Organophosphorus Chemistry (SPR Organophosphorus Chemistry (RSC)) (v. 9)

A Specialist Periodical Report

Organophosphorus Chemistry Volume 9

A Review of the Literature published between July 1976 and June 1977

Senior Reporter S. Trippett, Department of Chemistry, University of Leicester Reporters D. W. Allen, Sheffield Polytechnic R. S. Edmundson, University of Bradford J. B. Hobbs, The City University, London D. W. Hutchinson, University of Warwick R. Keat, University of Glasgow J. A. Miller, University of Dundee D. J. H. Smith University of Leicester J. C. Tebby, North Staffordshire Polytechnic, Stoke-on-Trent B. J. Walker, Queen's University of Belfast

The Chemical Society Burlington House, London, W I V OBN

British Library Cataloguing in Publication Data Organophosphorus chemistry. (Chemical Society. Specialist periodical reports). Vol. 9 1. Organophosphorus compounds I. Trippett, Stuart 11. Series 547.07 QD412.Pl 73-268317 ISBN 0-85186-086-9 ISSN 0306-0713

Copyright 0 1978 The Chemical Society All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means - graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems - without written permission from The Chemical Society

Printed in Great Britain by Adlard and Son Ltd Bartholomew Press, Dorking

Foreword

Perhaps the most surprising development during the year under review has been the synthesis by G. Becker (2.anorg. Chem., 1976, 423, 242; 430, 67) of methylenephosphines. Although partly prepared for this by phosphacyanins, phosphabenzenes, and more recently by the iminophosphines of E. Niecke and W. Fluck, it still comes as a shock to old hands at the game to be told of methylenephosphines, i.e. compounds of the general formula R1P=CR2R3,that are stable at room temperature. So much for poor 2p-3p overlap. One wonders what other cherished illusions will die in the coming year. The Chapter on Photochemical, Radical, and Deoxygenation Reactions does not appear this year because of illness of the Reporter at a critical time.

S.Trippett

Contents Chapter 1 Phosphines and Phosphonium Salts By D.W. Allen

1

1 Introduction

1

2 Phosphines Preparation From Halogenophosphines and Organometallic Reagents From Metallated Phosphines By addition of P-H to Unsaturated Compounds By Reduction Miscellaneous Reactions Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous

1 1 1 3 4 5

6 8 8

10 13 15

3 Phosphonium Salts Preparation Reactions Alkaline Hydrolysis Additions to Unsaturated Phosphonium Salts Miscellaneous

20

4 Phospholes

26

5 Phosphorins

28

Chapter 2 Quinquecovalent Phosphorus Compounds By S. Trippett

18 18 20 22 24

30

1 Introduction

30

2 Structure and Bonding

32

3 Acyclic Systems

33

4 Four-membered Rings

34

5 Five-membered Rings Phospholes

35 36

Contents

vi 1,2-Oxaphospholans lY3,2-Dioxaphospholans 1,3,2-Dioxaphospholens 1,3,2-Oxazaphospholidines Miscellaneous

37 37 40 42 43

6 Six-membered Rings

46

7 Six-co-ordinate Species

47

Chapter 3 Halogenophosphines and Related Compounds By J. A. Miller

48

1 Introduction 2 Halogenophosphines Preparation Reactions with A1kenes Reactions with Alkyl Halides Reactions with OH Groups and Epoxides Biphilic Reactions with Carbonyl Compounds Reactions with Phosphorus(n1) Compounds Miscellaneous Aspects Silyl and Related Phosphines

48 48 48 49 51 51 53 56

3 Halogenophosphoranes Preparation and Structure Reactions of Phosphoranes Uses of Phosphoranes in Organic Synthesis

59 59 62

Chapter 4 Phosphine Oxides and Sulphides By J. A. Miller

57

57

64

66

1 Introduction

66

2 Preparation

66

3 Reactions at Phosphorus or Arsenic

70

4 Reactions of the Side-chain

74

5 Miscellaneous Physical and Structural Aspects

77

Chapter 5 Tervalent Phosphorus Acids By B. J. Walker 1 Introduction

80 80

vii

Contents

80 80 80 81 86 86

2 Phosphorous Acid and its Derivatives Nucleophilic Reactions Attack on Saturated Carbon Attack on Unsaturated Carbon Attack on Nitrogen Attack on Oxygen Attack on Halogen Electrophilic Reactions Rearrangements Cyclic Esters of Phosphorous Acid Miscellaneous Reactions

90 90 95 96 99

3 Phosphonous and Phosphinous Acids and their Derivatives

99

Chapter 6 Quinquevalent Phosphorus Acids By R. S. Edmundson

101

1 Synthetic Methods General Phosphoric Acid and its Derivatives Phosphonic and Phosphinic Acids and their Derivatives

101 101 102 107

2 Reactions General Phosphoric Acid and its Derivatives Phosphonic and Phosphinic Acids and their Derivatives

113 113 115 124

Chapter 7 Phosphates and Phosphonates of Biochemical Interest 130 By D. W. Hutchinson 1 Introduction

130

2 Coenzymes and Cofactors Nicot inamide Nucleotides Coenzyme A Other Coenzymes and Cofactors

131 131 133 134

3 Sugar Phosphates

135

4 Phospholipids

137

5 Phosphonates

139

6 Oxidative Phosphorylation

141

7 Enzymology Enzyme Mechanisms Phosphoproteins

141 141 146

8 Other Compounds of Biochemical Interest

147

Contents

viii

Chapter 8 Nucleotides and Nucleic Acids By J. B. Hobbs

151

1 Introduction

151

2 Mononucleotides Chemical Synthesis Cyclic Nucleotides AffinityChromatography

151 151 157 159

3 Nucleoside Polyphosphates

161

Chemical Synthesis Afsnity Labelling

161 170

4 Oligo- and Poly-nucleotides Chemical Synthesis Enzymatic Synthesis Sequencing Other Studies

172 172 176 178 180

5 Analytical Techniques and Physical Methods

181

Chapter 9 Ylides and Related Compounds By D, J. H. Smith 1 Methylmephosphoran@

182

182

Preparation and Structure Reactions Aldehydes Ketones Miscellaneous

182 184 184 186 188

2 Phosphoranes of Special Interest

192

3 Selected Applications of Ylides in Synthesis

195 195 197 199 200 202

Heterocycles Pheromones Prostaglandins Carotenoids Non-Benzenoid Aromatic Compounds 4 Selected Applications of Phosphonate Carbaniom General Natural Products

204 204 208

ix

Contents

Chapter 10 Phosphazenes By R, Keat

210

1 Introduction

210

2 Synthesis of Acyclic Phosphazenes From Amines and Phosphorus(v) Halides From Azides and Phosphorus(m) Compounds Other Methods

210 210 210 214

3 Properties of Acyclic Phosphazenes Halogeno-derivatives Amino-, Alkoxy-, Alkyl, and Aryl Derivatives

216 216 216

4 Synthesis of Cyclic Phosphazenes

223

5 Properties of Cyclic Phosphazenes Halogeno-derivatives Amino-derivatives Alkoxy- and Aryloxy-derivatives Alkyl and Aryl Derivatives

224 224 225 228 230

6 Polymeric Phosphazenes

23 1

7 Phosphazenes as Fire Retardants

233

8 Molecular Structures of Phosphazenes that have been Determined by X-Ray Diffraction Methods 234

Chapter 11 Physical Methods By J. C. Tebby 1 Nuclear Magnetic Resonance Spectroscopy Biological Applications Chemical Shifts and Shielding Effects P ~ O S P ~ O I1X I S - ~ SP of PI1 Compounds dp of PI11 Compounds 8p of P I V Compounds Sp of P V Compounds Carbon-13 Fluorine-19 Oxygen-17 and Nitrogen-15 Hydrogen-1 Equilibria and Shift Reagents Pseudorotation Restricted Rotation

237 237 237 238 238 238 239 240 242 243 244 245 245 245 246 247

Contents

X

Non-equivalence, Configuration, and Medium Effects Spin-Spin Coupling JPPand JPM JPF,JPO,and JPN JPC JPH

JPC~H JPXCH and JPCXH Relaxation, C.I.D.N.P., and N.q.r. Studies

248 250 250 251 251 252 253 254 254

2 Electron Spin Resonance Spectroscopy

255

3 Vibrational and Rotational Spectroscopy Band Assignments and Structure Elucidation Stereochemistry Bonding

257 257 258 259

4 EIectronic Spectroscopy Absorption Photoelectron

260 260 261

5 Rotation

262

6 Diffraction X-Ray Electron

262 262 266

7 Dipole Moments, Conductance, and Voltammetry

266

8 Mass Spectrometry

268

9 pKa and Thermochemical Studies

270

10 Chromatography G.1.c. T.1.c. Paper Chromatography H.p.1.c. Column Chromatography

Author Index

27 1 271 271 27 1 27 1 27 1 273

Abbreviatiom*

AIBN DAD DBN DBU DCC DEAE DMF DMSO g.1.c. HMPT h.p.1.c. PEI QAE TDAP TFAA THF TPS t.1.c.

bisazoisobutyronitrile diethyl azodicarboxylate 1,5-diazabicyclo[4,3,0]non-5-ene

1,5-diazabicyclo[5,4,O]undec-5-ene dicyclohexylcarbodi-imide diethylaminoethyl dimethylformamide dimethyl sulphoxide gas-liquid chromatography hexamethylphosphortriamide high-performance liquid chromatography polyethyleneimine quaternary aminoethyl tris(dimethy1amino)phosphine triiluoroacetic acid tetrahydrofuran tri-isopropylbenzenesulphonylchloride thin-layer chromatography

* Abbreviations used in Chapters 7 and 8 are those included in the appropriate list of abbreviations in the Biochemical Journal, except for the following: poly(iA-U) the alternating copolymer prepared from adenosine 5’-0-(1-thiotriphosphate) and UTP

I

Phosphines and Phosphonium Salts BY D. W. ALLEN

1 Introduction Interest in the chemistry of phosphines and phosphonium salts continues at a high level, and, as in previous years, considerable selection has been necessary in the preparation of this Report. A noticeable feature has been the large number of papers concerned with the preparation of chiral phosphines and their use in the homogeneous catalysis of asymmetric synthesis. Of these, only those involving some new aspect of organophosphorus chemistry are included here. The use and significance of stereochemical reaction cycles in the reactions of chiral phosphines and phosphonium salts have been surveyed,l and a major review of the chemistry of polycyclic C-P heterocycles, much of which is concerned with tertiary phosphines and phosphonium salts, has appeared.2Procedures for the synthesis of a range of unidentate and polydentate phosphine ligands have been collected together Aspects of the chemistry of methylphosphines have been included in a single in a review of recent developments in the chemistry of simple P-C compounds.* 2 Phosphines Preparation.-From Halogenophosphines and Organometallic Reagents. A series of trimethylsilylcyclopentadienylphosphines,e.g. (l), has been prepared from the appropriate tr imethyl silylcyclopentadienyl-lithium and halogenophosphine. Similarly, the reaction of pentamethylcyclopentadienyl-lithium with chlorodimethylphosphine gives the phosphine (2), which is reported to be thermally stable.6

(2)

(1)

Direct metallation of cross-linkedpolystyrenes,using the n-butyl-lithium-TMEDA reagent, followed by treatment with chlorodiphenylphosphine,affords an improved 1 2

3 4

6 6

R. Luckenbach, N. Muller, and W. Endres, Chem.-Ztg., 1976, 100, 320.

S. D. Venkataramu, G . D. Macdonell, W. R. Purdom, M. El-Deek, and K. D. Berlin, Chcm.

Rev., 1977, 77, 121. Inorganic Syntheses, 1976, Vol. 16, pp. 153-206. H. Harnisch, Angew. Chem. Znternat. Edn., 1976, 15, 468. P. Jutzi and H. Saleske, Chem. Ber., 1977,110, 1269. P. Jutzi, H. Saleske, and D. Nadler, J. Organometallic Chem., 1976, 118, C8. 1

2

Organophosphorus Chemistry

route to polymeric tertiary phosphine ligands (3) that are suited to the formation of transition-metal catalysts for hydrogenation reactions. The optically active phosphines (4) and (S), of interest for the catalysis of asymmetric hydrogenations, have Me

(3)

(4)

(5)

been prepared from the reactions of chlorodiphenylphosphine with the Grignard reagents derived from (-)-menthy1 halides * and the optically active 2-halogenomethylpyrrolidine~,~ respectively. Two unusual fluorinated phosphines, (6) and (7), have been prepared by the reactions of organolithium reagents with appropriate halogenophosphines.lO*l1

The sterically bulky phosphines (8) have been prepared by the Grignard method from chlorodi(t-buty1)phosphine and chlorodicyclohexylphosphine. In certain iridium(1)complexes, metallation of these phosphines occurs on the terminal olefinic carbon atom.12Treatment of a,w-dialkynyl-lithiumreagents with chlorodi-(t-buty1)phosphine gives the diacetylenicdiphosphines (9),which form large ring compounds when they form complexes with transition metals.13 R',PCH,C(R2)=CH,

(8)

R' = But, R' = H ; R' = cyclohexyl, R' = Me

BU~,PC-C(CH,),C-CPBU~, (9) n = 4 or 5

Interest in the synthesis of compounds containing the P(CH,CO,R), grouping continues, and routes involving the reactions of chlorophosphines with sodium enolates of acetate esters14and Reformatsky reagents16have been reported. A range R. H. Grubbs and S.-C H. Su, J. Organometallic Chem., 1976,122, 151. I. Ogata and M. Tanaka, Japan. Patent 76 88942 (Chem. A h . , 1977,86, 72920). 9 1. Ogata, F. Mizukami, Y. Ikeda, and M. Tanaka, Japan. Patent 76 39662; 76 43754 (Chem. A h . , 1976, 85, 124143, 124144). lo D. H. Lemmon and J. A. Jackson, J. Fluorine Chem., 1976, 8, 23. 11 W. R. Cullen and A. W. Wu, J. Fluorine Chem., 1976, 8, 183. 1 2 S. Hietkamp, D. J. Stufkens, and K. Vrieze, J. Organometallic Chem., 1976, 122, 419. l3 H. D. Empsall, E. Mentzer, D. Pawson, B. L. Shaw, R. Mason, and G. A. Williams, J.C.S. Chem. Comm., 1977, 311. l4 2 . S. Novikova, S. N. Zdorova, V. N. Kirzner, and I. F. Lutsenko, J. Cen. Chem. (U.S.S.R.), 7

8

1976, 46, 572.

16

D. M. Malenko and Yu. G. Gololobov, Zhur. obshchei Khim., 1976,46,2391 (Chem.Abs., 1977,

86,43 785).

3

Phosphines and Phosphonium Salts

of N-phosphinylated heterocyclic systems has been prepared by the reactions of chlorophosphines with N-potassio-derivatives of pyrrolesls. and pyrazoles.l* 13C N.m.r. studies1' reveal that the product from the reaction of potassiopyrrole with phosphorus trichloride is (lo), and not (11) as reported earlier.lg

From Metallated Phosphines. The reactions of organophosphide anions with alkyl tosylates have been used to prepare the chiral diphosphines (12)20 and (13),21 and also a range of phosphines bearing chiral substituents derived from various naturaI products.2a

I'

'CH,OTs

/'

'.CH,PPh,

v

'CH,P

(13)

(12)

The reaction of lithium diphenylphosphide with a bis-benzylic halide has been employed in the synthesis of the diphosphine (14), which is of interest as a transspanning ligand.23Displacement of halide ion from a vinylic carbon atom occurs in the reaction of cis- and trans-/3-chlorovinyldiphenylarsineswith lithium diphenylphosphide, which proceeds stereospecifically with the formation of the corresponding cis- and trans-phosphine-arsines (15). Surprisingly, the reaction of lithium diphenylphosphide with a thirty-fold excess of cis-1 ,Zdichloroethene yields only the cis-diphosphine (16).24

g

CH,PPh,

'' '

CH,PPh,

(14)

H Ph,PCH=CH (15)

AsPh, Ph,P

L /

7

C \

PPh,

(16)

F. Marschner, H. Kessel, and H. Goetz, Phosphorus, 1976, 6, 135. S. Fischer, J. Hoyano, I. Johnson, and L. K. Peterson, Canad. J. Chem., 1976,54,2706. la S. Fischer, J. Hoyano, and L. K. Peterson, Canad. J. Chent., 1976, 54, 2710. l9 K. Issleib and A. Brack, Z . anorg. Chem., 1957, 292, 245. 2o W. Beck and H. Menzel, J. Organometallic Chem., 1977, 133, 307. 21 M. Tanaka, I. Ogata, Y. Ikeda, and T. Hayashi, Japan. Patent 76 101 956 (Chem. A h . , 1977,86, l6

22

23 24

190 198). J. Ben& and J. HetflejS, COIL Czech. Chem. Comm., 1976, 41, 2256. N. J. DeStefano, D. K. Johnson, and L. M. Venanzi, Helv. Chim. Acta, 1976,59, 2674. K.-K. Chow, W. Levason, and C. A. McAuliffe, J.C.S. Dalton, 1976, 1429.

4

Organophosphorus Chemistry

Further instances of the probable attack of phosphide anions on halogen have appeared. Lithium bis(trimethylsi1yl)phosphide reacts with 1,Zdibromoethane to form the diphosphine (13, together with ethylene.2s Similarly, the reaction of

-r'u + Br-CHz-CH2pBr

CH,=CH,

--+

(MejSi),P

+ (Me,Si),PBr

(Me, Si)*F

*

(Me,Si),P-P(SiMe,),

(17) lithium diphenylphosphide with 1,Zdi-bromo- or -di-iodo-adamantane affords the anti-Bredt olefin adamantene (isolated as the dimer), in addition to 1- and 2-diphenylphosphino-adamantanes (Scheme 1).

X = BrorI Reagent: i, LiPPha

Scheme 1

Dimetallodiphosphide reagents of type (18) react with difunctional halogen derivatives to form five-, six-, or seven-membered heterocycles of types (19) and (20).27s28The reagent (18; R=Ph, M=Li, n = 2 ) is conveniently prepared by the cleavage of 1,2-bis(diphenyIphosphino)ethane, using lithium.2a

RP-

M

(CH,),-PR

,P'R M

(18) R = Me,Bu,orPh M = Lior Na n = 2,3,or 4

R'P

,PR1

E

1\2/

(19)

r""7

r(c"'7

E = C,Ge,or Sn R' = Me, Bu, or Ph

\,APR1 R2

\p (20)

R2 = alkyl or Ph

E = P o r As R' = Me,Bu,orPh RZ = alkyl or Ph

By Addition ofP-H

to Unsaturated Compounds. There has been a marked reduction in the number of papers concerned with this route in the past year, but nevertheless a number of interesting studies have been reported. Thus, for example, the primary phosphine (21) undergoes free-radical-inducedintramolecularcyclization to form the bicyclic phosphine l-phosphabicyclo[3,3,l]nonane(22).20 (CH,=CHCHZ'),CHCH,PH,

(21) 15 10 17

18 SQ

cs_) (22)

H. Schumann, L. Rosch, and W. Schmid-Fritsche, Chem.-Ztg., 1977,101, 156. D. G. Gillespie and B. J. Walker, Tetrahedron Letters, 1977, 1673. K. Issleib and W. Bottcher, Synth. React. Inorg. Metal-Org. Chem., 1976, 6, 179. K. Issleib and P. Thorausch, Phosphorus and Sulphur, 1977, 3, 203. F. Krech and K. Issleib, 2.anorg. Chem., 1976, 425, 209.

5

Phosphines and Phosphonium Salts

The addition of secondary phosphines to vinylaminophosphines, e.g. (23), occurs under both free-radical30 and base-catalysed 31 conditions to form, e.g., (24) or (25). Similar addition of primary phosphines to (23) occurs to form either polymers, e.g. (26),3O or diphosphacyclohexanes, e.g. (27),31depending on the mode of initiation. Et,NP

/

CH,CH,PPh,

Ph,PH

1:l

\CH=CH,

CHzCH2{

!:

:1

E t,NP(CHZCH,PPhJ2 (24)


(25)

-

Ph,PH

Et,NP(CH=CH,),

n

HzCH2~CHzC H , I PCH,C H,PCHzC I H,NEt,

EtzNpWpP

NEt,

(26)

(27)

Phosphine and primary phosphines add to vinyl acetate to form (2-acetoxyethy1)phosphines, e.g. (28), which can be hydrolysed to form (2-hydroxyethyl)phosphines, e.g. (29).32The addition of phenylacetylene to phenylphosphine that is co-ordinated to a dicarbonylcyclopentadienylmanganese unit occurs stereospecifically, with the formation of (co-ordinated) phenylbis(trans-,%styryl)phosphine (30).33 ,CH=CH /Ph RP(CH,CH,OAc),

RP(CH,CH,OH),

(28) R = Phorcyclohexyl

(29)

PhP, CH=CH

‘*h (30)

By Reduction. Both conformational isomers of the phosphepin (31) have been obtained by reduction of the related conformationally isomeric oxides, using either trichlorosilane or a mixture of trichlorosilane and triethylamine, the reactions proceeding with retention of configuration at p h o s p h ~ r u s .The ~ ~ chiral chelating diphosphine (32) has been prepared similarly by reduction of the corresponding

Ph (31) 30 31 32 33 34

THz

Ph,P

CH, I PPh,

(3 2)

K. Issleib and H. Becker, 2. anorg. Chem., 1977,428, 282. R. B. King and W. F. Masler, J. Amer. Chem. SOC.,1977, 99,4001. I. Hechenbleikner and W. P. Enlow, Ger. Offen. 2601 520 (Chern. A h . , 1976, 85, 192883). G . Huttner, H.-D. Miiller, P. Friedrich, and U. Kolle, Chern. Ber., 1977, 110, 1254. W. Winter, Chem. Ber., 1976, 109, 2406.

6

Organophosphorus Chemistry

oxide, using the trichlorosilane-triethylamine reagent.36A procedure for the reduction of triarylphosphine oxides by heating with hydrogen under pressure in the presence of a sulphur (or selenium)-silicon tetrachloride catalyst has been d e ~ c r i b e d . ~ ~ Miscellaneous. A number of routes to phosphines bearing reactive groupings have been reported. The reactions of trimethylsilylphosphines with chloroacetonitrile afford a convenient route to cyanomethylphosphines (33),37and the aminomethylphosphine (34), which is accessible by the aminomethylation of di-isopropylphosphine, reacts with acid chlorides to form the acylphosphines (35).38The rather Ph,-,P<SiMe,),

+ n ClCH,CN

-

Pri,PCH,NMe,

\[A?>

5

(35) R = MeorMeO

CH,OH

CH,OH

H

(36)

+ n Me3SiC1

(33) Pri,PCOR

(34)

HOCH,

Ph3-,P(CH,CN),

"#H

HO OH

(37) R = ButorPh

unusual (hydroxymethy1)phosphine (36) is formed in the reaction of guanosine with tetrakis(hydroxymethy1)phosphonium chloride,3gand procedures for the preparation of the phenolic phosphines (37) by demethylation of the corresponding methyl ethers have been developed.4o Cyclization procedures involving the reactions of primary phosphines with carbonyl compounds have been described for the synthesis of the heterocyclic phosphines (38)41 and (39).4a

(38) R' = HorMe R2,R3 = H, alkyl, or aryl 35

36 37 38

39 4O

41

43

K. Tamao, H. Yamamoto, H. Matsumoto, N. Miyake, T. Hayashi, and M. Kumada, Tetruhedron Letters, 1977, 1389. J. M. Townsend and D. H. Valentine, U.S. Publ. Pat. Appl. B, 518326 (Chem. Abs., 1976, 85, 5882). 0. Dahl, Acta Chem. Scand. ( B ) , 1976, 30, 799. R. G. Kostyanovskii, Yu. I. El'natanov, and Sh. M. Shakhaliev, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1977, 249 (Chem. Abs., 1977, 86, 140167). H. Loewengart and B. L. Van Duuren, Tetrahedron Letters, 1976, 3473. H. D. Empsall, B. L. Shaw, and B. L. Turtle, J.C.S. Dalton, 1976, 1500. K. Issleib, P. Thorausch, and W. Reves, 2.Chem.. 1976. 16. 276. K. Issleib, H. Winkelmann, and H. P.-Abicht,2.anorg. Chem:, 1976,424,97 (Chem. Abs., 1976, 85, 143201).

7

Phosphines and Phosphoniurn Salts

(39) R’, R2 = H or alkyl

The preparation and reactions of ‘organotin phosphines’ continue to attract interest, and have been Cyclodehydrogenation of the secondary phosphine (40) with azobenzene in the presence of AIBN gives the 1,Zstannaphospholans (41).44 Radical-initiated addition of di-n-butylstannane to the dialkynylphosphines R,Sn(H) (CH,),PHPh

Ph!Fp+

(40)

u

R,Sn-PPh

(41) R = E t o r Bu

(42) gives a mixture of (43) and (44).The latter is of value for the preparation of diphosphacyclohexadiene systems by reaction with aryldichl~rophosphines.~S But

c’ RC@

But

P\C\

+

f

%R

(42) R = H, Me, or But

fy But

But, (43)

R

Sn But2 (44)

A number of unusual chelating diphosphines have been prepared. The bicycloalkenyl compound (45) reacts with diphenylphosphine to form the diphosphine (46).4s Diphenyl(0-vinylpheny1)phosphine is dimerized on heating with rhodium(II1)

(45)

(46)

chloride in 2-methoxyethanol to form the diphosphine (47), isolated as a rhodium complex from which it may be freed by treatment with sodium cyanide solution.47 The chiral diphosphines (48) and (49) have been synthesized and used, as rhodium complexes, to promote asymmetric hydrogenation reaction^.^^

43 44

45 46

47 48

(47) (48) (49) H. Schumann, J. Held, W.-W. du Mont, G. Rodewald, and B. Wobke, Adv. Chem. Ser., 1976, 157, 57.

H. Weichmann and A. Tzschach, East Ger. P. 118883 (Chem. Abs., 1977, 86, 121525). G. Mark1 and D. Matthes, Tetrahedron Letters, 1976, 2599. W. R. Cullen, A. W. Wu, A. R. Davis, F. W. B. Einstein, and J. D. Hazlett, Canad. J. Chem., 1976,54,2871.

M. A. Bennett, R. N. Johnson, and I. B. Tomkins, J. OrganometaIIic Chem., 1977, 133, 231. K. Achiwa, J. Amer. Chem. SOC.,1976, 98, 8265.

Organophosphorus Chemisrry

8

The reaction of t-butyldichlorophosphinewith magnesium in THF gives a mixture of the cycIopolyphosphines(50) and (51), from which the hitherto unknown trimer is easily se~arated.*~ The cyclopentaphosphine (52) is conveniently prepared by the reaction of methylphosphine with dibenzylmerc~ry.~~ BU~P-PBU~

I t

ButP-PBut

Me /p\ MeP\ P-P Me Me

/PMe

(50) (51). (5 2) The unstable phospha-alkenes CF,=PH, CH,=PCl, and CH,=PH have been identified by microwave spectroscopy as products of the pyrolysis of CF,PH,, CH3PCl,, and (CH,),PH, respectively.61These species also undergo further pyrolysis to produce the phosphyl H e P . The related compound CH,C=P has also been detected in the pyrolysis products of ethyldichlor~phosphine.~~ The synthesis of the enantiomeric forms of the phosphine (53) has been reported, resolution being achieved via the carboxylic acid

Reactions.-Nucleophilic Attack at Carbon. A number of studies of the kinetics of quaternization of phosphines have been reported, all of which lend support to an earlier suggestion- that the transition state for such reactions is reactant-like. From the rates of quaternization of a series of heteroaryldiphenylphosphines (54) with a-bromoacetophenone, it was concluded that the n-excessive heterocyclic substituents are not significantly involved in pa-dn conjugative stabilizationof the developing phosphonium centre in the transition state of the reaction.66Similarly, there is little evidence of NP,-+P3d, conjugative effects in the transition state for quaternization of a series of trisdialkylaminophosphines (55) with iodomethane.66A comparison of the rates of quaternization of triphenylphosphine and triphenylarsine with iodomethane and various 4-substituted benzyl halides has led to the conclusion that the transition states for the quaternization of the phosphine and the arsine are at quite different positions along the reaction co-ordinates,there being a much smaller degree of bond-making in the transition state for the quaternization of the p h ~ s p h i n e . ~ ~ 49 60

61 5'

6$

s6 6'

M. Baudler and C. Gruner, 2. Naturforsch., 1976, 31b, 1311. A. L. Rheingold and P. Choudhury, J. Organometallic Chem., 1977, 128, 155. M. J. Hopkinson, H. W. Kroto, J. F. Nixon, and N. P. C. Simmons,J.C.S. Chem. Comm., 1976,

513.

M. J. Hopkinson, H. W. Kroto, J. F. Nixon, and N. P. C. Simmons, Chem. Phys. Letters, 1976, 42,460. R. Luckenbach, 2.Naturforsch., 1976, 31b, 1135. W. E. McEwen, J. E. Fountaine, D. N . Schulz, and W.4. Shiau, J. Org. Chem., 1976,41, 1684. D. W. Allen, J. R. Charlton, and B. G. Hutley, Phosphorus, 1976, 6, 191. T. Thorstenson and J. Songstad, Acta Chem. Scand. (A), 1976,30,781. T. Thorstenson and J. Songstad, Acta Chem. Scand. (A), 1976, 30,724.

Phosphines and Phosphonium Salts

(54)

X

9 Me1 MeCN b-

A

= O , S , N H , o r NMe

(R,N),hMe I'

Me, Et, or Pr;

=

n XwN-

where X =

C q or 0

N-Methylpyridinium salts are easily demethylated by triphenylphosphinein DMF, the reaction being accelerated by electron-withdrawing substituents in the pyridine ring.S8Similarly, triphenylphosphine has been used to debenzylate benzylarsonium salts in the synthesis of asymmetric tertiary a r ~ i n e s . ~ ~ The competitive elimination (E2) and substitution (SN2) reactions of cyclohexyl tosylate with triphenylphosphine have been examined. Triphenylphosphine is considered to be representative of neutral weak bases which have good nucleophilic affinity for carbon, but it is a poor reagent for elimination when compared with anionic weak bases that are also good carbon nucleophiles. The reaction of triphenylphosphine with cyclohexyl bromide occurs with almost complete substitution.6o Tertiary phosphines react with fluorosulphonyl isocyanate61s 82 and with isothiocyanatess3to form the zwitterionic adducts (56) and (57). 0 ~

li -

R,P-c'-NSO,F (56) R = Me,N, alkyl, or phenyl

(57) R = Me, Ph, a-naphthyl, COMe, or COPh

Activated olefins are reduced rapidly and stoicheiometrically by some alkylphosphines in anhydrous methan01.~~ The reaction is thought to proceed via ylide formation, as shown in Scheme 2. R'CH=CHR~ + R ~ , P

+

R ~ ~ ~ C H R ~ C H R ~R ~ & C R ~ C H , R ~

poH

R' = C0,MeorCOPh R2 = Et, Prn, or Bun R'CH,CH,R' + R2,P0 +-+ MeOMe

RZ,P(OMe)CHR'CH,R'

+ Rz3kHR1CH,R1MeO'

Scheme 2

The reaction of triethylphosphine with dimethyl acetylenedicarboxylate in the presence ofp-chlorobenzaldehydeis reported to lead to the olefin (58) and the bicyclic lactone (59). In the presence of water, the initial dipolar adduct (60) is hydrolysed, with the formation of dimethyl fumarate and the phosphine oxide.66 58 59 60

61 82

63

I34

(55

U. Berg, R. Gallo, and J. Metzger, J. Org. Chem., 1976, 41, 2621. L. B. Ionov, V. I. Kornev, and L. A. Kunitskaya, J. Gen. Chem. (U.S.S.R.), 1976,46, 65. D. J. McLennan, J.C.S. Perkin 11, 1977, 293. H. W, Roesky and G. Sidiropoulos, Angew. Chem. Internat. Edn., 1976, 15, 693. R. Appel and M. Montenarh, Chem. Ber., 1977,110,2368. K. Akiba, T. Yoneyama, H. Hamada, and N. Inamoto, Bull. Chem. SOC.Japan, 1976,49,1970. M. G. Burnett, T. Oswald, and B. J. Walker, J.C.S. Chem. Comm., 1977, 155. K. Akiba, T. Yoneyama, and N. Inamoto, Bull. Chem. SOC.Jaoan. 1976. 2023-

10

Organophosphorus Chemistry

H’

‘C0,Me

h

(59) Ar = p-CIC,H,

( 5 8)

(60)

Triphenylphosphinereacts with the methyl 2-bromoalkanoates (61) to form either the betaine (62) or the ylide (63), depending on conditions and the nature of the solvent. In the presence of aldehydes, the betaines (62) undergo Wittig reactions via the ylides (63) without the addition of base.66 Ph,P + BrCHRC0,Me

__f

Ph,kHRCO,-

(61) R = alkyl

-co,

Ph,P=CHR

(63)

(62)

Treatment of the a-bromovinylphosphonateesters (64)with tri-n-butylphosphine gives the trans-betaines (65).g7Trimethylphosphinereacts with dichloroacetyleneto give the bis-ylide (6Qg8

c1

).

H,C=C(Br)P(O)

(OR),

Bu,P

(64) R = MeorEt

Bu3P r

HPMe3

\

‘CH=CH

‘P(0) (OR) 0‘

2-%

c1

Me3P

(65)

(66)

Nucleuphilic Attack at Halogen. The reactions occurring in the triphenylphosphinecarbon tetrachloride system continue to attraa attention. The salt (67), which is the first isolable product from the reactions of the above system, undergoes ready dechlorination on treatment with trisdimethylaminophophine (TDAP) to form the ylide (68) and the dichlorophosphorane(69). This reaction offers a convenient route to the ylide (68), and enables the course of other reactions occurring in the triphenylPh,kCl, C1’

(67)

: Ph,P=CCI,

(68)

+

(Me,N),PCl,

(69)

phosphine-carbon tetrachloride system to be clarified. Thus it was not clear as to whether the phosphorane (70) is formed directly from the reaction of the ylide (68) with triphenylphosphine or with the dichlorophosphorane (71) (also present in the a6 J. Portulas, F. SAnchez-Ferrando, and J. Shchez-Pardo, Tetrahedron Letters, 1976, 3617. 67 68

E. A. Berdnikov, E. G. Kataev, B. Ya. Margulis, and F. R.Tantasheva, Russ. P. 537081 (Chem. Abs., 1977, 86, 171598). E. Fluck and W. Kazenwadel, Phosphorus, 1976, 6, 195.

11

Phosphines and Phosphonium Salts

reaction mixture) and triphenylphosphine in an autocatalytic process, via the salt (72), that leads to the regeneration of (71). It has now been discovered that in fact the ylide (68) and triphenylphosphine do not react, and thus the latter route, involving the bisphosphonium salt (72), is implicated. This hypothesis is supported by the isolation of (72) from the reaction of the ylide (68) with the dichlorophosphorane (71) in the absence of triphenylphosphine.Not surprisingly, the salt (72) is rapidly decomposed by triphenylphosphine, the phosphorane (70) being The reaction of the phosphorane (70) with TDAP offers a convenient route to hexaphenylcarbodiphosphorane (73), which it has hitherto been difficult to prepare.?O Trimethylphosphine and dimethylphenylphosphine react with carbon tetrachloride in dichloroinethane solution to form (74) and (75) ; the dichlorophosphoranes (74) are insoluble in the solvent, and evaporation of the filtrate affords the pure phosphoranes (75).71 Cf

I

(73)

(74)

I

Me,(R) P= C= P(R)Me, C1'

Ph,P=C=PPh,

R = Meor Ph

(75)

The reaction of tertiary alkyl- or aryl-phosphines with hexachloroethaneresults in the formation of dichlorophosphoranes(76) and tetrachloroethene.72 In contrast, the silylphosphines (77) react with equimolar amounts of hexachloroethane to give a R,P + C,CI, R = alkyl or aryl R'R'PSiMe, + C,CI,

-

__f

R,PCl, + Cl,C=CCI, (76)

R'R2PC1

+ Me,SiCl + CbC-CCl,

(77)

halogenophosphine, chlorotrimethylsilane, and tetrachIoroethene. The reaction of the silylphosphine and hexachloroethane in a 2: 1 mole ratio also provides a route to tetraorganodiphosphines.73 A full account74has now appeared of the reactions of tri-t-butylphosphine with germanium and tin tetrahalides, preliminary details of which were noted in last year's Report. Details of new applications of phosphine-carbon tetrachloride and phosphine halogen reagents in synthesis continue to appear. The use of an insoluble cross-linked polymer-supported phosphine-earbon tetrachloride reagent in peptide synthesis 75 was noted in the previous Report; superior to this is the use of linear sotuble polymersupported phosphine-carbon tetrachloride reagents as condensing agents, enabling peptide synthesis in homogeneous solution. At the end of the reaction period the polymer is precipitated quantitatively and removed by filtration. High yields of 69 70

71 72

73 74 75

R. Appel and H. Veltmann, Tetrahedron Letters, 1977, 399.

R. Appel, F. Knoll, H. Scholer, and H.-D. Wihler, Angew. Chem. Internat. Edn., 1976,15,702. R. Appel, R. Milker, and I. Ruppert, Chem. Ber., 1977, 110, 2385. R. Appel and H. Scholer, Chem. Ber,, 1977, 110, 2382. R. Appel, K. Geisler, and H. Scholer, Chem. Ber., 1977, 110, 376. W.-W. du Mont, H.-J. Kroth, and H. Schumann, Chem. Ber., 1976,109, 3017. R. Appel, W. Struver, and L. Willms, Tetrahedron Letters, 1976, 905.

12

Organophosphorus Chemistry

dipeptides have been achieved by using this technique.76 The succinimides (78) mainly undergo chlorination to form (79) on treatment with triphenylphosphine and carbon tetrachloride, although the lactams (80) are also formed, arising from WittigR

.R

Ph.

(78) R = MeorPh

Ph.

(80)

(79)

type reactions with the ylide (68) that is present in the reaction mixt~re.~7 Some abnonnat reactions of saturated (5a-and 5/l-)19-hydroxy-steroidswith phosphinehalogen reagents have been reported. 78 The rates of dehalogenation of a-bromo- and a-iodo-m-cyanobenzyl phenyl sulphones (81) in aqueous DMF by series of alkyldiphenyl- and substituted triarylphosphines have been studied. The reaction of optically active benzyl(methy1)phenylphosphine with (81) proceeds with inversion of configuration at phosphorus, 79a

CN

CN (81) X = B r o r I

consistent with a mechanism involving attack of phosphine on halogen followed by hydrolysis of an intermediate halogenophosphonium salt. 78 Rate data for the triphenylphosphine-promoted dehalogenation of meso-l,2dibromo-1,Zdiarylethanes to form trans-stilbene in DMF are consistent with a concerted anti-elimination mechanism involving the attack of phosphine on bromine.8fAttack of triphenylphosphine on halogen also occurs in its reaction with the N-chloropyrrolidine-2,5-diones (82), leading eventually to the betaines (83).81 The

(82) R', R2 = Ph or PhCH,

(83)

reaction of triphenylphosphine with trichloro(pheny1)methane gives the cis-olefin (84) and dichlorotriphenylph~sphorane.~~ R. Appel and L. Willms, J. Chem. Res. ( S ) , 1977, 84; J. Chem. Res. ( M ) , 1977, 901. C. Gadreau and A. Foucard, Bull. SOC.chim. France, 1976,2068. 7 8 E. Santaniello, E. Caspi, W. L. Duax, and C. M. Weeks, J. Org. Chem., 1977, 42, 482. ?Q B. B. Jarvis and B. A. Marien, J. Org. Chem., 1976, 41, 2182. 80 B. B. Jarvis and B. A. Marien, Phosphorus and Sulphur, 1976, 1, 177. s1 S. Alunni, E. Baciocchi, and V. Mancini, J.C.S. Perkin II, 1976, 140. 8* D. Le Guern, M. A. Le Moing, G . Morel, and A. Foucaud, Tetrahedron, 1977, 33, 27. 8s V. P. Kukhar and E. I. Sagina, Zhur. obshchei Khim., 1976, 46, 2686 (Chem. Abr., 1977, 86, 76

77

121450).

Phosphines and Phosphonium Salts

13 Ph

Ph,P + PhCCI,

Ph

+

\C=:C’’

c1/

ph,PCI,

\Cl

(84)

The addition of chlorine to the A3-phospholen(85) gives the halogenophosphonium salt (86). Spectroscopic studies of (86) have yielded no evidence for the existence of

cispans-isomers, and yet, on hydrolysis or dehalogenation with magnesium, the resulting oxide and phosphine, respectively, are found to be mixtures of isomers. These results may be explained by assuming a rapid equilibration of the cis- and trans-forms of (86) via a quinquecovalent phosphorane intermediate, following attack of chloride at p h o s p h o r u ~The . ~ ~ 1:1 and 1:2 halogen adducts of l-methyl- and 1phenyl-phosphorinan have also been shown to have a largely ionic nature.86 Nucleophilic attack of triphenylphosphineon fluorine appears to be involved in its reaction with perfhoroisobutene, which yields the triolefin (87).8s (CF,),C=CF,

Ph,P

(C‘F;),C=C[CF=C(CF,),]~

i-

Ph,PFz

(87)

NucZeophiZic Attack at Other Atoms. The adduct of triphenylphosphinewith diethyl azodicarboxylate (DAD) continues to be employed in synthesis, and descriptions of a number of interesting and useful applications have appeared in the past year. New preparative methods, using the Ph,P-DAD combination, to facilitate nucleophilic substitution reactions in the steroid series have been d e v e l ~ p e d . ~In~ some * * ~ of these reactions, phosphonium salts have been used as the source of the nucleophile. A procedure for the direct conversion of a chiral alcohol into its enantiomeric tosylate, using toluene-p-sulphonyl chloride in association with the Ph,P-DAD combination, has been reported.8 8 The combination of Ph,P, DAD, and diphenylphosphoryl azide affords a reagent that is capable of the stereospecificconversion of alcohols into the corresponding azides with inversion of configuration at carbon.89 The reaction of benzophenone oxime with aromatic carboxylic acids in the presence of Ph,P-DAD leads to O-acyl derivatives of the oximes ; these undergo Beckmann rearrangement under very mild conditions, leading to NN-diacylated aromatic amines as the final products. 0-Alkyl ethers of benzophenone oximes result from the reaction of the 8* 85 86

87 88

89

L. D. Quin and R. C. Stocks, Phosphorus and Sulphur, 1977, 3, 151. J. B. Lambert and H. Sun, J. Org. Chem., 1977,42, 1315. I. L. Knunyants, E. G. Ter-Gabrielyan, Yu. V. Zeifman, Z. V. Safronova, N. P. Gambaryan, E. I. MYSOV, A. I. Lutsenko, and P. V. Petrovskii, Doklady Akad. Nauk S.S.S.R., 1976, 228, 1344 (Chem. A h . , 1976,85, 142515). H. Loibner and E. Zbiral, H e h . Chim. A d a , 1977, 60, 417. H. Loibner and E. Zbiral, Helu. Chim. Acta, 1976, 59, 2100. B. Lal, B. N. Pramanik, M. S. Manhas, and A. K. Bose, Tetrahedron Letters, 1977, 1977.

14

OrganophosphorusChemistry

oxime with alcohols in the presence of Ph,P-DAD.

Esterification of allylic alcohols,

e.g. (88), with inversion of configuration, but without allylic rearrangement, can be

achieved, using Ph3P-DAD in combination with benzoic acid.91

(88)

Thioamides are convenientlytransformed into nitriles by addition to DAD to form the intermediates (89), which decompose when subsequently treated with triphenylphosphine.ga RC=NH DAD+

RC-NH,

I

Ph,P

I

II

S

*

RCEN

+ Ph,PS + EtO,CNHNHCO,Et

Et0,CN-NHC0,Et (89)

The reaction of thiobenzophenone with tri-n-butylphosphine at 100 "C gives 1,1,2,2-tetraphenylethane, tetraphenylethylene, and the phosphine sulphide. A similar reaction occurs with dibenzocycfopentadienethione.93 Aryf thiocyanates react with primary alcohols in the presence of triphenylphosphine to give alkyl aryl sulphides in high yield. It has been suggested that the products arise from the collapse of a triphenyloxythiophosphorane (90) resulting from attack of the alcohol on the initially formed arylthiotriphenylphosphonium cyanide.94 Ph,P

ArSCN LArS-SPh,

CN-

-TN

ArS -PPh,

%

1

OR

-

fl+ + R-OPPh, The reaction of triphenylphosphine with N-arylsulphonylsulphimides in DMF ArSR

+ OPPh, +

]

ArS-

gives a sulphide and a phosphinimine via a lY3-dipolarsulphurane intermediate (91).g6 Ph-S-RII phJ+[;;;:

NTs R = Me, Et, PhCH,, or Ph

'S-RTs PPh,

PhSR

+ Ph,P=NTs

(91) S. Bittner and S. Grinberg, J.C.S. Perkin I, 1976, 1708. G. Grynkiewicz and H. Burzyliska, Tetrahedron, 1976, 32, 2109. 9z M. D. Dowle, J.C.S. Chem. Comm., 1977, 220. g3 Y. Ogata, M. Yamashita, and M. Mizutani, Bull. Chem. SOC. Japan, 1976, 49, 1721. 94 W. T. Flowers, G. Holt, F. Omogbai, and C. P. Poulos, J.C.S. Perkin I, 1976, 2394. 95 T. Aida, N. Furukawa, and S. Oae, J.C.S. Perkin 11, 1976, 1438. 91

15

Phosphines and Phosphonium Salts

Nucleophilic attack of tertiary phosphines at tellurium (and iodine) is indicated by rapid Te- (or I+-)transfer reactions in the systems R,PTe-PR, and R,PI-R,P (Y=Te or I+) (R=But or Me,N). Linear intermediates of the type [R,P-Y-PR,] have been The application of tertiary phosphines as co-reagents in dehydration reactions leading to the synthesis of peptides and nucleotides has been re~iewed.~'The triphenylphosphine-di-2-pyridyl disulphide combination, previously used as a condensing agent for peptide synthesis, has been modified by employing an insoluble, polymeric, triarylphosphine, enabling a convenient filtration procedure for separation of the products to be used.98 Deoxygenation of 2-nitrosophenols with triphenylphosphine affords dihydrophenazines, whereas similar deoxygenation of various metal complexes of 2-nitrosophenols yields phenazines or complexes of triphenyl(0-hydroxypheny1imino)phosphoranes, depending on the metal. The reactions are believed to involve nitrene intermediates.O 9 It has been suggested that the assumed zwitterionic intermediate (92) in the arylphosphine-induced deoxygenation of arylnitroso-compoundsarises by i

Ar,P

+ 0-N-Ar

-

Ar,6-

*O-NAr

-

Ar,;--O-NAr

(92)

a two stage electron-transfer mechanism, involving the formation of radical ions, rather than by a one-step process involving nucleophilic attack at oxygen.lo0 Miscellaneous. The addition of Grignard reagents to the functionalized phosphines (93) leads to the magnesium alkoxides (94), which react with methyl iodide selectively at phosphorus. The magnesium salts (95) of the resulting betaines undergo elimination, on heating with potassium t-butoxide, to form the olefins (96) and methyldiphenylphosphine oxide.lol R'MgX

(93)

Ph,P-CH,CO R ' + Ph,P-CH,CR1R2 R' = EtOorMeCO OMgX RZ =: alkyl, phenyl, benzyl, or ally1 (94 1 X = C1 or Br

I

+ Ph,P-CH,CR'

& Me

R2 I'

I OMgX

(95)

+IKOB

Ph,P(O)Me

AHMPT

+ CH,=CR1R2 (96)

The course of metallation, using n-butyl-lithium, of the o-halogenobenzylphosphines (97) depends on the nature of the halogen.lo2 The phosphine (98) reacts as expected with methylmagnesium iodide to give the 96

97

98

99 100 01 ;02

W.-W. du Mont and H.-J. Kroth, J. Organometallic Chem., 1976, 113, C35. T. Mukaiyama, Phosphorus and Sulphur, 1976, 1, 371. K. Horiki, Tetrahedron Letters, 1976, 4103. J. Charalambous, M. J. Kensett, and J. M. Jenkins, J.C.S. Chem. Comm., 1977, 400. P. Tordo, M. Boyer, F. Vila, and L. Pujol, Phosphorus and Sulphur, 1977, 3, 43. M. T. Reetz and F. Eibach, Annalen, 1977, 242. H. P. Abicht and K. Issleib, Z . anorg. Chem., 1976, 422, 237.

