Advances in Physica I Organic Chemistry
ADVISORY BOARD W J Albery, FRS Imperial College of Science and Technology, Lo...
33 downloads
1226 Views
10MB Size
Report
This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form
Advances in Physica I Organic Chemistry
ADVISORY BOARD W J Albery, FRS Imperial College of Science and Technology, London A L J Beckwith The Australian National University, Canberra R Breslow Columbia University, New York L Eberson Chemical Center, Lund H Iwamura Institute .for Molecular Science, Okazaki G A Olah University o f Southern California, Los Angeles Z Rappoport The Hebrew University o j Jerusalem P von R Schleyer Universitat Erlangen-Niirnberg G B Schuster University of Illinois at Urbana-Champaign
Advances in Physical Organic Chemistry Volume 24 Edited by
D. B E T H E L L The Robert Robinson Laboratories University of Liverpool P.O. Box 147, Liverpool L69 3BX
A C A D E M I C P R E S S 1988 Harcourt Brace Jovanovich, Publishers London San Diego New York Boston Sydney Tokyo Toronto
ACADEMIC PRESS LIMITED 24,28 Oval Road London NWI 7DX CJtiirc,d Siuics Edilion puhlislied by ACADEMIC PRESS INC. San Diego. CA 92101
Copyright 0 1988 by
ACADEMIC PRESS LIMITED
N o part of this book may be reproduced in any form by photostat. microfilm, or any other means. without the written permission from the publishers
ISBN 0-12-033524-7 ISSN 0065-3 160
TYPESET BY BATH TYPESETTING LTD., BATH, U.K. A N D PRINTED I N GREAT BRITAIN ny ST. EDMUNDSBURY PRESS, BURY ST. EDMUNVS.
Contents Contributors t o Volume 24
vii
Gas-phase Reactions of Organic Anions
1
N I C O M. M. N I B B E R I N G 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Introduction 1 Instrumental methods 2 Formation of anions 6 Some basic aspects of gas-phase ion/molecule reactions Hydrogen/deuterium exchange reactions 1 1 Addition-elimination reactions 14 Elimination reactions 22 Nucleophilic aromatic substitution reactions 28 Cycloaddition reactions 33 Hydride transfer reactions 36 Dipole-stabilized carbanions 38 Homoenolate and homoaromatic anions 40 Ion structures 43 Radical anions 46 Concluding remarks 50
7
Hydride Shifts and Transfers
C. I A N F. W A T T 1 2 3 4 5
Introduction 58 Metal-to-carbon transfers 66 Anionic carbon-to-carbon hydride transfers and shifts 74 Cationic carbon-to-carbon hydride transfers and shifts 86 Reactions of dihydropyridines and related species 94
57
CONTENTS
vi
The Principle-of Least Nuclear Motion and the Theory of Stereoelectric Control
113
M I C H A E L L. S I N N O T T Introduction I14 Failures of the antiperiplanar lone pair hypothesis (ALPH) 120 The theoretical basis of ALPH 145 The principle of least nuclear motion ( E W M ) 156 Reinterpretation of apparent kinetic afltiperiplanar lone pair effects in terms of the principle of least nuclear motion 161 Loss of leaving groups from trigonal centres 179 Reactions at phosphorus centres 184 Reactions of radicals 192 Envoi 198 Author Index
205
Cumulative Index of Authors
217
Cumulative Index of Titles
219
Contributors t o Volume 24 Nico M. M. Nibbering Laboratory of Organic Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands Michael L. Sinnott Department of Organic Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 ITS, U.K.
C. Ian F. Watt Department of Chemistry, University of Manchester, Manchester M I 3 9PL, U.K.
This Page Intentionally Left Blank
Gas-phase Reactions of Organic Anions N I C O M. M. N I B B E R I N G Luhoratory of Organic Chemistry, University of Amsterdam, Amsterdutn, The Nt.thtvlunil.s I 2 3 4 5 6
7 8 9 10 I1 12 13 14 I5
1
Introduction I Instrumental methods 2 Fourier transform ion cyclotron resonance (FT-ICR) Flowing afterglow (FA) 5 Formation of anions 6 Some basic aspects of gas-phase ion/molecule reactions Hydrogen/deutcrium exchange reactions 1 1 Addition-elimination reactions 14 Carbonyl centres I5 Nitrite esters 18 Silicon and phosphorus centres 20 Elimination reactions 22 Nucleophilic aromatic substitution reactions 28 Cycloaddition reactions 33 Hydride transfer reactions 36 Dipole-stabilized carbanions 38 Homoenolate and homoaromatic anions 40 Ion structures 43 Radical anions 46 Concluding remarks 50 Acknowledgements 50 Referenccs 50
2
7
Introduction
The chemistry of anions in the gas phase has received considerable research interest over the last decade. This can in part be ascribed to rapid development of the required instrumental methods which have taken place during that period. Techniques such as high pressure mass spectrometry (Kebarle, 1977), chemical ionization mass spectrometry (Harrison, 1983), flowing afterglow (Smith and Adams, 1979; DePuy and Bierbaum, 1981 a), selected ADVANCES IN PHYSICAL ORGANIC CHEMISTRY ISBN n - 1 2 - o v m - 7 VOLUME 24
CopirfRhl 0 1988 Acud<wnrc PMJFLirnircd A / / rryhr5 of reproducrion i n a n ) /arm rrxvved
2
NlCO M. M. NIBBERING
ion flow tube (Adams and Smith, 1976), ion cyclotron resonance (Baldeschwieler and Woodgate, 1971 ; Beauchamp, 197I ) and Fourier transform ion cyclotron resonance (Comisarow, 1985; Marshall, 1985) are applied frequently nowadays to study equilibria and reactions between ions and molecules so as to obtain information such as rate constants, electron- and proton-affinities and acidities of molecules and to determine structures of ions in the gas phase. Another important reason for the continuing and growing interest in the chemistry of ions in the gas phase is that corresponding studies can reveal the course of organic reactions in the absence of solvent molecules or counter ions and can provide a qualitative and often quantitative insight into the intrinsic properties and reactivity of the species involved. Several reviews on anions derived from organic compounds have appeared (Bowie, 1984a; Budzikiewicz, 1983) and some of them have been devoted entirely to bimolecular processes (Nibbering, 1981, 1986; Bowie, 1980, 1984b; DePuy et al., 1982a; DePuy and Bierbaum, 1981a). In this review organic anion/molecule reactions will be described, which have been studied mostly with the methods of Fourier transform ion cyclotron resonance mass spectrometry and flowing afterglow. As a general layout of this review, first the basic principles of these methods will be given. Subsequently, the formation of anions, the current theory of gas phase ion/ molecule reactions in a simple form and a variety of reactions of organic anions will be covered.
2
Instrumental methods
F O U R I E R T R A N S F O R M I O N C Y C L O T R O N R E S O N A N C E (FT-ICR)
FT-ICR, first developed more than a decade ago (Comisarow and Marshall, 1974a,b), has become very popular in recent years for both analytical and ion/molecule reaction studies. In the literature this method is also frequently termed Fourier transform mass spectrometry (FTMS). The term FT-ICR, however, indicates the physical principles of the method more precisely and is less confusing; the mathematical operation of Fourier transformation can also be applied to some other forms of mass spectrometry such as time-offlight mass spectrometry as has been demonstrated recently (Knorr et al., 1986). The many applications of FT-ICR, showing its versatility, have been reviewed recently in a number of publications (Laude et al., 1986; Russell, 1986; Baykut and Eyler, 1986; Marshall, 1985; Nibbering, 1984, 1985a,b; Gross and Rempel, 1984; Wanczek, 1984; Johlman et al., 1983). The basic principles of FT-ICR can best be outlined on the basis of Fig. 1. This
3
GAS-PHASE REACTIONS OF ORGANIC ANIONS
diagram shows a commonly used cubic cell, which is located in a highvacuum chamber (pressure < IO-’Pa) between the poles of an electromagnet or in a superconducting magnet. Ions in this cell are generated from gas-phase sample molecules by an electron beam pulse or from solid samples by, for example, a laser pulse. The ions travel in circular paths perpendicular to the direction of the magnetic field, B, and are trapped in the cell by a potential of about - 1 V, in the case of anions, applied to its trapping plates.
receiver or plates
/
w plates
trapping
j LIC field
transmitter or excitation plates
FIG. 1 Schematic drawing of a cubic FT-ICR trapped-ion cell. The side of such cells is typically u i 2.5 cm long
The angular or cyclotron frequency o, of the ions, which have low, nearly thermal translational energies and random phases in their so-called cyclotron motion, is given to a first approximation by eqn ( l ) , where q is the charge, v the velocity, rn the mass of the ion and r the radius of its circular path o,= v / r = qB/m
(1)
For example, at a magnetic field strength of 1.2 T, the mass range m/z 10 to rnjz 1000 corresponds to a frequency band from about”1.8MHz (m/z 10) to 18 kHz (rn/z 1000) and the radius of a circular path of an Ar * ion with
thermal velocity is 0.01-0.02 cm. After a certain trapping time of the ions,
NlCO M. M. NIBBERING
4
which for example may vary from 0.05 to 5 s following ion generation, the ions are accelerated as packets coherently in phase to larger orbits by applying a radiofrequency (RF) excitation pulse to the transmitter plates of the cell and sweeping the frequency of the excitation voltage across the frequency range of the ions. A typical sweep rate to cover the mass range mentioned above would be 1-2 MHz ms- known as a frequency “chirp” (Marshall and Roe, 1980). Other recently reported methods to achieve broad-band frequency excitation for recording a relatively broad mass range are pseudo-random-noise (Marshall er al., 1984a), random-noise (Ijames and Wilkins, 1984) and tailored (Marshall, 1985; Marshall et al., 1985) excitation. The coherently in-phase accelerated packets of ions move up and down between the top and bottom or receiver plates of the cell, generating image currents in the circuit connecting these plates. These image currents will decay with time as the coherent motion of the ions is destroyed by ion/ molecule collisions. The analogue signal induced in the receiver plates is thus a transient that is converted, after amplification, into a digital signal and stored in the memory of a digital computer. Ions are then removed from the cell with a quench pulse by inverting the polarity of the potential applied to one of the trapping plates. The pulse sequence, shown schematically in Fig. 2, is then repeated for a chosen number of times to improve the signal-tonoise (S/N) ratio. Finally, the summed transient and digitized time-domain signal is subjected to Fourier transformation to generate an ICR frequencydomain spectrum, which subsequently can be converted into a FT-ICR mass spectrum.
’,
cy EFl NFN
A
H
M
-
PULSEIS)
- - -- -- - -
Trapping time
____---
-
E
FIG.2 Typical sequence of pulses in a FT-ICR trapped-ion cell. During the trapping-time period, mass-selected ions or electrons may be ejected from the cell.
During the trapping time as defined in Fig. 2, ion/molecule reactions can take place where the ions have nearly thermal velocities and the molecules thermal velocities. Unwanted ions can be removed from the cell during this time by application to the transmitter plates of the cell of a series of ionejection pulses (see Fig. 2), which are appropriate to increase the radii of the ion orbits so much that the ions strike the walls of the cell, are discharged and pumped away. Other methods of removing unwanted ions frGm the cell
GAS-PHASE REACTIONS OF ORGANIC ANIONS
5
are by so-called notch ejection (Noest and Kort, 1983; Kleingeld and Nibbering, 1983a; Marshall et al., 1984b) or windowed tailored excitation (Marshall et al., 1985). With the former method all ions are ejected from the cell with the exception of ions of one specific mass-to-charge ratio by shifting the phase of the frequency-scanning ejection pulse of sufficient amplitude by 180" at the resonance frequency of the ion to be kept in the cell. This leaves the ion of interest overall unperturbed in the cell and is a powerful tool for ion/molecule reaction studies as described in this review. Another important feature of FT-ICR is, that it permits the progress of ion/molecule reactions to be studied as a function of the trapping time, so that a picture can be obtained of the evolution with time of the chemistry involved. FIXED INLETS
t
FIG. 3 Schematic drawing of a typical flowing afterglow ( F A ) instrument
FLOWING AFTERGLOW (FA)
A schematic drawing of the instrument used in FA, first developed in the 1960s (Ferguson ef d., 1969; Ferguson, 1970) is given in Fig. 3. A carrier gas, usually helium, is passed continuously through the central part of the instrument which is a stainless steel flow tube (0.08 m internal diameter, 1-2m long). The pressure in the flow tube is about 70Pa and the flow velocity 100 m s - ' . Positive or negative ions can be formed upstream by electron impact on added gases. The ions formed will be thermalized through multiple collisions with the carrier gas before reaction takes place with a substrate added downstream through a fixed or movable inlet. The ion population is sampled through a small orifice and mass analysed with a quadrupole mass spectrometer. The kinetics of the ion/molecule reactions can be measured by changing the point of substrate addition or the substrate concentration. This can show how the chemistry evolves with time in a similar way to variation of the
6
NlCO M. M NIBBERING
trapping time in FT-ICR (see above) although it should be stressed that FA and FT-ICR operate in very different pressure regimes. An important development for ion/molecule reaction studies by FA is the extension of the method using so-called selected ion flow tube (SIFT) facilities (Adams and Smith, 1976). In the latter configuration ions are generated in an external ion source, extracted and separated by a quadrupole mass filter, after which ionic species of a single mass-to-charge ratio are injected into the flow tube. This set-up permits the ion/molecule reactions of mass selected ions to be studied in the absence of ions of other masses (similar to studies of mass selected ions in FT-ICR after application of socalled ion ejection techniques; see above) and neutral precursors, while a wide choice of neutral substrates is possible. 3 Formation of anions
Gas phase anions may be generated by electron impact via one of the following three processes: (i) Resonance capture of low energy electrons (0-10 eV), provided that the molecules have positive electron affinities which correspond to the negative value of the enthalpy change for reaction: (2). This may become a particularly important process at high pressures, i.e. in the presence of a third body which can carry off the excess energy of AB'. Some examples of stable molecular anions are those of nitrobenzene, maleic anhydride, tetracyanoethylene and p-benzoquinone (Janousek and Brauman, 1979). AB
+ e - -AB'
(2)
(ii) Dissociative resonance capture of low energy electrons (0-1 5 eV) as in (3). AB
+ e--A-
+ B'
(3)
Examples are the formation of OH- (via H-) from H,O (6eV), 0' from N,O (1.5 eV), NH; from NH, (5 eV), F- from CF, (6 eV) and NF, (1.75 eV) and RO- from R O N 0 ( < 0.5 eV). (iii) Simultaneous formation of a pair of ions (4), which occurs over a wide range of electron energies above 10 eV. AB
+ e--A-
+ B+ + e-
(4)
Most organic compounds do not have a sufficiently high ionization crosssection for a workable yield of anions to be obtained. Most organic anions are therefore generated via ion/molecule reactions of organic molecules with
GAS-PHASE REACTIONS OF ORGANIC ANIONS
7
the limited number of reactive ions mentioned under (ii). I t is a fortunate situation that in the list of these reactive ions NH, and OH- (the latter can also be generated in the absence of water through hydrogen atom abstraction from methane or cyclohexane by 0') belong to the strongest class of gas-phase bases, so that they are capable of generating anions from many organic molecules by simple proton abstraction. The gas-phase acidities, defined as the enthalpy change for reaction ( 5 ) , of AH--.+
(5)
+A-
some common organic compounds are listed in Table 1 (taken from Bartmess and McIver, 1979). Note that, in the gas phase, molecules such as propene and toluene are more acidic than water and that benzene is more acidic than ammonia. This is quite different from the acidities of such molecules in solution where the order from most to least acidic is, for example, water > ammonia > toluene > benzene. Obviously, solvent effects obscure the intrinsic acidities of molecules as obtained from gas-phase measurements (for a further discussion, see Lowry and Richardson, 1987). TABLE 1
Gas phase acidity values in kJ rno1-l for the reaction RH selected molecules at 298 K
CH4 NH3 H2 H2O CH2=CHCH, CH,OH C,HSCH, 4
I743 1689 I675 1635 1635 I587 I586
C,H,OH n-C3H,0H t-C4H,0H CH3CN (CH3)2C0 CJSOH CfJSSH
-+
R-
+ H + of some
I574 1568 I562 1557 1543 1470 1389
Some basic aspects of gas-phase ion/molecule reactions
Reactions between ions and molecules occurring under the experimental conditions in a FT-ICR or FA instrument should be exothermic or thermoneutral. In both types of instrument the concentration of ions is approximately lo4 times lower than the concentration of molecules. A simple pseudo-first order kinetic law is therefore observed for the ion/molecule reactions, and these proceed much faster in the gas phase than in solution. This is well demonstrated by the corresponding rate constants measured for the reaction between methyl bromide and the hydroxide ion as a function of the number of water molecules added to the OH- ion and summarized in Table 2 (Bohme and Mackay, 1981). Note that the reaction in the gas phase is actually quenched by the addition of only three water molecules to OH-
a
NlCO M M. NIBBERING
TABLE 2 Room-temperature rate constants in units of cm3 mol- Is- I , measured for nucleophilic displacement reactions between hydrated hydroxide ions and methyl bromide for various degrees of hydration Hydroxide ion
Rate constant
OHOH-.H,O OH - . ( H 2 0 ) 2 OH .(H OH .(H,O),
(1.0 -t 0.2) 10-9 (6.3 2.5) x lo-’’ (2 f 1) x 1 0 - 1 2 <2 x 10-13 2.3 x
(for a detailed analysis of reaction intermediates and products see Henchman et al., 1986; Hierl et al., 1986; Henchman et al., 1983) and that the rate constant for the reaction in solution differs by sixteen orders of magnitude from that for the reaction in the gas phase, if the hydroxide ion is not solvated at all. This might suggest that every collision between methyl bromide and the hydroxide ion in the gas phase leads to reaction. Theoretically the collision or capture rate constant can be calculated by means of (6), which is the result of the Average Dipole Orientation (ADO) theory (Su and Bowers, 1979). This is the reason why the rate constant in (6) is marked as kADo. In this equation the parameters are q, the charge of the ion, a, the molecular polarizability of the molecule, p, the reduced mass of the ion/ molecule complex, pD, the permanent dipole of the molecule, C, the so-called dipole locking constant which may have a value between 0 and I ; k is Boltzmann’s constant and T the absolute temperature.
Studies of proton transfers involving small ions with localized charge have shown that these reactions may proceed indeed with rate constants close to or even slightly larger than the collision rate constants predicted by the ADO theory (Mackay et d.,1976). However, rate-constant measurements of proton-transfer reactions between delocalized anions (Farneth and Brauman, 1976) and sterically hindered pyridine bases (Jasinski and Brauman, 1980) and of S,2 displacement reactions (Olmstead and Brauman, 1977; Pellerite and Brauman, 1980; Pellerite and Brauman, 1983; Caldwell et al., 1984; for a review see Riveros e f al., 1985) have shown that the rate constants can span the range from almost collision controlled values down to ones too slow to be observed. For these reactions the wide variation in rate constants has been explained on the basis of a double potential-well model which for a hypothetical S,2 substitution is schematically shown in Fig. 4.
9
GAS-PHASE REACTIONS OF ORGANIC ANIONS
I
0
REACTION
FIG.4
COORDINATE
Potential cnergy surface for a gas phase S,2 substitution
In this model first the “loose” ion/molecule complex [Y-.RX] is formed, which is believed to correspond to a minimum in potential energy and to be relatively long lived. The binding energy Ed (Fig. 4) of such a complex may be as large as 100 kJ mol-l (Kebarle, 1977) and to a large extent can be accounted for by electrostatic interactions, that is, long range ion-induced dipole and ion-dipole interactions between the species. These electrostatic interactionsran be estimated by the use of (7), where E(r) is the drop in
potential energy upon approach of the ion and molecule from infinity to a distance r and the other symbols represent quantities which have been defined before. The potential energy drop E(r) will correspond to an energy gain of the complex [Y-.RX], which under the low pressure conditions used in FT-ICR will not be carried off because of the absence of third-body collisions. The complex [Y-.RX] therefore contains excess energy, mainly in the form of internal (rotational and vibrational) energy, and will not be stabilized, although radiative stabilization cannot always be excluded. At the higher pressures used in the FA method ( < 70 Pa) and In high pressure mass spectrometry (Kebarle, 1977) ( < 700 Pa), however, third body collisions may occur and lead to stabilization and direct observation of the complexes [Y-.RX].
10
NlCO M M NIBBERING
For the reaction to occur the complex [Y-.RX] must adopt the configuration of the activated complex which, in potential energy terms, corresponds to the maximum of the central barrier with height E t in Fig. 4. Passing over this central barrier will lead to the “loose” ion/molecule complex [X-.YR], which in turn corresponds to the potential minimum on the products side and will eventually separate. The height of the central barrier should not be higher than the energies of the species Y - and RX at infinite separation, otherwise the ion/molecule reaction, which must be overall thermoneutral or exothermic to occur, cannot proceed. Moreover, the height of this barrier will depend on the type of ion/molecule reaction and on the nature of the reactant ion, product ion and neutral species involved. It is just the variation of the height of the central barrier which is responsible for the wide variation in rate constants referred to above. This can be understood when it is realized that the number of energy states or density of states for simple dissociation of the complex [Y-.RX] at most energies will be higher than the density of states in the activated complex situation as schematically indicated by the corresponding level spacings in Fig. 4. The central barrier, although lower in energy than the reactants at infinite separation, constitutes therefore also a so-called entropy bottle-neck for the reaction (Dodd et al., 1984; Magnera and Kebarle, 1984). At this point it seems appropriate to mention briefly the essential differences between ion/molecule reactions in the gas phase and corresponding reactions in solution. As indicated by the horizontal, broken line in Fig. 4, that is at a constant total energy of the system, an ion/molecule complex in the gas phase goes from the reactants to the products side by crossing local, but lower lying, energy barriers. The ion-dipole and ion-induced dipole interaction energy gained upon the initial formation of the ion/molecule complex serves as the fuel of the reaction. Increasing the energy of the system will not result in a larger, but smaller overall rate constant for the reaction as the density of states of the initially formed ‘‘loose’’ ion/molecule complex increases more rapidly with energy than the density of states belonging to the activated complex at the local energy barrier. This is known as the negative temperature dependence of gas-phase exothermic ion/ molecule reactions and has been observed for several reactions (Meot-Ner, 1979; Caldwell et al., 1984; Magnera and Kebarle, 1984). In solution, however, where the excess energy due to ion-(induced) dipole interactions is carried off to the solvent molecules, only the central barrier of Fig. 4 remains. In that case the ion/molecule complex must acquire energy or become activated by increasing the temperature or by collisions with the surrounding molecules to come over the local energy barrier EZ. Nevertheless, ion/molecule reactions in the gas phase and solution both respond in the same way to an increasing height of this local energy barrier, that is, in
GAS-PHASE REACTIONS OF ORGANIC ANIONS
11
both cases the overall rate constants for reaction then become smaller. The overall rate constant kobsfor the reaction sequence in Fig. 4 is given by (8) when the system is treated according to the steady state assumption.
Here k , is the collision rate constant which for cases involving polar molecules can be estimated quite well by use of (6). The ratio between kobs and k , is termed the reaction efficiency, which gives an estimate of the number of collisions resulting in product formation. For an exothermic reaction it can be assumed that k - , << k,; kobswill then be given by (9), which leads to eqn (10) for the reaction efficiency. The efficiency of the
kobs
Reaction efficiency = -- = k, k-,
k2
+ k2
overall reaction given in Fig. 4 will be determined therefore by the competition between dissociation of the ‘‘loose’’ [Y-. RX] complex into separated reactants and crossing of the central energy barrier. This competition in its turn will be determined by the density of states for simple dissociation of the complex [Y-.RX] and the density of states in the activated complex situation mentioned above. Finally, it should be recognized that the double well potential model is simple and qualitative, although it can explain the results obtained for several gas-phase ion/molecule reactions. However, there are also many examples of ion/molecule reactions which proceed through a multistep mechanism as will be shown further on in this review. Of course, the corresponding potential energy surface is in that case much more complicated than the one in Fig. 4. At any rate, for a clear presentation of the many reactions of organic anions studied over the last decade, the discussion below will be focused both on several types of reactions and on various classes of anions. ,
5
Hydrogen/deuterium exchange reactions
Many organic anions have been found to undergo hydrogen/deuterium exchange in the presence of deuterated reagents, such as D.0 and CH,OD. Such exchange reactions have proved to be a valuable method of probing mechanisms of ion/molecule reactions and structures of ions in the gas phase.
12
NlCO M M. NIBBERING
The general mechanism of the hydrogen/deuterium exchange process can be explained on the basis of the potential energy-reaction coordinate diagram shown in Fig. 4 with the modification that the forward reaction is endothermic (Stewart el al., 1977; DePuy et al., 1978a, Squires et a/., 1981). In that case an organic anion R,CH-, formed by proton abstraction from R,CH,, can undergo hydrogen/deuterium exchange in the presence of D 2 0 , for example, via the sequence of steps given in (1 l).' R,CH-
+ D,O
[R,CH-.D,O]*
111 [R,CD-.HDO]*
[R,CHD.OD-I* 121
e
(1 1)
eR,CD- + HDO
[31
First the complex [l] is formed which has gained ion-dipole and ion-induced dipole energy upon approach of the reactants. This energy remains within the complex during reaction and can be used to convert complex [l] into complex [2] by deuteron transfer, provided that the energy of the transition state leading to [2] is less than the total energy of the reactants, given by the broken line in Fig. 4. Proton abstraction from the R,CHD molecule, which cannot escape from complex [2] because of the endothermicity mentioned above (the chance that the R,CHD molecule would become ionized again, if it were to escape from the complex, is exceedingly small because of the ratio [neutral molecules]/[ions] being > lo4; see above) leads then to complex [3]. The exchanged ion R,CD- can either escape from this complex as shown in (1 1 ) or undergo further exchange with the HDO molecule in the complex (Squires et al., 1981, 1983). Subsequent collisions of R,CD- with other D 2 0 molecules eventually may result in the replacement of all exchangeable hydrogen atoms by deuterium. It will thus be clear that, for the occurrence of hydrogen/deuterium exchange, the charge-carrying site in the ion must contain one or more hydrogen atoms. Moreover, the acidity difference between the conjugate acid of the ion and the exchange reagent should not be too large; otherwise the ion-(induced) dipole energy within the complex which can be as much as 80 kJ mol- cannot drive the endothermic deuteron transfer from the exchange reagent to the ion. For example, allylic anions as obtained by proton abstraction from 1-pentene exchange with D,O (Stewart et al., 1977), but enolate anions as obtained by proton abstraction from the more acidic 2- and 3-pentanones do not (DePuy et al., 1978a). These enolate anions, however, exchange with the more acidic exchange reagent CH,OD. Yet another important factor for hydrogen/deuterium exchange has been identified, which is the ion-(induced) dipole energy of the ion/molecule complex formed after the endothermic proton transfer (Grabowski et al., In ( 1 1 ) and throughout this chapter, an asterisk denotes excess energy in the species in question (see Section 4).
GAS-PHASE REACTIONS OF ORGANIC ANIONS
13
1983). This is demonstrated by the observation that the ion N-C-CH; exchanges fairly readily with D,O, while the ion HC-Cwhich is 12 kJ mol-' more basic does not exchange with D,O. In the former case deuterium transfer leads to DO-, solvated by CH,DCN. Acetonitrile has a large dipole moment and is highly polarizable, so that the ion-(induced) dipole energy may in fact be larger after deuterium transfer than before and could well compensate for part of the 79kJmol-' loss from basicity differences (Bartmess and McIver, 1979). Deuterium transfer from D,O to HC-Cis only 63 kJ mol-' endothermic, but transfer leads to DO-, solvated by HC-CD. Acetylene with no dipole moment and a low polarizability is, however, expected to form an ion/molecule complex with ODwhich contains less ion-(induced) dipole energy than before deuterium transfer. The loss of this energy will augment the loss in energy due to deuterium transfer so that no hydrogen/deuterium exchange is observed (Grabowski et al., 1983; DePuy, 1984). In addition to the fact that hydrogen/deuterium exchange reactions can be helpful to probe ion structures as will be shown later, they can also reveal mechanistic details such as the site of reaction within ions. For example, the pentadienyl anion exchanges four protons rapidly, demonstrating, as shown in (12). that proton addition occurs more rapidly at the ends of the conjugated system than in the middle (Stewart rt ul., 1977; DePuy rt al., 1978a). H,C=CH-~H-CH=CH
---
, ROD
D,C=CH--CH-CH=CD,
( I 2)
Another interesting example is the exchange of (M - H)- ions of methyl phenyl ether, generated by a ring proton abstraction with hydroxide ions in an exothermic reaction, with D,O (Kleingeld and Nibbering, 1983a). In this case not only the ring hydrogen atoms, but also the methyl hydrogen atoms are exchanged for deuterium. The latter hydrogen atoms are not abstracted directly as proton by O H - , because, as shown by D-labelling, even the stronger base NH; is not capable of inducing this reaction. However, the (M - H ) - ions generated from C,H,OCD, with NH, eliminate CD,O and CHDO in a 1 : 1 ratio. This can easily be explained by an equilibrated exchange between the methyl deuterium atoms and one hydrogen atom, most probably from the ortho-position. in the (M - H)- ions prior to the loss of formaldehyde as visualized in ( 1 3). This implies the occurrence of a gas-phase primary carbanion which must have a lifetime sufficiently long to account for the equilibrated methyllortho hydrogen atom exchange. Thus, the ring hydrogen atoms of the (M-H)- ions of methyl phenyl ether exchange in an intermolecular process with D,O, bhereas the methyl hydrogen atoms do so in an intramolecular process. Similar observations have been made for the (M - H ) - ions of 2-fluorophenyl and 4-fluorophenyl methyl ether in the presence of D,O (Ingemann and Nibbering, 1983).
14
M. NIBBERING
NlCO M
+
C,H,DCD,O mi= 78
C,H,D;
+ CHDO
mjr 79
A dramatic change is observed if the oxygen atom in methyl phenyl ether is replaced by sulphur. It then appears possible to abstract a proton from the methyl group not only with the strong gas-phase base NH;, but even with the much weaker gas-phase base CH,O- as shown by D-labelling (Ingemann and Nibbering, 1984a). Such increased acidity has been ascribed to a more effective interaction between the carbanionic lone pair and the antibonding o* orbital of the S-R bond compared with the 0-R bond, but not to d-orbital effects (Schleyer et al., 1984). From hydrogen/deuterium exchange experiments the relative gas-phase acidities of the different hydrogen atoms in methyl phenyl thioether have been determined to be methyl > ortho >meta, para (Ingemann and Nibbering, 1984a). Based upon D-labelling it has been found that NH; abstracts a proton from benzaldehyde where all positions are involved in statistical proportion (Kleingeld and Nibbering, 1984a). This shows that all hydrogen atoms of benzaldehyde are nearly equally acidic, which is further supported by the observation that the conjugate base of benzaldehyde exchanges all its hydrogen atoms for deuterium atoms in the presence of D,O. 6 Addition-elimination reactions
Addition4mination reactions, where chemical bonds between the reactant ions and substrate molecules are first formed leading to adducts which subsequently break up into products by elimination of neutral species, are an important class of reactions in organic chemistry. In the gas phase such reactions have received considerable research interest. They include reac-
15
GAS-PHASE REACTIONS OF ORGANIC ANIONS
tions at carbonyl-, nitrite-, silicon- and phosphorus centres, and these will be exemplified below. CARBONYL CENTRES
Attack of nucleophiles upon carbonyl centres may lead to species which have a tetrahedral structure [4] as given in (14). According to theory, the tetrahedral structure [4] can correspond to either a potential minimum or a potential maximum depending 2n the energy difference between the n*c=o and o*,-,MO's (Yamabe and Minato, 1983; Yamabe et al., 1984). For X = OR'; NR'R2 this energy difference is calculated to be so large that the corresponding o*cpxlevel is at such a high energy that no K*-* mixing occurs. In that case [4] would correspond to a potential minimum, that is a tetrahedral intermediate. For X = CI, however, the n*c=o and o*c-c, MO's would mix significantly with the result that structure [4] then becomes a transition state. 0
Nuc-
I1
+ R-C-X
-
[
0-
I
R-C-X N?c
[41
*
1
-
products
(14)
This analysis is supported by experimental observations in the gas phase. For example, CH,COCI; made by reaction of CI,' or COCl- with acetyl chloride has been found to transfer either of the chlorines with equal probability as CI- to CF,COCI, so that they at least have passed through a tetrahedral structure. However, the electron affinity of the CH,COCI, ions is very close to that of the C1- ions and much higher than the usual values of alkoxy anions which points to the loose complex CI-. CH,COCI rather than to the tetrahedral structure CH,COCI';' for the adduct of CI- and acetyl chloride (Brauman, 1979; Asubiojo and Brauman, 1979). An example of the existence of a tetrahedral intermediate is provided by the adduct of the monodeuterated acetate anion and a,a'-D, acetic anhydride. This adduct eliminates both CH,CO and CHDCO with a kinetic isotope effect varying from 1.2 to 2.4 depending on the lifetime of the adduct. These eliminations involve a I ,5-H and 1 3 - D shift, respectively, as indicated in structures [5] and [6], which therefore must have a certain lifetime and must correspond to a tetrahedral intermediate (Wilson and Bowie, 1975). This conclusion has been supported by ah initio calculations (Sheldon and Bowie, 1982).
..
16
NlCO M . M. NIBBERING
H
H
151
[61
The considerations given above imply that reactions of nucleophiles with carbonyl centres may be described on the basis of either a double potential well model as advanced for S,2 substitution reactions (cf. Fig. 4) or a triple potential well model depending on whether the tetrahedral structure corre-
proton dha
d c u ~ c i i > n.Ih\
11-CI I inI11.1I 1011
NH,
+ DCO,CH,
nil: 16
BAC
2
B A 2
S,?
-
[M - HIw / : 60
+ NH,
[M-D]t ? l / I 50
+ NH,D
CH,O-
+ CO + N H 2 D
ml: 31 CH,OIN/= 3I
AH,
=
-64 kJ inol-'
+ DCONH, A H : = -03 kJ m o l - '
DCONH-
+ CH,OH
mi: 45
DCO,
+ CH,NH,
In the literature many examples of attacks of nucleophiles upon carbonyl centres can be found and they have been covered adequately in a recent review (Bowie, 1984b). These attacks are rarely observed, however, without competition from other reaction channels. This is well demonstrated by the reactions of N H j with methyl formate deuterated in the formyl position, where at least five different primary product ions are formed as summarized in eqns ( 1 5a)-( 150. Some of these product ions are consumed by reaction with the NH, and DCO,CH, molecules present as can be seen from Fig. 5. This shows how the chemistry evolves as a function of reaction time in the FT-ICR instrument, and the results are in excellent agreement with the observations made for the same system in a FA apparatus (DePuy et al.,
GAS-PHASE REACTIONS OF ORGANIC ANIONS
-1. 'product ion rlproducl
loo
ions
50.
40.
P( NHJ)
I
17
*
cn,o-
0
DCONH-
A
OCOi
A
CHJO- NH3
o
[M-DJ[M-HI-
6 lo-* Pa
V 50
FIG. 5 Normalized ahundances of the principal product ions in the NH;/NH,/ DC0,CH3 system followed as a function of reaction time
1985a). For example, by ion-ejection experiments in the FT-ICR study, the two major secondary ions CH,O:DOCH, and CH,O:NH, have been found to arise through reactions (16) to (19). 0 CH3Om/z 31
/I + D-C-OCH, 0
CH,O'NH, mjz 48
II
+ D-C-OCH, 0
[M - D]mjz 59
II + D-C-OCH,
[M-DImjz 59
-
CH3OTDOCH3 mjz 64
-
CH,OyDOCH, mjz 64
+ NH, + CO
-
CH3OTDOCH3 mi; 64
+ NH3-CH,0TNH3 mjz 48
+ CO
+ CO
+ 2CO
(16)
(17)
(18)
(19)
18
NlCO M. M NIBBERING
Another example, which sbows an effective competition channel in the nucleophilic attack upon a carbonyl centre concerns the reactions of O H and 0- with methyl formate. Using 180-labelled reactant ions, a significant contribution of the S,2 mechanism (-20% for O H - and -40% for 0;) in addition to the pathway via a tetrahedral structure has been found for formation of the formate anion as summarized in (20) and (21) (Dawson and Nibbering, 197th; Johlman and Wilkins, 1985; van der We1 and Nibbering, 1986). Similar observations have been made for other methyl esters, such as those of trifluoroacetic and benzoic acid (Takashima and Riveros, 1978).
+
c!?
1 8 0 H - ( L 8 0 - . ) H-C-OCH,
u
[ u 1'
-
H--C-OCH, I
' 0H( 0')
HC0180-
+
P
1 8 0 H - ) L 8 0 - . ) CH,-OOCH
u
S,2
HCOO-
+ CH,OH(CH,O')
+ CH,180H(CH,L80')
(21)
NITRITE ESTERS
Another type of centre, which is susceptible to attack by nucleophiles in terms of addition-elimination, is the nitrite group. This has been shown in studies of various aliphatic nitrites (Noest and Nibbering, 1980a,b; Klass et al., 1981; King et al., 1981). However, depending on the nature of the alkyl group, S,2 substitution and E2 elimination. appear to compete effectively with the attack of the nucleophile upon the nitrogen atom of the nitrite group. An example is the reaction between CH,180- and methyl nitrite, where both Nl60; and N l 6 0 l 8 O - a re generated in a ratio of 83 : 17 as summarized in (2221) and (22b). Assuming a negligible l 8 0 / l 6 Oisotope effect on the branching ratio of the elimination step, the addition-elimination pathway accounts for 34% of the total rate constant for NO; formation. The elimination of dimethyl ether (unlabelled and 180-labelled) from the tetrahedral type intermediates most probably occurs following their break-up to give both CH, 8 0 - / C H 3 1 6 0 N 0 and CH, 6 0 - / C H 3"ON0 complexes which then each undergo an S,2 reaction without separation. The addition-elimination pathway can become very significant if the S,2 substitution and E2 elimination are largely suppressed, such as in the reaction of "0' with neo-C,HllONO. In that case the product ions N l 6 0 l 8 O - and Nl60> have been found to be formed in the ratio 20: 1
GAS-PHASE REACTIONS OF ORGANIC ANIONS
CH3180- + CH3ONO
/
SJ -(CH,),,"-
addition
[
19
p;
- (CH,),'
CH,180 cH3160~-O-]*\
[CH,"O-.
[83 f 4%]
N160;
(22a)
*O
CH,ONO]*
[I7
4%]
(Noest and Nibbering, 1980a). Moreover, the addition-elimination mechanism is particularly operative when the nucleophile is of a delocalized, soft type such as enolate, alkenyl and ketimide anions. An interesting example is provided by the enolate anions derived from 1,1,1 -trideuteroacetone (23a), where the (M -H)- ions react with n-butyl nitrite almost exclusively with expulsion of n-C,H,OH (23b) and the (M - D)- ions with expulsion of n-C,H,OD (23c) (Noest and Nibbering, 1980b). This type of attack, therefore, can also be exploited to establish the retention of positional integrity of deuterium atoms in labelled anions, such as in C,H,CD;. These anions have been shown to react with methyl nitrite by elimination exclusively of CH,OD from the collision complex, as summarized in (24) (Bowie, 1984b). (M-H)n-C,H,O-
CD,
C6H,CD; mlz 93
(M - D)-
kH k,
+ CH,ONO-C,H,CD=NOnijz 121
=
1.72
0.05
+ CH,OD
(234
(24)
20
NlCO M. M. NIBBERING
The reactions of the nitrites described have also been observed under FA conditions at much higher pressures. The increased pressure might explain the occurrence of an additional pathway observed in the reaction between enolate anions and nitrites and exemplified in (25b) (King et al., 1981). Path (b) has also been reported to occur in the reaction between the enolate anion of diisopropyl ketone and methyl nitrite in an ICR instrument operating at the relatively high pressure of lo-, Pa (Klass and Bowie, 1980). 0
+ /
(CH,),CCH,O-N=O
SILICON A N D PHOSPHORUS CENTRES
Another centre which can be attacked by nucleophiles to react vio an addition4imination pathway is silicon. This has been the subject of several studies in the last few years, and reactions between various anions and substituted silanes have been investigated in detail. It has been shown, for example, that under FA conditions the nucleophiles F - and CH,O- react with tetramethylsilane to give the (CH,),SiFand (CH,),SiOCH; adduct ions, while NH; and OH- yield (CH,),SiNHand (CH,),SiOby expulsion of methane from the corresponding collision complexes (DePuy et a/., 1980). In these reactions pentacoordinate silicon anions are probably the intermediates. Supporting arguments for such intermediates have been obtained from rate measurements (Damrauer et al., 1982), ab initio calculations (Sheldon et a/., 1984a) and chemical reactivity studies (DePuy and Damrauer, 1984). For example, the rate measurements have shown that trimethylchlorosilane reacts at virtually every collision for exothermic reactions or not at all for endothermic ones, whereas methyl iodide shows a gradual reduction in rate as the attacking nucleophile becomes less basic. In the chemical reactivity studies it has been found that pentacoordinate silicon anions can be distinguished from other isomeric anionic structures of silicon by ion/molecule reactions with N,O. In particular, pentacoordinate silicon anions do not react with N,O, silyl
21
GAS-PHASE REACTIONS OF ORGANIC ANIONS
anions themselves react with N,O to form siloxides by oxygen atom transfer, while silicon-stabilized carbanions also react to form siloxides, but with loss of carbon. Some specific examples are illustrated in (26), (27) and (28) (DePuy and Damrauer, 1984). The nucleophilic displacement reactions of silanes and substituted silanes in the gas phase have been reviewed recently (DePuy et al., 1987).
(CH,),Si-
+ N,O
F
I
CH,CH,CH,-Si-CH;
I
+ N,O
-
(CH,),SiO-
+ N,
(27)
F
I I
CH,CH,CH,-Si-W
CH,
+ CH,N,
(28)
CH,
The results of studies concerning reactions between nucleophiles and trimethyl phosphate and trimethyl phosphite should be mentioned briefly. In both esters the nucleophiles may attack the phosphorus centre to react in this way via pentacoordinate and tetrahedral type species, respectively, to products. Various nucleophiles, such as F-, CD,O-, DNO-, O H - and NH; have been allowed to react with trimethyl phosphate, but only OHand NH; have been found to attack the phosphorus centre to a minor extent. The most prominent process is nucleophilic attack on one of the carbon atoms to generate by an S,2 reaction the phosphate diester anion as Nuc-
+ NucCH,
+ OP(OCH,), -O,P(OCH,);
(29)
shown in (29) (Hodges et al., 1980). This is in sharp contrast with trimethyl phosphite, where a variety of nucleophiles has been observed to react predominantly, if not exclusively, by attack on the phosphorus centre. This attack leads to displacement of methoxide, which then reacts further with the newly generated molecule within the ion/molecule complex either by proton abstraction or by an S,2 mechanism depending on the nature of the original nucleophile (Anderson et al., 1984). An example is provided by the reaction of H " 0 - with trimethyl phosphite, where the "0 label is fully retained in the product ion as illustrated in (30). Hl80-
+ (CH,O),P
-
-
[H180-.P(OCH,),]
[H'*OP(OCH,),.CH,O-]
-
-[
-
OCH, H'sO-P-OCH,
(CH,0),P'80-
kCH,
+ CH,OH
] (30)
22
NlCO M. M. NIBBERING
Based upon observations made for the CD,O-/(CH,O),P system, the tetracoordinate phosphorus anion would be an intermediate rather than a transition state. Finally, it must be noted that an attack on one of the carbon atoms of trimethyl phosphite via an SN2 mechanism can only become competitive with the nucleophilic attack on the phosphorus centre, if displacement of methoxide by the latter is sufficiently endothermic (Anderson et al., 1984). 7 Elimination reactions
Elimination reactions are facile processes as far as they have been studied in the gas phase. It is, however, often difficult to distinguish them from SN2 substitution reactions since both reactions mostly lead to the same product ions, but not to the same neutral products which in most experiments are not known (Smith et al., 1980; Jones et al., 1985). In that respect the reactions of cyclic compounds, such as cyclic ethers, are good probes for the study of elimination reactions because the “leaving group” remains with the anion. For example, ‘the reaction of N H j with tetrahydrofuran leads to (M - H)ions. Deuterium labelling has shown that the proton is abstracted exclusively from the b-position (DePuy and Bierbaum, 1981b; DePuy et al., 1982b). NH;
+
a’o -
CH,=CH-CH,-CH,-O-
+ NH,
(31)
This points to the elimination process shown in (31). In some of the cyclic ethers the product ions may be formed with excess internal energy because of the strain relieved upon ring opening. An example is seen in the reaction of NH; with 2-methyloxetane. Although the initial product ion is the same as in the reaction of NH; with tetrahydrofuran, it has enough energy because of loss of ring strain to allow further fragmentation (DePuy et al., 1982b).
C,H;
+ CH,O
Interesting examples of elimination reactions have also been seen in the reactions of cyclic sulphides (Bartmess et al., 1981). 1,3-Dithiolane, for example, reacts with several bases in two ways as has been confirmed by
GAS-PHASE REACTIONS OF ORGANIC ANIONS
23
deuterium labelling and is shown in (33) and (34). For 2,2-dimethylthioxolane there are also two possible elimination pathways (35) and (36). However, no CH,CHO- ions are observed, so that it can be concluded that elimination proceeds by abstraction of the proton adjacent to sulphur. This results in the more stable product ion CH,CHS-, although the intermediate ion in (36) is less stable than that in (35). This might point to a concerted mechanism in which no such intermediate ion is formed, but it might also be that the higher acidity of the proton adjacent to sulphur compared to that adjacent to oxygen is the direction-controlling factor.
n -HCS;
n
yS
+ CH,=CH,
S
S
vs .S
7 -7s-
+CH,=S
vs
[ 02-j + A [-02 ] 7+A /=
0-
n O X S
S-
The direction of elimination has also been investigated by using mixed ethers (DePuy and Bierbaum, 1981b). It has been shown that N H ; preferentially abstracts a proton from the larger of the two alkyl groups, forming the smaller alkoxide ion. The most dramatic example is given in the reaction of NH; with ethyl t-butyl ether which yields almost exclusively C 2 H , 0 - and C,H,O-.NH,. This has been interpreted by means of an ElcB type mechanism in which the breaking of the carbon-hydrogen bond is most important; thus the stability of the intermediate carbanion plays a decisive role. Proton abstraction from the ethyl group would lead to ion [7], which will be less stable than ion [8] generated by proton abstraction from the tbutyl group. This order of stability is indeed in line with the gas-phase acidities of alkanes as predicted from the reactions of alkyl substituted trimethylsilanes with hydroxide ion (DePuy et al., 1984). The direction of elimination in the reaction of OH- with mixed ethers is less pronounced,
24
M. M
NlCO
NIBBERING
probably because the results are obscured by the high amount of hydrated alkoxide ions formed (DePuy and Bierbaum, 1981b). 7H3
H,N-. . . & + H. . . 6
-
~
~
,
~
~
,
~
~
C,H~O-C-CH~&( ~ ~ , ) 3
I
...
& + H. . .-NH,
CH,
PI
171
Also in the case of diethyl ether abundant water-solvated ethoxide ions in addition to free ethoxide ions are generated in the reaction with OH- (van Doorn and Jennings, 1981; DePuy and Bierbaum, I981b). These channels, generally represented by (37a) and (37b), have been studied recently in detail by FT-ICR with the aid of specific deuterium labelling (de Koning and Nibbering, 1987). Table 3 summarizes the measured overall kinetic isotope effects associated with the reactions (37a) and (37b) between not only O H - , but also RNH- (R = H, CH,, C,H,) and diethyl ether. From the data in Table 3 , which agree very well with those measured for the NH; and OH-/ diethyl ether systems by FA (Bierbaum et al., 1985), the overall kH/kD(Hp), the kH/kD(sec. H,) and k(OCH,CH,)/k(OCD,CD,) values for the reactions with either NHT or OH- can be calculated as listed in Table 4. The overall kH/kD(Hp) value corresponds to the product of kH/kD(prim. HP) x kH/kD (sec. Ha) where kH/kD(prim. HP) refers to the rates of p-H versus p-D abstraction and kH/kD(sec. HP)is the ratio of reaction rates upon substitution of the two remaining p-H’s by D. Similarly, kH/kD(sec. H,) corresponds to the ratio of reaction rates if both a-H’s are substituted by D, while k(OCH,CH,)/k(OCD,CD,) reflects the kinetic effect which arises from replacing H’s by D’s in the leaving ethoxy group.
B-
+ CH3iHzoCH,CH3
-c:
C2H50-
+ HB + C,H,
C,H,O-.HB
+ C,H,
(37a)
(37b)
The results show that, in the generation of free ethoxide, kH/kD(Hp) is a smooth function of the base strength and spans a scale from 2.2 for OH- up to 5.6 for the strongest base used, NH;. For both bases kH/kD(sec. H,) is found to be unity. The same is true for k(OCH,CH,)/k(OCD,CD,) if NH; is the base, but the value found for OH- points to a leaving group effect. These observations for the channel of free ethoxide formation have been interpreted as indicating a shift from an ElcB-type mechanism towards a more central E2 mechanism on going from the strong base NH; to the weaker base OH- as visualized by transition states [9] and [lo]. In other
TABLE3 Overall kinetic isotope effects associated with the reaction between B- and diethyl ether
NH; CH,NH C,H,NHOH-
-
02
5.60 f 0.04 4.03 & 0.06 3.50 0.05
0.45
2.20 f 0.03
1689 1687 1671
co
1635
cc
-
-
5.62 f 0.03 3.93 f 0.08 3.41 f 0.07
-
-
1.55 5 0.03
2.09 f 0.03
1.40 f 0.04
2.31 f 0.03
-
-
5.62 f 0.03
~
~
~
1.71 f 0.05
'Proton affinity data taken from Bartmess and McIver, 1979. The proton affinity of B - is defined as the negative of the enthalpy change for the reaction B- + H i + BH TABLE4 Kinetic isotope and leaving group effects associated with the reaction between B- and diethyl ether, calculated from the data in Table 3" B-
~IH/~ID(H ~ z~H) / ~ z D ( H~~I)H / ~ I D ( H , ) km/km(H,)" "
NH; OH
5.60 f 0.03 2.20 f 0.03
'I
-
1.55 f 0.03
1.01 f 0.01 1 .OO f 0.02
-
1.00 f 0.02
Errors calculated from the standard deviation data in Table 3.
ki(OCzHs)/k1(OCzD,)"
1.oo f 0.0 1 1.05 f 0.02
k~(OC2H,)/k~(OCzD5)' -
1.10 5 0.03
26
NlCO M. M. NIBBERING
words, in the reaction with NH;, the (3-hydrogen is situated more or less symmetrically between the (3-carbon and NH; and the C,-0 bond is only minimally stretched in the (reactant-like) transition state. In the reaction with OH-, however, the (3-proton is more than half transferred and the Ca-0 bond breaking is substantial in the (product-like) transition state. The results in Tables 3 and 4 also show a very significant difference in k,/k, (HB) for the production of free and solvated ethoxide ions in the reaction with OH-, indicating that these ions are formed via essentially different elimination mechanisms. An anti-elimination has been proposed for the free ethoxide formation and a syn-elimination for the water-solvated ethoxide ion formation as visualized by (38a) and (38b). Apart from the fact that in the syn-elimination no complicated reorganization of the reaction complex is required to arrive at the water-solvated ethoxide ion, this assignment is also in line with model calculations of isotope effects for anti- and syn-eliminations reported earlier (Melander and Saunders, 1980). Moreover, the importance of base/leaving group association in the transition state for synelimination as illustrated in (38b) is further corroborated by the observation that in reaction with diethyl ether dimethylamine-solvated hydroxide ions, OH-.HN(CH,),, yield the free ethoxide as the dominant ion rather than solvated ethoxide (de Koning and Nibbering, 1987). c -
NH2
1 6 IL
OEt [91
L
H syn
J
OEt
27
GAS-PHASE REACTIONS OF ORGANIC ANIONS
The elimination reactions discussed above for diethyl ether are suggested to proceed via a transition state with a periplanar geometry. This hypothesis has been tested by studying the stereoelectronic control in the base-induced elimination reactions of cis- and trans-4-t-butylmethoxycyclohexane(de Koning and Nibbering, 1987). Both compounds give free and water-solvated methoxide by reaction with O H - , as summarized in (39a) and (39b).
,+o + 1+o f
=OM' cis and trans
B-
k4
+ H B + MeO-
(39a)
+ HB.Me0-
(39b)
Assuming that the bulky t-butyl group fixes the methoxy group spatially, a perfect antiperiplanar relationship exists between the methoxy group and the P-hydrogens in the cis-compound, but not in the trans-compound. The formation of free methoxide from the cis-compound is therefore expected to be preferred over that from the trans-compound. This has been found to be indeed the case, the ratio being 2.6 in favour of the cis-compound. The formation of water-solvated methoxide from the cis-compound has also been found to be favoured (by a factor of 4.2) over that from the transcompound, suggesting that in the syn-elimination the methoxy-group leaves preferentially from an axial position as well. In that respect it must also be noted that a significant leaving group effect has been observed in the formation of both free and water-solvated methoxide from the trans compound, where the periplanarity required for elimination cannot be readily achieved. This indicates a drastic shift of the corresponding transition state towards the carbenium ion or El region of the E2-spectrum. For further details the reader is referred to the original publication (de Koning and Nibbering, 1987). Elimination reactions have also been observed in aromatic ethers (Kleingeld and Nibbering, 1980). The anions NH;, C,H,O- and n-C,H,O-, which hardly react or do not react at all with methyl phenyl ether, generate C,H,O- ions in high abundance from ethyl phenyl ether. This indicates that these bases react with ethyl phenyl ether by elimination, whereas they react with methyl phenyl ether mainly by S,2 substitution. However, deuteration of the ethyl group of ethyl phenyl ether has shown that the elimination reaction may not be as straightforward as one might think. For example, reaction of this deuterated compound with NH; yields mainly C,H,DO-, indicating that the elimination occurs after abstraction of a proton from the aromatic ring via an intramolecular process as shown in (40).
NlCO M M NIBBERING
28
0
+NH,
(40)
8
Nucleophilic aromatic substitution reactions
Although the attack of nucleophiles upon aromatic rings in the gas phase was reported more than a decade ago, not many publications on this topic have appeared since then. Thus, it was shown in earlier work that alkoxide ions react with fluorobenzene to give F- and with hexafluorobenzene to give pentafluorophenoxide anions (Briscese and Riveros, 1975), that ( M + NO,)- adducts can be formed from reaction of NO; with 0-,mandp-dinitrobenzenes (Bowie and Stapleton, 1977) and that (M - H 0)ions are generated in reactions of 0- ions with benzene, naphthalene, pyridine, alkylbenzenes, methylpyridines and fluorotoluenes by displacement of a ring hydrogen atom (Bruins ct ul., 1978).
+
'q: QI
+ CH,YH
F
F H,CO
+F*F
F HY--
F Y
=
F
O.~*O,NH
OCH, I
F+ *;"F Y-
(414
GAS-PHASE REACTIONS OF ORGANIC ANIONS
29
The chemistry involved in nucleophilic aromatic substitution is well reflected in the reactions of a variety of nucleophiles with methyl pentafluorophenyl ether (Ingemann et a/., 1982a). For most of the nucleophiles such as alkoxide, thiolate, enolate and (un)substituted ally1 anions, the dominant reaction channel is the attack upon the fluoro-substituted carbon atoms, as is the case for O H - . The latter ion reacts approximately 75% by attack upon the fluoro-substituted carbon atoms and the remaining 25% by S,2 (20%) and ipso (5%) substitution as summarized in (41). In the attack upon the fluorinated carbon atoms, the interesting observation is made that a F - ion is displaced via an anionic o-complex to form a F- ion/molecule complex, which is not observed to dissociate into F- as a free ionic product.
Loose ion/molecule complex
o-complex
F
(42)
ionimolecule complex
Instead, the displaced F- ion re-attacks the newly formed molecule within the complex, leading eventually to the products shown in (42). Although the lifetime of the F- ion/molecule complexes is not known, they must live sufficiently long to allow secondary reactions to occur. Depending upon the nature of the original nucleophile, the re-attack by the displaced F- ion can involve proton transfer, S,2 substitution and E2 elimination. Proton transfer to the displaced F- ions (43) is the dominant reaction if the neutral in the complex is more acidic than HF. This is the case when the primary
30
NlCO M. M. NIBBERING
reactant ions are NH;, O H - , S H - . Most of the even-electron ions formed are observed to undergo a fast unimolecular reaction to give radical anions if Y = NH, 0. With the assumption that the O H - ion has attacked the pposition with respect to the methoxy group, the radical anion of tetrafluorop-benzoquinone (electron affinity = 2.92 eV; Cooper et al., 1978) wiil be formed (44). C,F,OCH,
+ YH--[HYC6F40CH3.F-]*+CH3OC6F4Y(Y
=
+ HF
(43)
0, S, NH)
The formation of relatively long-lived F- ion/molecule complexes is demonstrated by the reaction of CD,O- with C,F,OCH,, which eventually leads to the formation of the ions CH,OC,F,Oand CD,OC,F,O- in a 1 : 1 ratio, showing that there is sufficient time for the displaced F ions to attack both the CH,O- and the CD,O group of the newly formed CH,OC,F,OCD, molecule with equal probability (45). The decisive role of the F- ion/molecule complexes is further corroborated by the observation that the same ratio between [CH,OC,F,O-] and [CH,CH,OC,F,O-] is obtained when CH,CH,O- reacts with C,F,0CH3 and when CH,Oreacts with C,F,OCH,CH, (Ingemann and Nibbering, 1984b). C,F,OCH,
+ CD,O-
-
mjz 34 [CD,0C,F,0CH3 .F-]*
50%
CD,OC,F,Omjz 198
+ CH,F
(45a)
CH,OC,F,Omjz 195
+ CD,F
(45b)
Such F--generated ion/molecule complexes offer the possibility of obtaining a valuable insight into the intramolecular competing reactions. For example, in the case of reaction (46) between CH,S- and C,F,OCD,, reattack by F- occurs nearly exclusively on the methyl group bonded to the oxygen atom (Ingemann et al., 1982a). This selectivity in re-attack has been rationalized as mainly being due to the greater electropositive character of the carbon atom bonded to the oxygen atom.
31
GAS-PHASE REACTIONS OF ORGANIC ANIONS
C,F,OCD,
+ CH,S
-
mjz 47
> 99% I-*
CH,SC,F,O-
+ CD,F
(46a)
mlz 211
[CH,SC,F,OCD,.F -]* < I Yo
CD,OC,F,S-
+ CH,F
(46b)
mjz 214
These results clearly show that the potential energy surface can contain a series of minima. The fact that selectivity in re-attack by the F - ions can be observed indicates that the differences between the energy barriers for the secondary reactions control the distribution of the final products. The multistep character of these processes is further illustrated by the reactions observed when enolate anions are used as reactant ions. The ambident enolate anions may react with methyl pentafluorophenyl ether at the carbon or the oxygen site. If they react with the carbon site at the fluorine-bearing carbon atoms, then the molecule in the F- ion/molecule complex formed contains relatively acidic hydrogen atoms so that proton transfer to the displaced F- ion may occur. An example is given in (47) where the enolate anion, generated by HF loss, is not observed. An intramolecular nucleophilic aromatic substitution occurs instead and leads to a second F- ion/ molecule complex. The F- ion in this complex then re-attacks the substituted benzofuran molecule formed, either by proton transfer or S,2 substitution.
l*
o:$F
-
CH=C
I
/ \
R
1) -
J
(R
=
H, CH,)
1'1
F-1 _.
proton _Products
transfer
32
C,F,OCH,
+ CH,CH,O-
r!
NlCO M. M. NIBBERING
-
mjz 45
[CH,CH,OC,F,OCH,.F-I*
CH,OC,F,Omi= 195 CH,OC,F,Omi: 195
+ CH,CH, + HF + CH,CH,F
CH,CH,OC,F,Omlz 209
+ CH,F
The displaced F - ions can also induce an E2 elimination, if the original reactant ion contains P-hydrogen atoms. An example is given in (48), where [CH,CH,OC,F,O-] : [CH,OC,F,O-] = 1 : 9. The observed ratio between the abundances of the two product ions indicates that the CH,OC,F,Oion is formed by an E2 elimination. Increasing the number of P-hydrogen atoms in the reactant ion favours formation of CH,OC,F,O- even more, as indicated in (49). The E2 elimination channel can be blocked, of course, if the nucleophile does not contain P-hydrogens. Such a reactant is the neopentoxide ion (CH,),CCH,O-, which reacts with C,F,OCH, as shown in (50) to give the product ions (CH,),CCH,OC,F,Oand CH30C,F,0- in a ratio of 96 : 4. This clearly reflects the steric effect of the neopentyl group in the S,2 reactions in (50) required to form the product ions (Ingemann rt al., 1982a).
(CH,),COC,F,OCH,OC,F,O-
96%
[(CH,),CCH,OC,F,OCH,.F~]*
+ CH,F
(49a)
+ (CH,),C=CH, + HF
(CH,),CCH,OC,F,Omjz 251 CH30C,F,0m/z 195
(49b)
+ CH,F (50a)
+ (CH,),CCH,F (Sob)
GAS-PHASE REACTIONS OF ORGANIC ANIONS
33
9 Cycloaddition reactions
Cycloaddition reactions in which anions are involved, have not been studied extensively to date as evidenced by the small number of publications which have appeared over the last few years. Indications of the occurrence of cycloaddition were first obtained from reactions of specifically deuterated allyl anions with tetrafluoroethylene. Assuming that no hydrogen/deuterium exchange occurs in the collision complex as shown for the allyl anioiis themselves (Dawson et ul., 1979a), the results obtained (Nibbering, 1979) may be interpreted as indicating that 65% of the allyl anions react by a linear addition (51), 20% by a [2 21 atom cycloaddition (52) and 15% by a [ 2 31 atom cycloaddition. (53). It should be noted here that the precise mechanistic details of the losses of H F molecules from the collision complexes in eqns (51)-(53) are not known. However, in view of the nucleophilic aromatic substitution discussed in the previous section, it is quite likely that they occur in a stepwise fashion in which complexes solvated by fluoride anions play a role.
+
+
The observations described prompted a study of the reaction between the 2-cyanoallyl anion and tetrafluoroethylene, since this system has the merit that the charge may be accommodated in the nitrile group of the reaction intermediate in the [2 31 atom cycloaddition (54). Elimination of two H F molecules indeed occurs, presumably in a consecutive way, although the product ions resulting from loss of one molecule of H F from the collision complex have not been observed (Dawson and Nibbering, 1980). However, reaction (54) has not yet been studied with specifically deuterated 2cyanoallyl anions, so that at present an “end-on” addition process ( 5 5 ) cannot be excluded.
+
NlCO M. M . NIBBERING
34
C=N
F%
HH
-
-2HF
*r
H
.-.
F
CN (54)
H
CN I CH,=C-CH;
+ CF,=CF,
-
It is interesting to note here that the ring-closed isomer of the 2-cyanoallyl anion, i.e. the (M - H)- ion of cyanocyclopropane, reacts with tetrafluoroethylene with expulsion of two molecules of hydrogen fluoride as well, albeit to a minor extent. Most of the corresponding collision complexes, however, appear to eliminate a molecule of ethylene, for which (56) represents the most satisfactory mechanism so far presented (Dawson and Nibbering, 1980).
