishimoto, K. 215 (53, 54), 245 Nishimoto, S. 833 (69), 836 Nishimoto, Y. 1108 (389), 1163 Nishimura, K. 593 (341), 623 Nishimura, T. 259, 262 (43), 292 Nishimura, Y. 650 (126), 661 Nishioka, M. 1181 (53), 1213 Nishioka, M.G. 1177 (38), 1213 Nishioka, T. 306 (34), 333 Nishizawa, K. 392 (73), 419 Nishizawa, M. 113 (44), 154 Nisikawa, M. 1119 (428), 1163 Nitta, M. 598 (375), 624, 715 (131), 742 Niu, J.E. 848 (43), 856 Niwa, O. 1103 (360 362), 1162 Niwa, Y. 259 (41), 292 Niyazymbetov, M.E. 851 (56 58), 852 (59, 60), 856 Nobes, R.H. 208 (12, 13), 211 (13), 214 (12, 52), 215 (55), 244, 245 Noble, G. 557 (126), 619 Noda, J. 1079 (212), 1159 Noda, K. 969 (65), 971 Noel, M. 845 (32a), 855 Noelting, E. 484 (36), 526 Nogami, T. 647 (104), 661 Noggle, F.T. 1063 (99), 1071 (152), 1157, 1158 Nogueira, L.C. 753 (13), 817 Nohl, H. 1022 (115), 1037 Nohmi, T. 1131 (486, 488), 1165 Nojima, K. 1180 (57), 1213 Nojima, M. 735 (190c), 745 Nokagaki, R. 758 (34a), 818 Nomura, M. 582 (268), 622, 692 (49), 741 Nomura, R. 590 (319), 596 (361a, 361b), 623, 624 Nonomura, S. 1090 (297), 1161 Noord, T.van 1085 (260), 1160 Noordhoek, J. 1129 (475), 1164 Nordenson, S. 95, 96 (44), 102 Nordgren, J. 171 (76), 203 Nordholm, L. 1137 (528), 1166 Nordling, C. 171 (76), 203
1359
Norfolk, E. 1069 (141), 1158 Norishima, I. 164, 170 (30), 202 Norman, J. 1174 (7), 1212 Norman, R.O.C. 670 (29), 680 Normant, J. 546 (73), 618 Noronha-Dutra, A. 674 (50), 681 Norrby, P.-O. 41, 42 (60), 82 Norris, A.R. 457 (235), 476 Norris, R.K. 833 (65), 836 Norskov-Lauritsen, L. 15, 16 (26a), 81 Northrup, D.B. 894 (4), 946 Northup, R.R. 1046 (15), 1155 Nose, A. 608 (428, 429), 625 Noss, M.B. 1032 (190), 1039 Noszal, B. 407 (164), 421 Notario, R. 1238 (93), 1285 (196), 1297, 1300 Noto, R. 100 (92), 103 Notto, R. 1241, 1262, 1264 (103a), 1298 Nouchi, G. 1136 (522), 1165 Novak, M. 405 (151a), 421 Novi, M. 100 (93), 103 Novotny, M. 1093 (320, 321), 1161 Nowak, K. 561 (144), 619 Nowek, A. 440 (136), 473 Nowick, J.S. 427 (19), 470 Nowicka-Scheibe, J. 435 (112), 473 Noyce, D.S. 1032 (188), 1039 Noyori, R. 106 (18), 113 (44), 120 (18), 153, 154 Nozaki, K. 685 (14), 740 Nozi`ere, B. 360 (80), 377 Nozoe, T. 863 (25), 889 Nsunda, K.M. 218 (81), 245 Nudelman, N.E.S. 396 (99), 420 Nudelman, N.S. 396 (98), 419, 434 (87), 469 (276 279), 472, 477, 1216 (1b, 4a, 4b), 1217 (4a, 4b, 10, 12), 1219, 1220 (1b), 1221 (48a c), 1222 (48b), 1232 (81), 1235 (1b, 4a, 4b, 81, 82), 1236 (107), 1237 (82, 83a, 83b), 1241 (102, 104a, 104b, 105a, 105b), 1242 (1b, 105a, 105b, 107), 1243 (82, 83a, 107), 1244 (1b), 1245 (10), 1247 (48c), 1250 (1b), 1251 (104a, 104b), 1261 (143a, 143b), 1262 (144), 1263 (12, 82, 144, 172, 174, 175, 180), 1266 (10, 143a, 143b, 144), 1267 (144), 1268 (143a, 143b, 144), 1269 (10, 172), 1271 (190), 1272 (174, 175), 1273 (10, 104a, 104b, 175, 177, 180), 1274 (1b, 177), 1275 (177), 1276 180, 1282 (143a, 143b, 144, 190), 1283, 1284 (190), 1286 (143a, 143b, 144), 1287 (144), 1288 (10), 1290 (1b, 102), 1293 (82), 1295 1300 Nugao, M. 888 (106), 891 Nugent, W.A. 543 (63), 617 Nussbaum, P. 582 (269), 622 Nussler, A.K. 979 (76, 78), 995
1360
Author index
Nyburg, S.C. 1241, 1242 (105a), 1298 Nyiredy, S. 1086 (274), 1160
Oae, S. 535 (11), 616, 654 (148), 662, 666 (6), 667, 670 (6, 11), 672 (6, 34), 677 (76), 678 (11, 78), 680 682, 865 (31), 866 (33), 868 (42), 889 Oancea, D. 411 (185), 422 Oates, M.D. 1079, 1080 (218, 219), 1159 Obara, H. 776 (65), 819 Oberhammer, H. 25 (38 40), 38 (38), 82, 164, 167 (35), 202 O’Brien, P.J. 1030 (172, 173), 1038 Occupati, G. 57 (90c), 83 Ochiai, M. 1130 (478), 1164 Ochterski, J. 848 (45), 856 O’Connell, A.M. 95 (42), 102 Oda, D. 605 (408), 614 (455), 615 (459), 616 (465), 625, 626 Oda, K. 728 (172), 730 (180a), 733 (183c), 734 (186, 187, 188a, 188b), 736 (194c), 744, 745 Oda, Y. 1131 (488), 1165 Odaira, Y. 722 (155), 743 Odaka, H. 571 (197), 620 Odingo, J. 139, 141 (116, 117), 143 (126), 156 Odintsov, V.V. 362, 363 (90), 377 Odiot, S. 303 (28), 332 Oehlke, J. 1080 (225), 1159 Oesch, F. 1185 (72), 1213 Oevering, H. 445 (169), 474 Ogana, T. 733 (183b), 744 Ogata, K. 585 (292), 622 Ogata, S. 590 (320), 623 Ogata, Y. 721 (151), 743 Ogawa, A. 563 (159), 596 (368), 620, 624 Oguchi, S. 774 (63), 819, 992 (126), 997 Ogura, F. 583 (276), 622 Oh, C.H. 1066 (120), 1157 Oh, S.M.N.Y.F. 667 (10), 680 Ohanessian, G. 443 (159), 474 Ohannesian, L. 448 (189), 474 O’Hara, D.S. 992 (133), 997 Ohashi, M. 240 (186), 248, 587 (297), 622, 647 (104), 661, 685 (12), 740, 1147 (587), 1167 Ohashi, Y. 722 (159c), 743 Ohba, S. 93 (17), 94 (31), 99 (83), 102, 103 Ohba, T. 843 (21), 855 Ohfune, Y. 595 (352), 624 Ohga, K. 712 (123), 714 (127), 742 Ohgi, H. 1119 (433), 1164 Ohkawa, S. 978 (66), 995 Ohkubo, K. 843 (21), 855 Ohlstein, E.H. 975 (21, 22, 27), 994
Ohmori, H. 676 (68), 681 Ohnishi, K. 978 (66), 995 Ohnishi, Y. 1129 (473), 1164, 1177 (37), 1180 (51), 1212, 1213 Ohno, A. 650 (126), 661, 1267 (169), 1299 Ohno, K. 730 (181f), 744 Ohnsorge, U.F.W. 131, 132 (93), 155 Ohnuma, T. 736 (194c), 745 Ohrui, S. 1065 (110 112), 1157 Ohsawa, T. 580 (251), 621 Ohta, H. 591 (326), 623 Ohta, T. 1029 (166), 1038 Oitkelinx, A. 697 (86), 741 Oka, T. 1090 (292), 1161 Okada, T. 694 (58), 698 (94), 741, 742 Okamoto, H. 437 (122), 473, 546 (75), 618, 778 (74), 819 Okamoto, I. 123 (72), 155 Okamoto, K. 96, 97 (59), 103 Okamoto, T. 1029 (166), 1038, 1256 (137, 138), 1298 Okamoto, Y. 488, 489 (82), 527 Okamura, K. 396 (93), 419 Okaniwa, K. 437 (122), 473 Okawara, T. 551 (94), 618 Okay, G. 657 (167), 662 Okazaki, M.E. 594 (350), 624 Okazaki, S. 685 (14), 740, 868 (42), 889 Oku, A. 638 (50), 660 Okuma, E. 1089 (287), 1161 Okuma, K. 591 (326), 623 Okumura, M. 868 (42), 889 Okumura, Y. 1114 (405), 1163 Okuno, S. 983 (81), 996 Okuno, Y. 722 (157c), 743 Okura, Y. 1080 (221), 1159 Okushi, T. 596 (365), 624 Okuyama, T. 1019 (89), 1037 Olafson, B.D. 37, 38, 40 (57), 82 Olah, G.A. 510 (204), 530, 550 (87), 551 (88), 604 (403), 605 (407), 618, 625, 639 (59), 651 (134), 657 (169), 660, 662 Ol´ah, K. 1047 (34), 1155 Olbrich, F. 396 (95), 419 Olbricht, T. 160 (13), 201 O’Leary, M.H. 894 (4), 935, 936 (52), 946, 947 Olefirowicz, E. 184 (105), 203 Olivato, P.R. 175 (83), 203 Olivella, S. 640 (67), 660 Oliver, A.M. 445 (169), 474 Oliver, S. 428 (42), 471 Olken, H.M. 990 (112), 996 Olken, N.M. 983 (83), 996 Ollagnier, M. 1063 (100), 1157 Ollis, W.D. 414 (200), 422 Olliver, S. 381 (20b), 417
Author index Olmstead, W.N. 308 (41), 333, 387 (52b), 410 (183), 413 (198), 418, 422, 436 (116), 473, 505 (163), 529 Olofson, R.A. 582 (263, 264), 622 Olson, E.S. 638 (46), 660 Olson, J.S. 989 (107), 996 Olson, S.L. 978 (71), 995 Omote, Y. 686 (29), 722 (159a), 740, 743 O’Neal, H.E. 354 (53), 375 Oneil, P.A. 396 (90), 419 O’Neill, I.K. 1182 (62), 1213 O’Neill, M.E. 629 (12), 659 Onigbinde, T.A. 1065 (106), 1157 O’Nions, P. 1175 (11), 1212 Onkenhout, W. 289 (115), 294 Ono, N. 458 (238), 476, 605 (409b), 610 (438, 439), 611 (440), 614 (452 454, 456, 457), 615 (458), 625, 626 Onoda, R. 873 (59), 890 Onodera, J. 776 (65), 819 Onuoha, G.N. 1266, 1267, 1276 1278, 1294 (162), 1299 Onyido, I. 1251 (127), 1266, 1267 (162), 1276 (162, 182), 1277 (162), 1278 (162, 182), 1290 (182), 1294 (162), 1298 1300 Onyido, J. 1262, 1264, 1276, 1288 (148a, 148b), 1299 Ooi, S.L. 672 (32), 680 Oosterbeek, W. 522 (248), 531 Opella, S.J. 322 (101), 334 Opgenorth, H.-J. 629 (11), 659 Opitz, A. 398 (108), 420 Oplinger, J.A. 991 (116), 996 Oplinger, J.G. 991 (117), 996 Oppenheimer, N.J. 132 (95), 155 Orb´an, M. 431 (61), 471 Orihara, Y. 1029 (166), 1038 Orioli, P. 391 (65), 419 Orito, K. 794 (119), 798, 799 (133), 820, 821 Oritz, M.J. 716 (139), 743 Orlek, B.S. 589 (310), 623 Orloff, G.J. 978 (68), 995 Orloff, S.L. 1024 (125, 126), 1037 Orlova, Zh.I. 576 (215), 621 Ornellas, D. 369 (95), 378 Oroszlan, S. 1024 (125), 1037 Orrel, K.G. 447 (177), 474 Orrell, K.G. 315 (60), 333 Ortega, F. 1217 (6a c), 1295 Ortiveros, C. 1047 (35), 1155 Ortiz, M.J. 718 (146), 743 Orton, K.J.P. 486 (61, 64), 526 Orvick, J.A. 1218, 1250, 1251 (19), 1295 Orwar, O. 1077 (193), 1159 Osajima, Y. 1106 (372), 1162 Osapay, K. 218 (81), 245 Osawa, E. 3 (1g), 4 (1g, 15), 5 (1g, 7), 13
1361
(15), 29 (1g), 77 (15), 81 Osawa, H. 163 166, 168 (27), 202 Osawa, Y. 990 (112), 996 Osborn, D.L. 795 (125), 820 Osborne, J. 673 (43), 681 Osborne, J.A. 673 (45), 681 Osipova, O.A. 1062 (94), 1156 Osowska-Pacewicka, K. 537 (32), 540 (44), 617 Ostwald, W. 493 (114), 528 Osugi, J. 460 (246, 247), 476 Oszczapowicz, J. 392 (74, 76), 419, 1284 (193), 1300 Otani, S. 467, 468 (274), 476, 1217 (7), 1256 (138, 139), 1295, 1298, 1299 Oth, J.F.M. 96 (49), 102 Otiono, P. 1267, 1288 (170), 1299 Otsubo, T. 583 (276), 622 Otsuji, Y. 703 (101), 742 Otsuka, H. 1180 (51), 1213 Ottenheijm, H. 1012 (77), 1036 Ouchabane, R. 581 (257), 622 Ouihia, A. 592 (335), 623 Ouyang, H. 381 (21), 417, 428 (43), 471 Overchuk, N.A. 639 (59), 660 Overman, L.E. 594 (350), 624 Overstraeten, A.van 630 (16), 659 Owers, R.J. 685 (9), 740 Oxford, A.E. 485 (47), 526 Oxman, J.D. 685 (19), 740, 759 (35a, 35b), 818 Oyadomari, S. 730 (181f), 744 Ozawa, H. 1064 (102), 1157 Ozbalik, N. 538 (37), 617 Ozer, N. 672 (36), 680 Ozin, G.A. 151 (159), 157 Pac, C. 561 (149), 619, 704, 706 (106), 742, 824 (11, 12), 835 Pacakova, V. 1148 (598), 1167 Pacheco, C.R. 1076 (187), 1159 Pacifici, R.E. 832 (60), 836 Packer, J. 516 (233), 530 Paddon-Row, M.N. 445 (169), 474 Padma, D.K. 584 (289), 622 Padmaja, S. 827 (29, 33), 835 Padmanabhan, K. 762 (39, 40), 818 Padva, A. 188 (113), 204 Padwa, A. 710, 717 (116a), 742 Paesen, J. 1118 (420), 1163 Pafizadeh, K. 786 (100), 820 Pafumi, E. 1133 (496), 1165 Pagani, G. 398 (107), 400 (128), 420 Pagani, G.A. 397 (104, 105), 398 (109a, 109b, 110, 111), 400 (105), 420, 509 (193 195), 530 Paimentier, J.P.F.P. 1145 (575), 1167
1362
Author index
Paine, J.S. 434 (85), 472, 511 (211, 212), 530, 1241, 1262, 1264 (103b), 1298 Paith, J.E. 991 (116, 117), 996 Pal, H. 441 (144), 473 Palacios, F. 573 (203), 620 Palacios, M. 976 (41), 994 Palacios, S.M. 655 (162), 662 Palazzolo, D.L. 1067 (132), 1157 Pale-Grosdemange, C. 590 (318), 623 Palenik, G.J. 554 (115a), 619 Paley, M.S. 933, 935, 936 (51), 947 Paliani, G. 99 (79), 103 Palladino, D.E.H. 1071 (151), 1158 Palleros, D. 469 (276 278), 477, 1236 (107), 1241 (104a, 104b, 105c), 1242 (105c, 107), 1243 (107), 1251 (104a, 104b), 1261 (143a, 143b), 1262 (144), 1263 (144, 172, 174, 175, 180), 1266 (143a, 143b, 144), 1267 (144), 1268 (143a, 143b, 144), 1269 (172), 1272 (174, 175), 1273 (104a, 104b, 175, 180), 1276 (180), 1282, 1286 (143a, 143b, 144), 1287 (144), 1298, 1299 Pallos, G. 310 (45), 333 Palm, V.A. 491, 500, 501 (107c), 508 (182), 510 (198), 528 530 Palmer, J.A. 58 (94), 83 Palmer, M.H. 171, 172, 174, 175 (75), 193, 197 199 (141), 203, 204 Palmer, R.M.J. 669 (19), 680, 975 (4, 8 12), 976 (11, 39, 41), 977 (47), 978 (39, 47, 62), 980 (39, 79), 994, 995 Palmer, T.F. 1102 (356), 1162 Palmero, S. 1078 (200), 1159 Palmisano, F. 1078 (197), 1159 Pan, Y. 322 (98, 100), 334, 595 (356), 624 Panczel, M. 259 (42), 292 Pande, R. 405 (152a, 152b), 421 Pandurangi, R.S. 148, 152 (148), 157 Paneth, P. 859 (14), 889, 935, 936 (52), 947 Panicucci, R. 1032 (186, 190, 192), 1039 Pankayatselvan, R. 571 (199), 620 Pankow, J.F. 1176 (26), 1212 Panneerselvam, K. 452 (197, 199), 475 Pannetier, G. 434 (85, 91), 472, 1262, 1266 (145), 1299 Panshin, S.Y. 338 (4), 356 (59), 372, 375 Pant, A.K. 93 (14), 102 Pant, L.M. 93, 98 (25), 102 Pantano, J.E. 933 935, 938 (49), 947 Panunto, T.W. 98 (68), 103, 433 (78), 472 Panunzio, M. 549 (81), 618 Paoletti, P. 391 (63 66), 396 (101), 418 420 Paoli, P. 396 (101), 420 Papadopoulos, P. 644 (91), 660 Papanastasiou, G. 844 (26), 855 Pape, B.E. 1047 (43), 1155 Papoutsis, A. 844 (26, 27), 855
Pappalardo, S. 286, 287 (105), 293 Paputa-Peck, M.C. 1177 (36), 1212 Paradisi, C. 1220 (29a c), 1296 Pare, J.R.J. 1134 (506), 1165 Parello, J. 1048 (60), 1156 Parhizkari, G. 1116 (411, 412), 1163 Park, B.K. 1028 (156), 1038 Park, C. 108 (27), 154 Park, J.W. 672 (35), 680 Park, K.H. 860, 861 (17), 889, 897 (22), 899 (23), 915 (36), 947 Park, M.K. 534 (3), 616 Park, S.-U. 599 (380), 624 Park, W.S. 114 (46), 154 P´ark´anyi, L. 93, 98, 100 (27), 102 Parker, A.J. 511, 515, 516 (213), 530 Parker, D. 124 (75), 130 (88), 155, 1089 (282), 1160 Parker, J.K. 98 (74), 103 Parker, V.D. 838 (6), 848 (42), 855, 856, 1246 (121), 1298 Parkes, O.W. 1136 (520), 1165 Parkhurst, L.J. 1003 (47), 1036 Parkin, C. 581 (255), 622 Parks, O.W. 1139 (543), 1166 Parks, S.K. 1047 (49), 1155 Parmeggiane, L. 1172 (1), 1212 Parola, A. 687 (39), 740 Paroni, R. 1085 (269), 1160 Parr, T. 795 (123), 820 Parris, K.D. 442 (150), 473 Parsons, G.H. 687 (39), 740 Partyka, R.A. 582 (262), 622 Pasa-Tolic, L. 200 (149), 204 Pascard, C. 592 (335), 623 Pashkevich, K.I. 1062 (94), 1156 Pasman, P. 696 (76), 741 Pasquato, L. 1012, 1015 (73), 1036 Pasto, D.J. 843 (20a), 855 Pastore, P. 1147 (592, 595, 596), 1148 (597), 1167 Patai, S. 534 (1a, 1d), 616 Patel, H.M.S. 667 (9), 680 Paterlini, M.G. 150 (154), 157 Pathak, P.V. 1074 (184), 1158 Patil, G. 584 (285a, 285b), 622 Patil, S.F. 1058 (77), 1127 (452), 1156, 1164 Patterson, B.W. 1059 (83), 1156 Patterson, P.L. 1047 (35, 36, 38), 1155 Patwardhan, M.D. 873 (60), 890 Pau, C.-F. 523 (252), 531 Paul, I.C. 347 (27), 373 Paul, M. 405 (152b), 421 Pauland, I.C. 447 (179), 474 Pauling, L. 427 (23), 471 Pauling, P.J. 143 (131), 156 Paulins, J. 437 (124), 473
Author index Paulus, A. 1093 (316), 1161 Pavlickova, L. 756 (21), 789 (105), 818, 820 Pav´on, P. 1077, 1098 (194), 1159 Pawelke, G. 164 166, 168 (38), 202 Pawlowska, M. 1090 (295), 1161 Payne, N.N. 674 (50), 681 Payzant, J.D. 235 (159), 247 Peach, M.J. 977 (51), 995 Peacock, V.E. 56 (80c), 83 Pearlstein, R.A. 13 (19), 81 Pearson, A.M. 1189 (95), 1214 Pearson, R.G. 674 (51), 681 Peat, I.R. 505 (156), 529 Pechy, P. 315, 316 (61), 333 Peck, B.M. 739 (207), 745 Pedersen, S.F. 549 (82), 618 Pederson, T.C. 1176 (22), 1212 Pedireddi, V.R. 792 (117), 820 Pedley, J.B. 218 (83), 245, 338 (2), 345 (17), 350 (35), 352 (44), 361 (2), 371, 372, 374, 410 (188), 422 Peel, J.B. 163 165 (25), 166 (55, 57 60), 202 Peerboom, R.A.L. 354 (54), 375 Peet, K.M. 405 (151a), 421 Peeters, D. 410 (187a, 187b), 422 Peevey, R.M. 575 (209), 621 Pelizza, F. 456 (225), 475 Pellerite, M.J. 220 (105), 246 Pellizzari, E.D. 1047 (45), 1155 Pellon, R.F. 584 (283), 622 Pemberton, P.W. 1097 (334), 1162 Pe˜na, M.E. 643 (88), 644 (92, 96), 645 (88, 98), 660, 661, 675 (57, 60), 677 (72), 681, 886 (101, 103), 888 (106), 891 Penais, B. 1079 (208), 1159 Penaud-Berruyer, F. 1284 (192), 1300 Penfold, J. 1119 (434, 436), 1122 (437), 1164 Peng, S. 188 (113, 115 117), 204 Peng, S.B. 1047 (25), 1155 Peng, W. 1127 (454), 1164 Pensabene, J.W. 1144 (569), 1145 (577 579, 581), 1166, 1167, 1189 (94, 97), 1214 Penso, M. 616 (462, 463), 626 Penwell, P.E. 605 (405), 625 Pepe, G. 710 (119), 742 Pepe, J.P. 582 (263), 622 Pepekin, V.I. 362, 363 (90), 377 Pereira, W.E.Jr. 130, 131 (92), 132 (95), 155 Perekalin, V.V. 604 (401), 625 Peres, T. 251, 254, 262 (7), 291 P´erez, J.A. 1138 (530), 1166 Perez, P. 780 (81), 819 P´erez-Arribas, L.V. 1135 (513), 1165 P´erez Bendito, D. 1077, 1098 (194), 1159 P´erez-Lanzac, M.T. 283, 284 (100), 293 Perez-Ossorio, R. 715 (129, 132), 716 (132), 742