16

Organophosphorus Chemistry

(97) X = C1 or Br

related alcohol (99), which undergoes both oxidation and quaternization with retention of configuration at 0

Ph

P6

(9 8)

(99)

Silylphosphines,e.g. (loo), react with pivaloyl chloride to form the unstable acylphosphines (101), which rearrange to form the ‘enol’ species (102); these appear to involve P=C p,,-pn bonding.lo4,lo6 RP(SiMe,),

Bu‘COCl

Bu‘COP(SiMe,) R

(100) R = Me,Si,Me,Buf, Cy, or Ph

(101)

-

R-P=C(But)OSiMe,

The chemistry of germylphosphines continues to develop. A full report of the insertion of carbonyl compounds and other unsaturated systems, e.g. acrylonitrile, into the Ge-P bond of germaphospholans (103) has now appeared.106 The Ge-P bond in (103) is cleaved by methoxide ion in methanol to form the secondary phosphine (104), which re-forms the germaphospholan during distillation under reduced M e CPhQ

11 ,PPh

PhP\

Sn

Me2

(106)

(103) +MezSnCh

hE;

Me,Ge(CH,),PHPh

OMe I

n ,PPh

PhP,

M

Me* (105) M = S i o r G e

(104) PhPCI,

PhP,

P

,PPh

Ph (107)

pressure. Ring cleavage also occurs with a variety of other reagents.107The 1,3diphospholans(105) undergo exchange reactions on heating with halogen derivatives of Group IV or V elements to form, e.g., (106) and (1O7).lo8 K.-C. Chen, S. E. Ealick, D. van der Helm, J. Barycki, and K. D. Berlin, J. Org. Chem., 1977, 42, 1170. 104 G. Becker, 2.anorg. Chem., 1976, 423, 242; 1977, 430, 66. 105 G. Becker and H. P. Beck, 2. anorg. Chem., 1977, 430, 77. 106 C. Couret, J. Escudik, J. Satgk, and G . Redoulks, Rec. Trav. chim., 1976, 95, 240. 107 C. Couret, J. EscudiC, J. Satge, and G . Redoulks, Synth. React. Inorg. Metal-Org. Chem., 1977, 7, 99. l o * C. Couret, J. SatgC, J. Escudie, and J. D. Andriamizaka, J. Organometallic Chem., 1977,132, C5. 103

17

Phosphines and Phosphonium Salts

Studies of the kinetics of the reactions of A3-phospholens (108) with diethyl peroxide are consistent with a mechanism involving rate-determining biphilic attack of the phospholen on the peroxide, followed by a fast fragmentation of the intermediate p h o s p h ~ r a n e . ~ ~ ~

(108)

R

= Me or Ph

The reaction of triphenylphosphine with @-hydroxyethanesulphenyl chlorides offers a useful method for the preparation of episulphides under mild conditions (Scheme 3).110 SH

Scheme 3

Diphenylvinylphosphine adds to the aza-allyl-lithium reagents (109) to give the phosphines (110).1l1

R’ = H , R2 = Ph

(110)

The steric course of oxidation of chiral phosphines by DMSO has been investigated. The reaction is cataIysed by electrophiles, and occurs with predominant inversion or retention of configuration at phosphorus, depending upon the nature of the groups attached to phosphorus and upon the nature and quantity of the catalyst.l12 The p-fluoro-substituent of the phosphine (111) can be replaced by a variety of C

N

~

P

l

’

hC N~

H

FoI’Ph2

i:!

+ H O 0 P P h 2

(111)

nucleophiles when in solution in HMPT. These reactions occur to a much smaller extent with the corresponding meta-isomer, indicating the mesomeric electronwithdrawing nature of tervalent 109

110

112

G. Scott, P. J. Hammond, C. D. Hall, and J. D. Bramblett, J.C.S. Perkin ZI, 1977, 882. J. E. Baldwin and D. P. Hesson, J.C.S. Chern. Comm., 1976, 667. T. Kauffmann, H. Ahlers, A. Hamsen, H. Schulz, H.-J. TiIhard, and A. Vahrenhorst, Angew. Chern. Internat. Edn., 1977, 16, 119. R. Luckenbach and G. Herweg, Annulen, 1976, 2305. G. P. Schiemenz and M. Finzenhagen, Annulen, 1976, 2126.

18

Organophosphorus Chemistry

Treatment of (+)-(S)-4-t-butylphenyl(methyl)phenylphosphine with t-butyllithium results in the displacement of both phenyl and 4-t-butylphenyl anions with complete inversion of configuration at phosphorus in each case, indicating the absence of pseudorotation in the potential hypervalent anion intermediates (112). It has been suggested that these substitution reactions are best considered as classical

[

B ~t , P --RZ R1/"'R3

(112)

]

Me

\

Ph-P: Z/

(113) 2 = Me0 or EtS

sN2 processes with no recognizable intermediate.l14Similarly, the chiral phosphines (113) undergo nucleophilicdisplacement of MeO- or EtS- with complete inversion of configuration at

3 Phosphonium Salts Preparation.-The macrocyclic phosphonium salts (1 14) have been prepared in high yield by a single-step process.116

Ph,P

Pt +P P h 2 W Ph,

c1 X = H,Me,orCl

(1 14)

Alkynylphosphonium salts (115) are now convenientlyaccessiblefrom the reaction of hexaphenylcarbodiphosphoranewith aroyl Ph, P=C=PPh,

+

[

* ~ c * - -
*

ArC=C;Ph,

C1-

(115)

Triphenylphosphine reacts with oxirans in the presence of phenol to form vinylphosphonium salts (116) in high yield.ll*

114

115 116 117 118

E. P. Kyba, J. Amer. Chem. SOC.,1976, 98, 4805. J. Omelanczuk and M. Mikolajczyk, J.C.S. Chem. Comm., 1976, 1025. S. D . Venkataramu, M. El-Deek, and K. D. Berlin, Tetrahedron Letters, 1976, 3365. H. J. Bestmann and W. Kloeters, Angew. Chem. Internat. Edn., 1977, 16, 45. H. Christol, H.-J. Christau, and M. Soleiman, Tetrahedron Letters, 1976, 3321.

Phosphines and Phosphonium Salts

19

The reaction between triarylmethyl perchlorates and triarylphosphines gives the triarylmethyl salts (117) in good yield.l19 The oxoalkylphosphoniumsalts (1 18) have been prepared from the reaction of methylenetriphenylphosphorane with esters.120 The cyclic phosphonium salts (119) arise from the cycloaddition of allyldiphenylphosphine to nitrilimines.121 t

Ar,C-PAr,

C10,-

Ph,&H,COR

r"\"

Pli,P+

I-

(1 18) R = alkyl, PhCH,, or CH,CN PhCH-CH-,

(117)

k d

NPh C1-

(1 19) R = aryl, CO,Et, or MeCO

The reaction of tetrachlorocyclopropene with di-isopropylphosphine gives the cyclopropenylphosphoniumsalt (12O).lz2Chloromethyl isocyanate reacts with tertiary arylphosphines to give the salts (121), which, on treatment with alcohols, form (122).123

c1

c1

Clk;HPr

2

C1-

Ar,kH,NCO CL- .

(1 20)

RoH

Ar,kH,NHCO,R Cl'

(121)

(122)

The reaction of triphenylphosphine with the oxadiazines (123) gives ureidomethylphosphonium salts (124).f24The synthesis of the isoxazolylmethylphosphonium salts (125) has been described; they are converted into the salts (126) on reduction with Raney 0

RNKNR

(i) Ph,P

Ph,~CM,N(R)CON(R)CH,OH Br(124)

(123) R = alkyl R ~ C H z h l i Br3 N\ (125) R = alkyi or Ph

H-Ni

+

H,NC(R)=CHCOCH,PPh,

Br-

(126)

A novel (and cheaper) method for the preparation of the peptide-coupling reagent benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (i.e. BOP reagent) has been described.lzfl M. Bjorray, B. B. Saunders, S. Esperbs, and J. Songstad, Phosphorus, 1976, 6, 83.

119 120

K.Lanyi, P. Lovasz, M. Fedor, J. Laczi, and A. Brencsan, Hung. P. 12241 (Chem. Abs., 1977,

121

I. A. Stepanov, V. I. Zakharov, V. N. Chistokletov, and A. A. Petrov,J. Gen. Chem. (U.S.S.R.),

122 123

2.Yoshida, Japan. Kokai 76 70756 (Chem. Abs., 1977, 86, 5626). B. N. Kozhushko, A. V. Gumenyuk, Yu. A. Paliichuk, and V. A. Shokol, Zhur. obshchei Khim.,

124 125 126

86, 43818).

1977,46, 2360.

1977,47, 333 (Chem. Abs., 1977, 86, 190109). H. Peterson and W. Reuther, Ger. P. 1768461 (Chem. Abs., 1977, 86, 106774). P. Bravo, A. Ricco, C. Ticozzi, and 0. Vajna de Pava, Gazzetta, 1976, 106, 743. B. Castro, J.-R. Dormoy, B. Dourtoglou, G. Evin, C. Selve, and J.-C. Ziegler, Synthesis, 1976, 751.

20

Organophosphorus Chemistry

Reactions.-Alkaline Hydrolysis. The presence of the oxygen atom as ring member in the oxaphospholanium salts (127) has no effect on the stereochemistry of alkaline hydrolysis,which proceeds with complete retention of configurationat phosphorus to yield the corresponding diastereoisomeric oxides (1 28). The stereochemical course is the same as that for hydrolysis of the ‘parent’ phospholanium salts (129)’ and this

indicates the absence of a ring ‘element effect’, which might influence the apicalequatorial preference of the ring by reducing the ring strain and which might allow the ring to occupy a di-equatorial position in the intermediate phosphorane, with consequent inversion at Alkaline hydrolysis of the cis- and trans-isomers (defined with respect to R and Ph) of the phosphorinanium salts (1 30) does not proceed stereospecifically.12*For both salts, the cis-isomer produces a different ratio of the diastereoisomeric oxides (131) than does the trans-isomer. For both trans-isomers, the product ratio is the same. However, the respective cis-isomers give markedly different amounts of the diastereoisomericoxides, there being a greater degree of retention of configuration at

(130) ‘R = Me or But

(131)

(1 32)

phosphorus for hydrolysis of (130; R = But) than for (130; R = Me). For the hydrolysis of both cis- and trans-(130; R=But), there is predominant retention of configuration at phosphorus, and this has been interpreted as indicating a resistance of the six-membered ring to occupying a diequatorial position in the intermediate phosphorane. Both cis-isomers produce more oxide of inverted configuration than do the trans-isomers. A comparison of the rate of hydrolysis of the isomers of (130; R =But) with that of the related salt (132) under pseudo-first-order conditions showed that both t-butyl ring-substituted salts hydrolyse faster than (132)’ indicating greater relief of steric crowding in the transition state for hydrolysis of the former. Rate studies under conditions previously used for the hydrolysis of (1 32) revealed that the previously reported rate data12@ (while reproducible) do not relate to the hydrolysis of the salt, but to some other competing reaction (possibly the reversible formation of ylide). 127

128 129

K. L. Marsi and M.E. Co-Sarno, J. Org. Chem., 1977, 42, 778. K, L. Marsi, J. L. Jasperse, F. M. Llort, and D. B. Kanne, J. Org. Chem., 1977, 42, 1306. S. E. Cremer, B. C. Trivedi, and F. Weitl, J. Org. Chem., 1971, 36, 3226.

21

Phosphines and Phosphonium Salts

An extensive study of the stereochemistry of alkaline hydrolysis of a range of acyclic phosphonium salts under various reaction conditions has been reported.lS0In general, the presence of bulky groups at phosphorus, as in the salts (133), leads to hydrolysis with predominant retention of configuration at phosphorus, whereas the salts (134) undergo hydrolysis with almost complete inversion of configuration. Me PhBut/

Me \+

P-CH,R

Br-

(133) R = aryl or vinyl

Ph-

\+

R

/

P-CH,Ph

Br-

(134) R = Pr", Pri, Cy, CH,CMe,, or aryl

Kinetic studies have shown that the alkaline hydrolysis of phosphonium salts (and phosphine oxides) is unaffected by the addition of the supernucleophilic hydroperoxide Salt, solvent, and substituent effects in the alkaline hydrolysis (and alkoxidepromoted decomposition) of phosphonium compounds have been reviewed.13aThe rate of alkaline hydrolysis of tetraphenylphosphonium chloride in DMSO-water mixtures increases by as much as 10lO-foldas the DMSO content is increased, due to desolvation of the reactant ions.133 A comparison of the kinetic data for alkaline hydrolysis and alkoxide-promoted decomposition of the salts (13 9 , their n-propyl analogues, and tetraphenylphosphonium bromide indicates that hexacovalent intermediates, e.g. (136), are involved +

Ph4-., P(CH,CH,CH,OH),

C1-

(135) n = 1 or 2 (1 36)

in the latter reaction. In the alkaline hydrolysis of phosphonium salts, the intermediates are not believed to pass beyond the five-co-ordinate state because the ionized phosphorane (137) is assumed to be sufficientlyenergetic to expel the carbanionic leaving group. When alkoxide ion is the nucleophile, however, the formation of a quinquecovalent anion by cleavage of a C-0 bond in an alkoxyphosphorane constitutes a pathway needing higher energy than cleavage of H-0 in a hydroxyphosphorane, and the formation of a six-co-ordinateintermediate (138) may well be the preferred path (Scheme 4).13* Unexpected cleavage of the benzylic group occurs when Wittig reactions of the sterically hindered phosphonium salts (139) are attempted in DMSO-DMSOsystems. This is thought to arise because there is solvolysis of the salts in the medium containing methylsulphinylmethanideion (Scheme 5).135 130 131

132 133 134 135

R. Luckenbach, 2. Naturforsch., 1976, 31b, 1127. L. Homer and A. Parg, Annalen, 1977, 61. G . Aksnes, Phosphorus and Sulphur, 1977, 3, 227. F. Y. Khalil and G . Aksnes, Phosphorus and Sulphur, 1977, 3, 27. G . Aksnes, F. Y.Khalil, and P. J. Majewski, Phosphorus and Sulphur, 1977, 3, 157. B. G . James, G. Pattenden, and L. Barlow, J.C.S. Perkin I , 1976, 1466.

2

Organophosphorus Chemistry

22 ,Ph Hob-Ph

HO-

I Ph

Hog

Ph;

v p h , , , ,ph MeO-P-Ph

I

-Oph.,' P - P,Phh

--+ Ph,PO + Ph-

I Ph

(1 3 7)

MeO-

Ph

(1 3 8)

J-Ph-

Ph Me,O

f

PhPO

MeO'

f-

A

Me-q-gPh,

4--Me0'

I

MeOyP-OMe ph'O 'Ph

Scheme 4

H

\

+.

H

\

Ar-C-PPh,

*

H

MeS=O CH2&H,

\ / R

Ar-C-+

Ph,PO

+ MeSCH,CII,SOMe

SOMe Scheme 5

(139) R' = HorMe RZ = H, Me, or Et

Additions to UnsaturatedPhosphonium Salts. In a review of nucleophilic substitution at acetylenic carbon, attention has been drawn to the synthetic potential of alkynylphosphonium salts, e.g. (140), which have received little study so far.ls6

aph Ph

O C O P h -NHNa

+ PhC=C$Ph, (140)

HMPT+

+ Ph,PO

The rates of acid-catalysed cyclization of certain alkynylphosphines to the cyclic diphosphonium salts (141) have been studied, and a mechanism has been proposed 136

S . I. Miller and J. I. Dickstein, Accounts Chem. Res., 1976, 9, 358.

23

Phosphines and Phosphoniuna Salts Ar,

that involves nucleophilic addition of the alkynylphosphine to the related alkynylphosphonium ~a1t.l~' The addition of nucleophiles to prop-2-ynyltriphenylphosphonium bromide (142) proceeds via the allenylphosphonium salt (143)to give the substituted vinylphosphonium salts (144).The salts formed by addition of primary amines to (143)exist, in many cases, exclusively in either the enamine (145) or imine (146) tautomers, Br- T-- [CH,=C=CH;Ph,

HC=CCH,sPh, (142)

NuH

Br-]

> CH3C(Nu)=C H6Ph3 Br-

(143)

RNH

\

/I1

Me/

';Ph,

c=c

(144)

NuH = MeOH or RNH,

R-N A 7

Br-

'C---CH,hPh3 / Me

Br*

(1 46)

(145)

although in some cases an equilibrium mixture is formed. Certain of these vinylphosphonium salts, e.g. (147),have been used in intramolecular Wittig reactions, leading to the synthesis of heterocyclic

base

+

& \

+ Ph,PO

N/Me

Me (147)

The addition of butanol or diethylamine to the allenylphosphonium salt (148)is reported to form the substituted allylphosphonium salts (149), which undergo acid hydrolysis to form (150).139 Ph,kH==C=CHPh U48)

Br-

Et,NH or BuOH

*

Ph,GCH,C(R)=CHPh

Br-

(149) R = Et,N or BuO

Ph3hCH2COCH,Ph Br (150) 137 138 139

J. C. Williams, jun., W. Hounshell, and A. M. Aguiar, Phosphorus, 1976, 6 , 169. E. E. Schweizer, S. DeVoe Goff, and W. P. Murray, J. Org. Chem., 1977, 42, 200. Z. A. Aklyan, R. A. Khachatryan, and M. G . Indzhikyan, Armyan. khim. Zhur., 1976,29, 461 (Chem. Abs., 1976, 85, 124049).

24

Organophosphorus Chemistry

Miscellaneous. The kinetics of the reaction of urea with the tetrakishydroxymethylphosphonium cation have been studied. The reaction involves the stepwise condensation of the hydroxymethyl groups with urea, and at least four different phosphonium species are present in the reaction mixture. The proposed mechanism involves the dissociation of the initial cation as the rate-limiting step (Scheme 6).140

-

+

(€IOCH2)~P

(IiOCH,),P + CH,O

CH20 + H,NCONH, HOCH,NMCONi4, + H'

+ H'

--+ HOCH,NHCONH, +

6H,NHCONH, + (HOCH,),P --+

6H,NHCONH, + K20

(MQC~I,),I:CH,NHCONH, etc.

Scheme 6

A delicate balance of steric and electronic effects at phosphorus controls the course of decomposition of the phosphonium betaines (151) that may be generated in protic ~0ivents.l~~ Electron-withdrawing heteroaryl substituents (e.g. 2-fury1 and 2-thienyl) promote intramolecular collapse of the betaine to form the norma1 Wittig products, as also does enclosure of the phosphorus in the ring-strained dibenzophospholium system. Except in such cyclic systems, both electron-donatingand bulky groups (e.g. o-tolyl and t-butyl) reduce the rate of intramolecular collapse and allow a dehydra+

Ar3P-

/

CH,

+

Ar,P-CH, + I

+ LIE---

Ar,PCH=CHPh

Ar,P(O)CH(Ar)CH,Ph

-OH

Ar,I'(O)CH=CIIPli

+ ArH

(153) (154) tion step to occur, with the formation of a vinylphosphonium intermediate (1 52). The mode of decomposition of (152) depends on the carbanionic stability of the group cleaved from phosphorus. Carbanions of moderate stability (e.g. phenyl,p-methoxyphenyl, or m-chlorophenyl) require the additional stabilization of negative charge afforded in the transition state of the hydrolysisreaction leading to the rearrangement product (153), whereas for carbanions of greater stability (e.g. 2-heteroaryl and mtrifluoromethylphenyl),simple cleavage of the leaving group can occur, with formation of the vinylphosphine oxide (154). An unusual migration of a trimethylsilyl group from nitrogen to carbon occurs in the reaction of the salt (155) with n-b~tyl-lithium.~~~ +

(Me, Si), NPMe, I - -Ihi"Li --+ (155) 140

[

Me, Si

CH,

hle3si,N--i; \

11

CH,SiMe,

Me]

--p

Me,SiN=PMe, I

A. Granzow, J. Amer. Cliem. Soc., 1977, 99, 2648. B. G. Hutley, and M. T. J. Mellor, J.C.S. Perkin I , 1976, 2529. Neilson, J.C.S. Chem. Comm., 1977, 308.

141 D. W. Allen, P. Heatley, 142J. C. Wilburn and R. H.

Phosphines and Phosphonium Salts

25

Development of the chemistry of the salt (1 56) continues. When converted into the alkoxyphosphonium salts (157) and treated with, e.g., methyl-lithium or lithium dimethylcuprate, alkylation at the alkoxy carbon to form R-Me derivatives only occurs to a small extent, due to competition from the strongly nucleophilic Nmethylanilideion. However, alkylation (and arylation) at the alkoxy carbon has been achieved by the reaction of the salt (156) with mixed cuprates derived from an allylic alcohol, copper(1) iodide, and an organolithium reagent, enabling direct substitution of the hydroxy-group of allyl alcohols by alkyl or phenyl groups in a regio- and stereo-selective manner.143 + Ph,PNMePh I (156)

KOH

[ ROPPh,]' [N;vlePh]-

(157)

The bis-phosphonium salt (158) promotes the Lossen rearrangement of phenylhydroxamic acids and also brings about the Beckmann rearrangement of ketoximes under mild ~0nditions.l~~ The salt (159), (formed from the reaction of 2-hydroxyethyltriphenylphosphonium chloride with phosgene) has been employed as an aminoPh,kH,CH,OC(O) C1 C1-

(Me2N),6-0-~(NMe,), (158)

2BF4-

(159)

\

NtI,CHRCO,H

Ph,kH,CH,OCONHCH(K)CO,H

C1'

(160)

protective function in peptide The 2-phosphonioethoxycarbonylaminoacid derivatives (160) (also accessible by quaternization, using the related 2-bromoethoxycarbonyl derivatives) are suitable for peptide synthesis, using the carbodiimide method. The protecting phosphonium group is removed by mild alkaline hydr01ysis.l~~ Retention of configuration at phosphorus is observed in the fission of the allyl group from acyclic chiral phosphonium salts that may be induced by adding lithium aluminium hydride.14' 1 -Adamantyltriphenylphosphoniumsalts behave similarly to the corresponding t-butyl salts on both electrolytic reduction and alkaline hydrolysis, the adamantyl group being cleaved in preference to phenyl.leaThe heteroaryl substituents are cleaved preferentially in the electrolytic reduction of the salts (161),149and the electrochemical reduction of a series of alkyltriphenylphosphonium salts in media of low proton availability has been studied.lS0Various reactions of steroidal phosphonium salts, e.g. (1 62), have been investigated.161 The p-oxoalkyl143

144 145

146 147 148 149 150

151

Y. Tanigawa, H. Kanamaru, A. Sonoda, and S. I. Murahashi, J. Amer. Chem. SOC.,1977,99, 2361. I. J. Galpin, P. F. Gordon, R. Ramage, and W. D. Thorpe, Tetrahedron, 1976, 32, 2417. H. Kunz, Chem. Ber., 1976, 109, 2670. H. Kunz, Annalen, 1976, 1674. R. Luckenbach and W. Endres, Z . Naturforsch., 1976, 31b, 1011. L. Horner and W.-D. Hohndorf, Phosphorus, 1976, 6, 71. L. Horner and J. Roder, Phosphorus, 1976, 6, 147. J. M. Saveant and S. K. Binh, J . Org. Chem., 1977, 42, 1242. Y. Nagao and L. Horner, Phosphorus, 1976, 6, 139.

OrganophosphorusChemistry

26

Ph,kH,COR X‘

(161) n = 1-3

X = OorS

(163) R = H,alkyl, or phenyl

phosphonium salts (163) display keto-enol tautomerism in solution, the fraction of enol tautomer increasing as the size of R decreases.162 4 Phospholes Interest in the controversial issue of the aromaticity of phosphole continues. The photoelectron spectroscopic (p.e.s.) data of Schafer et ~ 1 . l(noted ~ ~ in the previous Report), which were interpreted as indicating that the phospholes (164) are ‘aromatic’ systems which do not involve appreciable delocalization of the lone pair on phosphorus with the diene n-system, have now been re-evaluated, using a different theoretical approach.164It has been concluded that there is a significant interaction between the lone pair on phosphorus and the diene n-system, leading to a ‘traditional’ aromatic stabilization of the phosphole system in both planar and pyramidal geometries, consistent with earlier assessments of the aromaticity of phosphole that were based on studies of n.m.r. spectra, structure, and reactivity. The non-planarity

Ph

(164) R = H o r M e (165) R -- H o r M e U66) of phosphole (cf. pyrrole) is ascribed to the greater importance of o-interactions, which result in a pyramidal geometry at phosphorus in spite of the conjugation in the z-system, i.e. non-planarity does not require phosphole to be nonaromatic (cf. the conclusions of Palmer et Q Z . ~ ~ ~ )In . keeping with the above is the report that 1,2,5triphenylphosphole is a much weaker donor towards mercury(I1) halides than are other phosphines.166 An interesting new development in ‘aromatic’ phosphole chemistry has been the preparation and subsequent study of the electrophilic substitution reactions of transition-metal complexes of phospholyl anions, e.g. the ‘phosphaferrocenes’ (165), which are obtained by the reaction of the appropriate P-phenylphosphole with transi168 and which undergo acetylation at tion-metal cyclopentadienyls or carbonyl~,l~~# N. A. Nesmeyanov, S. T. Berman, P. V. Petrovsky, A. I. Lutsenko, and 0. A. Reutov, J. Organametallic Chem., 1977, 129, 41. lSs W. Schafer, A. Schweig, and F. Mathey, J. Amer. Chem. Sue., 1976, 98, 407. 154 N. D. Epiotis and W. Cherry, J. Amer. Chem. Sac., 1976, 98, 4365. 155 M. H. Palmer and R. H. Findlay, J.C.S. Perkin II, 1975, 974. 1513 M. J. Gallagher, D. P. Graddon, and A. R. Sheikh, Austral. J. Clzem., 1976, 29, 759. 1 5 7 F. Mathey, Tetrahedron Letters, 1976, 4155. 1 5 F. ~ Mathey, A. Mitschler, and R. Weiss, J. Amer. Chem. SOC.,1977, 99, 3537. 152

27

Phosphines and Phosphoniurn Salts

the 2-position of the phosphole ring under normal Friedel-Crafts conditions to form, e.g., (166). X-Ray studies show that the phosphaferrocenes have the traditional sandwich structure, the phospholyl system being almost planar. The structure and reactivity of these molecules clearly point to a n-aromatic nature for the n-COordinated phospholyl system. Metallation of the phosphole sulphides (167) with t-butyl-lithium, followed by treatment with an ester, gives the functionalized phosphole sulphides (168), which can be desulphurized by heating with, e.g., tri-n-butylphosphineto form the functionalized phospholes (169).lSD

RI'

"S

(167) R' = Bun, But, or Ph

R'

(168) R2 = Me or OEt

(169)

Phospholes bearing a functionalized exocyclic P-substituent have been prepared from the bromophospholen (1 70) by quaternization followed by dehydrohalogena-

DBU

X = halogen; Z = OR,SR,orCN

tion. Phosphonium salts derived from such phospholes undergo alkaline hydrolysis in the usual manner, leading to the expected ring-opened or ring-expanded products. O An attempted synthesis of the betaine (171) from the reaction of 1,2,5-triphenylphosphole and o-bromophenol at 250 "C leads to the formation of bromobenzene, diphenyl phenylphosphonate, hydrogen bromide, and 1,4-diphenyInaphthalene.The latter does not arise by addition of benzyne (from a possible mode of decomposition

Ph

0(171)

P h o P h

Ph/ 'OPh

Br-

*

0

It

PhP(OPh)2

(1 72)

of the betaine) to the phosphole, followed by extrusion of the P-phenyl moiety, but from the reaction of the phosphole with hydrogen bromide that is formed by thermolysis of the bromophenol. Diphenyl phenylphosphonate is also formed on thermolysis of the salt (172), which may therefore be an intermediate in the above reaction.161 159

160 161

F. Mathey, Tetrahedron, 1976,32, 2395. F. Mathey, J.-P. Lampin, and D. Thavard, Cunud. J . Chem., 1976,54, 2402. J. I. G . Cadogan, A. G. Rowley, R. J. Scott, and N. H. Wilson, J.C.S. Perkin I , 1977, 1044.

28

Organophosphorus Chemistry

The benzophosphole (173 ; R = Bun) undergoes the expected ring-expansion reactions on treatment with ethyl propiolate in the presence of water or benzoyl chloride followed by the addition of water.la2Compared with related acyclic phos-

(173) R = Bu"

phines, the benzopliosphole (173 ; R = o-PhC-CC,H,) undergoes oxidation and quaternization only slowly, implying that there is some delocalization of the lone pair on However, X-ray studies16$of the corresponding methiodide reveal that the endocyclicbond angle at phosphorus is only 95.4", indicating that there is considerable deformation of bond angle for quaternary phosphorus and implying that ring strain could also be responsible for the lack of reactivity of the phosphole. The dibenzophospholes (174) also undergo ring expansion on treatment with benzoyl chloride, forming (175).le6 PhCOCI, Et,N, I1,O

*

R (174) R = Me, Et, Pr: or Ph

5 Phosphorins The synthesis, properties, and reactions of A3-phosphorinshave been reviewed.las Whereas the 4-alkoxystannabenzoles (176; R2= alkyl) react with phosphorus tribromide to give the phosphorin (177), the corresponding reaction of the 4-hydroxyderivatives (176; R2= H) fails to give recognizable products.ls7Methyl-lithium adds to the phosphorus atom of (177; R1= H) to give the phosphine (178) after quenching with water.lSs

6 0 0- (J

R* OR2

PBr3=

Sn

(176)

R' = Ph, Cy,or But

*:L::

Hzo:

Me

Me

A. N. Hughes, K. Amornraksa, S. Phisithkul, and V. Reutrakul, J. Heterocyclic Chem., 1976, 13, 937. 163 W. Winter, Chem. Ber., 1977, 110, 2168. 164W. Winter and J. Strlhle, Chem. Ber., 1977, 110, 1477. 165 D. W. Allen and A. C. Oades, J.C.S. Perkin I , 1976, 2050. 186 G. Markl, Phosphorus and Sulphur, 1977, 3, 77. 1 6 7 G. Markl, P. Hofmeister, and F. Kneidl, Tetrahedron Letters, 1976, 3125. 168 A. J. Ashe, tert., and T. W. Smith, Tetrahedron Letters, 1977, 407.

162

29

Phosphines and Phosphonium Salts

A number of reactions of the diphosphabarralene (179), leading to the diphosphorin (1SO), have been described.le9~ 170 The latter reacts with hexafluorobut-2-yne to re-form (179).

(179)

(180)

The electronic structures of AS-phosphorinshave been investigatedby photoelectron spectroscopy and by CNDO/S calculations.171It has been concluded that the IIelectronic structure of these molecules is best described as a superimposition of the internal ylide structure (1Sl), involving a delocalized 6n-pentadienyl anion, and the Hiickel 6n-aromatic system (182), in which the phosphorus 3dvz orbital is involved in conjugation. Which form predominates seems to depend largely on the nature of

(181)

(182)

the exocyclic P-substituents. If these involve electronegative atoms bound to ~ ~ ~the l ~fully ~ aromatic structure (182) phosphorus, e.g. 0, N, S , or h a l ~ g e n , l then seems predominant, whereas if the substituents are electron-donating, e.g. methyl, the delocalized ylide form (181) is preferred.174

169 170 171

172

173

Y.Kobayashi, I. Kumadaki, A. Ohsawa, and H. Hamana, Tetrahedron Letters, 1977, 867. Y.Kobayashi, I. Kumadaki, A. Ohsawa, and H. Hamana, Tetrahedron Letters, 1976, 3715.

W. SchBfer, A. Schweig, K. Dimroth, and H. Kanter, J. Amer. Chem. SOC.,1976, 98, 4410. M. Luckoff and K. Dimroth, Angew. Chem. Internat. Edn., 1976, 15, 503. H. Kanter, W. Mach, and K. Dimroth, Chem. Ber., 1977, 110, 395. A. J. Ashe, tert. and W. T. Smith, J. Amer. Chem. SOC.,1976, 98, 7861.

2

Quinquecovalent Phosphorus Compounds BY S. TRIPPETT

1 Introduction The formation of quinquecovalent PH species (2) from the addition of phenols to the phosphonamidite (1) has now been extended1 to the addition of alcohols, thiols,

(2) X = OEt,OPh,SPr, SPh, OAc, or OBz

thiophenol, and carboxylic acids. With catechol and (1) in ether or benzene the correspondingPH-phosphorane (3) is formed whereas in chloroform or dichloromethane disproportionation occurs to give the spirophosphorane (4).2

Hydroxyphosphoranes, which as such or as their conjugate bases have long been postulated as intermediates in nucleophilic substitutions at phosphoryl centres, are beginning to attract attention. Interconversion of the isomeric phosphinates (5) and (8), via the hydroxyphosphoranes (6) and (7), has been monitored by variabletemperature n.m.r. (AG* N" 17 kcal mol-I) and the intermediates have been trapped as methoxyphosphoranes (9) on treatment with dia~omethane.~ As expected, the S . A. Terent'eva, M.A. Pudovik, and A. N. Pudovik, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1976, 1897. 2 M. A. Pudovik, S . A. Terent'eva, and A. N. Pudovik, Doklady Chem., 1976, 228, 355. a G. Kemp and S. Trippett, Tetrahedron Letters, 1976, 4381. 1

30

31

Quinquecovalent Phosphorus Compounds

(5)

R = Hor Me

barrier to interconversion of the diphenylphosphinates(10) and (1 1) was considerably higher, and no intermediate could be trapped. n.m.r. signals of the isomeric cyclic phosphates (12) and (15) move to The progressively higher fields on the addition of increasing amounts of triethylamine, but not of pyridine, and this is reversed on the subsequent addition of trifluoroacetic acid.4 'These changes are associated with changes in the equilibria between the isomeric phosphates and the conjugate bases of the corresponding hydroxyphosphoranes (Scheme 1). However, the continued existence of two separate n.m.r. signals in and the presence of base implies that whereas the processes (13)+(12)+(16) (14)+(15) ~ ( 1 7 are ) rapid on the n.m.r. time-scale at room temperature, the pseudorotations (13)+(14) and (16)+(17) are slow on the same time-scale. If substantiated, this would be of considerable significance. The synthesis of phosphoranes from tervalent phosphorus compounds, 1,2- or 1,3diols, and N-chlorodi-isopropylamineaccording to equation (1) has been extended to R,P

+

'.>

HO

+ Pri,NC1

__+I

R,P 'O) 0 '

+ Pr$H,

C1'

(1)

a wide range of acyclic phosphines, phosphinites, phosphonites, phosphites, phosphoramidites, and phosphorothioite~.~ 4 5

C. Bui Cong, A. Munoz, M. Sanchez, and A. KlakbC, Tetrahedron Letters, 1977, 1587. S. Antczak, S. A. Bone, J. Brierley, and S. Trippett, J.C.S. Perkin I, 1977, 278.

32

Organophosphorus Chemistry

1 1 ,

_.

Reagents: i, Et3N; ii, CF3C02H

Scheme 1 2 Structure and Bonding X-Ray analysis has revealed essentially trigonal-bipyramidal geometry in the spirophosphorane (1 8) and distorted trigonal-bipyramidal geometry in the phosphoranes (Ph2FPNMe)2,7(19),8(20),9(21),1° (22),11(23)>2and (24).12The nitrogen in (23)

f i C H 2 O H9 - 7

6

7 8 9

10 11 12

D Hellwinkel, W. Krapp, D. Schomburg, and W. S. Sheldrick, Z. Naturforsch., 1976,31b, 948. €2. K. Harris, M. 1. M. Wazeer, 0. Schlak, R. Schmutzler, and W. S. Sheldrick, J.C.S. Dalton, 1977, 517. A. Schmidpeter, J. Luber, D. Schomburg, and W. S. Sheldrick, Chem. Ber., 1976, 109, 3581. J. A. Gibson, G.-V. Roschenthaler, D. Schomburg, and W. S. Sheldrick, Chem. Ber., 1977,110, 1887. A. Schmidpeter, D. Schomburg, W. S. Sheldrick, and J. H. Weinmaier, Angew. Chem. Internat, Edn., 1976, 15, 781. J. E. Richman, Tetrahedron Letters, 1977, 559. J. H. Barlow, S. A. Bone, D. R. Russell, S. Trippett, and P. J. Whittle, J.C.S. Chem. Comm., 1976, 1031.

QuinquecovalentPhosphorus Compounds

33

Ph

(22)

(21)

MeN-P,

Me

OC,H, B1-p

CF3 (24)

(23)

is almost planar, with a dihedral angle between the nitrogen plane and the tbp equatorial plane of 81 In (24) the same preferential orientation of the nitrogen lone pair results in a boat conformation for the six-membered ring. Analysis of the distortions of cyclic phosphoranes from ideal trigonal-bipyramidal geometry shows that these are towards square-pyramidal geometry, i.e. along the pathway followed in Berry pseudorotation.13Ab initio calculationsl4 on the reaction of H,PO with H- support a transition state or intermediate with distorted trigonalbipyramidal geometry and equatorial 0-. O.

3 Acyclic Systems The penta-alkyl derivatives of Group V elements have been reviewed.16 The synthesis of pentaethoxyphosphoranefrom triethyl phosphite and ethyl benzenesulphenatehas been extended to the phosphoranes (RO),P, where R = Me, Pri, PhCH2, Me,CCH,, CyClO-cJ6H9, or CYCIO-C~H11.16 (25) is slow on the Pseudorotation of the tetra-2,6-dimethylphenoxyphosphorane n.m.r. time-scalebelow - 38 "C,presumably because of steric crowding in the squarepyramidal intermediate-l' The methyl protons of (25) are rapidly exchanged for deuterium in CDCI,, probably via the ylide (26). CH,P(OAr),

+ CH,$(OAr),

ArO'

(25)

(26) + CDCI,

__L

* CH,=P(OAr),

+ ArOH

(26)

+

DCH,P(OAr), C13C-

F%7 A,=-{

)

\ /

\d

Me R. R. Holmes and S. A. Deiters, J . Chem. Res. ( S ) , 1977, 92. l4 C. A. Deakyne and L. C. Allen, J. Amer. Chem. SOC.,1976,98,4076. 15 H. Schmidbaur, Adu. Organometallic Chem., 1976, 14, 205. 1 6 L. L. Chang, D. B. Denney, D. Z. Denney, and R. J. Kazior, J . Amer. Chem. Sac., 1977,99, 2293. 1 7 I. Szele, S. J. Kubisen, jun., and F. H. Westheimer, J. Amer. Chem. Soc., 1976, 98, 3533. l3

34

Organophosphorus Chemistry

Low-temperature n.m.r. studies of the trifluoromethylphosphoranes (CF,),P(OMe), and (CF,),PFY (Y =NMe,, OMe, SMe, or OSiMe,) show that the order of preference for the apical position in these phosphoranes is F, Cl > CF, > OMe, SMe, NMe,.18 At room temperature the lgFn.m.r. spectra of the trifluorophosphoranes PhPF,NHCHMePh and BuSPF,NHPri each show four separate signals due to apical fl~0rines.l~ These are caused by the combined effect of slow NP bond rotation, because of N H - O Fhydrogen-bonding, and the chirality of the CHMePh or Bus groups respectively. Among other acyclic phosphoranes prepared are (27),20 (28),,0 and Me,SiNMePF,, which is stable below 0 O C Z 1 (RO),P + F2C=C(CF3)COX

_ +

(RO),PFCF=C(CF,)COX

X = OMe, OEt, or NMe, (RiO),P

+ F,C=C(C0,R2)2

(27)

(R’ O)3PFCF=C(C0,R2)2 (28)

4 Four-membered Rings

Tetramethyldiphosphine and hexafluoroacetone gave the phosphoranes (29), (30), and (31) in which the chiral centres at phosphorus led to doubling of resonances in their n.m.r. spectra.,,

(29)

(31)

(30)

A number of phosphoranes have been prepared in which the phosphorus is part of a diazadiphosphetidine ring. Among them are (19),* (20),8 (32),,, (34) and (35),,*

ROP -NPh

1

I

PhN-POR R = Me or Et

+ (Phco),

-

\

’I oR

0‘P-NPh 1

I

PhN-P<

OR

“

R=Et>

Ph Ph

m

(33) 21% 1s

19

20

21 22

23 24

K. I. The and R. G. Cavell, Inorg. Chem., 1976,15,2518. M. Sanchez and A. H. Cowley, J.C.S. Chem. Comm., 1976,690. I. L. Knunyants, U. Utebaev, E. M. Rokhlin, E. P. Lur’e, and E. I. MYSOV,Bull. Acad. Sci., U.S.S.R., 1976, 25,853. A. H. Cowley and R. Chung-Yi Lee, J.C.S. Chem. Comm., 1977, 1 1 1 . J. A. Gibson, G.-V. Roschenthaler, and R. Schmutzler, 2. Naturforsch., 1977, 32b, 599. T. Kawashima and N. Inamoto, Bull. Chem. Soc. Japan, 1976,49, 1924. W. Zeiss, Angew. Chem. Internat. Edn., 1976, 15, 555.

35

QuinquecovalentPhosphorus Compounds

-

M e F o

R,NP-NSiK, I I R,SiN-PNR,

+ (MeCO),

R = Me

I

‘0 ‘P-NSiR,

RN , I’

Me

I

N-PNR, R, Si (34)

0 , ) RzN

Me: Me

R . /

SiMe,

I

N-P, Me,Si

I,NR,

I

0

eM’ O

o,, P /o R,N’

,P-N

(35)

‘NSiR,

Me

NSiMe, Me;PF,-PF,Me,

It

ether .f--

Me,P-PMe,

II

+

HF

FCC1,

Me,FP-NSiMe,

I

L

c

NSiMe, (Me, Si),N Me,SiN

(37) Me

(Me3si)2N,p/N\

\

yp=NSiMe,

+ MeN=P(NMe,),

t

Me, SiN-PFMe,

__t

a,/

P(NMe2)3

Me, SiN

SiMe,

(38)

(37),25 and (38),26 the first penta-aminophosphorane. Thermolysis of (32) gave the oxazaphosphole(33) whereas (35) dissociated at room temperature in solution to give the iminophosphorane (36). 5 Five-membered Rings Variable-temperature n.m.r. studies on a number of spirophosphoranes,among them (39), (40), and (41), having P-ethoxy- and P-ethylthio-groups have shown that ethoxy- and ethylthio-groupshave similar apicophilicities in these Despite

0-P

25 26

27

Me

(39) (40) (4 1) R. Appel, R. Milker, and I. Ruppert, 2.anorg. Chem., 1977,429, 69. R. Appel and M. Halstenberg, Angew. Chem. Internat. Edn., 1977, 16, 263. J. Brierley, S. Trippett, and M. W. White, J.C.S. Perkin I, 1977, 273.

Me

36

Organophosphorus Chemistry

the greater lone-pair orientation effect in sulphur than in oxygen, the energy required to place a sulphur-containing five-memberedring diequatorial in a tbp phosphorane is approximately the same as with the correspondingoxygen-containingring.28This is probably due to the greater ability of sulphur-containing rings to accommodate ring strain. Phospho1es.-The 31Pn.m.r. of the lithium salt (42) did not support the formation of any six-co-ordinatespecies (44).29 Protonation of (42) gave the oxaphosphorane (43). Similarly,the phosphorane (45) rearranged on heating to give the dioxaphosphorane (46). '

43

Me

I+

I-

-t

Li+

(43)

8.

R =

Me

HOCH,

-Q HOCH,

-'

225'C

~

R\L IR'

0

2

(45)

28

29

S. A. Bone, S. Trippett, and P. J. Whittle, J.C.S. Perkin I , 1977, 80.

D.Hellwinkel and W. Krapp, Chem. Ber., 1977, 110, 693.

31

Quinquecoualent Phosphorus Compounds Me e 2 0‘om Et

Me

Me

(47)

A kinetic investigation of the reaction of the phospholens (47) with diethyl peroxide in various solvents supports a mechanism involving rate-determining biphilic attack of the phosphine on the peroxide followed by rapid fragmentation of the resulting p h o ~ p h o r a n eA . ~further ~ paper purporting to describe stable hydroxyphosphoranes has appeared.31 1,2-0xaphospholans.-The distillable oxyphosphoranes (48) have been obtained from methylenephosphoranes and oxiran, and their low-temperature lH and 13C

Jy+ (4 8)

p h 3 p , g H 2 L

/O,

E’h,P=CH(CH,),CH-CH,

Ph,P ‘ 0

(49) n = 1-4

P h 3 P , q (51; n =

(51)

(50)

P

h

3

P

q OH

HICoh

OH

54%

n.m.r. spectra have been On refluxing in toluene, the epoxyalkylidenephosphoranes (49) gave the oxyphosphoranes (50) and/or (51): (50; n= 1) and (50; n= 3) were isolated; the others were detected by their ylide reactions with formaldeh~de.~~ Methyl diphenylphosphinite and o-hydroxycinnamicacid gave the bicyclic acyloxyphosphorane (52).34This rearranged above its melting point to give the coumarin (54) and was hydrolysed rapidly to give the phosphine oxide (53). 1,3,2-Dioxaphospholans.-The spirophosphoranes (56) have been prepared, using a-keto-esters or benzoyl cyanide.3sCyclic phosphoramidites ( 5 5 ; R1=NEt2) gave the 3O

31

32 33

34 35

G. Scott, P. J. Hammond, C. D. Hall, and J. D. Bramblett, J.C.S. Perkin I , 1977, 882. N. A. Kurshakova and N. A. Razumova, J. Gen. Chem. (U.S.S.R.), 1976,46, 1023. H. Schmidbaur and P. Holl, Chem. Ber., 1976, 109, 3151. A, Turcant and M. Le Corre, Tetrahedron Letters, 1977, 789. J. A. Miller and D. Stewart, J.C.S. Chem. Comm., 1977, 156. I. V. Konovalova, E. Kh. Ofitserova, I. G. Kuzina, and A. N. Pudovik, Zhur. obshchei Khim., 1977,[47, 37; I. V. Konovalova, E. Kh. Ofitserova, T. V. Yudina, and A. N. Pudovik, ibid., p. 476; I. V. Konovalova, E. Kh. Ofitserova, and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.), 1976, 46,130.