A specifically deuterated ally1 anion with an electron-withdrawing substituent in the 2-position, which has been allowed to react with some unsaturated substrates for the aimed [2 31 atom cycloaddition, has been the 2-formyl-1, I-dideuteroallyl anion. This ion has been found to react with the
+
35
GAS-PrlASE REACTIONS OF ORGANIC ANIONS
substrates hexafluorobenzene and methyl pentafluorophenyl ether by expulsion of ( H F + DF) and (HF + D F + CH,), respectively, as shown in (57) and (58) (Kleingeld and Nibbering, 1984b). No product ions are observed which correspond to the loss of either 2HF and (2HF CH,) or 2DF and (2DF + CH,) from the collision complexes. These observations strongly indicate that cycloaddition has indeed occurred, although it is not known whether this has taken place in a concerted or stepwise fashion. Support for the stepwise mode, however, is obtained from the reactions of unsubstituted I , 1 -dideuteroallyl anions with methyl pentafluorophenyl ether (Ingemann et d., 1982a). In this case, not only are product ions formed which correspond to the loss of (HF D F + CH,) from the collision complexes, but also product ions which result from the loss of both ( H F CH,) and (DF + CH,) from the collision complexes, are observed.
+
+
H C dC CHo ZI b C D 2
+
+
'*: -
CHO
- HDF F
F
F
F mjz 216
OCH,
I
mjz 228
CHO mjz 213
D
(57)
36
NlCO M M NIBBERING
10 Hydride transfer reactions
The earliest examples of such reactions are the hydride transfer from HCOto formaldehyde (Karpas and Klein, 1975), from DNO' as deuteride to (CH,),B (Murphy and Beauchamp, 1976), from the conjugate base of 1.4cyclohexadiene to benzaldehyde (DePuy rt a/., 1978b) and from alkoxide ions to singlet oxygen (Schmitt et a/., 1979). One of the reactions involving hydride transfer, which has synthetic importance in solution chemistry, is the Meerwein-Ponndorf-Verley reduction of carbonyl compounds by hydride transfer from alkoxide ions. Similarly, it has been found possible to reduce formaldehyde, benzaldehyde, 2.2-dimethylpropanal and 1 -adamantylcarboxaldehyde with methoxide ions in the gas phase (Tngemann et a/., 1982b). The reaction trajectory of the hydride transfer from the methoxide ion to formaldehyde has also been studied by ah iriitio calculations (Sheldon et a/., 1984b). An interesting hydride-transfer step has been observed in the reaction of hydroxide ion with formaldehyde (Kleingeld and Nibbering, 1983b). Once the corresponding collision complex is formed, the solvation energy allows a proton transfer from the formaldehyde molecule to O H - . However, the water-solvated formyl anion generated in this way cannot separate since water is more acidic than formaldehyde in the gas phase. Instead, a hydride transfer from the formyl anion to the water molecule in the complex takes place, leading to H,O- and carbon monoxide products as shown in (59). OH-
-
+ C H , O ~ [ O H ~ . C H , O ] * [H,O.HCO-I*
+
H30-
+ CO
(59)
The H,O- ion, which has also been prepared independently in an ion-beam experiment (Paulson and Henchman. 1982), contains exclusively the oxygen atom of the hydroxide ion as shown by '*O-labelling experiments, while Dlabelling experiments have indicated clearly that the hydrogen atoms in H,O- are not equivalent. For example, the H,DO- ion generated by reaction of OD- with CH,O transfers a hydride, but not a deuteride, to formaldehyde as summarized in (60a) and (60b). These observations together with the complementary results obtained for the OH-/CD,O system are consistent with the view that the H,O- ion can best be described as a hydride ion solvated by a water molecule. This has been confirmed recently by both photoelectron spectroscopy (Miller et a/., 1985) and theoretical calculations (Cremer and Kraka, 1986) which have indicated that the H,O- ion is most stable when the hydride ion is bonded to one of the hydrogen atoms of the water molecule. H,DO-
+ CH,O
+ CH30-
(boa)
+ CH,DO-
(bob)
HDO H,O
GAS-PHASE REACTIONS OF ORGANIC ANIONS
37
In a similar way, it has been possible to form NH; ions in the gas phase by reaction of the amide ion NH; with formaldehyde (Kleingeld et al., 1983). In this case the proton abstraction (61a) from formaldehyde by NH;, which is a stronger base than O H - , is exothermic and results in the formation of HCO-. This ion then transfers a hydride to ammonia in a subsequent ion/ molecule reaction (61b) to give NH, and carbon monoxide. D-labelling experiments have proved that the hydride ion transferred to ammonia retains its identity so that the NH; ion, like the H,O- ion discussed above, can best be described as a hydride ion solvated by an ammonia molecule. This has also been confirmed recently both by photoelectron spectroscopy (Coe et al., 1985), where the NH; ion was generated with a nozzle-ion source, and by theoretical calculations (Cardy et a/., 1986; Cremer and Kraka, 1986; Kalcher et al., 1984; Squires, 1984).
+ HCO+ CO
+ CH,O-NH, HCO- + NH,-NH,
NH,
(61a) (61b)
Very recently it has also been possible to synthesize the SiH, ion in a flowing afterglow instrument (Hajdasz and Squires, 1986). To this end hydride ions were first added to alkylsilanes via reaction (62). The R,SiHanions formed in this way behave as potent hydride donors, reducing a wide variety of substrates including the silanes themselves. In particular, both n-C,H,,SiH~ and Et,SiH; transfer a hydride to SiH, to produce the parent ion of the series, SiH;, in addition to SiHi as exemplified in (63). Although not yet shown for SiH; itself, deuterium labelling experiments have indicated that the hydrogen atoms bonded to silicon in Et,SiH; and nC,H, ,SiH; are chemically equivalent. H(R,Si
=
+ R,Si
He
(62)
Me,%. Et,SiH, Et,SiH,, n-C,H, ,SiH,) 3?'h
Et,SiH;
R,SiH
+ SiH,
SiH;
+ Et,SiH
SiH;
+ Et,SiH + H,
-t 68%
(63)
Finally, it should be noted that reduction of the carbonyl function by BH;, being an important synthetic reaction, has been studied recently for a limited number of substrates. It has been found that BH; is not capable of reducing formaldehyde in the gas phase (Kayser and McMahon, 1984). However, substrates, such as difluoroformaldehyde, hexafluoroacetone and methylmaleic anhydride can be reduced by BH; in the gas phase (van der We1 et al., 1987). On the basis of 13C-labelling experiments, it has been
NlCO M M NIBBERING
38
shown that, of the carbonyl groups in methylmaleic anhydride, the carbonyl group nearest to the methyl substituent is preferentially reduced, in agreement with its higher LUMO coefficient according to ab initio calculations. 11
Dipole-stabilized carbanions
Carbanions which bear an a-heteroatom, which is bonded to a functional group capable of inducing a partial positive charge on that heteroatom (64), are both of theoretical interest and of synthetic importance (Seebach et a/., 1983). Such have been termed dipole stabilized carbanions (Beak and Reitz, 1978).
\c-y-z
/
Y Z
-\c-+=z /
= NR, 0, S = N=O, C=O,
(64)
C=S
In the gas phase it has been found possible to generate dipole stabilized carbanions in the absence of counterions by abstraction of a proton from the methyl groups of methyl formate (Ingemann and Nibbering, 1985a), N,Ndimethylformamide (Ingemann and Nibbering, I985a; Bartmess et a/., 1983) and from those of N,N-dimethylthioformamide and N,N-dimethyl-N-nitrosamine (Ingemann and Nibbering, 1985b). In the case of methyl formate and N,N-dimethylformamide, where the formyl position is the most acidic site, a very strong base, such as -NH, [Proton affinity (NH;) = 1689 kJ mol- '3 is required to abstract a proton from the methyl group as evidenced by D-labelling. With the much weaker base CH,O- [Proton affinity (CH,O-) = 1587 kJ mol-'1, however, it is possible to abstract a proton from one of the methyl groups of N,N-dimethyl-N-nitrosamine, whereas in the case of N,N-dimethylthioformamide, such a reaction can even be accomplished with the less basic anion C,H,O- [Proton affinity (C,H,O-) = 1574 kJ mol-'I. An interesting observation has been made with the (M - H)- ion of DCON(CH,), in the presence of ND,. It quite rapidly exchanges two hydrogen atoms with ND,, but exchange of a third hydrogen atom occurs at a much lower rate as shown in Fig. 6 (Ingemann and Nibbering, 1985a). The proposed mechanism of this exchange reaction is given in (65). First, a complex is formed between the (M - H)- ions of DCON(CH,), and ND,, in which the ion-induced dipole energy gained upon approach is used to overcome the barrier to an overall endothermic deuteron transfer, leading to the second complex in (65). Rotation around the carbonyl carbon-nitrogen bond in the DCON(CH,)CH,D species of this complex is hindered by a
39
GAS-PHASE REACTIONS OF ORGANIC ANIONS
FIG.6 The hydrogen-deuterium exchange reaction between the (M from DCON(CH,), and ND, as a function of reaction time
-
H)- ions
m/z 13
0
II
D-C,
y ,CH, /.
+
NHD,
NlCO M. M . NIBBERING
40
large barrier which has been shown to be 8 1 kJ mol- at 298 K by gas-phase I3C nmr spectroscopy (Ross and True, 1984). The results shown in Fig. 6 can then be explained by assuming that proton abstraction in the second complex of (65) occurs from the same methyl group at which the charge was located in the (M - H ) - ion, i.e. the CH,D group. This interpretation demands that the two methyl groups in N,N-dimethylformamide have different gas phase acidities. This is in excellent agreement with theoretical calculations which have indicated that the anti methyl group is significantly more acidic than that in the s-yn position with respect to the carbonyl group (Rondan et al., 1981). Similar observations have been made for the two methyl groups of N,N-dimethyl-N-nitrosamine with CD,OD as exchange reagent, but not for those of N,N-dimethylthioformamide which have been found to be close in acidity (Ingemann and Nibbering, 1985b). 12
Homoenolate and homoaromatic anions
According to eqn (23) in the section on addition-elimination reactions it is to be expected that anions which lack a-hydrogen atoms with respect to their functional group, such as (CH,),CCN, c-C,H,=C=Nand CH2=CCN, will not react with aliphatic nitrites with expulsion of an alcohol molecule from the collision complex. Nevertheless, they d o react in that way, albeit with rate constants that are about 10 to 40 times slower than for example is the case with CH3CHCN (Noest and Nibbering, 1980a). A possible mechanism for the reaction between (CH,),&N and R O N 0 is presented in (66). The resulting ion would be a primary carbanion, which will derive stabilization from the combined effects of the dipole moments of the polar C N and NO groups acting upon the carbanion centre. In order to obtain more support for this view, 2-methyl-2-nitrosopropane and 2,2dimethylpropanal have been allowed to react with both O H - and NH; ions, in both cases giving, with unexpected ease, stable ( M - H)- ions (Noest and Nibbering, 1980~).The observation that these (M - H)- ions respectively exchange up to 8 or 9 hydrogen atoms for deuterium atoms in the presence of D,O has further been taken as evidence for the existence of the primary carbanions -CH,C(CH,),X (X = NO, CHO). The stabilization of these ions has been suggested to arise from an electrostatic attraction between the charge on the carbon atom in an sp3 orbital and the dipole of the N O or CHO group rather than from homoconjugation, as indicated in [ 1 11 for the ( M - H ) - ions of (CH,),CCHO. Homoconjugation would require a rehybridization of the charge-bearing sp3 orbital to a p orbital to allow a bonding overlap with the TC system of the polar groups. If that were to happen, it would lead for X = C H O to a homoenolate anion which belongs to a class of ions that has received considerable attention in the liquid phase
GAS-PHASE REACTIONS OF ORGANIC ANIONS
41
(Werstiuk, 1983). Moreover, such a homoenolate anion could eventually undergo ring closure leading to the formation of a cyclopropoxide anion (Chandrasekhar et a/., 1981).
C-CN
+
n
RO-N=O
-
H3CxcN --ROH
H,C
NO
[RO?
H,C,C ,, /CN
H-CH,
L,
1'
NO
Recently, the ionjmolecule chemistry of the (M - H)- ions generated by proton abstraction from 2.2-dimethylpropanal and 2,2-dimethylcyclopropanol has been studied in detail (Peerboom et d., 1985). Both (M - H)ions appear to behave similarly with regard to hydrogen/deuterium exchange with D,O and in reactions with hexafluorobenzene. The hydrogen/ deuterium exchange for the (M - H ) - ion of 2,2-dimethylcyclopropanol indicates that this ion may have the structure of a primary carbanion, i.e [ I I]. On the other hand, in reactions with hexafluorobenzene, both (M - H)ions give C,F,O-, indicating that those of 2,2-dimethylpropanal may have the cyclopropoxide structure as given in [12] like those of 2,2-dimethylcyclopropanol (for the mechanism of formation of C,F,O- see Section 8).
NlCO M. M. NIBBERING
42
Interestingly, the hydrogen/deuterium exchange of both (M - H)- ions with D 2 0 is not observed to go to completion, but stops after a certain reaction time. Evidence has been presented that this phenomenon is due to an irreversible isomerization of the (M - H)- ions to the enolate anion [I31 of 3-methylbutanal, which also gives the same product ions in reactions with hexafluorobenzene (Peerboom et al., 1985). The results obtained clearly point to a complex mixture of interconverting ion structures as shown in (67a-e). (CH,),CCO
(CH,),CCHO
+ H,O =[(CH,),CCO.H,O]* + HO-
(67a)
=[(CH,),CCHO.HO-I* [ ~CH,C(CH,),CHO.H,O]*
=
+H20
[11]-[13]
(67b) (CH,),C-CHOH
//
+ HO-
CH2
(CH ,), C-CHO \ / CH,
-[
-
.H,O [11]-[13]
+ H,O (67c)
[(CH3)2CCH,CHO.H ,O] *
=
[ 1 I]-[ 131
+ H20 (67d)
:CH3),CHCH2CH0
+ HO-
[(CH,),CHCH,CHO.HO-I*
[(CH,),CHCHCHO-.H,O]* (CH,),CHCHCHO-
-*
+
H,O (67e)
GAS-PHASE REACTIONS OF ORGANIC ANIONS
43
Within the concept of homoenolate anions the ions [ I I]-[I31 can also be regarded as resonance structures of the same non-classical ion [14]. Obviously, theoretical calculations could help to clarify whether the ion structures 11 11-11 33 are resonance structures or interconverting ions. Conceptually similar to the non-classical homoeno!ate ion [ 141 is homoaromaticity in anions in which the cyclic z-system is interrupted by a saturated centre, but in which the geometry still permits significant overlap of the p orbitals across the insulating gap. In a very recent and exciting publication, arguments from gas-phase acidity measurements have been put forward suggesting that the enhanced stability of the conjugate base [ 15a] derived from bicycJo/3.2.l]octa-2,6-diene is largely due to its bishomoaromatic character, as indicated in [15b] (Lee and Squires, 1986).
7 3 Ion structures
Although collision induced dissociation (CID) is a well-known method for investigating the structures of cations in the gas phase (McLafferty, 1983), it has been applied much less to anions (Bowie, 1986). Actually, in some cases CID has been used to study the fragmentation mechanisms of anions, such as the elimination of molecular hydrogen from alkoxide ions (Hayes et al., 1984) or the primary fragmentason routes of ester enolate ions (Froelicher et al., 1985). Another recent application of CID is the generation of anions which cannot be obtained easily by other means. For example, the unsubstituted vinyl (C2H;), 2-propenyl (CH,C=CH,), 1-propenyl (CH,CH=CH-) and cyclopropyl (CH,),CH- anions have been prepared by CID of the corresponding carboxylate anions through loss of carbon dioxide (Froelicher et al., 1986) and the dimethylsilanone enolate anion by CID loss of methane
44
NlCO M. M. NIBBERING
from the trimethylsiloxide anion (Froelicher et ul., 1984). Of course this does not exclude the formation of highly interesting and new ions by exothermic ion/molecule reactions, such as H 2 N S (Bierbaum et al., 1984), H C , S (DePuy, 1985) or the acetyl anion by the reaction of fluoride ion with acetyl trimethylsilane (DePuy et al., 1985b) and the methanimine anion CH,=Nby the reaction of trimethylsilylmethyl azide with NH; (Kass and DePuy, 1985). However, whether the anions are generated by CID or ion/molecule reactions, in most cases additional experiments are required to determine their structure. In the case of carbanions a versatile reagent for that purpose has been shown to be nitrous oxide (Kass et al., 1986). In general, primary carbanions react to produce diazo anions as the major products, secondary carbanions dehydrogenate, and tertiary carbanions afford adducts and products of oxygen atom transfer and cleavage. These results have been applied in an elegant way to distinguish and determine the isomeric C,H, ions mentioned above, including the ally1 anion, which could be generated by CID of the corresponding carboxylate anions (Froelicher et ul., 1986) as is summarized below.
m / z 39
GAS-PHASE REACTIONS OF ORGANIC ANIONS
45
First the ally1 anions react with N,O to give the anion of vinyldiazomethane by expulsion of H,O from the collision complex as visualized in (68). The initial addition to N,O at the terminal nitrogen and the expulsion of H,O containing the hydrogen atoms from one of the methylene groups in (68) is supported by previous "N- and D-labelling experiments (Dawson and Nibbering, 1978b; Dawson et a/., 1979a). The I-propenyl anions react with N,O essentially via two channels to generate the methylacetylide and (M - H)- ions of diazomethane, as shown in (69) and (70). It must be noted that vinyldiazomethane anions are also generated from the OH-/diazoethane complex in (69) by proton abstraction from the methyl group. The 2-propenyl anions, however, react with N,O to yield the enolate ions of acetone and the (M - H)- ions of diazoethane in equal abundances, for which the routes as visualized in (71a) and (71b) have been proposed. ,C=CH, H3C
+ N,O
=
Finally, the cyclopropyl anion appears to be exclusively dehydrogenated by reaction with N,O, for which the mechanism in (72) has been put forward.
Another useful reagent to distinguish isomeric carbanions is 0, (Schmitt et al., 1979; Bierbaum et ul., 1980). Many of them undergo cleavage, with oxygen at each carbon atom which bears a negative charge, so that in a delocalized ion the cleavage fragments aid in determining the structure of the
46
NlCO M. M. NIBBERING
r L
CH,-CH=CH-CHO
+ -O-CH=CH, (73b)
CH,CHO
+ -0-CH=CH-CH=CH, (73c)
ions. For example, the anion formed by proton abstraction from 2,4hexadiene reacts with 0, to form predominantly three enolate ions, as shown in (73a-c). The hydroperoxide ion HO; is also formed in small quantities. In contrast to these results, the isomeric anion formed from 1 5 hexadiene exhibits a simpler product ion spectrum (74a,b). In the latter case, HO; is the major product ion (74a), while the enolate anions as formed in (73b) and (73c) are absent. It is believed that these oxygen reactions occur by electron transfer from the RCH; ions to 0, followed by formation of RCH,OO- ions, which then decompose to the enolate anions. At any rate, such reactions with molecular oxygen have been applied successfully to distinguish the isomeric 1-phenylcyclopropyl and 2-phenylallyl anions from each other as has been achieved with the reagent N,O as well (Andrist et a/., 1984).
66CH2=CH-CH,-CH~€H~€H2
CH,=CH-CH=CH-CH=CH2
+ 0, CH,=CH-CH,-CHO
+ HO; (74a)
+
-O-CH=CH, (74b)
It must be stressed, however, that the hydrogen-deuterium exchange reactions discussed earlier are extremely informative and most useful in assigning structures to a wide variety of anions. Although the specific examples of the (M - H)- ions of 2,4- and 1,5-hexadiene, discussed above, cannot be distinguished by these reactions, the 1-phenylcyclopropyl and 2phenylallyl anions are easily shown to be distinct, non-interconverting species by their differing reactions with D,O (Andrist et al., 1984; Squires et ,al., 1981). 14
Radical anions
In addition to formation of radical anions via process (2), they can sometimes also be generated by the dissociative resonance capture process
GAS-PHASE REACTIONS OF ORGANIC ANIONS
47
(3) of low energy electrons mentioned in Section 3. Some examples of the latter are the generation of 0' from N,O, CO, and NO, (Jennings, 1977), C6H,N' from phenyl azide (McDonald and Chowdhury, 1980a) and c-C,H,' from diazocyclopentadiene (McDonald and Chowdhury, 1980b; McDonald et al., 1980). In this section, however, attention will be limited to the production of radical anions via ion/molecule reactions. For this purpose a very useful reactant ion is 0'. It can abstract not only a hydrogen atom or, because of its relatively high proton affinity ( I 590 kJ mol- '), a proton from many organic molecules to give O H - and (M - H ) - ions, but also a hydrogen atom and a proton from a single molecule to give (M - H2)T ions. In many cases studied, either deuterium labelling has shown, or strong indications have been found, that the formal abstraction of H,: occurs from the same carbon atom (Jennings, 1977; Jennings, 1979). The classical example is the reaction of 0 ' with ethylene, where deuterium labelling has established that H2C=CT ions are formed from the collision complex (Goode and Jennings, 1974). These ions react with N,O with expulsion of N O resulting from attack upon the terminal nitrogen atom (75) as shown by 'SN-labelling (Dawson and Nibbering, 1978b). Although details of the H,f abstraction reaction by 0' are not known, it is quite likely, on the basis of currently available knowledge of ion/ molecule reactions, that this reaction proceeds in a stepwise fashion. If so, arguments have been put forward on the basis of thermodynamic considerations that the CH,=C7 ion is generated by successive hydrogen atom and proton transfer to 0'. In principle, this could also lead to the formation of the acetylene radical anion which, however, will be unstable with respect to electron detachment (Nibbering, 198 I ) . CH,=C-
r+ + N-N-0-
U
CH,=C=N-
+ .NO
-
[CH,=C-N=N-O-]*
-
. -
[CH,=C-N-N=O]* U
Many other H,f abstractions by 0' from a single carbon atom can be explained in a similar way. For example, 0' abstracts.a proton from the methine position of cyanocyclopropane to give the (M - H)- ion, but abstracts H,f from one of the corners of the ring to generate the (M - H,)' ion as shown by deuterium labelling (Dawson and Nibbering, 1980). Abstraction of H,f from different carbon atoms would lead in this case either to the radical anion of I-cyanocyclopropene or to that of 3cyanocyclopropene. By comparison with the radical anion of acrylonitrile,
NlCO M M NIBBERING
48
which is unstable with respect to electron detachment (Dawson and Nibbering, 1980), 1 -cyanocyclopropene is expected to have a negative electron affinity since the extra electron should be accommodated in the antibonding (p, orbital. The same will be true for the radical anion of 3-cyanocyclopropene where the extra electron has to be put into the antibonding (p2 orbital.
0-
I
CID
CH,-C-CH, no methyl radical loss ________________.
(77)
Further arguments for the stepwise abstraction of H 2 + 0' can be obtained from several examples where the required hydrogen atoms originate from different positions. An obvious example is benzene, where, in the formation of C,H,' by reactions with 0-, the hydrogen atoms must come from different carbon atoms (Bruins et al., 1978), the electron affinity for the neutral counterpart of o-C,H,' having been determined recently (Leopold r t ul., 1986). Other examples are the H 2 f abstractions from rn-xylene, i.e. one hydrogen from each of the methyl groups (Bruins rr al., 1978), the HD: abstraction from 1 -deutero-I-nitrocyclopropane(Dawson and Nibbering, 1980), probably giving the molecular anion of 1-nitrocyclopropene in view of the fact that the molecular anion of nitroethylene has been observed as a long-lived species (Bartmess, 1980), the 1,3- and 3,3-H, f abstraction from propyne (Dawson r t ul., 1977) and the 1 , l - and 1,3-HZf abstraction from acetone (Dawson et al., 1979b) as shown by deuterium labelling. The two different radical anions from propyne could be distinguished from each other by their reactivity towards methyl formate, while those from acetone were distinguished by CID experiments. The results of the latter are displayed in (76) and (77). The reaction as given in (76) is more general in that the (M - H2); ions generated by H,: abstraction from the methyl groups of methyl alkyl ketones yield the HC-C-0ion by expulsion of the alkyl radical as well (Harrison and Jennings, 1976). Similarly, methyl radical loss (78) has been observed from the (M - H2)' ion derived from nbutyronitrile (Dawson and Jennings, 1976). T CH,-CH,-c
--CN
-
CH,=C-CN
+ CH,.
(78)
The fact that interesting radical anions can be generated with 0' is further demonstrated by the recently published observation of the H,O; ion (de
GAS-PHASE REACTIONS OF ORGANIC ANIONS
49
Koning and Nibbering, 1984). The ion has appeared to arise from reaction of 0' with any of the aliphatic amines methylamine, ethylamine or dimethylamine. Reaction of 0' with ammonia or trialkylamine, however, does not generate the H,OT ion which suggests that both a hydrogen from the nitrogen atom and from the a-carbon atom are necessary for its formation. This has been shown to be indeed the case on the basis of reaction of 0- with CD,NH, which generates HDO- as the product ion. In this reaction a notable isotope effect is operative with respect to that of O'with CH,NH,. On the basis of thermodynamic considerations, it has been proposed that the amino and a-hydrogens are transferred as hydrogen atoms to the 0' ions, but it is not known whether this takes place in a concerted or stepwise fashion, the latter being visualized in (79). The H,OT species has been found to react rapidly with formaldehyde to give O H - as the only observed product ion, suggesting that it might best be described as a hydroxide ion to which a hydrogen atom is attached.
CH,OCHCN
0 - + N 2 0 0
-[
ClD
N=N-O-
+
- O ~ H C N CH;
(80)
- / QN-N=O] \c
N-
Finally, it must be noted that in a few cases radical anions have also been observed to be generated from even electron anions! One example concerns the CID loss of a methyl radical from the (M - H ) - icm of methoxyacetonitrile (Dawson and Nibbering, 1980) as shown in (80). The capto-dative character (Viehe et al., 1979; Crans et ul., 1980) of the generated radical
50
NlCO M. M. NIBBERING
anion probably accounts for its ease of formation and stability. Another example is the loss of a methyl radical following H F loss in the reactions of O H - and NH; with methyl pentafluorophenyl ether (Ingemann et al., 1982a) as discussed in the section on nucleophilic aromatic substitution reactions [see especially (44)]. The third example is the recently published loss of NO from the adduct derived from a-deprotonated furan and nitrous oxide to generate the cyanoacrolein radical anion, for which the mechanism visualized in (81) has been proposed (Kass et al., 1986). 15 Concluding remarks
Considerable progress has been made in the past ten years in studying reactions of organic anions in the gas phase. This has become possible largely because of the rapid development of the required and now rather sophisticated instrumentation which has allowed, in addition to the reactions described, the determination of proton affinities (Aue and Bowers, 1979), electron affinities (Janousek and Brauman, 1979) and acidities (Bartmess and McIver, 1979) of molecules in the absence of solvent molecules. Increasingly also the chemistry of mono-solvated anions is becoming a topic of research (Hayes et al., 1985, 1986). It is hoped that this review has succeeded in showing that studies of reactions of organic anions in the gas phase can provide information which is invaluable to the field of physical organic chemistry. Acknowledgements
The author wishes to thank the former and present members of his group, listed in the references, for their contributions to the research carried out over the years and the Netherlands Organization for Pure Research (SON/ ZWO) for continuous financial support. He also takes great pleasure in thanking Professor C. H. DePuy and Dr V. M. Bierbaum (University of Colorado, Boulder, U.S.A.) and Professor R. R. Squires (Purdue University, West Lafayette, Indiana, U.S.A.) for their friendship, stimulating discussions and frequent exchange of manuscripts prior to publication. Finally, the author should also like to thank the Royal Society of Chemistry and the American Chemical Society for their permission to reproduce Figs 1 and 2 and Figs 3-6, respectively, in this chapter. References
Adams, N. G. and Smith, D. (1976). Int. J . Muss Spectrom. Ion Phys. 21, 349 Anderson, D. R., DePuy, C. H., Filley J. and Bierbaum, V. M. (1984). J . Am. Chem. Soc. 106, 6513
GAS-PHASE REACTIONS OF ORGANIC ANIONS
51
Andrist, A. H., DePuy. C. H. and Squires, R. R. (1984). J. Am. Chem. Soc. 106, 845 Asubiojo, 0. I. and Brauman, J. I. (1979). J. Am. Chem. Soc. 101, 3715 Aue, D. H. and Bowers, M. T. (1979). In “Gas Phase Ion Chemistry”, M. T. Bowers (ed.), Vol. 2, Academic Press, New York, p. 1 Baldeschwieler, J . D. and Woodgate, S . S. (1971). Ace. Chem. Res. 4, 114 Bartmess, J. E. (1980). J . Am. Chem. Soc. 102. 2483 Bartmess, J. E. and Mclver. R. T., Jr. (1979). It? “Gas Phase Ion Chemistry”, M. T. Bowers (ed.) Vol. 2, Academic Press, New York. p. 87 Bartmess, J . E., Hays, R. L., Khatri, H. N., Misra, R. N. and Wilson, S. R. (1981). J. Am. Cham. Soc. 103, 4746 Bartmess, J. E., Caldwell, G . and Rozeboom, M. D. (1983). J . Am. Chem. Soc. 105, 340 Baykut, G. and Eyler, J. R. (1986). Trends Anal. Cham. 5, 44 Beak, P. and Reitz, D. B. (1978). Chem. Rev. 78, 275 Beauchamp, J. L. (1971). Ann. Rev. Phys. Cham. 22, 527 Bierbaum. V. M.. Schmitt, R. J. and DePuy, C. H. (1980). Environ. Health Perspecr. 36, 119 Bierbaum, V. M., Grabowski, J. J. and DePuy, C. H. (1984). J . Phys. Chem. 88, 1389 Bierbaum, V. M., Filley, J., DePuy, C. H., Jarrold, M. F. and Bowers, M. T. ( 1 985). J . Am. Chem. Soc. 107, 28 18 Bohme, D. K. and Mackay, G . I. (1981). J . Am. Chem. Soc. 103, 978 Bowie, J. H. (1980). Ace. Chem. Res. 13, 76 Bowie, J. H . (1984a). Mass Spectrom. Rev. 3, 161 Bowie, J. H. (1984b). Mass Specrrom. Rev. 3. 1 Bowie, J. H. (1986) Adv. Mass Spectrom. 10. 553 Bowie, J. H. and Stapleton. B. J. (1977). Ausf. J . Chem. 30, 795 Brauman, J. I. (1979). It? “Kinetics of Ion-Molecule Reactions”. P. Ausloos (ed.) Plenum Press, New York, p. 153 Briscese, S. M. J. and Riveros, J. M. (1975). J . Am. Chem. Soc. 97. 230 Bruins. A. P., Ferrer-Correia, A. J. V., Harrison, A. G., Jennings. K. R. and Mitchum, R. K. (1978). Advan. Muss Spectrom. 7A. 355 Budzikiewicz, H. (1983). Mass Specfrom. Rev. 2, 515 Caldwell, G., Magnera, T. F. and Kebarle, P. (1984). J . Am. Chem. Soc. 106, 959 Cardy, H., Larrien, C. and Dargelos, A. (1986). Chem. Pliys. Left. 131, 507 Chandrasekhar. J.. Andrade, J. and Schleyer. P. von R. (1981). J. A m . Chem. Soc. 103, 5609 Coe, J. V., Snodgrass, J. T., Freidhoff, C. B., McHugh, K. M. and Bowen, K. H. (1985). J . Chcm. Phys. 83, 3169 Comisarow, M. B. (1985). Anal. Chin?.Acta 178. 1 Comisarow, M. B. and Marshall, A. G. (1974a). C h m . Phjv. Lett. 25, 282 Comisarow, M. B. and Marshall, A. G . (1974b). Can. J . Chem. 52. 1997 Cooper, C. D., Frey, W. F. and Compton, R. N. (1978). J . Chem. Phys. 69, 2367 Crans, D., Clark, T. and Schleyer, P. von R. (1980). Tetrahedron Lett. 21, 3681 Cremer, D. and Kraka. E. (1986). J . Phys. Chem. 90, 33 Damrauer. R., DePuy, C. H. and Bierbaum. V. M. (1982). Organornetallies 1, 1553 Dawson, J. H. J. and Jennings, K . R. (1976). J. Chem. Soc. Faraday Trans. 2 72, 700 Dawson, J. H. J. and Nibbering, N. M. M. (1978a). Lect. Notes Chem. 7, 146 Dawson, J . H. J. and Nibbering, N. M. M. (1978b). J . Am. Chem. Soc. 100, 1928 Dawson, J. H. J. and Nibbering, N. M. M. (1980). Int. J . Mass Spectrom. Ion Phys. 33. 3
52
N l C O M. M NIBBERING
Dawson, J. H. J., Kaandorp, Th. A. M. and Nibbering, N. M . M. (1977). Org. Mass Spectrom. 12, 330 Dawson, J. H. J., Noest, A. J. and Nibbering, N. M. M . (1979a). Int. J . Mass Spectrom. Ion Phys. 29, 205 Dawson, J. H. J., Noest, A. J. and Nibbering, N. M. M. (1979b). Int. J . Mass Spectrom. Ion Phys. 30, 189 DePuy, C. H. (1984). In “Ionic Processes in the Gas Phase”, M. A. AlmosterFerreira (ed.) Reidel, Dordrecht, p. 227 DePuy, C. H. (1985). Org. Muss Spectrom. 20, 556 DePuy, C. H. and Bierbaum, V. M. (1981a). Acc. Chem. Res. 14, 146 DePuy, C. H. and Bierbaum, V. M. (1981b). J . Am. Chem. Soc. 103, 5034 DePuy, C. H. and Damrauer, R. (1984). Organometallics 3, 362 DePuy, C. H., Bierbaum, V. M., King, G . K. and Shapiro, R. H. (1978a). J . Am. Chem. Soc. 100, 2921 DePuy, C. H., Bierbaum, V. M., Schmitt, R. J. and Shapiro, R. H . (1978b). J . Am. Chem. Soc. 100, 2920 DePuy, C . H., Bierbaum, V. M., Flippin, L. A., Grabowski, J. J., King. G . K., Schmitt, R. J. and Sullivan, S. A. (1980). J . Am. Chem. Soc. 102, 5012 DePuy, C. H., Grabowski, J. J. and Bierbaum, V. M. (1982a). Science 218, 955 DePuy, C. H., Beedle, E. C. and Bierbaum, V. M . (1982b). J . Am. Chem. Soc. 104, 6483 DePuy, C. H., Bierbaum, V. M. and Damrauer, R. (1984). J. Am. Chem. SOC.106, 405 1 DePuy, C. H., Grabowski, J. J., Bierbaum, V. M., Ingemann, S. and Nibbering, N. M. M. (l985a). J . Am. Chem. Soc. 107, 1093 DePuy, C. H., Bierbaum, V. M., Damrauer, R. and Soderquist, J. A. (1985b). J . Am. Chem. Soc. 107, 3385 DePuy, C. H., Damrauer, R., Bowie, J. H. and Sheldon, J. C. (1987). Acc. Chem. Res., 20, 127 Dodd, J. A,, Golden, D. M. and Braurnan, J. I. (1984). J . Chem. Phys. 80, 1894 Farneth, W. E. and Braurnan, J. I. (1976). J. Am. Chem. Soc. 98, 7891 Ferguson, E. E. (1970). Ace. Chem. Res. 12, 402 Ferguson, E. E., Fehsenfeld, F. C. and Schmeltekopf, A. L. (1969). Adv. A t . Mol. Phys. 5, I Froelicher, S. W., Freiser, B. S. and Squires, R. R. (1984). J . Am. Chem. SOC.106. 6863 Froelicher, S. W., Lee, R. E., Squires. R. R. and Freiser, B. S. (1985). Org. Mass Spectrom. 20, 4 Froelicher, S. W., Freiser, B. S. and Squires, R. R. (1986). J. Am. Chem. SOC.108, 2853 Goode, G . C. and Jennings, K . R. (1974). Adv. Mass Spectrom. 6, 797 Grabowski, J. J., DePuy, C. H. and Bierbaum, V. M. ( 1 983). J . Am. Chem. Soc. 105, 2565 Gross, M. L. and Rempel, D. L. (1984). Science 226, 261 Hajdasz, D. J. and Squires, R. R. (1986). J . Am. Chem. Soc. 108, 3139 Harrison, A. G. (1983). “Chemical Ionization Mass Spectrometry”. C. R. C. Press, Boca Raton, Florida Harrison, A. G . and Jennings, K. R. (1976). J . Chem. Soc. Faraday Trans. 172, 1601 Hayes, R. N., Sheldon, J. C., Bowie, J. H. and Lewis, D. E. (1984). J . Chem. Soc. Chem. Comm. 1431
GAS-PHASE REACTIONS OF ORGANIC ANIONS
53
Hayes, R. N., Paltridge, R. L. and Bowie, J. H. (1985). J . Chem. Soc. Perkin Trans. 2, 567 Hayes, R. N., Sheldon, J. C. and Bowie, J. H. (1986). Organometallics 5 , 162 Henchman, M., Paulson, J. F. and Hierl, P. M. (1983). J . Am. Chem. Soc. 105, 5509 Henchman, M., Hierl, P. M. and Paulson, J. F. (1986). A. C. S. Symposium on Nucleophilicity. In press Hierl, P. M., Ahrens, A. F., Henchman, M., Viggiano, A. A. and Paulson, J. F. (1986). J . Am. Chem. Soc. 108, 3142 Hodges, R. V., Sullivan, S. A. and Beauchamp, J. L. (1980). J . Am. Chem. Soc. 102, 935 Ijames, C. F. and Wilkins. C. L. (1984). Chem. P h p . Lett. 108, 58 Ingemann, S. and Nibbering. N . M. M. (1983). J . Org. Chem. 48, 183 Ingemann, S. and Nibbering, N. M. M. (1984a). Can. J . Chem. 62, 2773 Ingemann, S. and Nibbering, N. M. M. (1984t). Nouv. J . Chim. 8. 299 Ingemann, S. and Nibbering, N. M . M. (1985s). J . Org. Chem. 50, 682 Ingemann, S. and Nibbering, N . M. M. (1985b). Acra. Chem. Scand. B39, 697 Ingemann, S.. Nibbering, N. M. M . , Sullivan, S. A. and DePuy, C. H. (1982a). J. Am. Chem. Soc. 104, 6520 Ingemann, S., Kleingeld, J. C. and Nibbering. N. M. M. (1982b). J. Chem. Soc. Chem. Comm. 1009 Janousek, B. K. and Braurnan, J. I. (1979). In “Gas Phase Ion Chemistry”, M. T. Bowers (ed.). Vol. 2, Academic Press. New York. p. 53 Jasinski, J. M. and Braurnan. J. I. (1980). J. Am. Chem. Soc. 102. 2906 Jennings, K. R. (1977). In “Mass Spectrometry”, Vol. 4, R. A. W. Johnstone (ed.), The Chemical Society, London. p. 203 Jennings, K. R. (1979). Phil. Trans. Roy. Soc. Lond. A293, 125 Johlman. C. L. and Wilkins, C. L. (1985). J . Am. Chlw?.Soc. 107, 327 Johlman, C. L., White, R. L. and Wilkins, C. L. (1983). Mass Spectrom. Rev. 2. 389 Jones, M . E., Kass, S. R., Filley, J., Barkley, R. M. and Ellison, G. B. (1985). J . Am. Chem. Soc. 107, 109 Kalcher, J., Rosmus, P. and Quack, M . (1984). Can. J . Phj3.7. 62, 1323 Karpas, Z. and Klein. F . S. (1975). Int. J . Mass Spectrom. Ion Phy.7. 18, 65 Kass, S. R. and DePuy, C. H. (1985). J . Org. ChCw?.50. 2874 Kass. S. R., Filley, J., Van Doren. J. M. and DePuy, C. H. ( 1 986). J . Am. Chem. Soc. 108, 2849 Kayser, M. M. and McMahon, T. B. (1984). Tetrohrdron Lett. 25, 3379 Kebarle, P. (1977). Ann. Rev. P / ~ J xChlw?. . 28, 445 King, G. K., Maricq. M. M., Bierbaum, V. M. and DePuy. C. H . (1981). J . Am. Chem. Soc. 103, 7133 Klass, G . and Bowie, J. H . (1980). Aust. J . Chem. 33, 2271 Klass, G., Trenerry, V. C., Sheldon, J. C. and Bowie. J. H. (1981). Aust. J . Chern. 34, 519 Kleingeld, J. C. and Nibbering, N. M . M. (1980). Tetrahedron Lett. 21, 1687 Klcingeld, J. C. and N-ibbering, N. M. M. (19834. Tetrahedron 39. 4193 Kleingeld, J . C. and Nibbering, N. M. M. (1983b). Int. J . Mass Spectrom. Ion Phys. 49, 31 I Kleingeld, J. C. and Nibbering, N. M. M. (1984a). Tetrahedron 40, 2789 Kleingeld, J. C. and Nibbering, N. M. M. (1984b). R d . Trav. Chim. Pays-Bas. 103, 87
54
NlCO M. M NIBBERING
Kleingeld, J. C., Ingemann, S., Jalonen, J. E. and Nibbering, N. M. M. (1983). J . Am. Chem. SOC.105, 2474 Knorr, F. J., Ajami, M. and Chatfield, D. A. (1986). Anal. Chem. 58, 690 de Koning, L. J. and Nibbering, N. M. M. (1984). J . Am. Chem. Soc. 106, 7971 de Koning, L. J. and Nibbering, N. M. M. (1987). J . Am. Chem. SOC.109, 1715 Laude, D. A,, Jr., Johlman, C. L., Brown, R. S., Weil, D. A. and Wilkins, C. L. (1986). Mass Spectrom. Rev. 5, 107 Lee, R. E. and Squires, R. R. (1986). J . Am. Chem. SOC.108, 5078 Leopold, D. G., Miller, A. E. S. and Lineberger, W. C. (1986). J. Am. Chem. Soc. 108, 1379 Lowry, T. H . and Richardson, K. S. (1987). “Mechanism and Theory in Organic Chemistry”, 3rd Edn., Ch. 3. Harper and Row, New York Mackay, G. I., Betowski, L. D., Payzant, J. D., Schiff, H. I . and Bohme, D. K. ( 1 976). J . Phys. Chem. 80, 2919 Magnera, T. F. and Kebarle, P. (1984). In “Ionic Processes in the Gas Phase”, M. A. Almoster-Ferreira (ed.), Reidel. Dordrecht, p. 135 Marshall, A. G. (1985). Acc. Chem. Res. 18, 316 Marshall, A. G. and Roe, D. C. (1980). J. Chem. Phys. 73, 1581 Marshall, A. G., Wang, T.-C. L. and Ricca, T. L. (1984a). Chem. Phys. Lett. 108,63 Marshall, A. G., Wang, T.-C. L. and Ricca, T. L. (1984b). Chem. Phys. Lett. 105,233 Marshall, A. G., Wang, T.-C. L. and Ricca, T. L. (1985). J . Am. Chem. SOC.107, 7893 McDonald, R. N. and Chowdhury, A. K . (1980a). J. Am. Chem. SOC.102, 51 18 McDonald, R. N. and Chowdhury, A. K. (1980b). J . Am. Chem. SOC.102, 6146 McDonald, R. N., Chowdhury, A. K. and Setser, D. W. (1980). J. Am. Chem. SOC. 102, 6491 McLafferty, F. W. (1983). “Tandem Mass Spectrometry”, J. Wiley and Sons, New York Melander, L. and Saunders, W. H., Jr. (1980). “Reaction Rates of Isotopic Molecules”, Wiley-Interscience, New York Meot-Ner (Mautner), M. (1979). In “Gas Phase Ion Chemistry”, M. T. Bowers (ed.), Vol. 1, Academic Press, New York, p. 197 Miller, T. M., Leopold, D. G., Murray, K. K. and Lineberger, W. C. (1985). Bull. Am. Phys. SOC.30, 880 Murphy, M. K. and Beauchamp, J. L. (1976). J . Am. Chem. SOC.98, 1433 Nibbering, N. M. M. (1979). In “Kinetics of Ion-Molecule Reactions”, P. Ausloos (ed.), Plenum Press, New York, p. 165 Nibbering, N. M. M. (1981). Recl. Trav. Chim. Pays-Bas 100, 297 Nibbering, N. M. M. (1984). Nachr. Chem. Tech. Lab. 32, 1044 Nibbering, N. M. M. (1985a). In “Mass Spectrometry, Specialist Periodical Reports”, Vol. 8, M . E. Rose (ed.), The Royal Society of Chemistry, London, p. 141 Nibbering, N. M. M. (1985b). Adv. Mass Spectrom. 10, 417 Nibbering, N. M. M. (1986). Recl. Trav. Chim. Pa-vs-Bas 105, 245 ,Noest, A. J. and Kort, C. W. F. (1983) Comput. Chem. 7, 81 Noest, A. J. and Nibbering, N. M. M. (1980a) Adv. Mass Spectrom. 8A, 227 Noest, A. J. and Nibbering, N. M. M. (1980b) Int. J. Mass Spectrom. Ion Phys. 34, 383 Noest, A. J. and Nibbering, N. M. M. (1980~)J . Am. Chem. SOC.102, 6427 Olmstead, W. N. and Brauman, J. I . (1977). J . Am. Chem. SOC.99, 4219
GAS-PHASE REACTIONS OF ORGANIC ANIONS
55
Paulson, J. F. and Henchman, M. J. (1982). BUN. Am. Phys. Soc. 27, 108 Peerboom, R., Ingemann, S. and Nibbering, N. M. M. (1985). Reel. Trav. Chim. P U ~ S - B U104, S 74 Pellerite, M. J. and Brauman, J. I. (1983). J . Am. Chem. Soc. 105, 2672 Pellerite, M. J. and Brauman, J. I . (1980). J . Am. Chem. Soc. 102, 5993 Riveros, J. M., Jost, S. M. and Takashima, K. (1985). Adv. Phys. Org. Chem. 21, 197 Rondan, N. G., Houk, K. N., Beak, P.. Zajdel, W. J., Chandrasekhar. J. and Schleyer, P. von R. (1981). J . Org. Chem. 46, 4108 Ross, B. R. and True, N. S. (1984). J . Am. Chern. Soc. 106, 2451 Russell, D. H. (1986). M a s s Spectron?. Rev. 5, 167 Schleyer, P. von R., Clark, T., Kos, A. J., Spitznagel, G . W., Rohlde, C., Arad, D., Houk, K. N. and Rondan, N. G . (1984). J . Am. Chen7. Soc. 106, 6467 Schmitt, R. J., Bierbaum. V. M. and DePuy. C. H. (1979). J . Am. Chem. Soc. 101, 6443 Seebach, D., Lohmann. J. J., Syfrig, M. A. and Yoshifuji, M. (1983). Tetrahedron 39, 1963 Sheldon, J. C. and Bowie, J. H. (1982). Nouv. J . Chin?.6, 527 Sheldon, J. C., Hayes, R. N. and Bowie, J. H. (1984a). J . Am. Chem. Soc. 106, 771 1 Sheldon, J. C., Bowie, J. H. and Hayes, R. N. (1984b). Nouv. J . Chim. 8, 79 Smith, D. and Adams, N. G. (1979). In “Gas Phase Ion Chemistry”, M. T. Bowers (ed.), Vol. I , Academic Press, New York, p. 1 Smith, M. A,, Barkley, R. M. and Ellison, G. B. (1980). J . Am. Chem. Soc. 102,6851 Squires. R. R. (1984). In “Ionic Processes in the Gas Phase”, M. A. AlmosterFerreira (ed.), Reidel, Dordrecht. p. 337 Squires, R. R., DePuy, C. H. and Bierbaum, V. M. (1981). J . Am. Cliem. Soc. 103, 4256 Squircs, R. R., Bierbaum, V. M., Grabowski, J. J. and DePuy, C. H. (1983). J . Am. Chem. Soc. 105, 5185 Stewart, J. H., Shapiro, R. H., DePuy, C. H. and Bierbaum. V. M. (1977). J . Am. Chetn. Soc. 99, 7650 Su, T. and Bowers, M. T. (1979). In “Gas Phase Ion Chemistry”, M. T. Bowers (ed.), Vol. I . Academic Press, New York, p. 83 Takashima, K. and Riveros. J. M. (1978). J . Am. Cheni. Soc. 100, 6128 Viehe, H. G., Merenyi, R., Stella, L. and Janousek, Z. (1979). Angew. Chem. 91. 982 Wanczek, K.-P. (1984). I t i t . J . M a s s Spectrom. Ion Proc. 60, 1 1 van Doorn. R. and Jennings, K. R. (1981). Or,?. M a s s Spectrom. 16, 397 van der Wel, H. and Nibbering, N. M. M. (1986). hit. J . Mass Spectrom. Ion Proc. 72, 145 van der Wel, H., Kayser, M. M. and Nibbering, N. M. M. (1987). Manuscript in preparation Werstiuk, N. H. (1983). Tetrahedron 39, 205 Wilson, J. C. and Bowie, J. H. (1975). Aust. J . Clieni. 28, 1993 Yamabe, S. and Minato, T. (1983). J. Org. Chem. 48, 2972 Yamabe, S., Minato, T. and Kawabata, Y. (1984). Can. J . Chem. 62, 235
This Page Intentionally Left Blank
Hydride Shifts and Transfers C. IAN F. WATT Chemistry Department, University of Manchester, U.K. 1
2
3
4
5
Introduction 58 General considerations 58 Single step and multistep processes 58 Experimental characteristics of hydride transfers and shifts 60 Theoretical studies of hydride motion 63 Metal-to-carbon transfers 66 Alkenes and metal hydrides: experimental studies 66 Alkenes and metal hydrides: theoretical studies 67 Elimination of metal hydrides from organometallics 68 Complex metal hydrides and polar functional groups: experimental studies 69 Complex metal hydrides and polar functional groups: theoretical studies 72 Anionic carbon-to-carbon hydride transfers and shifts 74 Gas-phase and theoretical studies 74 Variants of the Meerwein-Ponndorf-Verley reaction 76 Variants of the Cannizzaro reaction 81 Possible single electron transfer mechanisms 84 Miscellaneous anionic reactions 86 Cationic carbon-to-carbon hydride transfers and shifts 86 Gas-phase and theoretical studies 86 Transfers between alkyl cations 88 Transfers to triarylmethyl and other stabilized carbocations 91 Reductions by dihydropyridines and related species 94 Kinetic and product isotope effect discrepancies 95 Oxidations by inorganic oxidants and quinones 95 Substituent effects on rates and equilibria 98 Miscellaneous reactions of dihydropyridines 101 Secondary hydrogen isotope effects 102 Theoretical studies 103 References 105
ADVANCES IN PHYSICAL ORGANIC CHEMISTRY VOLUME 24 ' ISBN 0-12-033524-7
Copyrighr Q 1988 Academic Press Limired A / / rights ofreproducrion in any form reserved
C. IAN F. WATT
58
1
Introduction
GENERAL CONSIDERATIONS
On a molar basis, most organic compounds contain similar amounts of hydrogen and carbon, and processes involving transfer of hydrogen between covalently bound sites rank in importance in organic chemistry second only to those involving the carbonxarbon bond itself. Most commonly, hydrogen is transferred as a proton between atoms with available electron pairs ( 1 ), i.e. Brmsted acid/base reactions. The alternative closed shell process, hydride transfer or shift, involves motion of a proton with a pair of electrons between electron deficient sites (2). These processes have four and two electrons respectively to distribute over the three atomic centres in their transition structures. It is the latter process, particularly when the heavy atoms are both first row elements, which is the subject of this review. The terms "transfer" and "shift" are used here only to differentiate intermolecular and intramolecular reactions. B - H" + : B"[B..H.. B]m+n-B:"-l + H - B"" (1) A
-
H"
+ A"-
[ A , . H . . A] "+"-Am-'
+ H - A"-'
(2)
Reactions apparently falling into this category range from the industrially important carbocationic processes involved in hydrocarbon cracking, through traditional reactions such as the Cannizzaro and Meerwein-Ponndorf-Verley-Oppenauer reactions, to biological redox couples involving nicotinamide- and flavin-based co-factors. In these examples, the hydride accepting and donating atoms are both carbon, but reactions involving atoms at the electropositive end of the first row are also common and fall within the scope of the survey. Not surprisingly, a number of reviews within the last five years have touched on the topic of hydride motion. The charge combinations in the reactions mentioned are typical; a neutral component reacts either with a cationic acceptor, or an anionic donor. Intermolecular transfers of hydrogen as hydride in neutral transition states are rare in non-enzymic redox reactions, borohydride reduction of a cyclopropenium perchlorate being one such (Pawlowski and Sinnhuber, 1980). However, migrating hydrogen in symmetry-allowed sigmatropic shifts may assume hydridic character in appropriate circumstances. Analysis of the electron density surfaces in the calculated transition structures for the [1,5]hydrogen shifts in 1,3-pentadiene, cyclopentadiene, and 3-cyanopentadiene show that the size and charge on the migrating hydrogen varies with the ability of the framework itself to accommodate charge (Kahn et al., 1985). Extreme cases, for example, in [ 131-sigmatropic shifts across cycloheptatrienes, may be viewed as migration of an anionic group across a stable carbocation.
59
HYDRIDE SHIFTS AND TRANSFERS S I N G L E S T E P A N D M U L T I S T E P PROCESSES
Net transfer of a proton and two electrons may occur other than by direct transfer of hydride ion between the bonding sites. Single electron transfer followed by hydrogen atom transfer, e/H-, (3), or indeed the reverse sequence, H./e, (4), achieves the same result, as do sequential electronproton-electron transfers, e/H+/e, (5). e/H. transfers: A
-
H"
+ A"-A
A - H F + ++ ' A:-'-A"+~
- H'!'+'
+ A?-'
+ H - A"-'
(3)
H * ie transfers: A A':
-
H"
+ A"-AF
+ H - A':-A"+'
+ H - A!' + H -A"-'
(4)
e/H +/e transfers:
+
+
A - H" A"-A - H'!"' A:-' A - H'!"' + Al-'-A"+ H - A" A? H - A : - A " + ' H - A"-'
+
+
(5)
Much effort has been devoted to experiments designed to distinguish concerted and stepwise processes. The single electron transfer sequences necessarily involve radical species, charged and otherwise, which may be detectable and shown to lie on the reaction pathway. However, a sequence of electron or atom transfers may occur completely within a donor-acceptor complex, and discrete free radicals may not be formed. If the intermediates proposed are very short lived, for example in the e/H+/e sequence (6), then the distinction between the sequence of intermediates and a concerted hydride transfer within the complex may well be a matter of semantics rather than science (Pross and Shaik, 1983; Pross 1985a,b). In the absence of detection of intermediate radicals, kinetic arguments as to the feasibility of single electron processes are increasingly being applied. A number of related empirical relationships are available (Murdoch, 1983), the most familiar of which is the Marcus equation (Marcus, 1968), shown in simplified form in (7). This relates free energy of activation for an electron (or group) transfer, AG*, to the free energy change in the process, AGO, and the average of the activation energies for the two appropriate identity reactions, AGZ. Provided the appropriate electrochemical data and estimate of self exchange rates are available to obtain AGOand AG: values, these permit at least order of magnitude calculation of rates of electron transfer within the reaction
60
C. IAN F WATT
complexes. Comparison with experimental data (Eberson, 1982, 1984) may possibly exclude stepwise processes. [A-H
'A']
C [A*H+*A']C [A. +H*A']C [A' AG' = AGO[I
H-A']
+ (ACo/4AG~)]2
(6) (7)
Substituent or solvent effects may be similar for concerted and stepwise processes. It has been shown that provided the rates of reverse reactions are almost independent of changes in oxidation potential, plots of E", the standard reduction potential for the half cell (8) against log k, for a series of acceptors, Ox', reacting with a hydride donor must have a slope of 30 mV/ log unit whether the rate-limiting step is hydride transfer, or hydrogen-atom transfer, or electron transfer (Kurz and Kurz, 1978). Ox'
+ H C + 2eC-RedH
(8)
Occasionally, extreme positions have been adopted, and arguments have been presented (Okhlobystin and Berberova, 198 1) and countered vigorously (Kashin, 1981), that all net transfers of hydride in organic reactions are stepwise processes. Net hydride transfer may also occur in a stepwise fashion without radical intermediates. There may be o-bond formation between donor and acceptor, particularly when resonance stabilized cationic acceptors react with a donor containing nucleophilic lone pairs on heteroatoms (9). Plausible fragmentations then lead to the products of transfer to the cation of hydride p- to the heteroatom.
EXPERIMENTAL CHARACTERISTICS OF H Y D R I D E TRANSFERS A N D SHIFTS
This introduction has outlined problems associated with a proper description of the hydrogen in motion. In many reactions, hydride motion is associated with complete transfer of an X-H bond, having hydridic character, to the ends of an unsaturated array. Isolation of the characteristics of the hydride transfer is rarely straightforward. With a reaction established as hydride transfer, the remaining questions relate to the timing of the bonding changes, looseness or tightness of the
HYDRIDE SHIFTS AND TFANSFERS
61
transition state, and to transition structure geometries. Much of the earliest discussion and speculation drew heavily on qualitative arguments from molecular orbital theory (Swain et al., 1961, Lewis and Symons, 1958) which suggested that, because antibonding orbitals were not populated, the hydride transfer transition states would be tighter than those of related proton transfers. Direct experimental comparisons of’ their requirements have not been made, but details of “in”-protonated 1,6-diazabicyclo[4.4.4]tetradecane [ I ] (Alder et af., 1983), and of the remarkably stable p-hydrido-bridged cation from the protonation of “in”-bicyclo[4.4.4]tetradec- 1 -ene [2] (McMurray and Hodge, 1984) are becoming available. In both cases, there is evidence that the encapsulated hydrogen occupies a single minimum potential energy well between the bridgehead sites, and structural comparisons may eventually be possible. It has also been suggested that bent arrays with closed orbital overlap might be favoured. Analogies have been drawn with borane structures, and calculations on H<, as the simplest transition state model indicate a triangular array (Christoffersen and Shull, 1968; Huang et al., 1972).
With hydrogen in motion, primary kinetic isotope effects (k.i.e.) afford a direct probe of transition-state structure. However, neither their absolute values, nor their temperature dependence are simply related to transition state geometry. An early compilation of hydride transfer data (Stewart, 1976) contained most values lower than the “normal” 6 or 7. Small primary k.i.e.’s have been associated with both unsymmetrical hydrogen transfers, and non-linear arrays, but modelling using bond-order methods (Sims and Lewis, 1984) makes it clear that the primary isotope effect measurement must be supported by judicious secondary isotope-effect data before any conclusions can be drawn. A proposal (Kwart, 1982) that temperature independent k.i.e.’s are associated with non-linear [A. . . H i . .A]* arrays has been examined closely (McLennan and Gill, 1985). Calculation of isotope effects in models with a bent array, using force constants generated from bond energy-bond order (BEBO) relationships, show that, within the semiclassical approximation, i.e., before application of any correction for light atom tunnelling, single value k,/k,-values are strongly model dependent, even for a given angle value. Furthermore, all k.i.e.’s are temperature
62
C
IAN F WATT
dependent to some degree. In terms of Arrhenius activation energies, E,, and probability factors, A , the k.i.e.'s are the result of isotopically induced energy differences, i.e., [AE,]; > 0, rather than differences in probability factors, i.e. A , / A , = 1. Similar conclusions follow from calculations of the non-linear proton transfer in monoprotonated methylenediamine, using force constants from an MNDO MO calculation (Anhede and Bergmann, 1984), and of [ 1,5]-hydrogen shifts in cis-l,3-pentadiene using force constants from ab initio MO calculation (Dormans and Buck, 1986). The organic reactions of interest are those involving formal motion of hydride ion between electron deficient centres. Before proceeding to detail of these transfers, examination of some relevant characteristics of the ion itself is in order. TABLE 1 Selected properties of hydride ions Gas phase ion dataa efH,(g)-+ H-(g) H-(g)-+ H- e H+(g) + H-(g)+
P.A.
143.2 kJ mol65.0 kJ molI771 .O kJ mol-
Solution data'sc H-(aq)+ tH,(g) eH-(aq)+ H. e H-(THF)-r H. e-
E" E" (est.) E" (est.)
-2.25 V vs NHE -0.14 V vs NHE -0.5 V vs NHE
+
+
+ +
+
AHfo I.P.
Crystallographic datad*' Apparent crystallographic radius in LiH Apparent crystallographic radius in CsH Estimated free ion radius
'
' '
I37 pm 152 pm 208 pm
" Rosenstock et a/.,1977; 'Latimer, 1968; ' Eberson, 1984; Greenwood and Earnshaw, 1984; Magee, 1968
Table 1 contains selected gas, solution and crystal data, and these clearly show that hydride combines high basicity with ease of oxidation, the characteristics of a soft base. Ionic hydrides can only be formed from the most electropositive elements. The ion is large, and the variation in crystallographic radius in the alkali metal salts indicates a readily polarized species. Ionic hydrides are not stable in either hydroxylic or amine solvents. yielding molecular hydrogen and lyate anion, but combinations of metal hydride and metal alkoxide are effective reducing agents (Caubere, 1983). Potassium hydride precipitates from solutions of potassium methylamide in methylamine under H, pressures above 1.4 MPa (Holtslander and Lockerby, 1978). Isotopic exchanges between D, and cyclohexylamine catalysed by alkali
63
HYDRIDE SHIFTS AND TRANSFERS
-
metal cyclohexylamide (Symons et al., 1979) have low activation energies. The lithium salt (E, = 16.5 kJ mol-’) is l o p 4 times as effective as the caesium salt. An approximate pK, of 37 has been estimated for hydrogen under the cyclohexylamine conditions (Buncel and Menon, 1976). Much slower isotopic exchange with H,O occurs in dimethyl sulphoxide (DMS0)water mixtures catalysed by tetramethylammonium hydroxide (Buncel and Symons, 1976). Free energies of activation (AG’) range from 1 1 1 kJ mol-’ for pure water to 86.7 kJ mol-’ for 96.9 mol % DMSO. Transfers of transition states from water to the aqueous dimethyl sulphoxide mixtures are endothermic (57.4 kJ mol-’ for 96.9 mol % DMSO), consistent with transition-state desolvation in the DMSO-rich mixtures. These exchanges are not believed to involve formation of deuteride ion. Rather, the data are rationalised in terms of rate-limiting attack of solvent on a transient complex between deuterium and either hydroxide or amide anion. In the low dielectric constant cyclohexylamine medium, ion-pair or other aggregates are certainly involved. Hydride ion is readily obtained in the gas phase by electron impact on ammonia or methane. Small molecule/hydride adducts are not produced directly, but NH, (Kleingeld el al., 1983) and H,O- (Kleingeld and Nibbering, 1983; Paulson and Henchman, 1982) are observed in the gas phase from the reaction of amide or hydroxide anions with formaldehyde. Labelling studies show that the hydrogens in these adducts d o not become equivalent, and both are best described as solvated hydride ions. Early MO calculations suggest that these adducts should revert to hydrogen and the amide or hydroxide anion without activation (Ritchie and King, 1968a,b,c). More recent studies of H i , with configuration interaction (Rayez et al., 1981) show it to be weakly bound ( - 4 kJ mol-’) relative to hydride and H,, and it is likely that improved calculations of the larger adducts will also show them to be bound species. THEORETICAL STUDIES O F H Y D R I D E MOTION
In practice, reactions involving motion of hydride alone are exceptional, and, indeed, may only occur in the rarefied atmosphere of the mass spectrometer or the even rarer atmosphere of theoretical calculations. Hydride has been a popular “test nucleophile” in theoretical studies of substitution or addition reaction pathways, and a number of high level calculations are available for model systems. In all these, absolute energies are strongly dependent on the level of theory applied. Relative stabilities change much less, however, so that reaction pathways are usually calculated with a small basis set (or using semi-empirical methods), and energies of special points on the PE surface then recalculated with larger basis sets, or
C. IAN F. WATT
64
with allowance for correlation effects. Details of transition structures do not appear to be strongly dependent on the level of theory applied, but it has been pointed out that minimal basis sets are unlikely to yield a physically plausible description of hydride ion (Tapia et af., 1985). Medium basis sets (double zeta type) are almost certainly necessary for this polar diffuse structure, and correlation effects may be large. Additions to ethylene (Strozier et al., 1979), propene (Paddon-Row et al., 1982) and acetylene (Dykstra et al., 1978; Eisenstein et af., 1978; Strozier et af., 1979) have been studied both with SCF and correlated wave functions. Vinyl anion formation from acetylene is exothermic by 109 kJ mol-' and the minimum energy approach of the hydride makes an angle He . .C-C of 126" which is slightly larger than that in the product. The acetylenic hydrogens take up a trans-motion to yield the bent vinyl anion. The process has an estimated barrier of 67 kJ mol- ', with the transition structure [3] occurring when the incoming H - . . .C distance is 2.10 A. Addition of hydride to the carbon of the isoelectronic hydrogen isocyanide (Nguyen et af., 1985) is more exothermic ( - 3 13.1 kJ mol- at the MP4/6-3 1 G** level), and occurs without barrier. The minimum energy approach angle is again similar to the final N-C-H angle of 1 16" in the methyleneimine anion. The lone pair on carbon and the N-H adopt a trans-relationship, so that the product anion has the Z-configuration. The formation of the ethyl anion from ethylene is less exothermic, but an activation energy similar to that for the acetylene addition has been obtained. In the transition structure [4], the H. . C=C angle (124") is again slightly larger than that in the product and the C . . .H distance is 1.894 A. The behaviour of the attached ethylenic hydrogens mimics that in the acetylene addition in that they move in a trans-fashion.