1363
Perez-Prieto, J. 568 (189), 620 Periasamy, M. 536 (17), 582 (266), 584 (281), 617, 622 Periasamy, N. 753 (10), 817 Pericas, M.A. 545 (70), 618 Perie, J.J. 587 (298), 622 Perillo, I. 433 (81), 472, 1245 1247, 1266 (115b), 1298 Perjessy, A. 313, 314 (58), 333 Perkins, M.J. 579 (239), 621 Perks, H.M. 339 (7), 372 Perrault, G. 1145 (580), 1167 Perrin, C.L. 949 (2), 966 (53), 970, 971, 1113 (404), 1163 Perrin, D.D. 381 (4a), 416, 431 (60), 471 Perry, J.A. 1072 (154), 1158 Perry, J.W. 444 (162), 474 Perry, R.A. 816 (172), 821 Persico, M. 803 (138), 821 Persson, J. 938 (55), 948 Petasis, N.A. 566 (181), 620 Petch, W.A. 448 (191), 474, 869 (44), 889 Petcher, T.J. 63 (110a, 110b), 84 Pete, J.P. 737 (195a c), 745 Peterson, M.R. 236, 238 (173), 248 Petillo, P.A. 56 (80a), 83, 184 (105), 203 Petrakis, L. 57 (90a), 83 Petri, A. 143 (125), 156 Petrich, J.W. 698 (98), 742 Petrillo, G. 1262, 1264 (151), 1299 Petrini, M. 608 (423, 425, 426b), 610 (436), 625 Petris, G.de 289 (110), 293 Petrov, E.S. 398 (114), 420 Petrov, V.A. 602 (389), 624 Petrova, M. 437 (124), 473 Petrucelli, L. 1089 (281), 1160 Petterson, L. 171 (76), 203 Petterson, I. 41, 42 (60), 82 Petty, J.T. 399 (120), 420 Petz, M. 1139 (536), 1166 Pevzner, M.S. 646 (102), 661 Peyser, J.R. 765 (43), 818 Pez, G.P. 587 (300), 622 Pfab, J. 188 (126, 128), 189, 190 (126), 191 (126, 128), 204, 803 (137, 139, 141), 821 Pfafferot, G. 25 (39, 40), 82 Pfeil, E. 628 (10), 659 Pfeilschifter, J.P. 992 (128), 997 Pfoertner, K.H. 717 (141), 743, 780 (80), 819 Pham, V.T. 939, 946 (58), 948 Phelps, M.E. 652, 653 (140), 656 (165), 662 Philipot, K. 588 (302a, 302b), 623 Philipsborn, W.von 297 (5), 320 (83), 332, 334 Phillips, J.G. 1144 (569), 1166 Phillips, R.J. 666 (5), 680
1364
Author index
Philpott, M.F. 1061 (89), 1156 Piancatelli, G. 777 (68), 819 Piatak, D.M. 563 (160), 620 Pickard, S.T. 112, 133, 135, 136 (38), 137 (38, 107), 148 (147, 148), 152 (147, 148, 164), 154, 155, 157 Pickering, M. 96 (52), 103 Pickering, R.A. 667 (8), 680 Pico, Y. 1048 (55), 1156 Piekarskagolebiowska, J. 824 (13, 14), 835 Pienta, N.J. 684 (5), 688 (33, 34), 740, 1220 (36), 1296 Pierpoint, C. 297 (9), 332 Pierre, J.-L. 669 (22), 680 Pietra, F. 467 (269), 476, 1220 (28), 1236, 1244, 1265 (111), 1295, 1298 Pietra, S. 773 (62), 819 Pietri, S. 991 (124), 996 Pignataro, S. 164 (37), 202 Pignatelli, B. 1147 (591), 1167 Pignato, S. 165, 166, 178 (46), 202 Pihlaja, K. 353 (45), 375 Pike, D.C. 348 (30b), 373 Pikulik, I. 638 (47), 660 Pikver, R.J. 1238 (89), 1297 Pilarski, B. 554 (112), 557 (126), 619 Pilati, T. 452 (197), 475 Pilcher, G. 218, 225 (82), 245, 339 (10), 357 (67), 358 (71 73), 372, 376 Pilichowska, S. 540 (48), 617 Pillai, V.N.R. 736 (193), 745 Pillay, K.S. 812 814 (165), 821 Pimental, D. 992 (127), 997 Pimentel, G.C. 427 (24), 471 Pinder, W.E. 131, 132 (94), 155 Pineschi, M. 544 (68), 545 (72), 617, 618 Pinhas, A.R. 545 (71), 618 Pinhey, J.T. 793 (118), 820 Pini, D. 143 (125), 156, 1112 (400), 1163 Pinkse, F.A. 260, 263 (51), 292 Pintauro, P.N. 845 (31), 855 Pinzauti, S. 1116 (409), 1163 Pirela, D. 1046 (19), 1155 Pirkle, W.H. 121 (67), 123 (73), 124 (74), 130 (86), 155, 427 (21, 22), 471 Pirmohamed, M. 1028 (156), 1038 Pirozhkov, S.D. 596 (360), 624 Pitacco, G. 165, 166, 178 (46), 202 Piteau, M. 582 (264), 622 Pittman, C.U. 171 (69), 203 Pitts, J.N.Jr. 1176 (27, 28), 1177 (39, 40), 1212, 1213 Piveteau, E. 551 (92), 618 Pizzarello, S. 1060 (87, 88), 1156 Plakas, S.M. 1139 (539), 1166 Plant, A.L. 1100 (348), 1162 Plante, R. 722 (153g), 743
Plapinger, R.E. 407 (157a), 421 Platt, J.R. 135, 136 (106), 155 Pleixats, R. 755 (20), 758 (30), 818 Pletcher, D. 844 (28), 855 Plomley, J.B. 1145 (574), 1167 Ploug-Sørensen, G. 93 (29), 98 (70), 102, 103 Poch, M. 545 (70), 618 Pochapsky, T.C. 121 (67), 123 (73), 124 (74), 155, 427 (21, 22), 471 Poggi, G. 173 (78), 203 Pohl, E. 396 (92, 96), 419 Pohl, L.R. 1025 (132), 1038 Poiana, M. 563 (163), 620 Poirer, R.A. 236, 238 (173), 248 Poirier, R.A. 896, 935, 941, 944 (19), 947 Poitras, J. 100 (88), 103 Pojopay, M. 1047 (20), 1155 Pokhodenko, V.D. 1272 (176), 1299 Pol, A.V. 578 (225), 621 Polavarapu, P.L. 148 (142 148), 152 (147, 148, 164 166), 153 (165 167), 156, 157 Politzer, P. 408, 409 (170), 421, 1001, 1007, 1008 (20), 1035 Polizzi, C. 575 (211), 621 Pollack, L. 1076 (188), 1159 Pollack, R.M. 361 (86), 377 Pollock, J.S. 977 (46, 49), 978 (49), 995 Polo, J.S. 817 (173), 821 Polo-Diez, L.M. 1135 (513), 1165 Poloni, M. 191, 199 (130), 204, 969 (66), 970 (67), 971 Polonski, T. 4, 13 (17), 69 (17, 116), 70 (118), 81, 84, 145 (134, 135), 156 Polynova, T.N. 636 (39), 659 Pommier, Y. 1024 (125), 1037 Poncet, J. 589 (308), 623 Ponomarchuk, M.P. 649 (118), 661 Ponomarev, I.L. 353 (50), 375 Pontecorvo, E.G. 975 (21), 994 Pont´en, E. 1105 (370), 1162 Ponti, A. 398 (107), 420 Poole, C.F. 121 (68), 155, 1222, 1226 (53), 1296 Popik, V.V. 658 (175), 663 Pople, J.A. 34 (48), 82, 208 (4), 244, 355 (55), 375, 384 (28a, 28b), 407 (163), 417, 421 Popowski, E. 396 (91d), 419 Popp, F.D. 838, 840, 848 (7b), 855 Poppek, R. 163 166, 170, 172, 175 (26), 186 (110), 189, 192, 195, 201 (26), 202, 204 Popper, K.R. 470 (280), 477 Poradowska, H. 561 (144), 619 Porai-Koshits, B.A. 636 (39, 40), 659 Porkashanian, M. 1175 (10), 1212 Pornet, J. 576 (217), 621 Porta, F. 578 (224), 621
Author index Portalone, G. 435 (100), 472 Porte, A.L. 804 (144, 145), 821 Porter, A.E.A. 585 (294), 622 Porter, C.J. 250 (1), 267 (76), 291, 293 Posch, W. 1130 (477), 1164 Pospisil, R. 1067 (134), 1157 Possanzini, M. 1081 (232), 1159 Postma, R. 215 (56), 245 Posynia, A. 1139 (533), 1166 Posyniak, A. 1139 (540), 1166 Potapov, V.M. 139 (114, 115), 156 Poteruca, J.J. 590 (322), 623 Potvin, P.G. 59 (99), 83 Pouchert, C.J. 1053, 1054, 1058, 1115, 1124, 1144 (71, 72), 1156 Pouet, M.-J. 512 (216), 530 Pouget, J. 697 (88), 741 Pounds, C.A. 1100 (349), 1162 Pourkashanian, M. 1174 (7), 1212 Powell, H.M. 461 (252), 476 Powell, J.B. 1186 (74), 1213 Powell, M.F. 1272 (173), 1299 Powlson, D.S. 330 (123), 335 Pozharskii, A.F. 552 (97), 618 Pozzi, G. 616 (463), 626 Prabhakaran, K.V. 1141 (555), 1166 Pradeep, T. 434 (82), 472 Prado, G. 1175 (17), 1212 Prados, P. 537 (23), 617 Prajapati, D. 569 (193), 608 (427), 620, 625 Prajer, K. 70 (118), 84, 145 (134), 156 Prakash, G.K. 651 (134), 662 Prakash, G.K.S. 510 (204), 530, 550 (87), 604 (403), 618, 625, 657 (169), 662 Prakash, I. 583 (273), 622 Prandini, P. 1133 (496), 1165 Prasad, A.S.B. 536 (17), 617 Prasad, L. 93, 100 (26), 102, 1241, 1242 (105a), 1298 Prasad, S.M. 91, 93, 99 (24), 102 Prasannan, S. 1217 (14), 1295 Prasthofer, T.W. 933, 935, 936 (51), 947 Prater, T.J. 289 (109), 293, 1177 (31, 36), 1212 Prati, M. 1078 (200), 1159 Pratt, A.C. 710 (116b), 715 (130a, 130b), 717 (116b), 742 Pratt, D.D. 676 (69), 681 Pratt, D.V. 575 (209), 621 Pratt, G.L. 290 (117), 294 Pratt, J.E. 693 (56), 741 Pregosin, P.S. 317 (67), 333 Prescher, K.-E. 977 (48), 995 Press, R.D. 436 (117), 473 Preston, S.B. 537 (25), 617 Preston-Martin, S. 1182 (61), 1213 Preussmann, R. 1148 (600), 1167, 1185 (70,
1365
71, 73), 1187 (83), 1188 (87, 88, 91, 92), 1189, 1190 (99), 1213, 1214 Prewo, R. 717 (142), 743 Price, C.G. 1047 (24), 1155 Price, E. 491, 503, 504, 515, 517 (96, 97), 527 Priebs, B. 482 (25), 525 Priesner, C. 640 (66), 660 Prince, E.C. 303, 305 (31), 333 Prior, D.V. 381 (17b e, 19, 20b, 20c), 395 (81), 417, 419, 428 (41, 42), 471, 1222 (50, 51), 1238 (51), 1296 Procter, G. 75 (126), 84, 569 (192), 620 Proctor, C.J. 267 (76), 293 Profeta, S. 3 (2a, 3c, 3d), 5, 27 (3c, 3d), 81 Profeta, S.Jr. 4, 6 12, 16, 23 (5), 24 (34, 35), 41, 61 (5), 81, 82 Prohaska, J.R. 1012 (76), 1036 Prokai, A.M. 1152 (620), 1168 Prokopczyk, B. 1150 (609), 1151 (617, 618), 1167 Prokschy, F. 186 (110), 204 Prosen, E.J. 339 (9, 12), 341, 342 (12), 372 Pross, A. 409 (173), 421, 510 (207), 530, 943 (68), 948, 1245 (119), 1298 Prout, K. 96 (46, 54), 102, 103 Prusoff, W.H. 453 (205), 475 Prutz, W.A. 827 (35), 835 Pryor, W.A. 1142 (558), 1166 Przybyl, J. 459 (243), 460 (248), 476 Psathaki, M. 1048 (53), 1156 Ptitsyna, D.A. 657 (173), 663 Puchades, R. 1104 (366, 367), 1162 Pufahl, R.A. 983, 985 (82), 991 (115), 996 Puhan, Z. 1046 (12), 1155 Puigdeu, M. 1085 (264), 1160 Pujol, M.D. 596 (366), 624 Pulley, S.R. 590 (316), 623 Pullman, A. 386 (47a c), 418 Purgstaller, K. 551, 552 (96), 618 Puskas, I. 265 (68), 293 Put, J. 695 (71), 741 Pytela, O. 494 (120, 121), 507 (120, 121, 176 180), 528, 529 Qi, X.H. 1151 (619), 1167 Qian, J.H. 524 (254), 531 Qian, Y.R. 1060 (86), 1156 Qin, X.-Z. 825 (18), 835 Qu, X. 150 (152), 157 Qu, Y. 608 (422), 625 Quadri, S.K. 1067 (132), 1157 Quan, R.W. 119 (57), 154 Quarmby, C. 1059 (80), 1156 Quartermous, T. 977, 979 (50), 995 Quereshi, M. 461 (250), 476 Quereshi, P.M. 461 (250, 251), 476 Quesada, A. 874 (64), 890
1366
Author index
Quian, J.H. 407 (161b), 421 Quinn, J.M. 434 (95), 472 Quintens, I. 1118 (420), 1163 Quintilli, U. 1220 (29c), 1296 Quinton, G.P. 678 (80), 682 Quirk, R.P. 400 (125), 420 Quir´os, M. 592 (336), 623 Raabe, E. 139 (113), 156 Rabalais, J.W. 160, 161 (4), 171, 174 (71), 188 (121), 191 (129), 192 (136, 139), 193 (136), 194, 197 (139), 200, 201 (136), 201, 203, 204 Rabalias, J.W. 255, 256 (31), 292 Raban, M. 1007 (53), 1009 (67), 1012, 1015 (83), 1036, 1112 (401), 1163 Rabenstein, D.L. 407 (164), 421, 1004 (44), 1036 Raber, D.J. 59 (102), 83 Rabinovich, I.B. 353 (50), 375 Rachwai, S. 554 (113, 114), 555 (116), 619 Rachwal, B. 554 (113, 114), 555 (116), 619 Rachwal, S. 556 (118), 619 Racklin, E.M. 975, 976 (30), 994 Raczynska, E.D. 395 (82), 419, 459 (244), 476, 1237, 1238 (84 86), 1284, 1285 (86), 1297 Rademacher, P. 163 (26), 164 (26, 36), 165 (26, 36, 45, 48, 49), 166 (26, 45, 48, 49), 170 (26), 171 (66), 172 (26), 174 (66), 175 (26, 82), 181, 182 (48, 97), 184 (66, 106), 186 (106, 110), 188 (66), 189 (26), 192 (26, 45, 138), 195, 201 (26), 202 204 Radhakrishnan, G. 795 (123), 820 Radhamani, K.N. 584 (289), 622 Radi, R. 992 (139), 997 Radner, F. 455 (218), 475, 790 (108, 111b, 111c, 112, 114), 820, 954 (34, 37, 38), 970 (37, 38), 971 Radom, L. 34 (48), 82, 208 (5, 8, 12, 13, 19 21), 209 (22, 25), 210 (19), 211 (13, 19, 20), 214 (12, 21, 52), 215 (20, 55), 235 (19), 244, 245, 355 (55), 375, 384 (28c, 31), 417, 510 (207), 530 Radomski, M.W. 673 (39, 40), 681, 975 (8 10), 994 Rae, I.D. 438 (127), 473 Raffellini, L. 1247, 1249 (123), 1278 1280, 1285 (184b), 1289 (123), 1298, 1300 Rafols, C. 1225 (65), 1228 (75), 1297 Ragauskas, A.J. 312 (55), 333 Raghavachari, K. 384 (28a, 28b), 417 Ragnarsson, U. 540 (46), 541 (46, 51), 542 (53), 617, 854 (63), 856 Ragunathan, R. 150 (152), 157 Rahkamma, E.J. 320 (91), 334 Raifer, J. 993 (144), 997
Raimbault, P. 1047 (20), 1155 Raisys, V.A. 1063 (98), 1157 Raithby, P.R. 396 (92, 96), 419 Rajadhyaksha, S.N. 579 (228b), 621 Rajan, J. 1140 (552), 1166 Rajput, S.K. 405 (151b), 421 Raju, B. 696 (80), 741 Raju, J. 1138 (532), 1166 Rakitin, O.A. 628 (8), 659 Rakova, G.V. 352 (43), 374 Rakshys, J.W. 381, 395 (14b), 416 Ramada, S.K. 596 (367), 624 Ramadas, K. 596 (363), 624 Ramaiah, P. 550 (87), 604 (403), 618, 625 RamaKrishna, N.V.S. 270 (81), 276, 277 (88, 89), 279 (89), 293 Ramamurthy, V. 762 (39, 40), 818 Ramana, D.V. 270 (81, 82), 276 (86 89), 277 (88, 89), 279 (86, 87, 89), 280 (90, 91), 286 (104), 293 Ramdahl, T. 1177 (40), 1213 Ramdev, P. 673 (44), 681 Ramesdonk, H.J.van 446 (171), 474 Ramesh, D. 769 (56), 819 Ramesh, M. 538 (37), 617 Ramette, R.W. 651 (135), 662 Ramis Ramos, G. 1086, 1088 (273, 278), 1160 Ramondo, F. 435 (100), 472 Ram´on Leis, J. 644 (92), 645 (98), 660, 661 Ramos, A. 716 (135), 718 (148), 742, 743 Ramos, G.R. 1067 (133), 1157 Ramsay, J.N. 958 (46), 971 Randall, D. 739 (202), 745 Randall, E.W. 297 (4), 317 (65), 319 (81), 320 (91), 321 (92, 93), 324 (104), 330 (123 127), 331 (125, 127, 128), 332 (129 131), 332 335 Randall, J.J. 466 (268), 476, 1216, 1219, 1220, 1235, 1244, 1250, 1274, 1290 (1d), 1295 Randez, F.J. 1285 (195), 1300 Randrianoelina, B. 576 (217), 621 Ranson, R.J. 1217 (14), 1295 Rao, C.N.R. 174 (80), 188, 191 (128), 192 (137), 193 (80, 137), 200 (137), 203, 204, 301 (17), 332, 434 (82), 441 (144), 472, 473, 1044 (2, 3), 1154 Rao, D.N.R. 824 (5), 835 Rao, D.V. 722 (153f), 743 Rao, H.S.P. 537 (27), 617 Rao, J.M. 688 (35), 740 Rao, K.K. 596 (360), 624 Rao, K.M. 854 (68), 856 Rao, K.R.N. 1090 (294), 1161 Rao, K.U.B. 876 (68), 890 Rao, R.N. 1137 (524), 1165 Rao, S.J. 541 (49), 617
Author index Rapley, P.A. 734 (185a, 185b, 189), 744 Rapp, M.W. 945 (70), 948 Rappa, A. 560 (138), 619 Rappe, A.K. 38 40 (58, 59), 82 Rasala, D. 286 (103), 293, 454 (210), 475, 555 (117), 619, 775 (64), 819 Rasbridge, M.R. 1027 (150), 1038 Raschig, F. 679 (88), 682 Rasmussen, K. 3 5, 29 (1f), 55 57 (81), 81, 83 Rathke, M.W. 552 (100b), 618 Rathore, R. 608 (421), 625 Ratkonis, F. 1266, 1267 (167a), 1299 Rattenbury, J.M. 1068 (137), 1158 Raue, R. 657 (171), 662 Rauhut, G. 956 (44), 971 Rauhut, M.M. 1105 (368), 1162 Rauk, A. 133 (98 101), 146 (136, 137), 148 (147, 149, 150), 149 (149 151), 152 (147, 149, 150), 155 157 Rauth, A.M. 1032 (186, 190, 191, 194), 1039 Raval, T. 991 (125), 997 Ravenscroft, M.D. 648 (107, 108), 661 Ravichandran, C. 845 (32a, 32b), 855 Ravichandran, R. 668 670, 672 (14), 680 Ravichandran, R.K. 1152 (620), 1168 Raymahasay, S. 880 (82), 890, 950 (6, 10, 11), 951 (10, 11), 970 Rayner, C.J. 1067 (129), 1157 Read, D. 188 (120), 204 Readman, J.M. 954, 962 (30), 971 Rebolledo, F. 592 (336, 337), 623 Reboul, J.P. 94 (37), 102 Rechsteiner, B. 589 (311), 623 Reddy, A.V.N. 537 (28), 617 Reddy, C.K. 582 (266), 622 Reddy, C.S. 1139 (544), 1166 Reddy, G.D. 686 (24, 27, 28, 30, 31), 687 (31), 699 (24, 28, 97), 700 (24, 99, 100), 701 (28, 99, 100), 704 (99), 706 (24, 28), 740, 742 Reddy, I.A.K. 854 (68), 856 Reddy, J.S. 580 (240), 621 Reddy, S.J. 1139 (544), 1166 Redey, G.D. 707 (109), 742 Redmont, W. 636 (37), 659 Reed, P.I. 1146 (585), 1151 (615), 1167 Reed, R.R. 976, 977 (44), 995 Reeder, D.J. 1092 (305), 1161 Rees, C.W. 1250, 1267 (126), 1298 Rees, D.D. 673 (39), 681, 977, 978 (47), 995 Rees, D.I. 192 (134), 204 Reetig, W. 697 (88), 741 Reetz, M.T. 547 (79), 618 Regezman, E. 1187 (79), 1213 Reginato, G. 551 (93), 618 Rehaber, H. 697 (83), 741