38

OrganophosphorusChemistry

Ph,POMe

PhaPO

I

(5 3)

PH-phosphoranes (56; R1=HI. a-Keto-acidsand the cyclic phosphite or phosphonite (57) gave the acyloxyphosphoranes (58).36 0

/ \

(C)? ,PR*

0

f

RaCOR3 +

(55) n = 2 o r 3

1R)[

(56) R1 = Me, Ph, or OMe Ra = Me or Ph R3 = C0,MeorCN

+ R2COCOzH

(57) R1 = Ph or OPh

5

.>’A (-JO*R1

0

(5 8)

The di.tluoro(methoxy)phosphorane (59), obtained as shown in Scheme 2, was

Reagents: i, PFs; ii, MesSiOMe 36

R = CF,

Scheme 2 T. Saegusa, S. Kobayashi, Y. Kimura, and T. Yokoyama, J, Amer. Chem. SOC.,1976,98,7843.

39

Quinquecovalent Phosphorus Compounds

stable at 150 "C for 2 days.37Pseudorotation of (59) was rapid on the n.m.r. timescale at - 90 "C. The variable-temperature1°Fand 31Cn.m.r. spectra of the difluorophosphoranes (60) have been

F

(60) R = F, Me,But, Ph, NR'R', or N(SiMe,),

Details have appeared of the reactions of a wide range of PH-spirophosphoranes (61) with aldehydes?imines, and aminals, from which the products are spirophos-

phoranes, and with acid chlorides, which acylate the phosphite form.*O Phenyl isocyanate reacts with the phosphorane when Y = O and with the phosphite when Y =NR. In the presence of AIBN, the tetraoxyphosphorane (62) adds to ethyl vinyl which is the major product in the absence of catalyst, ether to give (63) and (a), whereas the azatrioxyphosphorane (65) gives only (66) in the presence of AIBN and does not react in its absence.4O CH,OEt

I

H

[oj(]+ 0

CH,=CHOEt

OCH(0Et) Me

0

(62)

(63) 28%

(64) 37%

CH,OEt I

37

38 39 40

G.-V. Roschenthaler, J. A. Gibson, and R. Schmutzler, Chem. Ber., 1977, 110, 611. J. A. Gibson and G.-V. Roschenthaler, J.C.S. Dalton, 1976, 1440; J. A. Gibson, G.-V. Roschenthaler, R. Schmutzler, and R. Starke, ibid., 1977, 450. C. Laurenco and R. Burgada, Tetrahedron, 1976,32,2089. C . Laurenco and R. Burgada, Tetrahedron, 1976, 32, 2253.

40

Organophosphorus Chemistry

Enamines, e.g. (67), serve as oxidizing agents in the coupling of PH-spirophosphoranes with alcohols to give alkoxyspirophosphoranes,e.g. (68), and in the oxidation of the phosphonites (69) to spiropho~phoranes.~~ (62) +

PNa (67)

+

[

MeOH --+

y? 1 >ND

0 >P{ 0 0

+

(68)

3,3-Dimethyl-l ,Zdioxetan adds to the bicyclic phosphites (70) to give isomeric phosphoranes (71) and (72).41The n.m.r. spectra of the isomers coalesce at 74 "C (n= 1) and 80 "C (n= 2).

(70) n = 1 or 2

1,3,2-Dioxaphospholens.-In

the presence of tertiary amines the phosphate (73) isomerizes to the silyloxyphosphorane (74).42The order of efficiency of the base (imidazole> pyridine > Et3N)suggests that it is functioning as a nucleophile, and silyl transfer probably occurs in the adduct (75). Catalytic hydrogenation of the trimethyl phosphite-cc-diketone adducts (76) gives the ketones (77) essentially q~antitatively.~~ The dioxaphospholan (78), obtained from the trimethyl phosphite-biacetyl adduct and isopropylidene-D-glyceraldehyde, has been converted into isomericglycosidesof 1-deoxy-3-C-methyl-~-ribo-hexu1ose.~~ Another account has appeared of the reactions of (76) with aroyl and sulphonyl is~cyanates.~~ The five-co-ordinate species (80) and (81) formed by the oxidative addition of pseudohalogens to (79) have been detected by 31Pn.m.r. spectroscopy at low temp e r a t u r e ~ The . ~ ~ compound (80; R = OPh) was stable at room temperature. Phosphoranes have been obtained from the bicyclic phosphites (70) with perfluorobiacetyl and 3,4-bistrifluoromethyldithieten,and their variable-temperature 19Fn.m.r. 41 42 43

44

45 48

B. S. Campbell, N . J. De'ath, D. B. Denney, D. Z. Denney, I. S. Kipnis, and T. B. Min, J. Amer. Chem. SOC.,1976,98,2924. F. Ramirez, M. Nowakowski, and J. F. Marecek, J. Amer. Chem. Sac., 1976, 98, 4330. L. M. Stephenson and L. C. Falk, J. Org. Chem., 1976,41, 2928. S. David, M.-C. Lkpine, G. Aranda, and G. Vass, J.C.S. Chem. Comm., 1976, 747. R. Neidlein and R. Mosebach, Arch. Pharm., 1976, 309, 707 (Chem. Abs., 1977, 86, 106479). E. Krawcwk, .T. Michalski, M. Pakulski, and A. Skowronska, TetrahedronLetters, 1977, 2019.

41

Quinquecovalent Phosphorus Compounds

a>p
K,N_

-\

0

-\

(73)

OSiMe,

0

(74)

R' R2 H,-Pt

o,p,o

M e Me

R' R CO,$qo i S O 2 N y N S O 2R3 0

CHO

'

PhCONCO

R3S0,NC0

(76)

R1C*.7f0

0-N

Ph

42

Organophosphorus Chemistry

-a o j F t ' S

II

OP(OEt),

(79) + [(EtO),P(O)SI*

01

OP(0Et)z

II

(81)

S

spectra have been in~estigated.~~ Similar studies on the perfiuorobiacetyl adducts of phenyl dialkyl-and alkylaryl-phosphiniteshave shown that thegreatercompressionat the apical, as opposed to theequatorial, positionsin tbpphosphoranesplays a large part in determining the relative apicophilicitiesof alkyl and aryl groups in these 1,3,2-0xazaphospholidines.-Those PH-spirophosphoranes (82) that are in equilibrium in solution with the corresponding phosphorus(m) species (83) react with phenyl azide to give the P-anilinophosphoranes(84).48 Details have appeared of the H

R

I

4

(83)

NHPh

(84)

preparation of PH-spirophosphoranes, e.g. (85), from cr-amino-acid~.~~ With phosphorus trichloride and triethylamine in dimethylacetamide these acids give the phosphoranes (86).

H

47 48 49

S. A. Bone, S. Trippett, and P. J. Whittle, J.C.S. Perkin I, 1977, 437. M. Sanchez, J.-F.Brazier, D. Houalla, A. Munoz,and R. Wolf, J.C.S. Chem. Comm.,1976,730. B. Garrigues, A. Munoz, M. Koenig, M. Sanchez, and R. Wolf, Tetrahedron, 1977, 33, 635.

43

Quinquecoualent Phosphorus Compounds

The phenoxyphosphorane(88) has been prepared as shown.60The bisphosphorane (90) was obtained together with (91) from the reaction of o-aminophenol with the phosphazene (89).*l OPh

8-

Qo HN,

I

.N. H

f

/

(90)

(91)

Variable-temperature ‘H and n.m.r. spectroscopy has shown the presence of two diastereoisomers in the phosphorane (92) because of hindered rotation round the N-aryl bond.6aA polarimetric temperature-jump method has been used to deter-

mine thermodynamic and kinetic parameters for the interconversion of optically active phosphoranes, e.g. (93) and (94), to a greater accuracy than is possible by n.m.r. methods.63 Miscellaneous.-The 1:1 adduct of trimethyl phosphite and benzylidene-cc-tetralone has been described.64The rates of reaction of the phosphonites (95) with methyl vinyl ketone correlate with the ~7(Hammett) or on (Webster) constants of the subN. A. Tikhonina, V. A. Gilyarov, and M. P. Kabachnik, Izvest. Akad. Nauk S.S.S.R., Ser. khirn., 1976,2624. 5 1 H. R. Allcock, R. L. Kugel, and G. Y . Moore, Inorg. Chem., 1975,14, 2831. 62 J. I. G. Cadogan, R. S. Strathdee, and N. J. Tweddle, J.C.S. Chem. Comm., 1976, 891. 53 A. Klabbb, M. Koenig, R. Wolf, and P. Ahlberg, J.C.S. Dalton, 1977, 570. 54 B. A. Arbuzov, A. V. Fuzhenkova, and G. A. Tudrii, Izuest. Akad. Nauk S.S.S.R., Ser. khim.,

50

1976,2369.

44

Organophosphorus Chemistry As

stituents X.ss The negative p value confirms that the phosphorus is functioning as a nucleophile. At low temperatures, trialkyl phosphites and chloral give the 1,4,2-dioxaphospholans (96), which decompose above - 10 "C to give the vinyl phosphates (97).66 1,4,2-Dioxaphospholans are also formed from benzaldehyde and the tervalent phosphorus compounds (98).57 C13CCH0 + (RO),P

I;r -40"c b

(Ro"p$-cc13

0 -10°C

II

=- (RO) POCH= CCr,

(97)

H

NEt,

Ph

The products previously obtained from acyl hydrazides and phosphonic dichlorides in the presence of base have now been shown to be the spirophosphoranes (99).s8 The same compounds were also obtained using tetrachlorophosphoranes,

(99)

R'

phosphonothioic dichlorides, or even MeP(NMe,),. With dimethylphosphinyl acyl hydrazides gave the bisphosphoranes (100). At -50 "C, dimethyl phenylphosphonite and the nitro-olefin (101) give the phosphorane (102), which decomposes above 90 "C to give both the phosphinate

57

V. V. Vasil'ev, N. A. Razumova, and L. V. Dogadaeva, J. Gen. Chem. (U.S.S.R.), 1976,46, 461. A. N. Pudovik, T. Kh. Gazizov, V. I. Kovalenko, A. P. Pashinkin, and Yu. I. Sudarev, Dokludy Chem., 1976, 228,420; T. Kh. Gazizov, Yu. I. Sudarev, E. I. Gol'dfarb, and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.), 1976, 46, 920. M. M. Yusupov, N. K. Rozhkova, and N. D. Abdullaev, J. Gen. Chem. (U.S.S.R.),1976,46,

58

A. Schmidpeter and J. Luber, Chem. Ber., 1977, 110, 1124.

55 56

581.

45

Quinquecovalent Phosphorus Compounds

R

RCONHNH,

+

Me

Me,P(O)Cl --+

Me/’

O q N ‘P-N

1

/ [,Me

N-P

N

Go R (100)

(103) and the phosphonate (104).KBThe nitrile ylides (106) formed on thermal decomposition of the 1,3,5-oxazaphospholidines(105) have now been trapped with

;y7pri 0-

PriCH=:CHNO,

\

(101)

-50”c+

+

PhP(OMe),

PhI’

p,‘

90 “C

I PhP-C II

0

OMe OMe

0

OMe NCH2

I1

+ PhP(OMe),

‘Pri

(104)

(103)

(102)

nitrosobenzene,60 azobenzene,61 phenyla~etylene,~~ and the ester-phosphorane (107)63to give the products shown in Scheme 3.

liii

F

,

F3C

(1.06)

+

C Ph

S

+

F3C

Ph,P=CHCO,Et

Ph

+

(CF3),CHN=-CR-C--CPh

+ Ph,P=C(CO,Me)CR=NCH(CF,),

(107) Reagents: i,, PhNO; ii, PhN=NPh; iii, PhC=CH

Scheme 3

R. D. Gareev, G. M. Loginova, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 1906. 80 K. Burger, K. Einhellig, W.-D. Roth, and E. Dactrozzo, Chem. Ber., 1977, 110, 605. 6 1 K. Burger, H. Goth, and W.-D. Roth, 2.Naturforsch., 1977, 32b, 607. 62 K. Burger, W.-D. Roth, and K. Neumayr, Chem. Ber., 1976, 109, 1984. e3 K. Burger, K. Einhellig, and M. Froehler, Chem.-Ztg., 1976, 100, 340. 59

46

Organophosphorus Chemistry

The pKa's of the phosphoranes (2; X = OPh), (108; X = 0),and (108; X=NH) in propanol are recorded as 12.46,5.89,and 11.96 respe~tively.~~ The reactivity towards diphenyldiazomethane increased with increasing acidity.

6 Six-membered Rings The barriers to placing diequatorial the six-memberedrings in the spirophosphoranes (109) have been investigated by low-temperature 19Fn.m.r. spectroscopy,2sand the variable-temperature lH n.m.r. spectra of the phosphoranes (110; R = Me, CH2Ph, or Ph)have been recorded.*7

(109) (1 10) The orange oxaphosphorin (112)was obtained from the salt (111) on refluxing in toluene, or from the salt (113) and base as shown in Scheme 4.ss

(113)

Reagents: i, benzene, r.t.; ii, toluene, reflux; iii, OH-; iv, H+ Scheme 4 64

65

(112)

V. V. Ovchinnikov, M. A. Pudovik, V. I. Galkin, R. A. Cherkasov, and A. N. Pudovik, Zzvest. Akad. Nauk S.S.S.R., Ser. khim., 1977, 434. H. J. Bestmann and W. Kloeters, Tetrahedron Letters, 1977, 79.

47

Quinquecovalent Phosphorus Compounds

7 Six-co-ordinateSpecies The equilibrium shown in equation (2) is completeIy on the right-hand side, with two

moles of methoxide in benzene or HMPT. in the presence of l 8 - c r o ~ n - 6 . ~ ~ (Me0)5P

+ MeOK

(Me@& K+

(2)

The chirality of the six-co-ordinate anion in the salt (114) has been demonstrated by the diastereotopic nature of the methyl groups, as evidenced by their different 'H chemical shifts.67One form of the diethylammonium salt of the anion (115) has been

(115)

obtained pure by second-order asymmetric induction and equilibration of the two diastereoisomers followed by n.m.r. and by polarimetry.68More accurate thermodynamic and kinetic parameters for this interconversion, which probably proceeds via five-co-ordinate species, have been obtained by application of a polarimetric temperature-jump method.La

Chem. SOC.,1976,98, 6755. D. Hellcvinkel and W. Krapp, Phosphorus, 1976, 6, 91. M. Koenig, A. Klaebe, A. Munoz, and R. Wolf, J.C.S. Perkin IZ, 1976, 955.

e6 D. B. Denney, D. Z. Denney, and C.-F. Ling, J. Amer. 67

68

3

Halogenophosphines and Related Compounds BY J. A. MILLER

1 Introduction Research in halogenophosphines during this year’s coverage has in the main been directedat eithernew applicationsor a better understandingof known reactions. In the phosphorane field, structural studies continue to dominate, although a further decline is apparent in the number of papers devoted to M.O. calculations. The surprise of the year must be Becker’s phospha-alkene (65).

2 Halogenophosphines Preparation.-The importance of simple chlorophosphines to organophosphorus chemistry is reflected in the development of new routes to (1) and (2). For those requiring fairly large quantities of chlorodimethylphosphine (l), a one-pot preparation from red phosphorus is now avai1able.l The procedure involves a furnace, packed with red phosphorus, copper powder, glass wool, and active carbon, into which chloromethane is passed. Dichloro(methy1)phosphine (3) is also formed, and conditions can be adjusted to give (3) as the predominant product. MeCl Ph,PSiMe,

(4)

+

+

-

P(red)

Cl,CCCl,

4 Me,PCl + (1) (20%) Ph,PCl

MePCl,

(3)

+ MGSiC1 + Cl$=CCl,

(2) (65-95%)

One routea to chlorodiphenylphosphine (2) involves the treatment of the silylphosphine (4) with chlorine. The disadvantages of this preparation are overcome largely by the use of hexachloroethane, from which (2) can be obtained in good yield.3 have been used to reduce the complexes Simple silanes, such as trichlorosilane (3, formed by phosphorus pentachloride and a l k e n e ~ . The ~ ~ products are alkenyl(dich1oro)phosphines (6), although the yields are quite variable.* The related chlorophosphines (7)have been prepared from alkyl acetates.(I

5

F. W. Parrett and M. S. Sun, Synth. React. Inorg. Metal-Org. Chem., 1976, 6, 115. E. W. Abel, R. A. McLean, and T. H. Sabberwal, J . Chem. SOC.( A ) , 1968,2371. R. Appel, K. Geisler, and H. Scholer, Chem. Ber., 1977, 110, 376. A. F. Kolomiets, A. V. Fokin, L. S. Rudnitskaya, and A. A. Krolovets ,Bull. Acad. Sci. U.S.S.R., 1975, 171. A. F. Kolomiets, A. V. Fokin, A. A. Krolovets, and 0. V. Bronnyi, Bull. Acad. Sci. U.S.S.R.,

6

Z.S. Novikova, S. N. Zdorova, V. N. Kirzner, and I. F. Lutsenko, J. Gen. Chem. (U.S.S.R.).

1 2

3 4

1975,200.

1976,46, 572.

48

49

Halogenophosphines and Related Compounds PC1,

+

* complex

RCH=CH,

II CH,COR

(i) base (ii) PCI,

HSic,,(5) b

RCH=CHPCI, (6)

. Cl$’(CH,CO,R)3-, r

(7)

Iodo(perfluoroalky1)phosphines have been prepared by the reaction of perfluoroalkyl iodides with alkylpolyph~sphines.~ The yields can be quite high, as with the iodophosghine(8). Iodophosphines (9) have also been prepared by halogen exchange, using the ether complex of magnesium iodide as the iodide source.8 A standard exchange reaction using sodium azide leads to the azidophosphine

(8)

RPC1,

+

MgI,

ether ___f

RPI, (9)

(C,F,),PBr

+

NaN,

MeCN

(C,l?,),PN,

+ NaBr

(10)

Reactions with A1kenes.-Further examples have been reported of the cycloaddition of 1,3-dienes to chlorophosphines.lOJ1Certain of these reactions show a high overall stereoselectivitywhen hydrogen sulphide is used to quench the initial complex. Thus the sulphide (11) is formed as one isomer only.1° 15-Phospha-steroids and 17phospha-steroids have been prepared by this type of reaction.ll In general, both possible isomers (at phosphorus) are formed, as with the oxides (12).11

o^

+

MePC4 (3) , 1 ; : : ,

*

aMe H

11

s

(1 2) 7

I. G. Maslennikov, A. N. Lavrent’ev, V. I. Shibaev, and E. G. Sochilin,J. Gen. Chem. ( U S S R . ) ,

8

M. M. Kabachnik, Z. S. Novikova, E. V. Snyatkova, and I. F. Lutsenko, J. Gen. Chem.

1976, 46, 1841.

(u.s.s.R.), 1976,46,42a. H . 4 . Horn, M. Gersemann, and U. Niemann, Chem.-Ztg., 1976, 100, 197. l o C. Synimes and L. D. Quin, J. Org. Chem., 1976, 41, 1548. 11 C. Symmes, J. Morris, and L. D. Quin, Tetrahedron Letters, 1977, 335. 9

Organophosphorus Chemistry

50

Related reactions of 1,4- and 1,5-dienes have been extended to the preparation of bicyclic species, such as the oxides (13) and the oxides (14); see Scheme 1.12 The

isomers)

isomers) (16)

flMede i, ii

Me

Me //-Ph

(2 isomers)

0 (14)

Reagents : i, PhPCh, AlC13 ; ii, aq. NaHCOs

Scheme 1

structure of the starting diene is critical in determining the course of these reactions, as shown by the fact that unbranched diene (15 ;R = €3) gives largely the monocyclic oxides (16). Extensive use has been made of 13C n.m.r. in determining the stereochemistry of all these additions.l0-l2 Various aspects of the reactions of simple alkenes with phosphorus trihalides in the presence of oxygen continue to be a focus of a t t e n t i ~ n . l Thus ~ s ~ ~the dihalides (17) have been confirmed as products,13 while mechanistic work14 emphasizes the RCH=CH,

+ PX, -% RCHCHJ I px2

(17)

role of chlorine atoms - see ref. 15 for earlier reports on the same topic. The enol derivatives (18) and (19) react as shown with chlorodia1kylphosphines.le 12

19 l4 l5 l6

Y.Kashman and A. Rudi, Tetrahedron Letters,

1976, 2819.

S. V. Fridland, T. M. Shchukareva, and R. A. Salakhutdinov,J , Gen. Chem. (U.S.S.R.), 1976,

46, 1213.

V. A. Efanov, A. V. Dogadina, B. I. Ionin, and A. A. Petrov, J. Gen. Chem. (U.S.S.R.), 1976,

46,1392. J. A. Miller, in 'Organophosphorus Chemistry', ed. S. Trippett, (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 7, pp. 4 6 4 7 ; 1977, Vol. 8, p. 53. L. A. Lazukina, 0. I. Kolodyazhnyi, G. V. Pesotskaya, and V. P. Kukhar, J . Gen. Cliem. (U.S.S.R.), 1976, 46, 1931.

51

Halogenophosphines and Related Compounds

Reactions with Alkyl Halides.-The in situ generation and reaction of chlorodiphenylphosphine (2) with a-chloro-ethersgives good yields of a-alkoxyalkylphosphine oxides (20).17 The phosphine (2) is made from phosphorus trichloride and benzene, and the sequence looks like a very convenient one-pot procedure - the dangers of certain chloro-ethers aside!

Trichloromethylphosphonyl derivatives may be produced by the reaction of phosphorus trichloride with carbon tetrachloride, catalysed by aluminium chloride, followed by quenching.l* Thus quenching with water leads to the phosphonyl dichloride (21), while ethanethiol yields the analogous thioate (22). Similar conditions have been applied to the synthesis of the phosphorane (23) from l-fluoroadamantane. 0 PC1,

+ AICl, + CC1,

RF

+

PF,

_t

22;

Cl,Ckl, AlCl,

Ha'+

II

Cl,CPCl,

RPI$ (23) R = 1-adamantyl

Reactions with -OH Groups and Epoxides.-The formation of A3-1,2-oxaphospholen derivatives from propargylic alcohols and phosphorus trichloride has been studied in detail.20Intermediate phosphites (24) and allenic phosphonates (25) are described, and the A3-1,2-oxaphospholenis produced in the final stage,20as shown. Improved conditions have been outlined for the preparation of allylic bromides (26) from allylic alcohols and phosphorus tribromide.21 Related reactions of primary alcohols with the complex of phosphorus trichloride and DMF lead to the chloride (27).22The addition of zinc bromide to the reaction results in the formation of alkyl bromides, but an attempt to extend this exchange to the preparation of cyanides was not l7 l9

2o 21

22

G. Ya. Legin, J. Gen. Chem. ( U S S R . ) , 1976, 46, 540. M. Corallo and Y. Pietrasanta, Tetrahedron Letters, 1976, 2251. J.-V. Weiss and R. Schmutzler, J.C.S. Chem. Comm., 1976, 643. R. S. Macomber and E. R. Kennedy, J. Org. Chem., 1976,41, 3191. J. H. Babler, J. Urg. Chem., 1976, 41, 1262. A. G. Anderson, N. E.T. Owen, F. J. Freenor, and D. Erickson, Synthesis, 1976, 398.

Organophosphorus Chemistry

52

OH

Me PBr, pyridine

(92%)

R(Me)C=CHCH,Br (26)

OH

RCH2C1 (20-85%)

7t

RCH,OH

RCH,Br

At -60 "C, chlorodiphenylphosphine (2) reacts with simple oximes to form phosphinites (28), but at -40 "C the major products are phosphinic derivatives (29).23This interesting observation has been rationalized in terms of a facile rearrangement, which from rate and c.i.d.n.p. studies appears to occur by a radical pathway: see Scheme 2. The analogue of (28) produced from ethylene chlorophosPh,PCl (2) -40

+

R,C=NOH

ocbt. 0

II

Ph,PN=CR, (29)

-:::

> Ph,P-ON-CR,

-

(2 8)

'I

Ph2P-6

+

$J=CR,

Scheme 2

phite (30) is much more stable than (28), and this has been ascribed to strain factors in the intermediate phosphite radical, represented as (3 1).23

Base-catalysed condensation of a-hydroxycarboximidic esters (32) with phosphorus trichloride yields the new heterocycles (33), although minimal evidence has been presented in support of the structure as~ignment.~~ 23 24

C. Brown, R. F. Hudson, A. Maron, and K. A. F. Record, J.C.S. Chem. Comm., 1976, 663. V. E. Shishkin, Yu. M. Yukhno, and B. I. No, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1603.

53

Halogenophosphines and Related Compounds PC1, t HOCH,C

HNH 2E5N

CH,-COEt ~

/

\\

(kp/N c1 (33)

'OH

(32)

A number of examples of reactions of chlorophosphineswith ethylene oxide have been p ~ b l i s h e d . ~ ~Thus - ~ ' the phosphines (34)-(36) are each converted into pchloroethoxy-derivatives, presumably by nucleophilic attack at phosphorus by the epoxide oxygen.

+

QPcl2

+

QY(ocHzc~2c1~2

(ref. 25)

RCH-CHP(OCH,CH,Cl),

(ref. 26)

(34) 0

RCH=CHPC12

i-

-+

(35) POCH,CH,Cl

(ref. 27)

(36) Biphilic Reactions with Carbonyl Compounds.-The dichlorophosphine (34) undergoes a standard chloromethylationwhen heated with paraformaldehyde, and a good yield of the phosphinic chloride (37) is obtained.28At temperatures below 100 "C, somewhat speculatively, the the ester (38) is isolated, and the authors mechanism of the reaction; see Scheme 3. <100 "c (34)

+ CHzO 0

(3 7)

0 (38)

Scheme 3

27

R. S. Aliev, V. K. Khairullin, and S. F. Makhmutov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 59. A. F. Kolomiets, A. V. Fokin, and A. A. Krolovets, Bull. Acad. Sci., U.S.S.R., 1975, 442. A. 0. Vizel, V. K. Krupnov, L. I. Zyryanova, and B. A. Arbusov, J. Gen. Chem. (U.S.S.R.),

28

R. Z. Aliev and V. K. Khairullin, J. Gen. Chem. (U.S.S.R.), 1976, 46, 263.

25

26

1976,46, 1536.

3

54

Organophosphorus Chemistry

1-Chloro-3,4-dimethyl-A3-phospholen (36) reacts with aldehydes and ketones very ineffi~iently.~~ A number of reactions of chloral (39) with chlorophosphines have been described,29and the products shown to depend upon the phosphine used, and on the work-up conditions, as indicated in Scheme 4.

It

EGPCiOAc)-CCI, Reagents: i, EtPC12, heat; ii, EtOH-base; iii, EtzPCl; iv, ROH; v, Ac2O Scheme 4

Several papers this year have been devoted to the effect of acids, notably acetic acid, on reactions between carbonyl compounds and chlorophosphines. Thus dichlorophosphines react with cyclic ketones to give the phosphinic chlorides (a), but in the presence of acetic acid the products are a-hydroxyalkylderivatives, such as (41).30 When phosphorus trichloride and acetic acid are added to 1,5-diketonesY bicyclic phosphonates (42) are formed;31the authors suggest that the reaction is

CI JP

I

OH

(42) 29

** 31

S. Kh. Nurtdinov, S. V. Kazarin, N. M. Ismagilova, and V. S. Tsivunin, J. Gen. Chem. (U.S.S.R.), 1976, 46, 36. S . Kh. Nurtdinov, N. M. Ismagilova, T. V. Zykova, K. G . Sabirova, and V. S. Tsivunin, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1003. V. I. Vysotskii, K. G. Chuprakova, and M. N. Tilichenko, J . Gen. Chem. (U.S.S.R.), 1976,46

783.

55

Halogenophosphines and Related Compounds

initiated by electrophilic attack by phosphorus trichloride on one of the carbonyl oxygens of the diketone. Reactions of halogenophosphines with ccp-unsaturated carbonyl compounds include addition to a-bromoacrylicacid (43)32and additions to the ketones (44),33the EtPC1, Ph,PCl (*)

+

45OC

CH,=C(Br)CO,H

0 \ Ph,PH II

*

0

AcOH

+

I1

R’CH=C(R2)CR3

0

0

11

II

EtTCH,CHBrCCl

O=PPh,

I

_.+I

0

II

R’CHCHRTR’

latter occurring in the presence of acetic acid. The use of acetic acid in such reactions is assumed by most authors to provide a facile route from the phosphorus(II1) chloride to the corresponding

\ P(0)H derivative. For example, the reaction of (44) /

presumably occurs via diphenylphosphine oxide (45). A firmer basis for this view has been provided by an investigation of the reaction between acetic acid and chlorodiphenylphosphine (2),34in which this exchange is shown to occur rapidly. The final product of this reaction is, however, the unexpected oxide (46), and its mode of formation clearly distinguishes this system from the much studied one involving trifluoroacetic 0

I1

P h P H + AcCl

Ph,PCl + AcOH

(45)

(2)

0

0

It

Ph,PCH(OAc)Me

(46)

It

+ Ph,POH + AcCl + HCl

When chlorodiphenylphosphine (2) and benzaldehyde react in the presence of acetic acid, a-hydroxybenzyldiphenylphosphine oxide (47) is formed rapidly.36 Thereafter this is slowly converted into a mixture of the corresponding acetate and the ether derivative (48).36Further aspects of these phosphine oxides are discussed in Chapter 4. 32 33 34 35

36

V. K . Khairullin and G . V. Dmitrieva, J. Gen. Chem. (U.S.S.R.), 1976, 46, 269. C. A. Kingsbury and D. Thoennes, Tetrahedron Letters, 1976, 3037. J. A. Miller and D. Stewart, Tetrahedrm Letters, 1977, 1065. J. A. Miller, in ‘Organophosphorus Chemistry’, ed. S. Trippett, (Specialist Periodical Reports), The Chemical Society, London, 1977, Vol. 8, p. 55. J. A. Miller and D. Stewart, J.C.S. Pcrkitz I , 1977, 1340.

56

Organophosphorus Chemistry 0 f

Ph,PC1

PhCHO

AcOH

f

II

PbPCH(0H)Ph 3. AcCl

0

II

Reactions with Phosphorus(II1) Compounds.-The reaction of monochlorophosphines with secondary phosphine oxides generally gives diphosphine monoxides (49), except when R=CF8.37Another exception is the case with R=t-butyl, when the phosphinous anhydride (50; R = But) is the stable The isomeric mono-oxide (49; R=But) is formed when di-t-butylphosphine oxide reacts as its anion, but the product is readily isomerized. By contrast, the monoxide (49; R = Pri) is 0 R,PCl

f.

II

R,PH

0

II + R,PPR2

(50)

Reactions of the same type have been used to prepare the phosphine derivatives (51) from dichlorophosphines.3DThe arguments for structures (51) are supported by extensive n.m.r. data,sD which conclusively show that earlier as~ignments~~ of

R'PC1,

+

PX,

P(CN),

f

2(R20),P-0' __L

NCPX,

+

(NC),PX

( 5 2)

anhydride structures to the products were incorrect. Mixtures of phosphorus trihalides and the related nitrile (52) have been shown to scramble the halogen and nitrile sub~tituents.~' 37 58

39 40

41

L. Maier, in 'Organic Phosphorus Compounds', ed. G. M. Kosolapoff and L. Maier, WileyInterscience, New York, 1972, Vol. 1, p. 332. V. L. FOSS, Yu.A. Veits, V. A. Solodenko, and I. F. Lutsenko, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1606. K. M. Abraham and J. R. Van Wazer, Inorg. Chem., 1976, 15, 2322. B. A. Arbusov, N. I. Rizpolozhenskii, and M. A. Zvereva, Zzoest. Akad. Nauk. S.S.S.R., Ser. khim., 1957, 179. K.B. Dillon, M. G. C. Dillon, and T. C. Waddington, J . Znorg. Nuclear Chem., 1976,38, 1149.

57

Halogenophosphines and Related Compounds

Two studies of PI11 iodides indicate that disproportionation is a facile reaction, regardless of the other ligands attached to phosphorus. Thus iododiphenylphosphine (53) and di-iodo(pheny1)phosphine (54) each give iodophosphoranes on heating in U ~ C U O The . ~ ~ phosphite derivatives ( 5 5 ) disproportionate at lower temperatures, although prior ligand exchange appears to occur.43 PbPI

+ PbPPPh,

Ph,P13 (42%)

(53)

(33%)

PhP& + PhP(I)P(I)Ph (30%) (88%)

PhPI, (54)

ROPI, _I (RO),P

.f

PI,

=+

(RO),PI,

f

P21,

(55)

Miscellaneous Aspects.-Ab initiu M.O. calculations have been published for the phospha-alkenes (56).44 Blue ferrocenium complexes have been reported to be formed when benzene solutions of ferrocene are treated with simple dichloropho~phines.~~ R,C=PX (56) R = H o r F

X

= HorC1

F,PCI t 2NH3 (5 7)

I_+.

F,PH(NHJ, (58)

F,PN(Me) SiMe,

F,PN(Me) SiMe, (59) (60) Chlorodifluorophosphine (57) is converted into the phosphorane (58) when it reacts with ammonia.46Fluorination of the phosphine (59) leads to the phosphorane (60)47- see Section 3 of this chapter for details of these phosphoranes. Silyl and Related Phosphines.-A number of routes to the silylphosphines (4) and (61) have been d e s ~ r i b e d .Each ~ ~ involves lithiation of the diphenylphosphine derivatives (62), and subsequent trimethylsilylation, and the sequence works best for Me,SiCl,

PhPR

(62)

(4)

\ PhPL.

R = H, C1, or NMe, 42

43 p4

45 46 47 48

+ PhPSiMe,

2Me,SiCf

+ PhP(SiMq), (61)

N. G. Feshchenko, T. V. Kovaleva, and E. A. Mel’nichuk, J. Gen. Chem. (U.S.S.R.),1976,46, 248.

N. G. Feshchenko and V. G. Kostina, J. Gen. Chem. (U.S.S.R.), 1976, 46, 775. C. J. Thomson, J.C.S. Chem. Comm., 1977, 322. A. G. Landers, M. W. Lynch, S. B. Raaberg, A. L. Rheingold, J. E. Lewis, N. J. Mammano, and A. Zaikin, J.C.S. Chem. Comm., 1976, 931. D. E. 3. Arnold and D. W. H. Rankin, J.C.S. Dalton, 1976, 1130. A. H. Cowley and R. C. Lee, J.C.S. Chem. Comm., 1977, 11 1. R. Appel and K. Geisler, J. Organometallic Chenz., 1976, 112, 61.

58

Organophosphorus Chemistry

(62; R =H).48The preparation and properties of trifluorosilyl(dimethy1)phosphine (63) and the analogous arsine (64) have been described.49In both cases the bond to silicon is readily cleaved by polar reagents.4B MGSnPMe,

Me,PPMe,

+ F,SiBr

+

18

h

9

y

Me,PSiF,

F3SiSiF,

Me,AsSiF,

+ MeSH

(64)

-

HBr

+ BrSiF3

__t

Me,PH

Me,AsH

+ MeSSiF3

(6 3)

Quite the most unusual reaction of this year's literature is the formation of the phospha-alkenes (65) from the bis(trimethylsily1)phosphines (66) and pivaloyl The monoacylphosphines (67) have been shown to be intermediates, and 0 II

RP(SiMe,),

(66)

+

Me,CCOCl

-'OoC

+ RP

,CC&

RP=C

'SiMe,

(67)

,

OSiMe,

'CMe,

( 6 5 ) -100%

R = Me, Ph, But, or C,H,,

to rearrange quantitatively at room temperature to give (65). Spectral evidence for (65) includes detailed lH, 31P,and 13Cn.m.r. data, in which the unusual 31Pand 13C shifts of the P-C group are noteworthy.60 Diphenyl(trimethylsilyl)phosphine (4) reacts with the trifluorophosphorane (68) to produce the corresponding monofluorophosphine (69).K1 Trisilylphosphine (70) CF3 Ph,PSiMe, (4)

+ F,Po ,$; ' 0

_.)

C€$ (68)

Ph,PPPh,

+

F€?{3'" + 2Me@iF 0 CF3 CF3

(6 9)

has been monodesilylated, using methyl-lithi~m.~~ The diphosphine (71) has been prepared in excellent yield by treatment of 1,Zdibromoethane with lithium bis(trimethyl~i1yl)phosphine.~~ Other attempted preparations from the phosphine (72) were unsuccessfu1.53 A further study of germylphosphines by the French group has included the preparation of a series of 1,Zgermaphospholans (73).54The weak Ge-P bond is readily 49

50 51

52

53

54

R. Demuth, Z . anorg. Chem., 1976, 427, 221. G. Becker, Z . anorg. Chem., 1976, 423, 242. G.-V. Roschenthaler, J. A. Gibson, and R. Schmutzler, Chem. Eer., 1977, 110, 611. S. Cradock, E. A. V. Ebsworth, D . W. H. Rankin, and W. J. Savage, J.C.S. Dalton, 1976,1661. H. Schumann, L. Rosch, and W. Schmid-Fritsche, Chem.-Zrg., 1977,101, 156. C. Couret, J . Escudik, J. Satg6, and G . Redoults, Synth. Rencr. Znorg. Metal-Org. Chem., 1977, 7, 99.

59

Halogenophosphines and Related Compounds P(SiH,),

+

-

(70)

2LiP(SiMe3),

+

+ MeSiH,

MeLi + LiP(SiH,),

BrCH,CH,Br

+

(Mt$i),PP(SihQ%),

(71) (100%)

+

CH,=CH,

+ 2LiBr

or Pa,

xa P(SiM%), (72)

R',Ge(Cl) CH2CH,CH2C1

/R2 H' l (X = OH, OR, SR, OAc, ox hal) R',Ge(X)CH,CH,CH,P

FPLC

?\;. H -

R',Ge,

R1,Ge(X) CH2CH2CH2P,v /R2

/

X=Y=Br or X = Y = SMe or X = I, Y = Me

(73) /ph R',Ge(OMe) CH,CH,CH2P

H'

I

broken by protic reagents, or by other polar reagent^,^^ as shown. The application of the n.m.r. coalescence method to inversion at phosphorus in the Group IV derivatives (74) reveals that AG* is almost linearly related to the electronegativity of the element M.66

P'

Ph (74) M = Si,Ge, or Sn

3 Halogenophosphoranes Preparation and Structure.-A study of the reaction of phosphorinans (75) with elemental halogens has revealed the formation of three types of product in solution.66 For the phosphonium salt species (76), the counterion is sometimes a tri-

o I

R

56

s6

x,

R = MeorPh

X = Cl, Br, or I

L

Q 0Q

' R X'

X' or

or

/i

x-x

R'px

C. Couret, J. Escudib, J. Satgb, and G . Redoulh, Angew. Chem. Internat. Edn., 1976, 15, 429. J. B. Lambert and H.-N. Sun, J . Org. Chem., 1977, 42, 1315.

60

Organophosphorus Chemistry

halide anion, thus accounting for the observation of 1 :2 stoicheiometry in certain cases (e.g. X=Br and I).56 1-Adamantyltetrafluorophosphorane (23) cannot be prepared from the phosphony1 difluoride (77) by treatment with sulphur tetrafl~0ride.l~ Instead, it has been prepared in good yield by Lewis-acid-induced cleavage of l-fluoroadamantane ; the first time this has been achieved with an alkyl fluoride.lg 0

RF

+ PF3

*

RPF4 (80%)

II

W h

RPF2

4*-

(23) R = 1-adamantyl (77)

Preparative uses of the reactions of phosphorus pentachloride (78) with simple phosphines have been in~estigated.~' Thus tertiary phosphines give mainly the chlorophosphonium salts (79), whiIst chlorophosphines give chlorophosphoranes (80; n = 1 or 2).67An impressive combination of 31Pn.m.r. and 35Cln.q.r. spectroscopy has revealed that the phosphoranes (80) are molecular in the solid state, and that the phosphoranes (81) and (82) are ionic in the solid R3$Cl C1- :R3P (7 9)

Pc1, (78)

R,PCl, (81)

R = Ph,Et,orMe

mflpc'3-fl

n = lor2

F PhnPC1S-n

(80)

R2PCI, (82) R = EtorMe

Two recent papers have been devoted to studies of periluoropinacolylphosphoranes.69~60 Thus details of further methods of preparation of the phosphoranes (83) have appeared, and AG* for positional exchange has been found to be greater for F

F

(83) R' = H, alkyl, or SiMe, Rz = H, alkyl, or SiMe,

R1= H than for R1= alkyl or s i l ~ 1The . ~ ~conclusions reached as a result of earlier studies of intramolecular exchanges in the phosphoranes (84) have been confirmed by a study of 13Cn.m.r. spectra of (84).60 Diamino(difluoro)phosphorane (58) has been prepared,46and extensive spectros c o ~ i cand ~ ~electron-diffractions1studies reveal a tbp structure, with the aminogroups equatorial and freely rotating at room temperature. A CND0/2 calculation 57 58 59 6o

61

K. B. Dillon, R. N. Reeve, and T. C. Waddington, J. Znorg. Nuclear Chem., 1976, 38, 1439. K. B. Dillon, R. J. Lynch, R. N. Reeve, and T. C. Waddington, J.C.S. Dalton, 1976, 1243. J. A. Gibson, G.-V. Roschenthaler, R. Schmutzler, and R. Starke, J.C.S. Dalton, 1977, 450. J. A. Gibson and G.-V. Roschenthaler, J.C.S. Dalton, 1976, 1440. D. E. J. Arnold, D. W. H. Rankin, and G . Robinet, J.C.S. Dalton, 1977, 585.

61

Halogenophosphines and Related Compounds

suggests that the amino-groups are planar, and lie perpendicular to the equatorial plane of the phosphorane.61 A similar comparison of calculations with data from studies of electron diffraction has been published for tris(dimethy1amino)difluorophosphorane (85).62 Once again, the fluorines are axial and the configuration at nitrogen is almost planar.62

(86) a; R' = Ph, R2 = H, R3 = CH(Me)Ph b; R1 = Bus, RZ = H, R3 = Pri

Other aminophosphorane preparations that have been described include those of (86),63(87),64 and (60).47The trifluorophosphorane (86) is of interest because of the non-equivalence of the axial f l ~ o r i n e sThus . ~ ~ (86a) and (86b) show four lines for the l9Fresonances of the axial fluorines. The novel phosphoranes (87) are prepared by treatment of the silylated tetramine with phosphorus pentafluoride or its simple derivatives (Scheme 5).64 The strain in the heterocyclic rings is presumably responsible for the adoption of a structure intermediate between sp and t b ~ . ~ ~

(87) R = F,Me,orPh Reagents: i, BuLi; ii, MesSiCl; iii, RPFi

Scheme 5

The tetrafluorophosphorane (60) has been prepared by an unusual fluorination reaction, using sulphur tetrafluoride. 47 In (60), the axial fluorines are non-equivalent, as shown by l9Fn.m.r. spectroscopy at low temperatures. Above 0 "Cthe phosphorane decomposes, forming the expected phosphetidine (88).47 F Mt$iN(Me)PF2

+ SF4

F. _.)

Fl'

I

'P-N F

/Me 'SiMe,

(60)

,ooc

*

F,P-NMe I I MeN-PF,

+ Me,SiF

(88)

Multinuclear n.m.r. studies of the phosphoranes (89) have shown that the ligandexchange processes are intramolecular, provided Teflon or Kel-F cells are used. 65 The data for (89; R = Me, n = 2) are particularly convincing, and appear to settle a 62

63 64 65

H. Oberhammer and R. Schmutzler, J.C.S. Dalton, 1976, 1454. M. Sanchez and A. H. Cowley, J.C.S. Chem. Comm., 1976, 690. J. E. Richman, Tetrahedron Letters, 1977, 559. C. G. Moreland, G. 0. Doak, L. B. Littlefield, N. S. Walker, J. W. Gilje, R. W. Braun, and A. H. Cowley, J. Amer. Chem. SOC.,1976, 98, 2161.

Organophosphorus Chemistry

62

(90) X = Y = OMe X = F, Y = OMe, SMe, NMe,, or OSiMe,

(89) R = Meor Et n = 2or3

controversy on whether such exchanges are intramoleculareeor i n t e r m o 1 e ~ ~ l a r . ~ ~ A range of phosphoranes (90) with trifluoromethyl ligands has been prepared, and estimates have been made of the barriers to interconversion of the trifluoromethyl groups.ea The iodophosphoranes(91) and (92) have been isolated42from thermal disproportionation reactions, as shown. A related reaction yields the phosphorane (93), but this is unstable at room t e m p e r a t ~ r e . ~ ~ Ph,PI

__f

Ph,PI, + Ph,PPPh, (91) (42%)

PhPI, + Ph(I)PP(I)Ph (92) (30%) 0

PhPI,

ROPI,

-60"c

f

(RO),PI,

II

--+ (RO),PI + RI

(93)

Reactions of Phosphoranes.-Dimethyl(trich1oro)phosphorane (94) reacts with 1-acetyIsemicarbazides to form the bicyclic phosphoranes (95). e9 X-Ray analysis of the bicyclo[3,2,0]heptane derivative reveals a distorted tbp structure for (95). Me

(95)

A new phosphonium species (96) is produced when the phosphoranes (97)are treated with dimethylamine.70When (97; n = 2) is used, trifluoromethane is also produced. The salt was characterized as its hexafluorophosphate derivative, and its stability to water and other reagents is discussed in ref. 70. The silylaminophosphoranes (98) undergo the reactions outlined in Scheme 6.61p71 66

67 68

69 70

71

C. G. Moreland, G . 0. Doak, and L. B. Littlefield, J. Amer. Chem. SOC.,1973, 95, 255. T. A. Furtsch, D. S. Dierdorf, and A. H. Cowley, J. Amer. Chem. SOC.,1970, 92, 5759. K. I. The and R. G. Cavell, Inorg. Chem., 1976, 15, 2518. A. Schmidpeter, J. Luber, D. Schomburg, and W. S. Sheldrick, Chem. Ber., 1976, 109, 3581. D. D. Poulin, A. J. Tomlinson, and R. G . Cavell, Inorg. Chem., 1977, 16, 24. J. A. Gibson, G -V Roschenthaler, and D . Schomburg, Chem. Ber., 1977,110,1887.