'
+
H-
"\ [51
HYDRIDE SHIFTS A N D TRANSFERS
65
Carbonyl addition is arguably the most important and approach of hydride, or its delivery from a range of hydride sources, has been examined. The prototype reactions, addition of isolated hydride to formaldehyde yielding methoxide, was first mapped using SCF-LCAO-MO calculations (Burgi et d., 1974a,b). For this and other nucleophiles, the minimum energy approach lies in the plane which contains the C=O bond and is perpendicular to the plane of the trigonal carbon and its ligands. In the final stages of the approach, with C . . .H distances of less than 2.0 A, the PE surface shows a distinct cone of preference, with its axis an extension of that of the developing C-H bond. As the nucleophile approaches, adjustments in angles and distances at the trigonal carbon occur so that there is a smooth transformation to the near tetrahedral geometry of the product. The energy along the reaction path decreases monotonically, reaching a minimum for the methoxide anion at -204.3 kJ mol-' relative to formaldehyde and isolated hydride. Higher levels of theory (6-3 1 lG**) however, indicate the existence of an unsymmetrical H-bonded complex with a barrier of 23.9 kJ molpl separating it from the methoxide anion (Sheldon et al., 1984). This addition has been observed (Bohme et al., 1980) in the gas phase using flowing afterglow methods. With formaldehyde at relatively high pressures (-0.5 Torr) and inert helium (also 0.5 Torr) to remove energy appearing as internal vibration, the rate constant at 297 K is (2 f 1) x 1026cm6 molecule-' s- and under these conditions, hydride and hydroxide are equally reactive nucleophiles. Calculation of the structure of the addition product, methoxide (Steigerwald et al., 1979) points to the relative weakness of its C-H bonds. Bonddissociation energy, i.e. for homolysis yielding hydrogen atom and the formaldehyde radical anion. is Do = 310.6 kJ mol-' compared with 379.7 kJ mol-' for the corresponding fragmentation of methanol. In MO terms, the effect arises from transfer of electron density from oxygen lone pairs to C-H antibonding orbitals. Alternatively, it may be described in terms of negative hyperconjugation, with resonance between canonical forms [5] and [6]. This oxyanionic effect is reduced by coordination of the oxygen to alkali-metal ions, with lithium being the most effective of the series. Comparison of the structures of methanol and methoxide calculated using a 4-31G basis (Williams, 1983) shows that the C-H bonds are 5% longer in the anion, and the C-0 bond shortened correspondingly. Force constants show a loosening of the C-H bonds in the anion, and harmonic frequencies obtained thus, yield secondary P-deuterium equilibrium isotope effects KD-H3/KP-D3 = 2.634 at 25" for deprotonation of methanol, within experimental error of the measurement, 2.30 0.4, For the gas phase reaction (DeFrees et al., 1977). The availability of high quality, gas-phase pK,-data for alcohols, and
C. IAN F. WATT
66
proton affinities for ketones or aldehydes, permit the construction of a thermochemical cycle yielding hydride ion affinities of ketones (Hutchings and Gasteiger, 1986) provided that heats of formation of the ketone and its reduction product are known. These have been correlated by linear equations with two or three parameters reflecting inductive effects, polarizability, and hyperconjugation. An ab initio MO study of the approach of hydride to I-hydronicotinamide has been used to examine the relative electrophilicity of the 4-, 2- and 6-positions of the cation (Umeyama, 1980). 2
Metal-to-carbon transfers
ALKENES A N D METAL H Y D R I D E S : E X P E R I M E N T A L S T U D I E S
Transfers of hydride from boron or lithium to carbon usually occur in the context of addition of the complete M-H moiety to polar or non-polar unsaturation. Additions of boranes to alkenes have been extensively reviewed (Brown et al., 1983a), but the experimental characterization of the hydroboration transition state remains problematic. Dialkylboranes, including 9-borabicyclo[3.3. llnonane (Wang and Brown, 1980), borinane (Brown et al., 1984), and disiamylborane (Chandrasekharan and Brown, 1985) have now been shown to be dimeric in hydrocarbon and ethereal solvents. With unreactive alkenes, their additions are first order in alkene and half order in the dimer. With reactive terminal alkenes, the reactions are first order only in dimer, with intermediate behaviour between these extremes. A reaction scheme (10) involving reaction of monomeric borane with the alkene satisfies the data, with the observed order depending on the ratio k k,
(RZB-H), R,B-H
k- I
2 RZB-H
+ alkene-
k2
R,B-alkyl
(10a)
(lob)
Rationalizations of hydroboration stereoselectivity using models with dimeric boranes are thus not viable. Recent secondary isotope-effect measurements may suggest a model (Mann et al., 1986). Addition of a chiral dialkyl borane to 3-deuterio-cis-3-pentene, followed by alkaline oxidation, yields equal amounts of 3- and 4-deuterio-3-hexanols showing that the secondary isotope effects at these alkene sites are vanishingly small. Deuterium substitution at the allylic sites has a much larger effect. Thus similar treatment of 4,4-dideuterio-cis-5-decene yields a 2.86 : 1 mixture of 4,4dideuterio- and 6,6-dideuterio-5-decanols. The corresponding additions of lithium hydride to alkenes have not been
67
HYDRIDE SHIFTS A N D TRANSFERS
observed, probably because of its poor solubility in appropriate organic solvents. However, organometallics, including trialkylboranes, tetraorganoborates (Bubnov et al., 1986; Gurskii et al., 1983) and alkyllithiums, may decompose thermally with formation of alkene by P-hydride elimination. With organomagnesiums in particular, the metal hydride produced is extremely active, and, with its high energy density, is potentially an important energy storage medium (Bogdanovic, 1985). Stereochemical and labelling studies indicate cis-elimination of metal hydride in the thermal decomposition of alkyllithiums, severely restricting possible transition-state geometries. The simplest consistent with the data is a four centre cyclic arrangement. Decomposition of n-octyllithium in hydrocarbon solvent is strictly first order, suggesting that the rate-determining step involves P-hydride elimination from within a fully associated octyllithium unit, probably its hexamer (Li and San Filippo, 1983) and the activation parameters, E, = 127 kJ mol-' and A = 5.94 x lo", are the same as those for n-butyllithium decomposition. Primary hydrogen-isotope effects, from product analysis in the decomposition of (n-octyl-2-D,) lithium ranged from 3.658 at 120" to 3.270 at 150". These incorporate an unquantified secondary a-deuterium k.i.e on the hydrogen loss, so the interpretation is not entirely clear. However, the temperature dependence yields [AE]; = 4.6 5.0 kJ mol-', close to the zero point energy difference for C-H and C-D bonds, and the ratio A , / A , = 0.724 is in the range usually taken as suggestive of hydrogen tunnelling. Given the likelihood of the four-centre array, the result at least undermines the contention that non-linear hydrogen transfers are characterized by temperature-independent k.i.e.'s (Kwart, 1982). Kinetic isotope effects in the hydrogenolysis of octyllithium similarly show a temperature dependence and yield activation parameters not strongly different from hydrogen transfers thought to pass through linear three-centre arrays (Vitale and San Filippo, 1982).
-
ALKENES A N D METAL HYDRIDES: THEORETICAL STUDIES
These experimental measurements have prompted ab initio MO calculations of model additions of lithium hydride (Houk et a[., 1985). With ethylene, monomeric lithium hydride initially forms a stable n-complex [7], which passes through a four-centre cyclic transition structure [8] to yield the ethyllithium [9], with energies relative to reactants of - 50.0, 28.5, and - 84.14 kJ molrespectively. The calculated activation energy for decomposition of ethyllithium thus compares reasonably well with the experimental value for octyllithium. Similar behaviour is calculated for the more exothermic lithium hydride addition to acetylene to yield vinyllithium at - 160.0 kJ mol- relative to reactants. Because of electrostatic stabilization
-
C. IAN F. WATT
68
of the developing carbanion by the Li+, the activation energies are at least 40 kJ mol-' below those calculated for the corresponding additions of isolated hydride ion which were outlined earlier (Strozier et al., 1979). Developing C. . .H bonds in the transition structures are 10% shorter in the presence of the cation
-
[71
The course of these additions of lithium hydride resembles that found for the addition of borane (Nagase et a/., 1980; Graham et al., 1981). With ethylene, the initial step is exothermic formation of a It-complex without barrier, then rate-determining transformation to the borane via a four-centre transition structure. In both the borane and lithium hydride additions, there is relatively little development of the new C-H bond with distances of 1.692 and 1.736 8, respectively in the transition structures. When a carbanionic product is not formed, for example in the reaction of lithium hydride with cyclopropenyl cation yielding cyclopropene and lithium cation (Tapia et al., 1985), reaction again occurs via a hydride-bridged complex, but the C. . .H. . .Li array remains nearly linear throughout the reaction. ELIMINATlON OF METAL H Y D R I D E FROM ORGANOMETALLICS
P-Hydride elimination from organolithiums is also induced by triphenyl borane or triphenylcarbenium tetrafluoroborate (Reetz and Stephan, 1977). Organostannanes, silanes, plumbanes, and germanes, and mercurials similarly react with the carbocation as shown in (1 I), with the formation of triphenylmethane and alkene (Uglova et al., 1977, 1982). The reactions are accurately second order, and reasonably described as E,2 reactions. Rates increase with electron-withdrawing substituents in the cation and with electron-donating substituents in the organometallic (Traylor and Koermer, 1981). For a series of 1,3-dimetallopropanes, Me,M(CH,),M'Me,, rates obey a Hammett-type relationship, with log k , correlating with the sum of the 0 ' constants for the CH,MR, groups. The data are consistent with a mechanism involving rate-limiting hydride abstraction P- to the metal in a
HYDRIDE SHIFTS A N D TRANSFERS
69
transition state [ 101 in which the organometallic develops high carbocationic character with charge stabilization by C-metal (J-X electron donation.
A requirement for an anti-orientation of the hydridic p-C-H and C-metal bonds as in [lo] is indicated by the reaction of threo-3-deuterio-2(trimethylstanny1)butane with triphenylcarbenium tetrafluoroborate in methylene chloride at 24" which yields a mixture of 3-deuterio- 1 -butene, rrans-2-deuterio-2-butene, and undeuteriated cis-2-butene as the major product (Hannon and Traylor, 1981). Comparison of the product distributions for the protio- and deuterio-stannanes yields primary and secondary isotope effects of 3.7 and 1.1 respectively. These reactions appear to avoid the complications of adduct formation between the triarylcarbenium salt and the hydride donor, but the preferential formation of the cis-2-butenes is not fully explained. The requirement for the anti-orientation is also shown by the relatively low hydride-donating properties of tris[(triphenylstannyl)methylmethane (Ducharme et al., 1984a) which adopts a C,-conformation with the p-C-H gauche to all three C-Sn bonds. In contrast, 1,3,5-triphenyl2,4,6-trithia- 1,3,5-tristannyladamantane,in which anti-orientations with respect to the bridgehead C-H bond are locked, shows high reactivity (Ducharme et al., 1984b). C O MP L E X METAL H Y D R I D E S A N D PO L A R F U N C T I O N A L G R O U P S : EXPERIMENTAL S T U D I E S
Complex metal hydrides, based on boron, aluminium, and silicon, reduce polar functional groups, including alkyl or aryl halides and all carbonyl variants. While often conveniently regarded as hydride sources, some reactions, particularly those of the aluminium- or silicon-based reagents, may involve either hydride transfer, or e/H- transfer sequences. With an estimated E,, (THF solution) lying between -0.1 and -,0.3 volts (Eberson, 1984), AIH, is a moderately strong one-electron reducing agent. Clean inversion of stereochemistry and the absence of cyclic products in lithium aluminium hydride reductions of simple primary halides such as 6-halo- I -
C IAN F WATT
70
hexenes are consistent with S,2 displacements of chloride, bromide or iodide and arenesulphonate esters by hydride delivered from the A1H 4 ion. However, hindered primary and secondary halides, particularly iodides. yield methylcyclopentane derivatives, indicating the intermediacy of the readily cyclized hexenyl radical, and the reductions may proceed with loss of stereospecificity. With triphenylmethyl halides, the trityl radical is easily observed (Ashby et al., 1984). An e/H. transfer sequence is also proposed for reductions of some ally1 halides (Hirabe et ul., 1985). Aryl halides and polynuclear hydrocarbons such as perylene (reduction potential - 1.64 V) have been shown to react with simple and complex main-group metal hydrides to give the hydrocarbon radical anion (Ashby et al., 1981b). Radical intermediates have also been implicated in trialkylsilane reductions of aromatic ketones (Yang and Tanner, 1986). The value of E,, for BH, is not known, but the borohydride radical, BH,., has been characterized by e.s.r and UV spectroscopy in oxidations of the anion by hydroxyl or azide radicals under pulse-radiolysis conditions (Symons et al., 1983; Horii and Taniguchi, 1986). Most borohydride reductions seem to be straightforward hydride transfers, but stepwise processes occur in the reductions of aryl bromides or iodides under photochemical or di-t-butyl peroxide initiation. Radical intermediates are shown by the formation of 3-methyl-2,3-dihydrobenzofuranin the reduction of o-allyloxyiodobenzene (Abeywickrama and Beckwith, 1986). Borohydrides are usually considered as carbonyl reducing agents, and both borohydride and aluminium hydride reductions of ketones have been reviewed, with an emphasis on the origins of the stereoselectivity in reductions of asymmetric groups (Wigfield, 1979; Ashby and Boone, 1979; Nasipur et al., 1984a). They differ markedly from ketone reductions by boranes such as 9-borabicyclo[3.3.1]nonane(Brown et ul., 1983b). As with alkene hydroboration, the borane reactive species in T H F solution is the monomer. Electronic effects are small, and in the opposite sense to those for borohydride reduction. Despite the apparent bulk of the reagent, it is less sensitive to steric effects as shown convincingly by the norbornanone/ camphor rate ratios of 6 for the borane reduction compared to 900 for alcoholic sodium borohydride. In alcoholic solvents, or aqueous mixtures, borohydride reduction of ketones shows good second order behaviour, despite the likely involvement of borohydride itself, and up to three additional active hydride donors. In alcoholic medium, ketones are reduced to the free alcohol and alkoxyborate anion containing solvent derived alkoxide residues (Wigfield and Gowland, 1976). Mono- and dialkoxy-borohydrides, at least, are established as additional reducing species (Wigfield and Gowland, 1978). These reductions are exothermic, 210 kJ mol- for cyclohexanone (Wigfield, 19'79), and
-
-
71
HYDRIDE SHIFTS AND TRANSFERS
-
typically have low enthalpies of activation, < 45 kJ mol-', large negative activation entropies - 140 JK-' mot-', and are accelerated by electronwithdrawing substituents in the carbonyl compound. Thus rates of sodium borohydride reductions of substituted aryl trifluoromethyl ketones in 2propanol correlate with 0,p = +3.12 (correlation coefficient, r = 0.9798) at 20°, with the p-amino- and p-dimethylamino-substituted ketones omitted from the treatment. This value of p is close to that for the methyl ketones despite the trifluoromethyl series being lo5 times more reactive. For 4ethyl-a,a,a-trifluoracetophenone, AH* = 11.3 kJ mol-' and AS* = 159 JK-' mol-' (Stewart and Teo, 1980). For this series also, a plot of log k for reduction against log K for hydration yields a line of slope 1.12, consistent with a transition state with substantial hydride bonding to carbonyl carbon. A correlation ( r = 0.9785) between logk for reduction of a series of aliphatic ketones and log K for equilibration of the ketone and alcohol has a slope of 1. I , which has also been taken to support a productlike transition state (Muller and Blanc, 1980, 1981; Boyer et al., 1979). For sodium borohydride in 2-propanol, the activation volume for reduction of acetophenone is - 1 1 cm3 mol-' (Brower and Hughes, 1978). Compound primary and secondary isotope effects, from comparison of rates of reaction for NaBH, and NaBD,, are inverse, ranging from 0.59 to 0.77 (Wigfield and Phelps, 1972). Both carbonyl carbon-I4 and deuterium isotope effects have been determined for reduction of benzophenone by sodium borohydride, lithium borohydride and lithium aluminium hydride (Yamataka and Hanafusa, 1986). At 25", the carbon isotope effects, k,,/k,,, are 1.066, 1.043 and 1.024 respectively, while the deuterium effects kH4/kD4, are 0.75, 1.089 and 1.10, in good agreement with the earlier results. BEBO calculations show that the experimental results can be reproduced by transition-state models with developing C. . .H bond orders of 0.75 (NaBH,), 0.55 (LiBH,) and 0.37 (LiAIH,), assuming a linear C . . . H . . .M array. Primary tritium effects, k(BH1) / k(BH,T-), for reduction of aliphatic ketones are also small, 3.2-3.8, and scarcely sensitive to ketone structure (Pasto and Lepeska, 1976). Secondary isotope effects associated with reduction of deuteriated ketones have also been measured. For substitution adjacent to the carbonyl, the k.i.e.'s show a structural dependence ranging from 0.890 for cyclohexanone, through 0.958 for cyclopentanone, to 0.978 for a 3,3-dialkylcyclobutanone(Boyer and Lamaty, 1985). These values are in the sense expected for loss of hyperconjugative interaction between the C-H/D bond and the carbonyl group in the transition state, and the structural variation can be rationalized within the recognized conformational dependence of such an effect. The effects of more remote deuteriation are less explicable. For reduction of 7,7-D2-bicyclo[2.2.1 ]heptan-2-one, k,/kD = 0.959, while endo,endo-D,bicyclo[2.2.l]heptan-2-one shows no effect
-
72
C IAN F. WATT
(Boyer et a/., 1980). The effects of the deuteriation on the exolendo-alcohol product ratio in these reductions would be informative, but has not been reported. A number of experiments point to the importance of coordination by electrophile at the carbonyl oxygen. In hydroxylic solvents, hydrogen bonding by solvent dominates other interactions. In dry diglyme, acetone, acetophenone, and benzophenone are reduced with production of the corresponding sodium tetraalkoxyborates (Kayser et a/., 1983) at reduced rates compared to reactions in alcoholic media. The kinetic involvement of hydroxylic solvent is shown by the effect of added 2-propanol to reactions in diglyme which are approximately 3/2 order with respect to the added alcohol (Wigfield and Gowland, 1977). Sodium or tetramethylammonium borohydride reductions of acetone, pivalaldehyde, and benzaldehyde in aqueous DMSO show second order kinetics in water-rich mixtures (Adams et al., 1977a). Rates decrease dramatically as the water content is reduced, and deviations from second order kinetics occur in the later stages of the reaction in 100% DMSO. Isotope exchange between the aldehydic hydrogen of benzaldehyde and tritiated sodium borohydride has been observed under these conditions (Adams et a/., 1977b), and this may be associated with a Pfitzner-Moffat type reoxidation of benzyloxide by a DMSO/borane complex, rather than reversibility of the hydride-transfer step (Wigfield and Pon, 1979). Isotopic exchange involving solvent proton sources has been found during hydrolysis of borohydride in moist acetonitrile (Meeks and Kreevoy, 1939). In non-hydroxylic solvents, the effects of the cation co-ordination become important, particularly if the cation is Li’ or Zn+*. Lithium borohydride reductions of cyclohexanone, in THF, for example, are strongly inhibited by addition of the stoichiometric amount of the lithium specific [2.1.Ilcryptand (Handel and Pierre, 1975). In the reduction of a,p-unsaturated ketones, lithium borohydride shows a strong selectivity for 1,2-addition (D’Incan et al., 1982a,b) but in the presence of the cryptand, conjugate addition is favoured; indeed, the selectivity is then indistinguishable from tetrabutylammonium borohydride (D’Incan and Loupy, I98 I ; Loupy and SeydenPenne, 1979, 1980). C O M P L E X METAL H Y D R I D E S A N D P O L A R F U N C T I O N A L G R O U P S : THEORETICAL STUDIES
No clear consensus as to the nature of the transition state(s) for borohydride reduction has arisen from the experimental studies, but a number of recent MO calculations provide pictures which are consistent with available data, and serve to unify diverse results for the perplexed experimentalist. The
73
HYDRIDE SHIFTS AND TRANSFERS
prototype reaction of formaldehyde with borohydride anion has been studied by MNDO calculation (Dewar and McKee, 1978) and, more recently, by ah initio methods using 3-21G and 6-31G* basis sets (Eisenstein et al., 1982). While the results of the semi-empirical calculations strongly favour a two-step conversion to methoxyborane, with initial endothermic transfer of hydride from boron to carbon, followed by boron-oxygen bond formation, those from the ah initio methods indicated that the addition could proceed, without the intermediacy of borane and methoxide, via a four-centre transition structure [I I], but with strongly non-synchronous bond reorganization. Transfer of hydride from the boron to carbon is nearly complete, while boron-oxygen bonding is in its early stages. This structure lies at an energy 125.6kJmol-' above that of the reactants, but is still 21 kJ mo1-l below the intermediates in the two-step pathway. Inclusion of a single water molecule, hydrogen-bonded to the carbonyl oxygen, to model the effect of a protic solvent, does not strongly affect the transition-structure geometry, but it renders the overall process more exothermic, and lowers the activation energy to 38.1 kJ mol-'. These results are at least consistent with the observation by FT-ICR spectroscopy (Kayser and McMahon, 1984) that formaldehyde does not react with borohydride anion in the gas phase. Furthermore, the gas-phase reaction of perdeuteriomethoxide with diborane yields dideuterioformaldehyde, and B,H,D-, indicating that diborane, and presumably borane itself, has a higher hydride affinity than formaldehyde.
As might be expected, the course of the reaction is profoundly altered by inclusion of a lithium cation in the treatment of the complete borohydride salt. Ah initio calculation (Bonaccorsi rt al., 1982) shows that LiBH, in the gas phase is a tightly bound ion pair. The initial step of its reaction with formaldehyde or acetone involves coordination of the "lithium to the carbony1 oxygen to give a complex with a linear C=O. . .Li. . .B array, at 210 kJmol-' relative to reactants. This does not dissociate to BH; and
-
74
C IAN F. WATT
C H 2 0 L i f , but deforms to allow attack of the borohydride on the carbonyl in the transition structure [ 121. The barrier height is 277.5 kJ mol- relative to the complex. At this point, atomic overlap population analysis, and inspection of interatomic distances, indicates that only marginal development of the new C-H bond has occurred. Non-specific solvent effects have been modelled (Bonaccorsi et ul., 1983) by approximating the statistically averaged description of the solvent with a continuous dielectric. With a set of macroscopic values corresponding to diethyl ether, the effects on the mechanism were remarkably small. The complex hydride is more ionic, and the initial adduct now closely resembles an ion pair CH,OLi+BH,, and the looser interaction allows more favourable placing of the BH, for hydrogen transfer in the transition state. The barrier relative to the complex is lowered to 183.4 kJmol-'. The carbonyl additions of simpler hydrides, magnesium hydride (Nagase and Uchibori, 1982), lithium hydride monomer and dimer (Kaufmann et ul., 1985) show similar patterns. All are strongly exothermic reactions, being dominated by development of the favourable RO- M'" interaction. All involve initial exothermic formation of complexes with linear C=O. . .M arrays, which pass through transition structures, illustrated for the lithium hydride monomer [13], which do not have energies above the reactants, to the metal alkoxide. Like the lithium borohydride reaction, C. . . H bond formation is not appreciably advanced in the transition structures with C. . . H distances ranging from 2 to 2.7 A, and it has been pointed out that the trajectory of the hydride nucleophile is determined by the counterion. Integrated electron-population analysis indicates that the lithium carries a charge of +0.85 throughout the reaction. Molecular orbital analysis of the transition structures of the lithium hydride/formaldehyde or lithium hydride/acetaldehyde additions (Bachrach and Streitwieser, 1986), shows that their HOMOS are formed by mixing of the HOMO of lithium hydride with a linear combination of the HOMO and LUMO of the aldehyde, and it is the HOMO/HOMO interaction which allows transfer of electron density from the hydride to the oxygen. 3 Anionic carbon-to-carbon transfers and shifts GAS-PHASE A N D THEORETICAL STUDIES
Carbanions, alkoxides and alkylamides all behave as reducing agents under appropriate circumstances. The effect of hyperconjugative interaction between a C-H bond and negative charge on an adjacent atom has already been noted, and, in most but not all cases, the reductions are accommodated within the framework of hydride transfer from an activated C-H bond to an electrophile, usually carbonyl carbon.
75
HYDRIDE SHIFTS AND TRANSFERS
Gas-phase transfers of hydride from methoxide to CO,, CS, and SO, have been observed by the flowing afterglow technique (Bierbaum et a/., 1984) and by Fourier transform ion cyclotron resonance spectroscopy (FTICR) (Sheldon et al., 1985). With aldehydes and ketones, the normal gasphase reaction with methoxide is enolate formation, but FT-ICR methods have been used to demonstrate reduction of non-enolizable aldehydes including benzaldehyde, pivalaldehyde, and I-adamantylaldehyde, The formation of CD,HO, CDH,O and CH,O has been observed in reaction of CD,O- with formaldehyde (Ingemann et a/., 1982, 1984; Kleingeld rt a/., 1983), and the potential surface for hydride transfer between methoxide and formaldehyde has been explored by ah inifio SCF calculations (Sheldon et a/., 1984). These show initial formation of an unsymmetrical H-bonded complex, -93 kJ mol-’ relative to the isolated reactants, which may rearrange exothermically to a tetrahedral adduct over a low barrier of -20 kJ mol-’. The barrier to hydride transfer via a centrosymmetric transition structure [14], is higher, at -60 kJ mol-’ relative to reactants, or 33 kJ mol-’ relative to the complex. The closely related transfer of hydride between methylamine and methylene iminium ion (Hutley et af., 1986) is also calculated at the 3-21G level to pass through a centrosymmetric transition structure [ 151 at 38.1 kJ mol- relative to reactants, although the barrier to rotation about C. . .H. . .Cis less than 1 kJ mol- l . In both cases, these high level calculations show that there is no necessity for non-linearity in the hydride transfer. For the latter, normal mode analysis was carried out using scaled force constants from the MO calculations to yield the primary hydrogen k.i.e. Interestingly, the calculated semi-classical value of k,/k,, 2.34 at 25”, is well below the “normal” despite the symmetrical transition structure. The imaginary frequencies are quite high in the transition structures, resulting in an appreciable Bell correction of 1.44 for quantum mechanical tunnelling by hydrogen. Unfortunately, although the semiclassical k.i.e. is not strongly dependent on the basis set used, the tunnelling corrections are, and it is not possible to take tunnelling as a hydride transfer characteristic.
’
+ H
+.
H . . . ,, .H !:!28,
1-412
N, H H
76
C. IAN F. WATT
Semi-empirical MO calculations (MNDO) also indicate that the transition structure for transfer of hydride from methylamide anion to formaldehyde has a near linear C . . .H. . .C array, and a transoid arrangement of oxygen and nitrogen residues (McKee, 1985). In this case, the effect of introducing a lithium cation, i.e. reduction of formaldehyde by lithium methylamide, was explicitly examined. With monomeric amide, an initial complex is formed by lithium-coordination to the formaldehyde oxygen. Transfer of hydride then occurs via a six-centre transition structure [16], yielding a complex of lithium methoxide and methylene imine. Initial complex formation is exothermic so that the transition structure for its rearrangement still lies below reactant energies.
V A R I A N T S OF THE MEERWEIN-PONNDORF-VERLEY
REACTION
The preceding examples are closely related to the traditional MeerweinPonndorf-Verley ketone or aldehyde reductions in which the reducing agent is a metal alkoxide. Although its synthetic use has declined since the ready availability of complex metal hydrides, it has attracted attention as a model reaction since, involving transfer of hydride between carbonyl groups as it does, it is expected to have a high degree of local symmetry in the hydride transfer step. The traditional process uses aluminium alkoxides of primary or secondary alcohols as the hydride sources. Kinetic measurements are complicated by the different aggregation states of these alkoxides, but, for aliphatic reagents at least, the available data and stereochemical results are consistent with an associative mechanism in which the aluminium alkoxide coordinates to the receiving carbonyl partner, and then both hydride and metal are transferred in a chaii-like six-centre cyclic array resembling [ 171. Molecular orbital arguments applied to model arrays suggest that the carbonyl component is activated in the process, not by an electrostatic effect, but by orbitals on the aluminium which permit mixing between the K and K*
HYDRIDE SHIFTS AND TRANSFERS
77
MOs of the carbonyl group (Imamura and Hirano, 1975) and allow a better match of frontier orbital energies. Other metal alkoxides, including those of tin (Casiraghi rt d., 1980) and the alkali metals, also behave as hydride donors (Burnett and Kirk, 1976). The ordering of reactivity within the alkali metal series is Li > Na > K in the ratio 22 : 3 : I for reduction of acetophenone by 2-propoxide. This is the order of increasing ionic radii, and corresponding decreasing co-ordination ability, of the cations, and is consistent with the associative process proposed for the Al 3-mediated process. The p-values for reductions of substituted acetophenones range from 1.45 for lithium 2-propoxide to 1.75 for potassium 2-propoxide. It has been pointed out that if these are characteristic of hydride transfer with near symmetrical C . . . H bonding arrangements, the value p > 3 found for sodium borohydride reductions reflects considerably more transfer of negative charge to the receiving carbonyl group. However, different p-values cannot be taken as straightforward indicators of the degree of hydride transfer, because differing degrees of charge neutralization by the coordinating cation are likely. With these intermolecular reactions, there are no strong steric effects operating against achievement of the six-centre cyclic array, in which the 0.. .O distances, d, are likely to be between 3.0 (for M = Al+3) and 4.0 A (for M = K +). The intramolecular variant, base-induced rearrangements of hydroxy-ketones in which cdrbonyl and secondary alcohol functions are exchanged, are relatively common, and involve a shift of the alcohol methine hydrogen to the ketonic carbon. The longest range that has been characterized is a formal 1,6-shift occurring in the rearrangement of prephenate to p hydroxyphenyllactic acid (Danishevsky et al., 1979). In this case, the molecular framework may accommodate the six-centre cyclic array, but in most cases, particularly cyclic hydroxyketones. constraints imposed by the molecular framework do not permit their approach in the necessary fashion without a large increase in strain. The reaction occurs in the 4-hydroxycyclohexanone [ 181 (Warnhoff, 1976). This conveniently undergoes competitive intermolecular hydride transfer yielding [I91 and an intramolecular shift yielding [20] (Warnhoff et al., 1980). It has been elegantly demonstrated that, while the intermolecular reaction retains the traditional cation dependence, the ordering is reversed in the intramolecular process. With 2-propoxides in 2-propanol for example, the rate ratio for potassium and lithium alkoxides is and -2 for the inter- and intramolecular transfers respectively. Added crowns or cryptands enhance rates of the intramolecular process. Taken together, the observations suggest that, when a cyclic array with the metaf behaving as a bifunctional catalyst is stereochemically prohibited, a mechanism involving dissociation of metal alkoxide prior to hydride transfer intervenes. +
C. IAN F. .WATT
Strong supporting evidence for such a dissociative pathway has been obtained from the behaviour of the stereochemically rigid hydroxyketones [21] and [22] (Watt et al., 1986) in which the intramolecular 0. . .O distance is -4.7 A. Their salts, in DMSO solution, undergo rapid degenerate rearrangement by migration of the hydride between the oxygen-bearing carbons. Rates, determined by NMR line-shape analysis of the methyl signals, depend on the cation and on the total salt concentration. The cation dependence is K > Na > Li with a spread of lo4 in kobsacross the series, and, for all the salts, dilution of the solutions enhances the rate. The behaviour is entirely consistent with a dissociative mechanism ( 1 2 ) of the type proposed (Cram et al., 1959) to account for large cation dependences found in the fragmentation of alkoxide salts by expulsion of a benzylic anion, which is, on the basis of its basicity, a comparable leaving group to
-
hvdride Kip
M + + -OR$M+
-OR
(1 2 4
In DMSO, and in other organic solvents to an even greater degree, alkoxide salts are strongly associated, i.e. Kipis large. Ion pairs would be in equilibrium with small quantities of solvent-separated ion pairs or solvated ions; the latter are expected to be more reactive than associated species, and to react at rates not strongly dependent on the nature of the counterion, i.e. k , 9k,. Provided the ion-pairing constants are large, (1 3) is the rate law for the simplified scheme, where C is the total metal alkoxide concentration.
The large cation effects arise almost entirdy from differences in Kip for alkali-metal alkoxides, and available conductivity data on t-butoxide solutions in DMSO shows that the spread is large enough to account for the
HYDRIDE SHIFTS AND TRANSFERS
79
behaviour. The scheme also nicely accounts for the observed concentration dependence of pseudo first-order rate constants. With excess added [2.2.2] cryptand the concentration dependence of rates for the sodium and potassium salts was suppressed, but the cation dependence did not entirely vanish, suggesting that under these conditions, the hydride shift occurs in an ionpair formed between the alkoxide and an encapsulated sodium or potassium ion.
The closely related unsymmetrically methylated hydroxyketones [23] and [24] have been shown to interconvert under specific base catalysis in aqueous dioxan. Under these conditions, there is no cation effect (Davis et al., 1984). The rates of these intramolecular reactions have been compared with those of intermolecular reductions of cyclopentanone or cyclohexanone under the same conditions. Taking pK, = 17.6 for the alcohols, the first-order rate constant for conversion of the anion of [23] into [24] is k = 7.6 s- at 50°C. The second-order rate constant for reaction of cyclohexanone by cyclopentanol is 2.06 x M - ' s - ' , so that the effective molarity of the intramolecular process is lo5, rather higher than values normally observed for intramolecular proton transfers (Kirby, 1980). The near unity of the equilibrium constant in the rearrangement shows there is little strain relieved in the conversion, and molecular modelling and empirical force-field calculation, comparing the hydroxyketone with the related dione, shows that, at most, there is only 1.7 kcal mol-' of ground state strain which could be relieved in the transition state. The high effective molarity thus probably reflects differences in activation entropy in the two reactions, and, since the intramolecular reaction occurs in a rigid array, is mainly the result of a high degree of ordering in the transition state of intermolecular hydride transfers of this type. Effective molarity measurements for intramolecular hydride transfers are scarce, and a conclusion that high effective molarities are a feature of hydride shifts would be premature. Only two other measurements are available, a low value of 13 for the Cannizarro reaction of phthalaldehyde (McDonald and Sibley, 1981), discussed below, and a larger value, 200, for
-
-
ao
C. IAN F. WATT
hydride transfer between linked nicotinamidium ions (van Gerresheim et al., 1982), again discussed later. Since intramolecular reaction occurring in rigid frameworks permits close control over orientations of the reacting groups, it was suggested (Henry et al., 1976; Murray-Rust et al., 1979) that it might be possible to correlate rates with features of molecular geometry to reveal preferences in these hydride-transfer transition states. Rates characteristic of the anion are necessary, i.e. ion-pairing effects must be quantified or suppressed, or pK, for the alcohol obtained in aqueous media. Relative rates have been measured in a series of hydroxyketones [25] to [28] (Craze and Watt, 1981; Cernik et al., 1982) and X-ray structures have been determined either for the hydroxyketones or their p-nitrobenzoate esters (Cernik et al., 1984). The spread in the anionic reactivities is - l o 6 in the examples shown. For the homologues [25], [26], and [27], in which the hydride migrates in a 1,4fashion across a constrained 4-hydroxycyclohexanone, the variation in reactivity is associated with relief of ground-state compression between the functional groups with the C. . .C distances in the p-nitrobenzoate esters changing from 2.67A in [25] to 2.48A in [27]. Angular relationships are remarkably constant in the series. The large rate enhancement found in [28], where the hydride migrates across a 4-hydroxycycloheptanone, unfortunately cannot be associated with the change in any one geometric parameter. The larger ring permits a more open C . . . H . . . C arrangement, the C . . C distance is 2.58& but the angular arrangement is such that steric compression between the hydridic hydrogen and the accepting carbonyl carbon is also higher. This structure does differ from the others, however, in showing a clearly non-planar carbonyl group with displacement of the carbonyl carbon by 0.08 8, from the plane of its ligands in the sense expected for a distortion along the rearrangement reaction co-ordinate.
40 OH
OH
$0 OH
4
OH
0
Related hydride shifts have been proposed to account for stereoselective gas-phase reactions of epimeric alkoxides of cyclic diols (Beloeil et al., 1983) and of bicyclic hydroxyacetals (Tabet et al., 1985).
HYDRIDE SHIFTS A N D TRANSFERS
81
V A R I A N T S O F THE C A N N I Z Z A R O REACTION
The second classical organic reaction involving anionic carbon-to-carbon hydride transfer is the Cannizzaro base-induced disproportionation of aldehydes to alcohols and carboxylic acid salts. Experimentally, these are second order in aldehyde, and first or second order in hydroxide, depending on the aldehyde and the reaction conditions. Most recent experimental investigations (Swain et al., 1979a) have served only to support the general scheme in which the rate-limiting step is hydride transfer from either the anion or dianion of an aldehyde hydrate to an accepting carbonyl group. Interestingly, when benzaldehyde is treated with aqueous methanolic sodium hydroxide, the methanol can function as a reducing agent, contributing to the benzyl alcohol formed. At low benzaldehyde concentrations, this is the major reaction (Swain et al., 1979b) with an isotope effect kH3/kD3= 2.2. Hydride transfer from methoxide has also been implicated in the reduction of a high potential quinone, 1,2-dimethylbenzirnidazole-4,7-dione, by methanol (Skibo and Lee, 1985). The activation volume for the benzaldehyde Cannizzaro reaction is -27cm3 mol-' (Brower and Hughes, 1978). This may be an indication of hydride transfer tightness, but it is equally likely to reflect the effect of a doubly charged anion on solvent structure. The formaldehyde disproportionation has been examined by semi-empirical MO methods (Rzepa and Miller, 1985). With the MNDO procedure, transfer of hydride from hydrate mono-anion to formaldehyde is exothermic by 109 kJ mol- l, and the transition structure [29], corresponding to near symmetrical transfer of hydride, lies 72 kJ rno1-l above the separated reactants. Inclusion of two water molecules, to model solvation effects, stabilizes reactants and transition structures equally. Hydride transfer from the hydrate dianion was found to have a less symmetrical transition structure 1301 not unexpected for a more exothermic reaction, but the is unexpectedly high. Semicalculated activation energy, 213 kJ molclassical primary kinetic isotope effects, k,/k, = 2.864 and 3.941 respectively, have been calculated. Pathways involving electron or atom transfers have also been examined, and these are predicted to be competitive with concerted hydride transfers in reactions of aromatic aldehydes. Experimental evidence for these alternatives is discussed later.
',
82
C. IAN F. WATT
In an intramolecular Cannizzaro the hydroxide-induced rearrangement of phthalaldehyde to o-hydroxymethylbenzoic acid (McDonald and Sibley, 198l), the pseudo first-order rate constant for appearance of product obeys equation (14). Phthalaldehyde exists as a cyclic hydrate [31] and the scheme kobs =
a[OH-]/(l
+ b[OH-])
(14)
(1 5), involving ionization first to [32], then to [33], before ring-opening to [34] and rate limiting hydride transfer, is consistent with the behaviour of kobs with a = k K3K2 and h = K,. The first and second pK,-values of the hydrate are 11.56 and 14 at 25". The equilibrium constant for the ring
OH [311
An effective concentration for the second aldehyde group of -13 has been quoted, obtained by taking the value of (k,,,/[NaOH]) at low [NaOH] and comparing it with the third-order rate coefficient for the intermolecular Cannizzaro reaction of benazaldehyde under the same conditions. This does not compare inter- and intramolecular hydride transfer steps. The conversion of glyoxals to glyoxilic acids is a special case of the
83
HYDRIDE SHIFTS AND TRANSFERS
intramolecular Cannizzaro reaction, involving a 1,2-hydride shift. The rearrangement of phenylglyoxal hydrate [35], pKa, = 11.61 at 25°C (Hine and Koser, 1971), to mandelate in aqueous hydroxide is strictly first order in substrate and hydroxide at hydroxide concentrations greater than about 0.01 M. With an estimated second pKa 16 for the hydrate, the behaviour is consistent with (l6), with hydride transfer almost exclusively in the dianion [36], which is not formed in detectable quantities. The first-order rate constant for hydride shift within this dianion has been estimated to be 76 s at 40°C, remarkably close to that for the phthalaldehyde hydrate dianion
-
WI. A Hammett treatment of the reaction of substituted phenylglyoxals at pH 12 yields p = 2.0 (Vander Jagt e f al., 1972), and a surprisingly large kinetic isotope effect k,/k, = 5 has been reported for the migrating hydrogen (Vander Jagt and Han, 1973). The effects of added salts have been examined, and, as might be expected for reaction involving a dianion, strong positive salt effects were found. Specific acceleration by Ca”, Ba”, Sr+’ and TI’ has also been noted, with calcium being the most effective (Okuyama et al., 1982).
f
PhC-C-H
/OH \
OH
= PhC<-H \O H -k,[OH-]
kJOH-1
I I /
0-
0 0I1 / PhC-C-H \
0-
An unusual chain reaction involving an anionic hydride transfer has been found in the conversion of azibenzil to benzil azine (Bethell and McDowall, 1984). Addition of catalytic quantities of deoxybenzoin to a solution of azibenzil in DMSO containing excess tetraethylammonium hydroxide induces nitrogen evolution with formation of the azine. Nitrogen evolution was first order in azibenzil and deoxybenzoin, which could be recovered from the reaction mixture. The slow step in the cycle proposed is hydride transfer from the adduct [37] of deprotonated deoxybenzoin and azibenzil to the diazoketone. The resulting anion may then lose molecular nitrogen, regenerating deoxybenzoin carbanion.
84
C. IAN F. WATT
POSSIBLE SINGLE ELECTRON TRANSFER MECHANISMS
For some of these reductions, evidence has been presented that hydride motion is not the sole mechanism of hydrogen transfer. Rate-limiting electron transfer, followed by rapid disproportionation of alkyl and magnesium ketyl radicals has been proposed for the p-hydride reduction of diaryl ketones by Grignard reagents (Holm, 1974). With the sterically hindered dimesitylketone, relatively high concentrations of radical species were detected (Ashby and Goel, 1981) but the build-up of radical species has been shown to be associated with trace impurities of iron in the magnesium, rather than evidence of a change to rate-limiting hydrogen-atom transfer (Holm, 1982). An e/H- transfer sequence has also been proposed for the reduction of diaryl ketones by alkoxides (Ashby et al., 1982) or by lithium dialkylamides (Ashby and Argyropoulos, 1986; Ashby et al., 1981a). This rests on the observation of benzophenone ketyl in solutions of benzophenone and metal alkoxides, including lithium 2-propoxide, lithium t-butoxide and lithium neopentyloxide, and the demonstrated ability of benzophenone ketyl, generated separately, to react with lithium alkoxides of secondary alcohols yielding diphenylmethoxide. In presence of excess alkoxide, first-order rate constants for disappearance of ketyl are approximately equal to those for appearance of the diphenylmethoxide. Benzophenone ketyl has also been observed when benzophenone is in solution in the presence of lithium t-butoxide, although reduction product is not formed. The reverse sequence, i.e. an H-/e transfer sequence has been suggested for the reduction of cyclic ketones by alkoxyaluminium dichlorides where the alkoxy groups are derived from benzylic alcohols (Nasipur et al., 1984b). Radical intermediates were proposed at an early stage in the history of the Cannizzaro reaction, and this possibility has been resurrected to account for the detection of some 20% of a-D-benzyl alcohol in the products of the Cannizzaro reaction of a-D-benzaldehyde in aqueous alkaline dioxan. This has becn rationalized in terms of formation of the benzaldehyde radical anion, which abstracts a H-atom from the solvent (Chung, 1982). Epr spectroscopy of reacting solutions of p-C1-, p-NO2 and p-CF,-benzaldehyde as well as benzaldehyde itself in T H F : HMPA (9 : I ) yielded spectra of the aldehyde radical anions identical to those produced by the action of metallic
85
HYDRIDE SHIFTS A N D TRANSFERS
sodium on each aldehyde (Ashby et al., 1983). It was not, however, possible to correlate the appearance of the product with the appearance and disappearance of radicals, but the possibility of electron transfer from hydroxide or aldehyde hydrate monoanion was raised. The feasibility of some of these radical pathways has been examined using Marcus theory to obtain rate constants for comparison with the experimental data (Eberson, 1984). For some relevant anions, including hydroxide, methoxide, t-butoxide, the anion of benzaldehyde hydrate and di-2-propylamide, the necessary E"(RO-/RO-) values are available or can be estimated with sufficient accuracy. For the reaction of t-butoxide with benzophenone in THF, or the benzaldehyde hydrate anion with benzaldehyde in aqueous dioxan, direct electron transfers between the anion and the neutral are not feasible; the calculated rate constants are orders of magnitude too low to be compatible with the observed reduction rates. Any radicals observed in these reactions must arise by some other more complex mechanism. The behaviour of an aromatic aldehyde hydrate dianion has not been examined in this way, but MNDO calculation (Rzepa and Miller, 1985) suggests that such a species could easily transfer either a single electron or a hydrogen atom to an accepting aldehyde. Marcus treatment does not exclude a radical pathway in lithium dialkylamide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl- 1-hex-4-enamine in T H F containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines; no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (1 7) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportionates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case.
Ph,C=O Ph,CH-OLi (Ph,C-O)-'2Lit
+ LiNEt,
-
N \ E t
(1 7a)
+ LiNEt,
=( P h , C 4 ) - 2 2 L i + "+ HNEt,
(17b)
+ Ph,C=O
Ph,CH-OLi
-
2(Ph,C-O);
+v Lit
(17c)
86
C. IAN F. WATT
The generality of schemes of this type is not clear, but it is an alternative to the e/H. transfer sequences for a range of reactions in which oxidantderived radical anions are found, including the Meerwein-Ponndorf-Verley reduction of diary1 ketones outlined above. MISCELLANEOUS ANIONIC REACTIONS
Cyclohexadienyl anions, produced in a flowing afterglow by deprotonation of cyclohexadiene by amide, have been shown to donate hydride to benzaldehyde and acrolein (DePuy et al., 1978). In solution, substituted cyclohexadienyl anions behave similarly (Parnes et al., 1971). Jackson/ Meisenheimer hydride adducts of 1,3,5-trinitrobenzene and some 1,3dinitrobenzene derivatives (Gold et al., 1980) can be prepared by reaction of borohydride in DMSO with the parent aromatic. The 2,4-dinitroaniline adduct transfers hydride to 1,3,5-trinitrobenzene in DMSO solution. The process shows good second-order kinetics, and no detectable intermediates (Atkins et al., 1983). The activation parameters, AH* = 36kJmol-' and AS+ = - 104 J K - ' mol- resemble those for quinone reduction by 1,4dihydropyridines, and indeed, similar low activation enthalpies and large negative activation entropies are found for reactions of the adduct with quinones and 4-nitrobenzaldehyde. In the quinone reactions, long wavelength UV absorption bands were detected and tentatively assigned to a charge transfer complex which precedes the formation of the hydride transfer products (Atkins et al., 1986). Deprotonation of dimethyl trans-1,2dihydrophthalate in aqueous carbonate yields an anion which transfers hydride to 5-carbalumiflavin (Bruice and Farny, 1984).
',
4 Cationic carbon-to-carbon hydride transfers and shifts
Hydride shifts and transfers figure prominently in carbocation reactions and these have been thoroughly reviewed (Ahlberg et al., 1983; Brouwer and Hogeveen, 1972; Brouwer, 1980), and are the subject of a recent monograph (Vogel, 1985). GAS-PHASE A N D THEORETICAL STUDIES
MO calculations on simple species of particular interest for hydride motion are those on protonated methane, CH:, and protonated ethane, C,H: (Pronin and Holer, 1981; Pronin and Karchenko, 1982; Minyaev and Pavlov, 1982). These species have been examined (Raghavachari et af., 1981) by ah initio methods using extended basis sets with polarization functions, and corrections for the effects of electron correlation have been applied. At
a7
HYDRIDE SHIFTS AND TRANSFERS
the highest levels of theory, CH: has a structure corresponding to a threecentre bonded complex between H, and CH:. The barrier to turnstile rotation of the methyl group is only about 0.4 kJ mol-'. Other structures of higher symmetry were not minima on the PE surface, but, notably, the C,, structure was only 4.6 kJ mol-' above the minimum implying a low barrier to hydrogen scrambling in protonated methane. The most stable structure found for C,H: corresponds to ethane protonated on the C-C bond with a C . . . H . . . C angle of 105.8". The structure corresponding to C-H protonation of ethane, a three-centre bonded complex of ethyl and H,, is 28.5 kJ mol- ' less stable. Isomeric C,H: cations have been identified in the gas-phase reactions of ethyl cation with molecular hydrogen (Hiraoka and Kebarle, 1976), and the difference in their experimental heats of dissociation to ethyl cation and hydrogen (16.7 and 49.4 kJmol-') agrees with calculation. The gas-phase reaction of methyl cation with methane to produce ethyl cation and molecular hydrogen has been studied using deuterium-labelled reactants (Poirier et al., 1982). Scrambling between methane and methyl hydrogens does not occur, and molecular hydrogen is derived from the methane rather than the methyl cation. For the ethyl cation itself, C,H:, correlation corrections strongly favour a bridged ion and no minimum is found corresponding to classical structures. Similar behaviour is found for the vinyl cation, C,H:. Comparable, high level calculations are not yet available on larger molecules, but STO-4G calculation of hydride transfer between propane and the 2-propyl cation (Kirchen et al., 1981a) suggests that there is no electronic barrier in this case, and that the C. . .C distance in the (CH,),C. . .H. . C(CH,), complex is 2.5 A. B,H; is isoelectronic with C,H: and, as a stable species, provides an opportunity to examine bonding arrangements in such arrays in some detail. An X-ray structure has been determined for [(Ph,P),N]+[B,H,]- (Shore and Lawrence, 1982). The anion turns out to have a singly H-bridged structure, with a bent B. . .H. . .B array (136") and a B. . .B distance of 2.107 A. The terminal BH, units are staggered. Although more accurate hydrogen positions are desirable, the bridging hydrogen is apparently placed asymmetrically (B. . O Hlengths of 1.27 8, and 1.0 A), so that the structure may be described as a donor-acceptor complex between BH 4 and BH,. The bent arrangement is reproduced by ah initio MO calculation (Raghavachari et al., 1983) provided the basis set includes polarization functions on boron. The effects of electron correlation also favour the bent array, although the PE surface seems to be quite flat in the bending dimension. The calculations do not reproduce the asymmetry of the hydrogen-bridging bond lengths. The X-ray crystal structure of Na[(CH,),Al-H-AI (CH3)3], which also contains an acyclic X. . .He . .Y bond, affords an interesting contrast (Atwood et al., 1981). In this case, the AI...H...Al array is linear, with
-
88
C. IAN F. WATT
apparently symmetrical Al. . .H bonds (1.65 A) which are similar to those in more common electron-deficient bridged compounds such as [(CH,),AlH],. Since heats of formation are widely available for hydrocarbons, equilibria involving gas-phase hydride transfers between carbocations lead directly to relative carbocation stabilities, and, as such, have been extensively studied and the reactions reviewed (Meot-Ner, 1979). Hydride transfers turn out to be slower than corresponding chloride transfers (Meot-Ner and Field, 1976, 1978; Magnera and Kebarle, 1984; Sharma et al., 1985) and rates show a negative temperature dependence, increasing to the limiting collision rate at low temperature. Within the framework of transition-state theory, exothermic ion-molecule reactions of low collision efficiency, for example, transfer of hydride from isobutane to 2-propyl cation, have been associated either with a reaction coordinate in which there is a substantial electronic barrier to formation of the transition state within the collision complex or where loss of external rotation of the collision partners occurs when the internal barrier is small. Either model can rationalize the negative temperature dependence of the rates, but the latter is probably a better description of the hydridetransfer reactions, with rotations of alkyl groups becoming locked by steric interaction at the distances over which cation-to-cation hydride transfer occurs. Provided there is cancellation of electronic and vibrational contributions of initial- and transition-state partition functions, and the activation energy is small, the temperature dependence of the forward rate constant, k, is given by (18) (Meot-Ner, 1979), where r is the total number of rotations becoming hindered in the complex and C is a constant depending on the reactants. k f -- CT-'2 + r/2) (18)
TRANSFERS BETWEEN A L K Y L CATIONS
Intermolecular hydride transfers between t-alkyl centres are observed under stable ion solution conditions. These have very low activation enthalpies (Dirda et al., 1979) and accurate rate data are scarce. The simplest reaction, transfer from isobutane to the t-butyl cation in sulphur dioxide, has been shown to be first order in each component, and to have E, = 15.1 kJ mol-' and AS* = - 113 JK-' mol-' (Brownstein and Bornais, 1971). Adamantane catalyses solution hydride transfer between acyclic tertiary centres such as t-butyl, and it is believed that this reflects higher efficiency of hydride transfers to and from bridgehead 1-adamantyl cation. With its non-planar geometry, the non-bonded interactions between alkyl substituents on donor and acceptor are likely to be less than those between two acyclic reactants. If locking of rotation about the C . . .Ha ..C axis between the reactants does not
89
HYDRIDE SHIFTS AND TRANSFERS
occur with a bridgehead cation, then rates may be enhanced by factors of up to 10' over those for planar cations (Kramer, 1986; Kramer and McVicker, 1986). The corresponding shifts between linked tertiary centres have also been examined, In the homologous series [38; n = 0 to 31, activation energies for the 1,2-, 1,3-, 1,4- and 1,5-hydride shifts decrease in the order 1,4 > 1,3 > 1,5 > 1,2 (Saunders and Kates, 1978; Saunders et al., 1981; Saunders and Stol€ko, 1973), ranging from > 50 kJ mo1-l for the 1,4 shift to 12.9 kJ mo1-l at - 138" for the 1,2-shift. The barrier for the 1,5 shift in the 2,4,4,6-tetramethylheptyl cation has been determined as AG* = 21.8 kJ mol-' at - 122" (Siehl and Walter, 1985). Simple molecular modelling shows that the chain in the 1,5-shift can not only accommodate a near linear C . . .H. . .C array at the C . . .C distance of -2.5 A, but also permits a staggered arrangement of the terminal groups [39]. The 1,Sarrangement also allows alternation of partial charges in the linking chain (Verhoeven, 1980), and a perturbational frontier MO analysis shows favourable overlap of the three centre array with the carbon o-framework (Verhoeven and Pasman, 1981) in the 1,Sbridged array.
& 6-
s-
,.
.ti&
When the tertiary centres are held by cyclic arrays [40],the barriers for 1,Chydride shifts, for example in [40; n = 2, m = 2, 3, or 41 are comparable with those in the acyclic molecules. However, the 1,5-dimethylcyclooctyI [41, n = m = 31, 1,5-dimethylcyclononyl [41; n = 3, m = 41 (Kirchen et al., 1981a), lJ-dimethyl- and 1,6-dimethyl-cyclodecyl[41;n = 3 , m = 5 and n = m = 41 Kirchen et al., 1981b) cations have all been assigned the indicated phydrido-bridged structures. These rest on the presence in the 'H nmr spectra
90
C. IAN F. WATT
of single hydrogen signals at high field, (6 - 6.3 in [41; n = rn = 31, 6 - 3.9 [41; n = rn = 41) showing an unusual coupling, J 40 Hz, to the lowest field signals in the 13C nmr spectra. Isotopic perturbation shifts, using a deuteriated methyl group in each case, are also consistent with the single nonclassical structures rather than rapidly equilibrating classical pairs. Use of 6deuterio-1,6-dimethylcyclodecanolas a precursor [41; n = rn = 41 first yields the p-deuterio-l,6-hydrido-bridgedcation, but rapid exchange not involving solvent occurs, with hydrogen preferring the p-environment, indicating the relatively loose potential around the bridging hydrogen. There is a clear preference for IS-hydride bridging in these cations. Qualitatively, the most stable cation of the series is the 1,5-dimethylcyclooctyl, but the preference is also shown by the slow rearrangement of 1.5-dimethylcyclononyI to the 1 -ethyl-5-methylcyclooctyl cation or of the 1,6-dimethylcyclodecyl to the 1,5-dimethylcyclodecyl cation, kl,5/kl,6 2.8 (-84"). This, no doubt, reflects both steric and electronic requirements of the p-hydride, with the 1,5-arrangement now allowing alternation of partial charges around the ring. The I3C nmr spectrum of the 1,6-dimethylcyclodecyl cation shows six signals, consistent with a cis-decalin arrangement with C, symmetry. Comparisons may be made with the structure of the anion of [N(nC,H,),]+[B,(C,H,),H,]which has approximate C, symmetry [42] (Saturnine et al., 1975). The B. . .B distance of 2.43 A is notably longer than that in B,H .; In its 'H nmr spectrum, the bridging hydrogen gives a signal at 6 - 2.4, indicating its hydridic character, while the two terminal hydrogens appear at 6 2.3. The potassium hydride adduct of 1,8-naphthyIenediylbis(dimethylborane) [43] (Katz, 1985) also displays a non-linear B. . .H. . .B array, but with unsymmetrical bridging. The p-hydride is tightly retained, and will not, for example, reduce benzaldehyde in T H F solution at 60". As the B. . .H. . .B arrays form part of a cyclic arrangement in these structures, their experimental local geometry necessarily reflects the constraints of the ring system as well as any preferences of p-hydrido-bridging.
-
-
[421
91
HYDRIDE SHIFTS A N D TRANSFERS
As noted much earlier, the "in" isomer of bicyclo[4.4.4]tetradec- 1 -ene is protonated under remarkably mild conditions, trifluoroacetic acid in chloroform, to yield a solution, which is stable at room temperature, and whose spectroscopic properties are consistent with formation of the p-hydridobridged ion [2] (McMurray and Hodge, 1984). Its I3C nmr spectrum shows only three peaks, at 6 18.7, 40.8 and 139.3, and 'H nmr spectroscopy shows the familiar high field signal associated with a bridging hydride. Again, isotopic perturbation experiments are consistent with the single structure. The characterization of hydride transfers and long range shifts between secondary alkyl cations is complicated by competing 1,2 shifts with very low barriers. For the degenerate rearrangement of 2-butyl by I ,2-hydride shift, AG' < lOkJmol-' at -150" (Saunders and Kates, 1978; Myhre and Yannoni, 1981), and those in cyclopentyl are 14.7 kJ mol-'. Secondaries inevitably also rearrange to isomeric tertiaries. Nevertheless, the cyclooctyl, cyclononyl, cyclodecyl and cycloundecyl cations have all been observed directly by nmr methods (Kirchen and Sorensen, 1979) and show high field signals similar to those assigned to the bridging hydrogen in the corresponding dimethylated cations. The cyclodecyl cation, with a 1,6-bridging arrangement should resemble the bis(tetramethy1ene)diborate discussed above, but the spectroscopic evidence, and the behaviour of the dimethylated ion suggests (Kirchen et al., 1986) a 1,5-hydride bridged structure is more likely. This ion is almost unique in evolving molecular hydrogen, containing no hydrogen from the acidic solvent, to yield the I-decalyl cation.