1367
Rehorek, D. 807 (148), 821 Reichardt, C. 381 (11), 416, 424 (1), 425 (6, 7), 470 Reichart, C.F. 1220 1222, 1238 (37), 1296 Reichel, A. 1079 (207), 1159 Reichmanis, E. 767 (49, 50a, 50b, 51), 819 Reid, G.L.III 1095 (326), 1161 Reilly, J. 673 (44), 681 Reilly, J.P. 173 (79), 203 Reimlinger, H. 630 (16), 659 Rein, T. 542 (54), 568 (188), 617, 620 Reiner, E.J. 236 (173, 174), 237 (174), 238 (173, 174, 178), 239 (178), 248 Reiner, F.J. 1145 (575), 1167 Reinhardt, K. 1003, 1005 1007, 1009, 1011, 1012, 1014, 1019, 1027, 1029, 1030 (36), 1035 Reinheimer, J.D. 1217 (16), 1295 Reinhoudt, D.N. 969 (64), 971 Reinwein, D. 1000, 1020, 1021, 1027 (17), 1035 Reischi, A. 1180 (54), 1213 Reischl, A. 1182 (60), 1213 Reiser, A. 767 (48b), 819 Reisman, J.M. 1048 (60), 1156 Reistad, R. 1012, 1033 (84), 1036 Reix, T. 579 (235), 621 Rejou-Michel, A. 1049 (64), 1156 Rejwan, M. 251, 254, 262 (7), 291 Rekis, A. 437 (124), 473 Remedi, M.V. 1230 (79), 1297 Rempe, M.E. 178, 188 (92), 203 Ren´e, L. 589 (308), 592 (335), 623 Reno, D.S. 124 (74), 155, 427 (22), 471 Rentzepis, P.M. 455 (213), 475 Reppond, K.D. 895, 896, 936 (11), 947 Repucci, C.M. 846 (36a), 855 Resnati, G. 547 (78), 618 Resvukhin, A.I. (86), 334 Rettig, W. 174, 175 (81), 203, 693 (57, 62), 694 (62, 63), 697 (87), 741 Retting, W. 446 (172), 474 Rettschnick, R.P.H. 696 (79), 741 Reuben, J. 432 (70), 472 Reuhle, P.H. 1177 (36), 1212 Reutov, O.A. 657 (173), 663 Reuwer, J.F.Jr. 910, 933 (33), 947 Reybrouck, G. 1118 (420), 1163 Reyes, A. 1267, 1275 (161), 1299 Reynold, D.W. 727 (167), 744 Reynolds, G.A. 655 (156), 662 Reynolds, J. 1020 (95), 1037 Reynolds, W.F. 505 (156), 510 (199), 522 (247), 529 531, 642 (82), 660 Rezvukhin, A.I. 306, 311, 313 (38), 315 (59), 333, 866 (36), 889
1368
Author index
Rhee, E.S. 861 (20), 889, 923 (39, 40), 947 Rhee, J. 1134 (510), 1165 Rheinboldt, H. 668 (12), 672 (33), 680 Rheinbolt, H. 669 (24), 680 Rhodes, C.J. 825, 826 (16), 835 Rhodes, P. 992 (135), 997 Ribeiro da Silva, M.A.V. 349 (32, 33), 374 Ribeiro da Silva, M.D.M.C. 357 (67), 376 Ribick, M.A. 1047 (43), 1155 Ricci, A. 551 (93), 618 Rice, S. 96 (45), 102 Rice, W.G. 1024 (123, 125 127), 1037 Rich, R. 512 (221), 530 Richard, C.S. 615 (461), 626 Richard, H. 812 (166, 168), 813 (166, 168, 169), 816 (169), 821 Richard, W.G. 727 (169), 744 Richards, D.A. 1085 (263), 1160 Richards, K.E. 883 (90), 890, 954 (24 26), 961 (24), 968 (26), 970, 971 Richards, M.K. 983 (83), 989 (104), 996 Richards, N.G.J. 41 (63), 82 Richardson, E.N. 486 (61), 526 Richardson, G.D. 612 (446, 447), 626 Richardson, J.H. 401 (136), 420 Richardson, R.D. 635 (30), 659 Richartz, H. 1180 (54), 1213 Riches, K.M. 955 (40), 971 Richter, A.F. 440 (138), 473 Richter, W.J. 268, 269 (79), 293 Rickard, G.J. 219 (91), 246 Rickert, D.E. 1020 (97, 98), 1037 Ridd, H.J. 915 (35), 947 Ridd, J.H. 641 (72), 643 (86, 87), 645 (97), 660, 661, 877 (71), 879 (77 81), 880 (83), 881 (85), 883 (91), 890, 891, 952 (17, 18), 953 (19, 21), 954 (23), 966 (55, 56), 967 (57, 59, 60), 968 (63), 970, 971 Ridyard, J.N.A. 171, 172, 174, 175 (75), 193, 197 199 (141), 203, 204 Rieder, M.J. 1027, 1028 (154), 1038 Rieker, A. 649 (120), 661 Riel, H.C.H.A.van 753 (11), 817 Riera, A. 545 (70), 618 Rietjens, I.M.C.M. 1097 (335), 1162 Rife, T.K. 991 (123), 996 Rigaudy, J. 581 (257, 258), 622 Riggin, R.M. 1176 (25), 1212 ˇ ıha, V. 507 (178), 529 R´ Riley, D.P. 595 (356), 624 Riley, J.P. 1064 (104), 1157 Riley, T.L. 289 (109), 293, 1177 (36), 1212 Rimkus, G. 1127 (460), 1128 (461), 1164 Rimland, A. 932 (45), 947 Rinaldi, D. 456 (226), 475 Rindgen, D. 1119 (429), 1163 Ringdahl, B. 131 (93, 94), 132 (93 95), 144,
145 (133), 155, 156 Rios, A. 672 (37), 680 Rios, A.M. 675 (57), 681 Rios, M.A. 15, 16 (26e), 55 57 (82), 82, 83 Ripamonti, M. 1068 (136), 1157 Rising, A. 1000, 1019 (4), 1035 Ritchie, C.D. 1232 (80a c), 1233 (80c), 1297 Ritchie, J.P. 80 (136a, 136b), 84 Rithner, C.D. 46 (70), 83 Ritieni, A. 539 (39), 617 Riva di Sanseverino, L. 98 (77), 103 Rived, F. 1225 (62, 66), 1226, 1227 (62), 1297 Rivera-Nevares, J.A. 1134 (505), 1165 Riviello, J.M. 1093 (318), 1161 Rizzoli, C. 100 (91), 103, 426 (14), 470 Roa, M.V. 108 (30), 154 Rob, F. 696 (76), 741 Robards, K. 1045 (5), 1155 Robb, I.D. 844 (25c), 855 Robbana-Barnat, S. 1025 (137), 1038 Robe, W.E. 1059 (80), 1156 Robert, A. 544 (69), 618 Roberts, B.G. 1105 (368), 1162 Roberts, B.N. 317 (70), 333 Roberts, D.J. 317 (70), 333 Roberts, I. 510 (206), 530 Roberts, J.D. 310 (47, 48), (85), 333, 334, 491 (102), 527 Roberts, J.E. 325, 326 (108), 334 Roberts, S.M. 669, 673 (17), 680 Robertson, R. 370, 371 (103), 378 Robertson, R.E. 945 (71), 948 Robinson, B. 871 (55), 890 Robinson, G.N. 339, 340 (8), 357 (8, 68), 360 (8), 372, 376 Robinson, G.W. 446 (175), 474 Robinson, J.W. 160 (14), 201 Robinson, R. 485 (47, 49), 526 Robinson, S.R. 880 (83), 890, 952 (17), 970 Robinson, W.T. 456 (220), 475, 790 (112), 820, 883 (89, 92), 890, 891, 954 (27, 28, 30, 33, 35, 36, 39), 956 (28), 962 (30), 969 (36), 971 Rochin, G. 605 (407), 625 Roddy, P. 991 (123), 996 Roder, L. 584 (283), 622 Roderer, R. 950 (3), 970 Rodgers, A.S. 354 (53), 375 Rodgers, J.R. 37 (56), 82 Rodgers, M.T. 178, 188 (92), 203 Rodgers, S.L. 77 (130), 84 Rodier, N. 453 (206), 475 Rodina, L.L. 1278 (183), 1300 Rodriguez, F.J. 1074 (183), 1158 Rodriguez, M. 992 (139), 997 Roegler, M. 636 (32), 659 Roemming, C. 442 (149), 473
Author index Roets, E. 1118 (420), 1163 Roger, A. 578 (226), 621 Rogers, D.W. 356 (59), 375 Rogers, R.N. 371 (105), 378 Rogic, M.M. 570 (196), 620 Roizen-Towle, L. 1031 (182), 1039 Rojas-Walker, T.de 1189 (101), 1214 Rojo, J. 537 (23), 617 Rokach, J. 722 (154a), 736 (192a), 743, 745 Rokushika, S. 739 (204), 745 Rolando, C. 240 (188), 248 Roller, R. 234 (153), 247 Rollgen, F.W. 240 (184), 248 Rolli, E. 179 (94), 203, 218 (81), 245 Romani, M. 580 (249), 621 Romano, So. 718 (146), 743 Romeliotis, P. 1180 (55), 1213 R¨omelt, J. 188 191 (126), 204, 803 (139), 821 Romero, A.M. 1088 (279), 1160 Romero, D.L. 584 (287), 622 Romers, C. 15, 17 (25b), 81 Romesberg, F.E. 396 (89, 91e, 97), 419 Romm, I.P. 381 (9), 416 Rømming, C. 636 (41), 659 Rondon, M.A. 1049 (63), 1156 Ronnett, G.V. 993 (151), 997 Roos, B.O. 455 (218), 475, 790 (114), 820 Rooyakkers, D.R. 1078 (196), 1159 Ropp, G.A. 655 (156), 662 Rosa, E. 606 (411), 625, 882 (86), 890 R¨osch-Oehme, E. 1003, 1020, 1022 (34), 1035 Rose, J.D. 482, 483 (23), 525 Rosen, W. 1076 (187), 1159 Rosenblatt, D. 684 (1), 740 Rosenkranz, H.S. 1177 (30), 1212 Rosenquist, N.R. 522 (246), 531 Rosenstock, H.M. 208, 210, 217, 237 (18), 244 Rosenzweig, I.B. 1063 (98), 1157 Rosero, F.S. 1048 (58), 1156 Roses, M. 1222 (52), 1223 (72), 1225 (62, 65, 66), 1226 (62, 72), 1227 (62), 1228 (75), 1296, 1297 Rosini, C. 143 (125), 156, 1112 (400), 1163 Rosini, G. 607 (415), 610 (436), 625 Roskamp, E.J. 549 (82), 618 Ross, A.B. 827 (30), 835 Ross, J. 466 (265), 476 Ross, P.F. 1047 (28), 1155 Ross, S.D. 430 (55), 440 (55, 137), 463, 465, 466 (256), 471, 473, 476, 1266 (164), 1299 Rosseel, M.T. 1062 (93), 1156 Rosset, R. 1081 (227, 228), 1159 Rossi, P. 563 (162), 620 Rossi, R.A. 1219 (25), 1295 Rossi, R.H.de 458 (237 239), 476, 1218 (18), 1219 (25), 1220 (27), 1230 (78, 79), 1231
1369
(78), 1264 (18), 1295, 1297 Rossini, F.D. 339 (9, 12), 341 (12), 342 (12, 13), 372 R¨ossler, K. 649 (122), 661 Roth, M. 1077 (189), 1159 Rotunno, T. 1078 (197), 1159 Roucoules, X. 1061 (91), 1156 Roullier, L. 843 (16), 845 (33), 855 Roullier, R. 1129 (468), 1143 (565), 1164, 1166 Rounbehler, D.P. 1047 (41), 1155, 1184 (64, 68), 1213 Roundhill, D.M. 543 (59, 60), 617 Rousseau, D.L. 987 (100), 989 (105), 996 Roussel, C. 381 (18), 417 Rousselet, G. 590 (321), 623 Routledge, P.J. 457 (234), 476, 1218, 1237, 1251, 1293 (24), 1295 Roux, M.V. 357 (70), 376 Rowe, J.E. 878 (74), 890 Roy, B. 669 (16), 680 Roy, M.B. 833 (68), 836 Royer, G.P. 119 (60), 154 Rozeboom, M.D. 169 (63), 203 Rozen, S. 579 (230, 231), 607 (417), 621, 625 R´ozycka-Roszak, S. 431 (58), 471 Ruban, V.F. 1069 (148), 1133 (493), 1158, 1165 Rubanyi, G.M. 673 (42), 681 Rubin, R.L. 1023 (122), 1037 Rubio, M. 1266 (165), 1299 R¨uchardt, C. 184, 186 (106), 204, 604 (398), 625, 629 (11), 659 Rudchenko, V.F. 553 (107), 618 Rudd, K. 236 (172), 248 Rudman, R. 97 (63), 103 Rudolf, K. 72 (123), 84 Rudolph, J.P. 400 (125), 420 Rueden, H. 1127 (459), 1164 Ruehl, E. 164, 166, 168 (32), 202 Rufeh, F. 1189 (100), 1214 R¨uhl, J.C. 832 (63, 64), 836, 839 (8a, 8b), 850 (8b, 52a), 851 (8a, 8b), 855, 856 Rulliere, C. 697 (87, 89), 741 Rumpf, B.A. 236 (171), 248 Rundle, H.W. 235 (160), 247 Rundlett, K. 1095 (326), 1161 Runge, F. 481 (9), 525 Rupp, H.S. 1139 (539, 541), 1166 Rusche, K.M. 983 (83), 996 Ruscic, B. 199 (147), 204 Rusconi, L. 389 (60), 418 Rusic, B. 180 (95), 203 Rusling, J.F. 844 (25a), 855 Russegger, P. 810 (157), 821 Russell, C. 670 (27), 680
1370
Author index
Russell, G.A. 1020 (95), 1037 Russell, J.J. 215 (57), 245 Russell, S.W. 991 (125), 997 Russelle, M.P. 1049 (65), 1156 Russell-Hill, D.A. 511 (208), 530 Russu, W. 850 (50), 856 Rusyniak, D. 1106 (377), 1162 Rutherford, K.G. 636 (37), 659 Ruttink, P.J.A. 215 (56), 245 Ruyters, H. 1094 (324), 1161 Ryan, E. 1071 (153), 1158 Rybinov, V.I. 631 (20), 659 Ryerson, T.B. 1047 (51), 1155 Rylance, J. 96 (52), 103 Ryzhakov, A.V. 1278 (183), 1300 Rzepa, H.S. 215 (57), 245 Saavedra, J.E. 669 (25), 680 Sabatini, A. 57 (93), 83 Sabbah, R. 349 (32), 357 (69), 358 (75), 374, 376 Sabbioni, G. 1021 (106, 107), 1037 Sabek, O. 879 (77, 78, 80), 890 Sabljic, A. 180 (95), 203 Sacchetto, G.A. 1147 (595, 596), 1148 (597), 1167 Sack, T.M. 208 (16), 211 (36), 244 Saczewski, F. 607 (418), 625 Sadec, M. 310, 311 (44), 333 Sadeghi, M.M. 538 (35), 617 Sadler, I.H. 804 (145), 821 Saebo, S. 171 (69), 203 Saegusa, K. 616 (465), 626 Saenger, W. 1245, 1266 (112), 1298 Saenz de Tejada, I. 993 (146), 997 Safenova, T.S. 633 (26), 659 Saghir, N.S. 1048 (61), 1156 Saho, M.K. 1133 (499), 1165 Sahoo, M.K. 833 (67), 836 Sahu, D.P. 536 (20), 617 Saionz, K.W. 1132 (491), 1165 Saito, H. 863 (25), 889, 1078 (206), 1159 Saito, K. 1003 (37), 1004, 1007 (41), 1009 (37, 41), 1012, 1013, 1019 (37), 1034 (41), 1035 (37), 1035, 1083 (245), 1160 Saito, Y. 93 (17), 102 Sakai, K. 1106 (378), 1162 Sakai, S. 654 (149), 662 Sakai, T. 448 (191), 474, 869 (43), 889, 1116 (413, 414), 1163 Sakaino, Y. 812, 813 (166), 821 Sakaitani, M. 595 (352), 624 Sakamoto, T. 592 (331, 332), 623 Sakan, T. 123 (71), 155 Sakata, K. 585 (293), 622, 765 (47), 818 Sakata, T. 824 (12), 835 Sakata, Y. 695 (69), 741
Sake Gowda, D.S. 97 (63), 103 Sakito, Y. 112 (39), 154, 536 (15), 617 Sakiyami, M. 358 (73), 376 Sako, M. 722 (158a), 743 Sakuma, I. 976 (35), 994 Sakurai, H. 163 166, 168 (27), 202, 686 (26), 740 Sakurai, Y. 536 (14), 617 Saladino, R. 560 (135), 619 Salagoity, H.M. 1078 (199), 1159 Salamon, T. 1266, 1267 (167a), 1299 Salamone, S.J. 1106 (377), 1162 Salaun, J. 1112 (402), 1163 Salem, Z. 1024 (129), 1037 Salerno, A. 433 (81), 472 Salerno, S. 1245 1247, 1266 (115b), 1298 Salinas, F. 1139 (538), 1140 (546), 1166 Sallin, K.J. 574 (208), 621 Salter, M. 991 (117), 996 Saltiel, J. 778 (70b), 819 Saltzman, M.D. 484, 485 (44, 45), 526 Salvador, A. 1074 (174), 1158 Salvadori, P. 143 (125), 156, 1112 (400), 1163 Samet, A.V. 852 (59), 856 Sammes, P.G. 735 (191), 745 Samojlova, Z.E. 132, 133 (96), 155 Sample, S. 227 (124), 246 Samuelson, A.G. 569 (190), 620 Sana, M. 410 (187a, 187b), 422 Sanberg, M. 1077 (193), 1159 S´anchez, V.M. 592 (336), 623 Sanchez-Cabezudo, M. 408 (166), 421 Sandall, J.P.B. 877 (71), 881 (85), 883 (91), 890, 891, 915 (35), 947, 953 (21), 966 (55, 56), 967 (59, 60), 968 (63), 970, 971 Sandberg, M. 1074 (182), 1158 Sande, M.A. 1027 (153), 1038 Sander, J. 1127 (453), 1164 Sanders, D.R. 1177 (30), 1212 Sandford, G. 435 (107), 472 Sandhu, J.S. 569 (193), 608 (427), 620, 625 Sandi, E. 1189 (93), 1214 Sandine, W.E. 1116 (407), 1163 Sandman, D.J. 440 (138), 473 Sandoval, T.M. 1097 (336), 1162 Sandros, K. 779 (75), 819 San Filippo, J. 861 (21), 863 (21, 23), 889 San Filippo, J.Jr. 905 (29), 911 (34), 915 (36), 918, 920 (37), 947 Sankararaman, S. 455 (215, 216), 456 (221), 475, 790 (109a, 111a), 820 Sano, A. 1147 (587), 1167 Sano, T. 649 (120), 661 Sansone, E.B. 1197 (103), 1214 Santa, T. 1091 (303), 1161 Santa Ana, M.A. 456 (223), 475 Santamaria, J. 581 (257, 258), 622
Author index Santi, C. 1152 (625), 1168 Santiesteban, F. 1109 (392), 1163 Santini, S. 99 (79), 103 Santoni, G. 1116 (409), 1163 Santos, M.A. 59, 60 (101), 83 Santos-Delgado, M.J. 1135 (513), 1165 Santus, R. 781 (83), 819 Sarada, N.C. 854 (68), 856 Sarbolouki, M.N. 1074 (181), 1158 Sargeson, A.M. 851 (53, 54), 854 (54), 856 Sarker, H. 854 (66), 856 Sarma, J.C. 537 (29), 617 Sarofim, A. 1175 (17), 1212 Sarti-Fantoni, P. 780 (82), 819 Sartori, F. 93 (28), 102 Sartorius, I. 692 (52), 741 Sarwar, G. 1085 (262), 1160 Sasaki, M. 460 (246, 247), 476 Sasaki, S. 651, 657 (132), 661 Sasaki, Y. 595 (359b), 624, 1097 (338), 1162 Sastry, K.A.R. 565 (173), 620 Satapathy, S.N. 645 (100), 661 Satish, A.V. 401, 402 (133), 403 (140), 407 (159), 420, 421 Sato, D. 396 (93), 419 Sato, H. 308, 309 (42), 333 Sato, K. 587 (297), 622 Sato, M. 605 (408), 625, 1087 (276), 1160, 1218, 1219, 1237 (21a, 21b), 1295 Sato, S. 537 (22), 617, 1004, 1007, 1009, 1012, 1019 (43), 1033, 1034 (198), 1035 (43), 1036, 1039 Sato, T. 112 (40), 154, 649 (120), 661 Sato, Y. 730 (178, 181b, 181c, 182b), 734 (188a), 744 Satoh, T. 585 (293), 622 Satyamurthy, N. 652, 653 (140), 656 (165), 662 Saunders, K.H. 628, 629, 636 (5), 659 Saunders, M. 356 (59), 375 Saunders, R.A. 206, 207, 233 (2f), 243, 265 (69), 293 Saunders, W.H. 509 (191), 530, 859 (12), 889 Saunders, W.H.Jr. 894 (5), 895, 896, 936, 939 (10), 946, 947 Saupe, T. 176 (89), 203, 435 (101), 472 Saurina, J. 1097 (340), 1162 Sausa, R.C. 1125 (444), 1135 (519), 1164, 1165 Savage, W.J. 164 (39), 202 Sav¨eant, J.M. 840, 848 (9), 855 Savelli, G. 1220 (32a, 32b), 1296 Saville, B. 671 (30), 680 Savoia, D. 564 (168), 620 Sawaada, M. 1232, 1233 (80c), 1297 Sawada, M. 489, 496 (86), 504 (153), 521 (86), 527, 529, 1114 (405), 1163