63

Halogenophosphines and Related Compounds

F

I

F. F

Reagents: i, MezNH; ii, KPFe; iii, PFs; iv, MeaSiOMe Scheme 6

The reactions of phosphorus pentachloride (78) with electron-rich alkenes continue to be prominent in the Russian literature, and a few selected examples are given in Schemes 7 and 8. In the reaction of (78) with 2-methylpropeneYthe formation of Cl

1

/

0

0

II

I1

Me,CCH,PCl, + Me,C=CHPCl,

i, ii

PC1,

iii, iv

\ v, ii

(78)

(99) * RCH=CHPCl,

fl FI

PhCCC1,PCl

(100)

,

(102) Reagents: i, MezC=CHa; ii, SOZ;iii, RCH=CH2; iv, HSiXs; v, HzC=C(Ph)OSiMea (101) Scheme 7

the major products (99) and (100) has been shown to occur by different pathways, i.e. the main route to (100) is not via (99).73Silanes have been used to reduce the complexes formed by (78) and alkene~,~ and a brief study has been made of the mechani~m.~ ct-Trimethylsilyloxystyrene(101) reacts with phosphorus pentachloride (78) to give a complex from which sulphur dioxide releases the phosphonyl dichloride (102).l6The mixed hemiacetals (103) give the phosphonyl dichlorides (W4) and (105), depending upon the nature of the starting carbonyl A study has been 73 73

V. G. Rozinov, G. A. Pensionerova, V. I. Glukmikh, and E. F. Grechkin, J. Gen. Chem. (U.S.S.R.), 1976,46, 1840. V. V. Moskva, T. Sh. Sitdikova, A. I. Razumov, T. V. Zykova, and R. A. Salakhutdinov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1938.

64

Organophosphorus Chemistry

PC1,

(78)

I + MeC(SR1)R2 (103)

0 Cl,PCH=C, II /Me (105)

PCI, (78)

i-

3PhLi (106)

__f

'SR'

Ph,PCl, -% Ph,P

$ Ph,P=O

Reagents: i,

S02; ii,

PhLi; iii, H2O

Scheme 8

made of the stepwise reaction of phenyl-lithium (106) with (78), and of the conditions leading to triphenylphosphine, or its oxide. 74 Uses of Phosphoranes in OrganicSynthesis.-Triphenylphosphine dihalides(107) have been used to achieve cis-trans isomerization of simple a l k e n e ~as , ~shown ~ in Scheme 9. The key to the sequence is that epoxides undergo a net cis-addition of halogen on

4R H threo

Reagents: i, Zn-DMF

1 j qR2 cis

H

Scheme 9

treatment with (107) - the result of two inversions. Dehalogenation with zinc takes place with an anti-geometry, and hence overall isomerization results. Of the two dihalides used, (107; R = C1) displayed a higher stere~selectivity.~~ Deoxygenation of phosphine oxides can be achieved by the sequence outlined in Scheme Although the reaction mechanism was not established,'* it seems not unreasonable to suggest that the phosphorane (108) is an intermediate. Details of further applications of the triphenylphosphine-carbon tetrachloride system to 74 '5

76

B. V. Timokhin, V. I. Dmitriev, E. F. Grechkin, and A. V. Kalabina, J. Gen. Chem. (U.S.S.R.), 1976,46,488.

P. E. Sonnett and J. E. Oliver, J. Org. Chem., 1976, 41, 3279. M. Masaki and K. Fukui, Chem. Letters, 1977, 151.

Halogenophosphines and Related Compounds 0

65 R2SSR2 + R’,P

R,CHCl

(109)

alkenes

Reagents: i, (COC1)2, ii, RaSH-Et3N; iii, Ph3P-CC14; ivyexcess CCh; v, MeCN

Scheme 10

peptide synthesis have appeared.7 7 The same reagent reacts with secondary alcohols (109) to give either alkenes or chlorides, depending upon the solvent A number of reactions of phosphorus pentachloride (78) with carbonyl compounds have been reported. a-Hydroxycarboxylic acids, such as malic and tartaric acids, react with (78) to give phosphorodichloridates with general part-structure (1 lo).7 8 The heterocyclic hydrazide (1 11) is converted into the cyanide (1 12), and hence into the isomer (113), by treatment with (78) in refluxing benzene.*O 0 OH I RCHC0,H

II

(’@

*

0-PC1,

R&ICOCI (1 10)

PhCHCN

Me NHCOCH,Ph (1 11)

Me

(112)

CN

I

Me (113)

Other reactions of (78) described in the literature include that with p-maltose octa-acetate,E1and with 4-acetylisochroman-l,3-dione.82 The use of phosphorus pentafluoride in the polymerization of THF has been inve~tigated.~~

77 78

79 80

81

82

83

R. Appel and L. Willms, J. Chem. Res. ( S ) , 1977, 84; J . Chem. Res. ( M ) , 1977, 901. R. Appel and H.-D. Wihler, Chem. Ber., 1976, 109, 3446. L. I. Gurarii and E. T. Mukmenev, Bull. Acad. Sci., U.S.S.R., 1975, 2450. R. Fusco and F. Sannicolo, Tetrahedron Letters, 1976, 3991. K. Takeo, Carbohydrate Res., 1976, 48, 290. R. B. Tirodkar and R. N. Usgaonkar, Indian J. Chem., 1976,14B, 678. R. Hoene and K. H. Reichert, Makromol. Chem., 1976,177, 3545.

4

Phosphine Oxides and Sulphides BY J. A. MILLER

1 Introduction A somewhat featureless year's literature, with a decided lack of new reactions, and little advance in our understanding of old problems! Perhaps the most interesting papers have been on the synthesis of bicyclic and polycyclic structures, and on the pathways of two rearrangements which appear to involve hydride transfer. 2 Preparation Two of the elusive pimpernels of organophosphorus chemistry, the acyldiphenylphosphine oxides (l), have been isolated and adequately characterized for the fist time. Thus careful oxidation of the corresponding phosphines yields the oxides (la) and (lb).l Deliberate hydrolysis of the latter yields the bis-oxide (2),l and hence permits a fuller rationalization of the formation of (3) in earlier experiments on this system.* 0

11 Ph,PCR

0

--I+

Ph2P-CR

91;8EF3

0

II

CFjCOIeOH + Ph,PH

(1) a; R = Me b; R = CF3

Quite a different reaction of acetyldiphenylphosphine (4) is responsible for the formation of the oxide ( 5 ) from acetic acid and chlorodiphenylphosphine.5 The phosphine (4) is shown (Scheme 1) to be an intermediate in the reaction, and to undergo an unexpected addition of acetic acid to form (5).3 The involvement of an acylphosphine is the essential difference between the reactions of chlorodiphenylphosphine with acetic acid and with trifluoroacetic acid: the latter produces (3).4s6 1

E. Lindner, H.-D. Ebert, H. Lesiecki, and G. Vordermaier, Angew. Chem. Internat. Edn., 1977,

a

E. Lindner and H.-D. Ebert, Angew. Chem. Internat. Edn., 1971, 10, 565; E. Lindner, H.-D. Ebert, and H. Lesiecki, ibid., 1976, 15, 41. J. A. Miller and D. Stewart, Tetrahedron Letters, 1977, 1065. D. J. H. Smith and S . Trippett, J.C.S. Perkin I, 1975, 963. P. Sartori and R. H. Hochleitner, Z . Naturforsch., 1976, 31b. 76.

3

* 6

16, 269.

66

67

Phosphine Oxides and Sulphides PhPC1

+

AcOH

*

0

II

PhPH

+ AcCl

0

II

Ph,PCI + Ph,PH

0

==+

II

HCl + Ph,PPPh,

0

II

0

Ph,PPPh, + AcCl -+

II

Ph,PCI + AcPPh, (4)

P

0

II

Ph,PC H (0A c)Me

0 II Ph,POH + AcCl

(5)

Scheme 1

Simple, but potentially useful, alkoxymethyl(dipheny1)phosphine oxides (6) are produced in good yields from benzene.6A series of diphenylphosphinoyl acetals (7) has been prepared, and their n.m.r. spectra have been described.'

PhQCl

Cl I

R'OCHRf +

0

II

Ph2PCHRZOR' ( 6 ) Rz = H (75%)

Me,NC H (0R'

(i) Me1 (ii) Ph,POR2

0

II

+ Me,N + Ph,PCH(OR'),

+ R21

(7)

Hydrolysis of the cycloadditionproducts of chlorophosphineswith dienes has been a popular route to phospholen 1-oxides.8-10These sequences usually lead8$loto epimeric mixtures (at phosphorus), as illustrated for the preparation of the oxides (8), (9), (lo), (13), and (14) shown in Schemes 2* and 41°. When hydrogen sulphide is used as a quenching agent, forming the sulphides (11) and (12), much greater stereoselectivity is observed (Scheme 3).B Addition of chlorodiphenylphosphineto aldehydes in the presence of carboxylic acids or of aqueous acids has long been used as a preparative route to cc-hydroxyalkyl(dipheny1)phosphine oxides (15). A re-examination of this reaction, using benzaldehyde and acetic acid, has revealed that although (15;R = Ph) is the initial product, the final products are the acetate (16)and the bis-ether (17).11 It seems that (17)was fist isolated by Conant and his colleagues,12but that the analytical methods of fifty years ago failed to distinguish (15) from (17). G. Ya. Legin, J. Gen. Chem. (U.S.S.R.), 1976, 46, 540. B. Costicella and H. Gross, J . prakt. Chem., 1977, 319, 8 . 8 Y.Kashman and A. Rudi, Tetrahedron Letters, 1976, 2819. C. Symmes and L. D. Quin, J. Org. Chem., 1976,41, 1548. 10 C. Symmes, J. Morris, and L. D. Quin, Tetrahedron Letters, 1977, 335. 1.1 J. A. Miller and D. Stewart, J.C.S. Perkin I, 1977, 1340. 1 2 J. B. Conant, J. B. S. Braverman, and R. E. Hussey, J. Amer. Chern. Soc., 1923, 45, 165. 6

Q

Organophosphorus Cheinistry

68

Reagents: i, MCb; ii, H a 0

Scheme 2

(11) Reagents: i, MePCla; ii, Has

Scheme 3

Reagents: i, MePCla; ii, H a 0

Scheme 4

69

Phosphine Oxides and Subhides 0

Ph,PCl + AcOH

+

1

R = Ph

0

II

Ph,PCH(OAc)Ph

II

Ph,PCH(OH)R

RCHO

(15)

slow

+ (17)

(16)

Other carbonyl addition reactions of phosphorus(Ir1) derivatives have been used to prepare the oxides (18)-(2O).l3-l5 The oxide (20) is of interest because of its ability to form stable copper(@ complexes.15

+

RCHO

(ref. 13)

L+.

(18) (15%)

EGPCl + C1,CCHO 0

II

Bu,PH

(i) A

0

+

II

H02CCCH,CH2C0,H

RoH

-

0

+

II

Et,PCH(OH)CCI,

(ref. 14)

(19) 0

II

Bu,PC(OH) CH,CH,C02H

1

(ref. 15)

C02H (20)

Tetra-t-butyldiphosphine oxide (21) has been prepared from the anion (22), and found to rearrange readily to the anhydride (23).lS The corresponding tetra-isoBut2PCI

propyldiphosphine oxide is stable.l6Photolysis of dialkyl diselenides in the presence of tertiary phosphines yields the phosphine selenides (24), and the reaction pathway suggested by the authors is outlined in Scheme 5.17 13

A. 0. Vizel, V. K. Krupnov, L. I. Zyryanova, and B. A. Arbuzov, J. Gen. Chem. (U.S.S.R.),

14

S.Kh. Nurtdinov, S. V. Kazarin, N. M. Ismagilova, and V. S. Tsivunin,J. Gen. Chem. ( U.S.S.R.),

15

16 17

1976,46,1536. 1976,46, 36.

A. Kh. Miftakhova, M. G. Zimin, A. A. Sobanov, V. F. Toropova, and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1890. V. L. FOSS,Yu. A. Veits, V. A. Solodenko, and I. F. Lutsenko, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1606.

D. H. Brown, R. J. Cross: and D.Millington, J.C.S. Dalton, 1977, 159.

70

Organophosphorus Chemistry R'SeSeR' hv, 2R'Se.

R2,P

+

R'Se-

_+

R2,keR1 --+ RZ,P=Se

(24) R1* + R'SeSeR'

+ R'*

Rise* + R'SeR'

Scheme 5

3 Reactions at Phosphorus or Arsenic The stereochemical aspects of the conversion of phosphonium salts into phosphine oxides have beem examined in detail.ls In general, the reactions are third-order, and the stereochemicalconsequencesare highly dependent upon the nature of the ligands in the salt (25), uiz. (i) when one group is a relatively good leaving-group, predominant inversion is observed, e.g. when R =benzyl or ally1; (ii) when one group is very bulky, predominant retention is observed, e.g. when R=But; (iii) when the leaving-group is aromatic, predominant retention is observed, e.g. when R =Ph. These observations have been rationalized in terms of phosphorane stability and the relative ease of permutational isomerism as the ligands are varied.18 Phosphine oxides are mentioned in a brief review of stereochemical reaction cycles of organophosphorus RZ R4

OH (25) -OH/

t

-0

Hydrolysis by alkali of the 1,3-0xaphospholaniumsalt derived from the phosphine (26) yields the oxide (27) with retentionaoand shows that the retention observed2' in Me.,


Me

Me

ph/

'2'.

(26)

18 10 20

21

Me, (i) PhCH,Br (fi) -OH

t-k:

(P:. Ph

\o

(27)

R. Luckenbach, Z . Naturfursch., 1976, 31b, 1127. R. Luckenbach, N. Miiller, and W. Endres, Chem.-Ztg., 1976, 100, 320. K. L. Marsi and M. E. Co-Sarno, J. Org. Chem., 1977,42,778. A. Fitzgerald, G. D. Smith, C. N. Caughlan, K. L. Marsi, and F. B. Burns, J. Org. Chem., 1976, 41, 1155.

71

Phosphine Oxides and Sulphides

the simple phospholan analogue of (26) is not affected by the presence of the heteroatom. A study has been made of the relative rates of attack by hydroperoxide ion and hydroxide ion at various phosphorus centres.22For phosphine oxides there is no or-effect, and this is interpreted as signifyingthat P-C bond cleavageis rate-determining.22 Some interesting rearrangement reactions have been reported in this year's literature. In structural terms, the simplest of these is that by which the oxide (28) is Attempts to extend converted into the ester (29) on treatment with methoxide 0

0

0

II

(PhCH,),PCH,X

C-

II

-OMe +

(PhCH,),PCH,Cl

(30) X = SEt, NEt,, or OPh

II

PhCH,POMe

I

(28)

+ C1'

CH,CH,Ph

(29) (60% yield)

L-OH

0

II I

PhCH,PCH,CH,Ph OH

this reaction to other nucleophiles failed, and substitution products (30) were formed for X=SEt, NEt2, or OPh,24whereas, on the other hand, hydroxide ion brought about rea~rangement.~~ Bearing in mind the fact that the related oxide (31) does not 0

0

I1

II

Ph,PCH,CI + -0Me + Ph,PCH,OMe

+ Cl-

(31)

rearrange with methoxide ion, the explain these observationsby suggesting that the benzylphosphine oxides (28) readily form a phosphiran 1-oxide intermediate (see Scheme 6), which may ring-open by attack at carbon (substitution) or at phosphorus (rearrangement). PhCH,\?

€C ' H,Cl

-0Me

PKH(

PhCH,

lPH0

PhCH'

'CH,>l u

(28)

I;;

(attack at C) X

(29) R = Me

(PhCH,),PCH,X

Scheme 6

72

Organophosphorus Chemistry

The formation of the phosphinic acid derivative (32) by treatment of benzylbis-(ahydroxybenzy1)phosphineoxide (33) with alkali is also suggested to occur via a threemembered ring.2bIn this case, an intramolecular 1,2-hydride shift is proposed to occur as the intermediate ring is broken (see Scheme 7). 0

0 -

II

H,II PhCH,P

PhCH,P(CHPh),

I OH

‘CH(0H)

(33)

Ph

f

PhCHO

-OH//

0

II

(PhCH,),PO-

+ -

ph/!g

(32) (93%)

Scheme 7

Grignard reactions of the ketophosphine oxide (34) yield both isomers of the oxides (35), while reduction with borohydride gives predominantly the oxide (36).26 0

/ (i) MeMgI (ii)

7 J f-

Ph’

/

(34)

%o

NaBH,-E tOH

(4

.k’

(35) R’ = OH, RZ = Me or R‘ = Me, R2 = OH

\/ (36) R* = OH, R2 = H or R’ = H, R2 = OH

These products and others with different co-ordination at phosphorus are found to have the ‘butterfly’ structures shown.2s The P-P bond of tetramethyldiphosphine disulphide (37) is readily broken by p-benz~quinone~~ and by hydroxide ion.28 22

23 Z4

25

26 27

28

L. Horner and A. Parg, Annalen, 1977, 61. K. A. Petrov, V. A. Chauzov, and T. S. Erokhina, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1236. K. A. Petrov, V. A. Chauzov, T. S. Erokhina, and I. V. Pastukhova, J. Gen. Chem. (U.S.S.R.), 1976,46,2387. A. B. Pepperman and T. H. Siddall, J . Org. Chem., 1976, 41, 2931. K.-C. Chen, S. E. Ealick, D. van der Helm, J. Barycki, and K. D. Berlin, J. Org. Chem., 1977, 42, 1170. A. N. Pudovik, G. V. Romanov, and A. A. Lapin, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1384. R. A. Malevannaya, E. N. Tsvetkov, and M. I. Kabachnik, Bull. Acad. Sci., U.S.S.R., 1976,936.

Phosphine Oxides and Sulphides

S

S

II

Me,PO-

+

I'

Me,PH

- -OH

73

45

s s Me,P-PMe, II II

5

Me,PO II 0 O ! M e z

0

(37)

The a-diazo-@-keto-alkylphosphineoxides (38) and (39) undergo different fragmentation reactions2@ as shown. For the oxide (38), the predominant reaction involves acyl cleavage, i.e. the C--C=O bond breaks, whereas the oxide (39) displays cleavage 0

0

II

II

Ph,P-$-CPh

0

II

Et,N-MeOH

~

+ PhC0,Me

Ph,PCHN,

(86%)

I1

N*

(88%)

(38)

EbN-MeOH

0 ~

I'

0

II

PhHCH,CH,CCHN,

(8 1%)

I

P h/=No

OMe

(39)

of the C-P=O bond. 2 a The photochemical extrusion of phenylphosphinidene oxide ( P h P 4 ) from 1-phenyl-2,5-dimethyl-A3-phospholen 1-oxide (40) is highly stereoas shown. selective, but that from (41) is Me--

o--Me /q J%

p,

"Ph

96%

(40 Ph,P=O

+ Na + Ph,PO' + PhNa -% Na'(Nai Ph,P6)'-

(42)

An e.s.r. study of the reaction of alkali metals with triphenylphosphine oxide (42) in ether solvents has shown that a phenyl group is lost from (42).s1A two-step deoxygenation of tertiary phosphine oxides is illustrated for (42)in Scheme 8.32 29

30 31

32

H. Tomioka, N. Toriyama, and Y. Izawa, J. Org. Chem., 1977, 42, 552. H. Tomioka and Y . Izawa, J. Org. Chem., 1977,42, 583. A. G. Evans, J. C. Evans, and D. Sheppard, J.C.S. Perkin ZZ, 1976, 1166. M. Masaki and K. Fukui, Chem. Letters, 1977, 151.

Organophosphorus Chemistry

74

A

Ph,P=O

Ph,PCl,

-%

(42) Reagents: i, (COC1)2 or ClsCCOCl; ii, RSH-EtsN

Ph,P

+ RSSR

Scheme 8

Applications of the reactions of arsine oxide to general synthetic methods are relatively few, but the sequences outlined below are potentially useful ways of achieving the equivalent of a halogenomethylation reaction with a nucleophilic carbon, i.e. CH,X reactions.33The key step is the generation of the a-lithiated derivative of the oxide (43), which subsequently reacts with alkyl halides or carbonyl compounds. In both cases the sequence is completed by a reduction at arsenic, followed by halogen cleavage of the carbon-arsenic(Iz1) bond,33 as shown in Scheme 9. 0

I1

Ph,AsMe (43)

HOCR, iv. v I

Ph,AsBr

+

RCH,Br

4

Ph, A sC H,R

Ph,AsBr + R,C=CHBr

Reagents: i, LiNPA; ii, RaCO; iii, HsO; iv, LiAlH4; v, Brr; vi, RBr scheme9

By contrast, arsine sulphides (44) desulphurize on treatment with hydrogen halides, and arsine(v) dihalides are formed.34 S

It

R,As + 2HX (44)

-

R,AsX, + H,S

4 Reactions of the Side-chain

The Horner reaction, using phosphine oxides, continues to attract a t t e n t i ~ n . ~ ~ - ~ ' One study has been directed towards better understanding of the factors which inhence the geometry of the alkene product; in particular, the effects of changing the ylide counterion and of changing the substituents attached or adjacent to phosphorus have been described.36Thus the geometry of the products of reaction of benzaldehydewith reagents derived from the oxides (45) and (46) has been compared with that of the analogous products from (47).36 Further applications of allylphosphine oxides to diene synthesis have been described.ss Examples are shown in Scheme 10 of the reactions of cis-but-2-enyl33 34 35 86

T. Kaufmann, H. Fischer, and A. Woltermann, Angew. Chem. Internat. Edn., 1977, 16, 53. B. E. Abalonin, Yu, F. Gatilov, and G. I. Vasilenko, J . Gen. Chem. (U.S.S.R.),1976,46, 812. B. Deschamps, J.-P. Lampin, F. Mathey, and J. Seyden-Penne, TetrahedronLetters, 1977,1137. B. Lythgoe, J. A. Moran, M. E. N. Nambudiry, and S. Ruston, J.C.S. Perkin I , 1976, 2386.

Phosphine Oxides and Subhides

75 EtO,

P

,OEt

O"CH(CN)R

R R

(45) (46)

=

=

0 /-L!phz

H

(47) R = H or Me

Me

&

(48)

72%

(+ 3% geometric isomer)

Reagents: i, BunLi; ii, cyclohexanone

Scheme 10

(dipheny1)phosphine oxide (48) and its geometric isomer (49). Both isomers of the vinylphosphine oxides (50) are formed as shown in Scheme 11.37 Addition of hypobromous acid to diphenyl(viny1)phosphine oxide (51) is the first step in a synthesis of the epoxide (52) and hence of the substituted acetaldehyde (53).38 0

II

0

0

II

II R', PCH R2P(OR3), -@+ R',PC(R*)=CHPh ( 5 0)

0

II

Ph,PCH=CH,

0 iii' iv

II

+ Ph-J'CH-CHZ '0'

(51) ( 5 2) Reagents: i, base; ii, PhCHO; iii, HOBr; iv, KOH; v, H+

0

II

A Ph2PCHzCH0

(53)

Scheme 11

Othei reactions of allyl- and vinyl-phosphine oxides include a detailed study of their intermolecular cyclization by a Friedel-Crafts-type procedure.3g In certain cases, the unsaturated oxides are generated in situ from B-hydroxyalkyI(dipheny1)phosphine oxides. Examples are given in Scheme 12 for the oxides (54)-(56).39 Control of double-bond position in the products of acid treatment of the oxides (57) has been achieved by using an organosilicon s u b ~ t i t u e n tThus . ~ ~ simple alkyl 37

38 89

40

U. Lachmann, H.-G. Henning, and D. Gloyna, J . prakt. Chem., 1976, 318,489. V. K. Byistro, L. A. Krichevskii, and Z. M. Mildakhmetov, J. Gen. Chem. (U.S.S.R.), 1976,46, 781. J. I. Grayson, H. K. Norrish, and S. Warren, J.C.S. Perkin Z, 1976, 2556. A. H. Davidson, I. Fleming, J. I. Grayson, A. Pearce, R. L. Snowden, and S. Warren, J.C.S. Perkin Z, 1977, 550.

76

Qrganophosphorus Chemistry

Reagents: i, polyphosphoric acid; ii, base; iii, PriCHO

ty“ OH

R3

Scheme 12

0

R’

‘6-CH(R3)PPh, II

..---t

R2cH’

(57)

(_+

R2CH=-C /R‘ ‘CHR3

I

= CH,SiMe+

O=PPh,

0

w\\C-CH(R’)PPh,II

groups in (57) resulted in a preference for the most substituted alkene, but with (57; R1= CH,SiMe,) the least substituted alkene resulted from d e ~ i l a t i o n The . ~ ~ oxide products were then converted into 1,3-dienes. The isolation of the oxides (58) and (59) from the addition reactions of the allene (60)has been shown to depend upon whether or not the reaction is under kinetic control, which leads to (58), or thermodynamic control, which leads to (59).*1 0 CH,=C=CHPPh, (60) 4l

Me,CuLi

0

*

II

CH,=C(Me)CH,PPh, ( 5 8)

*

Me

0

‘C=CHPPh, Me/ (5 9)

J. Berlan, J.-P.Battioni, and K. Koooha, Tetrahedron Letters, 1976, 3351.

II

77

Phosphine Oxides and Sidphides

5 Miscellaneous Physical and Structural Aspects Ab initio M.O. calculations have been carried out on the phosphorane (61), formed A number of different by hypothetical addition of hydride ion to phosphine geometrieswere examined and a slightly distorted trigonal bipyramid was found to be the most stable, provided that the phosphoryl oxygen is placed in an equatorial site.

H

0 '

The dominant factor dictating this preference appears to be the better charge delocalization in (61), compared with (62).42This conclusion is in agreement with the earlier predictions of Hoffmann et al., although the latter emphasized r-donor repulsion as the most important single factor favouring equatorial placement of the 0-ligand.43 Another aspect of these calculations concerns the barrier to axial placement of the 0-ligand, as in (62). This barrier is estimated at 65 kJ m01-l.~~ If this is a fair reflection of the likely barrier in structures derived from tertiary phosphine oxides, it would adequately explain the observed optical stability of tertiary phosphine oxides in alkaline conditions and the difficultyof exchanging the labelled atom from l 8 0 labelled oxides on treatment with alkali. The pKa values of the oxides (63) in glyme and in DMSO have been determined by an exchange method, and values in the latter solvent ( 21-22) were found to be much larger than those in the former.44Dipole moments have been measured for the oxides (64)and for the corresponding pho~phines.~~ N

0

II

R,PCH,CQ,Et (6 3)

Ar,P=O (64)

A detailed structure has been published for triphenylphosphine oxide (42).46 Crystal structure analysis of the oxide (65 ;R1= Rs= Ph, RZ= Me) has been reported.47The diastereoisomers of general structure (65) have been prepared as shown, and have been ~ e p a r a t e dExtensive .~~ analysis of :+.JCPand 3JPH values has been used to suggest preferred conformations in which the vicinal hydrogens are, unexpectedly, always trans, e.g. structure (66).48 Other spectral studies include 13Cn.m.r. shifts and 13C-31P coupling constants, C. A. Deakyne and L. C. Allen, J , Amer. Chem. SOC.,1976,98,4076. R. Hoffmann, J. M. Howell, and E. L. Muetterties, J . Amer. Chem. SOC.,1972, 94, 3047. 44 E. S. Petrov, E. N. Tsvetkov, M. I. Terekhova, R. A. Malevannaya, A, I. Shatenshtein, and M. I. Kabachnik, Bull. Acad. Sci., U.S.S.R.,1976, 517. 45 1. P. Romm, E. N. Guryanova, N. A. Rozanelskya, and K. A. Kocheshkov, TetrahedronLetters, 1977, 33. 46 G . Ruban and V. Zabel, Cryst. Struct. Comm.,1976, 5 , 671. 47 R. 0. Day, V. W. Day, and C. A. Kingsbury, Tetrahedron Letters, 1976, 3041. 413 C. A. Kingsbury and D. Thoennes, Tetrahedron Letters, 1976, 3037. 42

*3

78 0 Ph,PCl

+

R1CH=C(R2)CR3

AcOti

Organophosphorus Chemistry 0

.O

II

Ph2PCHR'CHRzCR3 (65)

0

R3

(66) R' = R2 = R' = Ph

or R' = R2 = Ph; R3 = Me or R' = R3 = Ph; R2 = Me

(67) n = 3 , 4 , 5 , or 6

measured on the cyclic phosphine oxides (67).49 Electron-impact studies on a range of phosphine oxides have revealed fragmentation patterns and rearrangements.60 Varying aspects of the complexes of phosphine oxides and sulphides with Lewis acids have been covered in this year's literature. Thus the vibrational spectra of bismuth(u1) and antimony(Ir1) halide complexes of triphenylphosphine oxide (42) and triphenylarsine oxide (68) have been described.61Complexes of phenol or tin(rv) chloride with mixed triarylphosphine oxides (69) have been investigated by i.r. and colorimetric methods.62Thermodynamic data have been published on mercury(r1)

s s Ph3As=0 (6 8)

II

it

PhPAr,

Ph2PCH2PPh,

(6 9 )

(70)

chloride complexes of triphenylphosphine sulphide, its arsenic analogue, and the . ~ ~by disulphide (70).53Complexes of (42) have also been studied by 31Pn . m . ~ and U.V. spectroscopy.66 A vast amount of work continues to appear on the ability of tertiary phosphine oxides to extract either metal ions or acidic species from aqueous solutions. The 40 50

5a 53 54 55

G. A. Gray, S. E. Cremer, and K. L. Marsi, J. Amer. Chem. SOC.,1976, 98, 2109. G. L. Kenyon, D. H. Eargle, and C. W. Koch, J. Org. Chem., 1976, 41, 2417. S. Milicev and D. Hadzi, Inorg. Chim. Acta, 1977, 21, 201. A. A. Shvets, E. G. Amarskii, 0. A. Osipov, and L. V. Goncharova, J. Gen. Chem. (U.S.S.R.), 1976,46, 1654.

M. J. Gallagher, D. P. Graddon, and A. R. Shiekh, Austral. J. Chem., 1976, 29, 2409. S. 0. Grim and L. C. Satek, J. Coordination Chem., 1976, 6, 39. W. R. Gilkerson, J. Phys. Chem., 1976, 80, 2488.

79

Phosphine Oxides and Sulphides

favourite extractant is tri-n-octylphosphine oxide (71),66-66although tri-n-butylphosphine oxide (72) 6 6 - 6 8 and various alkylenediphosphine dioxides (73) 70 have 6Qp

0

(n-C, H,,),P=O 171)

Bu”,P=O (72)

II

0

It

R,P(CH,),PR, (73)

also been used. Quantum yields have been measured for the photochemical oxidation of triphenylphosphine to its oxide (42).’l

56 57 58 69

61 Ga

63 64

135 66

67 68

6Q

70 ’1

T. Sato, H. Watanabe, and M. Yamatake, J. Appl. Chem. Biotechnol., 1976,26, 697. T. Sekine, H. Honda, and Y . Zeniya, J. Inorg. Nuclzar Chem., 1976, 38, 1347. M. Mojski, J. Radioanalyt. Chem., 1977, 35, 303. T. Sekine, S. Iwahori, and R. Murai, J . Inorg. Nuclear Chem., 1977, 39, 363. Z. K. Karalova, L. M. Rodionova, Z. I. Pyzhova, and B. F. Myasoedov, Radiokhimiya, 1977, 19, 38.

2. K. Karalova, L. M. Rodionova, Z. I. Pyzhova, and B. F. Myasoedov, Radiokhimiya, 1977,

19, 42. M. Schroder-Nielson, Acta Pharm. Suecica, 1976, 13, 133. M. Schroder-Nielson, Acta Pharm. Suecica, 1976, 13, 145. M. Niitsu and T. Sekina, J. Znorg. Nuclear Chem., 1976, 38, 1053. M. Niitsu and T. Sekine, J. Inorg. Nuclear Chem., 1976, 38, 1057. B. N. Laskorin, D. I. Skorovarov, E. A. Filippov, and I. I. Volodin, Radiokhimiya, 1976, 18, 737. C. M. Mikulski, N. M. Karayannis, and L. L. Pytlewski, J.Less-Common Metals, 1977,51,201. G . Roland, M. Pondant, and G. Duyckaerts, Analyt. Chim. Acta, 1976, 85, 331. K. B. Yatsimirskii, M. I. Kabachnik, E. I. Sinyavskaya,T. Ya. Medved, and F. I. Bel’skii, Teor. i eksp. Khim., 1976, 12, 777. A. M. Rozen, Z. A. Berkman, L. E. Bertha, D. A. Denisov, A. I. Larubin, V. G. Kossykh, 2. I. Nikolotova, S. A. Pisareva, and K. S. Yudina, Radiokhimiya, 1976, 18, 493. G. L. GeoRroy, D. A. Denton, and C. W. Eigenbrot, Inorg. Chem., 1976, 15, 2310.

5

Tervalent Phosphorus Acids BY B.

J. WALKER

1 Introduction The Reporter notes an overall decrease in the number of papers in this area published during the year, although the number dealing with p,-bonded phosphorus compounds continues to increase. The reactions of disulphides with tervalent phosphorus compounds have been reviewed.l 2 Phosphorous Acid and its Derivatives Nucleophilic Reactions.-Attack on Saturated Carbon. Numerous undistinguished examples of the Arbusov reaction have appeared, mostly in the Russian literature. The reaction has been used to prepare the phosphonate analogue (1)2 of the initial H z 0 3 P hHO / Y M e

phosphorylated species in the terpene biosynthetic pathway, as well as the phosphonates (2)3 and (3),4 which have been used as Horner-Wittig reagents to give enol ethers and keten thioacetals, respectively (Scheme 1). Arbusov reactions involving halides that are more complex than simple alkyl are generally difficultto carry out ; R1CHC1(OR2) + (R30)3P

-

0

II

(R30),PCHR1(OR2) (2)

a R4,C=CR'

(OR')

0 R'S

\CHC1

+

(R20),P

L_)

I1

(R20)2PCH(SR*)2 % RJZC=C(SR*),

(3)

R' S' Reagents: i, base; ii, R4&O; iii, R3&0

Scheme 1 1

a

3

4

T. Mukaiyama and H. Takei, Topics Phosphorus Chem., 1976, 8, 587. V. Sarin, B. E. Tropp, and R. Engel, Tetrahedron Letters, 1977, 351. E. Schaumann and F. Grabley, Annalen, 1977, 88. M. Mikolajczyk, S. Grzejszczak, and A. Zatorski, Tetrahedron Letters, 1976, 2731.

80

81

Tervalent Phosphorus Acids

however, such a reaction has been used5 in the synthesis of the phosphinate (4). A similar reaction with chloroacetone gives mainly the Perkow product (5), whereas the corresponding iodo-compound gave the Arbusov product (6) (see Scheme 2).

PhP(OCH,Ph),

Ph

A

PhCH,O’ Ph\lI

/

P-CH,COMe

/

P-CH2C02Et (4) Me

11 ,O-C=CH,I

\ 0

0

0

\ 11

PhP,

PhCH,O’

‘OCH,Ph

(6)

(5)

Reagents: i, BrCHzC02Et; ii, CICM2COMe; iii, ICHzCOMe

(EtO),PCl

+

LiC-CPh

Scheme 2

* (EtO),P-C-CPh

$/

(7)

iii

0 ll,O-CPh=CH, EtOP \

“\CPh

‘+CPh

Reagents: i, ClCHzCOPh; ii, BrCHzCOPh

Scheme 3

Rather similar results (Scheme 3) were obtained with the alkynylphosphonite (7); reaction with a-chloroacetophenone gave the vinylphosphonate (8), whereas treatment with a-bromoacetophenone gave 3,5-diphenyl-1-ethoxy-1-oxo-4-oxa-1-phosphacyclohexa-2,5-diene (10). Support for the Arbusov product (9) as an intermediate in this latter reaction was provided by the formation of (10) on heating an independently synthesized sample. Aminomethanebisphosphonic acid derivatives (11) have been prepared by a number of methods,’ including the reaction of diethyl phosphite with amino-acetals and the reaction of triethyl phosphite with the halogenoiminium salts (12). Attack on Unsaturated Carbon. The Russian literature contains the usual examples of the addition of tervalent phosphorus to activated double bonds. The reaction of triethyl phosphite with 1,2-dichlorovinyl ethers to gives the phosphonate (13) is in 5 6

7 8

P. Brownbridge, P. K. G. Hodgson, R. Shepherd, and S. Warren, J.C.S. Perkin I, 1976,2024. M. S. Chattha, Chem. n n d I n d , 1976, 484. H. Gross, B. Costisella, T. Cnauk, and L. Brennecke, f. puakf. Chem., 1976, 318, 116. V. M. Ismailov, T. A. Babaeva, and Sh. T. Akhmedov, Zhur. obshchri Khini., 1976, 46, 1652 (Chem. Abs., 1976, 85, 143 205).

Organophosphorus Chemistry

82 0

II

2(EtO),PH

f

R'R2NCR3(OMe),

2(EtO),P

f

*

R'R2$=CC1R3

/f

C1'

(12)

direct contrast to the similar reaction of the fluoride (14), which gives the phosphorane (15) and no trace of the Arbusov p r o d ~ c tAs . ~ might be expected, the reactions (EtO),P + ClCH=CClOR

_.)

ClCH=C (13)

(R*O),P + F$=C

/OR 'P(OEt), // 0

+ EtCl

,I;

,C& --+ (K'O),P

C ' ORZ

\

,CF3

CF=C

'COR'

(15)

(14)

of phosphites with nitro-alkenes involve more than simple addition to the carboncarbon double bond, although this reaction does take place.l0 Depending on the conditions used, phosphoranes (16) or vinylphosphates (17) can also be isolated,l0$l1 and although solvent effects on the route followed seem logical, one suspects that the mechanism is more complex than the authors suggest. PhP(OMe),

+

OC

t

0

0 /Ph 'P-OMe

'0'"

Me,CHCH=CHNO,

" ' t

+

I

q'OMe CHMe,

CHMe,

i

(R'O),P-

(R'O),P

II

Ph(Me0)P-C=CH,

R'CH-CHNO,

7

-

CHR2CH,NO,

0

(R'O)2P-

CR2=CH, (17)

10

11

I. L. Knunyants, U. Utebaev, E. M. Rokhlin, E. P. Lure, and E. I. MYSOV, Izuest. Akad. Nauk S.S.S.R., Ser. khim., 1976, 875 (Cliem. Abs., 1976, 85, 63 127). E. E. Borisova, R. D. Gareev, T. A. Guseeva, L. M. Kozlov, and I. M. Shermergorn, Dokfady Akad. Nauk S.S.S.R.,1976,226, 1330 (Chem. Abs., 1976,85, 5801). R. D. Gareev, G. M. Loginova, and A. N. Pudovik, Zhur. obshrhei Khim., 1976, 46, 1906 (Chem. Abs., 1976,85,177 5 5 3 ) ; R. D. Gareev, G. M. Loginova, A. G. Abul'khanov, and A. N. Pudovik, Zhur. obshchei Khim.,1976, 46, 2385 (Clzent. Abs., 1977, 86, 16 754)-

TervalentPhosphorus Acids

83

0 +

-+ R CPh,

Ph,CH

CPh,

BF4-

Di-isopropyl pyridyl-4-phosphonates (18) are the exclusive products of the reaction of sodio di-isopropyl phosphonate with 1-triphenylmethylpyridiniumsalts,12 even in the cases of salts with no a-substituents. Surprisingly, the vinylphosphonate (19) is reported to be the major product from the reaction of triethyl phosphite with vinyl isocyanate.13 (See below for other reactions with isocyanates). Vinylphosphonates (20) are also the products of addition of phosphite to ethynyl ethers, with attack of phosphorus at the substituted end of the triple bond.14 0

(EtO),P

II p, * (EtO),P--C,N_, 1c-0

+ CH,=CHN=C=O

(19)

0

II

(R'O), P-C

(OR2)=CH, (20)

Both =-amino- (21) and a-hydrazino-phosphonic acids (22) have been prepared from aliphatic aldazines by the addition of dialkyl phosphites, followed by reduction and hydrolysis, respectively (see Scheme 4).16 R'CH=N-N=-CHR'

i

-A.(R20),P-CH-NH-"=.CHR1 R11

0

0

It

(RZO),P-CHR'

(NH,)

II

(RZO),P-CH-NH-NH,

1

R'

(21)

(22j

Reagents: i, (RzO)zPH(O); ii, Hz-Raney nickel; iii, H30+

Scheme 4 Redmore, J. Org. Chem., 1976,41, 2148. A. Shokol and N. K. Mikhailyuchenko, Zhur. obshchei Khim., 1977, 47, 75 (Chem. Abs., 1977, 86, 140 166). V. G. Salishchev, M. L. Petrov, and A. A. Petrov, Khim. Elementoorg. Soedin., 1976,91 (Chem. Abs., 1976, 85, 192 821). J. Rachori and C. Wasielewski, Roczniki Chem., 1976,50,477 (Chem. Abs., 1976,85, 108 708); M. Hoffmann, C. Wasielewski, and J. Rachon, Chimia (Swirz.), 1976, 300, 187 (Chem. Abs., 1976, 85, 33 133).

12 D. l3 V.

l4 15

84

Organophosphorus Chemistry

Several reports of the additions of phosphites l6, l7 and phosphoraniidites18 to carbonyl groups have appeared. In the case of aminophosphines, these involve the well-documented rearrangement to the a-amino-compound (23),18 and for the vinyl ketone (24) the product is (25), reaction at the carbonyl group competing favourably with Michael addition (Scheme 5).19The already extensively studied, but still some0 (Me,N),PNHCOMe

+

PhCHO

I_+.

II

Me,NP-NHCOMe

.I

CHPhNMe,

(23)

(25) Reagents : i, fR30)zPH(O)-EtzNH

Scheme 5

what confusing, reaction of phthalic anhydrides with triethyl phosphite has been further investigated, and the X-ray crystal and molecular structures of the major product, trans-biphthalyl (26), have been described.2o (See also Chapter 1 1). 0

0 (26)

As might be expected, keto-sugar acetates undergo the Perkow reaction with trimethyl phosphite to give a mixture of enol phosphates (27) and (2S).21In other cases the products appear to be dependent on the leaving group, and the Perkow products 16 17 18

19 20

21

K. A. Petrov, V. A. Chausov, and I. V. Pastukova, Zhur. obshchci Khim., 1976, 46, 1413 (Chem. Abs., 1976,85, 160 247). W. Kochmann, E. Guenther, an3 T. Roethling, 2. Chem., 1976, 16, 184. A. N. Pudovik, E. Batyeva, and E. N. Ofitserov, Khim. Elemenfoorg. Soedin., 1976, 124 (Chem. A h . , 1976, 85, 177 554). A. A. Avetisyan, A. N. Dzhandzhapanyan, and M. T. Dangyan, Zhur. obshchei Khim., 1976, 86, 2225 (Chem. A h . , 1977, 86, 29 918). F. Ramirez, J. S. Ricci, jun., H. Tsuboi, J. F. Marecek, and H. Yamanaka, J. Org. Chem., 1976,41, 3909. J. Thiem, D. Rasch, and H. Paulsen, Chem. Ber., 1976, 109, 3588.

85

Tervalent Phosphorus Acids

I

C-OP

+

A @ I O A c (MeO),P

_.t

OAc

CH~OAC

+[ A

(OMe),

A c O c=o joAc

OAc

I

CH,OAc

CH20Ac

C-

OP(OMe),

!!

OAc OAc

CH,OAc

CH,OAc

(27)

(28)

[e.g. (2911 or phosphonates [e.g. (M)] can be obtained. Those familiar with studies of

the mechanism of the Perkow reaction will shudder to speculate that we may have

phg;&Me phd--)oMe go&$ ,CH,

H

(Me0)3p+

0

OR

H

,CH,

Or

(MeO),P-0

%

(29)

OR

HO

(3 0)

to suffer the description of similar work on the reaction of a-halogenocarbonates (31) with phosphites to give enol phosphates, a case where there are at least four possible initial sites for attack.22 0

(3 1)

Examples of the reaction of tervalent phosphorus with isocyanates and their analogues include the addition of phosphites to carbonyl isothio- and isoseleno-cyanates to give the phosphonates (32)28 and the reaction of dialkyl phosphoramidites with trichloroacetyl isocyanate to give the rearranged product (33).24 Predictably, the betaine (34) is obtained from the reaction of TDAP with fluorosulphonylisocyanate; more surprising is the relative stability of (34) to hydroly~is.~~

2s

24 25

Y. Nu, T. Kunieda, and T. Takizawa, Tetrahedron Letters, 1976, 2323. W. J. Stec, K. Lesiak, and M. Sudol, Synthesis, 1975, 785. A. N. Pudovik, E. S. Batyeva, and E. N. Ofitserov,Zhur. obshchei Khim., 1976,46,1441 (Chem, A h . , 1976, 85, 160 252). H. W. Roesky and G. Sidiropoulos, Angew. Chem. Internat. Edn., 1976,15, 693.

4

86

Organophosphorus Chemistry R'X

(R'O),P

+ RZCO-N=C=X

+

0

I II

R*CON=C--P(OR'), (32) X = S or Se

0

(EtO),PNHR t Cl,CCON=C=O

II

(EtO),P-C=NCOCCl,

I

NHR (33) -10

FS0,N-C-0

,; I + (M%N),P + FS0,N-C-P(NMe,), +

(34)

Acetonitrile undergoes acid-catalysed addition of two moles of diethyl phosphite to give 1-aminoethyldiphosphonicacid derivatives (35).26

(35) R = H or Et

Attack on Nitrogen. A new route to phosphoramidates, involving the reaction of silyl phosphites with the appropriate azide, followed by hydrolysis, has been de~eloped.~' The mechanism (see Scheme 6) probably involves initial formation of the phosphite imine (36) followed by migration of a silyl group from oxygen to nitrogen, and it is exemplified by the synthesis of the oligoazanucleotide (37). Attack on Oxygen. Cyclic phosphites or phosphonites (38) react with a-keto-acids to give cyclic acyloxyphosphoranes (39), 28 which have previously been i m p l i ~ a t e das~ ~ intermediates in the hydrolysis of phosphoenolpyruvate; initial attack on ketooxygen has been suggested, as shown. Acyclic phosphites gave the MichaelisArbusov product (40), presumably because they lack the five-membered ring to stabilize the phosphorane (39). A new method of cyclization has been developed, through the reaction of suitably or tho-substit uted diethyl benzoylphosphonates (4 1),or their acid chloride precursors, with trialkyl p h o ~ p h i t e sAn . ~ ~analogous reaction takes place with (42) to give the fluorenylphosphonate (43). The mechanism suggested involves initial attack on carbony1 oxygen, and gains support from the formation of the benzofuranylphosphonate (45) in the reaction of (44)with triethyl phosphite. 26 27

2* 29

V. V. Orlovskii and B. A. Vovsi, Zhur. obshchei Khim., 1976, 46, 297 (Chem. Abs., 1976, 84, 164 946). D. E. Gibbs, Tetrahedron Letters, 1977, 679. T. Saegusa, S. Kobayashi, Y. Kimura, and T. Yokoyama, J. Amer. Chem. SOC.,1976,98,7843. G. D. Smith, C . N. Caughlan, F. Ramirez, S. Glaser, and P. Stern, J. Amer. Chem. SOC.,1974, 96, 2698. G. P. Chiusoli, G. Cometti, and V. Bellotti, J.C.S. Chem. Comm., 1977, 216.