-
TRANSFERS TO TRIARYLMETHYL A N D OTHER STABILIZED CARBOCATIONS
Compared to simple alkyl cations, triarylmethyl cations are well characterized in terms of structure and stability, and react with a number of readily oxidized species including aliphatic amines (El'tsov et al., 1978) and ethers (Kabir-ud-Din and Plesch, 1978). Their reduction by alcohols in acidic medium have an historic importance in the area (Bartlett and McCollum, 1956), and the use of triarylmethanes as hydride carriers is an area of continuing interest (Ivanov et a/., 1982). Primary kinetic hydrogen isotope effects in the reductions of triarylmethyl cations by formate in aqueous trifluoroacetic acid have been determined (Stewart and Toone, 1978). For 16 cations with pK,+ ranging from -2.25 (4-methoxy-4-methyl) to -7.63 (4,4'-dichloro), plots of log k, and log k, against pK,+ show poor linear fits with the best straight lines (least squares) having slopes of 0.473 (r = 0.973) for the H-data and 0:491(r = 0.983) for the D-data. Both plots show downward curvature, with the effect being more emphatic for the H-data. Least squares fit to quadratics better
C IAN F WATT
92
reproduces the data, but there is still substantial dispersion from the correlation line. The primary kinetic hydrogen isotope effects, k,/k, range from 1.8 to 3.2 at 25”, and as implied by the different curvatures of the separate Brunsted plots, a plot of k,/k, against pK,+ of the cations shows considerable scatter, but hints at a maximum at pKR+ -4. The interpretation of this pattern is not at all clear in this case. Such “Westheimer” maxima occur in proton transfers when the overall free energy change is zero; this does not seem to be the case in these reductions. Clearer cases of primary k.i.e. maxima in hydride transfer reactions are presented later. More recently, both primary hydrogen and carbon isotope effects have been determined for formate reduction of 10-methylacridinium ion in isopropyl alcohol/water and in DMF/water mixtures (Hutchins et al., 1986). In DMF/ water at 50” k,lk, = 2.74, and k , , / k I 3 = 1.027, values close to those (2.27 and 1.042 respectively) for oxidation of formate by NAD’ catalysed by yeast formate dehydrogenase (Hermes et al., 1984). Taking a value of lo’* for the equilibrium constant, and an intrinsic barrier AGZ 1000 kJ mol-I, the Marcus parameter for the fractional progress along the minimum energy pathway at the transition state, = 0.4 as an upper limit, and the low value is at least consistent with a low primary hydrogen k.i.e. It has been argued (Olah and Svoboda, 1973) that such reductions may not involve hydride motion, instead being an example of the sequence outlined in (9). Initial attack of a lone pair donor, formate in the cases above, on one of the ring sites, ortho with respect to the formal cationic centre, could form a o-complex which breaks down with transfer of the hydrogen to the aliphatic carbon. Such a mechanism could conceivably account for the clear drop off in k.i.e. for the least reactive of the triarylmethyl cations if complex formation were becoming partially rate determining. Supporting evidence for adduct formation has been obtained (Huszthy et a/., 1982) in the reduction of tris(4-methoxyphenyl)methyl chloride by refluxing methanol. With refluxing perdeuteriomethanol, not only was the central carbon completely deuteriated, but the product contained one, two or three CD30groups. Exchange of the methoxy groups was reasonably postulated as occurring viu an “SN2-Ar” displacement on the cation. With similar electronic factors governing ortho-attack, reversible addition of methanol is possible, and the ortho-adduct has open to it the slower irreversible decomposition to the reduction product. The contrasting behaviour of the tricyclic orthoamides [44] and [45] towards triphenylcarbenium tetrafluoroborate has also been rationalized in terms of the necessity of adduct formation in the removal of the tertiary hydrogen (Atkins, 1980; Erhardt and Wuest, 1980). The dominant conformer of [44] has C,, symmetry, so that the central C-H is antiperiplanar with respect to all three nitrogen lone pairs. This hydrogen shows
-
x
HYDRIDE SHIFTS A N D TRANSFERS
93
the remarkably low chemical shift (6 2.33), presumably reflecting transfer of electron density to the hydrogen by negative hyperconjugation, and is actively hydridic since the tetrafluoroborate salt remarkably, on heating at 113", yields the guanidinium ion [46] with the formation of molecular hydrogen (19). Similar activation by an antiperiplanar p-lone pair on a heteroatom has been proposed to account for the stereochemistry of reduction of a conformationally restricted cyclic oxenium ion (Deslongchamps et al, 1981a,b). The corresponding salt of [45], in which the nitrogen lone-pairs are constrained to be synperiplanar with respect to the central hydrogen, melts at 130" without decomposition, and its central hydrogen has a "normal" chemical shift at 6 5.03. However, triphenylcarbenium tetrafluoroborate in chloroform smoothly oxidizes [45] to the guanidinium ion [47], while similar oxidation of [44] does not involve abstraction of the central hydrogen, but (speculatively) a secondary hydrogen adjacent to the nitrogen (Erhardt et al., 1980). Decomposition of an ortho-adduct [48] of the type shown in (20) which demands transfer of a syn-hydrogen, may account for the behaviour. Additionally, it was observed that both orthoamides reduced methyl phenyl glyoxalate, but only in the presence of M g f 2 , and again [45] delivers the central tertiary hydrogen while [44] uses a secondary one.
H
Ortho-adduct formation is an unlikely complication in transfer of hydride to substituted 9-phenylfluoren-9-yl cations from triphenylmethane, or 4,4dimethoxydiphenylmethane (Bethell et al., 198 I). The log of the rates correlated with ' 0 constants, giving p-values of 2.44 when triphenylmethane is the donor and 3.02 when the diphenylmethane was thedonor. They also correlate with the difference in pK,+ between the product and acceptor carbocation. There does not seem to be a simple pattern of reactivity in the
C IAN F WATT
94
hyride donors. The primary kinetic hydrogen isotope effects for deuterium range from 1.65 to 4.82 (30") in the series, showing an increasing trend as ApK, + tends to zero, tracing a roughly parabolic curve,jather broader than that found for the formate reductions cited above, but showing a maximum with k H / k D= 4 at ApK,+ 0. Analysis of the data yields an intrinsic barrier for the formate reductions of 10.5kJmol-' and 14.7kJmol-' for the arylalkane reductions. A limited number of deuterium and tritium isotope effects were determined in the series for 4,4'-dimethoxydiphenylmethane reductions, giving k H / k Dvalues ranging form 2.62 to 3.50, and corresponding k,/k, values from 1.64 to 1.75. Although almost invariant within probable errors, the values of k,/k, agree with those calculated by the Swain-Schaad relationship, and thus do not permit any conclusion as to the importance of tunnelling in determining the k.i.e.'s. Equilibria have also been determined in hydride transfers between di- or triarylmethanes and the corresponding cations in trifluoroacetic acid, but have not been correlated with rate measurements (Abdellah er a/., 1983). The pressure dependence of the rates and primary kinetic hydrogen isotope effects in the reductions of chloranil (Isaacs et al., 1978) and tetracyanoethylene (Nishimura and Motoyama, 1984) by leucocrystal violet have been determined. The earliest studies of the chloranil reaction yielded AV' = -25 cm3 mol-' in acetonitrile solvent and -22 cm3 mol-' in propionitrile. The kinetic isotope effect was strongly pressure-dependent, ranging from 11.2 at ambient (29") to 8.0 at 2 kbar. The large isotope effect was associated with quantum mechanical tunnelling, and it was suggested that increased pressure forced solvent molecules closer to the reaction centre, thereby increasing the effective mass of the in-flight hydrogen and reducing the importance of tunnelling. The more recent study reproduces the remarkable pressure dependence, but spectroscopic evidence for a charge transfer complex was also obtained, and the chloranil radical anion was also detected by e.s.r. spectroscopy, although it is not clear whether these are on the reduction pathway. The TCNE reaction also exhibits a large negative AV* -30 cm3 mol-' but the k.i.e. of 5.56 at ambient (30" in chloroform) is "normal" and not dramatically changed by pressure. The TCNE radical anion is detectable under the reaction conditons by e.s.r. spectroscop.y, but again, it is not clear whether it lies on the reduction pathway.
-
-
5
Reductions by dihydropyridines and related species
These have been recently reviewed (Hemmerich er al., 1982; Postovskii et al., 1984) and serve as models for dehydrogenase catalysed processes involving the NADH or NADPH co-enzymes. In the pioneering studies, it was proposed that direct hydride transfer was
HYDRIDE SHIFTS A N D TRANSFERS
95
occurring in N-benzyl- 1,4-dihydronicotinamide,BNAH, reductions of thiobenzophenones (Abeles et al., 1957). However, much of the more recent experimental work with these heterocycles has been directed to the question of whether hydride is transferred in a single step, or by one of the equivalent pathways involving single electron transfer. Comment has been made (Verhoeven et al., 1986) that this aspect of the chemistry has rather overshadowed other perhaps more important questions, but some of these experimental approaches are presented below. K I N E T I C A N D P R O D U C T ISOT OP E E F F E CT D I S C R E P A N C I E S
A discrepancy between the primary kinetic isotope effect (kH/kD)and the isotope distribution in the product ( YH/Y,) in reductions of trifluoroacetophenone by N-propyl- 1,4-dihydronicotinamide, PrNAH, in aqueous medium was taken as evidence of a non-concerted process (Steffens and Chipman, 1971), in which the rate-determining step preceded hydrogen transfer. A number of studies followed this report, attempting to use such discrepancies as a tool to distinguish hydride transfer from e/H+/e- or e/H.transfer sequences. Nine years later, it was shown that kinetically significant side reactions, such as adduct formation or hydration of the PrNAH, could account for the original observations (Chipman et al., 1980). The literature of this aspect of hydride-equivalent transfers from 1 ,Cdihydropyridines has been reviewed (Powell and Bruice, 1983a) and reactions showing k H / k ,: YH/ Y , (disagreements have been re-examined. The arguments will not be repeated here, but it has become clear that two additional complications may also induce discrepancies. Firstly, secondary kinetic hydrogen isotope effects, although small, can have a large effect on apparent primary effects (Powell and Bruice, 1983b). Secondly, isotopic scrambling may occur by intermolecular hydride transfers between the pyridinium ions and their reduced congeners (Powell and Bruice, 1982; Roberts et al., 1983), and reactions of this type are not restricted to the N-heterocyclic series. 4HPyrans and thiopyrans, for example, rearrange to thermodynamically more stable 2H-isomers in reactions shown to be catalysed by the corresponding pyrilium ions (Oestensen et al., 1977; Abdallah and El Nahas, 1981). With all complications considered, there are no current examples of k H / k ,: Y,/ Y D disagreements in reductions by N-alkyl- or N-aryl- 1,Cdihydropyridines attributable to stepwise hydrogen transfers. OXIDATIONS B Y INORGANIC OXIDANTS A N D QUINONES
Measurements of one-electron oxidation potentials of NADH and other dihydropyridines would be extremely useful in establishing the feasibility of
96
C. IAN F. WATT
possible single electron transfer initiated reactions. Unfortunately, irreversible behaviour precludes direct determination in most cases, but an indirect method has been used to obtain E,, = 0.76 ? 0.02V (vs SCE at 20" in acetonitrile) for the BNAH/BNAH+ couple (Martens ef al., 1978), and an estimate of E,, = 0.78 V has been made for one-electron oxidation of Nmethylacridan, NMAH (Sturm et al., 1978). Only powerful one-electron oxidants are thus expected to react with these heterocycles by a one-electron pathway, and oxidants should also be kinetically suitable, having high selfexchange rates. Gibbs free energy changes for single electron transfers from BNAH or NMAH to a range of oxidants have been calculated (Verhoeven et al., 1986; Colter et al., 1983) using available electrochemical data. This sets a minimum for the free energy of activation for any proposed single electron transfer, and corresponding maximum rate for comparison with experimental measurements. By these criteria, oxidations of dihydropyridines by the inorganic reagents, tris(2,2'-bipyridyl)cobalt(III), Fe(CN);3, and ferrocenium cation, with one-electron Ered= 0.235, 0.21, and 0.16V respectively, may indeed be initiated by single electron transfer. The characteristics of these oxidations have been compared with those of reaction of the same dihydropyridines with high potential organic oxidants such as quinones. For example, oxidation of 9-phenyl-NMAH by the Co(II1) reagent shows second-order kinetics, and near zero primary hydrogen k.i.e.'s. 9-Phenyl-NMAH also shows good second-order behaviour in acetonitrile with quinones with oneelectron E" ranging from -0.51 V (benzoquinone) to +0.50V (DDQ). Primary kinetic isotope effects, however, are now substantial ranging from k,/k, = 11.9 for benzoquinone to 5.8 for DDQ at 25". There is no simple relationship between these k.i.e.'s and rates which span a range of 109-fold, increasing with quinone E" (Colter et al., 1985). Single electron transfer initiated oxidations by quinones are not excluded by thermodynamic arguments in the cases of DDQ or 2,3-dicyano-1,4-benzoquinone(E" = 0.30 V) but the primary k.i.e.'s, 5.8 and 8.0 respectively, are similar to those for less powerfully oxidizing quinones, and are most economically explained by onestep hydride transfer. The reactivity of 2- and 3-methoxy-NMAHs towards 7c-acceptors and the cobalt(II1) reagent have also been compared (Colter et al., 1984). The 3methoxy substituent better stabilizes the acridinium ion, while 2-methoxyNMAH is the better one-electron donor. With a series of quinones in acetonitrile, the 3-methoxy-NMAH is between 4 and 10 times more reactive than its isomer although absolute rates vary by more than lo5. With the cobalt(II1) oxidant, the 2-methoxy-NMAH is more than 50 times more reactive, suggesting that the quinones react with these acridans uniformly by one-step hydride transfer.
HYDRIDE SHIFTS A N D TRANSFERS
97
Oxidations of NADH itself and 1-(X-benzy1)-1,4-dihydronicotinamides,XBNAH, by Fe(CN)i3 in aqueous acetonitrile show inhibition by Fe(CN) i4 which decreases with the electronegativity of the pyridine nitrogens. Interestingly, a plot of log k for these ferricyanide oxidations against log k for rates of reaction of the same compounds with 10-methylacridinium ion (NMA'), a process believed to involve hydride transfer, is linear with a slope ca. 1, a finding which undermines any conclusions as to oxidation mechanism based solely on linear free energy relationships. Evidently, charge development on the heterocycle in one-electron transfer parallels that in hydride donation (Powell et al., 1984). The inhibition by Fe(CN)i4 is most marked in oxidation of NMAH, and general base catalysis has been demonstrated, consistent with rate-limiting deprotonation of the relatively stable intermediate NMAH t (Sinha and Bruice, 1984). In contrast, reduction of NMA+ by a low potential 5-carba-5-deazaflavin mimic is specifically base catalysed (Yuan and Bruice, 1984) and, in D,O, deuterium is not incorporated into the product NMAH. The pH-rate profile is sigmoidal, showing a point of inflexion at pH 4.6, close to pK,, of the reductant. Competing hydride transfers from the neutral reagent, and its more reactive mono- and dianions account adequately for the data. For a series of substituted ferrocenium cations, plots of log k for oxidation of NADH in aqueous isopropyl alcohol (Carlson and Miller, 1983; Carlson et al., 1984) against Eo-values for the ferrocenium/ferrocene couple gave a straight line segment with slope of 16/volt for the five weakest oxidants, in good agreement with endothermic one-electron transfer with the rate limited by diffusional separation of the electron transfer products. At the diffusioncontrolled rate limit log k = log kdi, and El = E" for the NADH/NADHt couple. This kinetic estimate yields a value of 1.05 V vs. NHE, in reasonable agreement with earlier estimates for BNAH. Application of the RehmWeller relationship yields AG: = 23.5 kJ mol-' for self-exchange so that, kinetically, NADH resembles ferrocene as a one-electron donor. Reactions of o- and p-quinones with NADH in aqueous medium are first order in each reactant and show no pH effect. Primary k.i.e.'s ( k N A D H / k N A D Hrange -D2) from 1.6 for 2,6-dichloro-1 ,Cbenzoquinone to 4.2 for 3,5-di-t-butyl-l,2benzoquinone but deuterium is not incorporated at hydroquinone carbon (Carlson and Miller, 1985). The available data allows application of the Marcus equation to calculate expected rates of electron transfer and these are lo4 to lo6 times less than the experimental rates. A mechanism of ratelimiting hydride transfer from NADH to carbonyl oxygen, followed by fast protonation of the hydroquinone monoanion is suggested, but the data do not exclude hydrogen atom transfer followed by rapid electron transfer. The log k values correlate well with the estimated Eo-values at pH 7 for (21) giving slopes of 16.9/volt for the p-quinones and 16.4/volt for the o-
98
C. IAN F WATT
quinones, but at the same E", the o-quinones are about a hundred times more reactive than the p-quinones. A similar transfer of hydride to carbonyl oxygen is believed to occur in reduction of quinones by triazoliothiohydroquinones (Youngblood, 1985). Q
+ 2e- + H + = QH-
(21)
Charge-transfer complexes between BNAH and quinones have been isolated from benzene solutions, and bands characteristic of these complexes have been detected in the course of the reduction of quinones by BNAH in acetontitrile (Fukuzumi et af., 1984). Rates of reduction vary with the E"(Q/ QT) and primary isotope effects (k,,,,/k,,,, -D,) are grouped between 5.3 and 6.2, with the exception of the two strongest oxidants, DDQ and dicyano-l,4-benzoquinonewhich gave k.i.e.'s of 1.5 and 2.6 respectively. In this study, the results were analysed in terms of an e/H +/e-transfersequence, with a short-lived radical ion pair, (BNAHt QT), being formed from the charge transfer complex. The variation of primary k.i.e. with quinone E" shows an unconvincing maximum at E" = 0.5 V, taken as occurring when the pK, of the BNAH'; and QH. were equal. It has, however, been pointed out (Colter et al., 1985) that these are likely to differ by > 7 pK, units. With added Mg+2, ternary complexes incorporating the metal ion have been detected, and the effect of the ion on the rate has been rationalized in terms of the same mechanism, with the effect of the metal ion on the redox potentials of quinone and BNAH taken into account (Fukuzumi rt af., 1985b). While most NADH models are acid labile, quinones and aromatic aldehydes have been reduced by NMAH in the presence of perchloric acid (Fukuzumi et uf., 1985a, 1986). S U B S T I T U E N T EFFECTS O N RATES A N D EQUILIBRIA
Substituent effects on rates and equilibria in hydride transfers between a range of N A D + analogues have been examined. Anhydrous and aqueous acetonitrile and aqueous isopropyl alcohol have been used as reaction media, and earlier caveats as to possible complicating kinetic effects of nonproductive adduct formation apply, particularly where hydroxylic solvents are used. Data from hydride transfers have been compared with equilibria, k , + , and rates for pseudo-base formation, or for formation of cyanide adducts. The aqueous alcoholic solvent has an added disadvantage that pK, +-values for the cations are necessarily composite. Second-order rates for reduction of 1-(z-benzy1)nicotinonitrile cations, z-BNN', by 1-(x-benzyl)-l,4-dihydronicotinamides,x-BNAH, in aqueous acetonitrile correlate well with Hammett o-constants (Bunting and Brewer, 1985). For substituents (z) in the nitrile, p = 0.63 for reductions by BNAH,
HYDRIDE SHIFTS AND TRANSFERS
99
and for substituents (X) in the 1,4-dihydronicotinamide, p = -0.64 for reductions of 1-(4-cyanobenzyl)nicotinonitrile.Charge neutralization in the receiving cation evidently balances charge development in the donating dihydronicotinamide. From substituent effects on the equilibrium dissociation of the corresponding X-BNAH-cyanide adduct, p = 0.95 for charge neutralization, so that a charge of ca. -0.3 can be associated with the migrating hydrogen. Primary k.i.e.'s k H Z / k D Z = 3.0 and 2.7 were obtained for reduction of 1-methyl- and 1-(4-cyanobenzyl)-nicotinonitrilecations by 4,4-Dz-BNAH. Reductions of 9-substituted-NMA' ions (Bunting et al., 1984) by XBNAH's in aqueous acetonitrile, however, yielded no simple relationship between the second-order rate constants and either the nature of the 9substituent, or pK, + of the acridinium ions. Hammett correlations with the substituents (X) in the X-BNAHs give p = -0.68 for NMA', -0.95 for 9-benzyl-NMA+, and -0.96 for 9-phenyl-NMA'. Primary k.i.e.'s for the reductions by 4,4-D2-BNAH are 1.56, 2.7 and 5.4 respectively. The anomalous behaviour of the unsubstituted NMA' ion seems to be associated with the complications of adduct formation in this solvent mixture. Change of solvent to dry acetonitrile (van Laar et al., 1983; van Gerresheim and Verhoeven, 1983) does not alter the primary k.i.e.'s for the reduction of the substituted NMA' ions, but that reported for the parent cation, k H Z / k D Z = 4.6, is markedly different. The temperature dependence of the primary k.i.e. in reduction of 9-phenyl-NMA' by 4,4-Dz-BNAH in acetonitrile (4.01 at 20" to 3.07 at 50") yields AH/AD = 0.74 and [AElE = 4.4 kJ mol-', so that the k.i.e. is dominated by the zero point energy differences. When NMA' reacts with phenyl-substituted N-phenyldihydronicotinamides, X-PhNAH, also in anhydrous acetonitrile (Powell and Bruice, 1983b), rate and equilibrium data yield a Brernsted plot with a slope of 0.5 1, consistent with a centrally located transition state. The primary k.i.e.3 k H z / k D Z , increase from 3.98 for X = p-methoxy to 4.77 for X = rn-trifluoromethyl at 50" and may indicate a trend to a more symmetrical transition state. Marcus treatment of the substituent dependence of the k.i.e.'s yields an intrinsic barrier AG: = 22.2 kJ mol- '. The temperature dependence of the k.i.e. for reduction by X-PhNAH with X = p-methyl gives [AE]; = 7.68 kJ mol-', but AH/AD = 4.3 is unusually large. A tunnelling correction of ca. 2 was estimated so that the semi-classical k.i.e. was in the range 2 to 3. Relative reactivities of N-heteroaromatic cations, including quinolinium (Bunting and Fitzgerald, 1985; Roberts et al., 1983), isoquinolinium (Bunting et al., 1982a,b; Bunting and Sindhuatmadia, 1981) and phenanthridinium (Roberts et al., 1983) to hydroxide addition (pseudo-base formation) and in reductions by 1,4-dihydronicotinamides have been compared (Bunting and Bolton, 1986). With rate and thermodynamic data available for the
100
C IAN F
WATT
pseudo-base formation for a range of substituted cations in each series, linear free energy relationships could be used to correct the relative reactivities of the cations for thermodynamic effects. The reference point chosen was pKR+= 10.0, which is the value for the NMA’ ion in water at 25”. In the same, way, intrinsic reactivities in reductions by 1,4-dihydronicotinamides requires comparison of rates in reactions having the same equilibrium constants, K,, for hydride transfer. The same range of data is not available, but the reasonable assumption is made that BNAH reduction of cations all having the same pK,, should approximate a series of reactions having similar KHconstants. Such treatment does yield reasonable estimates for the rates of reduction, k,. With the estimated k,, and k , values for acridinium, quinolinium [at C(4)], pyridinium [at C(4)], quinolinium [at C(2)], isoquinolinium, and phenanthridinium, the relative reactivities k,/k,, towards reduction and hydroxide are 1.6 x lo5, 3.4 x lo3, 8 x 10, <4, I , and 0.7 respectively. Clearly the acridinium, quinolinium [C(4)], and to a lesser extent, pyridinium [C(4)] cations are more reactive towards BNAH than the other ions. It is suggested that a mechanism other than simple hydride transfer is available for the formation of 1 ,Cdihydropyridine derivatives, but not for 1 ,2-dihydropyridines. Equilibria and rates for the reduction of 10-methylacridinium ion by a range of N-heterocyclic hydride donors have also been determined in aqueous isopropyl alcohol solution (Ostovic et al., 1985; Roberts et al., 1982). In this solvent also, the acridinium and phenanthridinium ions differ in reactivity by a factor of ca. lo4. The rates of hydride transfer are well described by Marcus theory (Kreevoy and Lee, 1984). Plots of primary hydrogen k.i.e. against equilibrium constants for hydride transfers between N-heterocyclic cations (Ostovic et al., 1983) or their pKR+ values (Bunting and Fitzgerald, 1983) yield curves showing maxima in several cases. Such behaviour has been shown to be consistent with the recent theory of hydrogen transfers which emphasizes the importance of quantum mechanical tunnelling associated with large curvature of minimum energy pathways in mass-scaled skewed axis representations of their potential energy contour maps. Importantly, the geometry of the heavy atom framework in which tunnelling takes place is not that of the saddle point of the surface connecting reactant and products, and transfers of hydrogen should occur in a more extended framework than of its heavier isotopes, effectively “cutting the corner” of the curved minimum energy pathway. Combination of these considerations with the Marcus relationship between rates and equilibria, leads to the conclusion that Brernsted lines should show isotope-dependent curvature (Kreevoy et al., 1986).
HYDRIDE SHIFTS A N D TRANSFERS
101
MISCELLANEOUS REACTIONS O F D l H Y D R O P Y R l D l N E S
Additional tests for net hydride transfers initiated by single-electron transfer include the use of substrates in which such pathways would necessarily involve readily ring-opened cyclopropylmethyl or readily cyclized 5-hexenyl radicals. Products from these radical reactions are not formed in N AD+ / NADH dependent enzymic reductions or oxidations (MacInnes et al., 1982, 1983; Laurie et al., 1986; Chung and Park, 1982). Such tests have also been applied in non-enzymic reductions. Thus cyclopropane rings in cyclopropyl 2-pyridyl ketones, or imines of formylcyclopropane (van Niel and Pandit, 1983, 1985; Meijer et af., 1984) survive Mg+’ catalysed reduction by BNAH or Hantzsch esters but are opened by treatment with tributylin hydride. Any reduction initiated by electron transfer might be completed by either H.- or H+/e-transfer. In one case at least, it has been shown that the H + / e sequence would be followed. Photochemical reaction of fluorenone with NMAH (Peters et a[., 1982) involves initial electron transfer from NMAH to singlet fluorenone yielding a contact radical ion pair, presumably identical to that expected from a hypothetical ground state reaction with initial electron transfer. Fast time-resolved spectroscopy shows that this decays to the ketylNMA- radical pair by proton transfer. Hantzsch esters or PrNAH in acetonitrile reduce y-ary1-a-keto-p.yunsaturated esters to the y-aryl-a-ketoester in the presence of magnesium perchlorate (Meijer and Pandit, 1985). A second equivalent of dihydropyridine reduces the ketonic carbonyl, and reductions with 4,4-D2-Hantzsch esters in the presence of OH-ethanol show that transfer of hydrogen occurs without scrambling from the dihydropyridine to first the y- then the aposition of the unsaturated keto-esters, consistent with simple hydride transfer. Cinnamoyl pyridines are similarly reduced to the corresponding dihydroketones (Gase and Pandit, 1979). The importance in activation of the a,p-unsnturated ketone of chelation of the M’’ ion involving the ketonic carbonyl is shown by the 1600-fold reactivity of the 2-pyridyl ketone compared to the 4-pyridyl isomer. Micellar and Zn” catalysis has been demonstrated in the reduction of pyridine-2-carboxaldehyde by 1 -dodecyl3,5-bis(pyrrolidinylcarbonyl)-1 ,4-dihydropyridine (Awano and Tagaki, 1985). Chiral dihydropyridines, with the bridges incorporating metal-ion coordinating functionality (Talma et ul., 1985, Newkome and Marston, 1985) reduce activated carbonyl compounds such as ethyl phenylglyoxylate in the presence of stoichiometric amounts of Mg” with up to 90% enantiomeric excess. Intermolecular transfers between the polymethylene linked nicotinamides
C. IAN F. WATT
102
in [49; n = 2, 3 and 41 have been examined in DMSO solution using nmr spin-saturation transfer techniques (van Gerresheim et al., 1982; Verhoeven et al., 1986). No transfer was observed in [49; n = 21, but rates for [49; n = 31 and [49, n = 41 were determined and comparison with intermolecular analogues yielded effective molarities of 210 and 4 respectively, remarkably large values considering the formal ring size of the necessary cyclic transition structures. The polymethylene chain enforces the indicated face-to-face arrangement of the pyridine residues, and seems to demand a non-linear C. . .H. . .C transfer. A primary k.i.e., kHZ/kDZ = 2.7, for rearrangement of [49; n = 31 has been measured and shows no detectable temperature variation from 5 to 45°C. In view of the difficulties in obtaining reliable activation parameters by this method and of the relatively small temperature range, it is difficult to attach significance to this result, but absolute value of the k.i.e. and activation parameters, A,/AD = 2.7 and [AE]: = 0 kJ mol-' differ notably from those of a close intermolecular analogue, determined by uv spectroscopic methods. In this case, kH2/kD2= 3.23 at 25"C, with AH/AD= 1.4 and [AE]: = 2.2 kJ mol-
'.
S E C O N D A R Y H Y D R O G E N ISOTOPE EFFECTS
As noted earlier, secondary kinetic isotope (a-deuterium) effects in reductions by NADH models complicate extraction of true values of the primary effects. With a conventional primary isotope effect of 5.5, the a-deuterium effect on the rate of the non-enzymatic NADH reduction of 4-cyano-2,6dinitrobenzenesulphonate by NADH (Kurz and Frieden, 1980) were found to be 1.156 (fO.018) and 1.1454 (fO.0093) by direct and intramolecular competition methods respectively, values not unexpected for a reaction involving tetrahedral to trigonal carbon conversion. However, they turn out to be significantly larger than the corresponding equilibrium isotope effect, 1.013 ( f0.020) and 1.0347 ( f0.0087), determined by the same methods, and it has been suggested that with the light leaving group, i.e. hydride, motion of the attached a-hydrogen is important in the reaction co-ordinate (Limbach et al., 1982; Saunders, 1984). BEBO calculations (Huskey and Schowen, 1983) using a 20-atom model of NADH reacting with acetaldehyde support the proposal. Large amplitudes of a-hydrogen motion are found to lower the k.i.e. below the equilibrium isotope effect, and because its amplitude is gained at the expense of motion of the transferring hydrogen, the primary k.i.e. is also reduced. A model which combines large a-deuterium amplitudes with a large imaginary frequency and concomitant quantum mechanical tunnelling, however, reproduces both secondary and primary k.i.e.'s. The calculations also show that the a-deuterium effect should be reduced when the transferring primary hydrogen is isotopically replaced, and the unusual a-deuterium
103
HYDRIDE SHIFTS A N D TRANSFERS
effects vanish when the mass of the migrating atom is increased to 16 amu. These considerations nicely rationalize the observation of a ca. 10% reduction in the magnitude of the a-deuterium k.i.e. when the transferred atom is itself deuterium in transfers between NADH analogues (Ostovic et al., 1983) and have recently been supported by measurements on the non-enzymatic and glutamate dehydrogenase catalysed reduction of A' -pyrroline-2-carboxylic acid (Srinivasan and Fisher, 1985). For the non-enzymatic reduction, the isotope effect obtained by product analysis after reduction by 4-D- 1,4dihydronicotinamides is the same as the kinetic isotope effect from 4,4-D,1,4-dihydronicotinamide reduction. The dehydrogenase-catalysed reductions stereospecifically transfer the B-side hydrogen from the non-equivalent 4Aand 4B-hydrogens in NADH. Rates were determined for 4,4-H,-, 4,4-D,-, 4B-D- and 4A-D-NADH. The primary kinetic isotope effects k(4,4-H2)/ R(4B-D) = 3.80 and k(4,4-H2)/k(4,4-D,) = 3.32 differ as predicted, as do the secondary isotope effects k(4,4-H2)/k(4A-D) = I .2 1 and k(4B-D)/k(4,4D,) = 1.06.
'\
-.
113
H I.*
a. CH,Ph
I
0
H
H
T H E O R E T I C A L STUDIES
A C, transition structure [50]for hydride transfer from 1 ,4-dihydropyridine to pyridinium ion has been calculated using the semi-empirical MNDO/MO
104
C
IAN F WATT
method (van der Kerk et al, 1984; Verhoeven et a/., 1986). The linear C. . .H. . .C array is strongly preferred but the PE surface is remarkably flat with respect to rotation about the C . . . H . . C linkage with a staggered arrangement of the rings being only 5.4 kJ mol- less energetic than the eclipsed array. As noted earlier, this small rotational effect is also found in higher level calculations on smaller models including (NH2CH,. . .H. . CH2-NH2)+ (Hutley et al., 1986). With constraints to the eclipsed array to enforcing parallel rings, the activation enthalpy is raised by over 67 kJ mol- and even here the C. . .H. . .C array is almost linear with an angle of 168.2'. The reactions of cyclopropene, 1 ,Cdihydropyridine, and cycloheptatriene with cyclopropenium ion have also been examined as models of the NAD+/NADH hydride transfer (Donkersloot and Buck, 1981a). M I N D 0 and ub initio methods agree that, in all cases, the transition structures contain essentially linear C. . .H. . .C fragments, and charge transfer and bond reorganization are synchronous. The cyclopropene + cyclopropenium ion transition structure has C,, symmetry, and an energy relative to reactants of 63 kJ mol-' (STO-3G). With the other hydride donors, the reactions are exothermic and barriers lower. The possible role of the carbamoyl group in control of stereoselectivity in NADH reductions has been modelled in MO calculations of the reaction of carbamoyl dihydropyridine with either cyclopropenium ion or protonated formaldehyde (Donkersloot and Buck, 1981 b). Variation of the torsion angle between the carbamoyl group and the ring has a marked effect on the activation enthalpy and the equivalence between Ha and H, is lost. At angles of 90 or 270" the activation enthalpy difference for transfer of the hydrogens is over 25 kJ mol-' and the origin of the difference is in charge-dipole interaction between the C=O group of the amide and the positively charged hydride acceptor. With boatconformation cycloheptatriene as the donor, the calculations favour endoover exo-hydrogen transfer (Brounts and Buck, 1983). Endo-selectivity was enhanced by introduction of a carbamoyl group at the 1-position of the cycloheptatriene, with its C=O dipole pointing towards the accepting cyclopropenium ion (de Kok et al., 1986). The structures and reactions of NADH models containing diastereotopic C(4) hydrogens have been examined (Ohno et a[., 1986; Rob et a/., 1980, 1984; van Lier et al., 1982). The most dramatic differential reactivity of the C(4) hydrogens in hydride exchange occurs in bicyclic structures such as [5 I ] and [52] (Rob et al., 1984; de Kok and Buck, 1985; de Kok et al., 1986). The bridge induces non-equivalence at C(4) in two related ways illustrated in the structure [52]. The constrained dihydropyridine adopts a boat conformation, with the amide group effectively orthogonal to its mean plane. The labile hydrogen occupies the axial position, syn to the amide carbonyl.
'
',
HYDRIDE SHIFTS A N D TRANSFERS
105
References
Abdallah, A. A. and El Nahas, H. M. (1981). J . Heterocyclic Chem. 18, 1517 Abdallah, A. A,, El Nahas, H. M.. and Kandel, S. H. (1983). Egypt. J . Chem. 26,331 [CAIOl:10733 le] Abeles, R. H., Hutton, R. F. and Westheimer, F. H. (1957). J . Am. Chem. Soc. 79, 712 Abeywickrama, A. N. and Beckwith, A. L. J . (1986). Tetrahedron Lett. 109 Adams. C., Gold. V. and Reuben, D. M. E. (1977a). J . Chem. SOC.,Perkin Trans. 2, I466 Adams, C., Gold, V . and Reuben. D. M . E. (1977b). J . Chem. Soc., Perkin Trans. 2, I473 Ahlberg, P., Jonsall, G. and Engdahl, C. (1983). Adv. Phys. Org. Chem. 19, 223 Alder, R. W., Orpen, G. A. and Sessions, R. B. (1983). J . Chem. SOC.,Chem. Commun. 28 Anhede, B. and Bergmann, N-A. (1984). J . Am. Chem. Soc. 106, 7634 Ashby. E. C. and Argyropoulos, J. N. (1986). Tetrahedron Lett. 465 Ashby, E. C. and Boone. (1979). Top. Stereochem. 11, 54 Ashby, E. C. and Goel, A. B. (1981). J . Am. Chem. Soc. 103,4983 Ashby, E. C., Goel. A. B. and Depriest, R. N . (1981a). Tetrahedron Lett. 4355 Ashby, E. C., Goel, A. B., Depriest, R. N. and Prasad, H. S. (1981b). J . Am. Chem. Soc. 103, 973 Ashby, E. C., Goel, A. B. and Argyropoulos, J. N. (1982). Tetrahedron Lett. 2273 Ashby, E. C., Coleman, T. C. and Gamassa, M . P. (1983). Tetrahedron Lett. 851 Ashby. E. C., Depriest. R. N., Goel, A. B., Wenderoth, B. and Pham, T. N. (1984). J. Org. Chem. 49, 3545 Atkins, P. J.. Gold, V. and Wassef, W. N. (1983). J. Chem. Soc., Perkin Trans2, 1197 Atkins, P. J., Gold, V. and Wassef, W. N. (1986). J . Chem. Soc., Perkin Trans 2, 463 Atkins, T. J . (1980). J . Am. Chem. Soc. 102, 6356 Atwood, J. L., Hrcnir, D . C., Rogers, R. D. and Howard. J. A. K. (1981). J . Am. Chem. Soc. 103, 6787 Awano. H. and Tagaki, W. (1985). J . Chem. Soc., Cheni. Commun. 995 Bachrach, S. M. and Streitwieser, Jr, A. (1986). J. Am. Chem. SOC.108, 3946 Bartlett, P. D . and McCollum, J. D. (1956). J . Am. Chem. Soc. 78, 1441 Beloeil, J. C., Bertranne, M., Stahl, D. and Tabet, J . C. (1983). J . Am. Chem. Soc. IM, I 3 5 5
Bethell, D. and McDowall, L. J . (1984). J . Chem. Soc., Chem. Commun. 1408 Bethell, D., Hare, G. J . and Kearney, P. A. (1981). J . Cliem. Soc., Perkin Trans. 2, 684 Bierbaum, V. M., Grabowski, J. J. and DePuy, C. H. (1984). J . Phys. Chem. 88, 1389 Bogdanovic, B. (1985). Angew. Chem., Int. Ed. Engl. 24, 262 Bohme, D. K., Mackay, G. I . and Tanner, S. D. (1980). J . Am. Chem. Soc. 102,407 Bonaccorsi, R., Palla. P. and Tomasi. J. (1982). THEOCHEM. 4, 181 Bonaccorsi, R.. Cimeraglia, R., Tomasi, J. and Miertus, S. (1983). THEOCHEM. 11, II Boyer, B. and Lamaty, G. (1985). Reel. Truv. Chim. Pays-Bas 104, 217 Boyer, B., Lamaty, G., Moreau, C. and Geneste, P. (1979). Can. J . Chem. 57, 2850 Boycr, B., Lamaty, G.. Roque, J . P. and Geneste, P. (1980). “Can.J . Chem. 58, 55 Brounts, R. H. A. M. and Buck, H. M. (1983). J . Am. Chem. SOC.105, 1284 Brouwer, D. M. (1980). NATO Adv. Studi, Inst. Ser. E, 39 (Chem. and Chem. Eng. Catal. Processes), 137
106
C. IAN F. WATT
Brouwer, D. M. and Hogeveen, H. (1972). Prog. Phys. Org. Chem. 9, 179 Brower, K. R. and Hughes, D. (1978). J . Am. Chem. Soc. 100, 7591 Brown, H. C., Chandrasekharan, J. and Wang, K. (1983a). Pure Appl. Chem. 55, 1387 Brown, H. C., Kung, K., Wang, J. and Chandrasekharan, J. (1983b). J. Am. Chem. Soc. 105, 2341 Brown, H. C., Chandrasekharan, J. and Nelson, D. D. (1984). J . Am. Chem. SOC. 106, 3768 Brownstein, S. and Bornais, J. (1971). Can. J . Chem. 49, 7 Bruice, T. C. and Farny, 0. L. (1984). J . Chem. Soc., Chem. Commun. 185 Bubnov, Yu. N., Gurskii, M. E., Grandberg, A. I. and Pershin, D. G. (1986). Tetrahedron, 42, 1079 Buncel, E. and Menon, B. C. (1976). Can. J . Chem. 54, 3949 Buncel, E. and Symons, E. A. (1976). J . Am. Chem. Soc. 98, 657 Bunting, J. W. and Bolton, J. L. (1986). Tetrahedron 42, 1007 Bunting, J. W. and Brewer, J. C. (1985). Can. J . Chem. 63, 1245 Bunting, J. W. and Fitzgerald, N. P. (1985). Can. J. Chem. 63, 655 Bunting, J. W. and Sindhuatmadja, S. (1981). J. Org. Chem. 46, 4211 Bunting, J. W., Chew, V. F. ‘3. and Chu, G. (1982a). J . Org. Chem. 47, 2303 Bunting, J. W., Chew, V. F. S. and Chu, G. (1982b). J . Org. Chem. 47, 2308 Bunting, J . W., Chew, V. S. F., Chu, G., Fitzgerald, N. P., Gunasekera, A. and Oh, H. T. P. (1984). Biorg. Chem. 12, 141 Burgi, H. B., Dunitz, J. D., Lehn, J. M. and Wipff, G. (1974a). Tetrahedron 30,1563 Burgi, H. B., Lehn, J. M. and Wipff, G. (1974b). J . Am. Chem. Soc. 96, 1956 Burnett, R. D. and Kirk, D. N. (1976). J . Chem. Soc., Perkin Trans. 2, 1524 Carlson, B. W. and Miller, L. L. (1983). J . Am. Chem. Soc. 105, 7453 Carlson, B. W. and Miller, L. L. (1985). J . Am. Chem. Soc. 107,479 Carlson, B. W., Miller, L. L., Neta, P. and Grodowski, J. (1984). J . Am. Chem. Soc. 106, 7233 Casiraghi, G., Casnati, G., Sartori. G. and Zanfredi, G. T. (1980). J . Chem. Soc., Perkin Trans. 2, 407 Caubere, P. (1983). Angew. Chem., Int. Ed. Engl. 22, 599 Cernik, R., Craze, G-A., Mills, 0. S. and Watt, I. (1982). J. Chem. Soc., Perkin Trans. 2, 361 Cernik, R., Craze, G-A,, Mills, 0. S., Watt, I. and Whittleton, S. N. (1984). J . Chem. SOC.,Perkin Trans. 2, 685 Chandrasekharan, J. and Brown, H. C. (1985). J . Org. Chem. 50, 519 Chipman, D. M., Yaniv, R. and van Eikeren, P. (1980). J . Am. Chem. Soc. 102, 3244 Christoffersen, R. E. and Shull, H., (1968). J. Chem. Phys. 48, 1790 Chung, S. K. (1982). J. Chem. SOC.,Chem. Commun. 480 Chung, S. K and Park, S . U. (1982). J . Org. Chem. 47, 3197 Colter, A. K., Lai, C. C., Williamson, T. W. and Berry, R. E. (1983). Can. J. Chem. 61, 2544 Colter, A. K., Plank, P., Bergsma, J. P., Lahti, R., Quesnel, A. A. and Parsons. A. G. (1984). Can. J. Chem. 62, 1780 Colter, A. K., Parsons, A. G . and Foohey, K. (1985). Can. J . Chem. 63, 2237 Cram, D. J., Mateos, J. L., Hauk, F., Langemann, A,, Kopecky, K. R., Nielsen, W. D. and Allinger, J. (1959). J. Am. Chem. Soc. 81, 5774 Craze, G-A. and Watt, I. (1981). J . Chem. Soc., Perkin Trans. 2, 175 Danishefsky, S., Hirama, M., Fritsch, N. and Clardy, J. (1979). J . Am. Chem. SOC. 101. 7013
HYDRIDE SHIFTS AND TRANSFERS
107
Davis, A. M., Page, M. I., Mason, S. C. and Watt, C. I. F., (1984). J . Chem. Soc., Chem. Commun. 167 1 Defrees, D. J., Bartmess, J. E., Kim, J. K., McIver, R. T. and Hehre, W. J. (1977). J. Am. Chem. SOC.99, 6451 de Kok, P. M. T and Buck, H. M. (1985). J . Chem. SOC.,Chem. Commun. 1009 de Kok, P. M. T., Donkersloot., M. C. A., van Lier, P. M., Meulendijks, G . H. W. M., Bastiaansen, L. A. M., van Hooff, H. J. G., Kanters, J. A. and Buck, H. M. (1986). Tetrahedron 42, 959 DePuy, C. H., Bierbaum, V. M., Schmitt, R. H. and Shapiro, R. H. (1978). J . Am. Chem. SOC.100, 2920 Dewar, M. J. and McKee, M. L. (1978). J . Am. Chem. SOC.100, 7499 Deslongchamps, P., Rowan, D. D. and Pothier, N. (1981a). Heterocycles, 15, 1093 Deslongchamps, P., Rowan, D. D. and Pothier, N. (1981b). Can. J. Chem., 53, 2787 D’Incan, E. and Loupy, A. (1981). Tetrahedron 37, 1171 D’Incan, E., Loupy, A., Restalli, A., Seydon-Penne, J. and Viout, P. (1982a). Tetrahedron 38, 1755 D’Incan, E., Loupy, A,, Maia, A., Seydon-Penne, J. and Viout, P. (1982b). Tetrahedron 38, 2923 Dirda, D., Rapp, D and Kramer, G. M. (1979). J . Org. Chem. 44, 2619 Donkersloot, M. C . A. and Buck, H. M. (1981a). J . Am. Chem. SOC.103, 6549 Donkersloot, M. C . A. and Buck, H. M. (1981b). J . Am. Chem. SOC.103, 6554 Dormans, G . J. M. and Buck., H. M. (1986). J. Am. Chem. SOC.108, 3253 Ducharme, Y., Latour, S. and Wuest, J. D. (1984a). J . Am. Chem. Soc. 106, 1499 Ducharme, Y., Latour, S. and Wuest, J. D. (1984b). OrganometaNics 3, 208 Dykstra, C. E., Arduengo, A. J. and Fukunaga, T. (1978). J . Am. Chem. SOC.100, 6007 Eberson, L. (1982). Adv. Phys. Org. Chem. 18, 79 Eberson, L. (1984). Acta Chem. Scand. B38, 439 Eisenstein, O., Proctor, G . and Dunitz, J. D. (1978). HeIv. Chim.Acta 61, 2538 Eisenstein, O., Schlegel, H. B. and Kayser, M. M. (1982). J . Org. Chem. 47, 2886 El’tsov, A. V., Pavlish, N. V. and Ketlinskii, V. A. (1978). Zh. Org. Khim. 14, 1751 [CA89:216812] Erhardt, J. M. and Wuest, J. D. (1980). J . Am. Chem. SOC.102, 6346 Erhardt, J. M., Grover, E. R. and Wuest, J. D. (1980). J. Am. Chem. SOC.102, 6356 Fukuzumi, S., Nishizawa, N. and Tanaka, T. (1984). J . Org. Chem. 49, 3571 Fukuzumi, S., Nishizawa, N. and Tanaka, T. (1985a). J. Chem. SOC.,Perkin Trans. 2, 37 1 Fukuzumi, S., Ishikawa, M. and Tanaka, T. (1985b). J . Chem. SOC.,Chem. Commun. 1069 Fukuzumi, S., Ishikawa, M. and Tanaka, T. (1986). Tetrahedron 42, 1021 Case, R. and Pandit, U. K. (1979). J . Am. Chem. Suc. 101, 7059 Gold, V., Miri, A. Y. and Robinson, S. R. (1980). J . Chem. SOC.,Perkin Trans. 2,243 Graham, G . D., Freilich, S. C. and Lipscomb, W. N. (1981). J . Am. Chem. SOC.103, 2546 Greenwood, N. N. and Earnshaw, A. (1984). In “The Chemistry of the Elements”, Pergamon, Oxford, p. 72 Gurskii, M. E., Baranin, S. V.. Shashkov, A. S., Lutsenko, A. I. and Mikhailov, B. M. (1983). J . Organomet. Chem. 246, 129 Handel, H. and Pierre, J. L. (1975). Tetrahedron 31, 2799 Hannon, S. J. and Traylor, T. G. (1981). J . Org. Chem. 46, 3645
108
C. IAN F. WATT
Hemmerich, P., Massey, V., Micel, H. and Schweig, C. (1982). Struct. Bonding (Berlin) 48, 93 Henry, R. S., Riddell, F. G., Parker, W. and Watt, C. I. F. (1976). J . Chem. Soc., Perkin Trans. 2, 1549 Hermes, J. D., Morrical, S. W., O’Leary, M. H. and Cleland, W. W. (1984). Biochemistry 23, 5479 Hine, J. and Koser, G . F. (1971). J. Org. Chem. 36, 3591 Hirabe, T., Takagi, M., Muraoka, K., Nojima, M. and Kusabayashi, S. (1985). J . Org. Chem. 50, 1797 Hiraoka, H. and Kebarle, P. (1976). J . Am. Chem. SOC.98, 6119 Holm, T. (1974). Acta Chem. Scund. B28, 809 Holm, T. (1982). Acta Chem. Scund. B36, 266 Holtslander, W. L. and Lockerby, W. E. (1978). A.C.S. Symposium Ser., No. 68, Ch.
3 Horii, H. and Taniguchi, S. (1986). J . Chem. Soc., Chem. Commun. 915 Houk, K. N., Rondan, N. G.. Schleyer, P. v. R., Kaufmann, E. and Clark, T. (1985). J . Am. Chem. Soc. 107, 2820 Huang, J. T. J., Schwartz, M. E. and Pfeiffer, G. V. (1972). J . Chem. Phys. 56, 755 Huskey, W. P. and Schowen, R. L. (1983). J. Am. Chem. Soc. 105, 5704 Perkin Huszthy, P., Lempert, K., Simig, G. and Tamas, J. (1982). J . Chem. SOC., Trans. 2, 1671 Hutchings, M. G. and Gasteiger, J. (1986). J . Chem. Soc.. Perkin Trans. 2, 447 Hutchins, J. E. C., Binder, D. A. and Kreevoy, M. M. (1986). Tetrahedron 42, 993 Hutley, B. G., Mountain, A. E., Williams, I. H., Maggiora, G. M. and Schowen, R. L. (1986). J. Chem. Soc., Chem. Comrnun. 266 (correction 1303) Imamura, A. and Hirano, T. (1975). J . Am. Chem. SOC.97, 4192 Ingemann, S., Kleingeld, J. C. and Nibbering, N. M. M. (1982). J . Chem. Soc., Chem. Commun. 1009 Ingemann, S., Kleingeld, J. C. and Nibbering, N. M. M. (1984). In “Ionic Processes in the Gas Phase”. M. A. Almoster Ferreira (ed.), D. Reidel Publishing Co., NATO AS1 Series Isaacs, N. S., Javaid, K. and Rannala, E. R. (1978). J . Chem. Soc., Perkin Trans. 2., 709 Ivanov, P. Y., Bychkov, N. N. and Stepanov, B. I. (1982). Zh. Org. Khim. 18, 391 [CA96:19917821 Kabir-ud-Din and Plesch, P. H. (1978). J . Chem. SOC.,Perkin Trans. 2, 937 Kahn, S. D., Hehre, W. J., Rondan, N. G. and Houk, K. N. (1985). J . Am. Chem. Soc. 107, 8291 Kashin, A. N. (1981). Zh. Org. Khim. 17, 891 [CA95:61073] Katz, H. E. (1985). J . Am. Chem. Soc. 107, 1420 Kaufmann, E., Schleyer, P. v. R., Houk, K. N. and Wu, Y-D. (1985). J . Am. Chem. Soc. 107, 5560 Kayser, M. M. and McMahon, T. B. (1984). Tetrahedron Lett. 3379 Kayser, M. M., Eliev, S. and Eisenstein, 0. (1983). Tetrahedron Lett. 1015 Kirby, A. J. (1980). Adv. Phys. Org. Chem. 17, 183 Kirchen, R . P. and Sorensen, T. S. (1979). J . Am. Chem. Soc. 101, 3240 Kirchen, R. P., Ranganayakulu, K., Rauk, A,, Singh, B. P. and Sorensen, T. S. (1981a). J . Am. Chem. Soc. 103, 588 Kirchen, R. P., Ranganayakula, P., Singh, B. P. and Sorensen, T. S. (I98 1 b). Can. J . Chem. 59, 21 73
YYDRIDE SHIFTS A N D TRANSFERS
109
Kirchen, R. P.. Sorensen, T. S., Wagstaff, K. and Walker, A. M. (1986). Tetrahedron 42, 1063
Kleingeld, J. C. and Nibbering, N. M. M. (1983). Int J . Mass. Spectrom. Ion Phys. 49, 311
Kleingeld, J. C., Ingemann, S., Jalonen, J. E. and Nibbering, N. M. M. (1983). J . Am. Chenz. Soe. 105, 2474 Kowaski, C., Creary, X., Rollin, A. and Burke, M. C. (1978). J . Org. Chem. 43, 261 I Kramer, G . M. (1986). Tetrahedron 42, 1071 Kramer, G . M. and McVicker, G. B. (1986). Acc. Chem. Res. 19, 78 Kreevoy, M. M. and Lee, I. S. H. (1984). J . Am. Chem. Soc. 106, 2550 Kreevoy. M. M., Ostovic, D., Truhlar, D. G . and Garrett, B. C. G . (1986). J. Phys. Chem. 90, 3766 Kurz, L. C. and Frieden, C. (1980). J . Am. Chem. Soc. 102, 4198 Kurz, L. C. and Kurz, J. L. (1978). Eur. J . Biochem. 90, 283 Kwart, H. (1982), Acc. Chem. Res. 15, 401 Latimer, W. M. (1968). “The Oxidation States of the Elements and their Potentials in Aqueous Solution”, Prentice-Hall, New York Laurie, D., Lucas, E., Nonhebel, D. C., Suckling, C. J. and Walton, J. C. (1986). Tetrahedron 42, 1035 Lewis, E. S. and Symons, M. C. R. (1958). Quart. Rev. Chem. Soc. 12, 230 Li, M. Y. and San Filippo, J. (1983). Organometallics 2, 554 Limbach, H-H, Hennig, J., Gerritzen, D. and Rumpek, H. (1982). Furaday Discuss., Chem. Soc. 74, 229 Loupy, A. and Seyden-Penne, J. (1979). Tetrahc.dron Lett. 2571 Loupy, A. and Seyden-Penne, J. (1980). Tetrahedron 36, 1937 MacInnes, I., Nonhebel, D. C., Orszulik, S. T. and Suckling, C. J. (1982). J . Chem. Soc., Chem. Commun. 121 MacInnes, I., Nonhebel, D. C., Orszulik, S. T. and Suckling, C. J. (1983). J . Chem. Soc., Perkin Trans. I , 2777 Magee, C. B. (1968). In “Metal Hydrides” (W. M. Mueller, J. P. Blackledge and G . G. Libowitz, eds), Ch. 6. Academic Press, New York Magnera, T. F. and Kebarle, P. (1984). In “Ionic Processes in the Gas Phase”, M. A. Almoster Ferreira (ed.), D. Reidel Publishing Co., NATO AS1 Series Mann, B. E., Cutts, P. W., McKenna, J.. McKenna, J. M. and Spencer, C. M. (1986). Angew Chem., Int. Ed. Engl. 25, 577 Marcus, R. A. (1968). J . Chem. Plzys. 72, 891 Martens, F. M., Verhoeven, J. W., Case, R. A,, Pandit, U. K. and de Boer, Th. J. (1978). Tetrahedron 34, 443 McDonald, R. S. and Sibley, C. E. (1981). Can. J . Chem. 59, 1061 McKee, M . L. (1985). J . Am. Chem. Soc. 107, 7284 McLennan, D. J. and Gill, P. M. W. (1985). J . Am. Chem. Soc. 106, 2971 McMurray, J. E. and Hodge, C. N. (1984). J . Am. Chem. Soc. 106, 6451 Meeks, B. S. and Kreevoy, M. M. (1979). J . Am. Chem. Soc. 101, 4918 Meijer, H. P. and Pandit, U. K. (1985). Tetrahedron 41, 467 Meijer. H. P., van Niel, J. C. G . and Pandit, U. K. (1984). Tetrahedron 40, 5185 Meot-Ner, M. (1979). In “Gas Phase Ion Chemistry”. M. T. Bowers (ed.), Ch. 6, Academic Press, New York Meot-Ner, M. and Field, F. H. (1976). J . Chem. Phys. 64, 277 Meot-Ner, M. and Field, F. H. (1978). J . Am. Chem. Soc. 100, 1356 Minyaev, R. M. and Pavlov, V. I. (1982). Zh. Org. Khim. 18, 1595 [CA97:161902]
110
C . IAN F. WATT
Muller, P. and Blanc, J . (1980). Helv. Chim. Acta 63, 1759 Muller P. and Blanc, J . (1981). Tetrahedron Lett. 715 Murdoch, J . (1983). J. Am. Chem. Soc. 105, 2159 Murray-Rust, J., Murray-Rust, P., Parker, W., Tranter, R. L. and Watt, C. I . F. (1979). J . Chem. Soc., Perkin Trans. 2. 1496 Myhre, P. C. and Yannoni, C. S. (1981). J . Am. Chem. Soc. 103, 230 Nagase, S. and Uchibori, Y. (1982). Tetrahedron Lett. 2585 Nagase, S., Ray, N. K. and Morokuma, M. (1980). J . Am. Chem. Soc. 102, 4536 Nasipur, D., Gupta, M. D. and Mahapatra, B. (1984a). Proc. Indian. Natl. Sci. Acad. 50A, 47 Nasipur, D., Gupta, M. D. and Bannerji, S. (1984b) Tetrahedron Lett. 5551 Newcomb, M . and Burchill, M. T. (1984a). J . Am. Chem. Soc. 106, 2450 Newcomb, M. and Burchill, M. T. (1984b). J. Am. Chem. Soc. 106, 8276 Newkome, G . R. and Marston, C. R. (1985). J . Org. Chem. 50, 4238 Nguyen, M. T., Hegarty, A. F., Sana, M. and Leroy, L. (1985). J . Am. Chem. Soc. 107, 4141 Nishimura, N. and Motoyama, T. (1984). Bull. Chem. Soc. Jpn. 57, 1 Oestensen, E. T., Abdallah, A. A., Skaare, S. H. and Mishrikey, M . M. (1977). Acta. Chem. Scand. B31,496 Ohno, A., Kashiwagi, M., Ishihara, Y., Ushida, S. and Oka, S . (1986). Tetrahedron 42, 961 Okhlobystin, 0. Yu. and Berberova, N. T. (1981). Zh. Org. Khim. 17, 888 [CA95: 6 I0721 Okuyama, T., Kimura, K. and Fueno, T. (1982). Bull. Chem. Soc. Jpn. 55, 2285 Olah, G . A. and Svoboda, J. J . (1973). J. Am. Chem. Soc. 95, 3794 Ostovic, D., Roberts, R. M. G . and Kreevoy, M . M. (1983). J. Am. Chem. Soc. 105, 7629 Ostovic, D., Roberts, R. M. G. and Kreevoy, M. M. (1985). J . Org. Chem. 50, 4206 Paddon-Row, M. N., Rondan, N. G. and Houk, K. N. (1982). J. Am. Chem. Soc. 104, 7162 Parnes, A. M., Shein, S. M., Kalinkin, M. I., Sidel’nikova, L. I . and Kursanov, D. N. (1971). Izv. Akad. Nauk SSSR, Ser. Khim. 10, 2350 Pasto, D. J. and Lepeska, B. (1976). J. Am. Chem. Soc. 98, 1091 Paulson, J. and Henchman, M. J . (1982). Bull. Am. Phys. Soc. 27, 108 Pawlowski, N. E., and Sinnhuber, R. 0. (1980). J . Org. Chem., 45, 2735 Peters, K. S., Pang, E., and Rudzki, J. (1982). J . Am. Chem. Soc., 104, 5535 Poirier, R. A,, Emilia, E., Abbe, J. C., Pererson, M. R. and Csizmadia, I. G. ( 1 982). THEOCHEM. 5,343 Postovaskii, I. Y., Chupakhin, 0. N. and Matern, A. I . (1984). Khim. Gerotsikl. Soedin 1299 [CA102:5201al Powell, M. F. and Bruice, T. C. (1982). J . Am. Chem. Soc. 104, 5834 Powell, M. F. and Bruice, T. C. (1983a). J . Am. Chem. Soc. 105, 1014 Powell, M. F. and Bruice, T. C. (1983b). J . Am. Chem. Soc. 105, 7139 Powell, M. F., Wu, J . C. and Bruice, T. C. (1984). J. Am. Chem. Soc. 106, 3850 Pronin, A. F. and Holer, J. (1981). Zh. Fiz. Khim. 55, 635 [CA94:208051] Pronin, A. F. and Karchenko, V . G. (1982). Izv. Vyssh. Ucebn. Zaved., Khim. Khim. Teknol. 25, 536 [CA97:717781 Pross, A. (1985a). Adv. Phys. Org. Chem. 21, 99 Pross, A. (1985b). Acc. Chem. Res. 18, 212 Pross, A. and Shaik, S . S. (1983). Acc. Chem. Res. 16, 363 Raghavachari, K., Schleyer, P. v. R. and Spitznagel, G. W. (1983). J . Am. Chew. SOC. 105, 5917
HYDRIDE SHIFTS A N D TRANSFERS
111
Raghavachari, K., Whiteside, R. A., Pople, J. A. and Schleyer, P. v. R. (1981). J. Am. Chem. SOC.103, 5649 Rayez, J . C., Rayez-Meaune, M. T. and Massa, L. J. (1981). J . Chem. Phys. 75, 5393 Reetz, M. T. and Stephan, W. (1977). Angew. Chem.. In?. Ed. Engl. 46, 1977 Ritchie, C. D. and King, H. F. (1968a). J . Am. Chem. Soc. 90, 825 Ritchie, C. D. and King, H. F. (1968b). J . Am. Chem. Soc. 90, 833 Ritchie, C. D. and King, H. F. (1968~).J . Am. Chem. Soc. 90, 838 Rob, F.. van Ramesdonk, H. J., Verhoeven, J . W., Pandit, U. K. and de Boer, Th. J. ( 1980), Tetrahedron Lett. 1549 Rob, F., van Ramesdonk, H. J . , van Gerresheim, W., Bosma, P.. Scheele, J. J. and Verhoeven, J. W. (1984). J . Am. Chem. Soc. 106, 3826 Roberts, R. M. G.. Ostovic, D. and Kreevoy, M. M. (1982). Furuday Discuss. Chem. SOC.74, 257 Roberts, R. M . G., Ostovic, D. and Kreevoy, M. M. (1983). J . Org. Chem. 48, 2053 Rosenstock, H . M., Draxl, K.. Steiner, B. W. and Herron, J. T. (1977). J . Phys. Chem. Rqf. Data 6, Suppl. 1 Rzepa, H. S. and Miller, J. (1985). J . Chem. Soc.. Perkin Trans. 2, 717 Sandhu, S. S. (1983). J. Chem. Sci. 9, 101 Saturnino, D. J., Yamauchi, M., Clayton, W. R., Nelson, R. W. and Shore, S. G. (1975). J . Am. Chem. SOC.97, 6063 Saunders, M. and Kates, M . R. (1978). J . Am. Chem. Soc. 100, 7082 Saunders, M. and Stofko, J. J . jr. (1973). J . Am. Cheni. Soc. 95, 252 Saunders, M., Kates, M. R. and Walker, G . E. (1981). J . Am. Chem. Soc. 103, 4623 Saunders, W. H. (1984). J . Am. Chem. Soc. 106, 2223 Sharma. R. B., Sen Sharma, D. K., Hiraoka. K. and Kebarle, P. (1985). J . Am. Chem. Soc. 107, 3747 Sheldon, J. C., Bowie, J. and Hayes, R. N. (1984). Nouv. J . Chim. 8, 79 Sheldon, J . C., Currie. G. J.. Lahnstein, J., Hayes, R. N. and Bowie, J. H. (1985). Nouv. J . Chim. 9, 205 Shore, S. G. and Lawrence, S. H. (1982). J . Am. Chem. Soc. 104, 7669 Siehl, H-U. and Walter, H . (1985). J . Chem. Soc., Chem. Commun. 77 Sims, L. B. and Lewis, D. E. (1984). In “Isotopes in Organic Chemistry”. E. Buncel and C. C. Lee (eds), Vol. 6, Elsevier. Amsterdam Sinha, A . and Bruice, T. C. (1984). J. Am. Chem. Soc. 106, 7291 107, 4591 Skibo, E. B. and Lee, C. H. (1985). J . Am. Chetn. SOC. Srinivasan, R. and Fisher. H. F. (1985). J . Am. Chem. Soc. 107, 4301 Steffens, J . J. and Chipman, D. M. (1971). J. Am. Chem. Soc. 93, 6694 Steigerwald, M. L., Goddard, W. A. and Evans, D. A. (1979). J . Am. Chem. SOC.101, I994 Stewart, R. (1976). In “Isotopes in Organic Chemistry“, E. Buncel and C. C. Lee (eds), Vol. 2, Elsevier, Amsterdam Stewart, R. and Teo, K . C. (1980). Can. J . Chem. 58, 2491 Stewart, R. and Toone, T. W. (1978). J . Chem. Soc.. Perkin Trans. 2, 1243 Strozier, R. W., Caramella, P. and Houk, K. N. (1979). J . Am. Chem. Soc. 101, 1340 Sturm, H., Kiesele, H. and Daltrozzo, E. (1978). Chem. Ber. 111, 227 Swain, C. G., Wiles, R. A. and Bader. R. F. W. (1961). J . Am. Chem. Soc. 83, 1945 Swain, C. G.. Powell, A. L., Lynch, T. J., Alpha, 5. R. and Duncap, R. P. (1979a). J . Am. Chem. Soc. 101, 3584 Swain. C. G., Powell, A. L., Sheppard. W. H. and Morgan. C. R. (1979b). J . Am. Chem. Soc. 101, 3576 Symons, E. A,, Powell, M . F., Schnittker, J . B. and Clermont, M. J. (1979). J . Am. Chem. SOC.101, 6704
112
C. IAN F. WATT
Symons, M. C. R., Chen, T. and Glidewell, C. (1983). J . Chem. Soc., Chem. Commun. 326 Tabet, J. C., Hanna, 1. and Fetizon, M. (1985). Org. Mass. Spectrom. 20, 61 Talma, A. G., Jouin, P., De Vries, J. G., Troostwijk, C. B., Buning, G . H. W., Waninge, J. K., Visscher, J. and Kellogg, R. M. (1985). J . Am. Chem. Soc. 107, 3987
Tapia, O., Andres, J., Aullo, J. M. and Braenden, C. I. (1985). J . Chem. Phys. 83, 4673
Traylor, T. G . and Koermer, G . S. (1981). J . Org. Chem. 46, 3651 Uglova, E. V., Grishin, Y u . K. and Reutov, 0. A. (1977). Izv. Akad. Nauk. SSSR., Ser. Khim. 11, 2478 [CA88:88726s] Uglova, E. V., Makhaev, V. D. and Reutov, 0. A. (1982). Zh. Org. Khim. 18, 1584 Umeyama, H. (1980). Chem. Pharm. Bull. 28, 1317 Vander Jagt, D. L. and Han, L-P. B. (1973). Biochemistry 12, 1 1 15 Vander Jagt, D. L., Han, L-P. B. and Lehman, C. H. (1972). J . Org. Chem. 37,4100 van der Kerk, S. M., van Gerresheim, W. and Verhoeven, J. W. (1984). Recl. Trav. Chim. Pays-Bas 103, 143 van Gerresheim, W. and Verhoeven, J. W. (1983). Red. Trav. Chim. Pays-Bas, 102, 339
van Gerresheim, W., Kruk, C. and Verhoeven, J. W. (1982). Tetrahedron. Lett. 565 van Laar, A,, van Ramesdonk, H. J., Verhoeven, J. W. (1983). Recl. Trav. Chim. PUYS-BUS 102, 157 van Lier, P. M., Donkersloot, M. C. A,, Koster, A. S., Van Hooff, H. and Buck, H. M. (1982). Red. Trav. Chim. Pays-Bas 101, 119 van Niel, J. C. G. and Pandit, U. K. (1983). J. Chem. Soc., Chem. Commun. 149 van Niel, J. C. G. and Pandit, U. K. (1985). Tetrahedron, 41, 6005 Verhoeven, J. W. (1980). Recl. Trav. Chim. Pays-Bas 99, 369 Verhoeven, J. W. and Pasman, P. (1981). Tetrahedron 37, 943 Verhoeven, J. W., van Gerresheim, W., Martens, F. M. and van der Kerk, S. M. (1986). Tetrahedron 42, 975 Vitale, A. A. and San Filippo, J. (1982). J . Am. Chem. Soc. 104, 7341 Vogel, P. (1985). “Carbocation Chemistry”, Elsevier, Amsterdam Wang, K. K. and Brown, H . C. (1980). J . Org. Chem. 45, 5303 Warnhoff, E. W. (1976). Can. J . Chem. 55, 1635 Warnhoff, E. W., Reynolds-Warnhoff, P. and Wong, M . Y. H. (1980). J . Am. Chem. Soc. 102, 5956 Watt, C. I. F., Whittleton, S. N. and Whitworth, S. M. (1986). Tetrahedron 42, 1062 Wigfield, D. C. (1979). Tetrahedron 35, 449 Wigfield, D. C. and Gowland, F. W. (1976). Tetrahedron Lett. 3373 Wigfield, D. C. and Gowland, F. W. (1977). J . Org. Chem. 42, 1 108 Wigfield, D. C. and Gowland, F. W. (1978). Can. J . Chem. 56, 786 Wigfield, D. C. and Phelps, D. J. (1972). Can. J . Chem. 50, 388 Wigfield, D. C. and Pon, R. T. (1979). J . Chem. Soc., Chem. Commun. 910 Williams, I. H. (1983). THEOCHEM. 14, 105 Yamataka, H. and Hanafusa, T. (1986). J . Am. Chem. Soc. 108, 6643 Yang, D. and Tanner, D. D. (1986). J . Org. Chem. 51, 2247 Youngblood, M. P. (1985). J . Am. Chem. SOC.107, 6987 Yuan, L. C. and Bruice, T. C. (1984). J . Am. Chem. Soc. 106, 1530
The Principle of Least Nuclear Motion and the Theory of Stereoelectronic Control M I C H A E L L. S I N N O T T Department of Organic Chemistry. University of Bristol, U.K. I 2
3
4 5
6 7
Introduction 114 Failures of the antiperiplanar lone pair hypothesis (ALPH) 120 Additions to imines 120 Acetal and glycoside hydrolysis 121 Gas-phase reactions of orthoesters 130 Aminolysis of penicillins 13 1 Hydrolysis of amidines and amidinium salts 132 Enzymatic reactions 134 The theoretical basis of ALPH: strengths and weaknesses 145 Electrons, orbitals and epiphenomena 145 The electrostatic explanation of the anomeric effect: successes and failures 146 The frontier orbital explanation of the anomeric effect: successes and failures 148 Calculations on tetrahedral intermediates 152 ALPH and the principle of least nuclear motion I54 The principle of least nuclear motion (PLNM) 156 Reinterpretation of apparent kinetic antiperiplanar lone pair effects in terms of the PLNM 161 Heterolytic reactions at carbon centres substituted with two additional oxygen atoms 161 Heterolytic reactions at carbon centres substituted with two additional nitrogen atoms 165 Heterolytic reactions at carbon centres substituted with one additional oxygen and one additional nitrogen atom 167 Reactions of proteinases I71 Loss of leaving groups from trigonal centres 179 Reactions at phosphorus centres 184
ADVANCES IN PHYSICAL ORGANIC CHEMISTRY V O L U M E 24 ISBN n - i ? - o m 2 4 - 7
Copyrighr 0 IYXX Arudrmic Press Limired ,411 righrs ofreproducriun in on? form reserved
MICHAEL L SINNOTT
114
8 Reactions of radicals 192 One lone pair: hydrogen atom abstraction from aliphatic amines 192 Formation and decomposition of a-oxygen-substituted radicals 194 Reactions of gas-phase radical cations 197 9 Envoi 198 Acknowledgements 198 References 199
1
Introduction
It is now 15 years since the group of P. Deslongchamps made the seminal observation that the susceptibility of various conformationally restricted acetals to oxidation by ozone depended dramatically on the stereochemistry of the acetal linkage (Deslongchamps et al., 1972a). The mechanism of this reaction, first reported by Deslongchamps and Moreau (1971), can now be written with some confidence as set out in Scheme 1: ozone abstracts a hydride ion to give a dioxocarbonium ion-hydrotrioxide ion pair which then collapses to a covalent hydrotrioxide. Covalent hydrotrioxide intermediates in this reaction have been detected and studied (KovaE and PlesniEar, 1979). Non-ionic routes for their formation, via free radicals or cyclic transition states, are unlikely, the former because structure-reactivity parameters (Taillefer et al., 1980) are similar to those observed for orthoester hydrolysis when the substituents are in the pro-acyl moiety (Cordes and Bull, 1974) and the latter because a primary deuterium kinetic isotope effect of 6.5 (Taillefer, R. J. and Thomas, S. E., unpublished data quoted in Deslongchamps, 1983, p. 44) is too big for a process involving non-collinear transfer of hydrogen.