1371
Sawada, T. 651, 657 (132), 661 Sawatzky, H. 1067 (125), 1157 Sawaura, M. 757 (28), 818 Sax, N.I. 1053, 1054, 1058, 1115, 1124, 1144 (69), 1156 Saxon, R.P. 882 (87), 890 Sayakhov, R.D. 506 (175), 529 Sayegh, H.S. 979 (75), 995 Sayo, H. 1015 (87), 1037 Scaiano, J.C. 658 (175), 663, 755 (19), 771 (58), 818, 819 Scaicno, J.C. 688 (38), 740 Scalan, R.A. 1188 (90), 1214 Scandroglio, A. 1085 (261), 1160 Scettri, A. 777 (68), 819 Schaad, L.J. 148 (145, 146), 157, 910, 933 (33), 947 Schaal, R. 415 (206), 422 Schadewaldt, P. 1060 (84), 1156 Schaefer, H.F.III 1285, 1290 (197), 1300 Schaefer, J. 322 (97, 98, 100), 325 (109), 334 Schaefer, W.P. 444 (162), 474 Schaeffer, C.A. 1024 (123, 125, 126), 1037 Sch¨afer, H.J. 849 (49), 856 Schafer, L. 5, 16, 22 (8), 24 (36), 56 (85), 81 83 Sch¨afer, W. 199 (148), 204, 1001 (24, 26), 1003 (24), 1004 (24, 26), 1007 (24), 1009 1012 (24, 26), 1013 (24), 1014 (24, 26), 1015 (26), 1035 Schaffrath, R.E. 554 (110), 618 Schamp, N. 569 (191), 620 Schanze, K.S. 444 (163), 474 Schappert, K.T. 979 (72), 995 Schecter, R.S. 844 (25b), 855 Scheepers, P.J.T. 1129 (475), 1164 Scheepers, P.T.J. 1132 (489), 1165 Scheffer, J.R. 710 (111), 742 Scheiner, S. 27 (41), 82 Schell, F.M. 728 (170), 744 Schep, L.J. 1118 (423), 1163 Schepens, P.J.C. 1142 (560), 1166 Scheper, T. 1103 (363), 1162 Scher, A.L. 1135 (518), 1165 Scherer, J.R. 151, 152 (160), 157 Scherer, T. 446 (171, 173), 474, 694 (61, 65), 741 Scheutzle, D. 1177 (36), 1212 Schiesser, C.H. 655 (161), 662 Schiff, H.I. 235 (160), 247 Schijndel, J.A.M.van 99 (86), 103 Schini-Kerth, V.A. 992 (140), 997 Schinke, U. 904 (27, 28), 947 Schlageter, M.G. 512 (217, 218), 530 Schleifer, L. 14 17, 19 21 (22a), 81 Schlemper, H. 394 (80a), 419 Schlessinger, R.H. 717 (143a), 743
1372
Author index
Schleyer, P.v.R. 3 5, 29 (1c), 34 (48), 81, 82, 356 (60), 375, 381, 395 (14b), 397 (103), 416, 420 Schmahl, D. 1185 (70), 1213 Schmalzing, D. 1083 (244), 1160 Schmeltekopf, A.L. 235 (161), 247 Schmid, H. 642 (77), 644 (94), 660, 860 (18), 889 Schmid, J.P. 1176 (27), 1212 Schmid, P. 899 (24), 947 Schmidt, B. 1063 (101), 1157 Schmidt, D.G. 652, 653 (140), 662 Schmidt, G.M. 436 (119, 120), 473 Schmidt, H.H.H.W. 977 (46, 48, 49), 978 (49), 995 Schmidt, H.L. 1059 (81), 1103 (359), 1156, 1162 Schmidt, K. 985 (92), 990 (109), 991 (122), 992 (136, 137), 996, 997 Schmidt, R. 762 (40), 818, 1063 (101), 1157 Schmidt, W. 187 (111), 204 Schmidtbase, D. 396 (91f), 419 Schmidtchen, F. 1220 (35), 1296 Schmidtchen, F.P. 393, 394 (78), 419 Schmitt, R.J. 605 (405), 606 (412), 625 Schmitt, W. 584 (288), 622 Schmitz, E. 553 (105), 618 Schmitz, L.R. 4, 7, 9, 12, 21, 23 (6), 24 (6, 34), 25 27 (6), 29 (42), 38, 61 (6), 81, 82 Schmutz, J. 63 (110a), 84 Schneider, H.R. 316, 317 (66), 333 Schneider, M.P. 1092 (306), 1161 Schneider, S. 685 (19), 686 (24, 31), 687 (31), 699 (24), 700 (24, 99), 701, 704 (99), 706 (24), 740, 742, 767 (53), 819 Schneider, T.W. 1081 (229), 1159 Schneller, M. 1001, 1003 (22, 23), 1006, 1007, 1009 1011 (22), 1025 (22, 23), 1035 Schneider, S. 697 (83), 741 Schnur, J.M. 795 (120), 820 Schnur, R.C. 582 (263), 622 Schoeler, H.F. 1134 (508), 1165 Schoemaker, H.E. 142 (124), 156 Schoen, P.E. 795 (120), 820 Schofield, K. 880 (84), 890, 949 (1), 958 (47 49), 969 (1), 970, 971 Scholer, H.F. 1134 (509), 1165 Schollenberger, M. 1079 (213), 1159 Sch¨oneich, C. 832 (55, 56), 836 Schoone, J.C. 90, 93 (19), 102 Schoonover, J.R. 739 (207), 745 Schorr, M. 584 (288), 622 Schouten, A. 99 (86), 103 Schreiber, J. 1019 (91), 1037 Schrem, G. 25, 38 (38), 82 Schr¨oder, D. 262 (57), 292 Schroeder, G. 435 (108, 112), 459 (242, 243),
460 (248), 472, 473, 476, 509 (190), 530 Schroeder, L.A. 1082 (238), 1160 Schuchmann, H.-P. 824 (6, 8), 829 (46), 835, 836 Schuchmann, M.N. 824 (6), 835 Schuddeboom, W. 697 (85), 741 Schuetzle, D. 289 (109), 293, 1176 (21), 1177 (31), 1212 Schug, J.C. 434 (86), 472 Schuhmann, W. 1103 (359), 1162 Sch¨ule, U. 184, 186 (106), 204 Schullery, S.E. 427 (25), 471 Schulltz, H.P. 838, 840, 848 (7b), 855 Schulman, J.M. 317 (71, 72), 333 Schulte-Frohlinde, D. 750 (7), 778 (70a, 72), 817, 819 Schultz, G. 983 (86), 996 Schultze, O.W. 482 (24), 525 Schumann, U. 396 (95), 419 Schupp, H. 767 (53), 819 Schurig, V. 121 (65, 66, 68), 122 (69), 123 (69, 70), 155 Schusslbauer, W. 697 (83), 741 Schuster, D.I. 688 (35 38), 740 Schwabe, M. 850 (50), 856 Schwalbe, C.H. 94 (39, 40), 102 Schwan, A.L. 589 (314), 623 Schwartz, M.A. 535 (9, 10), 616 Schwartz, S.E. 641 (70), 660 Schwarz, H. 206 (1), 208 (9, 10), 209 (24, 28, 31, 32), 211 (40), 216 (63c), 220 (96 98), 221 (97, 98), 232 (97, 98, 144), 234 (150), 243 247, 250 (2), 251 (6), 253 (12, 15), 254 (15, 17), 255 (15), 259 (46), 260 (15, 49), 262 (57), 264 (62), 268 (77, 79), 269 (79), 291 293 Schwarz, W. 650 (124), 661 Schwarz, W.H.E. 848 (43), 856 Schweig, A. 160 (13), 201 Schweizer, W.B. 60 (104), 84 Schwesinger, R. 393 (79), 394 (80a, 80b), 419 Schwetlick, K. 722 (153c), 743 Schwinck, K.F. 178, 188 (92), 203 Scopes, D.I.C. 598 (376), 624 Scorrano, G. 381 (5b), 405 (153), 416, 421, 1012 (78), 1036, 1220 (29a c), 1296 Scortichini, C.L. 846 (36a), 855 Scott, F.L. 632 (21), 646 (102), 659, 661 Scott, G.L. 1027 (150), 1038 Scott, J.A. 411 (193), 422 Scott, J.C. 1150 (610), 1167 Scott, P.M. 1189 (93), 1214 Scott, R.D. 724 (162f), 743 Scott, R.M. 427 (25), 471, 1267 (161, 169), 1275 (161), 1299 Scranton, M.I. 1058 (76), 1156 Scribe, P. 1068 (139), 1158
Author index Scrimin, P. 405 (150b), 421 Scriven, E.F.V. 537, 553 (24), 617 Scuseria, G.E. 319, 320 (82), 334 Sdmeier, J.L. 57 (90c), 83 Seaman, S.W. 1147 (588), 1167, 1187 (82), 1189 (96, 98), 1214 Seaver, S.S. 1077 (191), 1159 Sedaghat-herati, M.R. 1273, 1275, 1283 (178), 1299 Seddon, K.R. 428 (29), 471 Sedgwick, R.D. 234 (157), 247 Sedov, A.L. 633 (26), 659 Seebach, D. 96 (49), 102, 564 (169), 583 (275), 620, 622 Seebach, E. 405 (146), 421 Seeger, R. 407 (163), 421 Seel, F. 641 (74), 660 Seff, K. 96 (45), 102 S¨egalas, I. 100 (88), 103 Segre, A.L. 390 (62), 418 Seiber, J.N. 1132 (490), 1135 (515), 1165 Seibl, L. 251 (9), 291 Seiji, Y. 870 (47), 890 Seiler, P. 60 (104), 84 Seinfeld, J.H. 1180 (58, 59), 1213 Seitz, W.R. 1125 (442), 1164 Seitzinger, S.P. 1060 (85), 1156 Seki, S. 358 (73), 376, 1122 (440), 1164 Sekido, K. 96, 97 (59), 103 Sekiguchi, M. 651, 657 (132), 661 Sekiguchi, S. 457 (233), 458 (236, 238), 475, 476, 1218, 1219 (20b, 20c, 21a, 21b), 1220 (20b, 20c), 1237 (21a, 21b), 1290 (20b, 20c), 1295 Sekine, A. 722 (159c), 743 Sekiya, M. 553 (109), 618 Selala, M.I. 1142 (560), 1166 Selander, L. 171 (76), 203 Self, V.A. 1175 (13), 1212 Selim, S. 1187 (79), 1213 Selinger, A. 262 (54), 292 Sellers, P. 339 (11), 372 Semeniuk, S. 1139 (533, 540), 1166 Semenov, V.V. 852 (59), 856 Semsel, A.M. 1105 (368), 1162 Sen, D.C. 675 (58), 681 Sen, N. 1145 (573), 1166 Sen, N.P. 1145 (576), 1147 (588), 1167, 1187 (81, 82), 1189 (93, 96, 98), 1213, 1214 Senda, H. 94 (38), 102 Senda, M. 1122 (439), 1164 Senderowitz, H. 14 (22b), 15, 16 (22b, 26c, 26d), 17 19 (22b), 20 (27 29), 81, 82 Sendijarevic, V. 896 (17), 947 Senet, J.-P. 582 (264), 622 Sengupta, S. 536 (20), 617 Sen Hii, P. 442 (150), 473
1373
Senning, A. 591 (324), 623 Senoh, S. 123 (71), 155 Sension, R.J. 441 (144), 473 Sentier, L. 1069 (142), 1158 Sera, N. 1131 (487), 1165 Serjeant, E.P. 381 (3, 4b), 416, 491, 500 (107b), 519 (235), 527, 530 Sermon, P.A. 1175 (13), 1212 Serov, Y.V. 646 (102), 661 Servais, B. 434 (91), 472 Seshadri, R. 441 (144), 473 Sessa, W.C. 977 (51), 978 (57), 995 Sesse, W.C. 979 (73), 995 Sessions, R.B. 66, 67 (111), 84, 166, 168, 179 (52), 184 (52, 98, 105), 185 (52), 202, 203, 390 (67), 419 Setiarahardio, I.U. 1228, 1232 1235, 1239 (77), 1297 Seto, C.T. 430 (45, 49 52), 471 ˇ cik, J. 392 (75), 419 Sevˇ Sevilla, M.D. 830 (51), 836 Seyedrezai, S.E. 402 (139), 420 Sgarabotto, P. 99 (79), 103, 426 (14), 445 (164), 470, 474 Shaddock, J.G. 1033 (203), 1039 Shah, B. 447, 450 (181), 474, 854 (65), 856, 1000, 1005, 1007, 1016, 1019 (3), 1035 Shaik, S. 161, 173 (19), 202 Shaik, S.S. 409 (173), 421, 943 (68), 948, 1245 (118a, 118b, 120a, 120b), 1298 Shalaby, A.R. 1083 (247), 1160 Shang, M. 601 (385), 624 Shao, J.-D. 264, 265 (65), 293 Shapiro, M.J. 130 (91), 155 Shapiro, R.A. 979 (76), 995 Sharipova, S.Kh. 139 (114, 115), 156 Sharma, C.V.K. 452 (199), 475 Sharma, D.K. 765 (44 46), 818, 1109 (391), 1163 Sharma, R.D. 1109 (391), 1163 Sharma, R.P. 537 (29), 617 Sharma, S. 99 (81), 103 Sharma, S.K. 564 (167), 620 Sharma, V.K. 829 (47), 836 Sharping, G. 1081 (230, 231), 1159 Sharples, R.E. 369 (95), 378 Sharpless, K.B. 125 (77), 155, 572 (200, 201), 620 Shastri, L.V. 827 (27), 835 Shatenshtein, A.I. 398 (114), 420 Shaw, A.J. 1141 (556), 1166 Shaw, D. 297 (12), 332 Shaw, F.R. 486 (58), 526 Shaw, M.J. 581 (255), 622 Shaw, R. 354 (53), 375 Shaw, S.J. 1119 (425), 1163 Shea, R.G. 575 (209), 621
1374
Author index
Sheer, D. 979 (77), 995 Sheldrick, G.M. 99 (80, 84), 103 Shelkovskii, V.S. 1119 (431, 432), 1164 Shen, N.H. 1033 (199, 201), 1039 Shen, X. 827 (34), 835 Shepherd, M.G. 1118 (423), 1163 Sheppard, W.A. 515, 519 (230), 530 Sheridan, R.S. 353 (49), 375 Sherma, J. 1069 (141), 1158 Sherman, P.A. 991 (116), 996 Sherwood, C.H. 1116 (410), 1163 Sherwood, R.A. 1085 (263), 1160 Sheta, E.A. 989 (101), 996 Shevedlev, S.A. 550 (85), 618 Shevlin, G. 1148 (600), 1167 Shevlin, P.B. 633 (22), 659 Shi, X. 554 (111), 618 Shiao, M.J. 534 (6), 616 Shibasaki, M. 578 (223), 621 Shibata, S. 111 (37), 154, 442 (151), 473 Shibata, T. 123 (72), 155 Shibuya, T. 1073 (165), 1158 Shigemitsu, Y. 704 (108), 722 (155), 742, 743 Shiina, I. 593 (340), 623 Shim, S.C. 543 (61), 617 Shima, K. 561 (146, 147, 149), 562 (150), 588 (304), 619, 623, 704 (103 106), 706 (106), 742 Shimada, A. 502 (147), 529 Shimada, I. 396 (93), 419 Shimada, K. 722 (158a), 743 Shimada, R. 1067 (124), 1157 Shimada, T. 1131 (488), 1165 Shimao, I. 865 (31), 866 (32, 33), 889 Shimizu, K. 432, 443 (72), 472, 536 (14), 617, 1220 (44), 1296 Shimojo, T. 1089 (289, 290), 1161 Shimoni, L. 452 (199), 475 Shimorichi, A. 977, 979 (50), 995 Shin, D.M. 697 (90), 741 Shine, H.J. 859 (6, 9, 15, 16), 860 (17), 861 (16, 17, 19 21), 863 (21 23), 865 (27, 28), 867 (37, 39), 873 (58), 877 (72), 888 890, 897 (22), 899 (23, 24), 904 (26), 905 (29), 911 (34), 915 (36), 918, 920 (37), 922 (38), 923 (39, 40), 928 (41), 930 (42), 947 Shiner, V.J.Jr. 896 (16, 17), 945 (70), 947, 948 Shinhama, K. 654 (148), 662, 666 (6), 667, 670 (6, 11), 672 (6, 34), 677 (76), 678 (11, 78), 680 682 Shinkai, S. 448 (191), 474, 869 (43), 870 (47), 889, 890, 1119 (430), 1163 Shinohara, A. 724 (162b), 743 Shinohara, R. 1065 (113), 1157 Shioiri, T. 538 (34), 617 Shioji, K. 650 (126), 661 Shiomori, K. 562 (150), 619, 704 (104), 742
Shiota, T. 579 (232, 236), 621 Shiro, M. 324 (105), 334 Shiromaru, H. 193, 197 (142), 204 Shirosaki, T. 787 (101), 820 Shirota, O. 1093 (321), 1161 Shishulina, A.V. 592 (339), 623 Shivhare, P. 1138 (532), 1166 Shizuka, H. 704 (102), 722 (153b), 742, 743, 758 (32b), 818 Shizuma, M. 1114 (405), 1163 Shobana, N. 556 (119), 619 Shoichi Ide (88), 334 Shon, Y.S. 537 (30), 617 Short, R.L. 97 (66), 103 Shorter, J. 434 (85), 445 (165), 472, 474, 480 (1 6), 481 (1 3, 5, 6), 482, 483 (6), 484 (46), 485 (5, 46), 486 (5), 487 (70, 71, 75, 76), 488 (79, 81), 489 (75, 76, 84), 490 (76), 491 (103 105), 492 (108), 493 (79), 494 (119, 123), 496 (84, 127, 129, 130), 497 (132), 498 (104, 136), 501 (143, 144), 502 (143 145, 148), 503 (143, 144, 149), 505 (76), 511 (210 212), 512 (5, 6), 514 (5, 79), 515 (46), 517 (234), 519 (79, 234), 520 (143, 144), 522 (75, 76, 84), 523 (76), 525 530, 1241, 1262, 1264 (103b), 1298 Shosenji, H. 950 (14), 970 Shou, H. 694 (67), 741 Shoute, L.C.T. 824 (9), 827 (31), 835 Shpinell, Y.I. 636 (35), 659 Shreeve, J.M. 593 (345), 623 Shudo, K. 872 (56), 873 (57), 890, 1029 (166), 1038 Shuely, W.J. 381 (20b), 417, 428 (42), 471 Shug, J.C. 1262, 1266 (146), 1299 Shugard, A. 767 (50a), 819 Shustov, G.V. 133 (98 101), 146 (136, 137), 148, 149, 152 (149, 150), 155 157 Shutov, G.V. 149 (151), 157 Shuttleworth, L. 630 (13), 659 Siak, J.S. 1176 (22), 1212 Siam, K. 24 (36), 56 (85), 82, 83 Sibi, M.P. 303 (31), 305 (31, 32), 308 (36), 333 Sibi, M.S. 317 (76), 334 Sicinska, W. 310, 311 (50), 333 Sicking, W. 161 (20), 165, 166, 192 (45), 202 Sieck, L.W. 211 (37), 244, 384 (25a), 385 (36), 417, 418, 1238 (90), 1297 Siefhen, W. 666 (3), 680 Siegfried, B. 650 (128), 654 (148), 657 (168), 661, 662 Siepmann, T. 425 (6), 470 Sies, C.W. 954, 962 (30), 971 Sievers, R.E. 1047 (42, 51), 1155 Sievert, C. 1046 (12), 1155 Siew, P.-Y. 91, 93 (21), 102
Author index Sigsby, M.L. 238 (176), 248 Sik, V. 315 (60), 333 Silber, J.J. 433 (81), 440 (139 141), 463 (254), 464 (255), 467 (271), 472, 473, 476, 1217 (9), 1220 (33), 1235 1237 (9), 1244 (110), 1245 (110, 115a, 115b, 116a, 116b, 117), 1246 (9, 115a, 115b, 116a, 116b, 117), 1247 (9, 115a, 115b), 1266 (115a, 115b), 1276 (9), 1295, 1296, 1298 Silfer, J.A. 1049 (68), 1156 Siling, S.A. 353 (50), 375 Silva, J.M. 1030 (172, 173), 1038 Silverman, D.T. 1180 (52), 1213 Silverman, G.S. 567 (184), 620 Silvestro, A. 506 (166, 167), 510 (167), 529 Silvestro, T. 506 (170), 529 Simanek, E.E. 430 (47, 49, 51 53), 471 Simard, R.E. 1104 (366, 367), 1162 Simeonsson, J.B. 1125 (444), 1135 (519), 1164, 1165 Simic, M.G. 827 (36), 835 Simister, E. 1119 (436), 1164 Simister, E.A. 1119 (434), 1164 Simmaco, M. 1083 (250), 1160 Simmons, F.W. 1048 (62), 1156 Simmons, R.L. 979 (76), 995 Simmons, W.W. 992 (127), 997 Simoes, A.M.N. 1228 (75), 1297 Simon, D.I. 673 (43, 45), 681 Simon, J. 848 (45), 856 Simonne, E.H. 1046 (10), 1155 Simons, J.P. 1102 (356), 1162 Simons, S.S.Jr. 1077 (190), 1159 Simon-Sarkadi, L. 1069 (144), 1158 Simpson, D.J. 810 (156), 821 Simpson, J. 100 (94), 103 Simpson, J.T. 685 (18, 21, 22), 698 (22), 740 Sims, G.K. 1045 (4), 1154 Sims, L.B. 895, 896, 936 (11), 947 Sindona, G. 226 (120), 246 Singaram, B. 118, 119 (55), 154, 536 (18), 617 Singel, D. 673 (43), 681 Singel, D.J. 673 (44, 45), 681 Singh, G. 639 (62), 660, 722 (158b), 743 Singh, J.O. 440 (139, 140), 464 (255), 467 (271), 473, 476, 1217, 1235 1237 (9), 1244 (110), 1245 (110, 116a, 116b, 117), 1246 (9, 116a, 116b, 117), 1247, 1276 (9), 1295, 1298 Singh, M. 579 (233a, 233b), 621, 1049 (66), 1156 Singh, M.P. 537 (26), 617 Singh, T. 721, 722 (152), 743 Singh, U.C. 3 (2a), 60 (103b), 81, 83 Singhal, R.P. 1127 (453, 454), 1164 Singh Mankotia, A.K. 721, 722 (152), 743