Tervalent Phosphorus A cicls

87

0

OR'

I1 R'OP-0-

R'OP(OSiMe,),

H

i

-%- (Me,SiO),P=NR2 (36)

OR'

R'O *

\

R2NH-P=O -0/ (37)

&

I I1 0

Me, SiOP-NR'(SiMe,)

I

Reagents: i, M e e N S i M e a ; ii, R2N3; iii, HzO

Scheme 6

R'P<]

0

Rd"] /' 0 0

(38)

+

R2CC0,H 0

II

I

c_f

-

R'-P+-0

/

-C

R2'

'C0,H

R2 O g o 2 -

-

"3 I

R! )P-0 R2# 0

0

II

(EtO),P + R'CC0,H + (EtO),POCHR'CO,Et

II

0

(40)

The reactions of a variety of tervalent phosphorus compounds with 1,Zdioxan have been in~estigated.~~ Reactions with phosphites give either phosphate and THF or the phosphorane (46),depending on the phosphite used, and so are very similar to the analogous reactions with dialkyl peroxides.32Penta-alkoxyphosphoranes (47) 31 32

N. J. De'ath and D. B. Denney, Phosphorus and Sulphur, 1977, 3, 51. D. B. Denney, D. Z . Denney, C. D. Hall, and K. L. Marsi, J. Amer. Chem. Soc., 1972,94, 245.

Organophosphorus Chemistry

88

II

COP(OEt),

+ (MeO),P XMe (41)

X

=

0,NR,or S

-C i O=P(OEt),

0

C\O-i(OMe),

X-Me

1

O=P i(MeO),PO

+-

(OEtI2

' X

are also obtained from the reaction of tertiary phosphites with alkyl benzenesulphenates.s8 The reaction of phosphites with pseudohalogens, e.g. thiocyanogen, gives the corresponding phosphoranes [e.g. (48)].34 Initial attack by phosphorus on sulphur, 33 34

L. L. Chang, D. B. Denney, D. Z. Denney, and R. J. Kazior, J. Amer. Chem. SOC.,1977,99,

2293.

E. Krawcwk. J. Michalski. M. Pakulski. and A. Skowroliska. TetrahedronLetters. 1977

2019.

Tervalent Phosphorus Acids

89

a]-. N=C=S

SCN

a;,p.,cN \+/R

N=C=-S

(48) followed by rearrangement via a phosphonium salt species, is the Suggested mechanism. Aryl thiocyanates react with primary alcohols in the presence of tervalent phosphorus compounds to give hydrogen cyanide, an alkyl aryl sulphide, and the corresponding phosphoryl The mechanism suggested involves initial attack at sulphur by phosphorus to give (49), and evidence for the formation of thiophenoxide anion is provided by the isolation of 2,4-dinitrophenyl phenyl sulphide from experiments carried out in the presence of l-chloro-2,4-dinitrobenzene. ArSPR',

A~SCN+ R ~ , P rn A ~ s $ R ~ , RzoH:

@ a,H,

I

CN'

CN(49) /HCN

A ~ S+ R ~ o $ R ~ ,+-

A~SH

1

.1

ArSR2

(ArS),

( 5 0)

A~SPR*,

1

OR2

+ R1,PO

Trimethyl phosphite selectively reduces 2,3-disubstituted quinoxaline lY4-dioxides

(51) to the corresponding monoxides in high yield, whereas methods previously used

led to mixtures of monoxides and quinoxalines.36 In unsymmetrically substituted -0

I

35 36

W. T. Flowers, G. Holt, F. Omogbai, and C. P. Poulos, J.C.S. Perkin I , 1976, 2394. J. P. Dirlam and J. W. McFarland, J. Org. Chem., 1977, 42, 1360.

Organophosphorus Chemistry

90

cases, the reaction is highly selective for removal of the oxygen adjacent to the more electron-withdrawing group. Attack on Halogen. The effect of changing the phosphorus nucleophile used on the reactions with a-halogenosulphones that give the dehalogenated sulphone (52) has ArCHXS0,Ph

+

R,P

+

ArCHzSOzPh

+

R,PO

+ HX

( 5 2)

R = aryl, alkyl, Oaryl, or Oalkyl

been investigated kinetically in some detaiLa7Triarylphosphines showed a good correlation with normal Hammett c constants for substituents in the phosphine to give, for example, p(Br) = - 3.03, and alkyldiphenylphosphines equally gave a Taft o*/log k, correlation to give p(Br) = - 4.21. However, similar reactions with trialkyl phosphites showed no correlation with Taft o* constants, and, surprisingly, were slower than reactions with triaryl phosphites. Diazadiphosphetidines form the halogenophosphonium salts (53) on treatment with high-valent chlorides of tin, phosphorus, and antimony.38 But MeP / N \PCl

s

\N/

__ But -

Me\; /N\ C1/

But

pcl

\N/ But

M-

(53) M = SnCI,, PCb, or SbC1, Electrophilic Reactions.-A general method for preparation of phenylethynyldiarylphosphines (54) is provided by the reaction of diethyl phenylethynylphos(EtO),PC-CPh

+

2ArMgX

_ . f

Ar,PC--CPh

(54)

phonite with aryl Grignard reagents.39Good yields of amido-esters of hypophosphorous acids (55) have been obtained through the reaction of phosphonite esters

with dialkylamides.40 Substitution at electrophilic tervalent phosphorus by alcohols has been used to prepare the achiral biphosphinite (56)41 (useful in the synthesis of asymmetric hydrogenation catalysts) and in an improved synthesis of diary1 methyl.~~ to prepare lg-halogenated phosphonates (57) from triaryl p h o ~ p h i t e s Attempts 37 38

39 40

41

42

B. B. Jarvis and B. A. Marien, J. Org. Chem., 1976, 41, 2182. 0. J. Scherer and G. Schnable, Z . Nuturforsch., 1976, 31b, 1462. J. C. Williams, W. D . Hounshell, and A. M. Aguiar, Phosphorus, 1976, 6, 169. N. B. Karlstedt, T. P. Goranskaya, M. V. Proscurnina, and I. F. Lutsenko, Khim. Elementoorg. Soedin., 1976, 172 (Clrem. A h . , 1977, 86, 5541). R. H. Grubbs and R. A. DeVries, Tetrahedron Letters, 1977, 1879. M. L. Honig and E. D. Weil, J. Org. Chem., 1977, 42, 379.

Tervalent Phosphorus Acids

91

OPPh, OPPh,

0

(ArO),P

Me011

Mel

II

(ArO),PMe

catalyst

(57 )

steroids from the corresponding 19-hydroxylatedcompounds, using both phosphinehalogen and phosphite-methyl iodide as reagents, were unsuccessful, although a variety of other products were The diphosphorus(rI1)-substituted acetic acid esters (58) undergo phosphoruscarbon bond cleavage with various nucleophiles, to give (59).44 This is analogous to the behaviour of diphosphines (60),45 and the isolation of cleavage products containing tervalent phosphorus lends further support to the mechanism proposed for the latter reaction. R1,P

'

+ R4XH --+R1;P--CH,C02R3

'CHCO,R'

R2,P

+ Rz2PXR4

(59)

(58)

R4X = OH,EtO,

Q,

or MeCO,

(60)

As previously reported,4s oximes react with electrophilic tervalent phosphorus compounds to give the rearranged product (62). Hudson and his co-workers have R',PX

+ R2R3C=NOH

R2R3C=N-OpR',

+ RZR3C=N* + .OPR',

(61)

0 RZR3C=N-PR',

II

(62) 43 44 45

46

E. Santaniello, E. Caspi, W. L. Duax, and C. M. Weeks, J. Org. Chem., 1977, 42,482. Z. S. Novikova, S. Ya. Skorobogatova, and I. F. Lutsenko, Zhur. obshchei Khim., 1976, 46, 2213 (Chem. Abs., 1977, 86, 16 749). S. M. Nelson, B. J. Walker, and M. Perks, J.C.S. Perkin I , 1976, 1205. Yu L. Kruglyak, M. A. Landau, G. A. Leibovskaya, I. V. Martynov, L. I. Saltykova, and M. A. Sokalskii, Zhur. obshchei Khim., 1969, 39, 215.

0rganophosphorus Chemistry

92

now shown that the reaction takes place via a radical-cage mechanism involving the tervalent intermediate (61), which cannot usually be i~olated.~' The interest in multiply bonded tervalent phosphorus compounds continues to grow, and a number of papers dealing with the reactions of phosphorus-nitrogen pn-pr bonds have appeared. 1,2,3aa-Diazaphospholes(63) undergo addition with MeCO

MeCO

I

I

(63)

alcohols to give the corresponding diazapho~pholines.~~ What may be the first example of electrophilic aromatic substitution in 1,2,3a2-diazaphospholeshas been r e p ~ r t e d The . ~ ~ reaction of N-methylhydrazones with an excess of phosphorus trichloride gives initially the diazaphospholium salts (64); however, longer reaction times give 4-dichlorophosphino-2,5-dimethyl1,2,3a8-diazaphospholes(65).

The first X-ray structural analysis of an aminoiminophosphine (66) has been accomplished (see also Chapter 11).60 Stable zwitterions (67) and (68) containing

Me,Si'

(66) phosphorus with a co-ordination number of two have been prepared by the reaction of aminoiminophosphine with aluminium trichloride.61 While the initial product (67) slowly forms (69, the latter compound is extremely thermally stable, although 47 48 49

50 51

C. Brown, R. F. Hudson, A. Maron, and K. A. F. Record, J.C.S. Chem. Comm., 1976, 663. R. C. Bobkova, N. P. Ignatova, N . I. Shvetsov-Shilovskii, V. V. Negrebetskii, and A. F. Vasil'ev, Zhur. obshchei Khim., 1976,46, 590 (Chem. Abs., 1976, 85, 5800). J. Luber and A. Schmidpeter,J.C.S. Chem. Comm., 1976, 887. S. Pohl, Angew. Chem. Internat. Edn., 1976,15, 687. E. Niecke and R. Kroher, Angew. Chem. Internat. Edn., 1976,15, 692.

93

Tervalent Phosphorus Acids

treatment with t-butyl azide gives the spiro-zwitterion (69), presumably by the mechanism shown in Scheme 7. A number of new diazadiphosphetidines[e.g. (70)]

Y=Y

B U~N,;,NBU~ R”“R

‘d

c(

‘Cl (69)

Reagent: i, ButNs

2R,NP=NR R = %Me,

+ AI$I,

!1 But,

N

II

RN /p\N

‘d

/R

+

2R,N-P-N

(67)

1

R

Scheme 7

have been prepared from dichloromethylphosphine and aminoiminophosphines.s2 Of particular interest is the formation of the first example of a 1,3,2,4-diazadiphosphetidin-2-ylium salt (71)when (70) is treated with aluminium chloride. A novel tricyclodecane analogue (72) has been obtained by heating 2-phospha-l-tetrazene with arsenic t r i ~ h l o r i d e . ~ ~

The diaza-A3,ils-diphosphetidine(73) reacts with biacetyl at low temperatures to give the spirophosphorane (74);s4however, if the temperature is more strictly controlled, the reaction leads to the novel diaza-i16,i15-diphosphetidine(73, which slowly and irreversibly gives the phosphazene (76). Although previously proposed as intermediates in the formation of diazadiphosphetidines, chlorophosphines (77) have 5’3

53 54

0. J. Scherer and G. Schnabl, Chem. Ber., 1976, 109, 2996. 0. J. Scherer, W. Glassel, G. Huttner, A. Frank, and P. Friedrich, Angew. Chem. Internal. Edn., 1976, 15, 701. W.Zeiss, Angew. Chem. Internal. Edn., 1976, 15, 555.

Organophosphorus Chemistry

94 MeaSN-PNMe; I I Me,NP-NSiMe,

SiMe, M e c o \ P,,"\,PNMe,

(MeCO),

*

Me

(73)

dl

FiMe, NMe,

(74) 'SiMe,

Me,N

(76)

NMe, (75)

been isolated from such reactions for the first time (see Scheme 8).65 Treatment of (77) with phenyl-lithium gives the 1,3-2R3,4R3-diazadiphosphetidine (78) as a mixture of isomers (24 % cis, 33 % trans); geometric isomerism had not previously been observed in diazadiphosphetidines. Bu'P(NHMe),

A

Reagents: i, ButPClz-EtsN; ii, PhLi

Me

MeNHP-N-P

I

But (7 7)

,But 'c1

But P-NM e

I

I

MeN-PBut

Scheme 8

The synthesis of novel phosphorane structures continues to be fashionable. When methyl diphenylphosphinite is heated with 2-hydroxycinnamicacid, the spirobicyclic acyloxyphosphorane (79) is formed.66(See also Chapter 2). The now well established reaction of the tervalent phosphorus with compounds containing two suitably

separated acidic hydrogen sites has been used to prepare new spirophosphoranes [e.g. (SO)] from ~t-amino-acids.~~ Several reports of the synthesis of hexaco-ordinate phosphorus compounds [e.g. (Sl)] from tervalent phosphorus have appeared 58 (see Chapter 2). 31PN.m.r. studies 55

66

57

58

0. J. Scherer and G . Schnabl, Angew. Chem. Internat. Edn., 1976, 15, 772. J. A. Miller and D. Stewart, J.C.S. Chem. Comm., 1977, 156. B. Garrigues, A. Munoz, M. Koenig, M. Sanchez, and R. Wolf, Tetrahedron, 1977, 33, 635. e.g. M. A. Pudovik, S. A. Terent'eva, and A. N. Pudovik, Khim Elementoorg. Soedin.. 1976. 129 (Chern. A h . . 1976.85. 192 823).

Tervalent Phosphorus Acids

95

r

1-

Et

L (81) indicate that transesterification of the phosphite (82) with phenol takes place via the hexaco-ordinate intermediate (83). 69 ao\ / \lPhOH ?/03+

'0

N\

/

(82)

(83)

OH

N/

Rearrangements.-The previously reported reaction of phosphorus trichloride with various propargyl alcohols to give dichlorophosphites (84), and the subsequent rearrangement of the product to the corresponding allenic phosphonyl dichlorides (85), have been studied in some detail.60When the Reporter had unravelled the unusual symbolism relating to structures, it was clear that n.m.r. spectroscopy had

OH

,--.

+ PC1,

OPCI, (84)

'0

(85)

'0

shown that the conversion of (85) into the oxaphospholen (86) had taken place over several days. The allenic phosphoryl dichlorides (85) could be isolated from reactions 59 6o

C . B. Cong, A. Munoz, M. Koenig, and R. Wolf, Tetrahedron Letters, 1977, 2297. R. S. Macomber and E. R. Kennedy, J. Org. Chem., 1976,41, 3191.

96

Organophosphorus Chemistry

in which the hydrogen chloride produced was efficiently removed (but not neutralized). The initial product (87) from the reaction of dichlorophenylphosphine with perfluorocarboxylic acids apparently rearranges to the corresponding pyrophosphinate (88).61The information in the abstracte2is insufficient for one to be able to judge the PhPCI, + 2RC0,H

_.)

PhP(OCOR),

0

0

R

R

I II * PhP-0-PPh

(87)

(88)

implications of the reported rearrangement of trimethyl phosphite to dimethyl methylphosphonate on heating to moderate temperatures with sodium tetraphenylborate. Cyclic Esters of Phosphorous Acid.-The cyclic aminophosphite (go), prepared from the correspondinghalohydrin and the phosphoramidate (89), slowly forms the novel ammonium salt (91).63Both spectroscopic and chemical evidence appear to support the ionic structure over the alternative (92). Me

[.

Me

N*e

0 , ,PC1

NYf5° (92)

Me Cf

[>Pa

Me (91)

The stereochemistryand mechanism of the reaction of tervalent phosphorus esters with sulphenyl chlorides have been investigated.6 4 cis-2-Methoxy-4-methyl-1,3,2dioxaphosphorinan (95) and cis-2-hydro-2-oxo-4-methyl-1,3,2-dioxaphosphorinan (93) both gave trans-2-thiomethyl-2-oxo-4-methyl-1,3,2-dioxaphosphorinan (94), while the corresponding geometrical isomers gave the cis-compound (96). Similarly, the acyclic phosphonate (97) gave the thiol ester (98). The retention of configuration at phosphorus observed in all the cases studied makes a mechanism involving initial attack on halogen by phosphorus unlikely, since this would lead to inversion or 61 62

63 64

P. Sartori and R. Hochleitner, Inorg. Nuclear Chem., Herbert H. Hyman Memorial Vol., 1976,9 (Chem. A h . , 1976,85, 192 813). Yu. V. Belkin, N. A. Polezhaeva, and B. A. Arbuzov, Izvest. Akad. Nauk S.S.S.R.,Ser. khim., 1976, 949 (Chem. Abs., 1976,85, 33 143). H. Sliwa and J. P. Picavet, Tetrahedron Letters, 1977, 1583. M. Mikolajczyk, J. Krzywanski, and B. Ziemnika, J. Org. Chem., 1977, 42, 190.

Tervalent Phosphorus Acids

97 SR

0

,.

0 Pr’OPH

II

II

Meeoyp\SR

I

:z

Et (97)

(96)

0 Pr’OPSR

II I Et

(98)

racemization. The reaction of phosphites with N-chlorodialkylamines has been thoroughly inve~tigated.~~ With cyclic phosphites (99) and (100) the reaction was OMe

I

0

I1

NR2

I

non-stereospecific, and the ratio of the phosphoramidates formed was highly dependent on the reaction conditions. The results suggest that at least some proportion of the product is formed via phosphorane intermediates. The relative rates for a variety of tervalent phosphorus compounds were determined by competition, and their nonlinear correlation with nucleophilicity again supports a mechanism involving insertion into the nitrogen-halogen bond. The stereochemistries of isomers of 2-substituted 1,3,2-diazaperhydrophosphorines(101) have been investigated and compared with those of the corresponding dioxaphosphorinans.6sIsomer ratios of the products (101) obtained from the reaction of NN’-dimethylbutane-l,3-diaminewith

X

(101) X = lonepair R = OMe or NMe,

(102) 65

66

x

= 0 R = OMeorNMe,

L. L. Chang and D. B. Denney, J. Org. Chem., 1977,42,782. J. A. Mosbo, Tetrahedron Letters, 1976, 4789.

Organophosphorus Chemistry

98

phosphorus trichloride, followed by treatment with methanol or dimethylamine, were determined by 31Pand IH n.m.r. spectroscopy.These ratios appear to be equilibrium values. Unlike the intensively studied dioxaphosphorinans,the stereochemistry of (101) cannot be assigned with certainty from n.m.r. data; however, comparisons with the dioxa-analogues, and oxidation to the 2-oxo-derivatives (102), allow tentative allocation of the phosphorus substituents to the axial or equatorial positions in the more stable isomers of (101), depending on the substituents. Irrespective of the validity of these assignments, the thermodynamic stability of isomers is much more evenly balanced in these cases than in the corresponding dioxaphosphorinans. 1,3,2-Dioxaphosphorinansand 1,3,2-dioxaphospholansare known to dimerize to twelve- and ten-membered rings, respe~tively,~~ and now 1,3,Zdithiaphosphorinans have been shown to behave in a similar way.68Both dimers and monomer have been shown to interconvert when heated in an n.m.r. tube. The isolation of (103) provides a route to a variety of macrocyclic compounds analogous to (104). Attempts to pre-

@=\But

+ polymer

pare 2-t-butyl-l,3,2-dioxaphosphepans(105) from dichloroalkylphosphines and 1,4glycols gave mixtures of (105), dimers, and as had previously been observed for the corresponding 1,3,2-dioxaphosphorinans. The pure trans-isomer (106) was obtained by distillation from the reaction of (-)-ephedrine with phosphorus trichloride in the presence of base, although some cis-isomer was present in the crude reaction mixture.7o

(105)

(106)

(107)

Bicyclic phosphites (107) and related compounds have recently been shown to possess very high toxicity, and so their X-ray structural analysis is of interest 71 (see Chapter 11). 67 68 69

70

71

B. J. Walker in 'Organophosphorus Chemistry', ed. S. Trippett (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 7, p. 102. J. P. Dutasta, J. Martin, and J. B. Robert, J. Org. Chem., 1977, 42, 1662. J. P. Dutasta, A. C. Guimaraes, and J. B. Robert, Tetrahedron Letters, 1977, 801. C. R. Hall and T. D. Inch, Tetrahedron Letters, 1976, 3645. D. S. Milbrath, J. P. Springer, J. C. Clardy, and J. G. Verkade, J. Amer. Chem. SOC.,1976, 98, 5493.

Tervalent Phosphorus Acids

99

Miscellaneous Reactions.-A number of novel phosphite complexes, e.g. (1OS), have been prepared. 3-Substituted and the cage-forming compound (1 1,3,4,2A~~-oxadiazaphospholines (111) are the only products isolated from the re-

MeO\ Me0

Ni

/p/I, y‘,

/OMe OMe

o...K*.o

MeO\

’P,

Me0

(108)

R’CONHNHR’

Ni /OMe

gh?-“ I I

‘P,

OMe

0 0 \‘

p y

+ (Me,N),PX -+ 0, D,NR’ (111) X = NMe,orMe

action of aminophosphines with N-acylhydrazines, even when alternative modes of cyclization appear to be possible.74 3 Phosphonous and Phosphinous Acids and their Derivatives Continuing their investigation of the stereochemistry of tervalent phosphorus, Mikolajczyk and his co-worker have shown that optically active 0-methyl ethylphenylphosphinite (1 12) and S-ethyl ethylphenylthiophosphinite (113) react with methyl-lithium and sodium methoxide with predominant inversion of configuration at p h o s p h o r ~ sThe . ~ ~absolute configuration of (113) was established by conversion into ethylmethylphenylphosphine sulphide, and the stereochemical course of the nucleophilic displacements was determined by conversion of the initial products into the corresponding oxide and sulphides, as shown in Scheme 9. The unstable acyldiarylphosphine oxides, although previously postulated to e~ist,~G have only now been prepared, by the reaction of secondary phosphine 72

73 74

75

76

H. Werner and T. N. Khac, Angew. Chem. Internat. Edn., 1977, 16, 324. W. Klaui, H. Neukomm, H. Werner, and G. Huttner, Chem. Ber., 1977, 110, 2283. A. Schmidpeter, J. Luber, H. Riedl, and M. Volz, Phosphorus and Sulphur, 1977, 3, 171. J. Omelanczuk and M. Mikolajczyk, J.C.S. Chem. Comm., 1976, 1025. D. J. H. Smith and S . Trippett, J.C.S. Perkin I, 1975, 963 and references therein,

Organophosphorus Chemistry

100

Reagents: i, MeLi; ii,

2Lx \=Po

3H;iii,

S; iv, MeONa

Scheme 9

oxides with acid anhydrides and by the oxidation of the corresponding phosphines under anhydrous condition^.^^

77

E. Lindner, H.-D. Ebert,H. Lesiecki, and G. Vordermaier, Angew. Chem. Internut. Edn., 1977, 16, 269.

6

Quinquevalent Ph0spho ru s Acids BY R. S. EDMUNDSON

The year has seen marked activity in the synthesis (and biological examination) of derivatives and analogues of the important compound cyclophosphamide, and in the synthesis of phosphonic acid derivatives, particularly those from a-aminophosphonic acids, although much of this work has been of a developmental nature. Ramirez’s group has continued to examine the chemistry of cyclic enediol phosphates and their application as phosphorylating agents, and in so doing, they, and others, are increasingly bringing forward evidence of a more direct nature for the participation of five- (and six-)co-ordinateintermediates in displacement reactions of phosphorus(v) esters. The year’s reviews cover phosphorylated indoles,’ phosphorusselenium compounds,* phosphoryl carbenesYsphosphorus-sulphur compounds,* and steroid pho~phates,~ as well as the synthesis of phosphorus esters via oxyphosphoranes.6A review on phosphonates contains many interesting applications of some of the welltried syntheses of these as analogues of natural ph~sphates.~ 1 SyntheticMethods &neral.-Examples of compounds possessing the hitherto unrecorded 1,2,4azadiphosphetidine ring system have now been described. The reaction between methylenediphosphonic tetrachloride (1 ; R1= Cl) and primary aliphatic amines yields the lY2,4-azadiphosphetidine2,4-dioxides (2; Ra=But or Pri) as mixtures o cis- and trans-isomers; the reaction fails when R1is NMez, but the compound (2; R1=NMea may alternatively be prepared by heating compound (3).*

r

(1) (2) A. I. Razumov, P. A. Gurevich,and S. Yu. Baigl’dina, Khim. geterotsikl. Soedineniya, 1976,867. a J. Michalski, Chemica Scripta, 1975, 8, A, 58. a M. Regitz, New Synthetic Methods, 1975,2, 145. L. Almasi, ‘Les Composes Thiophosphororganiques’, ‘Monographie de Chimie Organique’ Masson, Paris, 1976, Tome 10. R. J. W. Cremlyn and I. Khattak, Phosphorus, 1976,6,237. 6 F. Ramirez and I. Ugi, Phosphorus and Sulphur, 1976,1,231. 7 R. Engel, Chem. Rev., 1977,77, 349. 8 G. Bulloch and R. Keat, J.C.S. Dalton, 1976, 1113. 1

101

102

Organophosphorus Chemistry

When NN-dimethylaniline is heated with phosphorus oxychloride there results a complex mixture of products, not all of them containing phosphorus; those identified include the NN-dimethylamino-derivatives of diphenylmethane and triphenylmethane, as well as the phosphine oxide (4), the phosphinic chloride (5), and the triamide (6).9 (4-Me,NC6H,),P(0)

(4-Me2NC6H,),P(O)C1

(PhMeN),P(O)NHPh

(4)

(5)

(6)

PhosphoricAcid and its Derivatives.-Di-t-butyl phosphorochloridateand phosphorobromidate are unobtainable by standard halogenation procedures, but may be obtained in high yield by phase-transfer halogenation (benzyltriethylammonium chloride in 20 % sodium hydroxide solution-dichloromethane)of di-t-butyl hydrogen phosphonate with carbon tetrachloride or tetrabromide, a procedure in which other dialkyl hydrogen phosphonates yield pyrophosphates.l* The benzylic alcohols R1CHR20H (R1=Ph or 3-CF,C6H,; R2=CF3or C3F,) give the corresponding phosphorodichloridateswhen treated with phosphorus oxychloride in the presence of metallic chlorides; however, the product is the ether (R1CHR2),0 when R1 is 4-toly1, and no phosphate is obtained.ll In the reaction between cholesteryl phosphorodichloridate and alcohols, the expected phosphate esters are accompanied by ethers, the relative proportions of the products depending on steric interactions on the part of the group R2; the more sterically hindered is the alcohol, the greater the extent of ether formation. Ethers are of greater importance in the products of the corresponding reactions with cholesteryl phosphorodichloridothionate.12 R’OP(O)G + R20H * R’OR’ R’ = cholesteryl

+ R’OP(0)(OR2),

Variables in the production of tributyl phosphate have been discussed.la In the presence of relatively large amounts (5-1 5 molar equivalents)of caesium fluoride or quaternary ammonium fluorides, 2,2,2-trichloroethyl phosphate esters readily transesterify with alcohols; the sequential replacement of trichloroethyl groups becomes slower, so allowing the preparation of mixed (including cyclic) trialkyl phosphate esters, with the exception of those from t-butyl An improved synthesis of 5-acetyl-2-methoxy-5-methyl-2,4-dioxo-1,3,2-dioxaphospholan (8), starting from the oxyphosphorane (7), has been reported,lS as has one of the enediol cyclic phosphoryl chloride (9; R = C1) from (9; R = OMe) via the corresponding pyrophosphate by reaction with phosgene-pyridine (see ‘Organophosphorus Chemistry’, Vol. 8, p. 1O6).ls lo 11

l2 l3 l4 l5

Ching Yee Cheng and R. A. Shaw, J.C.S. Perkin I, 1976, 1739. T. Gajda and A. Zwierzak, Synthesis, 1976, 243. L. S. Zakharov, E. I. Goryunov, S. T. Ioffe, L. L. Morozov, T. M. Shcherbina, and M. I. Kabachnik, Izvest. Akad. Nauk. S.S.S.R., Ser. khim., 1976, 1834 (Chem. Abs., 1976, 85, 176 984). R. J. W. Cremlyn, B. B. Dewhurst, and I. Khattak, Phosphorus, 1976, 6, 201. K. V. Rao and C. Chiranjur, Indian J. Technol., 1976, 14, 401. K. K. Ogilvie, S. L. Beaucage, N. Theriault, and D. W. Entwistle, J. Amer. Chern. SOC.,1977, 99, 1277. I. Ugi, P. Lemmen, and F. Ramirez, Chem. Ber., 1976, 109, 3738. F. Ramirez, H. Okazaki, J. F. Marecek, and H. Tsuboi, Synthesis, 1976, 819.

Quinquevulent Phosphorus Acids

103

Me Me<>P(OMe)3

(7) Ac (Me0,P /O 'OCMeCOcl

heat+Me

0

1'

120-130 "C

I

+

(8)

AC

(9; R = OMe)

Phosphorylation of alcohols by the reagents (9; R = Oalkyl) in aprotic solvents is catalysed by acetate ion, probably through penta- and hexa-co-ordinate intermediates (Scheme 1);17 that by the correspondingaryl esters is catalysed by phenoxide (9; R = OR')

Me

O Y 0

/ oR2

J

Me (R'O) (R20)P(0)OCHMeCOMe

__f

(R'O) (R20)P(0)OH

Reagents: i, AcO-; ii, R 2 0 H

Scheme 1

ion.l* Selective and efficient catalysis, particularly by imidazole, allows one-pot syntheses of unsymmetrical phosphodiesters from a large range of alcohols without the necessity for isolation of l 8 applications of this fascinating method of phosphorylation, based on enol phosphate activity coupled with cyclic oxyphosphorane formation, include the synthesis of phospholipids2o and deoxyribonucleotides.21 The reaction between alkyl (other than tertiary alkyl) bromides and phosphorus pentasulphide in the presence of aluminium trihalides yields mixtures of phosphorodi- and phosphorotri-thioic bromides, (RS)P(S)Br, and (RS),P(S)Br ; other alkylating agents have previously been shown to give tetrathioesters.22The 2,2-di17

1s

19 20

21 22

F. Ramirez and J. F. Marecek, Tetrahedron Letters, 1976, 3791. F. Ramirez, J. F. Marecek, H. Tsuboi, and H. Okazaki, J. Org. Chem., 1977, 42, 771. F. Ramirez, J. F. Marecek, and H. Okazaki, J. Amer. Chem. SOC.,1976, 98, 5310. F. Ramirez, P. V. Ioannou, J. F. Marecek, B. T. Golding, and G. H. Dodd, Synthesis, 1976, 769; Tetrahedron, 1977, 33, 599. F. Ramirez, E. Evangelidou-Tsolis, A. Jankowski, and J. F. Marecek, Synthesis, 1977, 45. I. V. Murav'ev and I. S. Fedorovich, Zhur. obshchei Khim., 1976,46, 1262 (Chem. Abs., 1976, 85, 160 246).

104

Organophosphorus Chemistry

cyanovinyl thiophosphate esters (10) are formed by phosphorylation of the sodium salt of the e n 0 1 ; ~the ~ ester (ll), readily separable into two diastereoisomers, is obtained from chloral and trimethyl phosphorothionate in concentrated sulphuric acid at low temperature~.~~ (R’O),P(S)OCR2=C(CN),

(MeO),P(O) SCH(CC1,) CH(0H) CCl, (11)

(10)

Five-membered cyclic phosphorotrithioates (12)are reported to be formed from 2-chloro-l,3,2-dithiaphospholansand sulphenyl chlorides in acetic acid or acetic anhydride.26

(12)

R = alkyl, aryl, or aralkyl

The phase-transfer technique has been employed in the mono- and NN’-diphosphorylation of hydrazine.26 Full papers dealing with the preparation of acyclic hydrazides,2 7 a preliminary and cyclic (perhydro-l,2,4,5-tetra-aza-3-phosphorine) report of some of which was given in ‘Organophosphorus Chemistry’ Vol. 7 (p. 114) have been published; of particular interest is the formation of cage compounds (13) and (14)from monocyclic compounds by further reaction with aldehydes or ketones. H Me R*C/N-N\P(S)NHNHPh \N-N/ H Me

4,

/NMe G
N

Ph

+ H

(1 3)

4,

/NMe G/:>NMe N U Ph

N

(14)

The reaction between methylhydrazine and phenyl phosphorodichloridothionate affords all three possible dihydrazides, which, with more of the acid dichloride, give the two isomeric perhydrotetra-azadiphosphorines (15).28 Considerable interest is still being displayed in the synthesis of derivatives and analogues of cyclophosphamide (I 6). The 4-hydroperoxy-derivative (1 7), formed by ozonolysis of (1 6), may be deoxygenated by triphenylphosphine to the 4-hydroxyderivative (18)2 9 (also formed by the hydrogenolysis of the 4-benzyloxy-compound30), which is reported to react with thiols to give the hydrosulphide (19). 23 24 26 26

27 28 29

30

H. Matschiner, P. Gallien, and B. Hesse, 2. Chem., 1976, 16,400. H. Sohr and A. Zschunke, Phosphorus, 1976,6, 107. Russ. P. 525 693 (Chern. Abs., 1977,86, 16 681). A. Zwierzak and A. Sulewska, Synthesis, 1976, 835. J. P. Majoral, R. Kraemer, J. Navech, and F. Mathis, J.C.S. Perkin 1,1976,2093; Tetrahedron, 1976, 32,2633. U. Engelhardt and H. J. Merrem, Z . Naturforsch., 1977, 33b, 715. G. Peter, T. Wagner, and H. J. Hohorst, Cancer Treat. Rep., 1976, 60, 429. A. Myles, C. Fenzelau, and 0. M. Friedmann, Tetrahedron Letters, 1977, 2475.

Quinquevalent Phosphorus Acids

105

a; R1 = R3 = Me, R2 = R4 = H b; R1 = R4 = Me, R2 = R3 = H

(15)

(16) (17) (18) (19)

R R R R

= = = =

H OOH OH SH

Hydroperoxy-derivatives of cyclophosphamide and its analogues are of especial interest because of their effectiveness in the treatment of cancers both in vivo and in uitro; such derivatives are also said to be formed by the ozonolysis of the acyclic phosphorodiamidates (20) as well as of compounds having the perhydro-1,3,2oxazaphosphorine CH,= CHCH,CH,O \pF+o

/\

R'CH,CH,NH (20)

- pFi(R1 03-30% H,O,

C, II tt R2 R2 N(R' )) C,

0O C

)--$

HOO

HOO

R' = Me or C,H,CI RZ = C1 or S03Me R3 = H or C2H,Cl

-N(R')) C, H4R2

A reinvestigation of the geometry of the four optically active forms of Cmethylcyclophosphamide, prepared from ( )- and ( -)-3-aminobutan-l-o1, has demonstrated the necessity for corrections to previous stereochemical assignment^.^^ The cyclization of a-amino-ketones with phosphorus(v) dichlorides affords the 2-0x0- 1,3,2-0xazaphospholines (21).

+

ButCOCH,NHBut + RP(O)Cl,

-

(21)

But

R'= CIorNMe,

Several further reports have appeared on the interaction of tervalent phosphorus isocyanates and a-ketocarboxylic esters, giving (22) (see 'Organophosphorus Chemistry' Vol. 7,p. 126; Vol. 8, p. 107);34in the case of ethyl benzoylformate, the isomeric compounds (23) and (24; R2= Ph, R3= C0,Et) are also formed, and the 31

32

33 34

Ger. Offen. 2 552 135 (Chem. Abs., 1976, 85, 63 098): T. Nagasaki, Y.Katsuyama, and H. Minato, J. Labelled Compounds Radiopharm., 1976, 12, 7: H. J. Hohorst, G. Peter, and R. F. Struck, Cancer Res., 1976, 36, 2278: A. Takemizawa, T. Iwata, K. Yamaguchi, 0. Shiratori, M. Harada, Y.Tochino, and S. Matsumoto, Cancer Treat. Rep., 1976, 60, 361. R. Kinas, K. Pankiewicz, W. J. Stec, P. B. Farmer, A. B. Foster, and M. Jarman, J. Org. Chem., 1977,42, 1650. Yu. V. Balitskii, M. Yu. Kornilov, and Yu. G. Gololobov, Zhur. obshchei Khim., 1977, 47, 227 (Chem. Abs., 1977, 86, 171 344). I. V. Konovalova, R. D. Gareev, L. A. Burnaeva, T. A. Faskhutdinova, and A. N. Pudovik, Zhur. obshchei Khim., 1976,46, 2384 (Chem. Abs., 1977, 86, 29 919).

Organophosphorus Chemistry

106

a-Oxophosphonic esters give all kinetics of these reactions have been three types of product [22-24; R1= Et, R2= P(O)(OEt),] 36 except trichloroacetylphosphonic acid esters, which undergo the more unusual formation of the linear ester (25).

+ (RO)2P(0)COCC13-

(EtO),P-NCO

R * MeorEt

(25)

'NCO

Phosphoryl di-isocyanates react with diaziridines to give perhydr0-2-0~0-1,3,5,6tetra-azaphosphepine-4,7-diones(26).38

('

NH

-t PriOP(0)(NCO),

_t

(-Jq

0

J-NH

>Pco,oai

kNH

9

(26)

Improved syntheses have been described for a variety of spin-labelledcoinpounds, including the aziridine derivatives (27),39phosphoramidates (28),40 esters (29),41and e~ter-amidates,~, the compound (29a) being the reagent of choice. ,OR2

(RO),P(O)(N3) .

(27) R = &-N

-3 -n..

M

Me2 85

36 37

38

39 40

41

42

(R'O),P(O) (NI-IR2), (2 8)

3

H

R'OP=, O

'R3 (29) a; R2 = Ph, R3 = imidazolyl b; R2 = Ph, R3 = Oalkyl

R' =

alkyl, cycloalkyl, Ph, or -N:

I. V. Konovalova, L. A. Burnaeva, G. S . Temnikova, and A. N. Pudovik, Zhur. obshchei Khim., 1976,46, 1444 (Chem. Abs., 1976, 85, 176 507). I. V. Konovafova, L. A. Burnaeva, L. S. Yuldasheva, and A. N. Pudovik, Zhur. obshchei Khim., 1976,46, 1733 (Chem. Abs., 1976, 85, 177 329). I. V. Konovalova, L. A. Burnaeva, N. K. Novikova, N. V. Mikhailova, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 1411 (Chem. Abs., 1976, 85,94 453). E. S. Gubnitskaya and Z . T. Semashko, Zhur. obshchei Khim., 1976, 46, 1183 (Chem. Abs., 1976, 85, 78 032). G. Sosnovsky and M. Konieczny, 2.Naturforsch., 1977, 32b, 87. G. Sosnovsky and G. Kavas, Phosphorus, 1976, 6, 123. G. Sosnovsky and M. Konieczny, 2. Naturforsch., 1977, 32b, 82. G, Sosnovsky and M. Konieczny, 2.Naturforsch., 1977, 32b, 321.

107

Quinquevalent Phosphorus Acids

Phosphonic and Phosphinic Acids and their Derivatives.-Oxidative chlorophosphon:ylation of ally1 chloride gives 60 % bis(chloromethy1)methylphosphonic dichloride, which may readily be monodehydrochlorinated by triethylamine. Phosphonic bromofluorides and dibromides are both obtained, together with other products, when terminal alkenes react with phosphorus trichloride or tribromide in the presence of FC104.44 2PX,, T:CIO, = CI or Br

x

R.CH=:CI-I,

RCHP(0)FX

* ICH, X

RCHP(O)X,.

+ I

3.

CH, X

RCHXCH,X

+ POX,

In an investigation of the reaction between isobutene and PC15, it has been shown that, as the temperature of reaction is raised, the proportion of unsaturated phosphonic dichloride (30) increases at the expense of the saturated compound (31); Me,C=CHP(O)

Cl,

Me,CClCH,P(O) C1,

(3 1)

(30)

since this is not the result of elimination of hydrogen chloride from the latter, the two products are thus probably formed by independent pathways (see 'Organophosphorus Chemistry', Vol. 8, p. 109).45 Chloromethyl alkyl sulphides and methyl phosphorodichloridite react together in a process that is catalysed by FeCl, or by BF, etherate, probably via a phosphonium intermediate (32).4s Me0 RSCHQ

+ MeOPC1,

FeCl,

-+ KSCH,P(O)Cb (3 2)

Secondary alkylphosphonates, obtainable only with difficulty by the standard procedures, can be obtained more satisfactorily through the hydrazine derivatives (33) (Scheme 2).41 R'E?C=NNHTos

(MeO),P(0)CR'RZNEINHTos

-b

(MeO),P(0)CHR1R2

(33)

R',

R2 = H, alkyl, cycloalkyl, or phenyl

Reagents: i, (:MeO)ZP(O)H;ii, NaBHeTHF

Scheme 2 V. A. Efanov, A. V. Dogadina, B. I. Tonin, and A. A. Petrov, Zhur. obshchei Khim., 1976, 46, 1416 (Chem. A h . , 1976, 85, 108 722). 44 S. V. Fridland, N. V. Dmitrieva, I. V. Vigalok, and R. A. Salakhutdinov, Zhur. obshchei Khim., 1976, 46, 1228 (Chem. Abs., 1976, 85, 160 245). 45 V. G. Rozinov, G . A. Pensionerova, V. I. Glukhikh, and E. F. Grechkin, Zhur. obshchei Khim., 1976, 46, 1903 (Chem. Abs., 1976, 85, 177 552). 413 A. F. Grapov, T. F. Kozlova, and N. N. Mel'nikov, Zhur. obshchei Khim., 1976, 46, 304 (Chem. Abs., 1976,84, 180 341). 47 S. Inokawa, Y. Nakatsukasa, M. Horisaki, M. Yamashita, H. Yoshida, T. Ogata, and H. Inokawa, Synthesis, 1977, 179. 43

OrganophosphorusChemistry

108

Diary1 methyl- and benzyl-phosphonates are conveniently prepared in high yields by heating mixtures of triaryl phosphites, methanol or benzyl alcohol, and a trace of methyl or benzyl halide.48In a reaction that is usefully complementary to the previously reported formation of pyridine-2-phosphonicacid derivativesfrom sodium dialkyl phosphonates and N-methoxypyridinium compounds ('Organophosphorus Chemistry', Vol. 7, p. 11l), N-triphenylmethylpyridiniumtetrafluoroborate affords the pyridine-4-phosphonic dialkyl ester when heated with sodium dialkyl phosphonates.49 When performed in ether at -70 "C containing HCI, the reaction between triethyl phosphite and either chloral or bromoacetone affords higher yields of the a-hydroxyphosphonates (34), relative to vinyl phosphate, than are normally obtained.60The rate-determining step in the formation of the phosphonate (35) from chloroacetone and dimethyl hydrogen phosphonate appears to be the tautomerism of dialkyl phosphonate to phosphite.61 (EtO),P(O)C(OH) R'R2

(34)

(MeO),P(O) CMe(0H) CH2Cl

(35)

a; R' = H, R2 = CCI, b; R' = Me, R2 = CH,Br

Cathodic reduction of l-hydroxy-2,2,2-trichloroethylphosphonates in 0.1 M sulphuric acid-methanol constitutes a route to 2,2-dichlorovinylphosphonates (Scheme 3).52 (MeO),P(O) CHCCI,

I OH

-$-+(MeO),P(O)CHCHC1, I

-

H'_

(MeO),P(O)CHCHCI,

OH

(MeO),P(O)CH=CCI,

-H+

I

+OHZ (MeO),P(O)~HCHCl,

Scheme 3

The acylation of organometallic derivatives of methylphosphonates provides an alternative and very convenient way of preparing 2-oxophosphonates (Scheme 4).63 (R'O),P(X) CH,

+ (RIO),P(X)CH,~Z

i, iii, iv

: (R'O),P(X) CHR2COR3

X = OorS Reagents: i,BuLi; ii, R2hal; iii, CuI; iv, R3COhal

Scheme 4

A synthesis of dialkyl 3-alkoxy-, 3-aryloxy-, or 3-arylthio-2-oxoalkanephosphonates starts from dialkyl 2,3-dibromoallylphosphonates(Scheme 5). 5 4 M. L. Honig and E. D. Weil, J. Org. Chem., 1977, 42, 379. D. Redmore, J. Org. Chem., 1976, 41, 2148. 50 T. Kh. Gazizov, Yu. I. Sudarev, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46. 2383 (Chem. Abs., 1977, 86, 16 753). 61 B. Springs and P. Haake, J. Org. Chem., 1977,42,472. sa H. Matschiner and C. Richter, J. prakt. Chem., 1976, 318, 768. 59 F. Mathey and P. Savignac, Synthesis, 1976, 766: P. Savignac and F. Mathey, Tetrahedron Letters, 1976, 2829. 54 M. Baboulene, A. BelbBoch, and G. Sturtz, Synthesis, 1977, 240. 48

49

109

Quin#quevalentPhosphorus Acids (E to):,P(0) CH,CBr =CHBr

A

,CH,Br

\

(E to), P(0) CH=C ‘NEt,

(EtO),P(O) CH,COCH,YR

/CH,Y R

(EtO),P(O)CH=C, NEt,

Reagents: i, EtzNH; ii, NaYR (YR = Oalkyl, Oaryl, or Saryl); iii, H+, HzO Scheme 5

Foiur diastereoisomeric forms of the phenylhydrazone (37) have been obtained by ring cleavage of a A4-l ,2,3-diazaphospholine-chlorineadduct with methanol,56as shown in Scheme 6. /OMe PhCCHPhP= 0 ‘Ph NNHPh

II

(3 7)

(3 6 ) Reagents: i, Clz; ii, MeOH Scheme 6

New syntheses of a-aminophosphonic acid derivatives involve aldazines (Scheme

7)56 and the action of Grignard reagents on various imino-compounds (Scheme 8).67 RCH:=N--N=CHR

(PriO),P(0)CHRNHN=CHR

A

(PriO),P(0)CHRNH,

/G (HO),P(O)CHRNH, Reaqerits: i, (Pri0)2P(O)H; ii, H2-Raney Ni; iii, HCI-HOAc, followed by

a

Scheme 7

i,

(EtO),P(O)C,Cl-NCO,Et

fl

’

Me2CNO) (OH),

I

NH2

Pr‘CHP(0) (OH),

.(EtO),P(O) C

/

SEt

*

I

NH, (EtO),P(O)CR(SEt) NHC0,Et

A

RCHP(0) (OH),

I

NH,

Reagents: i, MeMgI; ii, HBr; iii, excess PriMgI; iv, RMgI; v, NaBH4 Scheme 8 55

513 67

G. BaccoJini and P. E. Todesco, Tetrahedron Letters, 1976, 1891. M. Hoffmann, C. Wasielewski, and J. Rachod, Chirnia (Switz.), 1976, 30, 187. W. J. Stec and K. Lesiak, J. Org. Chem., 1976, 41, 3757.