Scheme 1
The dramatic effects that the stereochemistry of the substrate had on the reaction can be illustrated by the case of methyl a- and p-glucopyranosides: methyl p-D-glucopyranoside reacted smoothly with ozone under conditions where its anomer was totally inert. The preferred conformations of the two glycosides are shown in [ I ] and [2]:the ring is in the 4C, chair conformation, and the conformation about the exocyclic C(1)-0(1) bond is governed by the exo-anomeric effect (see p. 116). Deslongchamps et al. (1972a) realised that in these conformations, if the two lone pairs of electrons on the oxygen
115
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
atoms were considered to be in identical sp3 orbitals, then the hydrogen to be removed by ozone was antiperiplanar only to a lone pair on the exocyclic oxygen atom of methyl a-glucoside, but to a lone pair on the exocyclic oxygen atom and to one of the ring oxygen lone pairs in the case of methyl P-glucoside.
This observation was the genesis of what Deslongchamps termed the “Theory of Stereoelectric Control”. It is best described diagrammatically (Scheme 2), and in its original form is a statement about reactive groundstate conformations. Departure of a leaving group from a tetrahedral carbon atom, substituted with one or more heteroatoms bearing lone pairs of electrons, is favoured in an additive way if those lone pairs of electrons are antiperiplanar, and is for practical purposes forbidden if they are orthogonal or even synperiplanar. It seems to the reviewer that “stereoelectronic control” is far too general a term for such a specific phenomenon, and that the phrase “antiperiplanar lone pair hypothesis”, which results in the acronym ALPH, is to be preferred on the grounds of semantic precision (see also Kirby, 1984, especially footnote 10).
I -A
Good
I
-A
Better
Wrong
Scheme 2
The hypothesis gained considerable plausibility by appearing to be a simple extension of what was already accepted. Thus, an antiperiplanar lone pair of electrons can be considered to play essentially the same role as the pair of electrons in the breaking C-H bond in an E2 elimination, and the strong preference for anti-stereochemistry in such reactions had long been known. Moreover, the frontier-orbital explanation of the anomeric effect was receiving support at the expense of the antecedent electrostatic explanation, and the ALPH merely applied the same ideas to transition states.
116
MICHAEL L. SINNOTT
[The anomeric effect as originally defined is the preference of an electronegative substituent X at C( 1) of a tetrahydropyranyl ring to adopt the axial orientation. It was considered by Edward (1955) to arise from destabilisation of the equatorial orientation by electrostatic repulsion between the C( I)-X dipole and the resultant of the C(5)-O(5) and C( 1)-O(5) dipoles (Scheme 3a).] The frontier orbital explanation (Romers et al., 1969) envisages preferential stabilisation of the axial orientation by overlap between the p-type lone pair on the ring oxygen and the antibonding orbital of the C(1)-X bond (Scheme 3b). The exo-anomeric effect is the same phenomenon manifested in conformational preferences about the C( 1)-O( 1) bond. The anomeric effect has since been generalised to refer to any X-C-Y system (Kirby, 1983). According to the frontier orbital picture, this interaction significantly populates the orbital of the C(1)-X bond even in the ground state: in the transition state for C(1)-X cleavage this will be still more populated, as the C( 1)-O(5) bond obtains partial double bond character. C( 1)-X cleavage should therefore be subject to the same sort of stereoelectronic control as ground state conformational preferences.
fl It
X (a)
+
*qo-mo X
X-
(b)
Scheme 3
After formulation of ALPH, a very considerable body of data, largely of a preparative nature, was accumulated which was compatible with it. A typical result was the failure to observe any lactone product in the acidcatalysed hydrolysis of conformationally restricted orthoester [3]; the sole detectable product was hydroxyester [4] (Deslongchamps et al., 1975a). Rationalisation of the result in terms of ALPH is now as follows (Deslongchamps el al., 1985b). Since rotation about either of the exocyclic C-0 bonds is not seriously restricted, opening of the ring to give dioxocarbonium ion [5] can take place with the assistance of two antiperiplanar lone pairs of electrons, one on each methoxyl oxygen, and once the ring is open hydroxyester is the eventual product. Loss of either of the methoxyl groups can take
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
117
place with assistance from an antiperiplanar lone pair on the other, but because the orthoester is conformationally restricted, only the axial one can depart with assistance from an antiperiplanar lone pair on the ring oxygen atom. According to ALPH, then, only the axial methoxyl group will depart, to give dioxocarbonium ion [6]. By microscopic reversibility, attack of water or hydroxide on this ion will take place in the same stereochemical sense, that is to say, axially, to give hemiorthoester [7]. By the same argument as was used in considering the starting orthoester [ 3 ] , loss of equatorial methoxyl from [7] to give a lactone can take place only with the assistance of one of the lone pairs of electrons on the hydroxy group: the lone pairs on the ring oxygen cannot assist. Therefore, equatorial methoxy is not lost and [7] opens to give the hydroxyester. This type of experiment and approach, whilst having a predictive and correlative power of undoubted value to the synthetic organic chemist, whose reactions sometimes fail for unsuspected reasons anyway, has, at least in its original form, the following unsatisfactory features as an aid to the understanding of a physical event.
OH
I
[71 Scheme 4
/
118
MICHAEL L. SINNOTT
(i) It is largely non-quantitative. If the failure to detect one of two possible products is to be converted to a lower limit for the difference in free energies of the transition states leading to the two possible products, then some essentially subjective estimate of the detection-limit of the analytical system has to be made. Even if small quantities of minor products are detected, the experimental problems of ensuring that they do in fact arise from the reaction under study are non-trivial. In the present case these difficulties are illustrated by the fact that the monocyclic orthoester [8], originally stated to give no lactone (Deslongchamps et al., 1975a) is now known (Capon and Grieve, 1982; Deslongchamps et al., 1985b) to give about 20% lactone. Furthermore, direct measurement of transition-state free energy differences by Desvard and Kirby (1982) in the closely related system [9], revealed that they were small. These workers examined rates of acid-catalysed exchange of the methoxyl groups of [9] with 5% CD,OD in deuterated benzene, dichloromethane, and dimethyl sulphoxide, and found approximate axial/equatorial rate ratios of 12, 11 and 2, respectively
&OR
(ii) The thermodynamically more stable of the two products, the hydroxyester, is produced (Perrin and Arrhenius, 1982, and references therein). In the original ozonolysis experiment, likewise, only the less thermodynamically stable anomer of methyl D-glucopyranoside reacted. (iii) The conformation of a tetrahedral intermediate, whose formation and decomposition is complicated by proton transfers, is a key feature of the explanation. In the hydrolysis of orthoesters in general, it is now known that the proportions of ester and lactone are pH-dependent (McClelland and Alibhai, 1981; Deslongchamps et al., 1985b). Even at the inception of ALPH, however, there was one system already known where the pattern of reactivity apparently contradicted it. It was well known in carbohydrate chemistry that protected a-glycopyranosyl halides were less labile than their P-anomers, at least for the common sugars in the D series (Haynes and Newth, 1955). The pyranose ring in these compounds is strongly biased towards the 4C, conformation, so that the a-halides are axial and the (3-halides are equatorial. The a-halides have an antiperiplanar
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
119
lone pair, the p-ones do not. The lability of the P-halide is particularly pronounced in the case of mannose, so that neighbouring group participation by the substituent on C(2) (acetoxy, benzyloxy, etc.) is not the origin of this anti-ALPH pattern of behaviour. This pattern of reactivity at C( 1) of aldopyranosyl derivatives was first quantitated by O’Connor and Barker (1979), who studied the hydrolyses of aldopyranosyl phosphates: at acid pH, the reaction is an S,I departure of phosphate monoanion. Equatorial/axial rate ratios of 2.3 for glucose (cf. [I] and [2]), 1.9 for L-fucose [lo], 2.3 for D-galactose [I I] and 4. I for D-mannose [I21 were obtained. At around the same time, Kirby’s group obtained an equatorial/axial rate ratio of 3 for loss of p-nitrophenolate from compound [I31 (Chandrasekar and Kirby, 1978; Chandrasekar et al., 1983).
These figures are not compatible with ALPH in its simple form. However, both Deslongchamps (1983) and Kirby (1984), rather than re-examine ALPH critically to see which of its features could be reconciled in some new proposal that could accommodate both the acetal data and the data that supported ALPH, chose rather to rationalise the acetal data with an intrinsically untestable supplementary hypothesis. They argued that nonchair conformers would be more readily accessible from the equatorial compounds than the axial, and that the equatorial compounds were reacting from non-chair conformers in which there was a lone pair of electrons antiperiplanar to the leaving group. Deslongchamps (1983, p. 39) indeed stated that “a-glycosides must hydrolyse via their ground-state conformation whereas P-glycosides must first assume a boat conformation in order to fulfil the stereoelectronic requirement”. It is an axiom of transition-state theory that one can only enquire about the differences between ground states and transition states: the path between the two is not experimentally accessible. In the cases such as the present,
120
MICHAEL L. SINNOTT
where rapid conformational pre-equilibria are supposedly involved, this axiom becomes one statement of the Curtin-Hammett principle (reviewed by Seeman, 1983). This review is an attempt to resolve the conceptual and experimental difficulties encountered in the application of ALPH as an axiom. A physical theory has only to fail once for it to be discredited as a fundamental explanation; the electronic explanation of the data supporting ALPH in terms of a “kinetic anomeric effect” is therefore unlikely to be correct. Indeed, there are aspects of the operation of the ground-state anomeric effect itself which are not readily reconciled with the frontier-orbital view of its origin. In the second section of this review the failures of ALPH will be discussed: these failures occur very largely in the heterolytic chemistry of acetals. Such reactions are characterised by late transition states. The theoretical basis of ALPH, and the closely related frontier-orbital rationalisation of the static anomeric effect, will be described and various difficulties in these interpretations pointed out. In the third section, ALPH will be recast in terms of the principle of least nuclear motion, PLNM, which does not apply to reactions with late transition states. It will then be shown how for heterolytic reactions at saturated carbon, PLNM and ALPH make the same predictions. Key reactions of various compound types, which have been taken as evidence for ALPH, will be shown to be also predicted by PLNM. In later sections, heterolytic reactions at trigonal carbon centres, and at phosphorus, and reactions of radicals will be treated. 2
Failures of the antiperiplanar lone pair hypothesis (ALPH)
A D D I T I O N S T O IMINES
It might appear that the simplest possible type of system to which ALPH might apply is a system with one lone pair only, and which does not involve a proton transfer. Reactions of a-substituted amines, or their microscopic reverse, nucleophilic additions to iminium ions, thus suggest themselves as suitable testbeds for ALPH, but the information on such systems is sparse. Stevens (1984) has studied the addition of carbon nucleophiles to tetrahydropyridinium salts from the standpoint of utility in organic synthesis, and found a preference for axial attack, in accord with ALPH (Scheme 4).
x Scheme 4
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
121
However, in more quantitative work it was shown by A h a Astudillo et af. (1985) that equilibration of the hydroxy-substituted Schiffs bases [14a] with the oxazolidines [ 14b] in various solvents was governed by a time constant of less than about 10 s: similar results were obtained by Lambert and Majchrzak (1980) in the trifluoroacetic acid-catalysed equilibration of [15a] and [15b]. In the oxazolidine ring, the lone pair on nitrogen cannot become exactly antiperiplanar to the leaving oxygen without introducing strain into the ring, and this is difficult to reconcile with such large rate constants for opening and closing the ring. X
X
Ho*
ACETAL A N D GLYCOSIDE HYDROLYSIS
Replacement of nitrogen with oxygen, so that there are two lone pairs on the heteroatom which is electronically assisting the departure of the leaving group, gives results which in the two cases analogous to the nitrogen systems described above, both contradict ALPH. Experiments involving departures of leaving groups from axial and equatorial orientations at C( 1) of pyranosyl or tetrahydopyranyl rings, the oxygen analogues of the experiment of Scheme 4,have been described in the introduction. The result uniformly obtained is that departures of equatorial leaving groups are favoured by modest factors. As was also described in the introduction, attempts have been made to reconcile this observation with ALPH by invoking reaction through non-chair conformers, although the logical validity of this is questionable, because of violations of the CurtinHammett principle. In any event, no such phenomenon can explain the unretarded hydrolysis of 1,3-dioxolanes. The reaction is the exact analogue of {he ring-opening of oxazolidines, and so the leaving group cannot become antiperiplanar to an sp3-type lone pair orbital on oxygen. In a detailed study, Fife and Jao (1965)
MICHAEL L. SINNOTT
122
showed that dioxolanes [I61 were hydrolysed in 50% aqueous dioxan some 30-35 times slower than the corresponding diethyl acetals [17]. This rate difference had its origin entirely in the entropy of activation, and the effect of the substituent X on the two series was identical, indicating a close similarity in electron distribution in the transition state. The somewhat slower rate of the cyclic compounds can thus be attributed to the fact that the hydrolysis of [ 171, unlike the hydrolysis of [16], results in the production of two fragments, with a consequently more favourable entropy of activation.
n
CH(OEt),
0
X I
[I61
X
~ 7 1
Kirby (1983, pp. 91-94) has discussed possible ways of reconciling the hydrolytic lability of 1,3-dioxolanes with ALPH, and has come to the conclusion that whereas one anticlinal sp3 lone pair may not expel a leaving group, two might. This explanation of the ready opening of I ,3-dioxolanes cannot of course be applied to the opening of oxazolidines [14], where there is only one lone pair available. Three experimental approaches have been used to investigate further the discrepancies between ALPH and the reactivities of simple acetals. The approach taken by the groups of Kirby and to some extent Deslongchamps, has been to construct acetals with ever more circumscribed conformational possibilities. It is possible to argue, however, that positive results were inevitable in the systems in which stereoelectronic effects were eventually discerned. Two approaches have been taken by the author's group: the first was to use the leaving group as a conformational determinant, and the second was to probe transition-state conformation directly with geometrydependent kinetic isotope effects. The reverse anomeric effect (Lemieux and Morgan, 1965a,b) is the additional tendency of a substituent bearing a positive charge to adopt the equatorial orientation at C(1) of a pyranose ring. It results in both tri-0acetyl-a-D-xylopyranosylpyridiniumions and their deacetylated derivatives adopting the normally disfavoured 'C, conformation [ 18a,b] (Paulsen et al., 1974; Hosie et al., 1984), with all the other substituents on the pyranose ring axial. Because of the bulky acetoxymethyl group at C(5) of the tetra-0acetyl-a-~-glucopyranosyl-4-methylpyr~d~nium ion, however, the ion exists
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
123
in the B2,5conformation [19] in solution (Lemieux, 1971) and in the crystal (James, 1969): the deacetylated 4-bromoisoquinolinium ion exists in the IS, conformation [20] in solution (Hosie et al., 1984) and the 'C, conformation [18c], the same as that adopted by the xylo-compounds, in the crystal (M. N. G. James et al., unpublished results, 1986). Both p-xylo- and p-glucocompounds are of course firmly in the ,C, conformation [21] (Paulsen et ul., 1974; Hosie et al., 1984).
Q
(a, R
= Ac, Q = H) (b, R = Q = H) (c, R = H,Q = CH,OH)
If a pyridine is used as a leaving group to generate a glucopyranosyl cation then in the ground state conformation neither anomer possesses a lone pair of electrons antiperiplanar to the leaving group: the ground state conformational requirements of the leaving group and the requirements for the operation of ALPH are directly opposed, and, if ALPH is correct, both anomers must undergo a conformation-change before reacting. One can make the assumption that in the reactive conformer of one anomer the ring conformation is the same as it is in the ground-state conformation of the other anomer. In the case of the xylosyl pyridinium ions it is then possible to calculate, using Angyal's (1969) empirical carbohydrate conformational energies, the energy required to put the p-anomer in the ' C , conformation. This turns out to be 1.25 X Ykcal mol-I, where X is the conformational energy of an axial pyridine at C(1), and Y is the 1,3-diaxial interaction energy of a hydroxyl group and a pyridine. The energy required to put the a-anomer into the ,C, conformation is X - 1.7 kcal. Therefore, if ALPH is operating, the difference in energies required for the initial
+ +
MICHAEL L. SINNOTT
124
conformational change is 2.95 + Y kcal, as between the two anomers. If this is reflected in the rate ratio, the a-xylopyranosyl pyridinium salts should undergo loss of pyridine at least 150 times faster than their anomers at 25°C. In fact, depending on the leaving group, the rate ratio is between 3 and 24 (Hosie et al., 1984). More telling is the discrepancy with glucose: if one takes into account only the necessity of putting the p-anomer into a boat conformation, and putting the a-anomer out of a boat conformation into a 4C, chair, then the alp rate ratio predicted is around lo8. The experimental value is 80 (Hosie et al., 1984). This type of argument, however, takes much the same liberties with the Curtin-Hammett principle as the original formulation of ALPH: the calculations of energies required to reach the reactive ground state conformation can be converted to anticipated rate-ratios only by the assumption that conformational energies in the transition state are much the same as in the reactive conformer. A more direct probe of transition-state conformation is a kinetic isotope effect, and the multiple kinetic isotope effect study of Bennet and Sinnott (1986) provides direct evidence for the conformation of the transition states for acid-catalysed hydrolysis of methyl a- and p-glucopyranoside. The kinetic effects of isotopic substitution at each of the sites indicated in [22] were measured by the isotopic quasi-racemate method (Bergson et al., 1977). The leaving group l80 effects of a little over 2% established that the exocyclic C-0 bond was largely broken at both transition states, and the absence of any detectable nucleophilic component to the reactions of related species (e.g. ions [18b] and [21]) confirmed, as had long been thought, that the reaction of the protonated glycoside was unimolecular. Once these two features of the reaction had been established, then geometrical information could be extracted from both the p-deuterium- and the ring I80-effects.
2-
HO
The inertness of compound [23] to loss of X - by an S,I process (Briggs et al., 1983) confirms the intuitive expectation that stabilisation of an adjacent carbonium ion centre by electron release from an oxygen lone pair orbital is
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
125
efficient only if the lone pair is in the p-type orbital.' Acetal [23] can stabilise the positive centre formed by departure of X - only by electron release from the sp-type orbital. The bond strength of the 7c bond of an oxocarbonium ion thus varies as the square of the cosine of the dihedral angle between the two participating p orbitals (a),just as any other 7c bond. Since the ring l80isotope effect has its origin in the tightening of the 0(5)-C(l) bond as it acquires double bond character as the oxocarbonium ion is formed, we can write (1). Since the leaving group has been essentially lost at the transition WlI3/kl6)
= cos2 w
In (k16/k1€Jrnax
(1)
state, the maximum isotope effect will be close to the calculated equilibrium effect (I. H. Williams, unpublished work, 1987) for reaction (2), K , , / K , , = 0.978, and certainly less than that measured by Bennet et al. (1985) for CH,(OH)
+ H+
CH,
=
OH
+ H,O
(2)
the acid-catalysed hydrolysis of [24], which proceeds by a ring-opening mechanism.
PH
For each anomer, then, the dihedral angle about the C( 1)-O(5) bond is locatable between two limits. A similar argument with the P-deuterium kinetic isotope effect enables the dihedral angle about the C( 1)-C(2) bond to be located within limits. p-Deuterium isotope effects have their origin in the balance between two phenomena, a small inductive effect, and a geometry-dependent hyperconjugative effect, which again has a cosine squared dependence on dihedral angle, 0, between the electron-deficient porbital at C(l) and the C(2)-D bond. (The small electron-donating effect of deuterium, compared to hydrogen, is observed experimentally in several systems, and possibly has its origin in the slight anharmonicity of the C-H bond, which results in the bonding electrons lying slightly closer to the The two lone pair orbitals of a dicovalent oxygen atom in a symmetrical environment can be represented indifferently as two equivalent sp3 hybrids, one p plus one sp, or any intermediate combination. The same total electron density (the square of 4) results. If the environment of the oxygen is not symmetrical, as with [23], then the non-equivalent representation is to be preferred.
126
MICHAEL L. SINNOTT
carbon atom, the further down the potential energy surface the system lies.) We can then write (3), where (k,/k& is the inductive component of the effect In (k,/k,)
=
In (kH/kD)i+ cos2 8 In (kH/kD)O
and (kH/kD)Ois the maximum hyperconjugative effect which is obtained when the C(2)-H bond is exactly aligned with the electron-deficient porbital on C(1). It is possible to obtain an upper and lower limit of this parameter from experimental j3-deuterium effects, since it can be shown that the hyperconjugative component of a p-deuterium effect arising from a freely rotating CD, group is $ In (kH/kD)o. Siehl and Walter ( I 984) measured the equilibrium constant for the interconversion of ions [25a] and [25b] under stable ion conditions. The positive charge on the trivalent carbon of a full, simple carbocation under stable ion conditions must be less than that on the transition state of a reaction leading to an oxocarbonium ion: therefore the value of (kH/kD)o calculated using the equilibrium effect from [25] will be an upper limit. A lower limit can be placed using the CD,-effects on the acid-catalysed hydrolysis of acetaldehyde diethyl acetal (Kresge and Weeks, 1984). This is a much faster reaction than the acid-catalysed hydrolysis of methyl glucosides and therefore probably has an earlier transition state: consequently the charge on the reacting carbon will be less than that on C( 1) at the transition state for methyl a- and j3-glucoside hydrolysis. [The values of the extrema calculated from these two models are insensitive to the precise value of the inductive corrections to both the model effects and the effects for the glucosides: a value of (kH/kD)iof 0.96 was taken (Williams, 1985).] In this way four pairs of values of 8 and o were obtained for each anomer. With assumptions about the location of the anomeric hydrogen based on adeuterium kinetic isotope effects (which measure the degree of rehybridisation of the anomeric carbon atom), it was possible, using Allinger's (1 977) MM2 molecular mechanics program, to calculate the conformation of the rest of the molecule. All four structures produced for the transition state for methyl aglucopyranoside hydrolysis are flattened I S , skew-boat conformations (cf. [20]). As would have been anticipated in the early 197Os, but not more recently, protonation of the exocyclic oxygen atom of the a-glycoside introduces a positive charge on this atom which, by the operation of the reverse anomeric effect, flips the ring into the same conformation as a glucopyranosylpyridinium ion, and carbon-oxygen bond fission takes place from this conformation. If the calculated equilibrium '*O-isotope effects for reaction (2) are used
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
127
to “scale” the observed ring I80-kinetic isotope effect for hydrolysis of methyl P-glucopyranoside, then the transition-state structures calculated from the two values of o were both flattened 4C, chair conformers: the anomer is reacting from the ground state in which it is frozen by the operation of the reverse anomeric effect. If the l80kinetic isotope effect from hydrolysis of [24] is used to produce a value of 8 for this glycoside, however, MM2 produces two structures within 5 kcal mol-’ of each other for each value of 8. These are complex skew-boat structures which are almost certainly an artifact of the poor estimate of (k18/k16)max provided by the hydrolysis of [24]. These reasonably direct experimental probes of transition-state conformation thus produce results which are in flat contradiction to ALPH: the aanomer changes conformation before cleavage of the glycosidic bond, whereas the 0-anomer reacts from the ground-state conformation. Nonetheless, the laboratories of Kirby and Deslongchamps have investigated a number of acetal systems where, apparently, patterns of reactivity were in accord with ALPH. Bicyclic acetal [23] (Briggs et a/., 1983), which lost X - some 13 orders of magnitude more slowly than model compounds, was considered relevant to the application of ALPH to the mechanism of action of P-glycosidases, particularly lysozyme, and the authors concluded that “We have shown in this investigation that a conformational change of the sort proposed originally by Phillips and his co-workers is an essential preliminary to the cleavage of any P-glycoside”. In fact systems such as [23] necessarily give a perpendicular oxocarbonium ion, and it has been known for many years that perpendicular oxocarbonium ions are many kcal molless stable than their planar analogues. Thus, Farcssiu et a/. (1979) studied the stereomutation of the methoxymethyl cation (Scheme 5) under stable ion conditions by nmr spectroscopy and derived an enthalpy barrier of 1 1.9 kcal mol- to the magnetic equivalence of the methylene protons (AS* =4eu). More recently Cremer et al. (1985) showed that the precise figure obtained depended on the composition of the superacid medium, but varied between 9.6 and 14 kcal mol-’. High level ab initio calculations (HF/ 6-31G and MP2/6-31G) indicated that the lowest energy transition state for stereomutation in solution was perpendicular rather than coplanar [(a) rather than (b) in Scheme 51, that is to say, stereomutation took place by rotation about the C=O bond rather than by nitrogen-like inversion at oxygen. Acetal [23] is constrained to give a perpendicular oxocarbonium ion whereas 0-glycosides are not, and the inertness of [23] would be germane to glycosidase catalysis only if the enzymes in some way restricted the motion of the anomeric hydrogen so that it could not become coplanar with the rest of the oxocarbonium ion grouping!
’
128
MICHAEL L. SINNOTT
(b) Scheme 5
ALPH does however seem at first sight to apply to acetal formation and hydrolysis if the acetal concerned is part of a 1,8-dioxadecalin system. Thus, Kirby and Martin (1983a) found that the axial epimer [26a] was 60-fold more reactive in acid-catalysed hydrolysis than epimer [26b]. In spontaneous hydrolysis the gross factor favouring the axial epimer fell to 2, but these authors argued with some plausibility, on the basis of different solvent isotope effects (kH20/kD20= 1.74 for [26a] and 1.03 for [26b]), that in the axial case the nitrophenolate and oxocarbonium ion portions of the reactive intermediate recombined far more often than they went on to product.
(a)
(b)
[261
Kirby and Martin (1983b) went on to examine participation by the lone pairs of the second oxygen atom in the epimeric pair [27]: they found that spontaneous loss of p-nitrophenolate from [27a] was 200-fold faster than from [27b]: in the reaction catalysed by undissociated formic or acetic acid this factor fell to 40 and in catalysis by H,O+ to 13.6. Clearly, however, cleavage of the 1,8-dioxadecalin system was assisting the reaction of [27a] but not [27b].
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
129
aNoz
0
These experiments of Kirby and Martin (1983a,b) showed in essence that cis-1 &-dioxadecalin systems were cleaved more readily than their transepimers. Beaulieu et al. (1980) performed what was conceptually almost the
microscopic reverse of these experiments: they showed that mixed acetals [28] on treatment with acid gave tricylic acetal [29] as the sole kinetic product, which was then slowly converted into the equilibrium mixture of [29] and [30] ([30]/[29] = 1.2). Deslongchamps and Guay (1985) subsequently reported similar experiments leading to both monothio- and the dithioanalogues of [29] and [30]. These results can be compared with the kinetic data of van Eikeren (1980), who found, in the epimeric pair [31], a system identical to [29] and [30] for the dimethylene bridge, only a 1.5-fold greater lability of the axial epimer.
If one considers the key step in the experiment of Beaulieu et al. (1980) it becomes clear why the only systems where ALPH appears to apply to acetal hydrolysis and similar reactions involve the cleavage of a 1$-dioxadecalin.
130
MICHAEL L. SINNOTT
Acid-catalysed loss of a methoxyl group from [28] will give the oxocarbonium ion [32], which can cyclise either by axial attack to give [29] or by equatorial attack to give [30], with the newly formed carbon-oxygen bond of [29], but not [30], being antiperiplanar to an oxygen lone pair. However, simple, almost mechanical effects may also favour axial attack: the carbon chain by which the nucleophile is attached to the oxocarbonium ion is a definite length and by itself will introduce differential barriers for cis- and truns-attack. Examination of Dreiding models reveals that the solid angle in which the nucleophilic oxygen atom can approach the electron-deficient carbon without introducing strain into the chain is much smaller for transattack than for cis. It seems probable that this, rather than any antiperiplanar lone pair effect, is responsible for the results with 1,8-oxadecalin systems. Indeed, if these results are taken as support for ALPH, then the case for ALPH in acetal hydrolysis loses internal consistency. Chandrasekar et ul. (1983) observed that loss of 2,4-dinitrophenolate from the axial epimer of [33] was slower than loss from the equatorial epimer, and they rationalised their results by invoking reaction of the equatorial epimer through a chair-twist boat-chair conformation, which was readily accessible, and in which an antiperiplanar lone pair was presented to the leaving group. A similar conformation of [30] could present an antiperiplanar lone pair to the C-0 bond in ring A, thus making [30] comparably labile to [29], and comparably accessible from [32]. It is thus clear that in general, hydrolysis and related reactions of acetals d o not proceed through transition states whose geometries are such as to present the departing group with an antiperiplanar lone pair of electrons.
G A S - P H A S E REACTIONS OF ORTHOESTERS
The reactions of orthoesters in solution played a key role in the formulation of ALPH, and Caserio et al. (1981) examined the reactivities of a diastereoisomeric pair of orthoesters [34] with various proton donors in the gas phase, using ion cyclotron resonance techniques. With the isopropyl cation or methylthiomethyl cation as a proton donor, no difference in reactivity,
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
131
measured by the appearance of ion [35] at mi. 115, was detected when the two diastereoisomers were examined in separate experiments. When, however, a mixture of [34a]-l-d and [34b] was examined with the cations derived from diisopropyl ether or acetylacetone as proton donors, a very small ( - 10%) preference for cleavage of the axial methoxyl group was seen from the intensity ratio m / z 116 : mi: 115. This was not the consequence of a kinetic isotope effect since the same preference for loss of axial methoxyl was observed with [34a] and [34b]-l-d.
Y.q
OCH
E Z L O C H ,
, (b)
(a)
1341
Stereoelectronic effects in the gas-phase cleavage of orthoesters are thus barely detectable, if at all, in contrast to the situation in solution. AMINOLYSIS OF PENICILLINS
According to ALPH, nucleophilic attack on the lactam ring of penicillins should generate a tetrahedral intermediate with the lone pair on the bridgehead nitrogen antiperiplanar to the nucleophile. Such an attack from the a-face would result in a highly strained trans-fused bicyclo[3.2.0]octane system, whereas attack from the p-face would result in a less strained cisfused system. Nonetheless, during aminolysis of penicillins attack occurs from the a-face. The mechanism of aminolysis normally involves reversible formation of the zwitterionic tetrahedral intermediate, T', followed by its rate-limiting deprotonation and cleavage of the ring C-N bond (Page, 1984, 1987). However, intramolecular general base catalysis by the aminogroup in the aminolysis of 6-aminopenicillanic acid [36a] is not detectable (Gensmantel and Page, 1978), and would be anticipated for P-attack. Moreover, evidence that the lone pair on the bridgehead ,nitrogen is on the same side as the attacking amine comes from the anomalously high reactivity of monoprotonated ethylenediamine towards benzylpenicillin [36b]: it is about 100-fold more reactive than an amjne of comparable pK,. This is
132
MICHAEL L. SINNOTT
attributable to proton donation to the bridgehead nitrogen in the tetrahedral intermediate (e.g. [37]) which facilitates endocyclic C-N cleavage (Martin et al., 1979). It is thus clear that nucleophilic attack on penicillins takes place from the a-face to generate a tetrahedral intermediate (e.g. [37]) with the less strained cis-fused bicyclo[3.2.0]octane structure. The lone pair on the bridgehead nitrogen is syn to the nucleophile, in contradiction to ALPH.
(a, R (b, R
= =
H) COCH,Ph)
[361
[371
HYDROLYSIS OF A M I D I N E S A N D A M I D I N I U M S A L T S
Perrin and Arrhenius (1982) reported that the alkaline hydrolysis of amidines [38] resulted in the formation of the a-aminoamides as kinetic products and the lactams as thermodynamic products. Since the kinetic and thermodynamic products differed, there was a specific kinetic effect which required explanation, and Perrin and Arrhenius considered their results “the first unambiguous evidence for stereoelectronic control”. The key feature of their argument was that the tetrahedral intermediate had a lifetime long compared with the period of rotation about single bonds but short compared to the period for nitrogen inversion. Axial attack on the planar amidine function of the six-membered ring gives, according to ALPH, a tetrahedral intermediate in conformation [39a], which has two lone pairs antiperiplanar to the newly-attached hydroxyl group. Rotation about the exocyclic C-N bond can result in conformation [39b] in which the endocyclic C-N bond is antiperiplanar to lone pairs on oxygen and nitrogen and therefore cleaves. Ring-flipping to [40], without nitrogen inversion, results in a conformation in which the ring nitrogen lone pair is equatorial and therefore cannot assist the departure of the exocyclic amino-group to give the lactam. Even if a chair-chair flip does take place therefore, ALPH predicts preferential endocyclic cleavage to the a-aminoamide, as observed.
H
n
=
1,2,or3 ~381
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
133
OH
OH
H
I
n
=
1,2,or3 [411
This argument presupposes that the leaving group abilities of ammonia and a primary alkylamine are similar. In later work Perrin and Nuiiez ( 1 986) examined the products from the hydrolysis of amidines of basic structure [41], in which the acidities of the leaving groups for exocyclic and endocyclic C-0 cleavage were more closely matched. They found that with 5- and 7membered cyclic amidines the lactam and the aminoamide were formed in approximately equal amounts, whereas with the six-membered ring compound there was a 20-fold preponderance of endocyclic cleavage. In a detailed consideration of alternative mechanistic possibilities, the authors concluded that the results with five- and seven-membered cyclic amidines violated ALPH, and that ALPH was only weakly operative in the sixmembered ring case. In a recent, dramatic illustration of the inadequacies of ALPH in rationalising the reactions of amidines, Page et al. (1987) have shown that the four-membered cyclic amidinium salt [42] hydrolyses to give both [43] and [44]. By arguments similar to those set out above, endocyclic cleavage is favoured by ALPH and also in this case by release of ring-strain in the fourmembered ring, whereas exocyclic cleavage with participation by the ring nitrogen lone pair in an antiperiplanar orientation is possible only at the expense of yet more ring strain. Nonetheless, exocyclic cleavage, with presetvation of the four-membered ring happens.
134
MICHAEL L. SINNOTT
ENZYMATIC REACTIONS
Alcohol dehydrvogenuses
The reaction catalysed by alcohol dehydrogenases is a transfer of hydride ion from the alcohol to the 4-position of the pyridinium ring of the coenzyme NAD' (Scheme 6), [For a review of hydride transfer in model systems, see Watt (1988).] The two hydrogen atoms at the 4-position of the dihydro-pyridine ring of NADH are diastereotopic, and over the years it has become apparent that some alcohol dehydrogenases transfer the pro-R
+-R,
R,
=
Scheme 6
Mechanism of an NAD- or NADP-linked alcohol dehydrogenase. B is an acid-base group of the protein (e.g. His side-chain)
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
135
hydrogen, whereas others transfer the pro-S hydrogen. (In the biochemical literature these are termed A and B hydrogens, respectively.) The origin of these stereochemical differences remained a puzzle until Nambiar et al. (1 983) proposed a simple functional rationalisation: “thermodynamically unstable carbonyls are reduced by the pro-R hydrogen of NADH whereas thermodynamically stable carbonyls are reduced with the pro-S hydrogen”. The determinant of the stereospecificity of the reaction was the equilibrium constant, K , for the overall reaction, defined by equation (4). If -log K is K=
[R, R,C=O] [NADH] [H+] [R,R,CHOH] [NAD’I-
(4)
greater than 1 1.2, then the pro-R hydrogen is transferred, whereas if it were less than this value, then the pro-S hydrogen of NADH is transferred. Although there have been a number of objections to the validity of this correlation, usually on the grounds that the natural substrate of some of the enzymes is either not known, or wrongly attributed, so that the correct value of K is not accessible (e.g. Oppenheimer, 1984), there can be little doubt that the correlation is in general valid. Such a correlation must have a fundamental physico-chemical rationale. Since the organisms that produce enzymes are subject to natural selection, the genes coding for enzymes are under selection pressure to maximise the catalytic efficiency of the gene-product (at least for the enzymes of primary metabolism: it is possible to argue that for the enzymes of secondary metabolism other factors, such as the need to conserve ATP or protein, could counterbalance the selection pressure to increase the catalytic efficiency of the protein). If the gene coding for an enzyme has been under selection-pressure for the whole course of evolution, then it will have taken advantage of available, real physico-chemical phenomena to increase its catalytic efficiency. There is evidence that in the present case a fundamental physico-chemical phenomenon is operating, since even quite major mechanistic changes alter the stereospecificity only if the equilibrium constant is within ca 0.2 log units of the changeover point (-log K = 1 1.2). Thus, the ethanol dehyrogenase from the fruit fly, Drosophila melanogaster, has pro-S stereospecificity, whereas the yeast and horse liver enzymes have pro-R stereospecificity; -log K for the oxidation of ethanol by N A D + is 1 1.4 (Benner et al., 1985). Likewise, -log K for the oxidation of glycerol to dihydroxyacetone is 11.3, and the dihydroxyacetone reductase from Mucor javanicus exhibits pro-S specificity, and that from Bacillus megatrrium pro-R. The oxidation of alditols to ketoses by NAD’ is presumably governed b’y an equilibrium constant close to that for the oxidation of glycerol to dihydroxyacetone, and again it is found that the sorbitol dehydrogenase from sheep liver has pro-R
136
MICHAEL L. SINNOTT
specificity whereas that from Klehsiella pneumoniae has pro-S specificity (Schneider-Bernlohr et al., 1986). The major mechanistic difference between the pro-S and the pro-R specific enzymes in this area where thermodynamic constraints are weak or non-existent seems to be that the pro-R specific enzymes contain a zinc ion at the active site whereas the pro-S specific enzymes do not (SchneiderBernlohr et al., 1986). In the mechanism of an NAD+-linked alcohol dehydrogenase shown in Scheme 6, in the reduction direction the substrate carbonyl group was shown as polarised by partial proton donation from a Br~rnsted acid BH': this polarisation can equally well be achieved by coordination to an active site zinc, which acts as a Lewis acid. One thus has two mechanistic classes of enzyme, but even this difference affects the stereochemistry only in a very limited region close to the break-point. A clue to the physico-chemical basis of the correlation comes from the observation from the crystal structures of various dehydrogenase-NAD complexes that those enzymes which bind NADH in the syn-conformation [45a] transfer the pro-S hydrogen whereas those enzymes that bind NADH in the anti-conformation [46b] transfer the pro-R hydrogen (see e.g. You, 1984). The observed stereospecificities thus correspond to transfer of hydride towards the viewer from both rotamers of [45] +
H,NOC
dOH H
H
OH b H
Nambiar et al. (1983) suggested that the observed correlation of enzyme stereospecificity with overall equilibrium constant for the catalysed reaction arose because syn-NADH was a stronger reducing agent than anti-NADH. Elaborating arguments put forward first by Albery and Knowles (1976), they pointed out that the internal equilibrium constant for a highly evolved enzyme was closer to unity than the external equilibrium constant; that is, the free energies of enzyme-bound substrates and enzyme-bound products are more closely matched than the free energies of free substrates and free products. [In fact Albery and Knowles (1976) considered the case where substrate and product were maintained close to equilibrium and showed that
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
137
the greatest flux of product, given that the reaction in one direction was governed by diffusion together of enzyme and substrate, was obtained when the internal equilibrium constant was unity. Subsequently Chin (1983) and Stackhouse et af. (1985) showed that when equilibrium was not maintained, the greatest substrate flux was obtained with a free energy profile resembling a descending staircase: see Fig. 1.1 Nambiar et al. (1983) then went on to suggest that, at a certain value of the overall equilibrium constant, the evolutionary requirement for balanced internal thermodynamics would cause a different rotamer to be used. There is, however, no immediately apparent reason why the two rotamers should have differing reducing power.
IG
FIG. 1 Free energy profiles for evolutionarily optimised enzymes (a) maintaining substrate and product close to equilibrium and (b) catalysing a reaction in which the physiological concentration of the product is lower than its equilibrium concentration
138
MICHAEL L SINNOTT
To rationalise why both syn- and anti-rotamers of NADH transferred the hydrogen pointing towards the viewer, as the coenzyme is drawn in [45], Nambiar et al. (1983) invoked various stereoelectronic phenomena. These phenomena are not essential for the success of the correlation, and indeed, if they operate in the way indicated, they show that alcohol dehydrogenases are, at least vinylogously, anti-ALPH systems. These authors pointed out that the exo-anomeric effect would make the lowest energy conformer of both rotamers of NADH that with the nitrogen pyramidalised so that the lone pair on nitrogen was antiperiplanar to the C(1)-0(4) bond of the ribose ring. [Whether the preference is due to the hyperconjugative interaction of the nitrogen lone pair and the o*-orbital of the C(1)-0(4) bond, or the electrostatic repulsion of the resultant dipole of the two C-0(4) bonds and the resultant of the three C-N(1) bonds, is immaterial.] If indeed NADH reacts from a conformation in which nitrogen is pyramidalised in this sense, then the hydride being transferred is cis to the nitrogen lone pair, and thus, at least vinylogously, it is being transferred in an anti-ALPH sense. Nambiar el al. ( I 983) suggested that the boat conformation necessarily adopted by the 1,4-dihydropyridine ring was such as to make the transferred hydride axial (conformer [46a]).
6 etcRN etcG Y S
CONH, \
E;H2
OH
OH
OH
OH
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
139
There is no reason, other than stereoelectronic dogma, for ruling out conformer [46b]. Moreover, there is also no reason for assuming that the 'coenzyme reacts through the lowest energy conformer, and so conformers [46c] and [46d] are at least possible in principle. Oppenheimer (1986) has however shown that inversion of the anomeric configuration of the coenzyme has no effect on the stereospecificity of hydride transfer, although reactions with a-NADH are much slower. The pro-R-specific enzymes, pig heart malate dehydrogenase and yeast alcohol dehydrogenase, transfer deuteride from a-4R-NADD whereas the pro-Sspecific enzymes, rabbit muscle glyceraldehyde-3-phosphate dehydrogenase and Rhodopseudomonas spheroides 3-hydroxybutyrate dehydrogenase, transfer hydride (Scheme 7). Interactions between the nicotinamide and ribose moieties are thus not crucial in determining dehydrogenase stereospecificities. It thus appears that ALPH plays no essential role in the success of the Benner rationalisation of the stereochemistry of alcohol dehydrogenases.
(likewise p r o 3 enzymes) 2
etc-
Scheme 7
Glj'cosidases In many respects the application of ALPH to the catalytic mechanism of glycosidases represents its reductio ad absurdum. Because of the conformational flexibility of five-membered rings, ALPH makes no predictions about the geometry of transition states in reactions catalysed by furanosidases. Its predictions about transition states in catalysis by pyranosidases are the same as those for non-enzymic hydrolysis, viz. that a-glycopyranosides should be cleaved from their ground-state 4C, conformation and P-glycopyranosides should be cleaved from some boat conformation. However, "although inverting glycopyranosidases are known, most glycopyranosidases yield the product pyranose in the same anomeric configuration as the substrate (although
140
MICHAEL L. SINNOTT
it subsequently spontaneously mutarotates). The overall stereochemistry of these retaining glycosidases implies a double displacement mechanism, as was first pointed out by Koshland (1953), who drew a covalent glycosylenzyme intermediate with the enzyme nucleophile approaching from the side of the pyranose ring opposite to the departing aglycone. Thus, a 8glycosidase, working with overall retention of configuration, operates via a covalent a-glycopyranosyl enzyme intermediate. In all cases so far examined the enzyme nucleophile is the side-chain carboxylate group of an aspartate or glutamate residue (reviewed by Sinnott, 1987). If, as is widely accepted, the glycosyl residue in the transition states leading to and from these covalent glycosyl enzyme intermediates has substantial oxocarbonium ion character, then ALPH requires the following changes of ring conformation during the turnover sequence of a p-glycosidase (Scheme 8).
(i) From the substrate ground-state 4C, conformation to a reactive conformation of the substrate (say IS,) in which there is a lone pair antiperiplanar to the leaving group. (ii) During the bond cleavage step or steps, from the reactive conformation of the substrate to an oxocarbonium-ion-like structure on which nucleophilic attack by the enzyme nucleophile will generate the a-glycosyl enzyme in a conformation with a lone pair antiperiplanar to the newly attached enzyme carboxylate; say from 'S, through B2,5or 2,5Bto 4H3 and thence to 4C1 of the glycosyl enzyme.
OYO & :..... ....:......... .. ...... - .....
Scheme 8
Changes in the conformation of the substrate required by ALPH during the catalytic turnover of a retaining 0-glycosidase
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
141
(iii) The microscopic reverse of (i) and (ii) as the glycosyl-enzyme is hydrolysed. If the nature and stereochemistry of the glycosyl-enzyme intermediates have been assigned correctly, therefore, extraordinary conformational subtlety is required of retaining glycosidases. This is difficult to reconcile in evolutionary terms with retention being the commonest stereochemical outcome of glycosidase action. The evidence for the presence of an enzyme carboxylate group on the other side of the pyranose ring to the leaving group in the ES complex of a retaining glycosidase is unassailable. I t includes X-ray crystal structure evidence on the lysozymes of hens’ egg white (Blake et al., 1967) and bacteriophage T4 (Anderson rt al., 1981), and on Taka-amylase A (Matsuura et al., 1984), and a body of work from Legler’s laboratory (Legler, 1973; Lalkgerie et al., 1982) on affinity labelling of glycosidases with hydroxylated cyclohexene epoxides such as conduritol P-epoxide [47]. The D-enantiomer of [47] can resemble either an a-glucopyranoside or a pglucopyranoside. In an important experiment, Braun et al. (1977) showed that hydroxylamine liberated label from inactivated rabbit intestinal sucrase-isomaltase (an a-glucosidase) as inositol [48] but from inactivated Aspergillus wentii p-glucosidase A, as inositol [49]: the affinity-labelled enzymes must therefore have partial structures [50] and [51]. The enzyme carboxylate group of the p-glucosidase therefore attacks the epoxide ring in a sense corresponding to attack from the a-face of the sugar, and the carboxylate of the a-glucosidase in a sense corresponding to attack from the p-face of the sugar. Firm evidence that the carboxylate labelled by [47] is catalytically important comes from the demonstration that, in the case of the P-glucosidase A,, the carboxylate labelled is the same as that glycosylated during catalytic turnover of p-nitrophenyl 2-deoxy-P-~-glucopyranoside (Roeser and Legler, 1981) The evidence for covalent glycosyl-enzyme intermediates is sparser and the question has been confused by the textbook lysozyme mechanism (Blake et a[., 1967), in which the oxocarbonium ion species is envisaged as living long enough for the aglycone to diffuse away. It must be emphasised that there is no evidence on the nature of the glycosyl-enzyme intermediate in lysozyme catalysis one way or another, since no conditions are known under which the glycosyl-enzyme intermediate for this enzyme accumulates (see e.g. Sinnott, 1987). Only in those cases where, under steady-state conditions, most of the enzyme exists as the glycosyl-enzyme intermediate is it possible to use mechanistic probes to enquire as to its nature. This has been possible in four cases: the Mg2+-enzymeof the lacZ P-galactosidase of Escherichia coli (Sinnott and Souchard, 1973), the Mg2+-freeapoenzyme (Sinnott et al.,
MICHAEL L. SINNOTT
142
1978), the experimentally evolved ebga, ebgb, and &gab-galactosidases' of the same microorganism (D. Holdup and M. L. Sinnott, unpublished results, 1984), and the P-glucosidase of Stachybotrys atra (Van Doorslaer et al., 1984). In these four cases, a-deuterium kinetic isotope effects, k,/k, of between 1.1 and 1.25 were observed, indicating that at the transition state for hydrolysis of the glycosyl-enzyme intermediate there is more sp2character than in the ground state, a result totally incompatible with this ground state being an oxocarbonium ion.
. HO 0
q
z OH
+
f
Ho
OH
OH
.............. :::::::::::::>:.: .................... ....... [511
Application of ALPH to retaining glycosidases, then, presents the theory with insuperable difficulties if conventional mechanisms for these enzymes 2The genome of E. cofi possess two completely different genes coding for pgalactosidases.The widely studied gene product is coded for by the Z gene of the lac operon, but a second gene, ebg also exists. The product of the wild-type ebg gene, ebg", is too catalytically feeble to permit growth on lactose, but it is possible to select for catalytically improved enzymes. Depending on the type of DNA base changes in the organism, these are termed ebga, ebgb, &gab, etc. (see Burton and Sinnott, 1983, and references therein).
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
143
are assumed. The difficulties have been recognised, at least implicitly, by Fleet (1985) and Post and Karplus (1986), who proposed that the first chemical step in, respectively, p-glycosidase catalysis in general and lysozyme catalysis in particular might be opening of the pyranose ring, to give acylic oxocarbonium ion intermediates [52]. Such mechanisms are completely incompatible with the efficient hydrolysis of pyridinium ions such as [2 I ] by retaining P-glycosidases, or the hydrolysis of glycosyl fluorides. They are only compatible with negative &-values or direct '*O kinetic isotope effects with " 0 at C(1) for hydrolysis of aryl glycosides if an implausible supplementary hypothesis is advanced, namely, that decomposition of some form of hemiacetal is rate-limiting (see Sinnoit, 1987).
[521
Not only does the chemistry of glycosidase action provide examples of conformational changes required by ALPH which do not take place, it also provides an example of a system where conformation changes forbidden by ALPH are likely to be taking place. In catalysis by yeast a-glucosidase, the enzyme probably introduces a separate conformational step during which the substrate is distorted from its ground state, where an oxygen lone pair and the leaving group are antiperiplanar, into a boat conformation, where no such lone pair is available, before bond cleavage takes place (Hosie and Sinnott, 1985). The enzyme hydrolyses pyridinium ions [20] as well as aryl glucosides, and the ranges of absolute kc,,-values of the two sets of substrates overlap. However, neither first-order (V) nor second-order ( V / Q rate constants for hydrolysis of aryl glucosides show a detectable dependence on aglycone acidity, and there is no a-deuterium kinetic isotope effect on either V or V / K for the p-nitrophenyl compound, nor yet a leaving group "0effect on V . Some non-covalent event, therefore, limits both V and V / K . With the pyridinium salts it limits only V / K , since although this parameter
shaws no dependence on leaving group acidity, V does show such a dependence. Moreover, although no a-deuterium kinetic isotope effect on V / K for hydrolysis of the 4-bromoisoquinolinium ion can be detected, this compound exhibits large a- and P-deuterium kinetic isotope effects on V ( 1.22 and I . 13, respectively), as does the unsubstituted a-glycopyranosylpyridinium ion [ 1.15 and 1.08(5), respectively]. The question thus arises, why is the non-covalent event absolutely faster for the pyridinium salts than for the aryl glucosides? A reasonable supposition is that the difference in behaviour is related to the differing ring conformations of the two sets of substrates, and if the non-covalent event
144
MICHAEL L. SINNOTT
were the conjoint change of enzyme protein and substrate so that the pyranose ring of the substrate were placed in a boat conformation, then the faster rate of this event with substrates already in the boat conformation is readily understood. Classical boat conformationsor B2,5- are plausible candidates for the conformation of glycopyranosyl cations, since, depending on the sugar and the solvent, they can be the preferred conformations of aldono-&lactones (Nelson, 1979; Walaszek et al., 1982), in which C(5), 0(5),C(l) and C(2) have likewise to be coplanar: in the parent 6valerolactone system, in the gas phase, the classical boat conformation is only 0.6 kcalmol-' more energetic than the half-chair (Philip et al., 1981). In the present case the observation of a substantial P-deuterium kinetic isotope effect rules out the B,,,conformation, in which the C ( 2 F - H bond and the electron-deficient p-orbital on C( 1) are almost orthogonal. Support for the proposal that the non-covalent event required by the kinetic data results in the placing of the pyranose ring in the 2,5Bconformation comes from the failure of the alkaloid castanospermine [53] to inhibit this enzyme (Saul et af., 1983), even though deoxynojirimycin [54] does. Castanospermine cannot adopt the equivalent of the 2,5Bconformation, whereas deoxynojirimycin can. ' 3 ' B
HO H
OH
O H OH m H N
HO"
O
P
HO"
[531
o H NH
[541
The first step in the catalytic mechanism of yeast glucosidase that emerges from studies with these substrates is set out in Scheme 9: although only the glycone portion of the substrates is the same as that of the natural substrate (maltose?), the rate-enhancements brought about on even the pyridinium ions are large enough, lo8 (Hosie et al., 1984), for deductions to be made about the catalytic pathway of the enzyme.
-
HO HO
slow
faste -
0 H OAr
X [X = OAr or a pyridine] Scheme 9
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
145
Castanospermine does however inhibit mammalian lysosomal a-glucosidases quite powerfully (Saul er al., 1983). It is tempting to speculate that because of the closeness in conformational energy of a glucopyranosyl cation in the 4H3 and the classical boat conformation, a-glucosidases, can evolve in different organisms to stabilise oxocarbonium ion-like transition states in either conformation. The work on the stereochemistry of NAD(P)linked alcohol dehydrogenases indicates that such evolutionary indifference to stereochemical alternatives can coexist with only very small energy differences between them. If indeed a-glucosidases have evolved indifferently in the ALPH and an anti-ALPH sense, then the physical basis of stereoelectronic effects is most unlikely to be intrinsic to the molecules themselves.
3 The theoretical basis of ALPH: strengths and weaknesses E L E C T R O N S , O R B I T A L S A N D E PI P H E N O M E N A
As was mentioned in the introduction, ALPH is an extension of the qualitative frontier-orbital explanation of the anomeric effect. Any difficulties with this explanation of the anomeric effect, therefore, will undermine the basis of ALPH, although even if the explanation is substantially correct it does not necessarily follow that it is legitimate to extend the same ideas to transition states. There are indeed difficulties, both of inadequate agreement with experiment and of conceptual confusion. A problem in this whole area is that experimental scientists have taken the formalisms and constructs of theoreticians and endowed them with a reality they do not possess, as can be illustrated by the case of the lone pair orbitals on oxygen. Electrons are delocalised and one cannot see an orbital, even though it is possible, using for example very accurate X-ray crystallography (e.g. Dunitz and Seiler, 1983; Seiler and Dunitz, 1986), to see the total electron distribution in the molecule. It is therefore of questionable legitimacy to draw the two lone pairs of electrons on oxygen as in equivalent sp3 hybrid orbitals. For a molecule of C,, symmetry, such as water or dimethyl ether illustrated in Scheme 11, it is entirely immaterial whether one considers the orbitals containing the lone pairs as two sp3 orbitals (a), one sp orbital and one p orbital (b), or anything between these two extremes: the identical total electron distribution (c) results. If the system is not symmetrical, as in the case of the pyranose ring, then representation (b) is preferable. Representation (a) amounts to an a priori assertion that the total electron distribution, an experimentally accessible datum, is not perturbed by the asymmetry in the system. If representation (b) is adopted: it is readily seen (Scheme 3) that maximal possible overlap between the p-type oxygen lone pair orbital and the orbital of the C(l)-X bond of a tetrahydropyranyl
146
MICHAEL L. SINNOTT
or glycosyl derivative is not obtained in the axial case: the dihedral angle between these two orbitals is about 30". Kirby (1983, pp. 4142,135-136) has argued that the organic chemists' preference for using equivalent sp3 orbitals is not seriously misleading, since both sp- and p-type orbitals can overlap with an axial CT* orbital, but his own data on the inertness of [23] (Briggs et al., 1983), which can stabilise a developing positive charge only with an sp-type lone pair, makes this defence of organic chemical practice unconvincing.