1375
Sinibaldi, M. 1091 (298, 299), 1093 (314), 1161 Sinke, G.C. 338, 361 (2c), 363 (87), 372, 377 Sino-Alfonso, E.F. 1088 (278), 1160 Sinsheimer, E. 1247 (122), 1298 Sinsheimer, J.E. 434 (96), 472 Sinta, R. 658 (175), 663 Sintoni, M. 459 (240), 476, 1217, 1245 (8), 1295 Sintori, M. 1280 (186), 1300 Sioda, R. 847 (40a), 856 Sirois, M. 260 262 (52), 292 Sirvi¨o, H. 1118 (418), 1163 Sitrin, N.F. 979 (78), 995 Siuzdak, G. 226 (117), 246 Siva, P. 537 (27), 617 Skaane, H. 236 (172), 248 Skancke, P.N. 188 (124), 204 Skarjune, R. 554 (115a), 619 Skarping, G. 1063 (97), 1157 Skewes, L.M. 1177 (36), 1212 Skiff, W.M. 38 40 (58), 82 Skih, I.K. 1025 (140), 1038 Skinner, G.A. 949 (2), 970 Skipper, P.L. 1009, 1010 (61), 1021 (103, 108), 1030 (103), 1034 (61), 1036, 1037 Skjold, A.C. 638 (51), 660 Skolimowski, J. 53, 54 (78), 83 Skowronski, R. 53, 54 (78), 83, 1148 (602), 1167 Skrabal, P. 644 (93), 660 Skrobot, L. 1029 (159), 1038 Skrypec, D.J. 1189 (95), 1214 Skvortsov, I.M. 347 (25), 373 Sladowska, H. 561 (145), 619 Slayden, S.W. 338, 339 (1), 342 (1, 14), 343 (1, 15), 344 346 (1), 348 (29), 360 (14), 361 (83), 371 373, 377 Sleep, D. 1059 (80), 1156 Sleiter, G. 1262, 1264 (147a), 1299 Sliwka, H.-R. 152 (162), 157 Small, L.E. 400 (125), 411 (185), 420, 422, 436 (116), 473 Small, R.W. 96 (52), 103 Small, R.W.H. 98 (78), 99 (82), 103 Smentowski, F.J. 1000, 1009, 1019 (5), 1020 (95), 1035, 1037 Smetana, I. 1079 (215), 1159 Smeyers, Y.G. 1285 (195, 196), 1300 Smirnov, K.S. 352 (43), 374 Smith, B.J. 355 (55), 375, 384 (28c, 31), 417 Smith, B.L. 1189 (93), 1214 Smith, D.F. 1133 (503), 1165 Smith, D.J.H. 595 (357), 624, 737 (196), 745 Smith, D.W. 688 (34), 740 Smith, G.A. 227 (125), 246 Smith, G.G. 505 (160), 529
1376
Author index
Smith, G.R. 441 (144), 473 Smith, H.E. 106, 107 (1), 112 (38), 130 (1), 133 (1, 38, 102 105, 110), 134 (103, 105), 135, 136 (38, 104, 105), 137 (1, 38, 104, 107 110, 112), 138 (109, 110), 139 (110), 148 (142 144, 146 148), 152 (147, 148, 164), 153 157 Smith, H.W. 96 (48), 102 Smith, J.C. 485 (47), 526 Smith, J.H. 1266 (158), 1299 Smith, J.W. 380, 390 (1), 416 Smith, L.A. 457 (233), 475 Smith, N.K. 350 (37), 374 Smith, P.C. 1066 (114), 1157 Smith, P.J. 893, 933, 934, 938, 945 (1), 946 Smith, R.D. 220 (103), 246 Smith, R.E.A. 673 (40), 681 Smith, R.F. 540 (43), 617 Smith, R.L. 1064 (103), 1157 Smith, S.C. 429 (44), 471 Smith, T.W. 992 (127, 133), 997 Smith, W.C. 442 (148), 473 Smith, W.J. 1047 (24), 1155 Smith, W.M. 838 (5), 855 Smittle, D.A. 1046 (10), 1155 Smolskii, G.M. 1135 (517), 1165 Smooke, M.D. 1174 (4), 1212 Smyth, T.A. 950 (4, 7, 9), 958 (9), 970 Snaith, R. 396 (92, 96), 419 Snorn, E.C.G. 494, 495, 519 (124), 528 Snow, M.R. 58 (94), 83 Snowman, A.M. 991 (125), 997 Snyder, J.K. 130 (89), 155 Snyder, S.H. 976 (42 44), 977 (44), 978 (43, 69), 979 (76), 983 (43), 984 (90), 991 (125), 992 (42, 43, 142, 143), 993 (151), 995 997 Sobczyk, L. 322, 323 (96), 334, 435 (108 111), 472 Sobel, H. 674 (51), 681 Soda, S. 722 (159b), 743 Soenger, W. 427 (27), 471 Sohn, D.S. 936 (54), 948 Sokol, H.A. 1177 (34), 1212 Sokol, K. 993 (147), 997 Sokoluk, B. 1023 (119), 1037 Sole, A. 640 (67), 660 Solgadi, D. 810 (158), 821 Sollinger, S. 1127 (459), 1164 Soloshonok, V.A. 547 (78), 618 Somfai, P. 120 (61), 154 Somich, C. 733 (183a), 744 Somlai, C. 1089 (288), 1161 Sommer, S. 1046 (12), 1155 Sommer, S.G. 1047 (26), 1155 Son, H.S. 563 (155), 620 Son, Y. 108 (27), 154
Sonawane, H.R. 578 (225), 621 Sone, T. 448 (191), 474, 588 (304), 623, 869 (43), 870 (47), 889, 890 Song, X. 173 (79), 203 Songstad, J. 674 (51), 681 Songster, M.F. 564 (167), 620 Sonntag, C.von 824 (6 8), 828 (43), 829 (46), 835, 836 Sono, S. 565 (176), 620 Sonoda, N. 563 (159), 596 (368), 620, 624 Sonoda, T. 635 (31), 659 Sonola, O.O. 109 (33), 110 (33, 34), 113 (33, 42), 154 Sorensen, H. 779 (75), 819, 1096 (329), 1161 Sorriso, S. 85 (1), 86 (1, 2), 88, 95 (1), 99 (79), 102, 103 Sosnovsky, G. 551, 552 (96), 618 Sotomatsu, T. 506 (173), 529 Soucek, J. 1135 (514), 1165 Soucek, M. 756 (21), 757 (24), 789 (105), 818, 820 Soudais, P. 1217 (17), 1295 Sourbais, N. 1217 (16), 1295 Sousa, L.R. 738 (201), 745 South, M.S. 577 (221), 621 South, T.L. 1024 (126), 1037 Sowder, R.C. 1024 (127), 1037 Sozzi, G. 212 (43, 48 50), 216 (48 50, 60), 222 (43, 48 50), 233 (145), 244, 245, 247 Spagnolo, P. 1012, 1013 (79), 1036 Spaltenstein, A. 575 (209), 621 Spanka, G. 165, 166 (48, 49), 181, 182 (48), 202 Sparfel, D. 580 (252b), 621 Sparks, R.K. 795 (121), 820 Spaziano, V.T. 590 (322), 623 Spear, R.J. 303 (27), 332 Speck, L. 991 (118), 996 Speckamp, W.N. 166, 187 (54), 202, 568 (187), 620 Speckmann, A. 1004 (45), 1009, 1010 (63), 1014, 1015, 1019 (45), 1036 Speijers, G.J.A. 1188 (86), 1214 Speir, J.P. 390 (71), 419, 1284, 1285 (194b), 1300 Spellmeyer, D.C. 72 (122b), 84, 386 (46), 418, 655 (161), 662 Spencer, N. 396 (96), 419 Speranza, M. 232 (141), 247 Spevak, P. 537 (28), 617 Spiegelhalder, B. 1148 (600), 1167, 1184 (67), 1188 (86 88), 1213, 1214 Spiegelhalder, J.G. 1185 (73), 1213 Spiekermann, M. 1127 (455), 1164 Spielberg, S.P. 1001, 1007, 1009, 1011 (28), 1027 (28, 155), 1035, 1038
Author index Spiers, M. 171, 172, 174, 175 (75), 193, 197 199 (141), 203, 204 Spillane, J. 1220 (30a), 1296 Spillane, W.J. 404 (145), 405 (147, 148), 421 Spinelli, D. 100 (92), 103, 388 (56), 418, 1236 (160), 1241 (103a), 1262 (103a, 152), 1264 (103a), 1266 (152, 160), 1298, 1299 Spiteller, G. 206, 207, 233 (2d), 243 Splitter, J.S. 221 (111), 246 Spondlin, C. 1090 (296), 1161 Spragg, R.A. 57 (90b), 83 Spunta, G. 549 (81), 618 Spurr, N. 978 (70), 995 Squillacote, M. 353 (49), 375 Srai, S.K.S. 1012, 1033 (85), 1036 Sraidi, K. 381 (17d, 18), 417, 1222, 1238 (51), 1296 Srinivas, K. 1100 (351), 1162 Srinivasan, N. 596 (363, 367), 624 Srinivasan, R. 547 (77), 618 Srivastava, A. 571 (199), 620 Srivastava, R.S. 1152 (624), 1168 Staab, H.A. 176 (89), 199 (148), 203, 204, 435 (101), 436 (113), 472, 473 Stacey, M. 635 (30), 659 Stacey, T.M. 411, 412 (194), 422 Stafast, H. 810, 811 (159), 821 Stahl, D. 209 (31), 244 Stahl, N. 431 (68), 472 Staley, R.H. 235, 236 (165), 247, 353 (46), 375, 384 (33a), 417 St˚alhandske, C. 90, 93 (12), 102 Stamler, J.S. 673 (43 45), 674 (49), 681, 1150 (606), 1167 St.Amour, T.E. 312 (53), 333 Stan, H.J. 1128 (461), 1164 Stanescu, L. 353 (50), 375 Stanker, L.H. 1140 (552), 1166 Stanoeva, E. 569 (191), 620 Stanovnik, B. 639 (54), 660 Stanulonis, J. 859 (15), 889 Starkey, E.B. 636 (36), 659 Starova, G.L. 94, 100 (32), 102 Stavinoha, J.L. 710 (119), 711 (121), 712 (122), 742 Stedman, G. 674 (53), 675 (54, 63), 677 (53), 678 (81, 85), 679 (86), 681, 682 Steele, W.F. 350 (35), 374 Steele, W.V. 346 (20), 350 (37), 355, 356 (58), 373 375 Steenken, S. 827 (27, 28), 835 Stefaniac, L. 297, 300 (1a, 1b), 301, 317 (1b), 332 Stefaniak, L. 310 (49), 322, 323 (96), 333, 334 Steffek, D.J. 56 (80b), 83 Steffen, L.K. 830 (53), 836
1377
Stegel, F. 1217 (15a, 15b), 1262, 1264 (147a), 1295, 1299 Stehle, P. 1076 (188), 1159 Stein, S.N. 1048 (62), 1156 Steinberg, G.M. 407 (157c), 421 Steiner, B.W. 208, 210, 217, 237 (18), 244 Steiner, T.W. 815 (171), 821 Steinke, T. 956 (44), 971 Stella, L. 403 (138a, 138b), 420, 599 (379), 624 Stemerick, D.M. 543 (58), 617 Stenhouse, I.A. 303, 308 (37), 333 Stepanov, N.D. 646 (102), 661 Stephanou, E.G. 1048 (53), 1156 Stephens, O.B. 1030 (171), 1038 Stephens, P.J. 147, 148 (140), 156 Stephenson, D. 315 (60), 333, 447 (177), 474 Stephenson, L.M. 401 (136), 420 ˇ erba, V. 638 (52), 660 Stˇ Stercho, Y.P. 113, 114 (43), 154 Sterin, S. 553 (106), 618 Sterling, D.I. 106 (17), 153 Stern, C. 1127, 1143 (458), 1164 Stern, C.L. 729 (175a), 744 Sternson, L.A. 871 (51), 890 Sterzl, H. 1026, 1029 (144), 1038 Steuberg, V.I. 722 (153f), 743 Stevanovic, S. 1127, 1143 (457), 1164 Stevens, J.A. 1253 (132), 1298 Stevens, K. 993 (147), 997 Stevens, M.F.G. 633 (23), 659 Stevenson, D.P. 259 (40), 292 Stevenson, T.A. 345 (18), 361 (86), 373, 377 Steward, B. 1188 (92), 1214 Stewart, J.J.P. 161, 173 (18), 202 Stewart, J.M. 97 (62), 103 Stewart, R.J. 400 (123), 420 Stiegman, A.E. 444 (162), 474 Stigbrand, M. 1105 (370), 1162 Still, R.H. 669 (23), 680 Still, W.C. 41 (63), 82 Stinecipher, M.M. 369, 370 (99), 378 Stinson, S.C. 107 (19, 21), 153, 154 Stirling, D.I. 108, 109 (31), 154 Stivers, E.C. 910, 933 (33), 947 St.John, P.A. 1060 (85), 1079 (211), 1156, 1159 St¨ocklin, G. 649 (122), 661 Stoddart, J.F. 396 (96), 419 Stojek, J.W. 1080 (220), 1159 Stokes, D.L. 1101 (355), 1136 (521), 1162, 1165 Stokkum, I.H.M.van 446 (171, 173), 474 Stolze, K. 1022 (115), 1037 St¨orle, C. 1030 (174), 1039 Storm, C.B. 370 (100), 378 Stothers, J.B. 312 (55), 333
1378
Author index
Stover, L.R. 638 (51), 660 Stowe, G.T. 1032 (188), 1039 Stradiotto, N.R. 852 (62), 856 Stradowski, C.Z. 824 (13), 835 Strakovs, A. 437 (124), 473 Strangeland, L.J. 431 (63), 471 Strarness, S.D. 1238, 1240 (97), 1297 Stratis, J. 1139 (537), 1140 (547), 1166 Straub, B. 1079 (213), 1159 Straub, R.F. 1066 (123), 1073 (164), 1157, 1158 Strauss, M.J. 457 (228, 231), 475, 1217, 1220 (11a), 1295 Strazzolini, P. 563 (163), 583 (270a, 270b), 620, 622 Streets, D.G. 175 (84), 203 Streissguth, A.P. 1063 (98), 1157 Streitwieser, A.J. 398 (113a c), 399 (118 120), 420 Streitwieser, A.Jr. 399 (117), 420, 896 (14), 947 Strelenko, Y.A. 448 (192), 474 Strelenko, Yu.A. 609 (432), 625 Strepikheev, Y.A. 884 (95), 891 Stricher, O. 1086 (274), 1160 Strickland, S. 567 (184), 620 Strickler, P. 90 (11), 102 Strickson, J.A. 578 (227a, 227b), 621 Stridh, G. 339 (11), 372 Strijtveen, B. 127 (81), 155 Strojek, J. 1079 (216), 1159 Stromvall, E.J. 1098 (341), 1162 Struchkov, Yu.T. 363 (89), 377 Strydom, D.J. 1084 (256), 1160 Stryer, L. 1010 (69), 1036 Stryszak, E. 1047 (47, 48), 1155 Stuart, A.D. 1046 (18), 1155 Stuber, O. 482 (18), 525 Stubley, D. 96 (52), 103 Stuchlik, J. 1090 (293), 1161 Stuehr, D.J. 669 (21), 680, 976 (31, 35, 37, 38), 978 (31, 37, 38, 58, 64), 980 (31, 37), 983 (37), 984 (89), 985 (91, 95), 987 (98 100), 989 (105, 107), 990 (110), 991 (113), 994 996 Stulik, K. 1148 (598), 1167 Stull, D.R. 338 (2c), 352 (41), 361 (2c), 363 (87), 372, 374, 377 Stumpe, J. 722 (153c), 743 Sturgess, M.A. 588 (305), 623 Stutts, K.J. 846 (36a), 855 Stuzka, V. 1135 (514), 1165 Su, C.N. 147, 148 (141), 156 Su, T.J. 1122 (437), 1164 Suboch, G.A. 515 (231), 530, 1000, 1009, 1019 (7), 1035 Subong, A.P. 579 (237), 621
Subotkowski, L.K. 922 (38), 928 (41), 947 Subotkowski, W. 861 (21), 863 (21, 22), 867 (37), 889, 918, 920 (37), 922 (38), 928 (41), 947 Subramanian, G. 106 (16), 153 Suchan, V. 112, 113 (41), 154 Sudalai, A. 578 (225), 621 Sudha, M.S. 270 (82), 293 Sudlow, G. 1032 (196), 1039 Suehiro, T. 649 (120, 121), 661 Sueyoshi, S. 96 (47), 102, 886 (100), 891 Suezaki, H. 467, 468 (274), 476 Sugarbarker, D.J. 673 (44), 681 Sugawara, K. 1106 (373 375), 1162 Sugawara, T. 312 (52), 333 Sugihara, H. 609 (435), 625 Sugimoto, A. 703 (101), 742 Sugimoto, N. 460 (246, 247), 476 Sugimura, T. 677 (71), 681, 888 (106), 891, 1004, 1007, 1009, 1012, 1019 (43), 1029 (166), 1033, 1034 (198), 1035 (43), 1036, 1038, 1039 Suginome, H. 598 (375), 624, 794 (119), 798 (133), 799 (133, 134), 800 (134), 801 (135), 802 (136), 820, 821 Sugita, K. 650 (124a), 661 Sugita, N. 596 (362), 624 Sugiyama, N. 467, 468 (274), 476, 1281, 1282 (189), 1300 Suh, D. 216 (67), 245 Suhr, H. 1276, 1293 (181), 1299 Sukhodub, L.F. 1119 (431, 432), 1164 Sukumar, S. 330 (118), 335 Sultan, M.A. 1140 (550), 1166 Sultan, M.A.E. 1140 (545), 1166 Sultan, S.M. 1106 (376), 1162 Sulton, K.H. 883 (90), 890 S¨ulzle, D. 259 (46), 262 (57), 292 Sumida, R. 703 (101), 742 Sumida, T. 866 (34), 889 Summerhays, K.D. 510 (207), 530 Summers, M.F. 1024 (126), 1037 Sun, Ya.-P. 441 (145), 473 Sundahl, M. 1077 (193), 1159 Sundaram, N. 276, 279 (86, 87), 280 (90), 293 Sundberg, R.J. 722 (157a), 743 Sundell, C.L. 979 (72), 995 Sundell, S. 62 (107), 84 Sung, K.S. 1238 (93), 1297 Sunner, J. 384 (32), 417 Sunner, S. 339 (11), 372 Suortti, T. 1118 (418), 1163 Supan, S. 1220 (43), 1296 S¨us, O. 658 (174), 663 Suschitzky, H. 639 (57), 660 Susens, D.P. 757 (26), 818 Susskind, S.M. 319, 320 (82), 334
Author index Sustmann, R. 161 (20), 202, 985 (96), 996 Susuki, H. 1103 (358), 1162 Susuki, S. 1079 (212), 1159 Susumu, T. 686 (26), 740 Sutherland, I.O. 60 (103c), 84 Sutton, D. 329 (116), 334 Sutton, K.H. 954 (25 28), 956 (28), 968 (26), 970, 971 Sutton, L.E. 487 (66), 526 Suwinski, J. 781 (85), 819 Suyama, T. 604 (395), 624 Suznjevic, D. 447 (183), 474, 838 (4b), 855 Suzukamo, G. 112 (39), 154, 536 (15), 617 Suzuki, A. 565 (176), 620, 651 (132), 656 (166), 657 (132), 661, 662 Suzuki, H. 693, 694 (62), 741, 962 (51), 971 Suzuki, I. 534 (7), 616 Suzuki, J. 1030 (176), 1039, 1130 (478), 1164 Suzuki, K. 582 (268), 622, 1129 1131 (476), 1164 Suzuki, M. 1072 (162), 1158 Suzuki, N. 739 (204), 745, 1083 (253), 1160 Suzuki, S. 758 (32a), 818, 896 (14), 947, 1030 (176), 1039, 1119 (428), 1130 (478), 1163, 1164 Suzuki, T. 452 (196), 458 (236), 475, 476, 1079 (212), 1159, 1218, 1219, 1237 (21a, 21b), 1295 Svagrova, I. 1125 (441), 1164 Svard, H. 932 (45), 947 Svec, W.A. 445 (168), 474 Svensson, J. 790 (108), 820 Svensson, J.O. 790 (109b), 820, 954, 970 (37), 971 Svensson, K. 62 (107), 84 Swain, C.G. 522 (244, 246, 250), 531, 910, 933 (33), 938 (57), 947, 948 Swain, M.S. 522 (246), 531 Swalen, J.D. 24 (33), 82 Swallow, A.J. 827 (35), 835 Swamy, R.A. 289 (115), 294 Swanson, G.M. 1180 (52), 1213 Swanson, R. 711 (121), 712 (122), 742 Swartzendruber, J.K. 442 (147), 473 Sweeley, C.C. 1066 (116, 117), 1157 Swern, D. 94 (41), 102 Swiderek, K.M. 978 (63, 65), 995 Swidler, R. 407 (157c), 421 Swierezek, K. 781 (85), 819 Swift, H.R. 672 (31), 680 Swinnen, A.M. 694 (58), 695 (77), 741 Sydnes, L.K. 728 (171a, 171b), 744 Symons, M.C.R. 612 (448, 449), 626, 670 (29), 680, 795 (127), 820, 824 (5), 834 (74), 835, 836, 1019 (93), 1037 Szabo, L. 851 (55), 856 Szadkowskanicze, M. 824 (13), 835