110

Organophosphorus Chemistry

A modification of the standard procedure for the formation of a-aminophosphonic acids from Schiff bases allows a one-pot procedure by employing a tertiary benzyl group for protection purposes, readily removable by treatment with acid; the method (Scheme 9) 5 8 is thus potentially useful for the preparation of aminophosphonic acids possessing reduction-sensitive groupings. R'CHO

R'CH=NCR'Ph

ii iii

I

CH, Rz

R'CHP(0) (OH),

I

NH,

CH2Ra Reagents: i, Ph-kNHz, KzC03; ii, (Et0)2P(O)H; iii, HCI

R*

Scheme 9

Diazophosphorus(v) esters could well be useful for the labelling of biological substances. The preparation of an a-diazoalkylphosphonate system has now been described for the first time; the first cyanoethyl group (Scheme 10) is removable at pH 10, the second in 1M-NaOH PhCP(0) (OC2H,CN),

I1 NNHTos

Reagents: i, Na2C03; ii, OH-

A

PhCP(0) (OC,H,CN),

I

+N,

-% PhCP(0) (032

I

+N2

Scheme 10

a-Nitroalkyl-phosphonicand -phosphinic esters are obtained by direct nitration of 2-ethoxyvinyl-phosphonicand -phosphinic esters (38) (Scheme 11) and by the

Reagents: i, HN03-AczO-HzS04; ii, EtO-

Scheme 11

oxidation of a-aminomethyl-phosphonates61 or -phosphinates 6 2 with KMnO, in water, acetic acid, or acetone, but, with sodium tungstate-hydrogen peroxide, the same starting materials yield a-nitroso-alkyl esters (39).s3 58 59

6o

61 62

63

J. Lukszo and R. Tyka, Synthesis, 1977, 239. J. A. Goldstein, C. McKenna, and F. H. Westheimer, J. Amet. Chem. Sac., 1976, 98, 7327. K. A. Petrov, V. A. Chauzov, and N. N. Bogdanov, Zhur. obshchei Khim., 1976, 46, 1495 (Chem. Abs., 1976,85, 160 256); A. A. Neimysheva, S . S . Muratov, E. V. Smirnov, and L. N. Solntseva, ibid., p. 940 (Chem. Abs., 1976, 85, 21 552); K. A. Petrov, V. A. Chauzov, N. N. Bogdanov, and I. V. Pastukhova, ibid., p. 1242 (Chem. Abs., 1976,85, 143 194); K. A. Petrov, V. A. Chauzov, N. N. Bogdanov, and I. V. Pastukhova, ibid., p. 1250 (Chem. Abs., 1976,85, 143 195).

K. A. Petrov, V. A. Chauzov, I. V. Pastukhova, and N. N. Bogdanov, Zhur. obshchei Khim., 1976,46, 1246 (Chem. Abs., 1976,85,94 451). K. A. Petrov, V. A. Chauzov, I. V. Pastukhova, and N. N. Bogdanov, Khim. Elementoorg. Soedineniya, 1976, 209 (Chem. Abs., 1977, 86, 5545). Ya. A. Levin and M. S . Skorobogatova, Izvest. Akad. Nauk. S.S.S.R.. Ser. khim.. 1976 477 (Chern. Abs., 1976,84, 180 347).

Quinquevalent Phosphorus Acids (RO), P(0)CMe, NO,

‘KMnO,

:

111 (RO),P(O) CMe,NH,

Na,WO,-H,O,

(RO),P(O) CMe, NO (39)

A 2-nitroalkylphosphinic ester (40) has been obtained by the interaction of dimethyl phenylphosphonite and a-nitroisopentene, although the true nature of the The phosphinate (41) is obtained from p-benzointermediate is open to quinone and tetramethyldiphosphine disulphide.6s Conventional reactions have been employed in the preparation of the macrocyclic compounds (42)66 and the perhydro-1,Zazaphosphorines (43). 6 7 Ph ‘P(0)CHPriCH,NO,

Me0/

Me,P(S)O

(40)

‘ 0 (41)

‘0

(-JjNX

OP(S)Me,

$ ‘Ph

(43) X = 0 or S R = HorCH,Ph

0’

(42)

(44)

C-Phosphorylated malonic acid derivatives are conveniently obtained by the acylation of phosphonoacetic ester anions with chloroformic esters.6a Further consideration has been given to the formation (and properties) of A*-1,4,2-oxazaphospholine 2-oxides (44)by cyclization of cc-benzamidovinylphosphinicesters with PCI5.69 The mechanism of the cyclization step in the preparation of perhydro-1,4,2oxazaphosphorin-5-ones (45) from halogenoacetyl halides and a-aminomethylphosphonate esters (see ‘Organophosphorus Chemistry’, Vol. 8, p. 112) has been investigated, using l 8 0 labelling; of the two possible modes of cyclization, the correct one appears to involve the nucleophilicity of the phosphoryl group, as indicated in Scheme lZ70 64 65

66 67 68 69

70

R. D. Gareev, G. M. Loginova, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 1906 (Chem. A h . , 1976, 85, 177 553). A. N. Pudovik, G. V. Romanov, and A. A. Lapin, Zhur. obshchei Khim., 1976, 46, 1409 (Chem. Ahs., 1976,85, 108 719). K. B. Yatsimirskii, L. I. Budarin, A. S. Shtepanek, A. I. Telyatnik, and V. A. Smirnov, Teor. i eksp. Khim., 1976,12, 421 (Chem. Abs., 1976, 85, 108 727). D. G . Hewitt and G. L. Newland, Austral. J. Chem., 1977, 30, 579. B. A. Arbuzov, V. G . Sakhibullina, N. A. Polezhaeva, and V. S. Vinogradova, Zzvest. Akad. Nauk. S.S.S.R., Ser. khim., 1976, 2139 (Chem. A h . , 1977, 86, 16746). B. S. Drach and 0. P. Lobanov, Zhnr. obshchei Khim.,1976,46, 1417 (Chem. A h . , 1976,85, 108 723). Zh. M. Ivanova, E. A. Suvalova, I. E. Boldeskul, G . A. Kalyagin, 0. G . Strukov, andYu. G. Gololobov, Zhur. obshchei Khim., 1976, 46, 1697 (Chem. Abs., 1977, 86, 5540).

112

Organophosphorus Chemistry

Scheme 12

A further, detailed, study of the PC1,-paraformaldehyde system has been published; 71 the reaction between the same trichloride and 1,5-diketones is reported to yield bicyclic 1,4,2-dioxaphospholans when carried out in warm acetic acid

The cyclization of a-amino-acid amides with phosphorus(v) dichlorides gives 2,4-dioxo- and 4-oxo-2-thiono-l,3,2-diazaphospholidines (46). RzN 0

py

Y>P(JOR1

R3

II

RIP(X)Cl, + R2NHCCH2NHR3

Insertion of an aralkyl group into the exocycIic bond at phosphorus in 2-trimethylsilyloxy-l,3,2-dioxaphospholansand related compounds (47) occurs when they are treated with benzaldehyde under surprisingly mild conditions.7 p v 1.

PhCHO r.t.

(47)

*

C P ( 0 ) CHPhOSiMe,

a; X' = X2 = O o r NBu b; X' = 0,X2 = NMe or NBu

Enantiomers of t-butylphenyl-phosphinicand -thiophosphinic acids have been ~ e p a r a t e dand , ~ ~the absolute configuration of the (-) -menthy1ester of the former acid has been determined.76 71 72

73 74

75 76

R. W. Griffiths, J. C. Tebby, and H. Coates, Phosphorus, 1976, 6, 223. V. I. Vysotskii, K. G. Chuprakova, and M. N. Tilichenko, Zhur. obshchei Khim., 1976, 46, 785 (Chem. A h . , 1976,85, 21 549). M. Mulliez and M. Wakselman, Synthesis, 1977, 478. M. A. Pudovik, L. K. Kibardina, M. D. Medvedeva, T. A. Pestova, Kh. E. Kharlampidi, and A. N. Pudovik, Zhur. obshchei Khim., 1976,46, 1944 (Chem. Abs., 1977, 86, 5556). R. Luckenbach and H. H. Bechtolsheimer, 2. Naturforsch., 1977, 33b, 584. R. Luckenbach and H. H. Bechtolsheimer, 2. Naturforsch., 1977, 33b, 589.

113

Quinquevalent Phosphorus Acids

2 Reactions General.-A brief report indicates that phenylthiocarbamoylphosphonates (48) rearrange, evidently rather readily, to phosphate esters; phosphinates are obtained from phosphine oxides and sulphides.77 R,P(X)H + PhNCS

-+

R,P(X)CSNHPh

(48)

+ R,P(X)SCM==NPh

X = 0 or S R = alkyl or Oalkyl

Several mechanistic studies on the reactivity of sulphur-containing quinquevalent phosphorus acids have been recorded. The reactions investigated include addition to keten acetals,78protodemetallation with tetraethyl~tannane,~~ addition to methyl propiolate (for which there is cis-addition in propanol but a lack of stereospecificity in aprotic media),80and addition to acrylonitrile, with which five-membered-ring acids react faster than six-membered, which in turn react faster than acyclic acidss1 Further examples of the cleavage of diphosphinothioyl disulphides by amines, to give phosphinothioylsulphenamides, have been noted.82 When heated to temperatures higher than 130 "C, the monothioesters (49) decompose to give sulphur-free acids and the thiirans (50); for the compounds (49; R1= OMe, R2= Me, RS= H or Me), thermolysis in uacuu also gives some of the 1,3,2-oxathiaphospholan (51) 88 (see also ref. 114). R',P(O) SCHRZCHR30H

(49)

> 130 "C

S

Me

(50)

Y

(51)

A distinction between acyclic thio- and seleno-phosphoryl esters is to be found in their behaviour towards chlorine; whereas the former yield phosphorosulphenyl chlorides, the selenium compounds lose selenium on warming, the reaction evidently proceeding through a quaternary salt (52).84

(52)

R' = alkyl or aryl

RZ = alkoxy, arploxy, alkyl, or aryl

A. N. Pudovik, I. V. Konovalova, M. G . Zimin, and T. A. Dvoinishnikova, Doklady Akad. Nauk. S.S.S.R., 1976,228, 617 (Chem. Abs., 1976, 85, 142 738). 78 R. L. Dyer, P. G. Le Gras, and C. D. Hall, J.C.S. Perkin II, 1976, 1613. 79 R. A. Cherkasov, N. V. Kashina, I. G. Lushchits, A. I. Vinokurov, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 761 (Chem. Abs., 1976, 85, 32 197). 8 0 R. A. Cherkasov, G. A. Kutyrev, N. V. Kashina, T. I. Aleev, and A. N. Pudovik, Khim. Elementoorg. Soedineniya, 1976, 119 (Chem. A h . , 1977, 86, 4475). 81 R. A. Cherkasov, G . A. Kutyrev, V. V. Ovchinnikov, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 963 (Chem. A h . , 1976, 85, 32 204). 82 N. A. Torgasheva, B. A. Khaskin, N . N. Mel'nikov, and G. A. Kosminskaya, Zhur. obshchei Khim., 1976,46, 1467 (Chem. Abs., 1976,85, 160 253). 83 0. N. Nuretdinova and F. F. Guseva, Izvest. A k a d Nauk. S.S.S.R., Ser. khim., 1976, 2625 (Chem. Abs., 1977,86, 105 847). 84 E. V. Bayardina, R. Kh. Giniyatullin, and I. A. Nuretdinov, Izvest. Akad. Nauk. S.S.S.R., Ser. khim., 1977, 153 (Chem. Abs., 1977, 86, 155 158). 77

0rganophosphorus Chemistry

114

A further demonstration of the marked nucleophilicity of the selenophosphoryl bond is to be found in the ready reaction of alkyl bromides with seleno-phosphates, -phosphonates, and -phosphinates (53), the reaction increasing in ease in that order.8s EtOPR'R2

+

BuBr --+

(53) a; R' = R2 = EtO b; R' = Et, RZ = EtO c; R' = R2 = Et

R'R*P(O)SeBu

+

EtBr

A preliminary report on a study of the displacability of alkylseleno-groups from chiral quinquevalent phosphorus selenoesters has appeared. The substrates were prepared from 2-seleno-l,3,2-oxazaphospholidines (54) (Scheme 13), the latter in

Reagents: i, EtOH-HC1; ii, HO-; iii, Me1

Scheme 13

turn being available from ( -)-ephedrine and the appropriate tervalent phosphorus dichloride, followed by addition of S or Se.8s*Assignments of configurations were made partly on the basis of the stereospecificity of the latter oxidation reaction, and also on the oxidation of selenophosphoryl compounds to phosphoryl analogues with retention of chirality, as for thiophosphoryl compounds. For the phosphonate (55; R1= Me), reactions with (a)sodium methoxide, (b) bromine in methanol, or (c) methanolic silver nitrate all proceeded with complete inversion of configuration,whereas for the thioate analogue the reactions with (a) and (c) were only highly selective stereochemically. For the phosphoro-series (55 ; R1= OPri), reagent (a) brought about complete inversion for the selenium compound, but complete retention for the sulphur analogue; by contrast, the reaction of the latter with reagents (b) and (c) proceeded with complete inversion. From a study of the behaviour of the esters (56) towards alkaline hydrogen peroxide, Horner and PargS7conclude that the rate-determining step is nucleophilic

* The authors of this communication draw attention to the necessity for corrections to be made to configurational assignments made by them in their earlier papers. a5 8e 8'

E. V. Bayardina, I. A. Nuretdinov, and E. I. Loginova, Zzuest. Akad. Nauk. S.S.S.R., Ser. khim., 1976, 1627 (Chem. Abs., 1976, 85, 160260). C . R. Hall and T. D. Inch, Tetrahedron Letters, 1976, 3645. L. Horner and A. Parg, Annalen, 1977, 61.

115

Quinquevalent Phosphorr~~ Acids

attack on phosphorus; the reaction exhibits an a-effect, the alkaline hydrolysis being accelerated by a factor of ca. 100 in the presence of the peroxide. The reaction was formulated as proceeding through pentaco-ordinate peroxy intermediates, and indeed, peroxy intermediates were detected by a variety of techniques.

(56)

R' = R2. = Ph b; R' = OEt; R2 = Ph c; R' = R2 = OEt a;

(57)

I

R' = H or C0,Me

P(0) R2R3

( 5 8)

+

The compounds (57), formed by a 3 2 cycloaddition of phosphinyldiazotatesto acetylenic esters, undergo a carbon-to-nitrogen sigmatropic rearrangement to give (58); the latter can act as efficient phosphorylating agents towards alcohols (except tertiary alcohols), diols giving initially monoesters, which may cyclize.88 In the reaction between 1-oximino-2-oxononane (59) and phosphoro- or phosphono-fluoridates, the rate-controlling step is the liberation of F-, which is only marginally increased in the presence of micelle-forming substances.saOn the other hand, the rate of liberation of CN- is increased many times under the same conditions, possibly not only by straightforward elimination from the phosphorylated oxime but also by interaction of the starting material with acyl cyanide (Scheme 14) (see 'Organophosphorus Chemistry', Vol. 4, p. 124).

R1

' P ' 'O'R F '

0

*

+ R3CCH=N-OII

R' _t

\p/o

/ \

R20

(59)

R'

/'F' / R20

0

0

\o-

ON=CHCOR3

4-'?I

+

11

R3CCN

(59)

I__)

R3COCN

+ R3CO; +

CN-

+ H+

Scheme 14

Phosphoric Acid and its Derivatives.-Amongst hydrolysis studies reported during the year are those of di(2,4-dichlorophenyl)phosphate; tri(6iodobenzyl) phosphate in 0.5-4.5M-HCl in 50 % dioxan; 91 and l-nitro-2-naphthyl and 4-nitro-l-naphthyl phosphates in 0.01-6M-HC1.92 The hydrolysis of 2,4-dinitrophenyl dibenzyl phosphate exhibits a ISO kinetic isotope effect that is suggestive of the intermediacy of a monomeric metaphosphate species, whereas an S~2-likemechanism is apparent

O0

O2

U. FeIcht and M. Regitz, Chem. Ber., 1976, 109, 3675. J. Epstein, P. Cannon, R. Swidler, and A. Baraze, J. Org. Chem., 1977, 42, 759. M. M. Mhala and S. S. Bhatawdekar, J. Indian Chem. SOC.,1976, 53, 1002. M. M. Mhala and A. V. Killedar, J. Indian Chem. SOC.,1976, 53, 476. M. M. Mhala and P. Nand, Indian J. Chem. (A), 1976, 14, 344.

116

Organophosphorus Chemistry

when the hydrolysis is catalysed by buffer.g3Functional and non-functional micelles catdyse the reactions of 4-nitrophenyl phosphate by a factor of 6-10.94 Diesters of quinquevalent phosphorus are normally difficult to hydrolyse further. 4-Nitrophenyl quinolin-8-yl phosphate exhibits a pH-rate profile that has a plateau extending well into the alkaline region, consistent with the idea of intramolecular nucleophilic catalysis uia cyclization [as in (6011 rather than a mechanism based upon general base catalysis.g6 In an interesting paper there is a report of what is stated to be the first investigation into the elucidation of the charge distribution on identical geminal atoms which are

Me

Me

differentiated only geometrically. Such a situation exists for the exocyclic oxygens in cyclic phosphoric acids. The reaction investigated was that between salts of the anion (61) and diazomethane in methanol, the product of which consists of a mixture of axial and equatorial methyl Axial methyl phosphate was the preferred product from the sodium, caesium, and tetramethylammonium salts, the lithium salt afforded approximately equal amounts of axial and equatorial ester, while for the free acid and its ammonium and cyclohexylammonium salts the equatorial/axiaI product ratio was ca. 1.6. The results were discussed in terms of interactions between the orbitals of exocyclic and endocyclic oxygen atoms. The equilibrium between (62) and (63) is readily set up in the presence of amine or acid

Also in the presence of triethylamine, a mixture of trimethylsilyloxybenzene and the cyclic phosphate (64) rapidly equilibrates with (65).98A series of equilibria involving pentaco-ordinate intermediates seems a logical explanation (Scheme 15). 93 94 95

Q6 98

D. G. Gorenstein, Y.-G. Lee, and D. Kar, J , Amer. Chem. SOC.,1977,99,2264; D. G. Gorenstein and Y.-G. Lee, ibid., p. 2258. C. A. Bunton and M. McAneny, J. Org. Chem., 1977, 42,475. J. S. Loran and A. Williams, J.C.S. Perkin 11, 1977, 64. A. P. Hong, J. B. Lee., and J. G. Verkade, J. Amer. Chem. SOC.,1976,98, 6547. C. Bin Cong, A. Munoz, M. Sandez, and A. Klaebe, TefrahedronLetters, 1977, 1587. F. Ramirez, M. Nowakowski, and J. F. Marecek, J. Amer. Chern. Soc., 1976,98,4330.

117

’

a ) P R o \

+ PhOSiMe,

(PhO),P, /O

ii

‘OPh

(65)

I ,,OPh I ’0-

0-P’

R,N+

Me,SiO

11

0-p’.

H

1 0 ’-

+NR,

,OPh ‘0-P’

po

R,N+

Reagents: i, PhOSiMes; ii, Et3N

Scheme 15

The fundamental difference in phosphorylating behaviour between the two reagents 4,5-dimethyl-2-oxo-2-phenoxy-l,3,2-dioxaphospholen (66) and phenyl ophenylenc: phosphate (67) (Scheme 16) is that, in an uncatalysed situation, the former

O-P-OPh

II

0

( 66) X = Me (67) XX = CH=CH-CH=CH

PhO

/

RO

o x x POC=COH 5%

90% Scheme 16

+

O-P-OR

II

0 95%

10%

reacts predominantly with ring retention, whereas the latter reacts largely with ring opening, a difference which is explicable in terms of the relative leaving ability (and hence apicophilicity in the pentaco-ordinate intermediate) of the PhO- and -OCMe==CMeO- groups. 99

F. Ramirez, J. F. Marecek, H. Tsuboi, H. Okasaki, and M. Nowakowski, Phosphorus, 1976, 6 , 215.

118

Organophosphorus Chemistry

Diethyl phosphorocyanidate continues to be exploited for the purposes of conventional organic synthesis. Reported applications of the compound include a new conversion of carboxylic acids into esters or amideslo0and also a ring-expansion reaction of 1,3-thiazoles in the penicillin series.1o1 Diphenyl phosphorazidate has been employed in a modified Curtius reaction,lo2 in peptide synthesis,lo3and for ROH + (PhO),P(O)N,

+ Ph,P

i-

E tO,CN= NCO, Et

THF r.t.

RN,

+ Ph,PO + (PhO),P(O)NNHCO,Et

I

COzEt

the stereospecific synthesis of azides from The reaction of the phosphorazidate with enamines of cyclic ketones has also been studied. lo5 The ability of cyclic phosphite esters to polymerize, and their thermal depolymerization, are both well-known processes. Perhaps not so well known is the ability of the corresponding phosphate esters to polymerize. An interesting paper lo6reviews the modes of polymerization of such esters. Six-membered-ring esters readily polymerize with ionic initiation, yielding open-chain polymers with cyclic end groups ; five-membered-ring esters polymerize with organometallic initiators. The kinetics of the processes were determined, and trigonal-bipyramidal intermediates were invoked to outline a mechanism. Sosnovskylo7has continued his study of the properties of peroxy-esters with one of the thermolysis of esters of type (68), both neat and in solution. These esters

decompose under comparatively mild conditions(i.e.60-100 "C),with the formation of dialkyl and trialkyl phosphates, as well as methanol, acetone, and other products. There was no evidence for the formation of 'dimeric products', which might suggest a homolytic mechanism, and an ionic mechanism is consequently favoured. Trialkyl phosphates are useful for the N-alkylation of nucleic acid bases, and some regioselectivity is to be observed; lo8tris(2,2,2-trifluoroethyl) phosphate has been used for the trifluoroethylation of primary aromatic amines.lo9 Trimethyl phosphate containing phosphorus pentoxide is a useful medium for the halogenation of aromatic substances which are sensitive to hydrogen halides, and also for the nitration of phenanthrene.l1° T. Shiori, Y. Yokoyama, Y. Kasai, and S. Yamada, Tetrahedron, 1976, 32, 2211. K. Ninomiya, T. Shiori, and S. I. Yamada, Chem. and Pharm. Bull. (Japan), 1976, 24, 271 1. F. Bondavalli, P. Schenone, and L. Longobardi, Gazzetta, 1975, 105, 1317. K. Ozawa, T. Shiori, and S. Yamada, Chem. and Pharm. Bull, (Japan), 1977, 25, 122; Y. Hamada, T. Shiori, and S. Yamada, ibid., p. 221; Y. Hamada, S. Rishi, T. Shiori, and S. Yamada, ibid., p. 224. 104 B. Lal, B. N. Pramanck, M. S. Manhas, and A. K. Bose, Tetrahedron Letters, 1977, 1977. 105 S. Yamada, Y. Hamada, K. Ninomiya, and T. Shiori, Tetrahedron Letters, 1976, 4749. 108 S . Penczek, Pure Appl. Chem., 1976,48, 363. l o 7 G. Sosnovsky and E. H. Zaret, Z. Naturforsch., 1976, 31b, 820. lo*K. Yamouchi, T. Tanabe, and M. Kinoshita, J. Org. Chem., 1976. 41, 369; T. Tanabe, K. Yamouchi, and M. Kinoshita, Bull. Chem. Soc. Japan, 1976, 49, 3224. 1°9 E. R. Bissel, J . Fluorine Chem., 1977, 9, 513. l10 D. E. Pearson, M. G. Frazer, V. S. Frazer, and L. C. Washburn, Synthesis, 1976, 621.

100 101 l02 103

Quinquevalent Phosphorus Acids

119

A new synthesis of olefins involves carbon-oxygen bond cleavage in en01 phosphates, e.g. (69), with lithium copper reagents.lll

-

n

The full paper on the conversion of 1,2-diols into alkenes by reduction-elimination of appropriate 1,3,2-dioxaphospholans has appeared (see 'Organophosphorus Chemistry', Vol. 8, p. 123).l12The method was examined with particular regard to the conversion of cyclodecane- and cyclododecane-l,2-dioIs into the cycloalkenes, as mixtures of cis- and trans-isomers, and consists of the treatment of the cyclic ethyl esters or NN-dimethylamides with lithium in liquid ammonia or with Ti-THF. The kinetics of the methanolysis of thiophosphoryl chlorides have been studied.l13 The rat her unusual isomerization of 2-hydroxyethyl phosphorothioates (70) yields the 2-mercaptoethyl isomers after several days at room temperature instead of the expected Ihiono-ester~.~~~ This observation should be compared with those reported in ref. 83. (EtO),P(O) SCHR'CHR20R

+ (EtO),P(O)OCHR'

CHR'SH

(70) R', R2 = H, H; Me, Me; or H, CH2CI

Compared with acyclic analogues, cyclic hydrogen phosphorodithioates are highly reactive towards diphenylvinylphosphine oxide and diethyl [or-(ethoxycarbonyl)styryl]phosphonate, the six-membered-ringacids reacting more quickly than the five-membered-ringacids or the acyclic compounds. On the other hand, the nucleophilic reactivity of anions of the acids towards benzyl halides is less for the cyclic systems than for the acyclic ones.115 00-Dialkyl hydrogen phosphorodithioates react more readily with dialkylcyanamides than with alkyl cyanides, but the nature of the products is dependent upon the (RO),PS,H -+ Et,NCN

/

Et,WSNH2 + [(RO),P(S)],S (RO),P(S)SNEt, + (RO),P(S)NCS

(EtO),P(S)SNH,

(EtO),P(S) + EtOH + H,S + N, + NH,

order of mixing; the addition of the dithio-acid to the cyanamide yields trithiopyrophosphate and NN-dialkylthiourea, whereas reverse addition gives 00-dialkyl phosphorothio(thiocyanatidate) and 00-dialkyl phosphorothiosulphenamide.l16 111

112

118 11'' 115 1~

L. Blaszczak, J. Winkler, and S. O'Kuhn, Tetrahedron Letters, 1976, 4405. J. A. Marshall and M. E. Lewellyn, J. Org. Chem., 1977, 42, 1311. N. M. Loznikova, Yu. N. Sapozhkov, and K. D. Shvetsova-Shilovskaya, Zhur. obshchei Khim., 1976, 46, 1761 (Chem. Abs., 1977, 86, 4473). 0. N. Nuretdinova and F. F. Guseva, Zzuest. Akad. Nauk. S.S.S.R., Ser. khim., 1977, 487 (Chrm. Abs., 1977, 86, 170 783). R. A. Cherkasov, V. V. Ovchinnikov, and A. N. Pudovik, Zhur. obshchei Khim., 1976,46,957 (Chem. Abs., 1976, 85, 32 203). I. M. Kosinskaya, N. P. Pisanenko, and V. I. Kal'chenko, Zhur. obshchei Kliim., 1976, 46, 2227 (Chem. Abs., 1977, 86, 54 930).

120

Organophosphorus Chemistry

Primary phosphorothiosulphenamides may be acylated,l17 and with sodium ethoxide they are converted into trialkyl phosphorothionates.ll* Other reactions of phosphorothiosulphenamides include the loss of sulphur upon treatment with sodium, and translocation of the amino-function when treated with thiophosphoryl halides.l18 Treatment of the acyl chloride (71) with ethyleneimine gives an amide which undergoes ready conversion into the isocyanate (72).lls (R'O),P(S)SNHR'

+ 2Na

(Pr'O),P(S)SNHMe + (EtO),P(S)Cl

(RO),P(S) SCOCl + E N H -+

--+

(R'O),P(S)NHR2 + Na,S

7;:;-*

[(PriO),P(S)],S, + (EtO),P(S)NHMe

(RO),P(S) S C O N 3 --+

(RO),P(S) SCH,CH,NCO

00Se-Trialkyl phosphorodiselenoates are obtained from the potassium salts of 00-dialkyl phosphorodiselenoic acids with alkyl bromidesl 2 O , 121 and from 00dialkyl phosphoroselenoyl chloride with RSeH-Et3N.121 Under alkaline conditions, cleavage of both phosphorus-oxygen and phosphorus-selenium bonds has been shown to 122 While 00-diary1 Se-alkyl phosphorodiselenoates do not transesterify with alcohols under the influence of traces of acid, the potassium salts of 00-diary1 hydrogen phosphorodiselenoates do react with alcohols in the presence of traces of acid to give the potassium salts of 00-dialkyl hydrogen phosphorodiselenoates.123 The hydroxymethylation of phosphoramide and other primary phosphoramidates has been studied in some detail.124 When heated with benzene in the presence of A l Q , 00N-trialkyl phosphoramidates suffer both carbon-oxygen and carbon-nitrogen bond cleavage, and afford mono- or di-alkylbenzenes. When, on the other hand, 00-diphenyl N-(cyc1o)alkyl phosphoramidates or NWW-trialkyl phosphoric triamides are employed, only carbon-nitrogen bond cleavage takes place, and no reaction occurs with most amides from secondary amines.12s The kinetics of the alkaline hydrolysis of N-alkyl 00-diphenyl phosphoramidates have been studied,128as well as those of the acid hydrolysis of 00-dialkyl phosph0ramidates.l Russ. P. 541 850 (Chem. Abs., 1977, 86, 155 206). B. A. Khaskin, N. A. Torgasheva, and N. N. Mel'nikov, Zhur. obshchei Khim., 1976,46, 1472 (Chem. Abs., 1976,85, 142 542). 119 E. S. Gubnitskaya, L. A. Zolotareva, and Z. T. Semashko, Zhur. obshchei Khim., 1976, 46, 2233 (Chem. A h . , 1977, 86,43 334). 120 N. I. Zemlyanskii, L. M. Dzikovskaya, and V. V. Turkevich, Khim. Elementoorg. Soedineniya, 1976, 193 (Chem. Abs., 1976,85, 176 995). 121 Ya. I. Mel'nik, Ya. I. Kolodii, and N. I. Zemlyanskii, Zhur. obshchei Khim., 1977, 47, 305 (Chem. Abs., 1977, 84, 189 110). 122 L. M. Dzikovskaya, Visn. L'uiu. Derzh. Unio., Ser. khirn., 1975, 17, 60 (Chem. Abs., 1977, 86, 189 391). 133 N. I. Zemlyanskii, L. M. Dzikovskaya, V. V. Turkevich, and A. P. Vas'kiv, Zhur. obshchei Khim., 1976, 46, 1475 (Chem. Abs., 1976, 85, 123 281). 1 2 4 L. Meznik, J. Kabela, and K. Dostal, Coll. Czech. Chem. Comm., 1976,41,2484. G. Sosnovsky, E. H. Zaret, and B. Bohnel, 2. NuturJbrsch., 1976, 31b, 1526. 1 2 6 J. Mollin, F. Veveika, and F. Kasparek, Coll. Czech. Chem. Comm., 1976, 41, 3245. 12' H. Kuehne, H. A. Lehmann, and W. Toepelmann, 2. Chem., 1976, 16, 230. 117 118

Quinqueualent Phosphor us Acids

121 Compounds (73) and (74)undergo alkaIine hydroIysis with exclusive loss of ArO-, whereas similar cyclic compounds, although reacting faster by a factor of ca. lo4, afford mixtures of products, the nature of which depends on the substituents on ring nitrogen. In addition to loss of ArO-, compounds (75) hydrolyse to a small extent at each of the ring phosphorus-oxygen and phosphorus-nitrogen bonds; for

(73) R' = Me, R2 = H, Me, or NO, (74) R' = Ph, R2 = H

R' .= Me, R2 = H, 3-NO,, 4-N02,.. 4-Me, Or 4-OMe (76) R' = Ph, R2 = H, 4-No2, or 4-OMe

(75)

compounds (76), fission of the phosphorus-nitrogen bond was not detectable, but the extent of ring opening at the phosphorus-oxygen bond was quite appreciable.128 Phosphoramidate anions have been utilized in a one-step preparation of aziridines from oxirans, and although the yields are only low to moderate, the method (Scheme 17) scores on its convenience.129

[RpR1)] 0-

Ph$ (R'O), P(0) i R 2

+

._f

I

R2

R3

R' = Et or Ph; R2 = Ph, PhCH,, or But; R3 = H or Me Scheme 17

The use of diethyl NN-dihalogenophosphoramidates for the preparation of 2halogeno-amines has been extended to include reactions with cyclohexene, styrene, and 1 ,Zunsaturated esters under ionic and photoinitiated conditions; in the latter case, full regiospecificity for anti-Markownikoff additions accords with a photolytically initiated radical-chain mechanism.13oSuch reactions proceed through Nalkyl-N-halogenophosphoramidates,compounds which are also initially formed in the halogenation of N-phosphorylated aziridines, for which regioselective ring opening is observed.131 Dialkyl N-t-butyl-hr-chlorophosphoramidates carrying at least one long-chain 0-alkyl group undergo nitrogen-to-carbon photorearrangement. The isomer composition of the product is the same as that produced by photochlorination of the halogen-free phosphoramidate. The rearrangement is also reasonably regioselective, the major product being the 3-chloroalkyl ester for alkyl groups longer than b ~ t y 1 . l ~ ~ 128

129

130

131 132

C. Brown, J. A. Boudreau, B. Hewitson, and R. F. Hudson, J.C.S. Perkin 11, 1976, 888. I. Shahak, Y . Ittah, and J. Blum, Tetrahedron Letters, 1976, 4003. A. Koziara and A. Zwierzak, Tetrahedron, 1976, 32, 1649; A. Zwierzak and K. Ozowska, Angpw. Chem., 1976, 88, 302. A. Hassner and J. E. Galle, J . Org. Chenz., 1976, 41, 2273. M. Okahara, K. Ozawa, T. Yagimitna, M. Miki, and I. Ikeda, J . Org. Chem., 1977, 42, 617.

Organophosphorus Chemistry

& I

RCH(CH,),CH,O C1

Med

‘NHBd

Other interesting rearrangements of nitrogen-containing phosphoric acid derivatives newly reported or further exemplified during the year include the reversible 1,3-migration of trimethylsilyl groups in the phosphoramidate (77), the equilibrium and the nitrogen-to-oxygen lying well over on the phosphoramidate migration of the bis(dialky1phosphoramide) group, in (78)-+(79).134 4 0 (PhO) P ‘NPh

-

I

,OSiMe, (PhO),P. \NPh

11%

SiMe, (77) 89%

Particularly striking is the finding that chlorination of [180]phosphoryl-labelled diethyl N-(dichlorophosphiny1)-N-methyl-phosphoramidateyields a product in which the phosphoryl oxygen atom has been transferred from one phosphorus atom to the other (Scheme 18). Such a migration suggests a cyclic intermediate, and the labelling technique, used in conjunction with i.r. spectroscopy, suggests that (80) is more likely than (81).135 *80

I1 (EtO),PNMePCl,

*

l80

It

(EtO),PNMekI, C1‘ -+ c1

Me (80)

1

0

EtOPNMePCL & I Etl (S1) Scheme 18 133 134 135

P. K.G.Hodgson, R. Katz, and G. Zon, J. Organometallic Chem., 1976, 117, C63. R. Y.Ning, R. I. Fryer, I?. B. Madan, and B. C. Sluboski, J. Org. Chem., 1976,41,2720. Yu. G. Gololobov, I. E. Boldeskul, and I. T. Sarana, Zhur. obshcltei Khim., 1976, 46, 1268 (Chem. A h . , 1976, 85, 93 546).

123

Quinqueva/ent Phosphorus Acids

Phenyl NN'-dimethylphosphorodiamidate has been used for the synthesis of 3-methyl-4-oxo-3,4-dihydroquinazoline 136 (see also 'Organophosphorus Chemistry', Vol. 7, p. 125). Interest in HMPT continues; the year's papers cover its use as a in the carbonylation of Grignard for the synthesis of highly sterically hindered in the photoreduction of esters to acids and hydrocarbon~,~ and ~ "in the reduction of aromatic diazonium ~ a 1 t s . lMetals ~ ~ in HMPT HMPT has also been used in the catalyse the addition of amines to b~tadiene.l*~ preparation of 2,4-bis(dimethylamino)q~inolines.~~~ Whilst it has previously been reported that HMPT converts aryl benzyl ketones into tetra-arylpyridines, a further in~estigationl~~ has revealed the concomitant formation of considerable amounts of the oxazaphospholine (82; R1= NMe2, R2= Me), which is not an intermediate leading to the pyridine. Appreciable yields of other A4-1,3,2-oxazaphospholines and related cornpounds are also to be obtained from the reactions between 2,4-diethoxy1,3-dipheny1-1,3,2,4-diazadiphosphetidineand benzil, benzalacetophenone, or a-phenyliminobenzyl phenyl ketone (Scheme 19).145 [o)P(0)Ri N

OEt P

PhN

\Nph

'P' OEt

<

Ph

CHPhOH

Q(o)Ph

iii

17% (R' = OEt, R2 = Ph)

+ph<

Ph

P(0) (OEt) NHPh 7%

15%

20%

trace Reagents : i, benzil; ii, benzalacetophenone ; iii, PhCOC(==NPh)Ph

Scheme 19

40%

E. B. Pedersen, Synthesis, 1977, 180. P. Cayzergues and C. Georgoulis, Compt. rend., 1976,282, C , 1033; N. J. Lewis, S. Y. Gabhe, and M. R. De La Mater, J. Org. Chem., 1977,42,1479; U. M. Dzhemilev, R. I. Khusnutdinov, and G. A. Tolstikov, Iztiest. Akad. Nauk. S.S.S.R.,Ser. khim., 1976, 566 (Chem. Abs., 1976, 85, 45 923): G. Borkent, P. A. T. Tijssen, J. P. ROOS, and J. J. van Aartsen, Rec. Trau. chim., 1976, 95, 84. 138 W. J. 9. M. Sprangers, A. P. Van Swieten, and R. Louw, CJiimia (Switz.), 1976, 30, 199; W. J. J. M. Sprangers and R. Louw, J.C.S. Perkin IZ, 1976, 1895. 139 J. A. MacPhee and J.-E. Dubois, J.C.S. Perkin I, 1977, 694. l40 H. Deshayes, J. P. Pete, and C. Portella, Tetrahedron Letters, 1976, 2019. 1 4 1 F. Trondlin and C. Ruchardt, Chem. Ber., 1977, 110, 2494. 142 M. Kodomaro, K. Omote, and T. Ohkita, Yuki Gosei Kugaku Kyokai Shi, 1975, 33, 624 (Chem. Abs., 1976,85,4759). 143 E. B. Pedersen, Tetrahedron, 1977, 33, 217. 144 R. S. Monson and A. Baraze, Chem. Letters, 1976, 555. 145 T. Kawashima and N. Inamoto, Bull. Chem. SOC.Japan, 1976, 49, 1924.

1315 137

0rganophosphorus Chemistry

124

Heating 2-(2-halogenoethoxy)-2-thiono-perhydro-l,3,2-oxazaphosphorines (83) to ca. 150 "C results in two modes of isomerization, namely thione-thiol, with and without ring heat)

R'

co\p/o N'

R'

(83)

'SCHR4CHR3CI

R'

In the presence of iodine, compounds (84) oxidatively phosphorylate ethanol and diphenyl p h 0 ~ p h a t e . lWhen ~ ~ heated with sodium ethoxide, the azo-compound (85) (PhNH),P(O)NHNHR (84) R = CO,EtorSO,Ph (EtO),P(O)N=NPh

Eta-

*

(EtO),PfO)NPhNHPh

+

(EtO),P(O) NHNPh,

(85)

undergoes the unusual conversion into a mixture of the diethoxyphosphinyl derivatives of symmetrical and unsymmetrical diphenylhydrazines;the reaction is thought to proceed via phenylaza- and phenyl-anions, and radical-pair groups.14s Phosphonic and Phosphinic Acids and their Derivatives.-Differences in the reactivity of the halogen atoms in the halogenoalkylphosphonic dichlorides (86) towards 0

II

C1,PCHClCOCl (86)

nucleophiles are to be expected, and for the reaction with alcohols, at least, the differences are well defined and in the order carbonyl chloride > phosphoryl chloride > alkyl ~ h l 0 r i d e . l ~ ~ Cyclic trimetaphosphonic acids have been obtained as the products from the hydrolysis of phosphonic d i c h l ~ r i d e s151 , ~but ~ ~a~further report indicates an unusual reaction course during the hydrolysis of the 2-chloroalkylphosphonothioicdichlorides (87) with 6M-HCI, to give (88) and (89) in the approximate proportions 2: 1.152 RCHClCH,P(S) C1, (87)

146 147 148

149 150 151 152

RCHCH,P(S) (OH),

I

OH

+ RCHClCH,P(O) (OH), (89)

(S 8).

0. N. Nuretdinova, Zzoest. Akud. Nauk. S.S.S.R., Ser. khim., 1976, 2107. R. J. W. Cremlyn, M. J. Frearson, and D. R. Milnes, Phosphorus, 1976, 6, 207. Ya. A. Levin, I. P. Gozman, and E. I. Gol'dfarb, Izoest. Akad. Nauk. S.S.S.R., Ser. khim., 1976, 2796 (Chem. Abs., 1977, 86, 120 403). V. V. Mokva, S. A. Novruzov, T. V. Zykova, A. I. Razumov, and V. M. Ismailov, Khim. Elementoorg. Soedineniya, 1976, 18 1 (Chem. Abs., 1977, 86, 5542). K. A.Petrov, M. A. Raksha, and Le Dong Khai, Zhur. obshchei Khim., 1976,46,2003 (Chem. Abs., 1977, 86, 140 150). 0. N . Grishina, N. A. Andreev, and E. E. Sidorova, Zhur. obshchei Khim., 1976, 46, 1487 (Chem. Abs., 1976,85, 160 2 5 5 ) . G. K. Fedorova and L. G . Anan'eva, Zhur. obshchei Khim., 1976,46,549 (Chem. Abs., 1976, 85, 5792).

125

Quinquevalent Phosphorus Acids

Alkyl phosphorodichloridodithioates and dialkyl phosphorochloridotrithioates react with benzene in the presence of aluminium chloride to give the expected diand mono-aryl lS3 Diazomethane reacts with 1-oxophosphonic and phosphinic esters (90) with inserPhosphinomethyl sulphoxides (91) tion of a rnethylene group at undergo a rearrangement of the Pummerer type.155

R’

‘P(0)

COAr

ClI,N,

R‘

‘P(0)

t

CH,COAr

R2’0

R2’0

(90)

CHzNz

>

R‘

‘P(O)CH=C*r R20’

1

OMe

0

II

(EtO),P(O) CH,SR’

(R’CO).O MeSO;H

(EtO),P(0)CH?(OCOR2) SR’

(91)

A further rearrangement recently reported is that of the triaryl epoxyethylphosphonates (92) under the influence of BF3 etherate, when one or both of the compounds (93) and (94) may be obtained, representing migration of the phosphonogroup and of the aryl group, P h 2 q A r

P(0) (OMe),

-+

(MeO),P(O) OCPh,COAr -+ (MeO),P(O) COCPh, Ar

(93)

(94)

(9 2)

Partial dealkylation can take place during attempted reductions of dialkyl 2nitrophenylphosphonates with hydrazine and ni~ke1.l~’ Chlorination of dialkyl a-nitromethylphosphonate gives initially the aa-dichloro-a-nitro-methylphosphonate, but this, when treated with PC15,loses the nitro-group to give trichloromethylphosphonic d i c h l ~ r i d e . ~ ~ ~ Several addition reactions of unsaturated phosphonic and phosphinic esters have been reported during the course of the year. Dithiophosphoric acids add to 2-alkoxyvinylphosphine esters in the expected manner,159and in the addition of phenyl azide to vinylphosphonates, the initial triazole (95) may be thermolysed to a C-phosphoryIated aziridine, but in the presence of triethylamine the final products are 2-anilinoviny1phosphonates.16O 153 154 155 156

157 158 159 160

I. V. Murav’ev and I. S. Fedorovich, Zhur. obshchei Khim., 1976, 46, 789 (Chem. Abs., 1976, 85, 21 550). R. D. Gareev, A. N. Pudovik, and Yu. Yu. Samitov, Khim. Elementoorg. Soedineniya, 1976, 135 (Chem. Abs., 1977, 86,29 308). S . E. Dinizo and D. S. Watt, Synthesis, 1977, 181. C . E. Griffin and R. L. Ranieri, Phosphorus, 1976, 6, 161. E. N. Dolzhnikova, E. N. Tsvetkov, and G . S. Petrova, Zhur. obshchei Khim., 1976, 46, 1903 (Chem. Abs., 1976, 85, 192 819). K. A. Petrov, V. A. Chauzov, and N. N. Bogdanov, Zhur. obshchei Khim., 1976, 46, 1499 (Chem. Abs., 1976,85, 160 257). R. A. Cherkasov, N. V. Kashina, A. A. Musina, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 1181 (Chem. A h . , 1976,85, 108 713). N. G. Khusainova, Z . A. Bredikhina, F. Kh. Karataeva, T. I. Bychkova, and A. N. Pudovik, Zhur. obshchei Khim., 1976, 46, 1712 (Chem. Abs., 1976, 85, 177 551).

126

Organophosphorus Chemistry

The addition of diazoacetic ester to phosphinylallenes gives phosphinylpyrazoles.161Hydroxylamine adds to vinylphosphonates, and the products (96) rearrange under acid conditions.162Alkyl diallylphosphinates undergo prototropic isomerization when treated with t-butoxide

(CH,=CHCH,),P(O)OR

Buto‘+ (MeCHf CH),P(O) OR

A study has been made of the kinetics of epoxidation of allylph~sphinates~~~ and of the addition of C-benzoyl-N-phenylnitroneto vinyl- and allyl-phosphonates.16s Boron trifluoride stabilizes phosphorus(v) thiocyanates, preventing their isomerization to isothiocyanafes.ls6 Cleavage of the phosphinothioic methanesulphonic anhydride (97) with aluminium halides yields the phosphinic halide with retained ~hira1ity.l~ But,

S

\\pH

Ph‘

Buf

AIX,

L [Complex] -+

‘OS0,Me .(97)

Ph‘

‘\P/ X ‘

S

+ AlX,OSO,Me

X = halogen

Thiophosphinic N-heteroaromatic amides are alkylated at sulphur by MeI.lS8 a-Aminophosphonicesters having a free NH bond have been aminomethyIatedlB9 and phosph~nomethylated.~~~ They may also be partially or completely O-dealkylated under aprotic conditions by the action of LiBr in pyridine or BBr, in dichloro161 162 163

164 165 166 167

168

169

170

N. G . Khusainova, T. V. Timoshina, and A. N. Pudovik, Zhur. obshchei Klzim., 1976,46,2624 (Chem. Abs., 1977, 86,71 290). K. A. Petrov, L. V. Treshchalina, and V. M. Chizhov, Zhur. obshchei Khim., 1976, 46, 1986 (Chem. Abs., 1977, 86, 5557). A. I. Razumov, B. G . Liorber, T. A. Tarzivolova, and T. V. Zykova, Khim. Elementoorg. Soedineniya., 1976, 178 (Chem. Abs., 1976, €45, 192 826). A. I. Razumov, I. A. Krivosheeva, B. G . Liorber, Z. M. Khammatova, T. V. Zykova, T. V. Denisova, and N. A. Zhikhoreva, Zhur. obshchei Khim., 1976, 46, 1237 (Chem. Abs., 1976, 85, 93 625). A. B. Arbusov, Yu. Yu. Samitov, E. N. Dianova, and A. F. Lisin, Izuest. Akad. Nuuk., S.S.S.R., Ser. khim., 1976, 2779 (Chem. Abs., 1977, 86, 155 745). J. Michalski, A. Lopusinski, W. J. Stec, and E. Fluck, Z . Naturforsch., 1976, 31b, 1431. J. Michalski and Z . Skrzypazynski, J.C.S. Chem. Comm., 1977, 66. J. Boedeker, P. Koeckutz, and R. J. Shenke, J. Organometallic Chem., 1976, 111, 65. K. Issleib and R. Hannig, 2. Chem., 1976, 16, 150. Zh. M. Ivanova, T. V. Kim, E. A. Suvalova, I. E. Boldeskul, and Yu. G. Gololobov, Zhur. obshchei Khirn., 1976, 46, 236 (Chem. Abs., 1976, 85, 21 540).