Equivalent representations of the two oxygen lone pairs resulting in the same total electron distribution (c)
The interpretation of the results of theoretical calculations also calls for a clear distinction to be made between experimental fact, rigorously-based theoretical conclusions, and the gloss placed on those theoretical conclusions in order to provide a physical picture. Semi-empirical theoretical methods (extended Hiickel and CND0/2) do not reproduce the anomeric effect (TvaroSka and Bleha, 1975a,b), whereas ab initio methods appear to do so. However, the interpretation of the results of ab initio calculations in terms of supposed effects or phenomena is to some degree subjective. The result of an ah initio calculation is an equilibrium geometry and energy for the whole molecule, and decomposing this energy into various interaction terms depends on chemical intuition. A purely electrostatic effect will for example be reproduced by an ab initio calculation. For this reason Lehn (1970) has termed the quantum mechanical effects held to explain calculated energies and geometries epiphenomena. It seems to the reviewer, however, that, if epiphenomena are to be valid science, they must obey the usual scientific criteria of economy and falsifiability, and that their number should be kept in check by vigorous wielding of Occam's razor. THE ELECTROSTATIC E X P L A N A T I O N O F T H E A N O M E R I C EFFECT: SUCCESSES A N D FAILURES
As originally put forward by Edward (1959, the electrostatic explanation of the anomeric effect envisaged repulsion between the negative end of the C( 1)-X dipole of an electronegative substituent at C( 1) of a pyranose ring
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
147
and the lone pair electrons on oxygen, regarded as a concentration of negative charge. The idea was refined by Lemieux (1964) who considered the resultant of dipoles arising from the lone pair electrons and C(5)-O(5) bonds, essentially as set out in Scheme 3. An important piece of evidence in favour of this picture was that, apparently, the strength of the anomeric effect increased as electron-withdrawing substituents were introduced at C ( 5 ) (Lemieux, 1964). The strength of an electrostatic effect will depend on the dielectric constant of the medium, and results from a number of laboratories (summarised in Kirby, 1983, p. 9) indicate that the strength of the anomeric effect does indeed decrease in polar solvents. However, the main success of the electrostatic explanation is with the reverse anomeric effect, observed when the sense of the C(l)-X dipole is reversed. The objection that, in stable compounds, the reverse anomeric effect is observed only with bulky quaternary ammonium substituents which would be equatorial anyway, has been elegantly addressed by both Lemieux ( I97 1 ) and Paulsen et al. ( 1974) using a-glycopyranosyl imidazoles. These authors showed that in the gluco- and xylo-series respectively, the fully acetylated a-glycopyranosyl imidazoles in solution in organic solvents changed conformation on protonation in the sense predicted by the effect (Scheme 11). Protonation clearly cannot alter the steric requirements of the imidazole grouping. As is expected of an electrostatic interaction, it appears to be weaker in more polar solvents: a-glycopyranosyl imidazoles in water do not change conformation on protonation (Finch and Nagpurkar, 1976).
Scheme 11 Conformational equilibria of 2,3,4-tri-O-acetyl-a-~-xylopyranosyl imidazole. The neutral compound exists as a mixture of both conformations, the protonated species exclusively in the ' C , conformation
The main factor leading to the recent unpopularity of the electrostatic explanation is the failure to account for perceived patterns of bond length changes, even though with more data now available, it is clear that these are not simple. A further weakness of the electrostatic explanation was highlighted by Romers er af. (1969) who showed there were quantitative discrepancies between experiment and the strength of the anomeric effect
148
MICHAEL L. SINNOTT
calculated as a purely electrostatic phenomenon. The electrostatic picture however still receives theoretical support (TvaroSka and Kozar, 1980). T H E F R O N T I E R O R B I T A L E X P L A N A T I O N O F T H E A N O M E R I C EFFECT: SUCCESSES A N D FAILURES
Scheme 12 shows patterns of interaction involving the o*-orbital of the C(l)-X bond in the equatorial and axial orientation. It is seen that in the equatorial orientation this antibonding orbital can overlap only with the sptype lone pair on oxygen, being orthogonal to the p-type lone pair. Since the sp-type lone pair is tightly held the stabilising interaction energy is small. In the axial case the orbital can interact with both the sp-type and the p-type lone pair, but the interaction with the higher energy p-type lone pair will be dominant. In the frontier orbital view of the anomeric effect, it is a stabilisation of the axial anomer rather than a destabilisation of the equatorial. This pictorial scheme, an elaboration of the original proposals of Romers et al. (1969) was advanced by David et al. (1973). Instructively, two roughly contemporary ab initio calculations, that of Wolfe et al. (1971) on fluoromethanol, using a G T F basis set, and that of Jeffrey et al. (1972) on methanediol, using a 4-31G basis set, were interpreted in such a way as to reach different epiphenomological conclusions. The former adhered to the electrostatic picture and the latter to a version of the frontier orbital picture. A very extensive ab initio (STO-3G) study of molecules XCH,YH (Wolfe et al., 1979) was interpreted in terms of an elaboration of the orbital overlap pattern of Scheme 12, but the authors confused the reverse anomeric effect, as originally defined by Paulsen and Lemieux, with the situation where an anomeric substituent such as NH, had a lone pair of higher energy than the p-type lone pair of the ring oxygen. On the frontier orbital picture of the anomeric effect the overlap of the p-type lone pair on oxygen with the o*-orbital of a carbon-quaternary nitrogen bond should occur in exactly the same way as with a carbonoxygen or carbon-halogen bond. The reverse anomeric effect (the original, experimentally-based one) should not therefore exist on the frontier orbital picture. This represents its major failure. Its major success seems, or at least seemed, to be its ability to rationalise the shortening of the C ( l t O ( 5 ) bond, and lengthening of the C(1)-X bond ii. the equatorial, but not the axial case. Thus Jeffrey et al. (1978) examined the crystal structures of a wide range of carbohydrates and compared them with the results of ab initio calculations on dimethoxymethane (RHF/4-31G basis set). They found excellent agreement between experiment and theory, in particular finding that in a-glycosides both the
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
I--
I
- - ----__o*(c-x)
-I
149
- - - - - - - o*(c-x) -
-,
SP(a)
(b) Scheme 12
Interaction of the C( I)-X o*-orbital of a pyranosyl derivative with (a) the p-type lone pair on oxygen when the C(I)-X bond is axial and (b) the sp-type lone pair on oxygen when the C( I)-X bond is equatorial
C( 1)-0(5) and C( 1)-O( 1) bonds were shortened whereas in a-glycosides only the C( 1)-0( 1) bond was appreciably shortened. In a-glycosides anomeric and exo-anomeric effects of equal magnitude are operating, the exoanomeric effect lengthening C( 1)-0(5) and shortening C( 1 )-O( l), and, as with difluoromethane (Wolfe et af., 1979) the net result is a shortening of both bonds to the difunctional carbon. In P-glycosides, only the exoanomeric effect operates. However, more recent studies, using more extensive data-bases [111 carbohydrate structures (Fuchs et d.,1984) and 546 structures containing the C--0-C--0-C fragment (Cossk-Barbi and Dubois, 1987)] reveal a very wide dispersion of structural parameters. These simple structural studies with acetals, however, necessarily reveal only the balance between anomeric and exo-anomeric effects. A study by Kirby’s group has revealed a clear pattern of changes in bond lengths as the acidity of the exocylic substituent is increased: this work avoids the problem of the balance between the anomeric and exo-anomeric effects. In general, there is a linear relationship between the length of an X-0 bond in systems X-0-R, and the pK-value of ROH (Allen and Kirby, 1984); one is observing the early stages of the heterolysis of the X-0 bond. The n-o* interaction of Scheme 12 partly populates the antibonding orbital of the C(1)-X bond, so the bond is weaker the stronger this interaction. [Jones and Kirby (1984) indeed consider that it is possiblk to construct an experimental reaction coordinate using a combination of kinetic and X-ray crystallographic data.]
150
MICHAEL L. SINNOTT
In a series of six conformationally restricted axial tetrahydropyranyl ethers [55],Briggs et al. (1984) observed a good linear relationship between the length of both the exocyclic and the endocylic acetal bond with the pKavalue of ROH, according to (5) and (6).
x / A = 1.493 - 0.006495 pK,
(5)
+ 0.003639 pK,
(6)
n / A = 1.364
The trend, for n to decrease as the leaving group becomes more acidic is at first sight a most telling piece of evidence in favour of the orbital picture. However, closer examination reveals that similar effects are observed with equatorial tetrahydropyranyl ethers [56], where similar correlations, (7) and (8), are found, even though lone pair p-o*-orbital overlap is not possible with equatorial stereochemistry.
x / A = 1.456 - 0.00476 pK,
(7)
n / A = 1.394 - 0.00214pKa
(8)
Puzzlingly, in neither equatorial nor axial cases are systematic changes in bond angles observed. Moreover, the change in bond lengths is not seen with glucosides. Recently, Jones and Kirby (1986) have rationalised the absence of bond-length changes with glucosides as a reflection of their lower reactivity, finding that bond-length changes in the methoxymethyl system, of intermediate reactivity, lie between those of tetrahydropyranyl ethers and glucosides. The author finds this unconvincing for two reasons. Firstly, the data of Allen and Kirby (1984), show that lengthening of the R-0 bond of ethers R'-0-R increases with decrease in pKa of ROH at about 0.0023 &pK unit, irrespective of whether .R' is primary, secondary or tertiary. Secondly, the methoxymethyl system probably is only of greater reactivity than glycosyl systems because bimolecular nucleophilic attack is sterically favourable (Bennet and Sinnott, 1986). Whatever the epiphenomena that will eventually rationalise these results, it is clear that the simple frontier-orbital picture of the anomeric effect cannot account unaided for all the bond-length changes in a system carefully designed to test it.
LEAST NUCLEAR M O T I O N AND STEREOELECTRONIC C O N T R O L
151
The interactions set out in Scheme 12 imply that if the lone pair interacting with the o-bond is of higher energy (more available), then the anomeric effect should be stronger. Therefore replacement of the ring oxygen by nitrogen should increase the anomeric effect in sugars and tetrahydropyranyl derivatives, both because the nitrogen lone pair is of higher energy and also because, being in an sp3 orbital, it is exactly aligned in the axial case for overlap with the exocyclic C( I)-X bond, unlike the ptype lone pair of oxygen. The data on this point are ambiguous. Mario Pinto and Wolfe ( 1 982) reported that the anomeric effect in nojirimycin, 5-amino5-deoxyglucose [57]was slightly stronger than that in glucose itself, the a / @ ratio at 50°C being 1.7 compared with 0.56. This conclusion was based on 'H nmr measurements of intensities of signals attributed to the anomeric proton. However, Paulsen et al. (1966) had shown not only that the closely analogouscompound [58]existed to theextent of 10-20% as imine [59],but also was unstable in aqueous solution, giving the product of Amadori rearrangement [60]. An accurate X-ray crystal structure of p-D-galactopyranosylamine (Samudzi et al., 1985) revealed that the C( I)-N bond was shorter than the standard C-N Bond, but the effect was small. On the orbital interaction picture the exo-anomeric effect with this compound should be particularly powerful, and this should be revealed in bond lengths. The anomeric effect of the NHMe group is small, and indeed changes sense, from inverse to direct, if the reference system for steric interactions is changed from cyclohexane to tetrahydropyran itself (Franck, 1983). ,OH O H "-
H
OH
H
OH
Nai'vely, one would expect the effect of replacing oxygen by sulphur to be similar to the effect of replacing oxygen by nitrogen, but, experimentally, the effects are far from clear-cut. Mario Pinto et al. (1985) indeed showed that the conformational equilibrium of [61] showed the effect on the nature of R
152
MICHAEL L. SINNOTT
expected [K(ax)/K(eq) at 180K varies from 3.8 for R = NMe, to 19.0 for R = NO,]. Juaristi et al. (1986a) showed the existence of axial conformational preferences for X = SMe, SPh, COOMe, COOH, and COPh in compounds [62], but in deriving values for the strength of the anomeric effect in 1,3-dithianes used steric conformational energies obtained for cyclohexane, despite C-C bonds being much shorter than C-S bonds. The same group (Juaristi et al., 1984, 1986b) studied [62] with X = -P(O)Ph,, and related compounds, and found no evidence for any lengthening of the C-P bond in the axial case, despite an overall axial conformational preference. Schleyer et ul. ( 1 985) have concluded on theoretical grounds that n-o* overlap cannot account for “anomeric” effects at second row elements (Cl, S, P).
An unambiguous success of the n-o* overlap model of the anomeric effect is its ability to rationalise 35Cl nuclear quadrupole resonance frequencies in axial and equatorial glycopyranosyl chlorides (David, 1979). The axial chlorides invariably resonate at lower frequency, in accord with the more ionic nature of the C-CI bond and hence the more spherically symmetrical distribution of electrons around the chlorine nucleus. C A L C U L A T I O N S ON TETRAHEDRAL INTERMEDIATES
Perhaps because of the fewer opportunities for comparison with experiment, there have been fewer theoretical calculations on systems CHXYZ than on the XCH,YH systems germane to the anomeric effect. Lehn et al. (1974) performed ah initio calculations on methanol (CH,OH), methanediol [CH,(OH) (O‘H)], and methanetriol [CH(OH) (OH) (O”H)], and came to essentially the same conclusions as Romers et al. (1 969): the average C-0 bond length appeared to decrease with increase in the oxidation state of the central carbon, whilst an 0 lone pair trans antiperiplanar to a C-0” bond lengthened C-0” and shortened C-0. Lehn and Wipff (1978) performed ah initio calculations on all fifteen staggered rotamers of aminodihydroxymethane. They used three basis sets (DZ, 3G, and 4-31G) and confirmed that their conclusions were independent of the basis set used. They assumed
153
LEAST N U C L E A R MOTION A N D STEREOELECTRONIC C O N T R O L
tetrahedral geometry but optimised bond lengths. The results of the study were in conformity with ALPH; in particular, the longest C-N bonds were found in conformations in which the nitrogen lone pair was antiperiplanar (app) to the hydrogen, and the C-N bond was app to two oxygen (sp3) lone pairs. The most stable conformer was [63], in which the nitrogen lone pair is app to a C-0 bond, and one oxygen (sp3) lone pair is app to the other C-0 bond. These theoretical results are thus similar to those obtained with acetal systems. where there is a conflict between patterns of ground state bond lengths, whether observed experimentally or calculated theoretically, and patterns of reactivity. Incisive experimental tests of the predictions for tetrahedral intermediates are difficult to come by, for without a very detailed study it is not clear whether the rate-limiting step is the formation of the tetrahedral intermediate (when the most stable conformer may be favoured) or its decomposition (when the pathway via the least stable conformer may be favoured). H OH n*H
HO--CI-I;H,
I
H
OH
I
OX-NH,
I
H
A further complicating feature is the proton transfers normally associated with acyl transfer. Lehn and Wipff (1980) therefore performed similar calculations on the six fully staggered conformations of [64] (T') and the nine fully staggered conformations of [65] (T-); in a typical case they also optimised bond angles rather than assumed they were tetrahedral. As might be expected, protonation leads to a marked selective lengthening of the C-N bond, whereas the C-0 bonds are slightly shortened. This lengthening and shortening shows a strong conformational dependence, in accord with ALPH, the lengthening of the C--N bond on protonation increasing from 0.04 8, to 0.10 8, as the number of app lone pairs on oxygen increases from 0 to 2. These calculated bond-length changes are small in the light of the experimental effects seen with tetrahydropyranyl ethers (Briggs et al., 1984). Protonation of the nitrogen of aminodihydroxymethane corresponds to decreasing p K , of the leaving group by about 33 units (Buncel and Menon, 1977). According to equations (5) and (7), such a pK,-change would result in a bond length change of 0.21 A in the axial tetrahydropyranyl ethers, and even 0.16 A in the equatorial case where there is no app lone pair available. Moreover, since the dihydroxymethyl cation is more stable than the tetrahydropyranyl cation, because the positive charge is delocalised over two
154
MICHAEL L. SINNOTT
oxygen atoms rather than one, if the hypothesis of Jones and Kirby (1986) is correct, even bigger effects should be seen in the dioxygenated system than in the monooxygenated system. Deprotonation of an OH group in aminodihydroxymethane is calculated to lengthen both the C-N bond and the remaining C-OH bond; there is some conformational dependence of this lengthening, but it is similar to that observed in the neutral system and about a third of the effects calculated in the protonated system. Calculations on tetrahedral intermediates are thus broadly supportive of ALPH, even though, as with compounds at the aldehyde level of oxidation, there are difficulties in detail. These calculations, however, refer to ground states rather than transition states, and, in the light of the difficulties the lone pair n-o* epiphenomenon encounters even in rationalising the effects in ground state in detail, it is unwise to extend it to transition states as an axiom. Recently, a new pictorial representation of the antiperiplanar effect has been put forward. Inagaki ef al. (1986) proposed that antiperiplanar effects of both bonds and lone pairs were brought about by the continuity of phase of the bonding or nonbonding orbital, the antibonding orbital of the antiperiplanar bond, and the bonding orbital of the intervening bond. They supported their approach with extended Huckel calculations, a fairly low level of theory, so the status of their proposal is not clear.
A L P H A N D THE P R I N C I P L E O F LEAST N U C L E A R MOTION (PLNM)
We have seen how ALPH, whilst it successfully rationalises a number of observations of reactivity of compounds at the acyl level of oxidation, nonetheless fails as a general principle, and that these failures are particularly frequent in the reactions of compounds at the aldehyde level of oxidation, such as acetals. Moreover, its theoretical foundation, the frontier orbital explanation of the anomeric effect, seems to be, at the very least, incomplete in its rationalisation of ground state effects, and therefore an insecure basis on which to found a dogma about transition states. If the origin of the effects held to support ALPH were indeed electronic in origin, one would expect the differential effect of going from one antiperiplanar lone pair to two to be far less marked than the effect of going from no antiperiplanar lone pairs to one. Thus one would expect the effects to be more marked in reactions of sp3 carbon centres at the aldehyde level of oxidation than at the acid level of oxidation, whereas the reverse is the case. There is also, for this author at least, the difficulty inherent in ALPH of reconciling the physical picture of a lone pair of electrons driving off the
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
155
leaving group, with the usual picture of electrons instantaneously adjusting to nuclear motion. Electrons are much lighter than nuclei and hence their wave properties are more pronounced. The difference in mass is great enough for the motion of electrons and nuclei to be treated independently (Born and Oppenheimer, 1927). Consequently, chemical reactions are usually envisaged as nuclear motions to which the electrons instantaneously adjust. There are, however, other factors than the electronics at the bonding centre which affect nuclear motion, and their effects are governed by the Principle of Least Nuclear Motion (PLNM). which states that those reactions involving the least motion of nuclei are favoured. Least motion effects are small, elusive, and easily overridden, particularly in reactions with late transition states such as the cleavage of acetals (Hine, 1977). They, rather than some fundamental quantum-chemical effect, are the likely origin of stereoelectronic control, since in the cases tested the predictions of ALPH and the predictions of PLNM are equivalent. The equivalence of the predictions of ALPH and of PLNM are best illustrated by consideration of the reactions of axial and equatorial tetrahydropyranyl or pyranosyl derivatives3 (Scheme 13). The preferred conformation of the cationic intermediate is assumed to be the half-chair, and the nature of the atomic motions is best seen if one takes as a plane of reference the plane defined by C(1), C(2), O(5)and C(5) of the oxocarbonium ion intermediate, and considers motions about the C(1)-0(5) bond, set out in Newman projections in Scheme 13. In both cases the motions of C(2) and of C(5) can be described as a 30" rotation of the C( I)-C(2) and 0(5)-C(5) bonds, respectively, about the C(1)-0(5) bond. However, the motions of the hydrogen at C(1) in the two cases are very different: in the axial case, the C(I)-H(1) bond rotates only 30' about the C( 1)-O(5) bond whereas in the equatorial case it has to rotate through 90". More nuclear motion is thus required in the ALPH-disfavoured case. In subsequent sections of this review the systems apparently exhibiting "stereoelectronic control" will be considered in terms of the nuclear motions involved. Indeed, in one of them (nucleophilic attack on amides), the fact that "stereoelectronic control" predicted a least-motion path was recognised by Deslongchamps himself ( 1983, p. 102). Careful X-ray crystallographic study of molecules in which nucleophilic groups are in close proximity to a carbonyl group can reveal what is claimed to be the early stages of the reaction trajectory for nucleophilic attack cin the carbonyl: the geometrical distortions revealed are in accord with PLNM or ALPH (Biirgi et al., 1973). Carbohydrate numbering of the ring, rather than heterocyclic numbering with oxygen at position 1, is used throughout this article.
156
MICHAEL L SINNOTT
x
\
2
Scheme 13
Nuclear motions in the tetrahydropyranyl ring of a tetrahydropyranyl derivative. consequent upon departure of an axial and of an equatorial leaving group
Thus, in both [66] and [67], the 1,8-substituents appear to be attracting, rather than repelling one another and carbonyl substituents are twisted out of the plane of the aromatic ring and splayed back, in accord with the picture of the transition state given in 1681 (Schweizer et a/., 1978). Least motion effects are often energetically small and vary in importance with the nature of the transition state: they are frequently overridden by other factors. Therefore, even though the predictions of ALPH and PLNM are equivalent, the fact that ALPHjPLNM fails implies that the physical basis of the observed effects is not a supposedly fundamental electronic dogma like ALPH. 4 The principle of least nuclear motion (PLNM)
The commonsensical, intuitive idea that those reactions are favoured where the change in geometry is minimal found explicit expression exactly a century ago when Muller ( 1 886) enunciated his “principle of least molecular deformation” on the basis of studies of the pyrolysis of alkylamines. The
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
157
Nuc II
I
ideas were extended to a series of other pyrolyses (Muller and Peytral, 1924). Recognisably modern ideas of least motion start with the treatment by Rice and Teller (1938, 1939) of sites of attack by radicals on other organic species. These authors stated that “those elementary reactions will be favoured that involve least change in atomic position and electronic configuration”. As pointed out by Hine (1 977), there are really two ideas here, electronic configuration and nuclear motion, and it is useful to separate them. PLNM enshrines the very obvious idea that those reactions are favoured in which nuclear motions are minimised, but this obvious idea can rationalise a wide range of experimental facts. Thus, Hine (1966a) used PLNM successfully to rationalise the sites of attack on conjugated reactive intermediates (cations, radicals and anions). The data is puzzling since the thermodynamically less stable non-conjugated isomers predominate: protonation of the cyclohexadienyl anion, for example, yields predominantly cyclohexa- 1 ,4-diene. The PLNM rationalisation of this result is set out in Scheme 14 in terms of the resonance structures of the pentadienyl anion fragment. Simple resonance theory gives bond orders of 5/3, 4/3, 4/3 and 5/3, respectively, for the C( l)-C(2), C(2)-C(3), C(3)-C(4), C(4)-C(5) bonds of the pentadienyl anion. Protonation of C(3), to give penta-l,4-diene, gives a product in whiah the bond orders are 2, I , I , and 2, i.e. each bond order changes by one-third. Protonation at C( l ) , by contrast, gives a product, penta-1,3-diene, in which the bond orders are 1,2,1, and 2, i.e. although the C(2)-C(3) and C(4)-C(5) bonds change their bond order by one-third, the C(l)-C(2) and C(3)-C(4) bonds change their bond order by two-thirds. Therefore, end protonation of the pentadienyl anion results in bigger
158
MICHAEL L. SINNOTT
0
0
[-CH-CH=CH-CH=CH-
-CH=CH-CH=CH-CH--]
5/3
[-cH-CH:CH:CH-CH:]-
-CH=CH-CHZ-CH=CH-
43
413
A
53
-CH ,-CH=CH-CH=CH--
Scheme 14
changes in bond orders than protonation of the central carbon. As bond orders and bond lengths are correlated, more nuclear motion is required for end protonation. Hine (1966a) also addressed the question of the physical origin of least motion effects. He considered them to arise from bond stretches and deformations in the substrate molecule, and treated the energetic consequences of these stretches and deformations in terms of intersecting Morse curves which could be approximated by parabolas. PLNM could thus be recast in terms of energetics. The energy required for a molecular deformation was considered to vary as the square of the displacement from a stable equilibrium geometry, be it reactant or product. As a consequence, reactions with very early or very late transition states were anticipated to show only small least motion effects, which should be most pronounced in reactions with central transition states. This feature of PLNM immediately explains why least motion effects are not observed in cleavage of acetals, but are observed in cleavage of orthoesters and other substrates at the acyl level of oxidation: the transition state for acetal cleavage is late, whereas that for orthoester hydrolysis is more central (Sinnott, 1984; Cordes and Bull, 1974). Hine (1966b), by minimising the squares of atomic motions in the conversion of reactant to product, was able to show that the observed strong preference for anti- over syn-elimination of both vinyl and ethyl chlorides was predicted by PLNM. The case of vinyl chloride is particularly instructive: the major motions of the atoms destined t a constitute the acetylene product are bendings (bond deformations), and are thus likely to be less energetically effective than bond stretchings. [From the data on the protonation of cyclohexadienyl anion Hine ( 1 966a) estimated that bond stretchings of 0.02 8, could give energetic effects of 1 kcal mol-'.I Moreover, if one nayvely places the axis with respect to which one considers nuclear motion
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
159
coincident with the carbon<arbon double and triple bonds, then it may appear that the nuclear motions involved in the syn- and anti-eliminations are similar. In fact, of course, reactant and product should be displaced with respect to one another until nuclear motions (or their squares) are minimised. If this is done intuitively in the case of the elimination reactions of vinyl chloride, it is seen that indeed nuclear motions in syn-elimination are greater than in anti (Scheme 15).
(a)
(b)
Scheme 15 Atomic motions involved in the anti(a) and 3j.n (b) eliminations of hydrogen chloride from vinyl chloride
Tee (1969) presented an algorithm which displaced substrate and product with respect to each other until the sum of the squares of the displacements of those atoms common to both molecules was minimised. Presented with a number of stereochemical pathways for a reaction, it could calculate the minimum square atomic displacement for each pathway. The pathway with the smallest minimum square atomic displacement corresponded with the experimentally preferred pathway in the case of 1,2-eliminations, 1,2hydride shifts and enolisation. The approach was extended to various rearrangements (Tee and Yates, 1972) and various eliminations, enolisations and homoenolisations by Tee et al. (1974). These papers pushed the predictive power of simple PLNM arguments to their limits: of the 33 cases studied, in only two were there serious discrepancies between PLNM predictions and experiment. In these two cases, the 1,3-elimination of 2norbornyl tosylate and the ring closure of 1.3,5-hexatriene to 1,3-cyclohexadiene, there are identifiable causes for the failure in the non-concerted nature of eliminations from 2-norbornyl tosylates and the overriding requirements of the conservation of orbital symmetry (PLNM predicts a conrotatory closure of hexatriene, whereas the Woodward-Hoffman rules correctly predict a disrotatory mode). In a further study of complex rearrangements (Altmann et al., 1976), failures of these very simple PLNM arguments were noted only for the rearrangement of bicyclo[2.1.O]pentene to cyclopenta-
160
MICHAEL L. SINNOTT
diene, and of methylcarbene to acetylene. It appears therefore that least motion effects have modest predictive power if they are not overridden by other factors. In a series of papers, Ehrenson (1974a,b, 1976) attempted to put PLNM on a more rigorous footing. He weighted individual atomic motions according to atomic masses and appropriate force constants, but recorded few comparisons with experiment. Altmann et ul. (1976) commented that they used mass-weighted coordinates as a refinement of the simple Tee (1969) approach, and that it made no difference to their conclusions. It seems to the author that consideration of least motion effects in this fine detail with respect to the substrate is unlikely to give worthwhile insight into reactions in solution, particularly in solution in highly polar, and hence highly structured solvents. I t is precisely in these solvents that many of the heterolytic reactions whose stereochemical outcome IS held to support ALPH have been carried out. Most of these reactions are formally either the reaction of a delocalised carbocation with a nucleophile, or its microscopic reverse. The reactions of delocalized carbocations with nucleophiles have been studied extensively by Ritchie and co-workers, and the main conclusions of their work are particularly germane to considerations of least nuclear motion. Their initial experiments (summarised by Ritchie, 1972) indicated that the relative reactivities of nucleophile systems (nucleophile plus solvent) were independent of the cation attacked, i.e. the simplest possible iinear free energy relationship (9) was followed. The ineluctable conclusion from this 1% (klkH20) = N ,
(9)
correlation is that the rate-determining step does not involve bonding to the electrophile, but is probably desolvation of the nucleophile. In some systems it has been suggested that solvent motion may be part of the reaction coordinate (Ritchie et al., 1982), but whatever the fine details of the interaction, it is clear that solvent reorganisation plays a major role in the outcome of these reactions. Indeed the point has been repeatedly made (e.g. Troughton et ul., 1984) that, without the solvent, heterolytic reactions would rarely happen at all. In considering the applications of PLNM to heterolytic reactions, therefore, it seems unreasonable to consider the substrate in fine detail whilst ignoring the solvent. If a major contributor to least motion effects ir1,solution is the varying degrees of solvent reorganisation required for varying degrees of nuclear motion, then it is not clear what function of atomic displacements should be minimised to determine the least motion path. Following Hine (l966a), the square of the atomic displacement has been minimised, but if solvation forces are involved, this will be accurate only for small displacements.
LEAST NUCLEAR M O T I O N A N D STEREOELECTRONIC CONTROL
161
For this reason, in what follows no attempts have been made to use computer subroutines [such as XFIT used by, e.g. Alder et af. (1986)] to calculate minimum square atomic displacements for various pathways. The view has been taken, rather, that if it is not intuitively obvious that one pathway involves greater nuclear motion than another, then the answer one will get from displacement minimisation subroutines will depend on the function of the displacements minimised, and this is itself an intuitive choice. The importance of solvation in the systems presently considered is illustrated by the experiment of Caserio et af. (1981) referred to on p. 131 which small to non-existent ALPH effects were found in the gas-phase ion chemistry of orthoesters, when their solution chemistry provides many apparent examples of the operation of ALPH. If indeed solvent disruption is a major contributor to least motion effects, then its importance should be minimal in reactions with late transition states, since at the transition state the solvent shell will be already disrupted. 5
Reinterpretation of apparent kinetic antiperiplanar lone pair effects in terms of the principle of least nuclear motion
H E T E R O L Y T I C R E A C T I O N S AT C A R B O N C E N T R E S S U B S T I T U T E D W I T H T W O A D D I T I O N A L O X Y G E N ATOMS
As was mentioned in the introduction, ALPH had its genesis in the observation that the anomeric hydrogen of methyl P-, but not methyl aglucopyranoside was removed by ozone. The conformation of the dioxocarbonium ion intermediate has to accommodate the planarity of C(5), 0 ( 5 ) , C( I), C(2), O( I), and the aglycone, and is probably 4H,. Consequently, the motions of the glycosidic methoxyl are exactly analogous to the motions of the anomeric hydrogen in Scheme 13: in the case of methyl a-glucoside it has to move through 90" whereas in the case of the P-compound it has to move only through 30" (Scheme 16). PLNM thus correctly predicts the outcome of the paradigmal ozone oxidation experiment (Deslongchamps et af., 1972a).
.II:
~0% HO
-
OCH, "YH
+&
H O *
'\+
HO 30"
HO
OH
0
b
-OCH,
Scheme 16
OCH,
162
MICHAEL L SINNOTT
An exactly similar argument indicates why cis-I &dioxadecalin [68] is inert to ozone under conditions which convert the trans-isomer [69] to 4-(3hydroxypropy1)valerolactone(Deslongchamps et al., 1974): in attaining the planar dioxocarbonium ion [70] the whole shape of the cis- 1,8-dioxadecalin would have to alter.
As lactones can be alkylated with powerful alkylating agents, i t is possible to study the addition of nucleophiles to dioxocarbonium ions directly. The attack of nucleophiles on conformationally restricted dioxocarbonium ion [6] (or its ethyl analogue) has indeed been shown in the case of alkoxides (Deslongchamps et al., 1975a) and hydrosulphide ion (Kaloustian and Khouri, 1980) to take place in an axial sense. In the case of equatorial attack, the exocyclic methoxyl (or ethoxyl) group would have to rotate 90" about the endocyclic C-0 bond, but only 30" in the case of axial attack. ALPH was considered to apply to orthoester hydrolysis at the same time as it was applied to ozonolysis of acetals (Deslongchamps et al., 1972b). However, PLNM also predicts the products that are obtained in the paradigmal experiment, the hydrolysis of conformationally restricted orthoester [3] and its conformationally unrestricted analogue [8] (Deslongchamps et al., 1985a). Loss of the axial group is favoured since the remaining alkoxyl group has to move through 30°, rather than 90°, to achieve the geometry it has in the dioxocarbonium ion intermediate [6]. The ring can also open to give [5], and this can only give hydroxyester product. Axial attack on [6] is again favoured by least motion arguments, so hemiorthoester [7] is favoured over its equatorial epimer. The conformationally restricted case [7] can only give lactone by means of processes involving 90" motions of the hydroxyl group, and so lactone is not formed. However, in the moncyclic case the hemiorthoester intermediate can undergo a chair-chair interconversion which can then put the hydroxyl group equatorial; loss of axial methoxyl group then gives lactone. PLNM thus predicts directly the differing products in the two cases. Deslongchamps (1983, pp. 77-78) interprets the differing results in the moncyclic and bicyclic cases in terms of the balance between a secondary stereoelectronic effect and the reversibility of lactone ring opening. The PLNM explanation, by contrast, has the virtues of economy and conformity with the known long lifetime of hemiorthoesters (Capon r t al., 1981).
163
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
Deslongchamps el ul. (l985b) observed that orthoester [71] gave only hydroxypropyl lactone [72] on mild acid hydrolysis whereas its epimer [73] gave in addition dihydroxyester [74]. The methoxyl group of [71] is axial in both rings and is thus lost to give dioxocarbonium ion [70], in preference to any endocyclic cleavage which would require it to undergo a 90" motion. Axial attack should give hemiorthoester [75] which, as Deslongchamps pointed o u t (1983, p. 80) cannot collapse with stereoelectronic control; it nonetheless collapses to the hydroxypropyl lactone, rather than remains as such, as one might expect if fundamental electronic forces were at work. The initial mode of cleavage of orthoester [73] that involves least nuclear motion is cleavage of the endocyclic bond which is axial in the other ring to give dioxocarbonium ion [76]. The hydroxypropyl group will bias the chair-chair equilibrium of monocyclic intermediates towards the same conformation as the bicyclic starting material: consequently least motion arguments predict predominant formation of dihydroxyester from [73]. Stereoelectronic arguments predict exclusive formation of [74] from [73], and this was apparently the first result obtained (Deslongchamps 1983, pp. 80-82). In fact some 70%
OCH,
H - OH COOCH,
P
O
C
H
3
OH 1741
[751
hydroxypropyl lactone is formed as well, but Deslongchamps er a/. ( 1 985b) advanced evidence that it might arise by prior isomerisation of the cisorthoester to its trans-epimer, which gives more than 99% hydroxylactone. Such a process would explain these authors' results with conformationally further restricted substrates [77] and [78]. Both compounds give hydroxylactones [79] and [80] in the same ratio: [77] also gives dihydroxyester [81]. Hydroxylactones [79] and [80] are first formed in a 3: 1 ratio from both [77] and [78], but this changes slowly to the thermodynamic ratio of 1 :20.
MICHAEL L. SINNOTT
164
0 ’-
I
OCH,
OH
H
Beaulieu and Deslongchamps (1 980) described the hydrolytic stability of tricyclic orthoester [82]: no quantitative data were provided but from the observation that hydrolysis required reflux in aqueous dimethoxyethane at an acid concentration which hydrolysed “normal” orthoesters at room temperature in minutes, one can estimate that hydrolysis is retarded by 4 orders of magnitude at most. Beaulieu and Deslongchamps interpreted the stability of [82] on the basis that no orthoester C-0 bond was antiperiplanar to two oxygen sp3 lone pairs. However, 1,3,5-trioxaadamantane derivatives [83] are also impressively stable; rate retardations of between 6 and 9 orders of magnitude being reported (McClelland and Lam, 1984a). According to ALPH this system is exactly set up for bond cleavage. McClelland and Lam (1984a,b) performed a careful analysis of the reaction and showed that the low overall rate of reaction was a consequence of the reversibility of the first step: physical removal of the leaving group from the proximity of the dioxocarbonium ion was difficult when the ring-closed form was so stable. A similar effect is to be anticipated with [82], in which all the rings are perfect chairs (Banyard and Dunitz, 1976). I t is worth noting that conversion of a cis-1 ,S-&oxadecalin system to cation [70] requires a very considerable aniount of nuclear motion in both rings, since O(l), C(2), C(7), O(8). C(9), and C(10) must all be coplanar for full delocalisation of positive charge. These very big changes could contribute to the size of the apparent effect with [82] and the “all or nothing” result from the ozonolysis of [68] and [69].
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
165
R
HETEROLYTIC REACTIONS A T CARBON CENTRES SUBSTITUTED W I T H T W O ADDITIONAL NITROGEN ATOMS
The key experiments here are those of Perrin and Arrhenius (1982) and Perrin and Nuiiez (1986), who showed that whereas amidines [38] gave exclusive aminoamide products, substrates in which the leaving group ability for exocyclic and endocylic C-N cleavage was matched [41] showed a significant preference for endocyclic cleavage only in the case of the sixmembered cyclic amidines (p. 132). The original results with [38] were interpreted on the assumption that the time constant for inversion about nitrogen was greater than the lifetime of the tetrahedral intermediate. The discovery of large quantities of lactam from hydrolysis of [41] could therefore indicate a breakdown of this assumption. However, the production of substantial quantities of lactam from [84] also enables this possibility to be dismissed, since nitrogen inversion of hydroxylamine derivatives is known to be much slower than inversion of amines. Moreover, the production of 69% lactam from the conformationally restricted amidine [85] must be an ALPH-violating process.
In fact PLNM readily explains, not only why there is a preponderance of aminoamide in the hydrolysis of six-membered cyclic amidines [41], but also why this preponderance disappears in the hydrolysis of the five-membered amidines. Axial attack on the six-membered amidine will be favoured since then the exocyclic NHMe group makes only a 30°, rather than a 90", motion out of the plane of the amidine. For the same reason the hydrogen attached to the endocyclic nitrogen becomes equatorial rather than axial. Rotation about the exocyclic C-N bond of the tetrahedral intermediate [86a] can give a conformation [86b] whence collapse to the aminoamide is possible with
166
MICHAEL L. SINNOTT
only a slight flattening of the pro-amide group. Collapse of the tetrahedral intermediate to lactam [87] from conformation [86a] is possible only with a 90" motion of the oxygen atom. If the ring is inverted to conformation [86c], since there is no concurrent nitrogen inversion, the N-H bond is now axial, and so has to move through 90" in order to produce lactam. Consequently endocyclic cleavage to aminoamide is favoured. The contrast between the behaviour of cyclic orthoester [8], which gives comparable quantities of lactone and hydroxyester, and valeramidine [41, n = 21, which gives a preponderance of endocyclic cleavage, thus lies in the fact that the endocyclic heteroatom in the amidine case has a hydrogen atom attached, which has to undergo large displacements to give lactam product. OH I
In the cases of the butyramidine [41] the motion required of the oxygen atom as the tetrahedral intermediate is converted to the lactam is much less than in the case of the valeramidine. Figure 2 shows the results of a computer graphics calculation using the COSMIC package (Vinter, 1985); the program uses an abbreviated MM2 procedure to calculate geometries. This has been done with the lactam and with the tetrahedral intermediate and the carbonyl carbon and a methylene carbon have been superimposed in both cases. The motion of the oxygen atom is 60" or less. Therefore least motion does not favour endocyclic cleavage in the hydrolysis of the butyramidine. The situation in the case of caproamidine [41] is less clear: the geometries of the pentamethylene chain in the lactarn and the tetrahedral intermediate are calculated to be radically different, so a superposition of the two structures, as in Fig. 2, is uninformative, and in any event, at least in buffered solution, the seven-membered amidine gives a quantity of lactam ( 1 5%) intermediate between that from the five-membered amidine (39%) and the six-membered amidine (3%).
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
167
FIG. 2 Superposition of the tetrahedral intermediate in the basic hydrolysis of ybutyramidine and y-butyrolactam, - - - -oxygen, . . . . . . nitrogen. Conformations are calculated using the abbreviated MM2 subroutine in the COSMIC computer graphics package (Vinter, 1985) HETEROLYTIC REACTIONS AT CARBON CENTRES SUBSTITUTED W I T H O N E A D D I T I O N A L O X Y G E N A N D O N E A D D I T I O N A L N I T R O G E N ATOM
The base-catalysed hydrolyses of amides proceeds through tetrahedral intermediates [88]. If either nucleophilic oxygen or carbonyl oxygen is isotopically labelled, then, depending on the relative rates of formation and decomposition, carbonyl oxygen exchanges of unreacted amide may or may not be observed. The situation is complicated by the unwillingness of simple amines to leave as bare anions. The amino group has to be protonated (Jencks, 1972), and this protonation step may occur within the same encounter complex, thus making the decomposition to amine and carboxylic acid bimolecular. Carbonyl oxygen exchange occurs to a large extent during the alkaline hydrolysis of PhCONH,, to some extent during the hydrolysis of PhCONHMe, and not at all during the hydrolysis of PhCONMe, (Bunton et al., 1968). A similar pattern of reactivity is observed on increasing the steric bulk of the acyl moiety: Deslongchamps et al. (1978) showed that carbonyl exchange was significant with HCONMeCH,Ph, barely detectable with MeCONMeCH,Ph, and did not occur with EtCONMeCH,Ph. Interpretation of these patterns of reactivity in terms of an elaborate interplay of steric and stereoelectronic factors (Deslongchamps et al., 1978; Deslongchamps, 1983, pp. 110-118) does not seem warranted in the light of the recognition (e.g. Gravitz and Jencks, 1974) that the partitioning of a tetrahedral intermediate between two possible modes of fragmentation depends, not only on the leaving group ability of what is lost, but also the
168
MICHAEL L. SINNOTT
stability of what is left behind. It is clear that tetrahedral intermediates such as [88] will not lose hydroxide to regenerate amide if by so doing they generate an amide [89] in which two bulky groups must be cis to one another, so exchange is observed with tertiary amides only when the acyl fragment is small (formyl or acetyl). The ratio of exchange to hydrolysis increases with temperature (Deslongchamps et al., 1978) as would be anticipated for unimolecular loss of hydroxide in competition with bimolecular general acid catalysed departure of amine.
~ 9 1
[881
A phenomenon that does require explanation is the failure to observe carbonyl exchange in lactam [90] when it is observed with secondary amides (Deslongchamps et al., 1977). PLNM predicts axial attack to give tetrahedral adduct [9 1 a]: carbonyl-oxygen exchange will be observed only if this adduct lives long enough to undergo a chair-chair interconversion to give [91b] so that the axial OH can again be lost. In order to rationalise the absence of carbonyl exchange on the basis of ALPH, exactly the same assumption about the relative rates of conformational change and fragmentation has to be made.
e
o CH3
[901
-
YJo-
CH,\N
OH (b)
(a)
[911
A tetrahedral intermediate in which the central carbon atom is substituted by two oxygen atoms and a nitrogen atom can also be generated by the addition of water or hydroxide to an imidate salt. Least motion considerations can then affect the two possible modes of decomposition of this intermediate, to ester and amine or to amide and,alcohol. The balance between these two modes of fragmentation will depend on protonationdeprotonation processes as well as any least motion effects. However, despite attempts to rationalise results with various acyclic imidates in terms of interplay between steric and stereoelectronic interactions (Deslongchamps, 1983, pp. 118-147), it is quite clear from the incisive work of
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
169
Caswell and Schmir (1979) that PLNM/ALPH effects will be observed only in conformationally restricted systems. These authors studied products of hydrolysis of E-imidate [92] and an equimolar mixture of this and the Z imidate 1931 as a function of pH. The percentage of ester in both cases was quantitatively described by the same titration curve, the yield of 101% ester at low pH falling to 65% at high pH, with the change governed by an apparent pK,-value of 10.2. Rotation about the C-0 or C-N bonds of the tetrahedral intermediate [94] is thus fast compared with its decomposition across the whole pH range.
A result which does require explanation in terms of ALPH or PLNM is the production of aminoester [9S] exclusively from hydrolysis of [96] under conditions where' the analogous monocyclic compound [98] gives both aminoester and lactam (Deslongchamps ct ul., 197Sb). Least motion arguments predict axial attack by hydroxide ion on [98] to give tetrahedral intermediate [99a] in which the exocylic methyl and exocyclic ethoxy groups are equatorial: to have put either of them axial would have required 90" motions out of the plane of the imidate residue. This molecule can collapse to aminoester by a flattening of the pro-acyl group; alternatively, it can undergo a chair-chair inversion, coupled with an inversion about nitrogen to give [99b], in which loss of the now axial ethoxy group is favoured because the N-methyl group and the C-0 bond only have to make 30" motions to attain the geometry of the planar lactam. By contrast, the bicyclic imidate [96] will yield tetrahedral intermediate [97a] which can collapse to [9S] by a flattening of the pro-ester group. A simple chairxhair interconversion is however not possible in this trans-decalin system. If the bridgehead nitrogen atom is inverted. to yield the cis-decalin structure [97b], then indeed loss of the now axial ethoxy group is favoured by a least motion pathway, but this conformation, and transition states derived from it, will be little populated because of obvious steric clashes. Chair-chair inversion o'f both rings to give [97c] will relieve this strain but put the ethoxy group equatorial again. Hence lactam is not produced.
MICHAEL
170
L. SINNOTT
rnCOOMe OEt
[981
[991
N-Methylation of hydroxyamide [ 1001 retards the acid-catalysed N-0 acetyl migration by a qualitatively large factor, probably corresponding to some orders of magnitude in rate (Lyapova et al., 1981). Least motion attack of nucleophiles on amides takes place such that the nucleophile attacks perpendicularly to the plane of the amide, the carbon substituents bend away from the incoming nucleophile, and the nitrogen substituents bend towards it (cf.[68]). Least motion arguments thus predict structure [I011 for the tetrahedral intermediate in this reaction. Clearly, if the amide hydrogen is replaced by a methyl group there will be severe 1,3-diaxial interactions between this and the axial phenyl group, and formation of a tetrahedral intermediate analogous to [ 1011 will be disfavoured.
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
171
REACTIONS OF PROTEINASES
There are four basic mechanistic classes of enzyme which catalyse the hydrolysis of peptide bonds: serine proteinases such as trypsin and chymotrypsin. cysteine proteinases such as papain, acid (aspartic) proteinases such as pepsin, and zinc-containing metalloproteinases such as carboxypeptidase. X-ray crystal structures of representative examples of each class of enzyme are available, and the detailed reaction pathways probably taken by all four classes of enzyme have been subject to analysis in terms of ALPH. These analyses have been for the most part permissive rather than compelling, and are considered in turn below. ScJrineprotcwmws ' The catalytic apparatus of all serine proteinases contains a triad of aspartate, histidine, and serine residues hydrogen-bonded together in such a way as to enhance the nucleophilicity of the serine hydroxyl group. Hydrolysis of an ester or peptide substrate proceeds through a well-characterised acylenzyme intermediate and two presumed tetrahedral intermediates (Fersht, 1985, p. 405): the generally accepted mechanism for hydrolysis of a peptide substrate is shown in Scheme 17. Bizzozero and Dutler (198 1) performed an extended model-building study, using X-ray structures for the trypsinbenzamidine complex, the trypsin-pancreatic trypsin inhibitor complex, and tosyl-chymotrypsin. The conformation of the first tetrahedral intermediate was predicted to be [ 102aI from strong, specific interactions between enzyme and substrate. In this conformation the dihedral angle about the serine oxygen to serine carbon bond is such that collapse to the stable transconformer of the acyl-enzyme intermediate [ 1031, with expulsion of amine, can occur by a least-motion route as the serine carbon moves away from the viewer and the torsionally symmetrical oxygen atom moves towards him.
172
MICHAEL L SINNOTT
As Bizzozero and Dutler (1981) make quite clear, however, the stereochemistry about the nitrogen atom cannot be obtained by model building. They indeed state “This information can only be obtained by applying the stereoelectronic theory recently proposed by Deslongchamps and coworkers.. .”, and consequently they propose conformation [102b] for the tetrahedral intermediate, in which, in accord with least motion and ALPH, the nitrogen atom derived from the substrate amide group is pyramidalised with the substituents pointing towards, and the nitrogen lone pair pointing away from the incoming serine oxygen atom. However, if the nitrogen lone pair is pointing away from the serine residue it is also pointing away from the catalytic histidine residue. This nitrogen atom must be protonated in order to leave from the tetrahedral intermediate. If the protonation is to be carried out by the protonated imidazole side-chain of the catalytic histidine, then there must be a nitrogen inversion subsequent to the formation of [102b] to give [102c]. Nitrogen protonation of [102b] by solvent water is in principle possible, but this would leave the catalytic histidine still protonated in the acyl-enzyme intermediate, and thus incapable of acting as a general base catalyst for the attack of water. Application of ALPH to serine proteinases as an axiom thus results in a requirement for a separate kinetic event, nitrogen inversion. In the absence of additional evidence for such an event, therefole, serine proteinase action would be accounted an area in which ALPH probably fails, but two negative results provide some evidence that the tetrahedral intermediate is indeed first formed in conformation [102b]. Bizzozero and Zweifel (1975) found that amides [I041 and [ 1051 were not detectably hydrolysed by chymotrypsin,
ko
HYh C‘”‘
0
whereas analogous compounds in which the fissile amide bond was secondary rather than tertiary (AcPheGlyNH, and AcPheAlaNH,) were substrates. Model building reveals that the tetrahedral intermediates derived
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
173
from [ 1041 and [ 1051, if formed in conformation [ 102b], would experience severe non-bonded interactions between the second alkyl group on the nitrogen atom and the catalytic histidine residue, but that these interactions would be absent in conformation [102c]. There are of course many other possible reasons why these molecules need not be substrates, and the very high Kivalues (75 mM and 64 mM, for [ 1041 and [ 1051, respectively) suggest that these compounds might not be substrates because they are bound nonproductively. In the mechanism of serine proteinases drawn in Scheme 17, the oxygen atom derived from the carbonyl group of the substrate is shown as carrying a full negative charge: the three orthogonal lone pairs on oxygen thus make it torsionally symmetrical. Asboth and Polgar (1983) pointed out that in fact the negative charge was considered to be stabilised by hydrogen bonds to two NH groups of the polypeptide backbone, thus breaking the torsional symmetry. They demonstrated the importance of this hydrogen bonding in catalysis by chymotrypsin and subtilisin by comparing the thiono substrates [106a] and [107a] with their oxygen analogues [106b] and [107b]. The sulphur compounds were not hydrolysed, although they were bound to the enzymes as tightly as the oxygen substrates. Sulphur forms much weaker hydrogen
(a: X
=
S; b: X [I061
=
0)
(a: X
=
S; b: X
=
0)
~071
bonds than oxygen. These workers used model building to examine the stereochemistry of the hydrogen bonds connecting the oxyanion site with the peptide backbone. These were formed as shown in [log], i.e. the nonhydrogen bonded lone pair was antiperiplanar to the leaving amine rather than the incoming serine residue. It quite clearly cannot be antiperiplanar to both, yet, if a hydrogen-bonded lone pair “cannot be regarded as a real lone pair”, ALPH requires the hydrogen bonding patterns in the transition state for gain and loss of the serine residue from [ 1021 to be different from those in the transition state for gain and loss of the amine from [102]: another, otherwise unsubstantiated, conformation change has to be invoked to allow the enzyme to turn over.
Scheme 17 The catalytic mechanism of serine proteinases. Two protons are shown in flight at each reaction step, as is probably the case with specific substrates; non-specific Substrates appear to react with the operation of only one-proton catalysis (Elrod ef al., 1980)
175
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
Cysteine proteinuses The catalytic mechanism of cysteine proteinases is broadly similar to that of serine proteinases, in that there is an acyl-enzyme intermediate (Fersht, 1985, p. 414) and a histidine residue which is considered to act as a general acid-base catalyst; however the balance of evidence appears to favour the mechanism shown in Scheme 18 in which, in contrast to that for the serine
NHR'
...
N
R
\
. -................. .................. . . . . . ....... ....
H
..................... ......... ...
R
/s+\
fH2
0
.................. ..................... ............... .................. ...
Scheme 18
The catalytic mechanism of cysteine proteinases. The pathway tp the acyl-enzyme is shown: its hydrolysis probably involves general base catalysed attack of water in the near microscopic reverse of the above mechanism. Only one proton is in flight during deacylation (Szawelski and Wharton, 198 1 )
176
MICHAEL L. SINNOTT
proteinases, the enzyme nucleophile is fully deprotonated to begin with. A further difference is that hydrogen-bond stabilisation of the oxyanion site seems to be relatively unimportant, since thionoesters [106a] and [107a] are as good substrates as their oxygen analogues [106b] and [107b] (Asboth and Polgar, 1983). Analyses of the conformation of the first tetrahedral intermediate in papain catalysis in terms of ALPH and the known X-ray structure of the enzyme has been carried out (Brocklehurst and Malthouse. 1978; Angelides and Fink, 1979b). As with serine proteinases, application of ALPH to the substrate in the active site in the conformation determined by X-ray crystallography led to the prediction that the tetrahedral intermediate was generated in a conformation such that protonation of the leaving nitrogen by the histidine side chain was not possible without a conformation change of enzyme or substrate. Evidence for a conformation change of the enzyme had been advanced previously by Angelides and F i n k (1979a), but the unlikelihood of such an event has been pointed out in the review by Polgar and Halasz (1982). More recently, the experimental work on which Angelides and Fink (1979a,b) based their analysis has been called into question: Mackenzie et al. ( 1 985) resynthesised the substrate used by Angelides and Fink and found it to have completely different properties. The status of ALPHjPLNM effects in cysteine prcteinase catalysis is thus uncertain. Aspur t ic proteinuses The catalytic mechanism of aspartic proteinases has recently been put on a firmer footing by the availability of X-ray crystal structures, at 1.8 A resolution, of native penicillopepsin and of its complex with a derivative [I091 of the tight-binding inhibitor pepstatin (James and Sielecki, 1985). It is now accepted that there are no catalytic intermediates involving covalent bonds between enzyme and Substrate (see, e.g. Rich, 1985). James and Sielecki (1985) demonstrated the presence of a tightly bound water molecule held between the two catalytic aspartate residues, one of which was probably protonated and the other probably not. It is therefore likely that catalysis involves simply one tetrahedral intermediate formed by general base catalysed addition of the tightly bound water molecule to the substrate, followed by protonation of the amine leaving group and collapse to acid and amine. This sequence of events has been subjected to sterqochemical analysis in terms of ALPH, although the authors mention the equivalence of predictions based on ALPH and on PLNM. This analysis reveals that a nitrogen inversion is not required for protonation of the amine leaving group by the catalytic groups of the enzyme: the tetrahedral intermediate is first generated in a conformation in which the nitrogen lone pair is pointing towards the
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
177
catalytic groups, so that a nitrogen inversion would have to precede protonation by solvent. The likely mechanism is drawn out in Scheme 19. James and Sielecki (1985) consider the carbonyl group of the substrate to be polarised by transfer of a proton normally residing between the two catalytic groups: in order to protonate the nitrogen leaving group without a nitrogen inversion, this same proton has then to be transferred from one of the
I
[ 1091
oxygen atoms of the tetrahedral intermediate to the nitrogen of the leaving group. I t seems to the reviewer that the initial transfer of the proton to the substrate carbonyl group may not be necessary: papain hydrolyses [106a] and [107a] as well as [106b] and [107b] and so presumably works without such proton transfer. Proton donation to the substrate carbonyl oxygen is therefore not shown in Scheme 19. /ASP
215
32
H'
-0
I
~7 H
4
X
Asp 32
H '.
y .N
-\
9..v+ /OH
Y l c - H---, N -C
HHd
PO'4o H
x'
'C
I
X Scheme 19
A possible catalytic mechanism of aspartic proteinases, residues numbered as for
penicillopepsin
I 78
MICHAEL L. SINNOTT
Zinc-containing proteinases The mechanism of action of carboxypeptidase has been subject to analysis in terms of ALPH by Deslongchamps (1983, p. 351). Unfortunately, the balance of evidence is now that the covalency changes so analysed probably do not take place, and that zinc proteinases work by a substantially different mechanism to that assumed by Deslongchamps in his stereoelectronic analysis. Zinc proteinases contain a tightly-bound active site Zn2+ ion and a carboxylate group: in the two zinc proteinases whose X-ray crystal structures are known, carboxypeptidase A and thermolysin, these are Glu-270 and Glu-143 (Lipscomb, 1983). One thus has at least the following three possibilities for the initial catalytic event:
(i) Nucleophilic attack by the glutamate residue with polarization of the substrate carbonyl group by the zinc, resulting in a covalent anhydride intermediate. (ii) Nucleophilic attack by a water moleucle, general base catalysed by the catalytic carboxylate group, with polarisation of the substrate carbonyl group by coordination to the Zn2+. (iii) Nucleophilic attack by the anion of the water molecule coordinated to the zinc, with polarisation of the substrate carbonyl by general acid catalysis from the enzyme carboxylate. Deslongchamps (1983) conducted his analysis in terms of mechanism (i), assuming that there was a covalent anhydride intermediate and that the substrate carbonyl was coordinated to the active-site ZnZ+ . Subsequent work has shown these assumptions to be questionable. The X-ray structures of enzyme and enzyme-inhibitor complexes permit the anhydride intermediate only in the case of carboxypeptidase, not in the case of thermolysin, since in this enzyme the catalytic Glu-143 is too far away from the substrate carbonyl (Lipscomb, 1983). The proposal that carboxypeptidase works via an anhydride intermediate thus requires the supposition that two very similar enzymes work by different mechanisms. A more serious objection is that the evidence for an anhydride intermediate is based upon observation of a transient phase during the hydrolysis of an ester intermediate under cryoenzymological conditions, i.e. at low temperature and in the presence of an organic cosolvent (Makinen et al., 1979). No evidence was obtained by these workers as to the molecular nature of the transient, but subsequently Hoffman et al. (1983) examined the system by multichannel resonance Raman spectroscopy. The characteristic carbonyl stretching frequency of an anhydride should have been detected by their experiments, but was not. Kuo and Makinen (1985), however, re-
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
179
sponded to this work with an argument, based on internal evidence, that the cryoenzymological experiments of Hoffman et al. were flawed by inadequate mixing of solutions. Circumstantial evidence against the anhydride mechanism comes from the observation of Christianson and Lipscomb (1986) that the tight-binding inhibitor [ I 101 (Ki = 0.2 pM) binds as the hydrate, rather than as an adduct with Glu-270, as would be expected were Glu-270 a nucleophile rather than an acid/base catalyst. In the complex of carboxypeptidase and the hydrate of [ I lo], one of the oxygens of the gem-diol is hydrogen-bonded to Glu-270, whilst the other is coordinated to the zinc ion. Such a pattern of contacts is compatible with either mechanism (ii) or mechanism (iii), but mechanism (iii) is favoured by the observation of Christianson et al. (1985) that compound [ 1 1 I ] was bound with the carbonyl group pointing away from the active site zinc. It is thus clear that stereoelectronic or least motion analyses of the action of zinc proteinases are at best premature.
6
Loss of leaving groups from trigonal centres
So far apparent stereoelectronic effects have been considered in systems where the leaving group is attached to an sp3 centre, and in these systems all the atoms with lone pairs of electrons directed in space are connected to the reaction centre by single bonds, about which rotation is energetically permissible. The fact that ALPH fails in a number of such systems, and where it succeeds, only does so by small margins, thus admits, in principle, of two interpretations: (i) There is no antiperiplanar lone pair effect on transition states. (ii) There is an effect, but it is masked in saturated systems by the ability of rotation about single bonds to become part of the reaction coordinate; hence the identical predictions made by ALPH and by PLNM, and the very small kinetic effects.
180
MICHAEL L SINNOTT
Departure of a leaving group with its bonding electrons from a trigonal centre, to give an sp-hybridised intermediate can in principle distinguish between these two possibilities, since no rotation is possible about the double bond joining the atom bearing the lone pair and the reaction centre. ALPH then predicts that the addition of nucleophiles to diazonium ions, nitrilium ions and their equivalents and to acetylenes should occur with the stereochemistry shown in Scheme 20. Hegarty (1980) has made this point and also presented experimental evidence that nitrilium ions and their equivalents do indeed react according to the predictions of ALPH. With most of the systems studied it was possible only to place lower limits on the free energy difference between transition states leading to and from the ALPH and anti-ALPH products, since either, in the dissociative direction, the more reactive isomer could not be obtained or, in the associative direction, only the ALPH product could be detected. However, Hegarty and Mullane (1986) were able to quantitate the “stereoelectronic” effect in the loss of chloride ion from E- and Z-benzohydroxyimidoyl chlorides [112] to give nitrile oxides [114]. The rate of the reaction of the Z-chlorides was proportional to hydroxide ion concentration between pH 2.0 and 3.5; the reaction of the E chlorides which, being slower, could be followed at more alkaline pH values, accelerated to a plateau value, governed by a pK,-value of 9.6. The bimolecular ratt constants for specific base catalysed hydrolyses of the 2-isomers were between 7 and 8 orders of magnitude faster than those of the E-isomers; if the two isomers have similar pKa-values this ratio of bimolecular rate constants corresponds to the ratio of unimolecular rate constants for loss of chloride from the two conjugate bases [I 131 and thus to a very large apparent stereoelectronic effect.