1379
Szafran, M. 430 (54), 431 (59), 436 (114), 471, 473 Szajda, S. 1090 (294), 1161 Szantay, C. 851 (55), 856 Szarek, W.A. 15, 17 (23b), 81 Szarka, A.Z. 441 (144), 473 Szczesniak, M. 554 (115a), 619 Szekelhidi, L. 1113 (403), 1163 Szele, I. 648 (107, 109), 661 Szepes, L. 164 (31, 37), 165, 175 (31), 202 Szeverenyi, N.M. 330 (121), 335 Szoenyi, F. 540 (45), 617 Szokan, G. 1089 (288), 1161 Szpakiewicz, B. 561 (142, 143), 619 Szuleijko, J.E. 384 (25b, 25c), 417, 1238 (91, 92), 1297 Szulejko, J.E. 233 (149), 247 Szulejko, J.W. 385 (38c), 418 Taagepera, M. 66, 67 (111), 84, 166, 168, 179, 184, 185 (52), 202, 235, 236 (165), 247, 407 (161b), 421, 510 (207), 524 (254), 530, 531 Tabata, M. 1130 (478), 1164 Tabei, H. 1103 (360, 361), 1162 Tabet, D. 357 (69), 376 Tabet, J.C. 216, 222 (58), 245 Tabner, B.J. 848 (44), 856 Tabner, V.A. 848 (44), 856 Tada, Y. 724 (166a), 744 Tadayoshi Yoshida (88), 334 Taddai, M. 570 (194), 620 Taeger, K. 1000, 1009, 1023 (10), 1035 Taft, R.W. 235, 236 (165), 247, 303 (25, 26, 29), 308 (39 42), 309 (39, 42, 43), 310, 311 (44), 332, 333, 381 (6b, 14a, 14b, 15a, 15b, 16a d, 17d, 18, 20b), 384 (29, 33b), 386 (49, 50), 387 (51, 52a, 52b, 53), 395 (14a, 14b), 407 (161b), 408 (167b), 409 (6b), 416 418, 421, 428 (42), 433 (80), 439 (129), 443 (157, 158), 453 (203), 471 475, 489 (87 89), 490 (90, 92), 491 (89, 90, 96, 97, 106), 493 (87, 89), 496 (131), 503 (90, 96, 97, 106), 504 (87, 89, 92, 96, 97, 150 152, 155), 505 (131, 151, 155, 163), 509 (89), 510 (199, 207), 514 (150), 515 (96, 97, 150), 517 (87, 89, 96, 97, 150), 518 (150), 521 (92), 522 (92, 150, 151), 523 (151, 252), 524 (151, 253, 254), 527 531, 642 (83, 84), 660, 1006, 1024, 1026 1028, 1030 1032 (55), 1036, 1220 (38a, 38b, 39, 41a, 41b, 42), 1221 (38a, 38b), 1222 (38a, 38b, 39, 51), 1238 (38a, 38b, 51, 87a, 87b, 88, 93 95, 98), 1239 (87a), 1240 (98), 1241 (106a, 106b), 1244 (38a, 38b), 1273 (178, 179), 1275 (178), 1278 (179), 1283 (178), 1296 1299
1380
Author index
Taga, M. 1106 (373 375), 1162 Tagashira, S. 1097 (338), 1162 Taguchi, M. 649 (120), 661 Taguchi, V.Y. 1145 (575), 1167 Taha, Z. 992 (127), 997 Tahara, S. 77 (127), 84 Tahira, T. 677 (71), 681, 888 (106), 891 Tainor, R.R. 976, 980, 983 (34), 994 Taintor, R.R. 975 (29, 30), 976 (30), 978 (29), 994 Tajima, S. 218 (86), 246, 259 (41), 262 (58), 292 Takada, H. 751 (8), 817 Takagi, K. 7 (11), 81, 648 (108), 661, 721 (151), 743 Takahashi, A. 1101 (352), 1162 Takahashi, H. 765 (47), 818 Takahashi, K. 580 (251), 621, 1090 (292), 1161 Takahashi, M. 161, 163, 164 (22), 202 Takahashi, N. 1019 (91), 1037 Takahashi, S. 1114 (405), 1163 Takahashi, T. 553 (109), 618 Takahashi, Y. 654 (149), 662, 1029 (166), 1038, 1046 (13), 1155 Takai, K. 571 (197), 620 Takai, Y. 1114 (405), 1163 Takakuwa, K. 794 (119), 820 Takama, K. 1079 (212), 1159 Takamuku, S. 686 (26), 740, 824 (11, 12), 835 Takanohashi, Y. 536 (21), 537 (22), 617 Takao, N. 305 (33), 306 (34), 307 (33), 333 Takase, K. 863 (25), 889 Takashima, A. 1000 (1), 1035 Takasuka, M. 324 (105), 334 Takatera, K. 1074 (175), 1158 Takatsuki, K. 1144 (570), 1166 Takayama, N. 1079, 1083 (217), 1159 Takazawa, H. 93 (17), 102 Takeba, A.K. 1134 (504), 1165 Takechi, H. 730 (181f, 182a), 744, 798 (132), 820 Takeda, H. 1073 (165), 1158 Takeda, S. 437 (123), 473 Takeda, T. 580 (248), 621 Takemoto, T. 950 (14), 970 Takeuchi, H. 551 (89a, 89b, 90, 91), 618, 1069 (146), 1158 Takeuchi, T. 215 (53, 54), 245, 718 (147), 743 Takeuchi, Y. 305 (33), 306 (34), 307 (33), 333 Takeyama, T. 1067 (124), 1157 Taki, H. 580 (246), 621 Takitani, S. 1147 (587), 1167 Talberg, H.J. 96 (55), 103 Talbot, J.M. 1116 (417), 1163 Tallec, A. 849 (48), 856, 1107 (379 382), 1162, 1163
Talley, J.J. 510 (200), 530 Tamai, N. 703 (101), 742 Tamaru, K. 1245 (113), 1298 Tamatani, A. 582 (268), 622 Tamblyn, W.H. 675 (62), 681 Tamir, S. 1189 (101), 1214 Tamiya, E. 1103 (358), 1162 Tamiya, H. 592 (331), 623 Tamizi, M. 1126 (450), 1164 Tamura, K. 593 (342), 623 Tamura, M. 77 (127 129), 78 (128, 129), 79 (129), 84 Tamura, R. 605 (408, 409a, 409b), 610 (438), 614 (409a, 452, 455), 615 (459), 616 (465), 625, 626 Tamura, T. 112 (40), 154 Tamura, Y. 552 (98, 101), 618 Tanabe, H. 935 (53), 948 Tanabe, K. 4, 13, 77 (15), 81, 561 (147), 588 (304), 619, 623 Tanahashi, T. 551 (91), 618 Tanaka, H. 852 (61), 856 Tanaka, K. 609 (435), 625 Tanaka, N. 455 (217), 475 Tanaka, S. 795 (128, 129), 820, 1079, 1083 (217), 1106 (373 375), 1159, 1162 Tanaka, T. 749 (3a, 3b), 817, 1114 (405), 1163 Tandom, S.G. 405 (152a), 421 Tang, Y. 1089 (284), 1160 Tanigaki, K. 789 (106), 820 Taniguchi, H. 597 (370), 624, 1069 (146), 1158 Tanigushi, H. 654 (151), 662 Tanikaga, R. 609 (435), 625 Tanimoto, Y. 113 (44), 154, 751 (8), 817 Tanin, A. 505 (156), 529 Tannenbaum, S.R. 1009, 1010 (61), 1021 (103, 108), 1030 (103), 1034 (61), 1036, 1037, 1189 (101), 1214 Tanner, D. 106 (10), 120 (61), 153, 154 Tanno, M. 96 (47), 102, 886 (100), 891 Tanoury, G.J. 991 (116), 996 Tapia, O. 1285 (195), 1300 Tardivel, R. 849 (48), 856 Tarnawsky, I.W. 637 (45), 660 Tartakovskii, V.A. 448 (192), 474, 608 (424), 609 (432), 625 Tartakovsky, E. 15, 16 (26b, 26c), 82 Tasaki, K. 188 (119), 204 Tashiro, M. 848 (45), 856, 969 (65), 971 Tashiro, T. 649 (120), 661 Tasker, H.S. 666, 668 (4), 680 Tasnawskyj, I.W. 639 (53), 660 Tatchell, A.R. 109 (33), 110 (33 35), 113 (33, 42), 154 Tatlow, J.C. 635 (30), 659
Author index Tato, J.V. 643, 645 (88), 660, 677 (72, 73), 681, 886 (101, 103), 888 (106, 107), 891 Tatsuno, M. 1119 (428), 1163 Tauler, R. 1225 (67), 1297 Tauts, O.V. 1147 (593), 1167 Tavale, S.S. 93 (25), 96 (56), 98 (25), 102, 103 Tayeh, M.A. 976, 978, 983 (36), 994 Taylor, H.W. 1186 (76), 1213 Taylor, P. 381 (19), 417 Taylor, P.B. 1085 (258), 1160 Taylor, P.C. 594 (348), 623 Taylor, P.F. 1019 (93), 1037 Taylor, P.G. 510 (206), 530 Taylor, P.J. 381 (17a e, 20b, 20c), 395 (81), 417, 419, 428 (41, 42), 471, 1222 (50, 51, 57, 58, 60), 1238 (51), 1296, 1297 Taylor, P.S. 859 (13), 889 Taylor, R. 433 (74 77), 453 (205), 472, 475, 505 (162), 512 (223, 224), 513 (224 228), 529, 530 Taylor, R.J. 130 (88), 155 Teare, J.D. 1175 (18), 1212 Tebbett, I. 1068 (140), 1158 Tecklenburg, B. 396 (91f), 419 Tedesco, A.C. 753 (13), 757 (27), 817, 818 Teerlink, T. 1078 (203), 1159 Tein-Lo, M. 1189 (93), 1214 Teitel, C.H. 1033 (202, 203), 1039 Tejada, S.B. 1177 (31), 1212 Tejero, A. 546 (73), 618 Temchenko, T.P. 646 (102), 661 Tempst, P. 977 (52), 995 Tenge, B.J. 575 (209), 621 Tennant, G. 633 (23), 659 Teobald, J. 1046 (9), 1155 Terai, N. 1129 1131 (476), 1164 Teranishi, H. 776 (66), 819 Teranishi, S. 654 (151), 662 Terao, N. 654 (152), 662 Terao, S. 978 (66), 995 Terashi, A. 1065 (113), 1157 Terekhova, M.I. 398 (114), 420 Terenzani, A.J. 1009 (59), 1036 Terlouw, J.K. 208 (6, 7, 11), 209 (11, 32), 214 (11, 51), 215 (7, 56), 216 (63c, 67), 220, 221 (99), 233 (148, 149), 234 (148), 244 247, 251 (8), 254 (17, 18, 23), 255 (23), 291, 292 Termuehlen, H. 1175 (15), 1212 Tero-Kubota, S. 750 (6), 817 Terpstra, J.W. 667 (8), 680 Terrier, F. 415 (203, 207 210), 416 (212), 422, 457 (229, 231, 232), 475, 509 (188, 189), 512 (216), 529, 530, 1216 (1a, 5), 1217 (1a, 5, 11a, 17), 1218, 1219 (1a), 1220 (1a, 11a), 1222, 1232, 1235, 1241, 1243, 1244, 1250, 1274, 1290 (1a), 1295
1381
Tesarova, E. 1133 (502), 1165 Teshima, T. 1130 (478), 1164 Tessier, L. 1189 (96), 1214 Testaferri, L. 1152 (625), 1168 Texier-Boullet, F. 589 (311), 623 Tezuka, T. 812 814 (165), 821 Thatcher, G.R.J. 15, 17 (23d), 81 Thater, C. 985 (96), 996 Thea, S. 1262, 1264 (151), 1299 Theil, B.A. 987 (98), 996 Thellend, A. 591 (328), 623 Theodorakis, E.A. 548 (80), 618 Theodoridis, D. 1220, 1222 (31b), 1296 Thewalt, M.L.W. 815 (171), 821 Thiecke, J.R.G. 539 (40), 617 Thilmann, D. 1284 (191), 1300 Thoithi, G. 1118 (420), 1163 Thomas, C.B. 264, 266 (64), 293 Thomas, D.K. 426 (16), 470 Thomas, H.D. 4 (43), 21, 22 (31), 29 31 (43), 32 (31, 43), 82 Thomas, K.E. 354 (53), 375 Thomas, M.R. 673 (40), 681 Thomas, R.J. 1049 (63), 1156 Thomas, R.K. 1119 (434, 436), 1122 (437), 1164 Thompson, A.R. 636 (34), 659 Thompson, H.C. 1146 (583), 1167 Thompson, L.F. 767 (50b, 51), 819 Thompson, R.S. 954 (24, 25), 961 (24), 970 Thomsen, L.L. 992 (135), 997 Thomson, A. 685 (11), 740 Thonpson, D. 1176 (20), 1212 Thoraval, D. 769 (55), 819 Thorgeirsson, S.S. 1029 (167), 1038 Thornton, E.R. 943 (65), 948 Thorpe, T.E. 482 (21), 525 Threadgill, M.D. 650 (129), 661 Thuijl, J.van 282 (96 99), 283 (98, 99), 289 (114, 115), 293, 294 Thuillier, P. 1147 (591), 1167 Thuis, H.J.T.M. 1132 (489), 1165 Tidwell, T.T. 504 (154), 510 (201 203), 515, 518 (154), 529, 530, 658 (176), 663 Tie, J.K. 1076 (185), 1158 Tiecco, M. 1152 (625), 1168 Tiljander, A. 1081 (231), 1159 Tillett, J.G. 405 (150a), 421, 1009, 1011 (62), 1036 Timmons, C.J. 710 (113), 742 Timofeeva, L.P. 347 (25), 373 Tiner-Harding, T. 714 (124), 742 Tingle, M.D. 1027 (148), 1038 Tingoli, M. 1152 (625), 1168 Tingue, P.S. 540 (43), 617 Tipping, A.E. 408 (168), 421, 1153 (626 628), 1168
1382
Author index
Tiˇsler, M. 639 (54), 660 Titheradge, A.C. 1085 (263), 1160 Titova, S.P. 631 (20), 659, 884 (96), 891 Tivesten, A. 1093 (309), 1161 Tlahuext, H. 1109 (392), 1163 Tobin, G.D. 880 (84), 890 Tobin, J.C. 646 (102), 661 Toda, F. 722 (159b d), 743 Todesco, P.E. 455 (212), 459 (240), 465 (264), 467 (270), 475, 476, 1217, 1245 (8), 1295 Tokarskaya, O.A. 576 (215), 621 Tokiwa, H. 1129 (473), 1131 (487), 1164, 1165, 1177 (37), 1212 Tokiwa, T. 1177 (33), 1212 Tokles, M. 130 (89), 155 Tokuda, M. 598 (375), 624 Tokuda, Y. 448 (191), 474, 749 (2), 817, 869 (43), 889 Tokumaru, K. 438 (125, 126), 473, 778 (74), 819 Tokura, N. 735 (190c), 745 Tollari, S. 578 (224), 621 Toman, J. 870 (49), 890 Tomas Baer 264, 265 (65), 293 Tomasi, J. 803 (138), 821 Tomasik, P. 440 (136), 473 Tomer, K.B. 267 (75), 281 (94), 293 Tomilov, A.G. 352 (43), 374 Tominaga, Y. 585 (292), 622 Tominga, Y. 541 (50), 617 Tomino, I. 113 (44), 154 Tomioka, H. 767 (54), 819 Tomita, M. 93 (15), 102 Tommaselli, G.A. 434 (88), 472 Tompson, R.D. 308 (40), 333 Tondys, H. 561 (141), 619 Tong, L.K.J. 358 (76), 376 Toniolo, C. 142 (124), 156 Toole, G. 358 (71 73), 376 Toomas, H.T. 695 (72), 741 Toothill, J.R. 1139 (534), 1166 Topham, A. 265 (69), 293 T¨opner, W. 1000 (11), 1003 (11, 33), 1007, 1008 (33), 1009 (11, 33), 1011, 1012 (33), 1035 Topsom, R.D. 303 (25), 332, 491, 503 (100, 101), 504 (151, 154), 505 (151), 506 (164 172), 510 (167, 172, 199, 207), 515, 518 (154), 522 (151, 247), 523 (151, 171, 252), 524 (151), 527, 529 531, 642 (82, 84), 660, 1238 (88, 94), 1297 Toqan, M. 1175 (18), 1212 Torchinsky, Y.M. 1003 (48), 1036 Tordo, P. 854 (67), 856 Torii, S. 852 (61), 856 Torino, J.Z. 653 (145), 662 Torizuka, H. 774 (63), 819
Torroba, T. 780 (82), 819 Tortajada, J. 232 (142), 247 Tortelli, V. 463 (257), 464 (261), 476 Tosi, C. 55 57 (81), 83 Tosi, G. 441 (146), 473 T¨oth, J. 100 (89), 103 Toucas, L. 1025 (137), 1038 Toupet, L. 1107 (381), 1163 Touster, O. 675 (59), 681 Tovar, C.A. 55 57 (82), 83 Tovbis, M.S. 515 (231), 530 Towns, R.L. 433 (79), 472 Townsend, J.C. 1068 (137), 1158 Toyne, K.J. 695 (74), 741 Toyoda, J. 1256, 1257 (136), 1258 (142), 1298, 1299 Toyo’oka, T. 1080 (222, 223), 1081, 1091 (234), 1159 Toyosaki, T. 596 (361a, 361b), 624 Traeger, J.C. 220 (104), 246 Traetteberg, M. 188 (124), 204 Traficante, D.D. 1076 (187), 1159 Trainor, T. 1083 (243), 1160 Traldi, P. 94 (36), 102 Traunter, F. 1180 (54), 1213 Trautner, F. 1182 (60), 1213 Traynor, G.W. 1177 (34), 1212 Trazza, A. 191, 199 (130), 204 Tretheway, K.R. 695 (73), 741 Trevellick, S. 881 (85), 890, 953 (21), 966 (55, 56), 970, 971 Tricard, C. 1078 (199), 1159 Tricker, A.R. 1185 (73), 1187 (83), 1188 (85, 91), 1189, 1190 (99), 1213, 1214 Trifunac, A.D. 824 (10), 826 (25), 835 Trimmer, R.W. 638 (51), 660 Trinajstic, N. 180 (95), 203 Tritthart, P. 1130 (477), 1164 Trivedi, G.K. 285 (102), 293 Trnska, T. 1090 (293), 1161 Tronchet, J.M.J. 1152 (621), 1168 Troso, T. 978 (63), 995 Trost, B.M. 568 (185, 186), 590 (316), 620, 623 Trower, W.P. 1125 (443), 1164 Trucks, G. 384 (28b), 417 Truesdale, L.K. 572 (200), 620 Trumbauer, M. 993 (147), 997 Tsai, A.L. 989 (103), 996 Tsai, H.-W. 567 (182), 620 Tsai, S.-C. 209 (27), 244 Tsang, W. 360 (78), 376 Tsankov, D. 133 (101), 149 (151), 155, 157 Tse, R. 392 (73), 419 Tselinskii, I.V. 1137 (526), 1141 (554), 1166 Tso, J. 208, 210 212, 215 (17), 244 Tsoukali, H. 1139 (537), 1140 (547), 1166
Author index Tsuboi, M. 24 (32), 34 (46), 82 Tsuchihashi, H. 1119 (428), 1163 Tsuchiya, T. 259 (41), 262 (58), 292 Tsuda, M. 647 (104), 661, 677 (71), 681, 888 (106), 891 Tsuda, T. 579 (232), 621 Tsuji, M. 614 (455), 626 Tsujii, R. 722 (155), 743 Tsujimoto, K. 685 (12), 740 Tsukioka, T. 1064 (102), 1157 Tsuno, Y. 489, 496 (85, 86), 504 (153), 521 (85, 86), 527, 529 Tsuzuki, S. 4, 13, 77 (15), 81 Tsvetkov, E.N. 519 (238), 531 Tu, C.L. 714 (126), 742 Tuazon, E.C. 1177 (45), 1213 Tubergen, M.J. 431 (69), 472 Tucker, I. 1118 (423), 1163 Tucker, S.A. 357 (67), 358 (71 73), 376 Tufon, C. 1228, 1232 1235, 1239 (77), 1297 Tukada, H. 751 (9), 817 Tumas, W. 220 (105), 246 Tummavuori, J. 640 (69), 660 Tundo, A. 655 (158), 662 Tun Khin 317 (69, 73), 333 Turbanti, L. 143 (125), 156 Turcan, J. 639 (58), 660 Turecek, F. 206, 207 (3), 217 (69), 219, 226, 229, 233 (3), 243, 245, 254 (21), 292 Turesky, R.J. 1009, 1010 (61), 1021, 1030 (103), 1034 (61), 1036, 1037 Turnbull, K. 537, 553 (24), 617 Turner, C.A. 390 (71), 419, 1284, 1285 (194b), 1300 Turner, D.W. 160 (1, 16), 161, 163 (1), 164, 165 (42), 171 (42, 70), 174 (42), 175 (42, 70, 85), 201 203 Turner, E. 381 (20b), 417, 428 (42), 471 Turri´on, C. 357 (70), 376 Turro, N.J. 446 (170), 474 Turska, E. 431 (58), 471 Turteltaub, K.W. 1033 (201), 1039 Tuttle, J.V. 992 (132), 997 Tutuya, S. 585 (292), 622 Tvedten, O. 675 (61), 681 Tverdokhlebov, S.V. 636 (35), 659 Twiselton, D.R. 456 (224), 475 Tyler, A.N. 234 (157), 247 Tyler, J.K. 171 (68), 203 Tyllianakis, P.E. 1099 (345, 346), 1162 Tzeng, D. 97 (60), 103
Ublacker, G.A. 1032 (192), 1039 Uccella, N.A. 226 (120), 227 (122), 246 Uccello-Barretta, G. 1112 (400), 1163 Uchida, G. 1087 (276), 1160
1383