127

Quinqueualent Phosphorus Acids

methane.171Trichloroacetonitrile in pyridine will esterify a-aminophosphonic acids in alcohol solution to the monoester When 2-amino-l-hydroxyethylphosphonic acids (98) are treated with nitrous acid, a pinacolic-type migration takes place, evidently of the phosphorus-containing (HO),P(0) CPhCH, NH,

HNO,

I OH

*

+J

(HO), P(0) CPhCH,

iH

(HO),P(O) CH,COPh

__f

(98) H. Gross et al. have continued their studies on the carbon-to-nitrogen migrations in the arninornethanepolyphosphonic acid series17 4 (see ‘Organophosphorus Chemistry’, Vol. 8, p. 114; Vol. 7, p. 128). Fragmentation of N-substituted iminodi(methy1enephosphonic acids) (Scheme 20) occurs when their solutions in strong acids are electrolysed; the products are or-aminomethylphosphonic acids and formylphosphonic RN(CH,PO,H,),

-le-+

-H+

~%(cH~Po,H,),

+ RN-~HPO,H,

I

CH, P03H2 Ale-

RNHCH,PO,H, + OHC-PO~H,

-=

H2°

R~~=CHPO,H,

I

CH2m3H2

Scheme 20

Although the direct N-methylation of pyridine compounds by diazomethane is not normal except in the presence of HBF,, it has now been shown that treatment of pyridin-2-ylphosphonicmonoesters, e.g. (99; R = H),with diazomethane does result in direct N-methylation followed by rearrangement.l 78 Treatment of the A4-1,2-oxaphospholen(100; R1= OMe) with LiBr in MeOH yields the salt (101) together with the open-chain compounds (102) and (103) in the proportions 1:1 :2. The formation of (102), and particularly the high yield of (103), has been advanced as good evidence for the participation of the intermediate (104), from which transfer of axial methyl group to Br- occurs.177 Kluger et al. have continued their studies on phosphonobenzanilides and their hydrolysis.178 171 173 173 174

175 176

177 178

C. Wasielewski, A. Sobczak, and J. Szewczyk, Roczniki Chem., 1976, 50, 1795 (Chem. Abs., 1977, 86, 121 739). C. Wasielewski, M. Hoffmann, E. Wilkowska, and J. Rachob, Roczniki Chem., 1976,50,1613 (Chem. Abs., 1977, 86, 89 948). G. Richtarski, M. Soroka, P. Mastalerz, and H. Starzemska, Roczniki Chem., 1975,49,2001 (Chem. Abs., 1976,85, 5776). H. Gross, B. Costisella, T. Grauk, and L. Brennecke, J. prakt. Chem., 1976, 318, 116; H. Gross, LA. Brennecke, and B. Costisella, ibid., p. 272. J. H. Wagenknecht, J. Electrochem. SOC.,1976, 123, 620. J. S. Loran, R. A. Naylor, and A. Williams, J.C.S. Perkin 11, 1976, 1444. W. G. Voncken, A. M. C. F. Castelijns, S. A. J. de Leeuw, and H. M. Buck, Tetrahedron Letters, 1977, 729. R. Kluger and J. L. W. Chan, J. Amer. Chem. SOC.,1976,98,4913; R. Kluger and C.-H. Lem, Canad. J. Chem., 1977,55, 640.

Organophosphorus Chemistry

128

(100)

(102) R = OMe (103) R = 0-I.i'

In a comparative study of the rates of alkaline hydrolysis of the heteroaryl and heteroarylmethyl phosphonates (105) and (106), respectively, with those of aryl phosphonic 'analogues' (107), mesomeric interactions between phosphorus and the

ring systems were estimated, using i.r. and 31Pn.m.r. spectroscopy, and it was concluded that n-electron interactions with the rings were of little importance in the interpretation of the relative rates, which were best explained in terms of o-electron interactions. For the series (105 : R = Et, X = 0),the relative rates of hydrolysis were (105; 2=0)>(107)=(105; Z=S)>(105; Z=NMe) in the ratio 120:25:1. In addition, the esters (105; Z = 0 or S) hydrolyse faster than the correspondingcompound (106). For the phenyl esters (R=Ph), the order for (105) is (105; Z=O)=(107)> (105; Z=S)>(105; Z=NMe) in the ratio 25:16:1.179 Pyridin-2-ylphosphonate esters (99) are hydrolysed via attack by water on the neutral form of the ester, with no detectable anchimeric assistance on the part of the pyridine nitrogen atom.180 The alkylation of dipbenyl N-alkylphosphinic amides via the amide anion and subsequent cleavage of the NN-dialkylamide with toluene-p-sulphonic acid is a valuable, if not preferable, alternative to the preparation of secondary amines through the Hinsberg procedure.lS1 The phosphonium salt (108) loses the ethoxy-group with inversion of configuration under alkaline conditions, thus providing a route for the inversion of configuration of phosphinic amides, but in addition, treatment of the salt with a metallic hydride affords a phosphinimidate(109) with retention of chirality (seeScheme21).182 Although much of the work of the past few years has suggested that the acidpromoted hydrolysis of phosphinic amides proceeds by a continuous spectrum of mechanisms ranging from direct nucleophilic substitution to unimolecular dissociation, depending upon the nucleophilicity of the leaving group and the nature of the 179

180 181 182

D. W. Allen, B. G. Hutley, and M. T. J. Mellor, J.C.S. Perkin ZZ, 1977, 789. J. S. Loran, R. A. Naylor, and A. Williams, J.C.S. Perkin ZZ, 1977, 418. S. Coulton, G. A. Moore, and R. Ramage, Tetrahedron Letter$, 1976, 4005. K. E. DeBruin and L. L. Thomas, J.C.S. Chern. Comm., 1977, 33.

129

Quinquevalent Phosphorus Acids Me, ‘P /NHBu‘ I_

Ph‘

NHBd

‘\

Ph‘

/

P+

‘013

Me,

phPh.‘

‘

H0

‘P

‘NHBU~

substituents at phosphorus, there has been a lack of good stereochemical evidence for the existence of the two extreme cases. Japanese workers have now presented evidence, of a stereochemical nature, that the acid-catalysed methanolysis of the methylphenyl N-cyclohexylphosphinamide (1 10; R1= Me, R 2= cyclo-C,Hll) proceeds almost purely by direct replacement, irrespectiveof the acidity of the medium, and the compound thus behaves somewhat differently to the ani1ide.ls3Harger la4has shown that the N-4-nitroanilide (1 10; R1= Me, R2= C,H4N0,-4) is rapidly solvolysed in methanol containing 0.1SM-HCl with complete stereochemical inversion, most reasonably explained in terms of an associative mechanism.

Harger has also extended his 1975 reports on the series (110; R1=Et, Pri, But, cyclo-C,H,, or cyclo-C,H,Me, R2= H) with a study of the series for which Ra= Ph or substituted Ph.la5He concludes that, for the acid-catalysed hydrolysis at the phosphorus-nitrogen bond, a reduction in the nucleophilicity of the leaving group does not reduce, to any great extent, the sensitivity of the hydrolysis to steric hindrance on the part of the group R1. Yet further violations of the ‘rule’ that phosphetans undergo substitution with retention of configuration have come to light. The phosphetan amides (1 1l), normally resistant to hydrochloric, sulphuric, and trifluoroacetic acids, do, however, undergo methanolysis in the presence of BF,, when considerable inversion of configuration occurs at phosphorus.1S6 183 184

185 186

T. Koizumi, Y . Kobayashi, and E. Yoshii, Chem. and Pharm. Bull. (Japan), 1976, 24, 834. M. J. P. Harger, J.C.S. Chem. Comm., 1976, 520. M. J. P. Harger, J.C.S. Perkin I , 1977, 605. T. Koizumi, Y. Kobayashi, and E. Yoshii, Tetrahedron Letters, 1976, 2853.

7

Phosphates and Phosphonates of Biochemical Interest BY D. W. HUTCHINSON

1 Introduction Mitochondria1oxidative phosphorylation is the process by which ATP is synthesized in mitochondria during the passage of electrons along a chain of carriers. Chemical and chemiosmotic2theories for this process have been propounded by their respective adherents, and mechanisms in bioenergetics have been re~iewed,~ but experimental evidence to support these theories has been difficult to obtain with living systems. However, this year, reduced lipoic acid and unsaturated fatty acids have been shown4to function as cofactors in the energy-linked synthesis of ATP in mitochondria, and this observation has prompted much activity in this field which will be discussed more fully in Section 6 of this Chapter. With the development of mild methods for isolating proteins and for their analysis, it is becoming apparent that phosphorylated proteins are important intermediates in enzyme-catalysed phosphoryl transfer. Thus, it has recently been found that a phosphorylated enzyme is involved in the synthesis of glucose 1,Qbisphosphate from 1,3bisphosphoglycerate and glucose 1-phosphate in beef brain.bPhosphoproteins may also be constituents of control mechanisms for some biological processes, and the phosphorylation of cholera toxin and cardiac troponin 7 by CAMP-dependent protein kinases probably contributes to the biological activity of these macromolecules. Another development worthy of comment is the number of 31P n.m.r. studies on living tissue and cells that have been published during the past year.BResonances due to ATP, N’-phosphorocreatinine, and other compounds (such as glycerol 3-phosphorylcholine) have been observed with muscle preparations. loWith considerable experimental ingenuity, both heart tissuef1 and perfused, beating rat hearts12 have Q9

H. Wang, J. Bioenergetics Biomembranes, 1976, 8, 209. P. Mitchell, F.E.B.S. Letters, 1977,78,1; M . D. Brand and A, L. Lehninger, Proc. Nut. Acad. Sci. U.S.A., 1977, 74, 1955. 3 E. Racker, ‘A New Look at Mechanisms in Bioenergetics’, Academic Press, New York, 1976. 4 D. E. Griffiths, Biochem. J., 1976, 160,809. 5 L. J. Wong and I. A. Rose, J. Biol. Chem., 1976,251, 5431. 6 0. M. Rosen, Biochemistry, 1976, 15, 2902. 7 J. T. Stull and J. E. Buss, J. Biol. Chem., 1977, 252, 851. 8 C. T. Burt, T. Glonek, and M. BLBny, Science, 1977,195, 145. 9 C . T. Burt, T. Glonek, and M. BBrAny, J. Biol. Chem., 1976,251,2584. 10 C. T. Burt, T. Glonek, and M. Bhrhny, Biochemistry, 1976,15,4850. 11 D. G. Gadian, D. I. Hoult, G. K. Radda, P. J. Seeley, B. Chance, and C. Barlow, Proc. Nut. Acad. Sci. U.S.A., 1976, 73,4446. 1% P. B. Garlick, G. K. Radda, P. J. Seeley, and B. Chance, Biochem. Biophys. Res. Comm.. 1977. 1 J. 2

74, 1256.

130

Phosphates and Phosphonates of Biochemical Interest

131

been suspended in n.m.r. tubes of diameter 8mm and their 31P n.m.r. spectra measured. It is hoped12that this analytical technique can be developed so that events associated with cardiac ischemia might be followed, though it is difficult to see how this technique can be applied to humans without considerable refinement. The slP n.m.r. spectra of Ascites13 and Escherichia c01i14 cells have also been recorded and used to study the concentrations and fates of phosphorus metabolites in the intact cells.

2 Coenzymes and Cofactors Nicotinamide Nuc1eotides.-Di-n-butylphosphinothioyl bromide (1) reacts with nucleotides to give the corresponding nucleoside phosphoric di-n-butylphosphinothioic anhydrides in high yield (Scheme 1). These mixed anhydrides are stable in 0

S

AMP + Bu,P(S)Br

(1)

0

II II Bu,P-0-P-0-Ado

/

+ II CH20P-0I

I

HO

0

II

O-P-OCH, HOI

I

CONH,

HO

OH

(2) Keagent: 1, nicotinamide mononucleotide

Scheme 1

water, but in the presence of silver salts they react with phosphoric acid or its esters to give pyrophosphates. This method has been used to prepare NAD+ (2; R = H), FAD, and other nucleotide coenzymes in excellent ~ie1ds.l~ Other NAD+ analogues that have been prepared by more conventional means from NMN+ and the corresponding adenosine nucleotide include nicotinamide 8-azidoadenine dinucleotide (2; R = N3)l6 and the spin-labelled coenzyme [2; R = 8-(2,2,6,6-tetramethylpiperidin-4yl-1-o~yl)amino].~~ Glyceraldehyde 3-phosphate dehydrogenase catalyses the hydration of NADH to a new product (NADHX), which has the same spectroscopic properties as one of the 13

l4 15 16 17

G. Navon, S . Ogawa, R. G. Shulman, and T. Yamane, Proc. Nut. Acad. Sci. U.S.A., 1977,74,

87.

G. Navon, S . Ogawa, R. G. Shulman, and T. Yamane, Proc. Nut. Acad. Sci. U.S.A., 1977,74,

888.

K. Furusawa, M. Sekine, and T. Hata, J.C.S. Perkin 1, 1976, 1711. R. Koberstein, European J. Biochem., 1976, 67, 223. H. R. Wenzel and W. E. Trommer, F.E.B.S. Letters, 1977, 78, 184.

0rganophosphorus Chemistry

132

products obtained by the acid-catalysed hydration of NADH. This year, two papers have appeared almost simultaneouslyon the structure determinationof NADHX and l9 From 13C other important products of the acid-catalysed hydration of NADH.l8~ n.m.r. spectroscopic measurements NADHX is ~-6-hydroxy-l,4,5,6-tetrahydronicotinamide adenine dinucleotide (3), and the other products resulting from the acid-catalysedhydration are a-Oa’-6B- (4) and a-02’-6A-cyclotetrahydronicotinamide 0 CI-I,OP-0-P

H

I

OH H

(4)

II-0Ad0

I

OH

CONII,

R = adenosine 5’-pyrophosphoryl

(5)

adenine dinucleotide (5). The isomers (4)and (5), which differ in the stereochemistry of the fusion of the reduced nicotinamide and ribose rings, are formed in 3 :1 ratio during the acid-catalysed hydrolysis, and have the a-configuration. To achieve this inversion of configuration at C-1’, the ribose ring must open during the reaction, and a possible scheme for this process is shown in Scheme 2. In strong alkali, NAD+ reacts with opening of the nicotinamide ring to give a

p-NADH

‘H

Y Scheme 2 18 19

T.J. Williams, P. D. Ellis, T. A. Bryson, R. R. Fischer, and R. B. Dunlap, Arch. Biochem. Biophys., 1976, 176,275. S . L. Johnson and P. T. Tuazon, Biochemistry, 1977, 16, 1175.

Phosphates and Phosphonates of Biochemical Interest

133

Schiff base that has been assigned the structure (6).20The formation of this intermediate may play some part in the binding of NAD+ to dehydrogenases. CONH,

&

A

J

y

O

H

H (6) R = adenosine 5’-pyroyhosphoryl-5-(p-~-ribofuranosyl)

Coenzyme A.-Treatment of adenosine with an excess of pyridinium 2-dimethylamino-4-nitrophenyl phosphate (7)in the presence of DCC affords adenosine 2’,3’cyclic phosphate 5’-(2-dimethylamino-4-nitrophenyl)phosphate (8). The latter can react with D-pantethine 4’,4”-diphosphate in acetic acid-pyridine to give the 2’,3’cyclic phosphate of the disulphide of coenzymeA (9) in good yield (Scheme 3).21 The

HO‘

/

OH

0

\/

(7)

0 0

II II I I HO OH

SCH,CH,NHG(O) CH,CH,NHC(O)CH(3HC:(Me),CH;,oPoPo’

A

(9) Reagents : i, DCC in DMF ; ii, ~-pantethine-4’,4”-diphosphate in acetic acid-pyridine

Scheme 3 20 21

C. C. Guilbert and S. L. Johnson, Biochemistry, 1977, 16, 335. Y. Taguchi, N. Noriyuki, T. Kakimoto, and Y. Mushika, Bull. Chem. SOC.Japan, 1976, 49, 1122.

134

Organophosphorus Chemistry

synthesis of the S-benzoyl 8-azidoadenine analogue of CoA, using diphenyl phosphorochloridate to effect the condensation, has been reported.22This analogue has been used as a photolabile reagent to study the attachment of the acylated coenzyme to acyl CoA: glycine N-acyl transferase from beef liver. Two CoA-containing nucleotides which inhibit DNA-dependent RNA polymerase have recently been isolated from E. coZi and other organisms.23One consists of CoA and glutathione joined by a disulphide bridge; the other is a CoA dimer plus two equivalents of glutamic acid. The inhibition of the polymerase by these nucleotides is not due to an oxidation-reduction reaction but appears to involve their binding to the DNA-RNA polymerase complex.24 Other Coenzymes and Cofactors.-The chemical synthesis of riboflavin phosphates and their acetyl derivatives has been reinve~tigated.~~ Riboflavin 4’-monophosphate (10) is an important contaminant of commercial flavin mononucleotide (FMN), and OPO,H, I

CH,CI lOHCHOII~HCH,OH

I

0 (10)

is presumably formed by ring opening of the 4’,5’-cyclic phosphate, which is itself formed from the 5‘-phosphate during the isolation of the latter from natural sources. The acetylation of FMN under acidic conditions yields pure tri-0-acetyl-FMN; on the other hand, acetylation in pyridine leads to phosphate migration, together with acetylation at N-3 in the flavin ring. The most satisfactory procedure for the phosphorylation of riboflavin was found to be that reported by Flexser and Farkas26 when aqueous phosphoryl chloride (phosphoromonochloridic acid) is the phosphorylating agent. Pyridoxal 5’-phosphate (PLP) was noticed to be a constituent of rabbit muscle phosphorylase in 1957, and since that time it has been shown that all a-glucan phosphorylases which give phosphorolysis products with retention of configuration contain PLP.27The exact role of the PLP is still not known, though it has been shown that these a-glucan phosphorylases have an absolute requirement for PLP and that the Schiffbase formed between PLP and glycogen phosphorylase can be reduced with borohydride without eliminating the catalytic activity of the enzyme. The 31Pn.m.r. spectrum of PLP bound to phosphorylase b shows that deprotonation of the 5‘29 23 24 25

26 27

E. P. Lau, B. W. Haley, and R. E. Barden, Biochem. Biophys. Res. Comm., 1977,76, 843. P. C. Loewen, Biochem. Bioplzys. Res. Comm., 1976, 70, 1210. G. R. Klassen, R. A. Furness, and P. C. Loewen, Biochem. Biophys. Res. Comm., 1976, 72, 1056. G. Scola-Nagelschneider and P. Hemmerich, European J. Biochem., 1976, 66, 567. L. A. Flexser and W. G . Farkas, U.S.P. 2610177 (Chem. A h . , 1953, 47, 878ta). D. J. Graves and J. H. Wang, in ‘The Enzymes’, ed. P. D. Boyer, Academic Press, New York, 3rd edn., 1972, Vol. VII, p. 435.

Phosphates and Phosphonates of Biochemical Interest

135

group of I’LP is not related to external pH but that addition of AMP (the allosteric effector required for activity) and arsenate (which can substitute for phosphate in the phosphorolysis) causes a conformational change which leads to deprotonation.28 Since only one phosphorus resonance was observed for PLP, these experiments are at variance with studies2 9 when two- or three-component signals were observed. The latter have been ascribed to PLP in two different environments.

3 Sugar Phosphates Details have been published30of a large-scale (500 g) enzymatic synthesis of glucose 6-phosphate, using hexokinase and acetate kinase immobilized in polyacrylamide gel particles to catalyse the reaction. The yield of glucose &phosphate corresponds to 65 %, based on the amount of crude acetyl phosphate used as starting material, and the activities of the two enzymes are not greatly diminished at the end of the synthesis. This preparation illustrates the potential of immobilized enzymes for the synthesis of biochemical intermediates that are often accessible only after tedious and/or costly procedures. Glucose 6-phosphate reacts readily and non-enzymatically with deoxyhaemoglobin to give a product in which the phosphorylated glucose is linked covalently to the amino-terminus of the P - ~ h a i n Glucose .~~ 1-phosphate, fructose 1- and 6-phosphates, and fructose 1,6-bisphosphate do not react with haemoglobin in this manner, and it has been postulated that the glucosylated haemoglobin may be an intermediate in the conversion of haemoglobin A into a glycosylated form that is present as about 5 % of the haemoglobin in normal human red blood cells. 3-Deoxy-~-manno-octu~osonic acid, which is a component of the cell envelope of Gram-negative bacteria, is formed biosynthetically as its %phosphate (11) before being dephosphorylatedand converted into cytidine-5’ 3-deoxy-~-manno-octu~osonic acid 2-phosphate, the direct precursor of the cell envelope. Base-catalysed condensation of 2-O-benzyl-~-arabinose5-phosphate with oxalacetate, followed by catalytic hydrogenolysis of the benzyl ether group, proved to be a successful route to (ll), as shown in Scheme4.32Etherification of the 2-hydroxy-group of arabinose 5-phosphate prevents the base-catalysedisomerization of the latter to ribulose 5-phosphate during the synthesis. Among the products of the Perkow reaction between 1,3,4,5,6-pentaO-acetyl-keto-D-fructoseand trimethyl phosphite (Scheme 5 ) are the enol phosphates (1 2) and (1 3), hydrolysis of which gives 1 -deoxy-D-fructose and 3-deoxy-~-erythrohexulose, re~pectively.~~ Similarly, an enol phosphate is formed from trimethyl phosphite and 2,3,4,5,6-penta-O-acetyl-aldehydo-~-glucose, which can be hydrolysed to 2-deoxyglucose. The structures of keto-sugars in solution, together with those of their biologically important phosphate esters, have been reviewed,34and rapid-quench kinetic experi28 29

30 31 32 33 34

K. Feldman and E. J. M. Helmreich, Biochemistry, 1976, 15, 2394. S . J. W. Busby, D. G. Gadian, G . K. Radda, R. E. Richards, and P. J. Seeley, F.E.B.S. Letters, 1975, 55, 14; K. Feldman and W. E. Hull, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 856. A. Pollak, R. L. Baughn, and G . M. Whitesides, J. Amer. Chem. SOC.,1977, 99, 2366. D.N.Haney and H. F. Bunn, Proc. Nat. Acad. Sci. U.S.A., 1976,73, 3534. D. Charon and L. SzabB, J.C.S. Perkin I, 1976, 1628. J. Thiem, D.Rasch, and H. Paulsen, Chem. Ber., 1976, 109, 3588. G . R. Gray, Accounts Chern. Res., 1976, 9,418.

136

Organophosphorus Chemistry

CO,H

CO,H

I I

I C--0

c=o

I

CH,CO,H

. .. ~

Reagents: i, OH-; ii, Hz-Pd

CH,OAc

I c=o

CH2

R

O

H

OH

OH

CH,OPO,H,

CH,OPO, H,

(11)

rw *;"iScheme 4

OAc

1

CH,OAc

I P

C-OP(OMe),

C-OP(OMe),

*co~oAci ,

CH,OAc

0 OH ~

t

OAc OAC

CH,OAc

CH,OAc

Reagent: i, (MeO)3P

ments on fructose 1,6-bisphosphatasefrom rabbit liver show that the u- rather than the p-anomer is the substrate for this enzyme.36Chemical trapping experiments with the synthetic substrate analogue xylulose 1,5-bisphosphate indicate that the interconversion of the anomeric forms of the cyclic bisphosphate is retarded by their binding to the enzyme. Kinetic parameters for the inhibition of fructose 1,6-bisphosphatase by a number of substrate analogues suggest that the catalytic mechanism of the enzyme from rabbit liver differs from the catalytic mechanism of the enzyme from bovine liver.36 Rat liver plasma membranes contain an enzyme that can catalyse the formation of alkyl esters of adenosine 5'-phosphate, e.g. (14; R = CH,CH,OH) or (14; R = Me), from ATP and the corresponding The concentration of alcohol must be high for the syntheses to proceed at an appreciable rate, and hence (14) may be formed as a result of the diversion of some other metabolic pathway. 35

36

37

W. A. Frey, R. Fishbein, M. M. de Maine, and S . J. Benkovic, Biochemistry, 1977, 16, 2479. C. J. Marcus, J. Biol. Chem., 1976, 251, 2963. J. Ryan, G. N. Rogers, D. G. Toscano, and D. R. Storm, J. Biol. Chem., 1977,252, 1719.

Phosphates and Phosphonates of Biochemical Interest

137

0

Deoxy-sugars are inhibitors of virus multiplication, as they inhibit the synthesis of viral glycopr~teins.~~ For example, the incorporation of mannose into the glycoproteins of Semliki Forest virus is blocked in the presence of 2-deoxyglucose, although GDP-mannose accumulates in the virus. It has been postulated3@that the formation of GDP-2-deoxymannose is responsible for this inhibition, as it competes with natural substrates for glycosyl transferases. In yeast, GDP-2-deoxyglucose is transformed into a polyisoprenol 2-deoxyglucose phosphodiester. The latter can interfere with the glycosylation of proteins, which supports the above Glycosyl polyisoprenol phosphodiesters act as glycosyl carriers in a wide variety of biological systems, e.g. mammalian transformed cells,42 and yeast.44 The mannosyl residue in one of these compounds, D-mannosylretinyl phosphate (15),

(15)

which is found in rat liver microsomes, has the B-c~nfiguration.~~ This was deduced from the alkaline degradation of (15) to /?-D-mannosyl phosphate and aIso from the stability of (15) to hydrolysis by acid or a-mannosidase. 4 Phospholipids Cardiolipins (16) occur widely in membranes of subcellular components which display high metabolic activity. However, difficulties in the isolation or synthesis of (16) have hindered studies on structure-function relationships in these compounds. The publication of a synthetic route to (16) is of significance, because specific cardiolipins can now be prepared.46One remarkable feature of this synthesis, which makes C. Scholtissek, Current Topics Microbiol. Immunol., 1975, 70, 101. M. F. G. Schmidt, R. T. Schwarz, and C. Scholtissek, European J. Biochem., 1976, 70, 55. 40 L. Lehle and R. T. Schwarz, European J. Biochem., 1976, 67, 239. 41 A. Herscovics, B. Bugge, and R. W. Jeanloz, J. Biol. Chem., 1977, 252, 2271 ; J. Chambers, W. T. Forsee, and A. D. Elbein, ibid., p. 2498; A. Heifetz and A. D. Elbein, ibid., p. 3057; W. T. Forsee, J. A. Griffin, and J. S. Schutzbach, Biochem. Biophys. Res. Comm., 1977, 75, 799. 42 S. J. Turco and E. C. Heath, J . Biol. Chem., 1977, 252, 2918. 43 C. T. Brett and L. F. Leloir, Biochem. J., 1977, 161, 93. 44 A. J. Parodi, European J. Biochem., 1977, 75, 171. 45 G. C. Itosso, S. Masushige, C. D. Warren, T. C. Kiorpes, and G . Wolf, J. Biol. Chem., 1976, 38

39

251, 6465.

46

F. Ramirez, P. V. Toannu, J. F. Maracek, G. H. Dodd, and B. T. Golding, Tetrahedron, 1977,

33. 599.

138

Organophosphorus Chemistry

use of cyclic enediol phosphates as phosphorylating agents, is that 1,2-diacyl-snglycerols can be converted into the corresponding cardiolipins in four steps, two of which can be carried out in the one flask. Only one intermediateand the final product need to be purified, and this simple synthesis is in marked contrast to previous methods for the synthesis of (16). A prebiotic synthesisof phospholipids from glycerol (or monoglycerides), fatty acids, orthophosphate, and dicyanamide has been CH,OCOR I

I

CH,-O-P-

II 1 Hi)

0-CH,

I

(16)

rep~rted.~' The phospholipids formed in this manner readily form vesicles. Radioactively labelled 3,4-dihydroxybutyl 1-phosphonate, an analogue of glycerol 3phosphate, is incorporated into a polar lipid fraction of E. coli by means of a CDPdependent phosphatidyl transferase. The radioactive compound which is the chief product in E. coli, and which is the only product formed in vitro with the enzyme, is the analogue of phosphatidylglyceryl phosphate, i.e. (1,2-diacyl)-sn-glyceryl ~ - 4 ' phosphoryloxy-3'-hydroxybutyl-l'-phosphonate.** A number of papers have appeared recently on the study of phospholipid bilayers by 31Pn . m . ~ -and . ~ ~ other resonance techniques.60For example, slP chemical-shift data reveal that in dipalmitoyl-3-sn-phosphatidylethanolamine bilayers, the ethanolamino-group is rotating flat on the surface of the bilayer, there being rapid transition between two enantiomeric conformation^.^^^ Vitamin E and phytanic acid disrupt the packing of the hydrocarbon region of phospholipid bilayers, and the packing is also disturbed by the polar carboxy-group of the phytanic acid. From changes in the 31Pn.m.r. spectra of lecithin bilayers it has been concluded that phytanic acid and vitamin E increase the permeability of the bilayers to praseodymium ions.51 31PN.m.r. spectra indicate that the phosphate group of phosphorylcholine is partially immobilized on binding to mouse myeloma imm~noglobulin.~~ The phosphate oxygens of the phosphorylcholine are hydrogen-bonded to amino-acid sidechains at the binding site of the immunoglobulin, in agreement with the structure of W. R. Hargreaves, S. J. Mulvihill, and D. W. Deamer, Nature, 1977, 266,78. R. J. Tyhach, R. Engel, and B. E. Tropp, J. Biol. Chem., 1976,251, 6717. 49 (a) J. Seelig and H. U. Gally, Biochemistry, 1976, 15, 5199; (b) S. J. Kohler and M. P. Klein, ibid., 1977, 16, 519. 5O L. Stuhne-Sakalec and N. Z. Stanacev, Canad. J. Biochem., 1977,55, 173, 186. 61 R. J. Cushley and B. J. Forrest, Canad. J . Chem., 1977,55, 220. wa A. M.Goetze and J. €3. Richards, Biochemistry, 1977, 16, 228. 47

48

Phosphates and Phosphonates of Biochemical Interest

139

the solid complex that has been determined by X-ray ~rystallography.~~ Results from 31Pn.m.r. spectroscopy have also been used to show that glycophorin A, the major sialoglycoprotein of the membrane of the human red blood cell, contains one mole of diphosphoinositide per mole of glycophorin. However, this technique is unable to show whether the diphosphoinositide is covalently bound or whether it is bound to the hydrophobic region of the glycophorin by non-covalent Two experimental methods have been described recently which should help the analysis of phospholipids. Details of a high-performance liquid chromatographic method for the rapid separation of phospholipids have been published,55and hectorite clay matrices have been used to stabilize phospholipid bilayers so that their vibrational spectra can be The bilayers are incorporated into the clay to form ultra-thin, self-supporting films about 25 pm thick, and although some regions of the spectrum are masked by vibrations due to the clay, vibrations due to both the phosphoryl head-group and the acyl chain can be observed. 5 Phosphonates Few papers have appeared during the past year which have dealt with naturally occurring phosphonates. A diacylglyceryl ester of 2-aminoethylphosphonic acid (17)

+NH,CH,CH,PO,H’ (17)

has been isolated from bovine liver,57while a ceramide 2-aminoethylphosphonatehas been obtained from the fungus Pythium proZatum.s8 In the presence of certain divalent metal ions, pyridoxal will catalyse the non-enzymic transamination and dephosphonylation of 2-amino-3-phosphonopropionicacid (1 8) (see Scheme 6).58 Pyridoxamine and alanine are formed in this reaction, together with orthophosphate, which is formed in amounts greater than the amount of pyridoxal originally added. Presumably a S c h 8 base that is chelated to a metal ion (19) is formed in the first instance; this undergoes prototropic modification to (20). As (20) is a P-XYZ system,60it can break down with cleavage of the C-P bond. Di-isapropyl phosphite reacts with aliphatic aldazines (21) to give isolable monoaddition products (22). Hydrogenation of the latter over Raney nickel, followed by hydrolysis, affords 1-aminophosphonic acids in high yields (Scheme 7).61The latter have also been prepared in high yield by hydrolysis of the adduct obtained by treating 00-diethyl 1-(N-ethoxycarbony1imino)-1-thioethylmethylphosphonate(23) with methylmagnesium iodide.62 53 54 55

56 57 58 59 60 61

62

D. M. Segal, E. A. Padlan, G. H. Cohen, S. Rudikoff, M. Potter, and D. R. Davies, Proc. Nat. Acad. Sci. U.S.A., 1974, 71, 4298. I. M. Armitage, D. L. Shapiro, H. Furthmayr, and V. T. Machesi, Biochemistry, 1977,16,1317. W. S. M. Geurts van Kessel, W. M. A. Hax, R. A. Demel, and J. de Gier, Biochim. Biophys. Acta, 1977, 486, 524. R. C. Spiker, jun., T. S. Pinnavaia, and I. W. Levin, Biochim. Biophys. Acta, 1976, 455, 588. S. Hasegawa, M. Tamari, and M. Kametaka, J. Biochem. (Japan), 1976, 80, 531. M, K. Wassef and J. W. Hendrix, Biochim. Biophys. Acta, 1977, 486, 172. A. E. Martell and M. F. Langohr, J.C.S. Chem. Comm., 1977, 342. V. M. Clark and D. W. Hutchinson, Progr. Org. Chem., 1968, 7 , 75. M. Hoffmann, C. Wasielewski, and J. Rachon, Chimia (Switz.), 1967, 30, 187. W. J. Stec and K. Lesiak, J . Org. Chem., 1976, 41, 3757.

140

Organophosphorus Chemistry

O ,":

HOCHz&eo CHO

Scheme 6 0

It

+ HP(OPri),

RCH=N-N=CHK

I_)

(21)

/

RCH-NH-NH-CHR

I

O=P(OPr'),

i, ii

(22)

RCHPO,H,

'NH, C1-

E t 02CN=C

/

Me

SEt +

ii, iii f

I

NH,-C-PO,H-

I

Me

'P(OEt)l

//

0

(23) Reagents: i, Ha-Raney Ni; ii, H&+; iii, MeMgI

Scheme 7

Phosphates and Phosphonates of Biochemical Interest

141

6 Oxidative Phosphorylation As has been mentioned in Section 1, a new development in the field of oxidative phosphorylation has been the discovery that both reduced lipoic acid and unsaturated fatty acids are involved in ATP synthesis in mitochondria, E. coli, and Halobacterium h a l ~ b i u m 63 . ~Oleic , acid is the most effective fatty acid, and both oleoyl-Slipoate (24; R=C,5H2&and oleoyl phosphate (25;R= C15H20)maybeinvolvedinthe synthesis of ATP. Nothing is known at the present time about the redox system which results in the synthesis of the oleoyl lipoate (24; R = C15H29); however, sulphydryl groups have been suggested as intermediates in both oxidative 65 and photosynthetic 6 6 phosphorylation for some years. One scheme 65 appears to be particularly relevant. The key reaction in this is the formation of a sulphenyl carboxylate (26) arising from the reaction of a carboxylate residue with a -S-Sgroup. The sulphenyl carboxylate reacts with orthophosphate to give an acyl phosphate (25), which can transfer its phosphoryl group to ADP. An adaptation of this scheme is shown in Scheme 8, where A is an oxidizing and BH2is a reducing agent or group. Presumably, further experimental investigation will reveal the nature of these groups in the case of the synthesis of (24). From ii study of substrate binding, it has been concluded that, during oxidative phosphorylation in beef heart submitochondrial particles, ATP is formed at one site but is not released until ADP and inorganic phosphate bind at a second site, activating the membrane-bound A T p a ~ e The . ~ ~ addition of 2,4-dinitrophenol causes a change in the kinetic parameters of the overall oxidative phosphorylation reaction, which may indicate that there is an energy-linked step in the binding of the ADP and orthophosphate to the submitochondrial complex 6 8 and that inorganic phosphate may bind Reviews have been published in the past year on the uncoupling of oxidative phosphorylation 7 0 and on the soluble, proton-linked ATPase of mitochondria. 71 64s

7 Enzymology Enzyme Mechanisms.-Triose phosphate isomerase has been a popular enzyme recently, having been the chief example quoted in two reviews on perfection and efficiency in enzyme catalysis72g73 and the subject of seven successive papers in one including one on the evolution of enzyme function and the issue of Bi~chernistry,~~ development of catalytic efficiency. During glycolysis in muscle, fructose 1,6-bisphos63

64 65

66 67 68

69 70

71 72

7s

74

D. E. Griffiths, R. L. Hyams, and E. Bertoli, F.E.B.S. Letters, 1977,74, 38; M. D. Partis, R. L. Hyams, and D. E. Griffiths, ibid., 1977,75,47; D. E. Griffiths, R. L. Hyams, and M. D. Partis, ihid., 1977,78, 155; D. E. GrifFiths, R. L. Hyams, E. Bertoli, and M. Carver, Biochem. Biophys. Res. Cornm., 1977, 75, 449. T. Weiland and E. Bauerlein, Angew. Chem. Internat. Edn., 1968, 7, 893; E. Bauerlein and R. Keihl, F. E.B.S. Letters, 1976, 61,68. W.S. Allison and L. V. Benitez, Proc. Nut. Acad. Sci. U.S.A., 1972, 69, 3004. R. H. Vallejos and C. S. Andreo, F.E.B.S. Letters, 1976, 61,95. J. Rosing, C. Kayalar, and P. D. Boyer, J . Biol. Chem., 1977, 252, 2478, 2486. C. Kayalar, J. Rosing, and P. D. Boyer, Biochem. Biophys. Res. Comm., 1976, 72, 1 1 53. S. M. Schuster, G. D. Reinhart, and H. A. Lardy, J . Biol. Chem., 1977, 252, 427. W. G. Hanstein, Biochim. Biophys. Acta, 1976, 456, 129. 1. A. Kozlov and V. P. Skulachev, Biochim. Biophys. Acta, 1977, 463, 29. J. R. Knowles and W. J. Albery, Accounts Chem. Res., 1977, 10,105. W.J. Albery and J. R. Knowles, Angew. Chem. Internat. Edn., 1977, 16,285. W.J. Albery, J. R. Knowles et al., Biochemistry, 1976, 15, 5601 and subsequent papers.

Organophosphorus Chemistry

1 42

q, +

HS

(24)

+ AH,

A

s-s

SH

-r-r s-s

SCOR

+ RCo2-

’

HS =F+=

I

SOCR

II

0 (26) 0

HS

I SOCR

+ H,PO,

/I + RC-0-P

-T_

SOH

II

(26)

0 Il/H

‘OH (25)

0

-+ 5 HS

HS

+ B€12 ===+

0

II

RC-0-P

SOH 0 ll,OH

‘OH

+ B + H,O

SH

+ ADP

Tc_ ATP + RC0,H

Scheme 8

phate is cleaved into dihydroxyacetone phosphate (27) and glyceraldehyde 3-phosphate (28). The latter is converted, after several steps, into phosphoenolpyruvate, which in the presence of pyruvate kinase can phosphorylate ADP to ATP. There would be an evolutionary advantage for animals which possess an enzyme capable of converting (27) rapidly into (28). The greater amount of ATP that would arise from degradation of (28) in the glycolytic pathway could be used for effecting rapid contraction of muscles, thus helping both the hunters and the hunted to move. Triose phosphate isomerase is just such an enzyme, as it can rapidly convert (27) into (28), and kinetic studies 74 indicate that this enzyme is almost the perfect catalyst for this reaction. The chemical steps in this process have been elucidated, and are shown in Scheme 9. There is an essential carboxylate group at the active site which removes a proton from C-1 of (27) to generate a cis ene-diol, and the carboxy-group then transfers the same proton to C-2 of this ene-diol, generating (28). Lysine and histidine residues are also present in the active site of the enzyme, and when protonated these residues can form hydrogen bonds with the carbonyl group of (27), facilitating the removal of the proton from C-1. The protonated carboxy-group at the enzyme active

Phosphates and Phosphonates of Biochemical Interest

CH,OPO,H,

W

143

CH, OPO,H,

CH20P0, H,

site can also exchange hydrogen with the solvent, and hence hydrogen isotopes can be incorporated into both (27) and (28) from the solvent. Phosphoroglycerate kinase catalyses the transfer of a phosphoryl residue from 1,3bisphosphoroglycerate (29), a constituent of the glycolytic pathway, to ADP. It had been postulated that an intermediate in this reaction was a phosphoryl enzyme in which the phosphoryl group was attached to the y-carboxy-group of a glutamyl residue.76Recent however, show that the ‘phosphoryl enzyme’ contains a stoicheiometric amount of (29), and hence is probably a tightly bound (but not covalently linked) complex of the kinase and (29). The epirneric specificity of phosphofructokinase, an enzyme that has recently been purified by affinity chr~matography,~~ has been tested, using substrate analogues. ’* CH,OPO,H,

I I

HCOH CH,OPO, H,

€I0

CH,@H OH

(29)

OH (33) 75 76

77 78

A. Brevet, C. Roustan, G. Desvages, L.-A. Pradel, and N. van Thoai, European J. Biochem., 1973, 39, 141. P. E. Johnson, S. J. Abbott, G. A. Orr, M. SBrnCriva, and J. R. Knowles, Biochemistry, 1976,15,

2893.

C . S. Ramadoss, L. J. Luby, and K. Uyeda, Arch. Biochem. Biophys., 1976, 175, 487. T. A. W. Koerner,jun., R. J. Voll, A. L. E. Ashour, and E. S. Younathan, J . Biol. Chem., 1976, 251,2983.

144

Organophosphorus Chemistry

The kinetic parameters for the interaction of this enzyme with the 6-phosphates of D-fructose (30), D-psicose (31), D-tagatose (32), and L-sorbose (33) show that an (S)configuration at C-3 and an (R)-configuration at C-5 were essential for effective binding of the substrates to the enzyme, but the configuration at C-4 was unimportant. A new synthesis of D-psicose 6-phosphate from (30) was developed during this work. The conversion of (30) into 1,2,3,4-di-O-isopropylidene@-D-psicofuranose79 was followed by phosphorylation with diphenyl phosphorochloridate and removal of the protecting groups.78 Fructose 6-sulphate has been prepared by the direct sulphurylation of (30) with pyridine-sulphur trioxide.80The 6-sulphate was selected by two successive enzymic reactions from the mixture of isomers produced in this reaction. First the 6-sulphate was converted by phosphofructokinaseinto fructose 1-phosphate 6-sulphate, which was isolated and purified by ion-exchangechromatography. Treatment of this intermediate with fructose 1,6-bisphosphatase removed the phosphoryl group at C-1, leaving pure fructose 6-sulphate. The latter was a poor substrate for phosphofructokinase, even though the proportion of a- and B-anomers was the same as is found with fructose 6-phosphate. Thus the phosphoryl group appears to play a part in deciding the correct conformation of the active site-substrate complex for phosphofructokinase. An AMP-sensitiveelectrode has been developed which consists of AMP deaminase and an ammonia-sensitiveelectrode.81This electrode has been used to make direct binding measurements on the allosteric interaction between AMP and fructose 1,6bisphosphatase, as it can distinguish between bound and free AMP. 82 Four binding sites with the same binding constants were observed, which is consistent with the suggestion that the enzyme possesses four identical subunits. During the enzymic synthesis of carbamyl phosphate (34), two molecules of ATP are involved for every molecule of (34) that is synthesized. One molecule of ATP reacts with bicarbonate to form a mixed anhydride of orthophosphoric and carbonic acids, while the second molecule of ATP phosphorylates the carbamate once it is formed.83The half-life of the mixed anhydride is short (two minutes or less), but it can be trapped chemically, and moreover, la0is transferred from bicarbonate to orthophosphate during this reaction. PIP6-Diadenosine 5’-polypentaphosphateis an inhibitor of the enzyme from E. coli, while the equivalent diadenosine pyro- and polyhexa-phosphates are not. It has been suggested that the two molecules of ATP and the bicarbonate bind at the active site of the enzyme as shown in (35). Once the enzyme-bound mixed anhydride has been formed, this reacts with glutamine or ammonia to generate the enzyme-bound carbarnate, which is finally phosphorylated by the second molecule of ATP (Scheme 10). Oxovanadium(rv) [VO2+]and vanadium(v) [VO 3-] ions are potent competitive inhibitors of alkaline phosphatase from E. c ~ l iand , ~ oxovanadium(rv) ~ ions can also R. F. Brady, jun., Carbohydrate Res., 1971,20,1970; R. S . Tipson, R. F. Brady, jun., and B. F. West, ibid., 1971, 16, 383. T. M. Martensen and T. E. Mansour, J. Biol. Chem., 1976, 251, 3664. B1 D. S. Papasathopoulos and G. A. Rechnitz, Analyt. Chem., 1976, 48, 862. s2 T. L. Riechel and G . A. Rechnitz, Biochem. Biophys. Res. Comm., 1977,74, 1377. 8 3 V. Rubio and S. Grisolia, Biochemistry, 1977, 16, 321 ; S. G . Powers and A. Meister, Proc. NUT. Acad. Sci. U.S.A., 1976, 73, 3020. s4 V. Lopez, T. Stevens, and R. N. Lindquist, Arch. Biochern. Biophys., 1976, 175, 31. 7B

145

Phosphates and Phosphonates of Biochemical Interest

\\\\\\\\\\\\ -0-0 0AdoOPOPOPO-

I1 II II

0.0 0

\

-0 0AdoOPOPO-

-o,,c,o-

I

I

000

OH

0-0poco-

-0

o-o-

-0POPOPOAdo

(35)

t

-0 0-

1 -0

-0 0-

NH,COOP0,H2 + 2ADP (34)

-0 0-

+

enzyme

Scheme 10

inhibit acid phosphatases from a number of sources.85With water and other ligands these ions can form five-co-ordinate complexes which resemble possible trigonalbipyramidal intermediates formed between these enzymes and a phosphoryl group. These five-co-ordinate complexes might then inhibit the enzymic reactions. Arginine kinase, in the presence of a divalent metal ion, can catalyse the reversible transfer of the terminal phosphoryl residue of ATP to L-arginine. 31PN.m.r. spectroscopy has recently been used to determine the equilibrium constant for this reaction,86 and it appears that high enzyme concentrations favour the formation of phosphoroarginine, an observation which may have physiological significance. 85 86

R. L. Van Etten, P. P. Waymack, and D. M. Rehkop, J. Amer. Chem. SOC.,1974, 96, 6782. B. D. N. Rao, D. H. Buttlaire, and M. Cohn, J . B i d . Chem., 1976, 251, 6981.