+ R-N=N
+ NUC +
R-CGN-Y
-
R 3 - N
/Nu
>
R, oN=N,Nuc
+NucN uc
R-C-C-R
-
R
N uc
Scheme 20
>
R’ R\ / oc=c\Nuc
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
181
P
The situation is complicated, however, by two factors. Firstly, because of the substituent on nitrogen, reactions generating nitrilium ions are, in terms of atomic motions, analogous to bimolecular eliminations of vinyl halides to acetylenes, and thus pathways in which the two substituents of the triple bond in the product are originally trans to one another in the starting material are favoured by PLNM in exactly the same way as trans-eliminations of vinyl halides (Scheme 15). In [ 1 12a] and [ 1 13a], the E-isomers, the aryl group and the oxygen atom are cis to one another, and so more atomic motion is required to reach the linear configuration of [114] than with the Z isomers [ I 12b] and [ I 13b], in which the aryl group and oxygen atom are truns. Secondly, there is the problem of why deprotonation of [ I 131 appears to be required, when the lone pairs on oxygen are not directly involved in the reaction. Indeed, data on a system which is a good model for loss of chloride ion from [ 1 121 rather than [ I 131 is available in the work of Johnson and Cornell (1980), who studied the relative rates of loss of chloride ion from [ I 151 and [ I 161. The reactions can be followed readily only at fairly high temperatures (80-1 50" C), but have the classical characteristics of a unimolecular ionisation to give [ I 171, including a common-ion rate depression for both Ar ,Cl
Ar,
C
I1
CH,O
/N
E
[ I 151
-
I
A,'
-
C
Ill
N+ I OCH [ I 171
,
,Cl C
II
N\
t [I161
OCH,
182
MICHAEL L. SINNOTT
stereoisomers, and, in the case of [116], a strong dependence of the rate on the substituents in A r ( p + = -2.4). In this system the Z / E rate ratio was around 470 (at 12O"C), a comparatively modest effect in line with PLNM favouring loss of chloride from the 2 isomer. Moreover, the observation of a common-ion rate depression with [ I 151 requires that at least some attack of chloride ion on [ I 171 occurs in an anti-ALPH fashion to regenerate [ I IS]; attack in an ALPH sense to give the much more reactive [ 1 161 would have no kinetic effect. Loss of chloride ion from [ I 131 was considered by Hegarty and Mullane ( 1986) to be formally analogous to loss of chloride ion from [ 1 151 and [ 1 161, in that the driving force was provided by the nitrogen lone pair. From this standpoint, the effect of ionisation of the hydroxyl group is inductive. However, the effects of substituents in the arene ring of [I 13a] (p = -0.4 to -0.5) are much more modest than for the formally analogous reaction of [ 1 161. Moreover, loss of chloride from [ 1 13a] (Ar = Ph) is about 12 orders of magnitude faster than from [I 151, which, since 0- has a small inductive effect (0, = - 0.12) would correspond to an apparent p' value of around 32. It is clear therefore that the oxygen lone pair electrons of [ I 131 are intimately involved in bonding changes as the chloride is lost. Although a radically different mechanism may operate, such a mechanism cannot involve an addition-elimination pathway, since displacements of [ 1 151 and [I 161 with methoxide ion are known (Johnson et al., 1981), and are comparatively slow, with [115] and [I 161 reacting at identical rates. In the light of the theoretical results of Leroy et al. (1979), it seems to the reviewer that in this system a least motion effect of the type originally considered by Hine (1966a,b) in which atomic motions were energetically expensive because of the distortions of bond angles and lengths, rather than because of differential disruption of solvent shells, may be operating. Leroy et al. (1979) performed ab initio calculations on fulminic acid (HCNO), using, admittedly, a 4-31G basis set and a Gaussian 70 program, but the results on such a small molecule may well be reliable. They found that deformation of fulminic acid in a trans-sense was energetically far cheaper than the same angular deformation in a cis-sense, even in the absence of a nucleophile. It is clear (Scheme 15) that more geometrical distortion of the molecule is involved for the same angular distortions of the H-C-N and O-N-C bond angles from 180" if the distortions occur together in a trans-sense than in a cissense. Similar calculations on 0-protonated fulminic acid would be interesting to compare with the experimental results of Johnson and Cornell (1980): are the energetic costs of trans- and cis-deformation different by a comparable amount, or does the ready trans-deformation of fulminic acid reflect its having some of the character of nitrosocarbene? Whatever the physical origin of least motion effects in R-C-N-0
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
183
systems, it is clear that the least motion interpretation of the results of Hegarty and Mullane (1986) does not require solvent disruption effects to provide the whole of the apparent stereoelectronic effect of 10 kcal mol-'. It is ironic that the first reaction to which the idea of an antiperiplanar lone pair driving off a leaving group was applied, the reaction of arenediazonium ions with nucleophiles (Littler, 1963) is the only reaction in which apparent antiperiplanar lone pair effects are not also readily predicted by PLNM or from the intrinsic bias of the system. The Z-isomers of diazonium hydroxides, etc., are the kinetic products of such reactions whereas the Eisomers are in general the more stable thermodynamically, yet the atomic motions in the arenediazo group on departure of a leaving group from an E or Z covalent diazonium compound will be almost identical. However, there is independent evidence that the reactions proceed through contact ion pairs, and a PLNM analysis of the product-determining step in the associative direction, the collapse of the contact ion-pair, shows that less disruption to the solvent shell is caused by collapse to the Z-isomer than collapse to the Eisomer. Reactions of aromatic diazonium ions with various nucleoDhiles are correlated by the Ritchie N + scale (9). It follows that the rate-limiting step in this reaction is not formation of covalent diazo-compound but desolvation of the nucleophile to form a species in which there is no covalent bond formation with the electrophile (Ritchie, 1972). A reaction in the reverse sense has been studied by Broxton (1978, 1979) who found that Z-arylazo ethyl ethers [I 181 ionised in ethanol some 4 orders of magnitude faster than their E-isomers [I 191. As [ I 181 are formed from diazonium ions 400-1200 times faster than [119], the E-isomers, as has long been known, are the more thermodynamically stable by modest factors, and so the stereodifferentiating effect must operate largely on transition states. Importantly, the degree of charge development at the transition states is high, p-values of -5.44 and -4.22 being obtained for [ 1 181 and [ 1 191, respectively.
With this data, a single supplementary hypothesis about the molecular nature of the contact ion-pair enables the stereochemistry ofthe additions of aromatic diazonium ions to be rationalised by PLNM. The hypothesis is that in the intimate ion-pair, the anion is in contact with the cation at the site of highest charge density, vk., the central nitrogen atom. The atomic
184
MICHAEL L. SINNOTT
motions required to convert such an intimate ion-pair to the covalent Zdiazocompound would be fairly small, largely involving a decrease of the Ar-N=N angle from 180°, with minimal disruption of the solvent shell (Scheme 2 I). Conversion to the E-isomer, however, would involve both a bending away of the arene group and also significant translocation of the anion, with greater concomitant solvent disruption. Detailed calculations are not required to establish this point: in the Z-isomer the diazo-substituent (e.g. OEt) and the arene group are closer to one another than in the Eisomer; in the contact ion-pair the two groups are yet closer, and so less atomic motion is required to convert the ion-pair to the Z-isomer than to the E-isomer.
Scheme 21
Atomic motions involved in the conversion of a contact ion-pair between an aromatic diazonium ion and a nucleophile into the E and the Z-isomer of the covalent diazo-compound
7 Reactions at phosphorus centres
Bonding changes during nucleophilic displacements at phosphates and related pentavalent phosphorus centres are commonly described in terms of associative mechanisms involving discrete pentacoordinate intermediates and dissociative mechanisms involving metaphosphate, either as a discrete intermediate (Westheimer, 1981), or as the main resonance contributor to ,“exploded” bimolecular transition states (Bourne and Williams, 1983; Skoog and Jencks, 1984). Since all three of the oxygen ligands of phosphorus in metaphosphate are torsionally symmetrical, “stereoelectronic” effects will not be manifested in reactions adopting the dissociative (or dissociativelike) pathway. However, there is no reason a priori why “stereoelectronic” effects should not be operating in the associative mechanism.
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
185
The associative pathway of phosphoryl transfer was established by Westheimer and co-workers in the 1960s (Westheimer, 1968, 1985). The key finding was that methyl and ethyl ethylene phosphates [ I 201 hydrolysed between 3 and 5 orders of magnitude faster than acyclic analogues, but that significant quantities of ethylene phosphate [121] were produced. As the accelerated hydrolysis rate of the cyclic phosphate arose from the strain in the ring, yet the ring could be preserved in the products, it was clear that rate-determining and product-determining steps were different. Hence there was an intermediate, which was identified with a trigonal bipyramidal adduct. In such an adduct there are two types of substituent, apical and equatorial, and the following rules (Westheimer, 1968) governing apical and equatorial preferences hold, although apical and equatorial substituents can be interchanged by pseudorotations (Ramirez and Ugi, 1971). 1
2 3
Electron-donating substituents prefer an equatorial position. Entering and leaving groups must be apical. Five-membered rings must be apical-equatorial rather than diequatorial or afortiori diapical.
According to these rules a pseudorotation of the pentacoordinate intermediate in the hydrolysis of [ 1201 is required for exocyclic cleavage to [ 12 I].
(a, R
=
Me; b, R [ 1201
=
Et)
“211
Overlap of filled oxygen lone pair orbitals with P-0 o*-orbitals is in principle possible in both tetrahedral and trigonal bipyramidal phosphorus compounds, and calculations were performed along these lines on dimethyl phosphate monoanion (Gorenstein et al., 1977a) and on various pseudorotamers of the neutral and dianionic forms of (MeO),P(OH), (Gorenstein et al., 1977b). It was possible to discern a stabilising interaction similar to that of Scheme 12 in tetrahedral and trigonal bipyramidal phosphorus derivatives, and a decrease in overlap populations of P-0 bonds antiperiplanar to oxygen lone pairs. These calculations were, however, performed at a modest level of sophistication. The calculations on dimethyl phosphate monoanion were ab iniiio, but with iterative geometry optimisation, an STO-3G”basis set, and a Gaussian 70 program package: the calculations on the dianionic trigonal bipyramid were similar, but those on the neutral trigonal bypyramid were
186
MICHAEL L SINNOTT
semi-empirical (CNDO/2). CNDO/2 does not reproduce the anomeric effect at carbon (see p. 146). Later ah initio calculations (Taira and Gorenstein, 1984) used the same general procedure although single point calculations were checked with a 6-21G basis set. Given the presence of a second-row element, one would expect all these calculations to be less reliable than those of Lehn et al. (1974) and Lehn and Wipff (1978, 1980) on carbon-centred tetrahedral intermediates, even before the identification of supposed epiphenomena. Nonetheless, the results of the calculations were used to suggest that antiperiplanar lone pair effects were responsible for a nearly 6 kcal mol- ' stabilisation of transition states in the hydrolyses of cyclic phosphates. Gerlt et al. (1975) had compared the calorimetric heats of hydrolysis of [ 12I ] and diethyl phosphate with their relative rates of hydrolysis, and found that whereas AAG* was 10 kcal mol-', A A F was only 4.5 kcal mol-'. Strain relief, Gorenstein et al. (1977b) argued, was therefore unlikely to account for the enhanced rate of hydrolysis of [121], and antiperiplanar lone pair effects were the further accelerating factor. Such a far-reaching explanation was not required by the data, though: Gerlt et al. (1975) had pointed out that the discrepancy was not general and that the heats of hydrolysis of [I201 and dimethyl hydroxyethyl phosphate were such as to rationalise the faster rate of [ 1201 wholly. Moreover, an observation that was to prove fatal to the idea of anitperiplanar lone pair effects in phosphoryl transfer was already on record at the time these ideas were formulated. Workers in Westheimer's laboratory (Kluger et al., 1969) had found a complex dependence on pH of the proportions of [I211 to [I221 in the hydrolysis of [120a]: the dependence between H, - 1 and pH 12 could be rationalised on the basis of reasonable assumptions about the relative rates of cleavage and pseudorotation of neutral, cationic, and monoanionic forms of the trigonal bipyramidal intermediate, but above pH 12 the proportion of exocyclic cleavage increased with pH, after falling to nearly zero. Since the overall rate in this region varied linearly with [OH-] the rate of hydrolysis to [I211 must vary as [OH-I2. Kluger et al. (1969) proposed that alkaline hydrolysis to [I211 proceeded by way of the dianion of the trigonal bipyramidal intermediate: such an intermediate must be frozen in conformation [123] since the fivemembered ring must be apical-equatorial and the two electron-donating -0- substituents must be equatorial. Since the methoxyl group is now apical, it can be lost as well as the endocyclic P-0 bond can be broken. (Kluger et al. attributed the near-zero proportion of exocyclic cleavage near pH 1 1 to reaction through the monanion of the pentacoordinate intermediate, which is first generated in conformation [I241 and fragments before it can pseudorotate.) However, if the stereochemistry about the equatorial
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
187
endocyclic P-0 bond of [I231 is considered, it is seen that an oxygen lone pair can become antiperiplanar only to the apical P-0 bond of the ring, not to the apical P-OMe bond. The experimental results of Kluger et al. (1969) thus flatly contradict the theoretical predictions of Gorenstein et al. (1977b), which imply that only endocyclic cleavage should take place from [123]. 0
II I
HOCH,CH,OP-OCH, 0-
[I221
cp &
c" v
.so-
I
The hydrolysis of [120] in strongly basic medium was reinvestigated by Taira et ul. (1984a). They first examined the distribution of 180-label obtained when the reaction was carried out in 50% H2180,and found, by examination of 3 1 P resonances, only unlabelled and singly '80-labelled product [122]. This product at least is not arising from a hexacoordinate intermediate, but then, as pointed out by Kluger and Thatcher (1983, only the product whose formation is second order in base, i.e. [121], may conceivably arise through such an intermediate. Taira et al., using a rapid quench technique and 31P nmr detection, also examined the products of hydrolysis of [120] in strong base and found only [121]. Kluger and Thatcher (1985) repeated the work of Kluger et al. (1969), detecting products by both 31Pand proton nmr and working with and without quenching techniques. In all cases they were able to confirm the results of Kluger et al. (1969), that a proportion of exocyclic cleavage product, which increased with increasing sodium hydroxide concentration, was formed as kinetic product from the hydrolysis of [120]. In subsequent work, by looking at the pattern of '*Oincorporation into [I211 when the reaction was run in H2180, Kluger and Thatcher (1986) were able to show that [121] arose from an intermediate containing only one oxygen atom from solvent, i.e. [123]. In the light of the wealth of detail given in the papers of Kluger and Thatcher (1985, 1986), and the many analytical procedures used, it seems likely that their experimental work, rather than that of Taira et al. (1984a), is correct. Consequently, we can conclude that ALPH, applied to the trigonal bipyramidal intermediate
MICHAEL L. SINNOTT
188
in phosphate ester hydrolysis, and envisaged as operating by n-G* interaction, is in clear conflict with experiment. Antiperiplanar lone pair effects in phosphorane intermediates have been claimed (Yang and Gorenstein, 1984) to be responsible for interesting patterns of behaviour in phosphonamidates. Whereas [ 1251 undergoes basic hydrolysis to give [I261 exclusively, [ 127aI undergoes exclusive P-N fission to give [ 1281 (Boudreau et a[., 1975). However, if alkyl groups are placed in the ortho-positions of the N-phenyl group of [127], P-0 fission becomes predominant to give [I291 (95% in the case of [127b] and 100% in the case of [127c] (Yang and Gorenstein, 1984). Formation of [I261 may involve trigonal bipyramidal intermediates [ 1301 or [ 1313, formation of [1281 may involve [ 1321and formation of [ 1291may involve [ 1331. Yang and Gorenstein (1984) claim that the nitrogen lone pair of the N-phenyl group is unavailable because of conjugation with the aromatic ring, but that in [I301 the endocyclic P-0 bond is antiperiplanar to two oxygen lone pairs on the equatorial substituents. In [I 331 the endocyclic P-0 bond is antiperiplanar only to one oxygen lone pair, the nitrogen lone pair being unavailable, and so reaction through [I331 does not take place unless ortho-substituents destroy the conjugation between the nitrogen lone pair and aromatic ring.
(a, R
=
H; b, R
=
CH,; c, R
=
(CH,),CH)
~ 7 1 [I281 This explanation requires the nitrogen lone pair of an aniline-type amine to be less available than the oxygen lone pair of an ether-type oxygen, a suggestion at variance with extensive chemical experience of basicity and
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
189
nucleophilicity of anilines and ethers. It seems rather that with these very hindered systems, distortion of the trigonal bipyramid, perhaps as far as the square pyramid [ 1341 originally suggested by Boudreau et al. (1975) as an intermediate in the hydrolysis of [127], is taking place. Boudreau et al. (1975) comment that in such a square-planar structure all the basal bonds are labile; thus, the balance between P-0 and P-N cleavage could depend on the ease of proton donation to the leaving nitrogen, which is essential for C-N cleavage, at least in the sense of hydrogen bonding. Clearly, introduction of o-alkyl groups into the N-phenyl group will sterically hinder this protonation and tip the balance towards P-0 fission.
[I291
MICHAEL L. SINNOTT
190
[ 1341
It has long been accepted that, since the phosphorus atom in tetracoordinate, pentavalent phosphorus compounds is to some extent coordinatively unsaturated, there is a small amount of double bond character in formally P-0 and P-N single bonds in such compounds as alkyl phosphates (see e.g. Murray et al., 1971). This double bond character could in principle introduce conformational preferences about P-0 or P-N double bonds, but because the double bond is a p-d n-bond, rather than a p-p Ir-bond as with carbon esters and amides, the conformational preferences will be less pronounced. Effects of this type, as well as ground state n-o* interactions may be responsible for the free energy difference between [ 135aI and [ 136a1 (1.95 kcal mol- '). Taira rt al. (1986) found that this greater stability of [ 135aI was parallelled by the 8-fold greater reactivity of [ 136aI than [ 135aI in base-catalysed hydrolysis. If ALPH were operating in this system, then [ 1351 should be more reactive than [136]. It is likely that in these systems, with an excellent leaving group, the monoanionic trigonal bipyramidal intermediate does not live long enough to pseudorotate, indeed that it is too unstable to exist and the reactions are really SN2(P). It is well known from carbon chemistry that SN2reactions of axial substituents are favoured over similar displacements of equatorial substituents. Therefore, alkaline hydrolysis of [I351 is favoured by ordinary steric effects. Any antiperiplanar lone pair effects on the stabilities of transition states in SN2(P) reactions must necessarily be differential, as lone pairs which are antiperiplanar to the leaving group are synperiplanar to the incoming nucleophile. In the present system interaction between the two ring-oxygen lone pairs and the orbital of the P-p-nitrophenoxy bond in the SN2(P) transition state for hydrolysis of [I351 should be greater than interaction of the oxygen lone pair orbitals with the o*-orbital of the P-OH bond of the SN2(P) transition state for hydrolysis of [ 1361, since p-nitrophenoxide is more electronegative than hydroxide. Nonetheless, [136] is more reactive. (A complication is that [ 136aI adopts a boat conformation; [ 136bI adopts the chair conformation shown and reacts 0.72 times as fast as [136a]; [135a] and [135b] react at the same rate.) The results with this system, therefore, although ambiguous, on balance argue against ALPH in phosphates.
191
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
Fanni ef al. (1986) have claimed the lo2- to 103-fold greater reactivity of compounds [I371 in 0.6 M NaOH, compared to their acyclic analogues, as evidence for antiperiplanar lone pair effects. However, the monoanionic trigonal bipyramidal intermediates involved in the hydrolysis of cyclic phosphates at mildly alkaline pH do not live long enough to pseudorotate (Kluger et al., 1969): they are too unstable to exist and the reactions supposedly involving them are S,2(P). That S,2 ring-opening reactions of strained rings such as [I371 are faster than S,2 reactions of acyclic systems should occasion no surprise. Xdo?CH,
f O 3 C H 3
\'o
0 (a, X = 0; b, X
[I371
;;>P;02cH3 0
=
S) [ 1381
[I391
Taira and Gorenstein (1984) have also suggested on theoretical grounds that, in tricovalent phosphorus compounds, the lone pair on phosphorus is made more available for reaction with a proton or an electrophile by interaction with antiperiplanar lone pairs of electrons on phosphorus substituents. Taka et al. (1984b) have advanced evidence for this in the form of (i) the failure of [138] to give [139] with diethyl peroxide or ethyl benzenesulphenate, whereas triethyl phosphitegivesP(OEt), underthesameconditions, and (ii) the reaction of [I381 as a Michael nucleophile towards 3-benzylidenepentan-2,4-dione, which was some 250 times slower than that of triethyl phosphite. The origin of these far from dramatic effects is not clear. Product [ 1391 may be more strained than [ 1381, the claim to the contrary (Taira et al., 1984b) being based on a misunderstanding. Taira ef al. (1 984b) found that P(OEt), and CH,C(CH,OH), on standing gave [139]. Equation (10) gives
192
MICHAEL L SINNOTT
the overall reaction, which is strongly dissociative and hence strongly entropically favoured, irrespective of the strain in [ 1391. [I381
+ P(OEt), = [I391 + 3 EtOH
(10)
At the time of writing, therefore, we can conclude that, whereas in carbon systems there is firm evidence for a phenomenon of some sort which demands rationalisation, in phosphorus systems no such evidence exists. 8
Reactions of radicals
Whereas the course of many heterolytic reactions has been treated in terms of ALPH, the data on the effect of heteroatom orientation on homolytic reactions is quite limited: the area is experimentally taxing and moreover the geometry of the radical and radicakation intermediates involved is far from obvious. Nonetheless, the idea that pairs of electrons in spatially directed orbitals selectively weaken bonds antiperiplanar to them was implicit in the theoretical studies of Kost et al. (1979) and Bernardi et al. (1976), who calculated, using quantitative perturbation molecular orbital theory, that C-H bonds antiperiplanar to heteroatom lone pairs were weakened with respect to those gauche to heteroatom lone pairs. Indeed, Kost et al. (1979) attributed C-H stretching bands of amines that were-observed at lower than normal frequencies (the Bohlmann bands at 2800-2650 cm- ') to the stretching of C-H bonds weakened by n-o* interaction similar to the anomeric effect (Scheme 12), although previously the same group (Wolfe et al., 1974) appears to have reached the opposite conclusion, and warned against using the Bohlmann bands in structural elucidation. The idea of radicals selectively abstracting hydrogen atoms from C-H bonds weakened by this n-o* interaction was also used by Deslongchamps et al. (1972a) in their initial treatment of the ozonolysis of [ I ] and [2]. Although the balance of evidence now points to this reaction being one of hydride abstraction, at the time a hydrogen atom abstraction mechanism was entirely reasonable. In fact, although in some radical reactions there appear to be antiperiplanar lone pair effects, they are always modest, and, where they are not equally well considered as least motion effects, they arise from the intrinsic bias of the system examined. In this section systems supposedly giving rise to ALPH effects will be treated in order of increasing complexity. ONE LONE PAIR: H Y D R O G E N ATOM ABSTRACTION FROM A L I P H A T I C AMINES
Substitution of a carbon radical by an a-amino group dramatically increases
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
193
its stability. Grela and Colussi (1984) estimated CH,NHMe and CH,NMe, to be 16.4 kcal mol-' and 17.6 kcal mol-' respectively more stable than the methyl radical, on the basis of the kinetics of low temperature pyrolyses, the initiation step of which was the generation of these radicals. The stabilisation arises by overlap of the half-filled p-orbital on carbon and the nitrogen lone pair (Scheme 22). Lyons and Symons (1972), recorded the esr spectra of radicals R,CHNR,R, in aqueous glasses at 130 K, and on the basis of the coupling constants between the electronic spin and the a-proton and 14N nuclei, estimated the spin density to be about 30% on N and 70% on C.
~ - N R , R ,
-
.+ CH,-NR,R,
Scheme 22 Orbital overlap responsible for stabilisation of radicals by an a-amino group
The radical geometry resulting from this interaction is not obvious. The radicals can be regarded as Mannich ions RlCH=fiR,R3 to which an electron has been added in the antibonding n*-orbital. Lyons and Symons (1972) on the basis of e.s.r. hyperfine coupling constants concluded, however, that the distortion from the all-planar structure of the Mannich ion was small, with the carbon essentially planar and the nitrogen atom pyramidalised somewhat, but not wholly, towards tetrahedral. Later studies of Kaba et al. (1974) were in accord with this proposal. A reactivity difference that was interpreted in terms of ALPH was the finding by Griller el al. (198 1) that at 22°C bicyclic amines [ 1401 reacted with the t-butoxy radical (CH,),CO. about an order of magnitude less rapidly than trimethylamine or triethylamine. The nitrogen lone pair of [ 1401 indeed cannot become antiperiplanar to a C-H bond, but in these systems the radical intermediate [141] is precluded by the bicyclic ring system from taking up their preferred near-planar geometry. In heterolytic reactions the effect would be much bigger (removal of the antibonding electron of [I411 would give an anti-Bredt Mannich ion): the smallness of the kinetic consequences of imposing an unfavourable geometry on the radical intermediate can be taken as evidence that the barrier to rotation about the C-N bond in unrestricted systems is low. The results with compounds [140] thus arise from the bias of the system, which has no choice but to give a high-energy intermediate with an unfavourable geometry.
194
MICHAEL L. SINNOTT /
X-NI
\
X-hI
\
/
F O R M A T I O N A N D DECOMPOSITION OF U-OXYGEN-SUBSTITUTED RADICALS
Stereochemical data on reactions involving radicals substituted with one, two or three oxygen atoms at the radical centre is more extensive than data on the corresponding nitrogen species, and apparent "stereoelectronic" effects of around an order of magnitude in relative rates are known in a number of systems. A problem has been, however, that until recently the geometry of the radical intermediates has not been well defined. Oxygen-substituted carbon radicals are more stable than simple alkyl radicals, and they owe this stability to overlap between a lone pair orbital on oxygen and the half-filled p-orbital on carbon. The most efficient overlap in a n-sense would be that depicted for nitrogen in Scheme 22: overlap between a pure p-orbital on carbon and the p-type lone pair on oxygen. Were this interaction to be dominant, then the geometry of alkoxyalkyl radicals would be the same as alkoxyalkyl cations (see Scheme 5), but the electronegativity of substituents also affects the geometry of the radical centre. If a radical is pyramidal, then the bonds to the three substituents are constructed from sp3 carbon orbitals, whereas if it is planar they are constructed from sp2 carbon orbitals. When the substituents are electronegative, therefore, a pyramidal geometry will be favoured because of the readier availability of sp3 than sp2 electrons. In the case of oxygen-substituted radicals it is not clear a priori at what point the inefficient sp3-sp3 bond overlap will be compensated by the electronegativity effect. However, very recently it has become apparent that carbon radicals substituted with a single oxygen atom are nearly planar, like the analogous nitrogen species. Thus, Bernhard et al. (1984) studied the e.s.r. and ENDOR spectra of radicals C H 2 0 R formed on radiolysis of methyl p-D-galactopyranoside at 6 K and found that hyperfine splitting constants were consistent with structure [ 1421; the C-H bonds of the methylene group were bent out of the node of the p-orbital by a mere 2.3". In an important series of experiments Giese and coworkers established, from e.s.r. hyperfine splittings, that glycopyranosyl radicals were planar (Dupuis et al., 1984; Korth et al., 1986a). Galactopyranosyl, lyxosyl, and mannosyl residues adopted the 4H3 confor-
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
195
1yxopyranosyl
[ 1421
[I431
O' . .:
/---qt'(J()
OR
OR
('.YO
glucopyranosyl [ 1441
[I451
mation [I431 whereas glucosyl and xylosyl radicals adopted the B2.5 conformation [ 1441, although the 4,6-O-benzylidene glucopyranosyl radical (unlike its protected derivatives) adopted the 4H, conformation. It was proposed that the glucosyl and xylosyl derivatives adopted the boat conformation because of interaction between the ring oxygen p-type lone pair. the halffilled p-orbital on C(l), and an axial substituent at C(2) in the sense of an incipient fragmentation to the radical cation of the glycal, and anion (Scheme 23). Glucopyranose rings with the radical sites at C(2), C(3), or C(4) all adopt the normal 4C, chair conformation (Korth et a/., 1986b). It is clear that attempts to rationalise the axial stereochemistry of coupling reactions of pyranosyl radicals in terms of configurationally stable o-radicals are incorrect. The preferences for formation of axial C-glycosides by attack of radicals on olefins (Adlington et al., 1983; Albrecht and Scheffold. 1985;
q
8 ,o,-:c,,, 0 (J ...._._ . .... .... ... . ~
OR
P
........ .. .. ...... .........:
? .+,
--
:::...,,, :.....;;:. .....:. ..
OR
, o d kI c , +*
\
Scheme 23
Orbital interactions considered by Koth ef 01. (1986a) to be responsible for the predilection of glycopyranosyl radicals to adopt conformations with the substituent at C(2) axial or isoclinal
196
MICHAEL L SINNOTT
Baumberger and Vasella, 1983),. for axial deuteration by tri-n-butyltin deuteride (Praly, 1983; Giese and Dupuis, 1984), and for axial reductive lithiation of sulphones (Beau and Sinay, 1985) must have their origin in other phenomena. When the glycopyranosyl radical adopts a B2,s conformation then the preference for axial coupling products is readily understood on the basis of well-known steric interactions. Approach of a reagent from the p-face is significantly sterical4y hindered, particularly by the substituent at C(3), whereas attack from the a-face is less so. If ease of approach to position-2 of the norbornyl system [ 1451 is taken as a model for ease of approach to C( 1) of a pyranose ring in the B2,s conformation, then the favoured approach to the carbohydrate corresponds to the favoured exo-approach to the norbornyl system. If the glycopyranosyl radical adopts the 4H, conformation, then axial reaction is favoured by the least motion effects set out in Scheme 13. Although carbon radicals with one oxygen substituent are nearly planar, when there is more than one oxygen substituent the importance of radicalcentre hybridisation increases, and the effect of inefficient x-bonding, now that there is more than one donor, decreases, so that the radicals become increasingly bent. A measure of the degree of pyramidalisation of a radical is the coupling constant between the electron spin and a '3C-nucleus at the radical centre: the size of the coupling depends upon the spin density at the nucleus and hence on the degree of s character in the half-occupied orbital. Values are in the range 45-65 G for monooxygenated radicals, 95-1 10 G for dioxygenated radicals and 153 G for (CH,O),C. (Brunton et al., 1977). Thus, whereas small least motion effects may be seen in reactions of the (presumably flattened) dioxygenated radicals, they will not be seen in reactions of trioxygenated radicals, since the atomic motions in the radical as it forms a fourth covalent bond are small. Although there has been a series of reports of small stereoelectronic effects in hydrogen atom abstractions of acetals and orthoester, the data, taken as a whole, lack internal consistency. For example, hydrogen-atom abstraction by benzophenone triplet in benzene at ambient temperature is eight times faster from trans-[146] than from cis-[l46] (Hayday and McKelvey, 1976), as measured from rates of disappearance of product, whereas the factor favouring removar of the axial hydrogen by (CH,),CO. in cyclopropane in the closely related epimers [ 1471 was only 4 at -60°C (corresponding to 2.7 at ambient temperature), as measured by e.s.r. integration (Malatesta and Ingold, 198I).
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
197
McKelvey and Iwamura (1985) found a 16-fold factor favouring axial hydrogen abstraction by benzophenone triplet from the epimeric orthoesters [34] at ambient temperature, whereas Beckwith and Easton (1981) found that the factor favouring axial abstraction by (CH,),CO* was between 9 and 1 1. Interestingly, these authors measured relative reactivities per hydrogen atom both by a direct analysis of unreacted starting material, as did McKelvey et al., and by the e.s.r.-integration method of Malatesta and Ingold (1981): the relative reactivities per hydrogen atom obtained by the two methods differed by up to a factor of 2. In the case of the epimeric pairs [146], [147], and [34], the experiments are open to the objection that the thermodynamically most stable epimer is the slowest to react, as would be expected anyway. This is not the case with epimeric pair [ 1481, where abstraction of axial hydrogen by (CH,),CO- is still preferred despite the epimer with the axial methyl group being the less stable (Beckwith and Easton, 1981). However, since the electron-”C coupling constants indicate that dialkoxy radicals are not completely tetrahedral, it follows that there will be some least motion effects favouring axial hydrogen abstraction, as there will with the epimeric pairs [ 1461 and [147]. Further stereoelectronic effects on hydrogen abstraction reactions have been claimed by Malatesta and Ingold (1981) on the basis of their failure to observe the e.s.r. signal for the appropriate radical. Their necessary assumption, however, that rates of decomposition of product radical are the same as those of the reference radical is merely a pious hope. REACTIONS OF GAS-PHASE RADICAL CATIONS
It has been the theme of this article that apparent kinetic antiperiplanar lone pair effects in solution are in reality the energetic consequences of intermediates having different geometries from starting materials: for these isothermal reactions, the more geometrical rearrangement there has to be, the higher the energetic cost. If, however, one starts from a highly energetic species, then it may be possible to generate by adiabatic processes intermediates in unfavourable conformations, and then observe the release of the potential energy stored in the geometrical distortion. This seems to have been done by TureEek and HanuS (1983) who studied the loss of bridgehead hydrogen atoms from the molecular ions derived from [ 1491, [1501, [ 15 11 and [ 1521 by electron impact. Loss of the hydrogen atom from [I491 and [I 511, to generate oxocarbonium ions [I 531 and [ 1541, respectively, occurred at much lower critical energy than from [I501 and [152]. Although TureEek and HanuS themselves interpreted their results in terms of ALPH, if it i”s assumed that the molecular ions of compounds [149]-[ 1521 have closely similar geometries to the parent ethers, it is clear that reorganisation involved in conversion of the cis molecular ions to [I531 and [154] is greater than involved in
198
MICHAEL L SINNOTT
conversion of the trans molecular ions to the same intermediates. However, kinetic energy release on loss of hydrogen from the molecular ions derived from the cis-isomers was greater than that derived from the trans-isomers, and TureEek and HanuS themselves suggested on this basis that ions [ 1531 and [ 1541 were formed from the cis molecular ions in non-relaxed conformations.
9
Envoi
Although the picture of an antiperiplanar lone pair of electrons driving off a leaving group had occurred intermittently in the literature at least as early as 1963 (Littler, 1963), it is largely the initial work of Deslongchamps’ group which presented a systematic body of work which demanded explanation. It is the message of this article that ALPH, the explanation supported by Deslongchamps, Kirby and others is too fundamental: it requires no exceptions, and there are plenty, whereas the explanation provided by the principle of least nuclear motion also accommodates the exceptions. Perhaps the best evidence that ALPH is too fundamental is the confusion that results when ALPH is taken as an axiom. Such confusion can be illustrated by the multiplicity of otherwise unsubstantiated conformational changes required during the action of various enzymes, the successful rationalisation of inadequate or incorrect data, and, worst of all, the calling into question of perfectly sound data (e.g. those of Kluger et al., 1969) which happen not to fit an extension of the theory. Acknowledgements
Experimental work in the author’s laboratory was supported by the United Kingdom Science and Engineering Research Council.
LEAST NUCLEAR MOTION AND STEREOELECTRONIC CONTROL
199
References
Adlington, R. M., Baldwin, J. E., Basak, A. and Kozyrod. R. P. (1983). J . Chem. Soc., Chem. Commun. 944 Albery, W. J. and Knowles, J. R. (1976). Biochemistry 15, 5631 Albrecht, S. and Scheffold, R. (1985). Chimiu 39, 21 1 Alder, R. W., BoniFaEii., M. and Asmus, K-D. (1986). J . Chem. Soc. Perkin Truns. 2, 277 Allen, F. H. and Kirby, A. J. (1984). J . A m . Chcm. Soc. 106. 6197 Allinger, N. L. (1977). J . Am. Chem. Soc. 99, 8127 Altmann, J. A., Tee, 0. S. and Yates, K. (1976). J . Am. Chem. Soc. 98. 7132 Alva-Astudillo, M. E., Chokotho, N. C. J., Jarvis, T. C., Johnson, C. D., Lewis, C. C. and McDonnell, P. D. (1985). Tetrahedron 41, 5919 Anderson, F., Griitter, M. G., Remington, S. J., Weaver, L. H. and Matthews, B. W. (198 I). J. Mol. Bid. 147, 523 Angelides, K. J. and Fink, A. L. (1979a). Biochemistry 18, 2355 Angelides. K. J. and Fink, A. L. (l979b). Biochemistry 18, 2363 Angyal, S. J. (1969). Angew. Chcm., Int. Ed. Engl. 8, 157 Asboth, B. and Polgar, L. (1983). Biochemistry 22. 117 Banyard, S. H. and Dunitz, J. D. (1976). Actu Crystullogr. ( B ) , 32, 318 Baumberger, F. and Vasella, A. (1983). Helv. Chim. Acta 66, 2210 Beau, J.-M. and Sinay, P. (1985). Tetrahedron Lett. 26, 6185 Beaulieu, N. and Deslongchamps, P. (1980). Can. J . Chem. 58, 875 Beaulieu, N., Dickinson, R. A. and Deslongchamps, P. (1980). Cun. J . Chem. 58, 253 1 Beckwith, A. L. J. and Easton, C. J. (1981). J . Am. Chem. Soc. 103, 615 Benner. S. A., Nambiar, K. P. and Chambers. G. K. (1985). J . Am. Chem. Soc. 107, 5513 Bennet. A. J. and Sinnott, M. L. (1986). J . Am. Chem. Soc. 108, 7287 Bcnnet, A. J., Sinnott, M. L. and Wijesundera, S. (1985). J . Chem. Soc. Perkin Trans. 2, 1233 Bcrgson, G., Matsson, 0. and Sjoberg, S. (1977). Chem. Scr. 11. 25 Bernardi, F., Schlcgel, H. B. and Wolfe, S. (1976). J . Mol. Struct. 35. 149 Bernhard, W. A., Homing, T. L. and Mercer, K . R. (1984). J . Phys. Chem. 88, 1317 Bizzozero, S. A. and Dutler, H . (1981). Bioorg. Chem. 10, 46 Bizzozero, S. A. and Zweifel, B. 0. (1975). FEBS Lett. 59, 105 Blake, C. C. F., Mair, G. A., North, A. C. T., Phillips, D. C. and Sarma, V. R. (1967). Proc. R. Soc. London, Ser. B, 167, 365 Born, M. and Oppenheimer, J. R. (1927). Ann. Phys. (Leipzig) 84, 457 Boudreau, J. A., Brown, C. and Hudson, R. F. (1975). J. Chem. SOC.,Chem. Commun. 679 Bourne, N. and Williams. A. (1983). . , J. Am. Chem. SOC.105, 3357 Braun, H., Legler, G., Deshusses, J. and Semenza, G. (1977). Biochim. Biophys. Acta 483. 135 Briggs, A. J., Evans, C. M . , Glenn, R. and Kirby. A. J. (1983). J . Chem. Soc. Perkin Truns 2, 1637 Briggs, A. J., Glenn, R., Jones, P. G., Kirby, A. J. and Ramaswamy, P. (1984). J . Am. Chem. Soc. 106, 6200 Brocklehurst. K . and Malthouse, J. P. G. (1978). Biochem. J . 175, 761 Broxton, T. J. (1978). Aust. J . Chem. 31, 1519 Broxton, T. J. (1979). Aust. J . Chem. 32, 1031
200
MICHAEL L. SINNOTT
Brunton, G., Ingold, K. U., Roberts. B. P., Beckwith, A. L. J. and Krusic, P. J. (1977). J . Am. Chem. Soc. 99. 3177 Burgi, H.-B., Dunitz, J. D. and Shefter, E. (1973). J . Am. Chem. Soc. 95, 5065 Buncel, E. and Menon, B. (1977). J . Organomet. Chem. 141, I Bunton. C. A,, Nayak, B. and O’Connor, C. (1968). J . Org. Chem. 33, 572 Burton, J. and Sinnott, M. L. (1983). J . Chem. Soc. Perkin Trans. 2, 359 Capon, B. and Grieve, D. McL. A. ( 1 982). Tetrahedron Lett. 23, 4823 Capon, B., Ghosh, A. K. and Grieve, D. McL. A. (1981). Act.. Chem. Res. 14, 306 Cascrio, M. C., Sooma, Y. and Kim, J. K. (1981). J. Am. Chenz. Soc. 103, 6712 Caswell, M. and Schmir, G . L. (1979). J . Am. Chem. Sot.. 101, 7323 Chandrasekhar, S. and Kirby, A. J. (1978). J . Chem. Soc., Chem. Commun. 171 Chandrasekhar, S., Kirby, A. J. and Martin, R. J. (1983). J . Chem. Soc., Perkin Trans. 2, 1619 Chin, J. (1983). J . Am. Chem. Soc. 105, 6502 Christianson, D. W. and Lipscomb, W. N. (1986). J . A m . Chem. Soc. 108, 4998 Christianson, D. W., Kuo, L. C. and Lipscomb, W. N. (1985). J . Am. Chem. Soc. 107, 8281 Cordes, E. H. and Bull, H. G . (1974). Chem. Rev. 74, 581 Cosse-Barbi, A. and Dubois, J.-E. (1987). J . Am. Chem. Soc. 109, 1503 Cremer, D., Gauss, J., Childs, R. F. and Blackburn, C. (1985). J . Am. Chem. Soc. 107, 2435 David, S. (1979). In “Anomeric Effect-Origin and Consequences” W. A. Szarek and D. Horton (eds), American Chemical Society, Washington D.C. p. 1 David, S., Eisenstein, O., Hehre, W. J., Salem, L. and Hoffmann, R. (1973). J . Am. Chem. Soc. 95, 3806 Deslongchamps, P. (1983). “Stereoelectronic Effects in Organic Chemistry”. Pergamon, Oxford Deslongchamps, P. and Guay, D. (1985). Can. J . Chem. 63, 2757 Deslongchamps, P. and Moreau, C. (1971). Can. J . Chrm. 49, 2465 Deslongchamps, P., Moreau, C., Frehel, D. and Atlani, P. (1972a). Can. J . Chem. 50, 3402 Deslongchamps, P., Atlani, P., Frehel, D. and Malaval, A. (1972b). Can. J. Chem. 50, 3405 Deslongchamps, P., Atlani, P., Frehel, D., Malaval, A. and Moreau, C. (1974). Can. J . Chem. 52, 3651 Deslongchamps, P., Chsnevert, R., Taillefer, R. J., Moreau, C. and Saunders. J. K. (1 975a). Can. J. Chem. 53, 160 1 Deslongchamps, P., Dube, S., Lebreux, C., Patterson, D. R. and Taillefer, R. J. (1975b). Can. J . Chem. 53, 2791 Deslongchamps, P., Cheriyan, U. O., Guida, A. and Taillefer, R. J. (1977). N o w . J. Chim. 1, 235 Deslongchamps, P., Gerval, P., Cheriyan, U. O., Guida, A. and Taillefer, R. J. (1978). N o w . J. Chim. 2, 631 Deslongchamps, P., Guay, D. and Chhevert, R. (1985a). Can. J . Chem. 63, 2493 Deslongchamps, P., Lessard, J. and Nadeau, Y. (1985b). Can. J. Chem. 63, 2485 Desvard, 0. E. and Kirby, A. J. (1982). Tetrahedron Lett. 23, 4163 Dupuis, J., Giese, B., Riiegge, D., Fischer, H., Korth, H-G. and Sustmann, R. (1984). Angew Chem., Int. Ed. Engl. 23, 896 Dunitz, J. D. and Seiler, P. (1983). J . Am. Chem. Soc. 105, 7056 Edward. J. T. (1955). Chem. Ind. (London), 1102
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
201
Ehrenson, S. ( 1 974a). J. Am. Chem. Soc. 96, 3778 Ehrenson, S. (1974b). J . Am. Chem. Soc. 96, 3784 Ehrenson, S. (1976). J . Am. Chem. Soc. 98, 6081 Elrod, J. P., Hogg, J. L., Quinn, D. M., Venkatasubban, K . S. and Schowen, R. L. (1980). J . Am. Chem. Soc. 102, 3917 Fanni, T., Taira, K., Gorenstein, D. G., Vaidyanathaswamy, R. and Verkade, J. G. (1986). J . Am. Chem. Soc. 108, 631 1 Fgrcasiu, D., ODonnell, J. J., Wiberg, K . B. and Matturro, M . (1979). J . Chem. Soc., Chem. Commun. I124 Fersht, A. R. (1985). “Enzyme Structure and Mechanism”, 2nd edition, W. H. Freeman, New York Fife, T. H. and Jao, L. K. (1965). J . Org. Chem. 30, 1492 Finch, P. and Nagpurkar, A. G . (1976). Carbohydr. Res. 49, 275 Fleet, G. W. J. (1985). Tetrahedron Lett. 26, 5073 Franck, R. W. (1983). Tetrahedron 39, 3251 Fuchs, B., Schleifer, L. and Tartakovsky, E. (1984). Nouv. J . Chim. 8 , 275 Gensmantel, A. and Page, M. I. (1978). J . Chem. SOC.,Chem. Commun. 374 Gerlt, J. A,, Westheimer, F. H. and Sturtevant, J. M. (1975). J . Biol.Chem. 250, 5059 Giese, B. and Dupuis, J. (1984). Tetrahedron Lett. 25, 1349 Gorenstein, D . G., Findlay, J. B., Luxon, B. A. and Kar, D. (1977a). J . Am. Chem. SOC. 99, 3473 Gorenstein. D. G., Luxon, B. A,, Findlay, J. B. and Momii, R. (1977b). J . A m . Chem. Soc. 99, 4I70 Gravitz, N . and Jencks, W. P. (1974). J . Am. Chem. Soc. 96, 499 Grela, M. A. and Colussi, A. J. (1984). J . Phys. Chem. 88, 5995 Griller, D., Howard, J. A,, Marriott, P. R. and Scaiano, J. C. (1981). J. Am. Chem. Soc. 103, 619 Hayday, K. and McKelvoy, R. D. (1976). J . Org. Chem. 41, 2222 Haynes, L. J. and Newth, F. H. (1955). Adv. Curbohydr. Chem. 10, 207 Hegarty, A. F. (1980). Acc. Chem. Res. 13, 448 Hegarty, A. F. and Mullane, M. (1986). .I. Chem. Soc., Perkin Trans. 2, 995 Hine, J. (1966a). J . Org. Chem. 31, 1236 Hine, J. (196613). J . Am. Chem. Soc. 88, 5525 Hine, J. (1977). Adv. Phys. Org. Chem. 15, 1 Hoffman, S. J., Chu, S. S-T., Lee, H., Kaiser, E. T. and Carey, P. R. (1983). J . Am. Chem. Soc. 105, 6971 Hosie, L. and Sinnott, M. L. (1985). Biochem. J . 226, 437 Hosie, L., Marshall, P. J. and Sinnott, M. L. (1984). J . Chem. Soc., Perkin Trans. 2, 1121 Inagaki, S., Iwase, K. and Mori, Y. (1986). Chem. Lett. 417 James, M. N. G. (1969). Proc. Can. Fed. Bid. Sci. 13, 71 James, M. N. G . and Sielecki, A. R. (1985). Biochemistry 24, 3701 Jeffrey, G. A,, Pople, J. A. and Radom, L. (1972). Carbohydr. Res. 25, 1 17 Jeffrey, G . A., Pople, J. A., Blinkley, J. S. and Vishveshwara, S. (1978). J . Am. Chem. Soc. loo, 373 Jencks, W. P. (1972). Chem. Rev. 72. 705 Johnson, J. E. and Cornell, S. C . (1980). J . Org. Chem. 45, 4144 Johnson, J. E., Nalley, E. A., Weidig, C. and Arfan, M. (1981). J . Org. Chem. 46, 3623 Jones, P. G. and Kirby, A. J. (1984). J . Am. Chem. Soc. 106, 6207
202
MICHAEL L SINNOTT
Jones, P. G . and Kirby, A. J. (1986). J . Chem. SOC.,Chem. Commun. 444 Juaristi, E., Valenzuela, B. A., Valle, L. and McPhail, A. T. (1984). J . Org. Chem. 49, 3026 Juaristi, E., Tapia, J. and Mendez. R. (1986a). Tetrahedron 42, 1253 Juaristi, E., Valle. L.. Valenzuela, B. A. and Aguilar, M. A. (1986b). J . Am. Chem. SOC. 108, 2000 Kaba, R. A., Griller, D. and Ingold, K. U. (1974). J . Am. Chem. SOC.96, 6202 Kaloustian, M. K. and Khouri, F. (1980). J. Am. Chem. SOC.102, 7579 Kirby. A. J. (1983). “The Anomeric Effect and Related Stereoelectronic Effects at Oxygen”, Springer-Verlag, Berlin Kirby, A. J. (1984). Ace. Chem. Res. 17. 305 Kirby, A. J. and Martin, R. J. (1983a). J . Chem. Soc. Perkin Trans. 2, 1627 Kirby. A. J. and Martin, R. J. (1983b). J . Chem. SOC.Perkin Trans. 2, 1633 Kluger, R. and Thatcher, G . R. J. (1985). J . Am. Chem. Soc. 107, 6006 Kluger, R. and Thatcher, G . R. J. (1986). J . Org. Chem. 51, 207 Kluger, R., Covitz, F., Dennis, E., Williams, L. D. and Westheimer, F. H. (1969). J . Am. Cheni. Sor. 91, 6066 Korth, H-G., Sustmann, R., Dupuis, J. and Giese, B. (1986a). J . Chem. Soc., Perkin Truns. 2. 1453 Korth. H-G., Sustmann, R., Groninger, K-S., Witzel, T. and Giese, B. (1986b). J . Chcvn. Soc., Perkin Truns. 2, 1461 Koshland, D. E. (1953). Bid. Rev. 28, 416 Kost, D., Schlegel, H. B., Mitchell, D. J. and Wolfe, S. (1979). Can. J . Chem. 57, 729 KovaE, F. and Plesniear, B. (1979). J . Am. Chem. Soc. 101, 2677 Kresge, A. J. and Weeks, D. P. (1984). J. Am. Chem. Soc. 106, 7140 Kuo, L. C. and Makinen, M. W. (1985). J . Am. Chem. Soc. 107, 5255 Lalegerie. P., Legler, G. and Yon, J. M. (1982). Biochimie 64, 977 Lambert, J. B. and Majchrzak, M. M. (1980). J . Am. Chem. SOC.102, 3588 Legler, G. (1973). Mol. Cell. Biochem. 2, 31 Lehn, J-M. (1970). Top. Curr. Chem. 15, 31 I Lehn. J-M. and Wipff, G . (1978). Helv. Chim. Actu 61, 1274 Lehn, J-M. and Wipff, G. (1980). J . Am. Chem. Soc. 102, 1347 Lehn. J-M., Wipff, G. and Burgi, H-B. (1974). H e h . Chim. Actu 57, 493 Lemieux, R. U. (1964). In “Molecular Rearrangements”, P. De Mayo (ed.), p. 740, Interscience, New York Lemieux, R. U. (1971). Pure Appl. Chem. 25, 527 Lemieux. R . U . and Morgan, A. R. (1965a). Can. J . Chem. 43. 2205 Lemieux, R . U . and Morgan, A. R. (1965b). Can. J . Chem. 43, 2214 Leroy, G., Nguyen, M. T., Sana, M., Dignam, K. J. and Hegarty, A. F. (1979). J . Am. Chmi. Soc. 101, 1988 Lipscomb, W. N. (1983). Annu. Rev. Biochem. 52, 17 Littler, J. S. (1963). Trans. Faraduy Soc. 59, 2296 Lyapova, M. J., Pojarlieff, I. G. and Kurtev, B. J. (1981). J . Chem. Res. S 351, M 4083 Lyons, A. R. and Symons, M. C. R. (1972). J. Chem. Soc., Faraday Trans. 2,68,502 McClelland, R. A. and Alibhai, M. (1981). Can. J . Chem. 59, 1169 McClelland, R. A. and Lam, P. W. K. (1984a). Can. J . Chem. 62, 1068 McClelland, R. A . and Lam, P. W. K. (1984b). Can. J . Chem. 62, 1074 McKelvey, R. D. and Iwamura, H. (1985). J . Org. Chem. 50, 402 Mackenzie. N. E., Malthouse. J. P. G. and Scott, A. I. (1985). Biochem. J . 226, 601
LEAST NUCLEAR MOTION A N D STEREOELECTRONIC CONTROL
203
Makinen, M. W., Kuo, L. C., Dymowski, J. J. and Jaffer. S. (1979). J . Biol. Chem. 254, 356 Malatesta, V. and Ingold, K. U. (1981). J . Am. Chem. Soc. 103, 609 Mario Pinto, B. and Wolfe, S. (1982). Tetrahedron Lett. 23, 3687 Mario Pinto, B., Sandoval-Ramirez, J. and Sharma, R. D. (1985). Tetrahedron Lett. 26. 5335 Martin. A. F.. Morris, J. J. and Page, M. I . (1979).J . Chem. Soc., Chem. Commun. 298 Matsuura, Y., Kusunoki, M. Harada, W. and Kakudo, M. (1984). J . Biochem. (Tokyo) 95, 697 Muller, J-A. (1886). Bull Soc. Chim. France 45, 438 Muller, J-A. and Peytral, E. ( 1 924). C. R . Hebd. Sbances Acad. Sci. 179, 83 1 Murray, M., Schmutzler, R., Grundemann, E. and Teichmann, H. (1971). J . Chem. Soc. B, 1714 Nambiar, K. P., Stauffer, D. M., Kolodziej. P. A. and Benner, S. A. (1983). J. Am. Chem. Soc. 105, 5886 Nelson, C. R. (1979). Carbohydr. Res. 68, 55 O’Connor, J. V. and Barker, R. (1979). Carbohydr. Res. 73, 227 Oppenheimer, N. J. (1984). J . Am. Chem. Soc. 106, 3032 Oppenheimer, N. J. (1986). J . Biol. Chem. 261, 12209 Page, M. I. (1984). Acc. Chem. Res. 17, 144 Page, M. I. (1987). Adv. Phys. Org. Chem. 23, 165 Page, M. I., Webster, P., Bogdon, S., Tremerie, B. and Ghosez, L. (1987). J. Chem. Soc. Chem. Commun. 318 Paulsen, H., Leopold, F. and Todt, K. (1966). Justus Liebigs Ann. Chem. 692, 200 Paulsen, H., Gyorgydeak, Z. and Friedmann, M . (1974). Chem. Ber. 107, 1590 Perrin, C. L. and Arrhenius, G . M. L. (1982). J . Am. Chem. Soc. 104, 2839 Perrin, C. L. and Nutiez, 0. (1986). J . Am. Chem. Soc. 108, 5997 Philip, T., Cook, R. L., Malloy, T. B., Allinger, N. L., Chang, S. and Yuh, Y. (1981). J . Am. Chem. Soc. 103, 2151 Polgar, L. and Halasz, P. (1982). Biochem. J . 207, 1 Post, C. B. and Karplus, M. (1986). J . Am. Chem. Soc. 108, 1317 Praly, J-P. (1983). Tetrahedron Lett. 24, 3075 Ramirez, F. and Ugi, I. (1971). Adv. Phys. Org. Chem. 9, 25 Rice, F. 0. and Teller, E. (1938). J . Chem. Phys. 6 , 489 Rice, F. 0. and Teller, E. ( 1 939). J . Chem. Phys. 7, 199 Rich, D. H. (1985). J. Med. Chem. 28, 263 Ritchie, C. D. (1972). Acc. Chem. Res. 5, 348 Ritchie, C. D., VanVerth, J. E. and Virtanen, P. 0. I. (1982). J . Am. Chem. Soc. 104, 349 1 Roeser, K-R. and Legler, G. (i981). Biochim. Biophys. Acta 657, 321 Romers, C., Altona, C., Buys, H. R. and Havinga, E. (1969). Top. Stereochem. 4, 73 Samudzi, C. T., Ruble, J. R. and Jeffrey, G. A. (1985). Carbohydr. Res. 142, 39 Saul, R., Chambers, J. P., Molyneux, R. J. and Elbein, A. D. (1983). Arch. Biochem. Biophys. 221, 593 Schleyer, P. von R., Jemmis, E. D. and Spitznagel, G. W. (1985). J . Am. Chem. Soc. 107, 6393 Schneider-Bernlohr, H., Adolph, H-W. and Zeppezauer, M. (1986). J. Am. Chem. Soc. 108, 5573 Schweizer, W. B., Procter, G., Kraftory, M. and Dunitz, J. D. (1978). Helv. Chim. Acta 61. 2783