Uchida, T. 1256 (137), 1298 Uchimaru, T. 4, 13, 77 (15), 81 Ueda, C. 676 (68), 681 Ueda, T. 1096 (328), 1161 Uehleke, H. 1000 (15), 1029 (160), 1035, 1038 Ueji, S. 524 (254), 531 Uematsu, M. 977 (53), 995 Uetrecht, J. 1023 (119, 120), 1037 Uetrecht, J.P. 1009, 1023 (60), 1036 Uffer, P.M. 356 (59), 375 Uggerud, E. 236 (170, 172), 248 Uhlich, U. 668 (13), 680 Ukai, T. 654 (149), 662 Ukeda, H. 1106 (372), 1162 Ukhin, L.Yu. 576 (215), 621 Ulivi, P. 570 (194), 620 Ullman, E.F. 710 (115), 742 Ullrich, J.W. 714 (124, 125), 742 Umeda, T. 650, 652 (130), 661 Umekawa, H. 655 (155), 662 Umemoto, A. 1004, 1007, 1009, 1012, 1019, 1035 (43), 1036 Umezu, M. 866 (34), 889 Underwood, G.R. 873 (61), 890 Undheim, K. 579 (234), 621 Uneyama, K. 593 (342), 623 Unger, K.K. 1180 (55), 1213 Unger, S.H. 522 (245, 246), 531 Ungureanu-Longrois, D. 992 (127), 997 Unruh, L.E. 1003, 1004, 1009, 1011, 1012, 1031 (35), 1035 Unterhalt, B. 405 (146), 421 Unverdorben, O. 481 (8), 525 Uozumi, Y. 578 (223), 621 Upadiheva, A.V. 636 (40), 659 Uppal, J.S. 384 (33a), 417 Upthagrove, A.L. 729 (174), 744 Urano, S. 188 (118), 204 Urasaki, I. 1000 (1), 1035 Uray, G. 985 (92), 996 Urban, J.J. 60 (103d), 84 Urb´anczyk-Lipkowska, Z. 98 (68), 103, 433 (78), 472 Urba´nski, T. 484 (33), 526 Urbas, L. 482, 483, 507 (22), 525 Uri, J.V. 1148 (601), 1167 Urogdi, L. 554 (112), 555 (117), 556 (120), 558 (130, 131), 559 (133, 134), 619 Urˇsi´c, S. 450 (194), 474 Uryu, T. 1256 (138), 1298 Utaka, M. 498 (137), 528 Utimoto, K. 571 (197), 597 (372), 620, 624 Utting, B.D. 6 (9), 81 Uvarova, L.V. 607 (419), 625 Uwakwe, P.U. 1287 (199), 1290 (199, 200), 1293 (199), 1300 Uzu, S. 1091 (301, 302), 1161
1384
Author index
Vacca, A. 57 (93), 83 Vahadati, M.M. 1175 (11), 1212 Vaid, B.K. 583 (273), 622 Vaid, R.K. 583 (273), 622 Vainiotalo, P. 353 (45), 375 Vajta, Z. 1047 (34), 1155 Valc´arcel, M. 1137 (527), 1166 Valentin, E. 165, 166, 178 (46), 202 Valentine, D. 312 (53), 333 Valeri, C.R. 673 (43), 681 Valero, Y. 1083 (246), 1160 Valeur, B. 697 (88), 741 Valik, D. 1067 (134), 1157 Vallat, A. 845 (33), 854 (69), 855, 856, 1129 (468, 469, 471), 1144 (471), 1164 Valpiana, L. 634 (29), 659 Valraven, G. 1116 (417), 1163 VanAllen, J.A. 655 (156), 662 Van Alsenoy, C. 24 (36), 56 (85), 82, 83 Van Bennekom, W.P. 1119 (426), 1163 Van Boecxlaer, J. 1061 (92), 1156 Van Cauwenberghe, K.A. 1176 (27), 1212 Van Damme, J.C. 1076 (186), 1159 Van Dantzig, N.A. 694 (67), 741 Vandeberg, P.J. 1074 (176), 1158 Vanden Eynde, J.-J. 558 (128), 619 Van der Auweraer, M. 693 (57), 694 (58, 59), 695 (77), 741 Van der Haak, H.J. 1217 (13b), 1295 Van der Kleijn, E. 1128 (464), 1164 Vanderlaan, M. 1140 (552), 1166 Van der Plas, H.C. 561 (140a c, 141, 145), 619 Van der Wal, S. 1094 (324), 1161 Van Dyke, D.A. 675 (62), 681 Van Eijk, A.M.J. 754 (16), 818 Van Eijk, H.M.H. 1078 (196), 1159 Vanhessche, K.P.M. 125 (77), 155 Van Hoof, W. 763 (41), 818 Vanhoutte, P.M. 974 (3), 994 Vanier, N.R. 398 (115), 420 Vankar, P.S. 608 (421), 625 Vannerem, A. 695 (77), 741 Vannoort, R.W. 954 (32), 971 Van Opdenbosch, N. 36 38, 42 (52), 82 Van Ramesdonk, H.J. 696 (78), 741 Van Sant, K. 577 (221), 621 Van Vechten, D. 356 (61, 62), 376 Van Veldhuizen, A. 561 (145), 619 Van Zoonen, P. 1116 (415), 1163 Vapirov, V.V. 1278 (183), 1300 Varadarajan, T.S. 696 (80), 741 Varaghese, K.I. 866 (35), 889 Varandas, A.J.C. 409 (180), 422 Vargas, E.B.de 458 (237 239), 476, 1230 (79), 1297
Vargas, E.R.de 1220 (27), 1295 Vargas, M.C.de 1046 (16, 19), 1155 Varghese, A.J. 1031 (181, 184, 185), 1039 Varghese, J.N. 95 (42), 102 Varlamov, S.V. 133 (99), 155 Varlamov, V.T. 401 (135), 420 Varma, C.A.G.O. 754 (16), 818 Varma, R.S. 284, 285 (101), 293, 565 (170), 616 (464), 620, 626 Varnes, M.E. 1031 (182), 1039 Varshney, R.K. 461 (251), 476 Varty, T.C. 1083 (252), 1160 Vasapollo, G. 595 (357), 624 Vasudevan, D. 845 (32b), 846 (37), 855, 856 Vaughan, J. 510 (205), 516 (233), 530, 883 (89, 90), 890, 954 (24 29), 956 (28), 961 (24), 968 (26), 970, 971 Vaultier, M. 566 (177), 620 Vavricka, S. 869 (45), 889 Vavrin, Z. 975 (29, 30), 976 (30, 34), 978 (29), 980, 983 (34), 994 Vazques, J.T. 143 (128), 156 Vecchi, C. 456 (225), 475 Vecchi, E.de 1085 (269), 1160 Veˇceˇra, M. 494, 507 (120, 121), 528 V´egh, Z. 1086 (275), 1160 Veglia, A.V. 458 (237), 476, 1230, 1231 (78), 1297 Veigl, E. 1130 (477), 1164 Veith, H.J. 227 229 (128), 230, 231 (133), 240 (185, 187), 246, 247, 248 Veith, M. 396 (91d), 419 Velders, D.D. 1129 (475), 1164 Velek, J. 756 (21), 818 Velluz, L. 106 (8), 153 Venanzi, T. 317 (71, 72), 333 Venayak, N.D. 303, 308 (37), 333 Ven der Plas, H.C. 1217 (13a, 13b), 1295 Venema, R.C. 979 (75), 995 Venkataraman, B. 753 (10), 817 Venkatasubramaniam, K.G. 381, 410 (7), 416, 436 (117), 473 Venkatasubramanian, R. 1049 (66), 1156 Venkatesan, K. 762 (39, 40), 818 Veno, S. 215 (54), 245 Ventura, K. 1077 (192), 1159 Ventura, O.N. 453 (206), 475 Veracine, C.A. 321 (93), 334 Verardo, G. 53 (77), 83, 563 (163), 583 (270a, 270b), 620, 622 Verbit, L. 117 (53), 154 Verboom, W. 969 (64), 971 Verdaguer, X. 545 (70), 618 Verh´e, R. 569 (191), 620 Verhoeven, J.W. 166, 187 (54), 202, 263 (60), 292, 445 (169), 446 (173), 474, 694 (61, 64,
Author index 65), 695 (70), 696 (76, 78, 79), 697 (86), 741 Verin, I.A. 592 (339), 623 Verkade, P.E. 489, 490 (83), 527 Verlaque, J.H. 447 (177), 474 Verma, A. 993 (151), 997 Vermeer, J.M.P. 1119 (426), 1163 Vernier, N.R. 410 (182), 415 (205), 422 Veronese, A.C. 96 (51), 103 Versichel, W. 433 (75 77), 472 Vertal, L.E. 165, 166 (44), 202 Vervoort, J. 1097 (335), 1162 Verzijl, B.H.M. 91, 93 (20), 102 Vespalec, R. 1133 (500), 1165 Vessiere, R. 598 (373), 624 Vevers, R.J.S. 633 (23), 659 Vicente, J. 1134 (512), 1165 Vidal, J. 553 (106), 618 Vidal, M. 165, 166 (44), 202 Vidal-Carou, M.C. 1079 (214), 1159 Viehe, H.G. 403 (138a, 138b), 420, 630 (16), 659 Vieira, R. 1078 (204, 205), 1159 Vig, S.K. 848 (41b), 856 Vigliano, G. 1093 (314), 1161 Vilarrasa, J. 631 (17), 659 Vilinger, F. 1024 (125, 126), 1037 Vilkov, L.V. 8, 24 (14a, 14b), 81 Villadao, M. 1116 (407), 1163 Villalobos, E. 1046 (16), 1155 Villari, G.M. 975 (14 16), 994 Villieras, J. 597 (371), 624 Vincent, C. 428, 430 (35), 471 Vinogradov, V.M. 550 (85), 618 Vinogradova, S.V. 353 (50), 375 Vinson, L.K. 435 (97), 439 (130), 472, 473 Violeau, B. 609 (433), 625 Virtanen, P.O.I. 1232 (80b), 1297 Visandul, G. 1272 (176), 1299 Viswanadham, S.K. 280 (91), 293 Vita, J. 673 (43), 681 Vitali, D. 467 (269), 476, 1236, 1244, 1265 (111), 1298 Vivona, N. 388 (56), 418, 1236 (160), 1262 (152), 1266 (152, 160), 1299 Vlasov, V.M. 1238 (93), 1297 Vo, D.T. 1136 (521), 1165 Vo Dinh, T. 1101 (354, 355), 1162 Voelter, W. 302, 303 (22), 332 Vogel, E. 165, 166, 182 (47), 202 Vogel, F.R. 667 (8), 680 Vogel, M. 588 (306), 623 Vogel, W. 491, 500 (107a), 527 V¨ogtle, F. 428 (31), 439 (131), 471, 473 Vohra, S.K. 94 (41), 102 Voixner, R.D. 1073 (164), 1158 Volkonskii, A.Y. 1238 (93), 1297
1385
Volmer, D. 1068 (138), 1127 (455), 1133 (498), 1158, 1164, 1165 Volyanskii, Y.L. 1119 (431, 432), 1164 Vona, M.L.D. 165 167 (24), 202 Vong, M.S. 1175 (13), 1212 Vonminden, D.L. 1134 (505), 1165 Voogd, J. 91, 93 (20), 102 Vorbr¨uggen, H. 560 (139), 603 (391), 619, 624 Vorl¨ander, D. 484 (39), 526 Vottero, L.R. 1221 (48a c), 1222 (48b), 1247 (48c), 1296 Vouk, M.V. 583 (271), 622 Vouros, P. 1119 (429), 1163 Vovna, V.I. 160 (10), 201 Voyksner, R.D. 1066 (123), 1157 Voznakova, Z. 1133 (502), 1165 Vree, T.B. 1128 (464), 1164 Vries, H.de 1026 (141), 1038 Vsetecka, V. 494 (122), 528 Vulpius, T. 236 (172), 248 Vuorela, H. 1083 (251), 1160
Wachter, H. 983 (86), 993 (148), 996, 997 Wacker, C.D. 1184 (67), 1213 Wada, E. 934 (50), 947 Wada, F. 654 (152), 655 (153), 657 (170), 662 Wada, M. 730 (182b), 744 Wada, O. 1072 (155 160, 162), 1158 Wada, T. 833 (69), 836 Wade, F. 657 (172), 662 Wagner, K. 552 (104), 618 Wagner, K.-G. 639 (64, 65), 640 (66), 660 Wagner, L. 353 (50), 375 Wagner, P.J. 687 (40), 740 Wagner, W. 238 (177), 248 Wahl, G.H. 648 (110), 661 Wainwright, R.J. 673 (40), 681 Wait, A.R. 1222 (57, 58, 60), 1296, 1297 Wakabayashi, K. 677 (71), 681, 888 (106), 891, 1033, 1034 (198), 1039 Walash, M.I. 1140 (545, 550), 1166 Waldman, T.E. 596 (364), 624 Waldmann, H. 106 (11), 153 Waldmuller, D. 396 (91c), 419 Waldner, A. 512 (220), 530 Waldron, K.C. 1096 (330, 331), 1161 Walker, E.A. 1047 (41), 1155 Walker, G. 992 (128), 997 Walker, M.J. 1102 (356), 1162 Walker, R. 1188 (86), 1214 Walker, S. 1152 (622), 1168 Wall, C.G. 739 (207), 745 Wallace, G.C. 991 (114), 996 Waller, A.G. 954, 963 (31), 971 Waller, H.D. 1000, 1020, 1021, 1027 (17), 1035
1386
Author index
Walsh, R. 354 (53), 375 Walter, R.I. 968 (61), 971 Walters, T.R. 579 (238), 621 Walton, D. 1093 (311), 1161 Walton, R.A. 234 (156), 247 Waltz, H. 426 (16), 470 Wambsgans, A. 113, 114 (43), 154 Wa Muanda, M. 1245, 1266 (114b), 1298 Wan, P. 749 (4), 782 (86 89), 783 (88, 89), 784 (94), 785 (95, 96, 97a, 98), 786 (99), 817, 819, 820 Wanczek, K.P. 235 (163), 247 Wang, A.H.-J. 347 (27), 373 Wang, C.N. 685 (15), 740 Wang, D. 1108 (385 387), 1163 Wang, D.-A. 4, 14 (21), 81 Wang, D.G. 829 (46), 836 Wang, D.T. 1145 (575), 1167 Wang, E. 1073 (171), 1158 Wang, H. 839 (8c), 848 (42), 851 (8c), 855, 856 Wang, J. 557 (124, 125), 619, 987 (100), 989 (105), 996, 1066 (119), 1105 (371), 1157, 1162 Wang, J.T. 232 (143), 247 Wang, K.-T. 592 (330), 623 Wang, P. 697 (82), 741 Wang, Q. 550 (87), 618 Wang, Q.W. 1076 (185), 1158 Wang, R. 562 (153), 619 Wang, S. 346 (19), 373 Wang, S.C. 979 (76), 995 Wang, Y. 171 (69), 203, 431 (67), 441 (144), 446 (174), 472 474, 694 (75), 741, 896, 935, 941, 944 (19), 947, 978 (71), 995, 1136 (521), 1165 Wang, Z. 566 (179a, 179b), 620 Wangbo, M.H. 15, 17 (24b), 81 Ward, C. 1106 (377), 1162 Ward, L.D. 738 (201), 745 Ward, R.S. 1090 (294), 1161 Warkentin, J. 589 (314), 623 Warma, K.R. 552 (100b), 618 Warman, J.M. 696 (78), 697 (85), 741 Warner, T.O. 977, 978 (49), 995 Warzecha, L. 1130 (482), 1165 Wasielewski, M.R. 445 (168), 474, 698 (98), 742 Wasylishen, R.E. 317 (68), 333 Watanabe, H. 593 (342), 623, 787 (101), 820 Watanabe, I. 161, 163, 164 (22), 202 Watanabe, K. 1101 (352), 1162 Watanabe, M. 595 (355), 624, 1067 (124), 1131 (486, 488), 1157, 1165 Watanabe, S. 535 (8), 579 (232), 616, 621 Watanabe, T. 1074 (175), 1158 Watanabe, Y. 1047 (40), 1155
Waters, B.W. 297 (9), 332 Waters, J. 1116 (408), 1163 Waters, W.A. 484 (43), 526 Watkin, D. 60 (103c), 84 Watkins, B.E. 1140 (552), 1166 Watnick, C.M. 318 (78), 334 Watson, D.G. 37 (56), 82, 1063 (95, 96), 1157 Watson, H.B. 486, 487 (65), 498 (135), 526, 528 Watson, J.T. 1066 (119), 1157 Watts, D.W. 641 (71, 75), 655 (71), 660 Watts, W.E. 507, 512 (181), 529 Weast, R.C. 1010 (70), 1036 Weaver, M.A. 630 (13), 659 Webb, G.A. 297, 300 (1a c), 301 (1b), 310 (49, 50), 311 (50), 317 (1b, 69, 73, 74), 318 (78, 79), 322, 323 (96), 332 334 Webb, H.M. 164 (33, 34), 165 (44), 166 (44, 50), 178 (34), 202, 236 (167, 168), 247, 386 (48a, 48b), 418 Webb, N.B. 1047 (24), 1155 Weber, D. 1145 (573, 576), 1147 (588), 1166, 1167 Weber, H.P. 63 (110a, 110b), 84 Weber, K.A. 600 (383), 624 Weber, R.U. 638 (47), 660 Weber, S.G. 1074 (182), 1158 Weger, H. 175 (82), 203 Wegewijs, B. 696 (79), 741 Wei, J. 541 (49), 617 Weiden, N. 99 (81), 103 Weidlein, J. 396 (91b), 419 Weigel, L.O. 544 (66), 617 Weigold, J.A. 438 (127), 473 Weil, K.G. 262 (54), 292 Weil, L. 1128 (462), 1164 Weiner, C.P. 992 (134), 997 Weiner, P. 3 (2a), 60 (103a), 81, 83 Weiner, S.J. 3 (2a, 2b), 81 Weinfeld, M. 833 (70), 836 Weinman, S. 15, 16 (26c), 82 Weinraub, D. 827 (40), 835 Weinreb, S.M. 595 (353), 624 Weintraub, S.T. 1066 (114), 1157 Weir, D. 688 (38), 740 Weisburger, E.K. 1020 (96), 1037 Weisburger, J.H. 1020 (96), 1037 Weise, M. 978 (58), 995 Weiske, T. 211 (40), 220 (96 98), 221, 232 (97, 98), 244, 246, 259 (46), 292 Weisman, G.R. 56 (80c, 80d), 83, 130 (87), 155, 184 (105), 203 Weiss, A. 99 (81), 103 Weiss, B. 648 (108), 661, 738 (200a), 745 Weiss, C.S. 1118 (421), 1163 Weiss, E. 396 (95), 419 Weiss, R. 639 (64, 65), 640 (66), 660
Author index Weiss, R.G. 783 (92), 820 Weissbuch, I. 1108 (388), 1163 Weister, M. 1139 (535), 1166 Weisz, A. 208 (10), 244, 992 (126), 997 Welch, L.E. 1073 (166), 1085 (268), 1158, 1160 Welch, W.M. 595 (354), 624 Wen, Y.X. 765 (45), 818 Wenck, A. 1079 (209), 1159 Wendt, J.O.L. 1175 (14), 1212 Wenska, G. 728 (171a, 171b), 744 Wentrup, C. 274, 275 (85), 293 Wenz, G.C. 313 315 (57), 333 Wepster, B.M. 489, 490 (83), 494, 495 (117, 124, 125), 498 (125), 519 (124, 125, 236), 520 (239), 522 (248), 527, 528, 531 Werner, A.E. 674 (52), 681 Werner, E.R. 983 (86), 990 (109), 993 (148), 996, 997 Werner, R.L. 434 (95), 472 Werner-Felmayer, G. 993 (148), 997 Wernick, D.L. 128 (83), 155 Werst, D.W. 826 (25), 835 Wesdemiotis, C. 208, 210 212, 215 (17), 240 242 (189), 244, 248, 254 (16), 292 Wessling, M. 849 (49), 856 West, F.G. 578 (222), 621 West, W.R. 1047 (37), 1155 Westaway, K.C. 893 (1), 896 (15), 933, 934, 938 (1), 940 (60), 941 (61 63), 942, 943 (61), 944 (60, 61), 945 (1), 946 948 Westaway, K.C.Jr. 896, 935, 941, 944 (19), 947 Westerholm, R. 1130 (480), 1165 Westhauser, T. 1090 (291), 1161 Westheimer, F.H. 895 (12), 947 Westmore, K. 992 (135), 997 Westover, D.L. 692, 702, 709 (53), 741 Westrum, E.F.Jr. 338, 361 (2c), 363 (87), 372, 377 Westwood, N.P.C. 166 (56), 202, 290 (116), 294 Wettermark, G. 710 (112), 742 Whalon, M.R. 43 (68), 46 (70), 83 Whang, Y.. 403 (140), 421 Whang, Y.E. 407 (159), 421 Wheat, T. 1085 (265), 1160 Wheeler, J.F. 1023 (121), 1037 Wheeler, P.A. 1047 (21), 1155 Wheland, G.W. 443 (156), 474, 497 (133), 528 Whetsel, K.B. 434 (89, 93, 94), 472 Whincup, P.A.E. 678 (81), 682 White, H.S. 877 (70), 890 White, J.C. 727 (167), 744 White, J.G. 94 (35), 102 White, J.M. 184 (105), 203, 883 (89), 890, 954 (27), 971
1387