204
MICHAEL L SINNOTT
Seeman, J. I. (1983). Chem. Rev. 83, 83 Seiler, P. and Dunitz, J. D. (1986). Helv. Chim. Acta 69, 1107 Siehl, H-U. and Walter, H. (1984). J . Am. Chem. SOC.106, 5355 Sinnott, M. L. (1987). In “Enzyme Mechanisms”, M. I. Page and A. Williams (eds), p. 259, Royal Society of Chemistry, London Sinnott, M. L. and Souchard, I . J. L. (1973). Biochem. J . 133, 89 Sinnott, M. L., Withers, S. G. and Viratelle, 0. M. (1978). Biochem. J . 175, 539 Skoog, M. T. and Jencks, W. P. (1984). J . Am. Chem. SOC.106. 7597 Stackhouse, J., Nambiar, K. P., Burbaum, J. J., Stauffer, D. M. and Benner, S. A. (1985). J . Am. Chem. Soc. 107, 2757 Stevens, R. V. (1984). Ace. Chem. Res. 17, 289 Szawelski, R. J. and Wharton, C. W. (1981). Biochem. J . 199, 681 Taillefer, R. J., Thomas, S. E., Nadeau, Y., Fliszar. S., and Henry, H. (1980). Can. J . Chem. 58, 1138 Taira, K. and Gorenstein, D. G . (1984). J . Am. Chem. SOC.106. 7825 Taira, K., Fanni, T. and Gorenstein, D. G. (1984a). J . Org. Chem. 49, 4531 Taira, K., Mock, W. L. and Gorenstein, D. G. (1984b). J . Am. Chem. Soc. 106, 7831 Taira, K., Lai, K . and Gorenstein, D. G. (1986). Tetrahedron 42, 229 Tee, 0. S. (1969). J . Am. Chem. Soc. 91, 7144 Tee, 0. S. and Yates, K . (1972). J. Am. Chem. Soc. 94, 3074 Tee, 0. S., Altmann, J. A. and Yates, K. (1974). J . Am. Chem. Soc. 96, 3141 Troughton, E. B., Molter, K. E. and Arnett, E. M. (1984). J . Am. Chem. SOC.106, 6726 TureEek, F. and HanuS, V. (1983). Tetrahedron 39, 1499 TvaroSka, I. and Bleha, T. (1975a). J . Mol. Struct. 24, 249 TvaroSka, I . and Bleha, T. (1975b). Tetrahedron Lett. 36, 249 TvaroSka, I. and Koiar, T. (1980). J . Am. Chem. SOC.102, 6929 Van Doorslaer, O., Van Opstal, O., Kersters-Hilderson, H. and De Bruyne, C. K. (1984). Bioorg. Chem. 12, 158 van Eikeren, P. (1980). J . Org. Chem. 45, 4641 Vinter, J. G. (1985). Chem. Br. 21, 32 Walaszek, Z., Horton, D. and Ekiel, I. (1982). Carbohydr. Res. 106, 193 Watt, C. I . F. (1988). Adv. Phys. Org. Chem. 24, 57 Westheimer, F. H. (1968). Arc. Chem. Res. 1. 70 Westheimer, F. H. (1981). Chem. Rev. 81,313 Westheimer, F. H. (1985). Adv. Phys. Org. Chem. 21, 1 Williams, I. H. (1985). J . Chem. SOC.,Chem. Commun. 510 Wolfe, S., Rauk, A,, Tel, L. M. and Csizmadia, I. G. (1971). J . Chem. Soc. B, 136 Wolfe, S., Schlegel, H. B., Whangbo, M-H. and Bernardi, F. (1974). Can. J . Chem. 52, 3787 Wolfe, S., Whangbo, M-H. and Mitchell, D. J. (1979). Carbohydr. Res. 69, 1 Yang. J.-C. and Gorenstein, D. G. (1984). Tetrahedron Lett. 25, 4627 You, K . (1984). CRC Crit. Rev. Biochem. 17, 313
Author Index Numbers in italic refer to the pages on which references are listed at the end of euch article
Abbe, J. C., 87, 110 Abdallah, A. A,, 94, 95, 105, 110 Abeles, R. H., 95, 105 Abeywickrama, A. N., 70, 105 Adams, C., 72, 105 Adams, N. G., I , 2 , 6, 50, 55 Adlington, R. M., 195, 199 Adolph, H.-W., 136, 203 Aguilar, M . A,, 152, 202 Ahlberg, P., 86, 105 Ahrens, A. F., 8, 53 Ajami, M., 2, 54 Albery, W. J., 136, 199 Albrecht, S., 195, 199 Alder, R. W., 61, 105, 161, 199 Alibhai, M., 118, 202 Allen, F. H., 149, 150, 199 Allinger, J., 78, 106 Allinger, N. L., 126, 144, 199, 203 Alpha, S . R., 81, 111 Altmann, J. A,, 159, 160, 199, 204 Altona, C., 116, 147, 148, 152, 203 Aha-Astudillo, M. E., 121, I 9 9 Anderson, D. R., 2 I , 22, 50 Anderson, F., 141, 159 Andrade, J., 41, 51 Andres, J., 64, 68, 112 Andrist, A. H., 46, 51 Angelides, A. J., 176, 199 Angyal, S. J., 123, 199 Anhede, B., 62, I05 Arad, D., 14, 55 Arduengo, A. J., 64, I07 Arfan, M . , 182, 201 Argyropoulos, J. N., 84, 105 Arnett, E. M., 160, 204 Arrhenius, G. M . L., 118, 132, 165, 203 Asboth, B., 173, 176, 199 Ashby, E. C., 70, 84, 85, 105 Asmus, K.-D., 161, 199
Asubiojo, 0. I., 15, 51 Atkins, P. J., 86. 105 Atkins, T. J., 92, 105 Atlani, P., 114, 161. 162. 192, 200 Atwood, J. L., 87, 10.5 Aue, D. H., 50, 51 Aullo, J . M., 64, 68, 112 Awano, H., 101, 10.5 Bachrach, S. M., 74, I05 Bader, R. F. W., 61, 111 Baldeschweiler, J. D., 2, 51 Baldwin, J. E., 195. 199 Bannerji, S., 84, I10 Banyard, S. H . , 164. 199 Baranin, S. V., 67, I07 Barker, R., 119. 203 Barkley, R. M., 22. 53, 55 Bartlett, P. D., 91. 105 Bartniess, J. E.. 7, 13, 22. 38, 48, 50, 51, 65, 107 Basak, A., 195, 199 Bastiaansen, L. A. M., 104, 107 Baumberger, F., 195, 199 Baykut, G., 2, 51 Beak, P., 38, 40, 51, 55 Beau, J.-M., 195, 199 Beauchamp, J. L., 2, 21, 36, 51, 53 Beaulieu, N.. 129, 164, 199 Beckwith, A. L. J., 70, 105, 196, 197, 199, 200 Beedle, E. C., 22. 52 Beloeil, J. C., 80, 105 Benner, S. A., 135, 136, 137, 138, 199, 202, 204 Bennet, A. J., 124, 12,5, 150, 199 Berberova, N. T., 60, 110 Bergmann, N.-A.. 62, 105 Bergsma, J. P., 96, 106 205
206
Bergson, G.. 124, 199 Bernardi, F., 192, 199, 204 Bernhard, W. A,, 194, 199 Berry, R. E., 96, 106 Bertranne, M., 80, 105 Bethell, D., 83, 93, 105 Betowski, L. D., 8, 54 Bierbaum, V. M., I , 2, 12, 13, 16, 18, 20, 21, 22, 23, 24, 36, 44, 45, 46, 50, 51, 52, 53, 55, 75, 86, 105, 107 Binder, D. A,, 92, 108 Bizzozero, S. A., 171, 172, 199 Blackburn, C., 127, 200 Blake, C. C. F., 141, 199 Blanc, J., 71, I10 Bleha, T., 146, 204 Blinkley, J. S., 148, 201 Bogdanovic, B., 67, 105 Bogdon, S., 133, 203 Bohme, D. K., 7, 8, 51, 54, 65, 105 Bolton, J. L., 99, 106 Bonaccorsi, R., 73, 74, 105 BonifaEiC, M., 161, 199 Boone, J. R., 70, 105 Born, M . , 155, 199 Bornais, J., 88, 106 Bosma, P., 104, 111 Boudreau, J. A., 188, 189, 199 Bourne, N., 184, 199 Bowen, K . H., 37, 51 Bowers, M. T., 8, 24, 50, 51, 55 Bowie, J. H., 2, 15, 16, 18, 19, 20, 21, 28, 36, 43, 51, 52, 53, 55, 65, 75, 1 I 1 Boyer, B., 71, 72, I05 Braenden, C. I., 64, 68, 112 Brauman, J. I., 6, 8, 10, 15, 50, 51, 52, 53, 54, 55 Brewer, J. C., 98, 106 Briggs, A. J., 124, 127, 146, 150, 153, 199 Briscese, S. M. J., 28, 51 Brocklehurst, K., 176, 199 Brounts, R. H . A. M., 104, 105 Brouwer, D. M., 86, 105, 106 Brower, K . R., 71, 81, 106 Brown, C., 188, 189, 199 Brown, H. C . , 66, 70, 106, I12 Brown, R. S., 2, 54 Brownstein, S., 88, 106 Broxton, T. J., 183, 199
AUTHOR INDEX
Bruice, T. C., 86, 95, 97, 99, 106, 110, 111,112
Bruins, A. P., 28, 48, 51 Brunton, G., 196, 200 Bubnov, Yu. N., 67. 106 Buck, H. M., 62, 104, 105, 107, 112 Budzikiewicz, H., 2, 51 Bull, H. G., 114, 158, 200 Buncel, E., 63, 106, 153, 200 Buning, G. H. W., 101, 112 Bunting, J. W., 98, 99, 100, 106 Bunton, C. A,, 167, 200 Burbaum, J. J., 137, 204 Burchill, M. T., 85, 110 Biirgi, H.-B., 65, 106, 152. 155, 186, 200, 202 Burke, M. C., 85, 109 Burnett, R. D., 77, 106 Burton, J., 142, 200 Buys, H . R., 116, 147, 148, 152, 203 Bychkov, N. N., 91, 108 Caldwell, G., 8, 10, 38, 51 Capon, B., 118, 162, 200 Caramella, P., 64, 68, 111 Cardy, H., 37, 51 Carey, P. R., 178, 201 Carlson, B. W., 97, 106 Caserio, M. C., 130, 161, 200 Casiraghi, G., 77, 106 Casnati, G., 77, 106 Caswell, M., 169, 200 Caubere, P., 62, 106 Cernik. R., 80, 106 Chambers, G. K., 135, 199 Chambers, J. P., 144, 145, 203 Chandrasekhar, J., 40, 41, 51, 55 Chandrasekhar, S., 119, 130, 200 Chandrasekharan, J., 66,.70, 106 Chang, S., 144, 203 Chatfield, D. A,, 2, 54 Chen, T., 70, I12 Chsnevert, R., 116, 118, 162, 200 Cheriyan, U. O., 167, 168, 200 Chew, V. F. S., 99, 106 Childs, R. F., 127, 200 Chin, J., 137, 200 Chipman, D. M., 95, 106, I 1 1 Chokotho, N. C. J., 121, 199
AUTHOR INDEX
Chowdhury, A. K.. 47, 54 Christianson, D. W., 179, 200 Christoffersen, R. E., 61, 106 Chu, G., 99, 106 Chu, S. S.-T., 178, 201 Chung, S. K., 84, 101, 106 Chupakhin, 0. N., 94, 110 Cimeraglia, R., 74, 105 Clardy, J., 77, 106 Clark, T., 14, 49, 51, 55, 67, 108 Clayton, W. R., 90, I l l Cleland, W. W., 92, 108 Clermont, M. J., 63, I l l Coe, J. V., 37, 51 Coleman, T. C., 85, 105 Colter, A. K., 96, 98, 106 Colussi, A. J., 193, 201 Comisarow, M. B., 2, 51 Compton, R. N., 30, 51 Cook, R. L., 144, 203 Cooper, C. D., 30,51 Cordes, E. H., 114, 158, 200 Cornell, S. C., 181, 182, 201 Cosse-Barbi, A., 149, 200 Covitz, F., 186, 187, 191, 198, 202 Cram, D. J., 78, 106 Crans, D., 49, 51 Craze, G.-A,, 80, 106 Creary, X., 85, 109 Cremer, D., 36, 37, 51, 127, 200 Csizmadia, I. G., 87, 110, 148, 204 Currie, G. J., 75, 111 Cutts, P. W., 66, 109 Daltrozzo, E., 96, I l l Damrauer, R., 20, 21, 23, 44, 51, 52 Danishefsky, 77, 106 Dargelos, A., 37, 51 David, S., 148, 152, 200 Davis, A. M., 79, 107 Dawson, J. H. J., 18, 33, 34, 45, 47, 48, 49, 51, 52 de Boer, Th. J., 96, 104, 109, 111 De Bruyne, C. K., 142, 204 DeFrees, D. J., 65, 107 de Kok, P. M . T., 104, 107 de Koning, L. J., 24, 26, 27, 48, 54 Dennis, E., 186, 187, 191, 198, 202 Depriest, R. N., 70, 84, 105
207
DePuy, C. H., I , 2, 12, 13, 16, 18, 20, 21. 22, 23, 24, 29, 30, 32, 35, 36, 44, 45, 46, 50, 51, 52, 53, 55, 75, 86, 105, 107 Deshusses, J., 141, 199 Deslongchamps, P., 93, 107, 114, 116, 118, 119, 127. 129, 155, 161, 162. 163, 164, 167, 168, 169, 178, 192, 199, 200 Desvard, 0. E., 118, 200 De Vries, J. G., 101. 112 Dewar, M . J., 73, 107 Dickinson, R. A,, 129, 199 Dignam, K . J., 182, 202 D’ Incan, E., 72, 107 Dirda, D., 88, 107 Dodd, J. A., 10, 52 Donkersloot. M. C. A,, 104, 107, 112 Dormans, G. J. M., 62, 107 Draxl, K., 62, I l l Dubois, J.-E., 149, 200 Ducharme, Y., 69, 107 Dube, S., 169, 200 Duncap, R. P., 81, 111 Dunitz, J. D., 64, 65, 106, 107, 145, 155, 156, 164, 199, 200, 203, 204 Dupuis, J., 194, 195, 196, 200, 201, 202 Dutler, H., 171, 172, 199 Dykstra, C. E., 64, 107 Dymowski, J. J., 178, 202 Earnshaw, A,, 62, 107 Easton, C. J.. 197, 199 Eberson, L., 60, 62, 69, 85, 107 Edward, J. T., 116, 146, 200 Ehrenson, S.. 160, 201 Eisenstein, 0..64. 72. 73, 107, 108. 148. 200 Ekiel, I., 144, 204 Elbein, A. D., 144. 145, 203 Ellev, S., 72, 108 Ellison, G . B., 22, 53, 55 El Nahas, 94, 95, 105 Elrod, J. P., 174, 201 El’tsov, A. V., 91, 107 Emilia, E., 87, I10 Engdahl, C., 86, 105 Erhardt, J. M., 92, 93, 107 Evans, C. M., 124, 127, 146, 199
208
Evans, D. A., 65, 111 Eyler, J . R., 2, 51 Fanni, T., 187, 191, 201, 204 Fircasiu, D., 127, 201 Farneth, W. E., 8, 52 Farny, 0. L., 86, 106 Fehsenfeld, F. C., 5, 52 Ferguson, E. E., 5,52 Ferrer-Correia, A. J. V., 28, 48, 51 Fersht, A. R., 171, 175, 201 Fetizon, M., 80, I12 Field, F. H., 88, 109 Fife, T. H., 121, 201 Filley, J.. 21, 22, 24, 44, 50, 51 Finch, P., 147, 201 Findley, J. B., 185, 186, 187. 201 Fink, A. L., 176, 199 Fischer, H., 194, 200 Fisher, H. F., 103, 111 Fitzgerald, W. B., 99, 100, 106 Fleet, G. W. J., 143, 201 Flippin, L. A,, 20, 52 Fliszar, S., 114, 204 Foohey, K., 96, 98, 106 Franck, R. W., 151, 201 Frkhel, D., 114, 161, 162, 192, 200 Freidhoff, C. B., 37, 51 Freilich, S. C., 68, 107 Freiser, B. S., 43, 44, 52 Frey, W. F., 30, 51 Frieden, C., 102, 109 Friedmann, M., 122, 123, 203 Fritsch, N., 77, 106 Froelicher, S. W., 43, 44, 52 Fuchs, B., 149, 201 Fueno, T., 83, I10 Fukunaga, T., 64, 107 Fukuzumi, S., 98, 107 Gamassa, M . P., 85, 105 Garrett, B. C . G., 100, 108 Case, R. A,, 96, 101, 107, 109 Gasteiger, J., 66, 108 Gauss, J., 127, 200 Geneste, P., 71, 72, 105 Gensmantel, A., 131, 201 Gerlt, J. A., 186, 201
AUTHOR INDEX
Gerritzen, D.. 102, I09 Gerval, P., 167, 168, 200 Ghosez, L., 133, 203 Ghosh, A. K., 162, 200 Giese, B., 194, 195, 196, 200, 201, 202 Gill, P. M. W.. 61, 109 Glenn, R., 124, 127, 146, 150, 153. 199 Glidewell, C . , 70, 112 Goddard, W. A., 65, 111 Goel, A. B., 70, 84, 105 Gold, V., 72, 86, 105, 107 Golden, D. M., 10, 52 Goode, G . C., 47,52 Gorenstein, D. G., 185, 186, 187, 188, 190, 191, 201, 204 Gowland, F. W., 70, 72, 112 Grabowski, J. J., 2, 12, 13, 16, 20, 44, 51, 52, 75, 105 Graham, G. D., 68, 107 Grandberg, A . I., 67, 106 Gravitz, N., 167, 201 Greenwood, N. N., 62, 107 Grela, M. A., 193, 201 Grieve, D. McL. A., 118, 162. 200 Griller, D., 193. 201, 202 Grishin, Yu. K., 68, 112 Grodowski. J., 97, 106 Groninger, K.-S., 195, 202 Gross, M. L., 2, 52 Grover, E. R., 93. 107 Grundemann, E., 190, 203 Grutter, M. G., 141, 199 Guay, D., 127, 162, 200 Guida, A , , 167, 168, 200 Gunasekera, A., 99, 106 Gupta, M. D., 70, 84, 110 Gurskii, M. E., 67, 106, 107 Gyorgydeak, Z . , 122, 123, 203
. Hajdas, D. J., 37, 52 Halisz, P., 176, 203 Han, L.-P. B., 83, 112 Hanafusa, T., 71, 112 Handel, H., 72, 107 Hanna, I., 80, I12 Hannon, S . J., 69, 107 HanuS, V., 197, 198, 204 Harada, W., 141, 202 Hare, G. J., 93, 105
AUTHOR INDEX
Harrison, A. G., I , 28, 48, 51,52 Hauk, F., 78, 106 Havinga, E., 116, 147, 148, 152, 203 Hayday, K., 196, 201 Hayes, R. N., 20, 36, 43, 50, 52,53,55, 65, 75, 111 Haynes, L. J., 1 1 8, 201 Hays, R. L., 22, 51 Hegarty, A. F., 64, 110,180, 182, 183,
201,202
Hehre, W. J., 58, 65, 107,108,148, 200 Hemmerich, P., 94, 108 Henchman, M. J., 8, 36,53, 55, 63, 110 Hennig, J., 102, 109 Henry, H., 114, 204 Henry, R. S., 80, 108 Hermes, J. D., 92, 108 Herron, J. T., 62, 111 Hierl, P. M., 8, 53 Hine, J., 83, 108,155, 157, 158, 160, 182, 183, 201 Hirabe, T., 70, 108 Hirama, M., 77, 106 Hirano, T., 77, 108 Hiraoka, H., 87, 108 Hiraoka, K., 88, 111 Hodge, C. N., 61, 91, 109 Hodges, R. V., 21, 53 Hoffman, S. J., 178, 201 Hoffmann, R., 148, 200 Hogeveen, H., 86, 106 Hogg, J. L., 174, 201 Holer, J., 86, 110 Holm, T., 84, 108 Holtslander, W. L., 62, 108 Horii, H., 70, 108 Horning, T. L., 194, 199 Horton, D., 144, 204 Hosie, L., 122, 123, 124, 143, 144, 201 Houk, K. N., 14, 40, 55, 58, 64,67, 68, 74, 108,110,111 Howard, J. A,, 193, 201 Howard, J. A. C., 87, 105 Hrcnir, D. C., 87, 105 Huang, J. T. J., 61, 108 Hudson, R. F., 188, 189, 199 Hughes, D., 71, 81, 106 Huskey, W. P., 102, 108 Huszthy, P., 92, 108 Hutchings, M. G., 66, 108
209
Hutchins, J. E. C., 92, 108 Hutley, B. G., 75, 104, 108 Hutton. R. F., 95, 105 Ijames, C. F., 4, 53 Imamura, A., 77, 108 Inagaki, S., 154, 201 Ingemann, S.. 13, 14, 16. 29, 30, 32, 35, 36, 37, 38, 40, 41, 42, 50 52,53,54, 55, 63, 75, 108,109 Ingold, K . U., 193, 196, 197, 200,202,
203
Isaacs, N. S., 94, 108 Ishihara. Y., 104, I10 Ishikawa, M., 98, 107 Ivanaov, P. Y., 91, 108 Iwamura, H., 197, 202 Iwase, K., 154, 201 Jaffer, S., 178, 203 Jalonen, J. E., 37, 54, 63, 75, 109 James, M. N. G., 123, 177, 201 Janousek, B. K., 6, 50, 53 Janousek, Z., 49, 55 Jao, L. K., 121, 201 Jarrold, M . F., 24, 51 Jarvis, T. C . , 121, IY9 Jasinski, J. M., 8, 53 Javaid, K., 94, 108 Jeffery, G. A., 148, 151, 201,203 Jemmis, E. D., 152, 203 Jencks, W. P., 167, 184, 201,204 Jennings, K. R.,24, 28, 47, 48, 51, 52, 53,s Johlman, C. L., 2, 18, 53,54 Johnson, C. D., 121, 199 Johnson, J. E., 181, 182, 201 Jones, M. E., 22, 53 Jones, P. G., 149, 150, 153, 154, 199,
201,202
JonsaII, G., 86, 105 Jose, S. M., 8, 55 Jouin, P., 101, 112 Juaristi, E., 152, 202 Kaandorp, Th. J. M., 48, 52 Kaba, R.A., 193, 202
21 0
Kabir-ud-Din, 9 I , 108 Kahn, S. D., 58, 108 Kaiser, E. T., 178, 201 Kakudo, M., 141, 202 Kalcher, J., 37, 53 Kalikin, M . I., 86, 110 Kaloustian, M. K., 162, 202 Kandel, S. H., 94, 105 Kanters, J. A,, 104, 107 Kar, D., 185, 201 Karchenko, V. G., 86, 110 Karpas, Z., 36, 53 Karplus, M., 143, 203 Kashin, A. N., 60, 108 Kashiwagi, M., 104, I10 Kass, S. R., 22, 44, 50, 53 Kates, M. R., 89, 91, 111 Katz, H. E., 90, 108 Kaufmann, E., 67, 74, 108 Kawabata, Y., 15, 55 Kayser, M . M., 37, 53, 55, 72, 73, 107, 108
Kearney, P. A,, 93, 105 Kebarle, P., 1, 8, 9, 10, 51, 53, 54, 87, 88, 108, 109, 111 Kellogg, R. M., 101, 112 Kersters-Hilderson, H., 142, 204 Ketlinskii, V. A,, 91, 107 Khatri, H. N., 22, 51 Khouri, F., 162, 202 Kiesele, H., 96, 111 Kim, J. K., 65, 107, 130, 161, 200 Kimura, K., 83, I10 King, G. K., 12, 13, 18, 20, 52, 53 King, H. F., 63, 111 Kirby, A. J., 79, 108, 115, 116, 118, 119, 122, 124, 127, 128, 129, 130, 146, 147, 149, 150, 153, 154, 199, 200, 201, 202 Kirchen, R. P., 87, 89, 91, 108, 109 Kirk, D. N., 77, 106 Klass, G., 18, 20, 53 Klein, F. S., 36, 53 Kleingeld, J. C., 5, 13, 14, 27, 35, 36, 37, 53, 54, 63, 75, 108, 109 Kluger, R., 186, 187, 191, 198, 202 Knorr, F. J., 2, 54 Knowles, J. R., 136, 199 Koermer, G . S., 68, 112 Kolodziej, P.A., 135, 136, 137, 138,203
AUTHOR INDEX
Kopecky, K. R., 78, 106 Kort, C. W. F., 5 . 54 Korth, H.-G., 194, 195, 196, 200, 202 Kos, A. J., 14, 55 Koser, G . F., 83, 108 Koshland, D. E., 140, 202 Kost, D., 192, 202 Koster, A. S., 104, 112 KovaE, F., 114, 202 Kowaski, C., 85, 109 Koiar, T., 148, 204 Kozyrod, R. P., 195, 199 Kraftory, M., 156, 203 Kraka, E., 36, 37, 51 Kramer, G. M., 88, 89, 107, 109 Kreevoy, M . M., 72, 92, 95, 99, 100, 103, 108, 109, 110, I l l Kresge, A. J., 126, 202 Kruk, C., 102, 112 Krusic, P. J., 196, 200 Kung, K., 70, 106 Kuo, L. C., 178, 179, 200, 202, 203 Kursanov, D. N., 86, I10 Kurtev, B. J., 170, 202 Kurz, J. L., 60, 109 Kurz, L. C., 60, 102, 109 Kusabayashi, S., 70, 108 Kusunoki, M., 141, 203 Kwart, H., 61, 67, 109 Lahnstein, J., 75, I l l Lahti, R., 96, 106 Lai, C. C., 96, 106 Lai, K., 190, 204 Lalkgerie, P., 141, 202 Lam, P. K. W., 164, 202 Lamaty, G., 71, 72, 105 Lambert, J. B., 121, 202 Langemann, A,, 78, 106 Larrien, C., 37, 51 Latimer, W. M., 62, 109 Latour, S., 69, 107 Laude, D. A., Jr., 2, 54 Laurie, D., 101, 109 Lawrence, S. H., 87, I l l Lebreux, C . , 169, 200 Lee, C. H., 81, 111 Lee, H., 178, 201 Lee, I. S. H., 100, 109
AUTHOR INDEX
Lee, R. E., 43, 52, 54 Legler, G., 141, 199, 202, 203 Lehman, C. H., 83, 112 Lehn, J.-M., 65, 106, 146, 152, 153, 186, 202 Lemieux, R. U., 122, 123, 147, 202 Lempert, K., 92, 108 Leopold, D. G., 36, 48, 54 Leopold, F., 147, 151, 203 Lepeska, B., 71, 110 Leroy, G., 182, 202 Leroy, L., 64, 110 Lessard, J., 116, 118, 163, 200 Lewis, C. C., 121, 199 Lewis, D. E., 43, 52, 61, I l l Lewis, E. S., 61, 109 Li, M. Y., 67, 109 Limbach, H.-H., 102, 109 Lineberger, W. C., 36, 48, 54 Lipscomb, W. M., 68, 107 Lipscomb, W. N., 178, 179, 200, 202 Littler, J. S., 183, 198, 202 Lockerby, W. E., 62, 108 Lohmann, J. J., 38, 55 Loupy, A., 72, 107, 109 Lowry, T. H., 7, 54 Lucas, E., 101, 109 Lutsenko, A. I., 67, 107 Luxon, B. A,, 185, 186, 187, 201 Lyapova, M. J., 170, 202 Lynch, T. J., 81, 111 Lyons, A. R., 193, 202 MacInnes, I., 101, 109 MacKay, G. I., 7, 8, 51, 54, 65, 105 MacKenzie, N. E., 176, 202 Magee, C. B., 62, 109 Maggiora, G. M., 75, 104, 108 Magnera, T. F., 8, 10, 51, 54, 88, 109 Mahapatra, B., 70, 110 Maia, A., 72, 107 Mair, G. A,, 141, 199 Majchrzak, M. M., 121, 202 Makhaev, V. D., 68, 112 Makinen, M. W., 178, 179, 202, 203 Malatesta, V., 196, 197, 203 Malaval, A., 162, 200 Malloy, T. B., 144, 203 Malthouse, J. P. G., 176, 199, 292
21 1
Mann, B. E., 66. 109 Marcus, R. A,, 59, 109 Maricq, M. M., 18, 20, 53 Mario Pinto, B., 151, 203 Marriot, P. R., 193, 201 Marshall, A. G., 2. 4, 5 , 51, 54 Marshall, P. J., 122, 123, 124, 144, 201 Marston, C. R., 101, I10 Martens, F. M., 95, 96, 102, 104, 109, 112 Martin, A. F., 132, 203 Martin, R. J., 119, 128, 129, 130, 200, 202 Mason, S. C., 79, 107 Massa, L. J., 63, 111 Massey, V., 94, 108 Mateos, J. L., 78, 106 Matern, A. I., 94, 110 Matsson, O., 124, 199 Matsuura, Y . , 141, 203 Matthews, B. W., 141, 199 Matturro, M., 127, 201 McClelland, R. A., 118, 164, 202 McCollum, J. D., 91, 105 McDonald, R. N., 47, 54 McDonald, R. S., 79, 82, 109 McDonnell, P. D., 121, 199 McDowall, L. J., 83, 105 McHugh, K. M., 37, 51 McIver, R. T., Jr, 7, 13, 50, 51, 65, 107 McKee, M. L., 73, 76, 107, 109 McKelvey, R. D., 196, 197, 201, 202 McKenna, J., 66, 109 McKenna, J. M., 66, 109 McLafferty, F. W., 43, 54 McLennan, D. J., 61, 109 McMahon, T. B., 37, 53, 73, 108 McMurray, J. E., 61, 91, 109 McPhail, A. T., 152, 202 McVicker, G. B., 89, 108 Meeks, B. S., 72, 109 Meijer, H. P., 101, 109 Mendez, R., 152, 202 Menon, B. C., 63, 106, 153, 200 Melander, L., 26, 54 Meot-Ner, M., 10, 54, 88, 109 Mercer, K. R., 194, 199 Merenyi, R., 49, 55 Meulendijks, G. H. W. M., 104, 107 Micel, H., 94, 108
21 2
Miertus. S., 74, 105 Mikhailov, B. M., 67, 107 Miller, A. E. S., 48, 54 Miller, J.. 81, 85, 111 Miller, L. L., 97, 106 Miller, T. M., 36, 54 Mills, 0. S.. 80, 106 Minato, T., 15, 55 Minyaev, R. M., 86, 109 Miri, A. Y., 86, 107 Mishrikey, M. M., 95, I 1 0 Misra, R. N., 22, 51 Mitchell, D. J., 148, 149, 192, 202, 204 Mitchum, R. K., 28, 48, 51 Mock, W. L., 191, 204 Molter, K. E., 160, 204 Molyneux, R. J., 144, 145, 203 Momii, R., 185, 186, 187, 201 Morgan, A. R., 122, 202 Morgan, C. R., 81, 111 Morokuma, M., 68, 110 Moreau, C., 71, 105, 114, 118, 161, 162, 192, 200 Mori, Y . , 154, 201 Morrical, S. W., 92, 108 Morris, J. J., 132, 203 Motoyama, T., 94, I10 Mountain, A. E., 75, 104, 108 Mullane, M., 180, 182. 183, 201 Miiller, J.-A,, 156, 157, 203 Miiller, P., 71, 110 Muraoka, K . , 70, 108 Murdoch, J., 59, I10 Murphy, M. K., 36, 54 Murray, K. K., 36, 54 Murray, M., 190, 203 Murray-Rust, J., 80, 110 Murray-Rust, P., 80, 110 Myhre, P. C., 91, I10 Nadeau, Y., 114, 116, 118, 163, 200, 204 Nagase, S., 68, 74, 110 Nagpurkar, A. G., 147, 201 Nalley, E. A., 182, 201 Nambiar, K . P., 135, 136. 137, 138, 199, 203, 204 Nasipur, D., 70, 84, 110 Nayak, B., 167, 200
AUTHOR INDEX
Nelson, C. R., 144, 203 Nelson, D. D., 66, 106 Nelson, R. W., 90 111 Neta, P., 97, 106 Newcomb, M., 85, 110 Newkome, G. R., 101, I10 Newth, F. H., 118, 201 Nielsen, W. D., 78, 106 Nguyen, M. T., 64, 110, 182, 202 Nibbering, N. M. M., 2, 5, 13, 14, 16, 18, 19, 24, 26, 27, 29, 30, 32, 33, 34, 35, 36, 37. 38, 40. 41, 42, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 63, 75, 108, 109 Nishimura, N., 94, 110 Nishizawa, N., 98, 107 Noest, A. J., 5, 18, 19, 33, 40, 45, 48, 52, 54 Nojima, M., 70, 108 Nonhebel, D. C., 101, 109 Nuiiez, O., 133, 165, 203 North, A. C. T.. 141, 199 O’Connor, C., 167, 200 O’Connor, J. V., 119, 203 O’Donnell, J. J., 127, 201 Oestensen, E. T., 95, 110 Oh, H. T. P., 99, 106 Ohno, A,, 104, 110 Oka, S., 104, 110 Okhlobystin, 0. Yu., 60, I10 Okuyama, T., 83, 110 Olah, G. A., 92, I10 O’Leary, M. H., 92, 108 Olmstead, W. N., 8, 54 Oppenheimer, J. R., 155, 199 Oppenheimer, N. J., 135, 139, 203 Orpen, G. A,, 61, 105 Orszulik, S. T., 101, 109 Ostovic, D., 95, 99, 100, 103, 109, 110, Ill Paddon-Row, M. N., 64, I10 Page, M. I., 79, 107, 131, 132, 133, 201, 203 Palla, P., 73, 105 Paltridge, R. L., 50, 53 Pandit, U. K., 96, 101, 104, 107, 109, I l l , 112
AUTHOR INDEX
Pang, E., 101, I10 Park, S. U., 101. 106 Parker, W., 80, 108, 110 Parnes, A. M., 86, I10 Parsons, A. G., 96, 98, I06 Pasman, P., 89, 112 Pasto, D. J., 71, 110 Patterson, D. R., 169, 200 Paulsen, H., 122, 123, 147, 151, 203 Paulson, J. F., 8, 36, 53, 55, 63, 110 Pavlish, N. V., 91, 107 Pdvlov, v. I., 86, 109 Pawlowski, N. E., 58, 110 Payzant, J. D., 8, 54 Peerboom, R., 41, 42, 55 Pellerite, M. J., 8, 55 Pererson, M. R., 87, 110 Perrin, C. L., 118, 132, 133, 165, 203 Pershin, D. G., 67, I06 Peters, K. S., 101, 110 Peytral, E., 157, 203 Pfeiffer, G. V., 61, 108 Pham, T. N., 70, 105 Phelps, D. J., 71, I12 Philip, T., 144, 203 Philips, D. C., 141, 199 Pierre, J. L., 72, 107 Plank, P., 96, 106 Plesch, P. H. 91, 108 PlesniEar, B., 114, 202 Poirier, R. A., 87, 110 Pojarlieff, I . G., 170, 202 Polgar, L., 173, 176, I99, 203 Pon, R. T., 72, 112 Pople, J. A., 86, I l l , 184, 201 Post, C. B., 143, 203 Postovskii, I. Y . , 94, I10 Pothier, N., 93, 107 Powell, A. L., 81, 111 Powell, M . F., 63, 95, 97, 94, 110, I 1 1 Praly, J.-P., 195, 203 Prasad, H. S., 70, I05 Proctor, G., 64, 107, 156, 203 Pronin, A. F., 86, I10 Pross, A , , 59, I10 Quack, M., 37, 53 Quesnel, A. A,, 96, 106 Quinn, D. M., 174, 201
21 3
Radom, L., 148, 201 Raghavachari, K., 86, 87, 110, 111 Ramaswamy, P., 150, 153, 199 Ramirez, F., 185, 203 Rapp, D., 88, I07 Ranganayakula, K . , 87, 89, 108 Rannala, E. R., 94, 108 Rauk, A,, 87, 89, 108, 148, 204 Ray, N. K., 68, 110 Rayez, J. C., 63, 111 Rayez-Meaune, M. T., 63, 111 Reetz, M. T., 68, 111 Reitz, D. B., 38, 51 Remington, S. J., 141, I99 Rempel, D. L., 2, 52 Restalli, A,, 72, 107 Reuben, D. M . E., 72, I05 Reutov, 0. A,, 68, 112 Reynolds-Warnhoff, P., 77, 112 Ricca, T. L., 4, 5, 54 Rice, F. O., 157, 203 Rich, D. H., 176, 203 Richardson, K. S., 7, 54 Riddell, F. G., 80, 108 Ritchie, C. D., 63, I I I , 160, 183, 203 Riveros, J. M., 8, 18, 28, 51, 55 Rob, F., 104, I I I Roberts, B. P., 196, 200 Roberts, R. M. G., 95, 99. 100, 103, 110, I 1 1 Robinson, S. R., 86, 107 Roe, D. C., 4, 54 Roeser, K.-R., 141, 203 Rogers, R. D., 87, 105 Rohlde, C., 14, 55 Rollin, A., 85, 109 Romers, C., 116, 147, 148, 152, 203 Rondan, N. G., 14, 40, 55, 58, 64, 67, 108, I10 Roque, J. P., 72, 105 Rosenstock, H. M., 62, I l l Rosmus, P., 37, 53 Ross, B. R., 40, 55 Rowan, D. D., 93, 107 Rozeboom, M . D., 38, 51 Ruble, J. R., 151, 203 Rudzki, J., 101, 1111 Ruegger, D., 194, 200 Rumpek, H., 102, 109 Russell, D. H., 2, 55
21 4
Rzepa, H. S., 81, 85, I l l Salem, L., 148, 200 Samudzi, C . T., 151, 203 San Filippo, J., 67, 109, 112 Sana, M., 64, 110, 182, 202 Sandoval-Ramirez, J., 15I , 203 Sandhu, S. S., 111 Sarma, V. R., 141, 199 Sartori, G., 77, 106 Saturnino, D. J., 90, I l l Saul, R., 144, 145, 203 Saunders, J. K., 116, 118, 162, 200 Saunders, M., 89, 91, 111 Saunders, W. H., Jr., 26, 54, 102, 111 Scaiano, J. C . , 193, 201 Scheele, J. J., 104, 111 Scheffold, R., 195, 199 Schiff, H. I., 8, 54 Schlegel, H. B., 73, 107, 192, 199, 202, 204 Schleifer, L., 149, 201 Schleyer, P. von R., 14, 40, 41, 49, 51, 55, 61, 74, 86, 87, 108, 110, I l l , 152, 203 Schmeltekopf, A. L., 5, 52 Schmir, G. L., 169, 200 Schmitt, R. J., 20, 36, 45, 51, 52, 55, 86, 107 Schmutzler, R., 190, 203 Schneider-Bernlohr, H., 136, 203 Schnittker, J. B., 63, 111 Schowen, R. L., 75, 102, 104, 108, 174, 201 Schwartz, M . E., 61. 108 Schweig, C., 94, 108 Schweizer, W. B., 156, 203 Scott, A. I., 176, 202 Seebach, D., 38, 55 Seeman, J. I., 120, 204 Seiler, P., 145, 200, 204 Semenza, G., 141, 199 Sen Sharma, D. K., 88, 111 Sessions, R. B., 61, 105 Setser, D. W., 47, 54 Seydon-Penne, J., 72, 107, 109 Shaik, S. S., 59, 110 Shapiro, R. H., 12, 13, 36, 52, 55, 86, 107
AUTHOR INDEX
Sharma, R. B., 88, 111 Sharma, R. D., I5 I , 203 Shashkov, A. S., 67, 107 Shefter, E., 155, 200 Shein, S. M., 86, I10 Sheldon J. C . , 15, 18, 20, 21, 36, 43 52, 53,55, 65, 75, 111 Sheppard, W. H., 81, 111 Shore, S. G., 87, 90, I l l Shull, H., 61. 106 Sibley, C. E., 79, 82, 109 Sidel’nikova, L. I., 86, I10 Siehl, H.-U., 89, I l l , 126, 204 Sielecki, A. R., 177, 201 Simig, G., 92, 108 Sims, L. B., 61, 111 Sinay, P., 195, 199 Sindhuatmadja, S.. 99, 106 Singh, B. P., 87, 89, 108 Sinha, A,, 91, I l l Sinnhuber, R. O., 58, I10 Sinnott, M. L., 122, 123, 124, 125, 140, 141, 142, 143, 144, 150, 158, 199, 200, 201, 204 Sjoberg, S., 124, 199 Skaare, S. H., 95, I10 Skibo, E. B., 81. I / / Skoog, M . T., 184, 204 Smith, D., 1, 2, 6, 50, 55 Smith, M. A,, 22, 55 Snodgrass, J. T., 37, 51 Soderquist, J. A,, 44, 52 Sooma, Y., 130, 161, 200 Sorensen, T. S., 87, 89, 91, 108, 109 Souchard, I. L. J., 141, 204 Spencer, C . M., 66, 109 Spitznagel, G. W., 14, 55, 87, 110, 152, 203 Squires, R. R., 12, 37, 43. 44, 46, 51, 52, 54, 55 Srinivasan, R., 103, I l l Stackhouse, J., 137, 204 Stahl, D., 80, 105 Stapleton, B. J., 28, 51 Stauffer, D. M., 135, 136, 137, 138, 203, 204 Steffens, J. J., 95, 111 Steigerwald, M. L., 65, 111 Steiner, B. W., 62, I l l Stella, L., 49, 55
21 5
AUTHOR INDEX
Stepanov, B. I., 91, 108 Stephan, W., 68, I l l Stevens, R. V., 120, 204 Stewart, J. H., 12, 13, 55 Stewart, R., 61, 71, 91, 111 Stoflo, J. J., Jr., 89, 111 Streitweiser, A,, Jr., 74, 105 Strozier, R. W., 64, 68, I I I Strum, H., 96, I l l Sturtevant, J. M., 186, 201 Su, T., 8, 55 Suckling, C . J., 101, 109 Sullivan, S. A., 20, 21, 29, 30, 32, 35, 50, 52, 53 Sustmann, R., 194, 195, 196, 200, 202 Svoboda, J. J., 92, 110 Swain, C. G., 61, 81, 111 Syfrig, M. A., 38, 55 Symons, E. A., 63, 106, 111 Symons, M. C. R., 61, 70, 112, 193, 202 Szawelski, R. J., 175, 204 Tabet, J. C., 80, 105, 112 Tagaki, W., 101, 105 Taillefer, R. J., 114, 116, 118, 162, 167, 168, 169, 200, 204 Taira, K., 186, 187, 190, 191, 201, 204 Takagi, M., 70, 108 Takashima, K., 8, 18, 55 Talma, A. G., 101, 112 Tamas, J., 92, 108 Tanaka, T., 98, 107 Taniguchi, S., 70, 108 Tanner, D. D.. 70, 112 Tanner, S. D., 65, 105 Tapia, J., 152, 202 Tapia, O., 64, 68, I12 Tartakovski, E., 149, 201 Tee, 0. S., 159, 160, 199, 204 Teichmann, H., 190, 203 Tel, L. M., 148, 204 Teller, E., 157, 203 Teo, K. C., 71, I l l Thatcher, G. R. J., 187, 202 Thomas, S. E., 114, 204 Todt, K., 147, 151, 203 Tomasi, J., 73, 74, 105 Toone, T. W., 91, I I I
Tranter, R. L., 80, I10 Traylor, T. G., 68, 69, 107, 112 Tremerie, B., 133, 203 Trenerry, V. C.. 18, 53 Troostwijk. C . B., 101, 112 Troughton, E. B., 160, 204 True, N. S., 40, 55 Truhlar, D. G., 100, 109 TuruEek, F., 197, 198, 204 TvaroSka, I., 146, 148, 204 Uchibori, Y.. 74, 110 Ugi, I.. 185, 203 Uglova, E. V., 68, 112 Umeyama, H., 66, 112 Ushida, S., 104, 110 Vaidyanathaswamy, R., 191, 201 Valenzuela, B. A,, 152, 202 Valle, L., 152, 202 Vander Jagt, D. L., 83, I12 van der Kerk, S. M., 95, 96, 102, 104, 112 van der Wel, 18, 37, 55 van Doorn, R.. 24, 55 van Doorslaer, C . , 142, 204 Van Doren, J. M., 44,50, 53 van Eikeren, P., 95, 106, 129, 204 van Gerresheim, W., 80, 95, 96, 99, 102, 104, 111, 112 van Hooff, H. J. G., 104, 107, 112 van Laar, A., 99, 112 van Lier, P. M., 104, 107, I12 van Niel, J. C . G., 101, 109, 112 Van Opstal, O., 142, 204 van Ramesdonk, H. J., 99, 104, 111, 112 VanVerth, J. E., 160, 203 Vasella, A., 195, 199 Venkatasubban, K. S., 174, 201 Verhoeven, J. W., 80, 89, 95, 96, 99, 102, 104, 109, I l l , 112 Verkade, J. G., 191, 201 Viehe, H. G . , 49, 55 Viggiano, A. A., 8, 53 Vinter, J.G., 166, 167, 204 Viout, P., 72, 107 Viratelle, 0. M., 141, 204
21 6
Virtanen, P. 0. I., 160, 203 Vishveshwara, S., 148, 201 Visscher, J., 101, 112 Vitale, A. A., 67, 112 Vogel, P., 86, 112 Wagstaff, K . , 91, 109 Walaszek, Z., 144, 204 Walker, A. M., 91, 109 Walker, G. E., 89, 111 Walter, H., 89, 111, 126, 204 Walton, J. C., 101, 109 Wanczek, K.-P., 2, 55 Wang, J., 70, 106 Wang, K. K., 66, 106, 112 Wang, T.-C. L., 4, 5, 54 Waninge, J. K., 101, 112 Warnhoff, E. W., 77, 97, 112 Wassef, W. N., 86, 105 Watt, C. I. F., 78, 79, 80, 107, 108, 110, 112, 134, 204 Watt, I., 80, 106 Weaver, L. H., 141, 199 Webster, P., 133, 203 Weeks, D. P., 126, 202 Weidig, C., 182, 201 Weil, D. A., 2, 54 Wenderoth, B., 70, 105 Werstiuk, N. H., 41, 55 Westheimer, F. H., 95, 105, 184, 185, 186, 187, 191, 198, 201, 202, 204 Whangbo, M.-H., 148, 149, 192, 204 Wharton, C. W., 175, 204 White, R. L., 2, 53 Whiteside, R. A., 86, 111 Whittleton, S. N.,78, 80, 106, 112 Whitworth, S. M., 78, 112 Wiberg, K . B., 127, 201 Wigfield, D. C., 70, 71, 72, 112 Wijesundera, S., 125, 199
AUTHOR INDEX
Wiles, R. A,, 61, 111 Wilkins, C. L., 2, 18, 53, 54 Williams, A,, 184, 199 Williams, I. H., 65, 75, 104, 108, 112, 126, 204 Williams, L. D., 186, 187, 191, 198, 202 Williamson, T. W., 96, 106 Wilson, J. C., 15. 55 Wilson, S. R., 22, 51 Wipff, G., 65, 106. 152, 153, 186, 202 Withers, S. G., 141, 204 Witzel, T., 195, 202 Wolfe, S., 148, 149, 151, 192, 199, 202, 203, 204 Wong, M. H. Y., 77, 112 Woodgate, S. S., 2, 51 Wu, J. C., 97, I10 WU, Y.-D., 74, 108 Wuest, J. D., 69, 92, 93, 107 Yamabe, S., 15, 55 Yamataka, H., 71, I12 Yamauchi, M., 90, I l l Yang, D., 70, 112 Yang, J.-C., 188, 204 Yaniv, R., 95, 106 Yannoni, C. S., 91, 110 Yates, K., 159, 160, 199, 204 Yon, J. M.. 141, 202 Yoshifuji, M., 38, 55 You, K., 136, 204 Youngblood, M. P., 98, 112 Yuan, L. C., 97, 112 Yuh, Y., 144, 203 Zajdel, W. J., 40, 55 Zdnfredi, G. T., 77, 106 Zeppezauer, M., 136, 203 Zweifel, B. O., 172, 199
.
Cumulative Index of Authors Ahlberg, P., 19, 223 Albery, W. J., 16, 87 Allinger, N. I., 13, 1 Anbar, M.. 7. 115 Arnett, E. M., 13, 83 Bard, A. J., 13, 155 Bell, R. P., 4, 1 Bennett, J. E., 8, I Bentley, T. W., 8, 151; 14, 1 Berger, S., 16. 239 Bethell, D., 7, 153; 10, 53 Blandamer, M. J., 14, 203 Brand, J. C. D., I , 365 Brandstrom, A., 15, 267 Brinkman, M. R., 10, 53 Brown, H. C.. I , 35 Buncel, E., 14, 133 Bunton. C. A,, 22, 213 Cabell-Whiting, P. W., 10, 129 Cacace, F., 8, 79 Capon, B., 21, 37 Carter, R. E., 10, 1 Collins, C. J., 2, I Cornelisse, J., 11, 225 Crampton, M. R., 7, 21 1 Davidson, R. S., 19, I ; 20, 191 Desvergne, J. P., 15, 63 de Gunst, G . P., 11, 225 de Jong, F., 17, 279 Dosunmu, M. I., 21, 37 Eberson, L., 12, I ; 18, 79 Engdahl, C., 19, 223 Farnum, D. G., 11, 123 Fendler, E. J., 8, 271 Fendler, J. H., 8, 271; 13, 279 Ferguson, G., I , 203 Fields, E. K., 6, 1 Fife, T. H., 11, I
Fleischmann, M., 10, 155 Frey, H. M., 4, 147 Gilbert. B. C., 5, 53 Gillespie, R. J.. 9, 1 Gold, V., 7, 259 Goodin, J. W., 20, 191 Could. I . R., 20, 1 Greenwood, H. H.. 4. 73 Hammerich, O., 20. 55 Havingd, E.. 11, 225 Henderson, R. A,, 23. 1 Henderson, S., 23, 1 Hibbert, F., 22. 113 Hine, J., 15, 1 Hogen-Esch, T. E., 15, 153 Hogeveen, H., 10,29,129 Ireland, J. F., 12, 131 Johnson. S. L., 5, 237 Johnstone, R. A. W., 8. 151
Jonsall, G., 19. 223 Jose, S. M., 21, 197 Kemp, G., 20, 191 Kice, J. L., 17, 65 Kirby, A. J., 17, 183 Kohnstam, G., 5, 121 Kramer, G . M., I I . 177 Kreevoy, M. M.. 6 , 63; 16, 87 Kunitake, T., 17. 435 .Ledwith, A,, 13, 155 Liler, M., 11, 267 Long, F. A., 1, 1 Maccoll, A., 3, 91 Mandolini, L., 22, 1 McWeeny, R.. 4. 73 Melander, L., 10, 1 Mile, B., 8. 1 Miller, S. I., 6, 185 Modena, G., 9, 185 More O’Ferrall, R. A., 5 , 33 1 21 7
Morsi, S. E.. 15, 63 Neta, P., 12, 223 Nibbering, N . M. M., 24, 1 Norman, R. 0. C., 5, 33 Nyberg, K., 12, 1 Olah. G. A,, 4, 305 Page, M. I., 23, 165 Parker. A. J., 5, 173 Parker, V. D., 19, 131: 20, 55 Peel, T. E.. 9, I Perkampus, H. H., 4, 195 Perkins. M. J.. 17, 1 Pittman, C. U. Jr., 4, 305 Pletcher, D., 10. 155 Pross, A,, 14, 69; 21, 99 Ramirez. F., 9, 25 Rappoport, Z., 7, 1 Reeves, L. W., 3. 187 Reinhoudt, D. N., 17, 279 Ridd, J. H., 16, 1 Riveros, J. M.. 21, 197 Roberston, J. M., I . 203 Rosenthal, S. N., 13, 279 Russell, G . A,, 23, 271 Samuel, D., 3, 123 Sanchez, M. de N. de M.. 21, 37 Savelli, G., 22. 213 Schaleger, L. L., 1, 1 Scherdga, H. A,, 6 , 103 Schleyer, P. von R., 14, 1 Schmidt, S. P., 18, 187 Schuster. G . B., 18, 187; 22, 311 Scorrano, G., 13, 83 Shatenshtein, A. I., 1, 156 Shine. H. J., 13, 155 Shinkai, S., 17, 435 Siehl, H.-U., 23, 63 Silver, B. L., 3, 123
21 8
Simonyi, M., 9, 127 Sinnott, M. L., 24, 113 Stock, L. M., 1, 35 Symons, M. C. R.,1, 284 Takashima, K., 21, 197 Tedder, J. M., 16, 51 Thomas, A., 8, 1 Thomas, J. M., 15, 63 Tonellato, U., 9, 185 Toullec, J., 18, 1
CUMULATIVE INDEX OF AUTHORS
Tiidos, F., 9, 127 Turner, D. W., 4, 31 Turro, N. J., 20, 1 Ugi, I., 9, 25 Walton, J. C., 16, 51 Watt, C. I. F., 24, 57 Ward, B., 8, 1 Westheimer, F. H., 21, 1 Whalley, E., 2, 93 Williams, D. L. H., 19.381
Williams, J. M. Jr., 6, 63 Williams, J. O., 16, 159 Williamson, D. G., 1, 365 Wilson, H., 14, 133 Wolf, A. P., 2, 201 Wyatt, P. A. H., 12, 131 Zimmt, M. B., 20, 1 Zollinger. H., 2, 163 Zuman, P., 5, 1
Cumulative Index of Titles Abstraction, hydrogen atom, from 0 - H bonds, 9, 127 Acid solutions, strong, spectroscopic observation of alkylcarbonium ions in, 4, 305 Acid-base properties of electronically excited states of organic molecules, 12, I3 I Acids and bases, oxygen and nitrogen in aqueous solution, mechanisms of proton transfer between, 22, I I3 Acids, reactions of aliphatic diazo compounds with, 5, 331 Acids, strong aqueous, protonation and solvation in, 13, 83 Activation, entropies of, and mechanisms of reactions in solution, 1, 1 Activation, heat capacities of, and their uses in mechanistic studies, 5, 121 Activation, volumes of, use for determining reaction mechanisms, 2, 93 Addition reactions, gas-phase radical, directive effects in, 16, 51 Aliphatic diazo compounds, reactions with acids, 5, 33 1 Alkylcarbonium ions, spectroscopic observation in strong acid solutions, 4, 305 Ambident conjugated systems, alternative protonation sites in, 11, 267 Ammonia. liquid, isotope exchange reactions of organic compounds in 1, 156 Anions, organic, gas-phase reactions of, 24, 1 Antibiotics, p-lactam, the mechanisms of reactions of, 23, 165 Aqueous mixtures, kinetics of organic reactions in water and, 14, 203 Aromatic photosubstitution, nucleophilic, 11, 225 Aromatic substitution, a quantitative treatment of directive effects in, 1. 35 Aromatic substitution reactions, hydrogen isotope effects in, 2, 163 Aromatic systems, planar and non-planar, 1, 203 Aryl halides and related compounds, photochemistry of, 20, 191 Arynes, mechanisms of formation and reactions at high temperatures, 6, 1 A-S,2 reactions, developments in the study of, 6, 63 Base catalysis, general, of ester hydrolysis and related reactions, 5. 237 Basicity of unsaturated compounds, 4, 195 Bimolecular substitution reactions in protic and dipolar aprotic solvents, 5, 173
' 3C N.M.R. spectroscopy in macromolecular systems of biochemical interest, 13,279 Carbene chemistry, structure and mechanism in, 7, 163 Carbenes having aryl substituents, structure and reactivity of, 22, 31 1 Carbanion reactions, ion-pairing effects in 15, 153 Carbocation rearrangements, degenerate, 19, 223 Carbon atoms, energetic, reactions with organic compounds, 3, 201 Carbon monoxide, reactivity of carbonium ions towards, 10, 29 Carbonium ions (alkyl), spectroscopk observatiot,in strong acid solutions, 4, 305 Carbonium ions, gaseous, from the decay of tritiated molecules, 8, 79 Carbonium ions, photochemistry of, 10, 129 Carbonium ions, reactivity tcwards carbon monoxide, 10, 29 Carbonyl compounds, reversible hydration of, 4, 1 21 9
220
CUMULATIVE INDEX OF TITLES
Carbonyl compounds, simple, enolisation and related reactions of, 18, 1 Carboxylic acids, tetrahedral intermediates derived from, spectroscopic detection and investigation of their properties, 21, 37 Catalysis by micelles, membranes and other aqueous aggregates as models of enzyme action, 17, 435 Catalysis, enzymatic, physical organic model systems and the problem of, 11, 1 Catalysis, general base and nucleophilic, of ester hydrolysis and related reactions, 5, 237 Catalysis, micellar, in organic reactions; kinetic and mechanistic implications, 8, 271 Catalysis, phase-transfer by quaternary ammonium salts, 15, 267 Cation radicals in solution, formation, properties and reactions of, 13, 155 Cation radicals, organic, in solution, kinetics and mechanisms of reaction of, 20, 55 Cations, vinyl, 9, 135 Chain molecules, intramolecular reactions of, 22, 1 Chain processes, free radical, in aliphatic systems involving an electron transfer reaction, 23, 271 Charge density-N.M.R. chemical shift correlations in organic ions, 11, 125 Chemically induced dynamic nuclear spin polarization and its applications, 10, 53 Chemiluminescence of organic compounds, 18, 187 CIDNP and its applications, 10, 53 Conduction, electrical, in organic solids, 16, 159 Configuration mixing model: a general approach to organic reactivity, 21, 99 Conformations of polypeptides, calculations of, 6 , 103 Conjugated, molecules, reactivity indices, in, 4, 73 Crown-ether complexes, stability and reactivity of, 17, 279 D,O-H,O mixtures, protolytic processes in, 7,259 Degenerate carbocation rearrangements, 19, 223 Diazo compounds, aliphatic, reactions with acids, 5, 331 Diffusion control and pre-association in nitrosation, nitration, and halogenation, 16, 1 Dimethyl sulphoxide, physical organic chemistry of reactions, in, 14, 133 Dipolar aprotic and protic solvents, rates of bimolecular substitution reactions in, 5, 173 Directive effects in aromatic substitution, a quantitative treatment of, 1, 35 Directive effects in gas-phase radical addition reactions, 16, 51 Discovery of the mechanisms of enzyme action, 1947-1963, 21, I Displacement reactions, gas-phase nucleophilic, 21, 197 Effective molarities of intramolecular reactions, 17, 183 Electrical conduction in organic solids, 16, 159 Electrochemical methods, study of reactive intermediates by, 19, 13I Electrochemistry, organic, structure and mechanism in, 12, 1 Electrode processes, physical parameters for the control of, 10, 155 Electron spin resonance, identification of organic free radicals by, 1, 284 Electron spin resonance studies of short-lived organic radicals, 5, 23 Electron-transfer reaction, free radical chain processes in aliphatic systems involving an, 23, 271 Electron-transfer reactions in organic chemistry, 18, 79 Electronically excited molecules, structure of, 1, 365
CUMULATIVE INDEX OF TITLES
221
Electronically excited states of organic molecules, acid-base properties of. 12, 131 Energetic tritium and carbon atoms, reactions of, with organic compounds, 2, 201 Enolisation of simple carbonyl compounds and related reactions, 18, I Entropies of activation and mechanisms of reactions in solution, I , I Enzymatic catalysis, physical organic model systems and the problem of, 11, 1 Enzyme action, catalysis by micelles, membranes and othcr aqueous aggregates as models of, 17, 435 Enzyme action, discovery of the mechanisms of, 1947-1963, 21, 1 Equilibrating systems, isotope effects on nmr spectra of, 23. 63 Equilibrium constants, N.M.R. measurements of. as a function of temperature, 3, 187 Ester hydrolysis, general base and nucleophilic catalysis, 5, 237 Exchange reactions, hydrogen isotope, of organic compounds in liquid ammonia, I , I56 Exchange reactions, oxygen isotope, of organic compounds. 2, I23 Excited complexes, chemistry of, 19, I Excited molecules, structure of electronically, 1, 365 Force-field methods, calculation of molecular structure and energy by, 13, 1 Free radical chain processes in aliphatic systems involving an electron-transfer reaction, 23, 271 Free radicals, identification by electron spin resonance, 1, 284 Free radicals and their reactions at low temperature using a rotating cryostat, study of8, 1 Gaseous carbonium ions from the decay of tritiated molecules. 8, 79 Gas-phase heterolysis, 3, 9 I Gas-phase nucleophilic displacement reactions, 21, 197 Gas-phase pyrolysis of small-ring hydrocarbons. 4, 147 Gas-phase reactions of organic anions, 24, I General base and nucleophilic catalysis of ester hydrolysis and related reactions, 5, 237 H,O-D,O mixtures, protolytic processes in, 7, 259 Halogenation, nitrosation, and nitration, diffusion control and pre-association in, 16, 1
Halides, aryl, and related compounds, photochemistry of, 20. 191 Heat capacities of activation and their uses in mechanistic studies, 5 , 121 Heterolysis, gas-phase, 3, 91 Hydrated electrons, reactions.of, with organic compounds, 7. I I5 Hydration, reversible, of carbonyl compounds, 4, 1 Hydride shifts and transfers, 24, 57 Hydrocarbons, small-ring, gas-phase pyrolysis of, 4, 147 Hydrogen atom abstraction from 0-H bonds, 9, 127 Hydrogen isotope effects in aromatic substitution reactions, 2, 163 Hydrogen isotope exchange reactions of organic compounds in liquid ammonia, 1, 156
Hydrolysis, ester, and related reactions, general base and nucleophilic catalysis of, 5, 237 Intermediates, reactive, study of, by electrochemical methods, 19, 131
222
CUMULATIVE INDEX OF TITLES
Intermediates, tetrahedral, derived from carboxylic acids, spectroscopic detection and investigation of their properties, 21, 37 Intramolecular reactions, effective molarities for, 17, 183 Intramolecular reactions of chain molecules, 22, 1 Ionization potentials, 4, 31 Ion-pairing effects in carbanion reactions, 15, 153 Ions, organic, charge density-N.M.R. chemical shift correlations, 11, 125 Isomerization, permutational, of pentavalent phosphorus compounds, 9, 25 Isotope effects, hydrogen, in aromatic substitution reactions, 2, 163 Isotope effects, magnetic, magnetic field effects and, on the products of organic reactions, 20, 1 Isotope effects on nmr spectra of equilibrating systems. 23, 63 Isotope effects, steric, experiments on the nature of, 10, 1 Isotope exchange reactions, hydrogen, of organic compounds in liquid ammonia, 1, 150 Isotope exchange reactions, oxygen, of organic compounds, 3, 123 Isotopes and organic reaction mechanisms, 2, 1 Kinetics and mechanisms of reactions of organic cation radicals in solution, 20, 55 Kinetics, reaction, polarography and, 5, 1 Kinetics of organic reactions in water and aqueous mixtures, 14, 203 0-Lactam antibiotics, the mechanisms of reactions of, 23, 165 Least nuclear motion, principle of, 15, 1 Macromolecular systems of biochemical interest, 13CN.M.R. spectroscopy in 13,279 Magnetic field and magnetic isotope effects on the products of organic reactions, 20. 1 Mass spectrometry, mechanisms and structure in: a comparison with other chemical processes, 8, 152 Mechanism and structure in carbene chemistry, 7, 153 Mechanism and structure in mass spectrometry: a comparison with other chemical processes, 8, 152 Mechanism and structure in organic electrochemistry, 12, 1 Mechanisms and reactivity in reactions of organic oxyacids of sulphur and their anhydrides, 17, 65 Mechanisms of reactions of p-lactam antibiotics, 23, 165 Mechanisms, nitrosation, 19, 381 Mechanisms of proton transfer between oxygen and nitrogen acids and bases in aqueous solution, 22, 113 Mechanisms, organic reaction, isotopes and, 2, 1 Mechanisms of reaction in solution, entropies of activation and, 1, 1 Mechanisms of reactions of 0-lactam antibiotics, 23, 165 Mechanisms of solvolytic reactions, medium effects on the rates and, 14, 10 Mechanistic applications of the reactivity-selectivity principle, 14, 69 Mechanistic studies, heat capacities of activation and their use, 5, 121 Medium effects on the rates and mechanisms of solvolytic reactions, 14, 1 Meisenheimer complexes, 7, 21 1 Metal complexes, the nucleophilicity of towards organic molecules, 23, 1 Methyl transfer reactions, 16, 87 Micellar catalysis in organic reactions: kinetic and mechanistic implications, 8, 27 1
CUMULATIVE INDEX OF TITLES
223
Micelles, aqueous, and similar assemblies, organic reactivity in, 22, 21 3 Micelles, membranes and other aqueous aggregates, catalysis by, as models of enzyme action, 17, 435 Molecular structure and energy, calculation of, by force-field methods, 13, I Nitration, nitrosation, and halogenation, diffusion control and pre-association in, 16, 1 Nitrosation mechanisms, 19, 381 Nitrosation, nitration, and halogenation. diffusion control and pre-association in, 16, 1 N.M.R. chemical shiftxharge density correlations, 11, 125 N.M.R. measurements of reaction velocities and equilibrium constants as a function of temperature, 3, 187
N.M.R. spectra of equilibrating systems, isotope effects on, 23, 63 N.M.R. spectroscopy, I3C, in macromolecular systems of biochemical interest, 13, 279 Non-planar and planar aromatic systems, 1, 203 Norbornyl cation: reappraisal of structure, 11, 179 Nuclear magnetic relaxation, recent problems and progress, 16, 239 Nuclear magnetic resonance, see N.M.R. Nuclear motion, principle of least, 15, 1 Nuclear motion, the principle of least, and the theory of stereoelectronic control, 24, 113 Nucleophilic aromatic photosubstitution, 11, 225 Nucleophilic catalysis of ester hydrolysis and related reactions, 5, 237 Nucleophilic displacement reactions, gas-phase, 21, 197 Nucleophilicity of metal complexes towards organic molecules, 23, 1 Nucleophilic vinylic substitution, 7, 1 OH-bonds, hydrogen atom abstraction from, 9, 127 Oxyacids of sulphur and their anhydrides, mechanisms and reactivity in reactions of organic, 17, 65 Oxygen isotope exchange reactions of organic compounds, 3, 123 Permutational isomerization of pentavalent phosphorus compounds, 9, 25 Phase-transfer catalysis by quaternary ammonium salts, 15, 267 Phosphorus compounds, pentavalent, turnstile rearrangement and pseudorotation in permutational isomerization, 9, 25 Photochemistry of aryl halides and related compounds, 20, 191 Photochemistry of carbonium ions, 9, 129 Photosubstitution, nucleophilic aromatic, 11, 225 Planar and non-planar aromatic systems, 1, 203 Polarizability, molecular refractivity and, 3, 1 Polarography and reaction kinetics, 5, 1 Polypeptides, calculations of conformations of, 6, 103 Prelassociation, diffusion control and, in nitrosation, nitration, and halogenation, 16, 1 Products of organic reactions, magnetic field and magnetic isotope effects on, 30, 1 Protic and dipolar aprotic solvents, rates of bimolecular substitution reactions in, 5, 173
224
CUMULATIVE INDEX OF TITLES
Protolytic processes in H,O-D,O mixtures, 7, 259 Protonation and solvation in strong aqueous acids, 13, 83 Protonation sites in ambident conjugated systems, 11, 267 Proton transfer between oxygen and nitrogen acids and bases in aqueous solution, mechanisms of, 22, 113 Pseudorotation in isomerization of pentavalent phosphorus compounds, 9, 25 Pyrolysis, gas-phase, of small-ring hydrocarbons, 4, 147 Radiation techniques, application to the study of organic radicals, 12, 223 Radical addition reactions, gas-phase, directive effects in, 16, 5 1 Radicals, cation in solution, formation, properties and reactions of, 13, 155 Radicals, organic application of radiation techniques, 12, 223 Radicals, organic cation, in solution kinetics and mechanisms of reaction of, 20, 5 5 Radicals, organic free, identification by electron spin resonance, I , 284 Radicals, short-lived organic, electron spin resonance studies of, 5, 53 Rates and mechanisms of solvolytic reactions, medium effects on, 14, 1 Reaction kinetics, polarography and, 5, 1 Reaction mechanisms, use of volumes of activation for determining, 2, 93 Reaction mechanisms in solution, entropies of activation and, 1, 1 Reaction velocities and equilibrium constants, N.M.R. measurements of, as a function of temperature, 3, 187 Reactions of hydrated electrons with organic compounds, 7, 115 Reactions in dimethyl sulphoxide, physical organic chemistry of, 14, 133 Reactive intermediates, study of, by electrochemical methods, 19, 131 Reactivity indices in conjugated molecules, 4, 73 Reactivity, organic, a general approach to: the configuration mixing model, 21, 99 Reactivity-selectivity principle and its mechanistic applications, 14, 69 Rearrangements, degenerate carbocation, 19, 223 Refractivity, molecular, and polarizability, 3, 1 Relaxation, nuclear magnetic, recent problems and progress, 16, 239 Short-lived organic radicals, electron spin resonance studies of, 5, 53 Small-ring hydrocarbons, gas-phase pyrolysis of, 4, 147 Solid-state chemistry, topochemical phenomena in, 15, 63 Solids, organic, electrical conduction in, 16, I59 Solutions, reactions in, entropies of activation and mechanisms, 1, 1 Solvation and protonation in strong aqueous acids, 13, 83 Solvents, protic and dipolar aprotic, rates of bimolecular substitution-reactions in, 5, 173 Solvolytic reactions, medium effects on the rates and mechanisms of. 14, 1 Spectroscopic detection of tetrahedral intermediates derived from carboxylic acids and the investigation of their properties, 21, 37 Spectroscopic observations of alkylcarbonium ions in strong acid solutions, 4, 305 Spectroscopy, 13C N.M.R., in macromolecular systems of biochemical interest, 13, 279 Spin trapping, 17, 1 Stability and reactivity of crown-ether complexes, 17, 279 Stereoelectronic control, the principle of least nuclear motion and the theory of, 24, 113 Stereoselection in elementary steps of organic reactions, 6 , 185
CUMULATIVE INDEX OF TITLES
225
Steric isotope effects, experiments on the nature of, 10. 1 Structure and mechanisms in carbene chemistry, 7, 153 Structure and mechanism in organic electrochemistry, 12, 1 Structure and reactivity of carbenes having aryl substituents, 22, 31 1 Structure of electronically excited molecules, 1, 365 Substitution, aromatic, a quantitative treatment of directive effects in, 1, 35 Substitution, nucleophilic vinylic, 7, 1 Substitution reactions, aromatic, hydrogen isotope effects in, 2, 163 Substitution reactions, bimolecular, in protic and dipolar aprotic solvents, 5, 173 Sulphur, organic oxyacids of, and their anhydrides, mechanisms and reactivity in reactions of, 17, 65 Superacid systems, 9, 1 Tcmperature, N.M.R. measurements of reaction velocities and equilibrium constants as a function of, 3, 187 Tetrahedral intermediates derived from carboxylic acids, spectrosopic detection and the investigation of their properties, 21, 37 Topochemical phenomena in solid-state chemistry, 15, 63 Tritiated molecules, gaseous carbonium ions from the decay of 8, 79 Tritium atoms, energetic, reactions with organic compounds, 2, 201 Turnstile rearrangements in isomerization of pentavalent phosphorus compounds, 9, 25 Unsaturated compounds, basicity of, 4, 195 Vinyl cations, 9, 185 Vinylic substitution, nucleophilic, 7, 1 Volumes of activation, use of, for determining reaction mechanisms, 2, 93 Water and aqueous mixtures, kinetics of organic reactions in, 14, 203
This Page Intentionally Left Blank