White, K.A. 978 (67), 983, 984 (87), 995, 996 White, M.G. 192, 193, 200, 201 (136), 204 White, T.G. 63 (110a), 84 White, W.N. 877 (70), 890 Whiteford, R.A. 164 (39), 202 Whitesides, G.M. 108 (28), 128 (82, 83), 129 (82), 154, 155, 430 (45, 47 53), 471 Whiting, G.S. 1222 (56), 1226 (71), 1296, 1297 Whitman, R.H. 1105 (368), 1162 Whitmore, G.F. 1031 (184, 185), 1039 Whitten, D.G. 444 (163), 474, 693 (54), 697 (90), 727 (169), 741, 744 Whittle, A. 955 (40), 971 Wiberg, K.B. 355 (56), 375, 403 (142), 421 Wicks, G.E. 604, 605 (404), 625 Widdowson, D.A. 215 (57), 245 Widmer, H.M. 1093 (315), 1161 Wiebcke, M. 86, 88 (4), 102 Wieboldt, R. 769 (56), 819 Wieder, M.J. 317 (67, 69), 318 (78), 333, 334 Wiedner, J.H. 992 (131), 997 Wieland, E. 1021 (102), 1037 Wierenga, W. 639 (60), 660 Wiese, G. 1119 (426), 1163 Wieser, H. 133 (101), 148 (149, 150), 149 (149 151), 152 (149, 150), 155, 157 Wieser, K. 291 (119), 294 Wiesler, D. 1093 (320), 1161 Wiesler, W.T. 143 (129), 156 Wiezorek, C. 829 (45, 49), 836 Wigfield, Y.Y. 1145 (571), 1147 (594), 1166, 1167 Wikstrom, H. 62, 64, 65 (108), 84 Wilante, G. 410 (187a, 187b), 422 Wilcox, D. 673 (42), 681 Wilcox, J. 979 (72), 995 Wild, D. 1034 (205), 1039 Wild, F.R.W.P. 115 (49), 154 Wildemann, M. 175 (82), 203 Wilderink, A.H.C.M. 1048 (57), 1156 Wilen, S.H. 106 (12), 153, 1009 (66), 1036 Wilkes, A.J. 1116 (417), 1163 Wilkes, J.G. 1146 (583), 1167 Wilkie, R.J. 641 (75), 660 Wilkins, A. 98 (78), 99 (82), 103 Wilkins, C.W.Jr. 767 (49), 819 Willard, P.G. 724 (162f), 743 Willemse, R.J. 694 (61), 741 Willer, R.L. 96 (53), 103 Willett, G.D. 163 165 (25), 166 (55, 57), 202, 236 (171), 248 Willey, G.R. 453 (209), 475 William, D.Lyn H. 448 (190), 474 Williams, A. 1174 (6, 7), 1175 (10), 1212 Williams, A.E. 206, 207, 233 (2f), 243, 264 (63), 265 (69), 293
1388
Author index
Williams, D.H. 206, 207 (2c, 2e), 218 (87), 225 (116), 226 (121), 227 (122, 123, 125, 126), 232 (144), 233 (2c, 2e), 236 (123, 169), 239 (182, 183), 243, 246 248 Williams, D.L.H. 448 (191), 474, 629 (12), 641, 644 (73), 659, 660, 666 (1, 2), 667 (9, 10), 669 (20, 26), 670 (26, 27), 672 (31, 32, 37), 675 (55, 56, 60, 65), 676 (66, 67, 70), 677 (66, 74, 75), 678 (79, 80, 82), 679 (86), 680 682, 865 (30), 869 (44), 883 (93), 884 (94), 886 (103), 887 (104), 888 (105), 889, 891 Williams, F. 232 (143), 247 Williams, G.J.B. 94 (39, 40), 102 Williams, K. 1127, 1143 (458), 1164 Williams, P.T. 1176 (23), 1178 (48), 1212, 1213 Williams, S.C.R. 330 (123, 124, 127), 331 (127), 332 (130, 131), 335 Williard, P.G. 396 (91c), 419 Willisma, F. 825 (18), 835 Willoughby, C.A. 115 (47, 48, 51), 116 (51, 52), 117 (48, 52), 154, 546 (74a, 74b), 618 Willson, C.G. 767 (48a), 819 Wilson, A. 1126 (450), 1164 Wilson, C.A. 402 (139), 420 Wilson, D. 1267 (169), 1299 Wilson, G.E. 1059 (82), 1156 Wilson, G.E.Jr. 325 (109), 334 Wilson, I.S. 486 (57, 58), 526 Wilson, J.C. 895, 896, 936 (11), 947 Wilson, K. 833 (65), 836 Wilson, N.K. 302 (18), 332, 1133 (503), 1165 Wilson, P. 733 (183e), 744 Wilson, R.H. 1031 (178), 1039 Wilson, W.R. 329, 330 (111), 334 Wilson, W.S. 877 (69), 890 Windels, C. 695 (77), 741 Winer, A.M. 1177 (35, 40), 1212, 1213 Wing, M.R. 1098 (341), 1162 Winitz, M. 107 (25), 154 Wink, D.A. 669 (25), 680 Winkle, M.R. 767 (52a), 819 Winkler, J.D. 724 (162f), 743 Winkler, R. 641 (74), 660 Winstein, S. 424 (4), 470 Winter, J.G. 905 (32), 947 Wipff, G. 60 (103a), 83 Wirth, P.J. 1029 (167), 1038 Wirth, T. 604 (398), 625 Wise, M.B. 1047 (49), 1155 Wiseman, J. 985 (91), 996 Wishnok, J.S. 976 (33), 991 (115), 994, 996, 1188 (86), 1189 (101), 1214 Witanowski, M. 297, 300 (1a c), 301 (1b), 310 (49, 50), 311 (50), 317 (1b), 318 (79), 332 334
Withey, J.R. 1189 (93), 1214 Witkiewicz, Z. 1047 (47, 48), 1155 Wittel, K. 188 (114), 204 Wittfoht, W. 977 (48), 995 Wittig, C. 795 (123), 820 Wittner, R. 1090 (291), 1161 Woerpel, K.A. 119 (56), 154 Wokaum, A. 297 (11), 332 Wold, S. 522 (242), 531 Wolf, J.L. 235, 236 (165), 247 Wolf, M. 1127 (460), 1164 Wolf, W.J. 1096 (332), 1161 Wolfe, R.R. 1059 (83), 1156 Wolfe, S. 14 (22a), 15 (22a, 24b), 16 (22a), 17 (22a, 24b), 19 21 (22a), 81, 896, 935, 941 (18), 947 W¨olfel, G. 553 (108a, 108b), 618 Wolff, A. 1266 (157), 1299 Wolff, D.J. 991 (119 121), 996 Wolff, G.A. 1064 (104), 1157 Wolff, H. 434 (84, 89, 92), 472 Wolford, L.T. 606 (413), 625 Wolfsberg, M. 894 (7), 947 Wollmann, T.A. 112 (40), 154 Wolz, E. 1034 (205), 1039 Wong, C.C. 760 (37), 818 Wong, C.-H. 108 (28), 154 Wong, F.F. 534 (6), 616 Wong, J.M. 1132 (490), 1135 (515), 1165 Wong, M.H. 59 (99), 83 Wong, S.S. 1065 (106), 1157 Woo, K.L. 1085 (259), 1160 Wood, E.R. 992 (132), 997 Wood, K.S. 974 (2), 976 (32), 993 (144), 994, 997 Woodrow, J.E. 1132 (490), 1165 Woods, S.P. 957 (45), 971 Woodworth, R.C. 956 (43), 971 Worley, S.D. 164, 165, 168 (40), 170 (65), 202, 203 Worrell, C. 166, 187 (54), 202 Worsfold, P.J. 1045 (5), 1108 (384), 1155, 1163 Worthen, H.G. 1082 (242), 1160 Worthing, C.R. 1053, 1054, 1058, 1115, 1124 (75), 1156 Wozniak, K. 437 (121), 473 Wozniak, M. 561 (140c, 142 144), 619, 1217 (13b), 1295 Wright, A.D. 231 (136, 138), 232 (138), 247 Wright, D.J. 434 (85), 472, 511 (211), 530, 1241, 1262, 1264 (103b), 1298 Wright, D.P. 1187 (79), 1213 Wright, D.R. 933 935, 938 (49), 947 Wright, G.J. 954 (30 33), 962 (30), 963 (31), 971 Wright, J.D. 1126 (450), 1164
Author index Wu, A.-H. 657 (169), 662 Wu, A.H.B. 1065 (106), 1157 Wu, H.P. 992 (130), 997 Wu, J. 556 (118), 619 Wu, K.K. 989 (103), 996 Wu, M. 1151 (618), 1167 Wu, M.-J. 567 (182), 620 Wu, S. 697 (82), 741, 1096 (331), 1161 Wu, Y.-D. 72 (122a), 84 Wu, Y.M. 447 (185), 474 Wu, Z. 1284, 1285 (194a), 1300 Wu, Z.Z. 811 (163), 812 (167), 814 (170), 815 (171), 821 Wubbels, C.G. 785 (97b), 820 Wubbels, G.G. 756 (22), 757 (26), 759 (35a, 35b), 818 Wuchner, K. 1145 (572), 1166 Wuis, E.W. 1128 (464), 1164 W¨urthwein, E.-U. 165, 166, 192 (45), 202 Wurtz, C.A. 481 (14), 525 Wurtz, R. 434 (89), 472 Wyman, J.F. 1134 (505), 1165 Wynberg, H. 539 (40), 617 Wyn-Jones, E. 57 (87), 83
Xiao, H.-M. 4, 14 (21), 81 Xiao, L. 509 (188, 189), 529, 530 Xie, H.-Q. 415 (208), 416 (212), 422 Xie, J. 991 (123), 996 Xie, Q.-W. 978 (63, 65), 992 (129, 131), 993 (147, 150), 995, 997 Xiong, H. 886 (97), 891 Xu, C.D. 583 (277), 622 Xu, G. 1146 (585), 1167 Xu, G.P. 1151 (615), 1167 Xu, H. 557 (124), 619, 1148 (604), 1167 Xu, W. 690 (45 47), (44), 740, 741, 978 (70), 979 (77), 995 Xu, Y. 1103 (362), 1162
Yabroff, D.L. 499, 520 (139), 528 Yacobson, G.G. 315 (59), 333 Yagi, M. 722 (159b, 159c), 743, 789 (106), 820 Yagupolskii, L.M. 1238 (93), 1297 Yagupolskii, Yu.L. 1238 (93), 1297 Yakechi, H. 609 (431), 625 Yakobson, G.G. 306, 311, 313 (38), 333, 866 (36), 889 Yamada, H. 565 (174), 620, 1114 (405), 1163 Yamada, J. 544 (67), 617 Yamada, K. 795 (128, 129), 796 (130), 820, 950 (14), 970 Yamada, M. 543 (56), 617, 1085 (270, 271), 1129 1131 (476), 1160, 1164
1389
Yamada, T. 824 (12), 835, 1090 (297), 1092 (307), 1161 Yamada, Y. 590 (319), 623 Yamagami, C. 305 (33), 306 (34), 307 (33), 333 Yamagami, M. 868 (42), 889 Yamaguchi, F. 467, 468 (274), 476, 1217 (7), 1295 Yamaguchi, J. 580 (248), 621 Yamaguchi, K. 96 (47), 102, 872 (56), 890 Yamaguchi, S. 114 (45), 154, 390, 391 (68), 419 Yamaguchi, T. 843 (21), 855 Yamaizumi, Z. 1004, 1007, 1009, 1012, 1019, 1035 (43), 1036 Yamakawa, K. 585 (293), 622 Yamamoto, H. 863 (25), 889 Yamamoto, J. 866 (34), 889 Yamamoto, K. 1089 (289, 290), 1118 (424), 1161, 1163 Yamamoto, M. 215 (53, 54), 245, 574 (205), 620, 695 (68), 741, 795 (128, 129), 796 (130), 820 Yamamoto, T. 616 (465), 626 Yamamoto, Y. 459 (244), 476, 544 (67), 617 Yamamuchi, S. 724 (162b), 743 Yamamuro, A. 112 (40), 154 Yamano, M. 561 (146), 619 Yamanobe, M. 1122 (438), 1164 Yamanouchi, K. 24 (32), 82 Yamaoka, T. 787 (101), 820 Yamasaki, T. 551 (94), 618 Yamashina, K. 1106 (378), 1162 Yamashita, T. 561 (146 149), 562 (150), 595 (355, 358), 619, 624, 704 (104 106), 706 (106), 742 Yamashita, Y. 452 (196), 475 Yamataka, H. 409 (174), 421, 933 (47), 934 (50), 935 (53), 947, 948 Yamato, T. 848 (45), 856, 969 (65), 971 Yamauchi, A. 1119 (433), 1164 Yamazaki, S. 580 (247), 581 (254), 621, 622 Yamazaki, T. 161, 163, 171 173, 193, 197 (21), 202 Yamazaki, Y. 581 (254), 622 Yamazari, M. 718 (147), 743 Yamazoe, Y. 1004, 1007, 1009, 1034 (41), 1035 Yan, D.-S. 567 (182), 620 Yan, J. 346 (19), 373 Yan, L. 4, 33, 35 (44), 82 Yanagida, K. 870 (50), 890 Yanagida, S. 824 (12), 835 Yanai, T. 610 (439), 611 (440), 614 (457), 625, 626 Yanez, M. 407 (161b), 408 (168), 421 Yang, C.C. 581 (259), 622
1390
Author index
Yang, D. 133 (101), 148 (147, 149, 150), 149 (149 151), 152 (147, 149, 150), 155, 157 Yang, M. 173 (79), 203 Yang, N.C. 445 (168), 474, 694 (67), 698 (98), 741, 742 Yang, S.S. 1079 (215), 1159 Yang, X. 188 (118, 119), 204 Yang, X.H. 1058 (76), 1156 Yang, Z.-Z. 184 (105), 203 Yannakopoulou, K. 554 (115a, 115c), 555 (115c, 117), 556 (121, 123), 558 (129), 619 Yano, Y. 605 (406), 625 Yarwood, J. 442 (153), 473 Yasuda, M. 561 (146, 147, 149), 562 (150), 588 (304), 619, 623, 704 (103 107), 706 (106), 742 Yasui, S. 650 (126), 661 Yasumura, Y. 1089 (290), 1161 Yasuoka, T. 676 (68), 681 Yates, B.F. 208 (19 21), 209 (22), 210 (19), 211 (19, 20), 214 (21), 215 (20), 235 (19), 244 Yates, K. 381 (5a), 416, 641 (76), 660, 785 (96, 97a, 98), 786 (99, 100), 820 Yavari, I. (85), 334 Ye, J.N. 1093 (319), 1161 Yeh, H.J.C. 317 (69), 318 (78), 333, 334 Yen, G.C. 1081 (226), 1159 Yeo, A.N.H. 239 (183), 248 Yeung, E.S. 1118 (422), 1163 Yeung, T.-C. 1032 (196), 1039 Yi, K.Y. 602 (386), 624 Yildirir, Y. 657 (167), 662 Yinon, J. 281 (92, 95), 289 (111), 293 Yip, R.W. 765 (44 46), 811 (163), 818, 821 Yoffe, A.M. 1047 (24), 1155 Yoganarasimhan, S. 876 (68), 890 Yoho, L.L. 990 (110), 996 Yokosu, H. 1081 (233), 1159 Yokoyama, K. 758 (34a, 34c e), 818 Yokoyama, T. 308, 309 (39, 42), 333, 439 (129), 443 (157), 473, 474 Yokozeki, A. 56 (84a, 84b), 83 Yoneda, N. 651 (132, 133), 656 (166), 657 (132), 661, 662 Yonemitsu, O. 722 (157b, 157c), 743 Yonemitzu, O. 736 (194a, 194b), 745 Yonemura, K. 582 (265), 622 Yoneyoshi, Y. 112 (39), 154, 536 (15), 617 Yoon, B.A. 729 (175a, 175b), 744 Yoon, H. 108 (27), 154 Yoon, N.M. 534 (2), 537 (30), 563 (155), 616, 617, 620 Yoon, P.S. 976 (33), 994 Yoon, U.C. 685 (16), 688 (43), 690 (45), 714 (127), (44), 740, 742 Yoshida, E. 734 (188b), 744
Yoshida, K. 561 (148), 605 (406), 619, 625 Yoshida, T. 77 (127), 84, 1067 (125), 1157 Yoshida, Y. 595 (355, 358), 624 Yoshida, Z. 498 (137), 528 Yoshihiro Kuroda 320 (84), 334 Yoshikawa, K. 164 (30), 165, 166 (23), 170 (30), 202 Yoshikoshi, A. 611 (441), 625 Yoshimine, M. 882 (87), 890 Yoshimizu, H. 322, 323 (96), 334 Yoshimura, A. 535 (11), 616 Yoshioka, H. 565 (173), 620 Yoshioka, M. 597 (372), 624 Yost, R.A. 238 (180), 248 Young, A.P. 991 (123), 996 Young, H.L. 1016 (88), 1037 Young, M. 1024 (125), 1037 Young, P.N.W. 669 (23), 680 Young, R.J. 1048 (56), 1156 Yousaf, T.I. 593 (344), 623 Youssefyeh, R.D. 1001, 1003 (21), 1035 Yssa, Y.M. 439 (134), 473 Yu, C. 188 (115 117), 204 Yu, G.-S. 153 (167), 157 Yu, J. 1071 (153), 1158 Yu, X. 1024 (127), 1037 Yu, Z.S. 1046 (15), 1155 Yuasa, M. 576 (212), 621 Yuh, Y.H. 3 (3c, 3d, 4a), 4 (4a), 5 (3c, 3d, 8), 16 (8), 20, 21 (4a), 22 (8), 27 (3c, 3d, 4a), 59 (102), 81, 83 Yui, Y. 978 (59, 66), 995 Yukawa, Y. 489, 496 (85, 86), 504 (153), 521 (85, 86), 527, 529 Yumoto, M. 544 (67, 67), 617 Yunes, R.A. 1009 (59), 1036 Yunis, A.A. 1024 (129, 130), 1025 (130, 135, 136, 138), 1037, 1038 Yus, M. 396 (88), 419 Zabicky, J. 1044 (1), 1045, 1047 (6), 1154, 1155 Zabrowski, D.L. 579 (229), 621 Zachariadis, G. 1139 (537), 1140 (547), 1166 Zacharias, D.E. 94 (41), 102, 452 (199), 475 Zachariasse, K.A. 697 (84, 85), 741 Zahradnik, R. 426 (10, 12), 428 (30), 431 (12), 434 (83), 470 472 Zaitsev, V.P. 139 (114, 115), 156 Zajac, W.W.Jr. 579 (237, 238), 621 Zaleta, M.A. 639 (60), 660 Zaltsgendler, I. 550 (86a), 618 Zamboni, R. 574 (206), 621 Zambonin, P.G. 1078 (197), 1159 Zamora, L.L. 1099 (344), 1162 Zanardi, G. 655 (158), 662 Zanathy, L. 164, 165, 175 (31), 202
Author index Zanoni, M.V.B. 852 (62), 856 Zapardiel, A. 1138 (530), 1166 Zapico, J. 1085 (266), 1160 Zard, S.Z. 613 (451), 615 (461), 626 Zavattarelli, F. 447 (187), 448 (188), 474 Zawadzki, J.V. 975 (5, 13), 994 Zawadzki, S. 537 (32), 540 (44), 617 Zebrowski, B.E. 698 (95), 742 Zeegers-Huyskens, T. 387, 388 (54), 418 Zeeuw, R.A.de 1048 (57), 1156 Zeitlin, A.L. 108, 109 (31), 154 ` Zelazna, M. 459 (242), 476 Zelenetskii, A.N. 352 (43), 374 Zeman, S. 1142 (564), 1166 Zeng, D. 977 (51), 995 Zeng, Z. 1132 (491), 1165 Zerban, H. 1185 (71), 1213 Zerkowski, J.A. 430 (49), 471 Zhang, A.Q. 1064 (103), 1157 Zhang, F. 431 (67), 472 Zhang, F.Z. 1073 (172, 173), 1158 Zhang, J. 992 (142), 997 Zhang, M. 688 (42), 740 Zhang, R. 979 (73), 995, 1126 (449), 1164 Zhang, X.-M. 401 (133), 402 (131 133), 420, 690 (46), 740 Zhang, Y. 381 (21), 417, 428 (43), 471 Zhang, Z.-L. 346 (19), 373 Zhao, B. 1022 (116), 1037 Zhao, C. 608 (422), 625 Zhao, N. 143 (130), 156 Zhao, W.-Y. (68), 971 Zhao, X. 556 (122), 604 (394), 619, 624 Zheng, M. 1148 (604), 1167 Zhong-zhi, Y. 181 (96), 203 Zhou, G. 810 (156), 821 Zhou, O. 589 (309), 623 Zhou, P. 143 (129), 156 Zhou, W.-S. 120, 142 (62), 154 Zhou, X. 557 (124, 125), 562 (152), 619 Zhu, S.Z. 1238 (93), 1297 Zhu, X.-Y. 120, 142 (62), 154 Zibarev, A.V. 306, 311, 313 (38), 333 Zielinska, B. 1177 (35, 40 43, 46), 1179 (47), 1212, 1213 Zijlstra, R.W.J. 1110 (395), 1163 Zima, J. 1128 (466), 1135 (516), 1138 (529, 531), 1148 (598), 1164 1167
1391
Zimmer, H. 639 (62), 660, 811 (164), 821, 1023 (121), 1037 Zimmerman, S.C. 1132 (491), 1165 Zimmermann, J. 655 (162), 662 Zincke, Th. 952 (16), 970 Zingaretti, L. 463 (254), 476, 1245 1247, 1266 (115a), 1298 Zinin, N.N. 481 (11), 525 Zipplies, M.F. 535 (12), 616 Zlatkis, A. 121 (68), 155 Zmuda, H. 860 (17), 861 (17, 19), 889, 897 (22), 899 (23), 904 (26), 947 Zmudzki, J. 1139 (533), 1166 Zoebisch, E.G. 161, 173 (18), 202 Z´oke, A. 1047 (34), 1155 Zollinger, H. 628 (2, 3, 7), 631 (18), 636 (42), 637 (3, 7), 638 (47), 643 (89), 644 (7, 93), 646 (2, 7), 647 (2, 7, 106), 648 (107 110), 649 (3, 7), 650 (124), 651 654, 657 (7), 658 661, 1220 (34), 1241 (103c), 1262, 1264 (103c, 147c), 1266 (163a, 163b), 1268 (163a), 1296, 1298, 1299 Zou, X. 1256 (135), 1258 (135, 140, 141), 1259 (135), 1260 (140, 141), 1261 (141), 1298, 1299 Zsolnai, L. 115 (49), 154 Zubler, H. 634 (29), 659 Zucco, C. 1217 (6a), 1295 Zuckerman, J.J. 330, 331 (125), 335 Zuckermann, H. 795 (124), 820 Zuk, W.M. 148 (146), 150 (154, 156), 157 Zukowski, J. 1089 (284), 1090 (295), 1160, 1161 Zuman, P. 447 (181, 183, 186), 450 (181), 474, 838 (4a, 4b), 846 (36c), 848 (41a, 41b), 854 (65), 855, 856, 1000 (3), 1005 (3, 50), 1007, 1016, 1019 (3), 1035, 1036 Zummack, W. 216 (63c), 245 Zweifel, G. 117 (54), 154 Zweig, G. 1187 (79), 1213 Zweigenbaum, J.A. 1118 (419), 1163 Zweipfenning, P.G.M. 1048 (57), 1156 Zwierzak, A. 537 (32), 540 (44, 48), 617 Zwisler, W.H. 369 (96), 378 Zygmunt, J. 860, 861 (17), 877 (72), 889, 890, 911 (34), 947
Index compiled by K. Raven
Supplement F2: The Chemistry of Amino, Nitroso, Nitro and Related Groups. Edited by Saul Patai Copyright 1996 John Wiley & Sons, Ltd. ISBN: 0-471-95171-4