146

Organophosphorus Chemistry

Phosphoproteins.-Details of the amino-acid sequences at the phosphorylation sites 88 and they of two proteins involved in glycogen metabolism have been show unusual features. For example, there is an unusually high proportion of hydroxyl side-chainsnear the phosphoserine at one of the phosphorylation sites in glycogen synthetase. The second protein, phosphatase inhibitor-1, regulates protein phosphatases during glycogen metabolism once it has been activated by a CAMP-dependent protein kinase. The phosphorylated site in phosphatase inhibitor-1 is a threonine residue, and this is preceded by the sequence Arg-Arg-Arg-Arg-Pro.8s Another protein that is activated by phosphorylation by a CAMP-dependentkinase is phenylalanine hydroxylase,8Dalthough the site of the phosphorylation has not been determined. In Staphylococcus aureus the transport of P-D-galactosides is mediated by a phosphoenolpyruvate-dependent transferase system which phosphorylates the galactosides and prevents their exit from the cell. Some lH and 31Pn.m.r. studies have shown that the transfer system contains a protein that is phosphorylated on N-1 of a histidine ring, which acts as the phosphoryl carrier.goThe structural assignment was made after considering the similarities in changes in the chemical shift of the 31Psignal from the protein and from 1-phosphorohistidine(36) that occur when the pH is ,CO,H

changed. The other isomer of phosphorohistidine also occurs naturally and, for example, alkaline hydrolysis of the enzyme pyruvate, phosphate dikinase from Bacteriodes symbiosus gives rise to 3-pho~phorohistidine.~~ The phosphorylated histidine residue in this enzyme is also believed to function as a phosphoryl carrier. Galactose 1-phosphate uridylyl transferase catalyses the interconversion of UDPGlc and galactose 1-phosphate with UDPGal and glucose 1-phosphate.92Galactosemia, an inherited disease in humans, is caused by a defect in this enzyme. This defect prevents the metabolism of galactose to glucose and toxic levels of galactose and its metabolites accumulate as a consequence. During this interconversion, a uridylylenzyme intermediate is formed in which the uridylyl residue is bound to the enzyme by a phosphoramidate link.92 a-Chymotrypsin is inactivated when Ser-195 is phosphorylated by di-isopropyl phosphorofluoridate, and the slP n.m.r. spectrum of the inactivated enzyme shows T. S. Huang and E. G. Krebs, Biochem. Biophys. Res. Comm., 1977, 75, 643. P. Cohen, D. B. Rylatt, and G. A. Nimmo, F.E.B.S. Letters, 1977, 76, 182. 89 S. Milstein, J. P. Abita, N. Chang, and S. Kaufman, Proc. Nat. Acad. Sci. U.S.A., 1976, 73, 1591. 90 M. Gassner, D. Stehlik, 0. Schrecker, W. Hengstenberg, W. Maurer, and H. Riiterjans, European J. Biochem., 1977, 75, 287. 9 1 A. M. Spronk, H. Yoshida, and H. G. Wood, Proc. Nut. Acad. Sci. U.S.A., 1976, 73, 4415. 9 % L. J. Wong, K. R. R. Sheu, S. L, Lee, and P . A. Frey, Biochemistry, 1977, 16, 1010. 87

88

Phosphates and Phosphorrates of Biochemical Interest

147

two, pHdependent signals.93These have been ascribed to two slowly interconverting conformational isomers of the phosphorylated enzyme, but these signals may also be associated with the transfer of the phosphoryl residue from His-57 to Ser-195. Acetylcholinesteraseis another enzyme that is inactivated by the phosphorylation of an essential serine residue and recent studies show that the chiral phosphotriester(+)methyl n-butyl4-nitrophenyl phosphate (37) inactivates the enzyme more effectively

(37)

than the ( - )-enanti~mer.~* On the other hand, serum phosphotriesteraseshydrolyse the (-)-enantiomer more rapidly than the (+)-enantiomer. If it is assumed that the phosphorylation of the serine residue takes place with inversion of configuration at phosphorus, then serum phosphotriesterases may play a part in the regeneration of the active form of acetylcholinesterase from its inactive, phosphorylated form. The metabolism of those organophosphorus insecticides which act by destroying acetylcholinesterase has been reviewed.g5 8 Other Compounds of Biochemical Interest The synthesis of isosteric phosphonic analogues of pyrophosphate intermediates in terpene biosynthesis(e.g. geranyl and farnesyl pyrophosphates)was mentioned in last year’s Report.g6The series has now been completed by the synthesis of 5-carboxy-4hydroxy-4-methylpentyl-1-phosphonic acid (38), the isostere of 5-phosphomevalonic acid, as shown in Scheme 11.97The C-P bond in (38) was formed by means of an Arbusov reaction between the ethylene ketal of 5-chloro-2-pentanoneand triethyl phosphite. The Arbusov product (39) was converted into the tertiary @-hydroxy-acid in one step by the addition of acetic acid, the latter reacting as the dianion in the presence of lithium naphthalenide. The ethyl groups were removed from the The bioproduct (40) of this reaction by the action of trimethyl~hlorosilane.~~ synthesis of terpenoid pyrophosphates involves the head-to-tail condensation of isopentenyl pyrophosphate and an allylic pyrophosphate catalysed by prenyl transferase, an enzyme which has now been purified from avian liver.gsThe mechanism of this head-to-tail condensation has been the subject of some speculation, and recent experiments with 2-fluorogeranyl pyrophosphate (41) indicate that this analogue is incorporated into a C , , fluorine-containinganalogue of farnesyl pyrophosphate by an ionization-condensation-elimination sequence rather than by a displacement-elimination reaction.100Squalene synthetase couples two molecules of farnesyl D. G. Gorenstein and J. B. Findlay, Biochem. Biophys. Res. Comm., 1976, 7 2 , 640. N. P. B. Dudman, J. De Jersey, and B. Zerner, Biochirn. Biophys. Acta, 1977, 481, 127. 95 J. J. Menn, J. R. DeBaun, and J. B. McBain, Fed. Proc., 1976, 35,2598. 96 D. W. Hutchinson, in ‘Organophosphorus Chemistry’, ed. S. Trippett (Specialist Periodical Keports), The Chemical Society, London, 1977, Vol. 8, p. 133. 97 V. Sarin, B. E. Tropp, and R. Engel, Tetrahedron Letters, 1977, 351. 98 R. Rabinowitz, J. Org. Chem., 1963, 28, 2975. 99 B. C. Reed and H. C. Rilling, Biochemistry, 1976, 15, 3739. 100 C. D. Poulter, J. C. Argyle, and E. A. Mash, J. Amer. Chem. SOC.,1977, 99, 957. g3

g4

148

Organophosphorus Chemistry

0

CO,H (40)

(3 8) Reagents: i, heat; ii, dil.HaO+; iii, Li'

0 @ --MeCOzH; 03

CO,H

iv, MeaSiCI; v, He0

Scheme 11

pyrophosphate together head-to-head, to generate first presqualene pyrophosphate and then squalene. From a study of analogues of farnesyl pyrophosphate it appears that the C-6-C-7 and C-11-C-12double bonds serve to orient the molecule correctly, so that binding to the synthetase can occur and the methyl groups also play a part in binding the farnesyl residue to the enzyme, presumably by hydrophobic interactions.1o1 The cyclization of polyolefin terpenes occurs readily once they have been converted into terminal epoxides.lo2The tetracyclic diterpenes 3a-and 3p-kaurene have been prepared enzymically from chemically synthesized (R,S)-l4,15-oxidogeranylgeranyl pyrophosphate (42), providing another example of this cyc1i~ation.l~~ Trimethylaluminium can promote the non-enzymic cyclization of the diethyl ester of neryl phosphate (43),presumably via a carbonium ion, to 4-t-butyl-l-methylcyclohexene.104 Two pathways are possible for the acid hydrolysis of N1-phosphorocreatine (44) to orthophosphate. Both pathways involve metaphosphate as an intermediate, but at pH > 1 creatine (45) is the major product, while at pH < 1 creatinine (46)is formed as the major product.lo5This observation has led to the prediction that, in the creatine-kinase-catalysed phosphorylation of ADP by (44),metaphosphate W. N. Washburn and R. Kow,TetrahedronLetters, 1977,1555; P. R. Ortiz de Montellano and A. S. Boparai, Biochem. Biophys. Res. Comm., 1977, 76, 520. l o 2 E. E. van Tamelen, Accounts Chem. Res., 1968, 1, 111. 108 R. M.Coates, R. A. Conradi, D. A. Ley, A. Akeson, J. Harada, S. C. Lee, and C. A. West, J. Amer. Chem. SOC.,1976, 98, 4659. 104 Y.Kitagawa, S. Hashimoto, S. Iemura, H. Yamamoto, and H. Nozaki, J. Amer. Chem. SOC., 1976,98, 5030. 105 G. W. Allen and P. Haake, J. Amer. Chem. SOC.,1976, 98, 4990. 101

Phosphates and Phosphonates of Biochemical Interest

149

f

,yNH2

H3P04 + NHi-Ck..

0

It

NCH,CO,H

I

(45)

.NH,

HO-PNH--C<.-

+.y

I

N-CH2C0,H

0-

I

Me (44)

Me

\ H,PO, +

HzN~N MeN

(46)

is probably the reactive phosphorylating species, and that a proton-donating group must be near the P-N bond in the active-site complex.The phosphorylation will also be facilitated if the phosphoryl group of (44)is bound to the enzyme through two negative charges on phosphoryl oxygen atoms. Polyfunctional aminoglycosidic antibiotics have been modified by an ingenious combination of enzymic phosphorylation and chemical displacement of the phosphoryl group.lo6Thus, kanamycin B can be phosphorylated to its 3’-phosphate (47), using an enzyme from a resistant strain of Pseudomonas aeruginosa. Treatment of (47) with trimethylchlorosilane and hexamethyldisilazanein pyridine converts it into 3’-chloro-3’-deoxykanamycin B. Hydrogenation of the latter over Raney nickel gives 3’-deoxykanamycin B. 108

T. Okutani, T. Asako, K. Yoshioka, K. Hiraga, and M. Kida, J . Amer. Chem. SOC.,1977,99, 1278.

6

150

urganopnosphorus Chemistry

(47) R = 3-acetylglucosyl-1-a

Trimethyl phosphate is a mutagen that functions as an alkylating agent, and it is degraded to dimethyl phosphate. In animals S-methylcysteinelo' is the major metabolite that is excreted in the urine, but nucleic acid bases can also be alkylated by trimethyl phosphate,lo8 and this may be the main reason for the mutagenicity of this phosphate. Trimethyl phosphate is used industrially as a solvent for paints and polymers, and these studies could lead to some restrictions being placed on itsuse.Tris(2,3dibromopropyl) phosphate is used in the United States for flameproofing fabrics. However, this compound has been shown to cause mutations in bacteria.log The mutations are of the base-pair substitution type, and the complexity of the doseresponse curves suggests that at least two different compounds are causing the mutation.llO It is not known at the present time whether these different compounds are metabolites of tris(2,3-dibromopropyl) phosphate or whether they are impurities in the samples tested.

K. Yamauchi, T. Sugimae, and M. Kinoshita, Tetrahedron Letters, 1977, 1199. Yamauchi, T. Tanabe, and M. Kinoshita, J. Org. Chem., 1976, 41, 3691. A. Blum and B. N. Ames, Science, 1977, 195, 17. M. J. Prival, E. C. McCoy, B. Gutter. and H. S. Rosenkranz, Science, 1977, 195, 75.

lo7

la8 K. 109

110

8

Nucleotides and Nucleic Acids BY J. B. HOBBS

1 Introduction The past year has been one of methodological refinement, rather than of innovation. Requirements in polynucleotide sequencing and recombinant work have spurred the synthesis of oligonucleotides of defined sequence. Papers concerning X-ray and lH n.m.r. studies on nucleotides and oligonucleotides have been omitted from this chapter, although a review1 can be recommended to fill the latter deficit. Many studies on metal-nucleotide complexes have also been omitted. Reports of meetings have not been abstracted, but one Symposiumreport deserves particular commendation for its interesting content.a

2 Mononucleotides Chemical Synthesis.-Nucleosides may be conveniently thiophosphorylated by treatment with thiophosphate monoanion in anhydrous DMF at 70 0C.3 Thymidine, treated thus, yields its 5’- and 3’-phosphorothioates in 2:l ratio in a total yield of 50 %, and 2’,3’-ethoxymethyleneadenosinecan be thiophosphorylated in high yield. Under these conditions, monothiophosphate appears to give rise to monothiopyrophosphate, which is probably the phosphorylating agent. However, nucleoside 0-phosphorothioates may also be prepared in similar yields, using the bis(triethylammonium) salt of dithiophosphoric acid in DMF at room temperature. In order to investigatethe mechanism, 02,2’-cyclocytidine(1) was phosphorylated using the same reagent, giving rise to the corresponding 3’- and 5’-phosphorothioates and, by facile cyclization with ring-opening of the cyclonucleoside, 2’-thio-2’-deoxycytidine2’,3’0,s-phosphorothioate (2). Since no trace of the corresponding cyclic phosphorodi-

1 2

3

D. R. Kearns, Progr. Nucleic Acid Res. Mol. Biol.,1976, 18, 91. Special Publication No. 2, Ni4cEeic Acid Res., 1976. D. Dunaway-Mariano, Tetrahedron, 1976, 32, 2991.

151

152

Organophosphorus Chemistry

thioate was found, it was surmized that it is not formed, and that the phosphorylation mechanism consists of monothiophosphoryl transfer from sulphur. Surprisingly, the thiophosphorylation of (1) gives rise to the 3’- and 5’-phosphorothioates in yields of 43 and 5 %, re~pectively.~ It is thought that interaction between the 5’-hydroxy-group and the stereochemically fixed base renders the former less nucleophilic than the 3’hydroxy-group, Such interactions between 5’-substituents and bases in nucleotides have been considered in a recent re vie^.^ A further example of a strained ring being opened by phosphate anion is provided by the preparation of ara-adenosine 3’phosphate by treatment of 2’,3’-anhydro-~-~-lyxofuranosyladenine (3) with phosphate in HMPA.6An alternative approach to the synthesis of nucleoside phosphorothioates employs anilidates. Treatment of 5’-monomethoxytritylthymidinewith an 0-aryl-N-phenyl phosphoramidochloridate generates anilidates of type (4). In the case of the 2-chlorophenyl esters, asymmetric synthesis was observed, Treatment of (4) with sodium hydride in dioxan and carbon disulphide, followed by methyl iodide, generates S-methylphosphorothioatesof type (3,(see Scheme l).’ The conversions involved are completely stereospecific. MMTrO-

MMTrO-

(5)

(4)

Ar = Ph or 2-chlorophenyl; MMTr = monomethoxytrityl Reagents: i, NaH; ii, CS2; iii, Me1

Scheme 1

The majority of newly reported nucleoside 5’-monophosphates have been prepared using phosphorus oxychloride in trialkyl phosphate solution. These include the monophosphates of 2-fluoroadenosine,* 2-amino-6-chloro-9-(~-~-ribofuranosyl)p ~ r i n e bredinin ,~ (6),1° cordycepin (7),119 l2 2’-azido-2’-deoxyadenosine,132’-fluoro2’-deoxycytidine,14 5-iodoa~etarnidomethy1-~~ and 5-methoxymethyl-, 5-benzyloxymethyl-, 5-acetyl-, 5-allyl-, and 5-azidomethyl-2’-deoxyuridine,1gand several N4 5 6

7 8

9

lo 11 l2 l3 l4 l5

l6

E. Bradbury and J. Nagyvary, Nucleic Acid Res., 1976, 3, 2437. T. K. Bradshaw and D . W. Hutchinson, Chem. SOC.Rev., 1977, 6 , 4 3 . R. Mengel and H. Wiedner, Angew. Chem. Internat. Edn., 1977, 16, 317. W. S. Zielinski, Z . J. Lesnikowski. and W. J. Stec, J.C.S.Chem. Comm., 1976, 772. T. P. Zimmerman, J. L. Rideout, G. Wolberg, G. S. Duncan, and G. B. Elion, J. Biol. Chem., 1976, 251, 6757. V. Amarnath and A. D. Broom, Biochemistry, 1976, 15, 4386. K. Mizuno and T. Miyazaki, Chem. and Pharm. Bull. (Japan), 1976, 24, 2248. M. Blandin, J. Carbohydrates Nucleosides Nucleotides, 1976, 3, 341. R. I. Gumport, E. B. Edelheit, T. Uematsu, and R. 1. Suhadolnik, Biochemistry, 1976,15,2804. M. Ikehara, T. Fukui, and N. Kakiuchi, Nucleic Acid Res., 1976, 3, 2089. W. Guschlbauer, M. Blandin, J. L. Drocourt, and M. N. Thang, Nucleic Acid Res., 1977, 4, 1933. R. L. Barfknecht, R. A. Huet-Rose, A. Kampf, and M. P. Mertes, J . Amer. Chem. SOC.,1976, 98, 5041. A. Kampf, R. L. Barfknecht, P. J. Shaffer, S. Osaki, and M. P. Mertes,J. Medicin. Chem., 1976, 19,903.

Nucleotides and Nucleic Acids

153

substituted derivatives of 5-aminomethyI-2’-deoxy~ridine.~~ 9-(/?-~-Xylofuranosyl)guanine (8), when treated with this reagent, gives the 3’,5’-cyclic phosphate as the major product, with some 5’-monophosphate as by-product.ls Other nucleosides have been phosphorylated using more delicate methods ; 5-formyl-2’-deoxyuridine using thymidine kinase,16 6-0-methyl- and 6-0-ethyl-guanosinel 9 and 3,N4ethanocytidine (9) 2o using carrot phosphotransferase with 4-nitrophenyl phosphate as phosphate donor. The ‘stretched-out’ analogue Zin-benzoadenosine (10) has been phosphorylated using pyrophosphoryl chloride.214’-Fluoroadenosine (11) was con-

HovA

OH

HO

OH

(61

HO

OH (9)

(7)

HO

OH OH

OH (10)

(11)

verted into the 2’,3’-O-isopropylidene derivative and phosphorylated using bis(2,2,2trichloroethyl) phosphorochloridate. Removal of the isopropylidene group with acid, and of the trichloroethyl groups with zinc and silver acetate in DMF, afforded the alkali-labile 5’-monophosphate of (11).22The non-glycosidicnucleosideanalogues (12) and (13) were phosphorylated using 2-cyanoethyl phosphate (CEP) and mesitylenesulphonyl chloride. Alkaline deblocking of the products, and successive treatments with acid and sodium borohydride, afford the ‘open-chain’ nucleoside 3’phosphate analogues (14) and (15). Compound (12) is also easily converted into the corresponding 5’-phosphate, using similar methods, and condensation with further (1 2) allows elaboration of the dinucleoside monophosphate (16).23These compounds were prepared in order to examine the effect of the ‘open ring’ on the c.d. spectra, 17 18

19 20

21 22 23

M. S. Edelman, R. L. Barfknecht, R. Huet-Rose, S. Boguslawski, and M. P. Mertes, J . Medicin.

Chem., 1977, 20, 669. G . R. Revankar, J. H. Huffmann, R. W. Sidwell, R. L. Tolman, R. K. Robins, and L. B. Allen, J. Medicin. Chem., 1976, 19, 1026. J. R. Mehta and D. B. Ludlum, Biochemistry, 1976, 15, 4329. M. J. Murphy, E. J. Goldman, and D. B. Ludlum, Biochim. Biophys. Acta, 1977, 415, 446. D. 1. C. Scopes, J. R. Barrio, and N. J. Leonard, Science, 1977, 195, 296. G. R. Owen, J. P. H. Verheyden, and J. G. Moffat, J. Org. Chem., 1976, 41, 3010. S. N. Mikhailov, L. I . Kolobushkina, A. M. Kritzyn, and V. L. Florentiev, Tetrahedron, 1976, 32,2409,.

Organophosphorus Chemistry

154

(12) B = N6-benzoyladenine (13) B = N4-benzoylcytosine

(14) B = Ade (15) B = Cyt

(17) R = H; Z = benzyloxycarbonyl (18) R = PO,H,; Z = benzyloxycarbonyl

which, surprisingly, are very similar to those of the corresponding ribonucleosides. 5’-phosphate (glycinIn a new synthesis of 2-amino-(N-~-ribofuranosyl)acetamide amide ribonucleotide, an intermediate in the synthesis of purine nucleotides), (17) is phosphorylated using CEP and DCC.24Treatment with base removes the cyanoethyl group to afford (18), but when this is treated with acid to remove the isopropylidene group, a mixture of the CC- and B-anomers is formed. Hydrogenolysis affords the anomeric mixture of the desired product. Facile anomerization is also observed on treatment of ribonucleotides containing 5-formyluracil with alkali.25 Phosphoramidates may conveniently be prepared from silyl phosphites and azides, and this has been applied to the construction of 5’-Wphosphoramidate internucleotidic links. Treatment of thymidine 3’-phosphite with bis(trimethylsily1)acetamide and 5’-azido-5’-deoxythymidineaffords (19), after deprotection.26 5’-Azido-5’deoxythymidine and -2’-deoxyadenosine have been 3’-phosphorylated with CEP and DCC, and the latter has been converted into the corresponding 3’-phosphorimidazolidate (20) by treatment with imidazole, triphenylphosphine, and 2,2’-dipyridyl disulphide. Reduction with triphenyIphosphine affords 5’-amino-2’,5’-dideoxyadenosine 3’-phosphorimidazolidate, which cyclizes spontaneously in aqueous solution to give the cyclic 3’, 5’-0,N-phosphoramidate (21). 24

25

26 27

G. Chettur and S. J. Benkovic, Carbohydrate Res., 1977, 56, 75. V. W. Armstrong, J . K. Dattagupta, F. Eckstein, and W. Saenger, Nucleic Acid Res., 1976, 3, 1791. D. E. Gibbs, Tetrahedron L’etters, 1977, 679. D. E. Gibbs and L. E. Orgel, J . Carbohydrates Nucleosides Nircleotides, 1976, 3, 315.

Nucleotides and Nucleic Acids

155

H 0 i

-0

Alkylsilyl groups are useful for protecting hydroxy-functions during the synthesis of nucleosides and nucleotides.28In the presence of acetic acid, fluoride ion removes alkylsilyl groups rapidly and quantitatively, without removing phenyl or 2,2,2trichloroethyl groups, which may be protecting a phosphate moiety or an internucleotidic bond. In the absence of acetic acid, fluoride ion displaces these groups, and in the presence of an alcohol it affords high yields of transesterified phosphof r i e s t e r ~30, ~thus ~ ~ providing a method for changing the group that protects an internucleotidic bond. Nucleoside 3’-phosphotriesters are valuable intermediates for use in ‘triester’ oligonucleotide synthesis, and may be prepared from suitably base- and sugarprotected nucleoside 3’-phosphates by treatment with TPS and alcohols. Optimum conditions for this method have been defined.31The 2-cyanoethyl group, which is frequent1.y used to protect the phosphate function, may be selectively removed, using anhydrous triethylamine and pyridine, without removal of sugar-protecting acetate groups. 2-Hydroxyethyl esters of 5’-ribonucleotides may be prepared by treating the 2’,3’-O-isopropylidene derivative of the nucleoside with 2-chloro-2-oxo-l,3-dioxaphospholan (22) in p ~ r i d i n e ;subsequent ~~ treatment with formic acid gives the desired products. 2’,3’-0,O-(1 -Adamantyl)phosphonates of uridine and of 6-aza-, 5-fluOrO-, and 5-bromo-uridine have been obtained by treating the nucleosides or their 5’-O-acetates with 1 -adamantylphosphonodichloride(23) i n ~ y r i d i n eIn. ~some ~~~~ cases the stereoisomers of the products were separable, and synthesis was found to have proceeded asymmetrically, affording more (R)-isomer than (S). A series of nucleotidyl(5’+N) amino-acid esters (24) has been prepared by coupling the aminoacid ester to the nucleotide, using DCC.35As expected, the phosphoramidates are 28 29

30 31 32

33

3* 35

K. K. Ogilvie, S. L. Beaucage, D. W. Entwistle, E. A. Thompson, M. A. Quilliam, and J. B. Westmsre, J. Carbohydrates Nucleosides Nucleotides, 1976, 3, 197. K. K. Ogilvie and S. L. Beaucage, J.C.S. Chem. Comm., 1976, 443. K. K. Ogilvie, S. L. Beaucage, N. Theriault, and D. W. Entwistle, J. Amer. Chem. Soc., 1977,99, 1277. R. W. Adamiak, M. 2. Barciszewska, E. Biala, K. Grzeskowiak, R. Kierzek, A. Kraszewski, W. T. Markiewicz, and M. Wiewiorowski, Nucleic Acid Res., 1976, 3, 3397. W. S. Zielinski, Nucleic Acid Res., 1976, 3, 1769. M. N. Preobrazhenskaya, S. Y . Mel’nik, D. M. Oleinik, T. P. Nedorezova, K. F. Turchin, E. S. Shapeleva, and P. I. Sanin, Bio-org. Khim., 1976, 2, 627. S. Y . Mei’nik, T. P. Nedorezova, and M. N. Preobrazhenskaya, J. Carbohydrates Nucleosides Nucleotides, 1976, 3, 129. B. Juodka, S. Sasnauskiene, V. Meskenaite, and K. Kadziauskiene, Zhur. obshchei Khim.,1976, 46, 586.

Organophosphorus Chemistry

156

POCl,

I

/O]

c1/p\* 0 R1O,(=CH(R’)N-P-O H

0

11

II I -0

R-CH-CH20-P--o~Ade

I

+NH, HO

OH

HO

OH

(24) B = Ura, Ade, or Cyt; R’ = Me or Et R2 = amino-acid sidechain

readily hydrolysed in acid, with cleavage of the phosphorus-nitrogen bond. Aminoalkyl adenylates (25) have been prepared by reducing the or-carboxylic acid groups of amino-acids and then coupling the resulting amino-alcohols with AMP, using diphenyl phosphorochloridate as the condensing agent.36The compounds bind strongly to isoleucyl tRNA synthetase, and have been used to estimate the free energies of binding for the amino-acyl and AMP portions of the corresponding amino-acyl-AMP derivatives. A number of reports concerning dinucleoside monophosphates have appeared. In the most innovative, a method is described for selection of their diribonucleoside phosphate containing the 3’+ 5‘ internucleotide link from a mixture containing both 2’+5’ and 3‘+5’ links.37It is required that the nucleoside forming the 5’-terminal should be 2-thiouridine or uridine (although the method could probably be extended to cytidine, as well). In the former case, heating a mixture of acetylated s2Up(2’-+5‘)U and sWp(3’+5’)U in DCC and pyridine causes the 2-thiouridine in the 2’ -+ 5’-linked isomer to cyclize to S2,2’-cyclo-2-thiouridine,with breakage of the internucleotidic bond. Deblocking then affords the pure 3’+5’-linked isomer. If the 5’-terminal is uridine, the internucleotidic links are first esterified with t-butyl salicylate and TPS, and the acetylated compounds are then treated with 1,5-diazabicyclo[5,4,0]undec-7ene under fairly mild conditions. The 2’ +5’-linked isomer is selectively cleaved, and deblocking affords UpU. While the chemistry is entertaining, the method seems likely to find rather limited application, but could be significant in the ‘prebiotic’ selection of internucleotide links. A number of 3’ --f 5’4inked dinucleosidephosphates in which the bases are modified with aromatic residues have been prepared: cytidine residues were modified with bisulphite and aniline or 2-naphthylamine to give N4phenyl- and N4-(2-naphthyl)-cytidine,respectively, and guanosine residues were a1kylated with 7-bromomethylbenz[a]anthracene or treated with N-acetoxy-2acetylamin~fluorene.~~ Each dinucleoside phosphate contained only one modified residue, either at the 3’- or the 5’-end. The compounds were tested as model sub36 37 38

J. Flossdorf, R. Marutzky, K. Messer, and M.-R. Kula, Nucleic Acid Res., 1977, 4, 673. M. Sat0 and Y . Mizuno, Chem. and Pharm. Bull. (Japan), 1976,24, 2903. H. S. Brciwn and R. Shapiro, Biochim. Biophys. Acta, 1977, 475, 241.

157

Nucleoticles and Nucleic Acids

strates for venom and spleen exonucleasesand pancreatic RNase: all were cleaved to give the expected products. Micrococcal nuclease was inhibited when the modification occurred in the 3‘-terminal, in some cases. Analogous results were obtained when using DNA that had been modified by the same methods. Dinucleoside monophosphates containing (26), (27), and (28) have been prepared, using standard condensation methods with DCC.39 The constraint of the fixed torsional angle

HO

HO

OH (28)

I

HO

(29)

imposes unusual stacked conformations, which have been investigated by U.V. and c.d. measurements. DinucIeoside monophosphates containing (29),40 and CpA analogues in which the adenosine moiety is 2’-O-methylated or 2’- (or 3’-)aminoacylated, have been prepared,41 the latter as model compounds for investigating ribosome function. Computer analysis of the titration properties of the common homodinucleoside monophosphates has been used to determine overlapping ioniza43 tion constants and intramolecular stacking equilibrium Cyclic Nuc1eotides.-New analogues of CAMP and cGMP that have been reported include 2-fluoroadenosine 3’,5’-monopho~phate,~ 9-j3-D-xylofuranosylguanine 3’3‘monophosphate,18 S-carbamoyl- and 8-carboxy-adenosine 3’,5’-monophosphates4* (prepared from 8-bromo-cAMP, using standard transformations), and a series of 2-substituted-1,N6-ethenoadenosine 3’,5’-monopho~phates,~~ prepared by ring reclosure of (30), which is the product of alkaline hydrolysis of 1,N6-etheno-CAMP. The last-named have useful fluorescent properties, like the parent compound. So, also, have 8-azido-1,W-ethenoadenosine 3’,5’-rnonopho~phate*~(also prepared 39 40 41 42

43

44 45 46

S. Uesugi, J. Yano, E. Yano, and M. Ikehara, J . Amer. Chem. SOC.,1977, 99, 2313. N. Cerletti and C. Tamm, Heterocycles, 1976, 5, 245. L. A. Alexandrova and J. Smrt, Coll. Czech. Chem. Comm., 1977, 42, 1694. N. Ogasawara and Y. Inoue, J. Amer. Chem. SOC., 1976, 98, 7048. N. Ogasawara and Y. Inoue, J. Amer. Chem. Soc., 1976, 98, 7054. T. Naka and M. Honjo, Chem. and Pharm. Bull. (Japan), 1976, 24, 2052. N. Yamaji, Y. Yuasa, and M. Kato, Chem. and Pharm. Bull. (Japan), 1976, 24, 1561. E. K. Keeler and P. Campbell, Biochem. Biophys. Res. Comm., 1976, 7 2 , 575.

158

Organophosphorus Chemistry

from 8-bromo-CAMP by standard methods, as a photoaffinity label) and the 3’3’monophosphate of (lo), prepared by treatment of the nucleoside with trichloromethylphosphonyl chloride and subsequent ring closure with potassium t-butoxide.21 A number of previously reported 8-substituted derivatives of cAMP have been converted into their corresponding N 6,02’-dibutyryl-, N6-monobutyryl-, and 02’monobutyryl-derivatives by treatment with butyric anhydride and controlled deacylation, where necessary, and have been tested for their ability to stimulate thyroid function in mice.47 While no simple generalization could be made, N 6 monobutyryl derivatives were generally more potent than N 6 , 0 2-dibutyryl derivatives. This is not inconsistent with results obtained 011 investigating the ability of the same butyrylated derivatives of cAMP to inhibit m i t o s j ~By . ~ ~correlating the antisymmetric phosphoryl stretching frequency of the cAMP derivatives with its activity, it has been suggested that, owing to the trans fusion of the phosphate and ribose rings, esterification at the 2’-position alters the geometry, the charge distribution, and thus the binding properties of the phosphate group to its Again, studies of the relaxation time following ultrasonic perturbation indicate that two rapidly equilibrating glycosyl conformations exist in cAMP in aqueous solution,49and it seems likely that 2’-O-acylation would disturb this equilibrium, resulting in different binding characteristics. The interaction of cAMP and a given receptor will probably only be correctly understood when the intimate geometry of the receptor is known. Consider, for instance, the chemotactic response elicited in the slime mould Dictyostelium discoideunz by cAMP analogues.6o Compound (31) is as potent as CAMP, and (32) and (33) are also highly aciive, yet (34) is inactive. With respect to modification at the 3’-position, cAMP is far more potent than (35) and (36). The doubly modified compound (37) has about one-hundredth of the activity of CAMP, and, surprisingly, 5’-amino-5’-deoxyadenosine3’-phosphateand adenosine 5‘-0phosphorothioate 0-methyl ester are each about one thousandth as potent as CAMP, showing that a closed cyclophosphate ring is not even a prerequisite for obtaining the chemotactic response. A series of esters of uridine 3’,5’-monophosphate has been prepared by treatment of the free acid or its 2’-O-acylated derivatives with dia~oalkanes.~~ Mixtures of the diastereoisomeric phosphotriester products are obtained, which in some cases are 47 48

49 50 51

G. Cehovic, M. Bayer, and N.-B. Giao, J. Medicin. Chem., 1976, 19, 899. G. Forrest, A. J. T. Millis, and A. P. Whipple, Arch. Biochem. Biophys., 1977, 178, 51. P. Hemmes, L. Oppenheimer, and F. Jordan, J.C.S. Chem. Comm., 1976, 929. J. M. Mato and T. M. Konijn, F.E.B.S. Letters, 1977, 75, 173. J. Engels and J. Hoftiezer, Chem. Ber., 1977, 110,2019.

159

Nucleotides and Nucleic Acids 0

II

AcO

I

(31) (32) (33) (34) (35) (36) (37)

-0 x = 0; Y = s; z = 0 X = NH; Y = 0 ; Z = 0 X = CH2; Y = 0; Z = 0 x = s; Y = 0 ;z = 0 X = 0; Y = 0 ;Z = NH X = 0; Y = 0 ; Z = CH2 X = NH; Y = S; 2 = 0

separable by t.1.c. The X-ray structure of one diastereoisomer of 2’-O-acetyluridine 3’,5’-monophosphate benzyl ester (38) was determined. It was also found that the stretching frequency of the ‘axial’ P-0 bond in the 1,3,2-dioxaphosphorinan-2-0ne (as drawn), which is lower than that of the corresponding ‘equatorial’isomer, correlates reliably with a lower stretching frequency for a band near lo00 cm-l that may be assigned to a P-0-C mode, which is higher in the equatorial isomer. Thus, knowing the absolute configuration of (38) allows the configurationin other separated diastereoisomericpairs to be assigned by inspection of their i.r. spectra. Reducing the reaction temperature, increasing the size of the 2’-substituent, and increasing the stabilization of a carbonium ion formed from substituted phenyldiazomethanes used for alkylation favoured the formation of the ‘axial’ isomer. On treatment of guanosine 2’,3’-monophosphate with ethanol, propanol, or glycerol in the presence of RNase N1,the corresponding 3’-guanylyl esters are formed, in modest yield.52In the last case, subsequent digestion with snake venom phosphodiesterase affords a mixture of D- and g glycerol 3-phosphates in 1 :2 ratio. Affinity Chromatography.-Uridine nucleotides have been immobilized via phosphoramidate linkages by successive treatments of the nucleotide with mesitoyl chloride and with 1,6-diaminoethaneto afford (39), which is then coupled to cyanogen br~mide(CNBr)-Sepharose.~~

I

HO

I

OH

(39) n = 1 or 2

On the basis of inhibition experiments of ribonucleases from Ehrlich ascites (EA) tumour cells by nucleoside 2’(3’),5’-bisphosphates, it has been concluded that these 52 53

F. Tamanoi, T. Uchida, F. Egami, and T. Oshima, J. Biochem. (Japan), 1976, 80, 27. V. N. Shibaev, Y. Y. KUSOV, N. A. Kalinchuk, and N. N. Kochetkov, Bio-org. Khim., 1977, 3, 120.

160

Organophosphorus Chemistry

compounds are well suited as ligands for affinitychromatography for ri bonucleases from these cells.53This appears to be generally true for ribonucleases: certainly agarose-coupled 5’-(4-aminophenylphosphoryl)uridine 2’(3’)phosphate is an effective and specific adsorbent for ribon~cleases,~~57 allowing the separation of RNase and DNase activities. 8-(6-Aminohexyl)aminoadenosine 2’-monophosphates8 and N4-(uamino-a1kyl)cytidine 2’(3’)-rnonopho~phate,~bound to Sepharose, have also been used for this purpose. The latter is conveniently prepared by treating cytidine 2’(3‘)monophosphate with bisulphite and the desired diamino-alkane, to displace the 4-amino-group of cytidine. In an interesting comparative study, a number of derivatives of cAMP in which diamino-alkane chains are attached to C-2, C-6, and C-8of the purine ring have been studied for their ability to stimulate CAMP-dependent protein kinase before and after immobilization on CNBr-Sepharo~e.~~ For the soluble derivatives, the N 6substituted cAMP species were as effective as cAMP itself, and more effective than the 8- and 2-substituted derivatives. The effectiveness of the immobilized N s substituted compounds in retaining protein kinase was little affected by the length of the spacer arm, or the coupling density. 8-(2-Aminoethyl)aminoadenosine 3 ‘ 3 monophosphate, attached to Sepharose, has been used to purify cGMP-dependent protein kinase. * In another comparative study, the influence of the nature of the spacer arm on ligand-binding properties has been examined.61 Several derivatives (40)-(43) of 8(Ado-5’-MP)-8-NH(CH,),NH2 (40) (Ado-5‘-MP)-8-NH(CHz),NHCOCHZNH, (41) (Ado-5’-MP)*8*NH(CH2),NHCO(CH,)2NH,

(4 2)

(Ado-5 ’-MP)*&NHCH,CH(OH)CH2NHCOCH2NH,

(43)

amino-AMP were elaborated, bearing spacer arms of similar length but differing hydrophobicity, and they were attached to CNBr-Sepharose. Binding studies using lactate and alanine dehydrogenases showed that increasing hydrophilicity decreased the strength of the binding interaction. Most studies employing,immobilized nucleotides that have been reported this year 54 55 56

57 58 69

61

E. Egberts, P. B. Hackett, and P. Traub, 2.physiol. Chem., 1977, 358, 475. I. H. Maxwell, F. Maxwell, and W. E. Hahn, Nucleic Acid Res., 1977, 4, 241. 0. Brison and P. Chambon, Analyt. Biochem., 1976, 75,402. R. E. Scofield, R. P. Werner, and F. Wold, Analyt. Biochem., 1977, 77, 152. L. H. Lazarus, C.-Y. Lee, and B. Wermuth, Analyt. Biochem., 1976, 74,138. W,L. Dills, jun., J. A. Beavo, P. J. Bechtel, K. R. Myers, L. J. Sakai, and E. G. Krebs, Biochemistry, 1976, 15, 3724. G. N. Gill, K. E. Holdy, G. M. Walton, and C. B. Kanstein, Proc. Nat. Acad. Sci. U.S.A., 1976, 73,3918. C. R. Lowe, European J. Biochem., 1977, 73,265.

Nucleorides and Nucleic Acids

161

have used coupling via the 8-position 62* 63 or the N6-position64-70of adenosine nucleotides. Kinases 7 0 and dehydrogenases 65 requiring NAD+ as cofactor 7 0 The have been purified on immobilized 65 ADP,63and ATP NADP+-requiring dehydrogenases are conveniently separated on columns of immobilized 2‘,5‘-ADP 62, 7--69 and coenzyme-A-dependent enzymes on 3’,5’-ADP 66 An immobilized derivative of 6-thiopurine ribonucleoside 5’-triphoscolumns.62* phate (44) has been used to purify a micrococcal ATPase.’l 62p

62p

G3p

649

639

S(CH,), CHCONH(CH,),NH(CH,),NH-polymer I I 0

II

0

I1

-o-P--o-P-o-P-o

I

0

It

I

HO

OH (44)

Adenosine triphosphate, when oxidized to its dialdehyde with periodate and condensed with Sepharose-adipic (or sebacic) acid hydrazide, has been used to isolate poly(A) polymerase,72 and also myosin and its fragments from different sources.73 A poly(A)-linked resin has been prepared by condensing 4,4’-diaminodiphenylmethane with periodate-oxidized starch, reducing the resulting Schiff bases with borohydride, diazotizing, and then coupling with the polynucleotide.74 The resulting material may be used to isolate poly(U) sequences. In the purification of an enzyme by affinity elution chromatography, the crude preparation is adsorbed non-specifically on an ion-exchange column, and washing with an appropriate enzyme-specific ligand, e.g. ADP for myokinase, or ATP for creatine kinase, elutes the required enzyme.75 The purification achieved is generally not as impressive as with bound-ligand affinity chromatography, but far better than with conventional ion-exchange techniques. A microassay for cAMP has been devised in which cAMP is bound non-covalently on QAE-Sephadex and infinity elution by protein kinase is used to estimate the amount of cyclic n u c l e ~ t i d e . ~ ~ 3 Nucleoside Polyphosphates Chemical Synthesis.-Di-n-butylphosphinothioyl bromide (45) reacts readily with C.-Y. Lee and C.-J. Johansson, Analyt. Biochem., 1977, 77, 90. C.-Y. Lee, L. H. Lazarus, D. S. Kabakoff, P. J. Russell, jun., M. Laver, and N. 0. Kaplan. Arch. Biochem. Biophys., 1977, 178,8 . e4 R.-A. Walk and B. Hock, European J. Biochem., 1976, 71,25. 65 C. R. Lowe and M. G. Gore, F.E.B.S. Letters, 1977, 77, 247. B6 S. Barry, P. Brodelius, and K. Mosbach, F.E.B.S. Letters, 1976, 70, 261. 67 K. K. Yeung and R. J. Carrico, Analyt. Biochem., 1976, 74, 369. 6s B. Hojeberg, P. Brodelius, J. Rydstrom, and K. Mosbach, European J. Biochem., 1976,66,467. 69 B. Mannervik, K. Jacobsson, and V. Boggaram, F.E.B.S. Letters, 1976, 66, 221. 70 C. S. Ramadoss, L. J. Luby, and K. Uyeda, Arch. Biochem. Biophys., 1976, 175,489. 7 1 F. W. Hulla, M. Hockel, S. Risi, and K. Dose, European J. Biochem., 1976, 67,469. 7 2 M. Grez and J. Niessing, F.E.B.S. Letters, 1977, 77, 57. 73 A. Oplatka, A. Muhlrad, and R. Lamed, J. Biol. Chem., 1976, 251, 3972. 74 S. Venkatesan, H. Nakazato, and M. Edmonds, Nucleic Acid Res., 1976, 3, 1925. 75 R. K. Scopes, Biochem. J., 1977, 161, 265. 713 A. K. Sinha and R. W. Colman, European J. Biochem., 1977, 73, 367. 62

63

162

Organophosphorus Chemistry 0

S

+ - 0 - IIP - O w B

\I1 P-Br

Bun

I

Bun/

-0

HO R R = H or OH; B = Base

(45)

(46)

HO

R

nucleoside 5’-phosphates in pyridine to form adducts of type (46), which are stable even in aqueous ~yridine.?~ It is thought the stability may be due to a hydrogenbonded structure, as illustrated. In the presence of silver salts, however, hydrolysis is very rapid. Treatment with phosphate or pyrophosphate in the presence of silver salts in dry pyridine yields nucleoside di- and tri-phosphates, respectively. If tri-nbutylamine is added, and phosphate is omitted, 3’,5’-cyclic phosphates are obtained in high yield. The method has also been used to prepare the P1,P3-dinucleoside triphosphates (‘cap’ structures) found at the 5’-terminus of eukaryotic mRNA. 78 Nucleoside 5’-5-methyl phosphorothioates are readily prepared by treatment of 2-methylthio-4H-l,3,2-benzodioxaphosphorin 2-oxide (47) with the nucleoside in the

(47) presence of cyclohexylamine,and may be readily converted into 5’-diphosphates and -triphosphates by treatment with iodine in dry pyridine in the presence of phosphate or pyrophosphate, respecti~ely.~~ Yields are only moderate, due to work-up difficulties, but should be capable of improvement. The use of triphenylphosphine and 2,2’-dipyridyl disulphide in preparing phosphoromorpholidates,anilidates, and other condensed intermediates for use in polyphosphate or oligonucleotide synthesis has been summarized.8o Some nucleoside polyphosphates are very conveniently prepared using enzymic methods. For instance, the reaction: ATP

+

pyruvate -+ AMP

+ phospho-en01 pyruvate + phosphate

is catalysed by phospho-enol pyruvate (PEP) synthetase. Not only AMP, but also dAMP, ara-AMP, 2‘- and 3’-O-methyl-AMP, N1- and N 6-monomethyl-AMP,and the 5’-monophosphates of tubercidin (48) and formycin (49) are all substrates for this reaction.*l Since the 8-phosphate that is incorporated comes from PEP, and the yphosphate from the phosphate buffer employed, specific radiolabelling should be 77

7s 18

80

81

K. Furusawa, M. Sekine, and T. Hata, J.C.S. Perkin I , 1976, 1711. T. Hata, I. Nakagawa, K. Shimotohno, and K. Miura, Chem. Letters, 1976, 987. M. Iio, K. Yano, M. Eto, H. Omura, and M. Eto, Agric. andBio2. Chem. (Japan), 1977,41,155. T, Mukaiyama, Phosphorus Sulphur, 1976, 1, 371. D. Johnson, M. MacCoss, and S. Narindrasorasak, Biochem. Biophys. Res. Comm.,1976, 71, 144.

163

Nucleotides and Nucleic Acids

30

HO OH

OH

feasible. Another nucleotide analogue, 8-bromoinosine 5'-diphosphate, is a phosphate acceptor for nucleoside diphosphate kinase, affording the triphosphate.82 With regard to specific radiolabelling, two enzymic methods have been described for preparing [LX-~~PIATP. In the firstYa3 adenosine 3'-phosphate is phosphorylated at the 5'-position, using [Y-~~P]ATP and polynucleotide kinase, and the 3'-phosphate is then removed with nuclease PI (Penicillium citriizum), which specifically cleaves 3'phosphate esters. In the [Y-~~PIATP is used as a substrate for adenosine kinase. The intermediate[32P]AMPproduced in each procedure is further phosphorylated to the triphosphate, using myokinase and pyruvate kinases3 or creatine phosphokinase 84 to afford [E-~~PIATP. Samples of [!?-32P]ATP and [p-32P]GTPhave been prepared by phosphorolysis of poly(A) or poly(G) by polynucleotide phosphorylase, using H332P04,isolating the [%32P]ADPor [%32P]GDPproduced, and using these as substrates for 3-phosphoglyceratekinase in the presence of 1,3-diphosphoglycerate (Glynn and Chappell's procedure).85 An ingenious method for detecting the transfer of the terminal phosphate of ATP in ATP-coupled enzyme reactions has been devised.86If an enzyme becomes reversibly phosphorylated, and the /?-phosphateof the bound ADP is free to rotate, an isotopic label in the terminal oxygen bridge will become scrambled between three oxygen atoms (Scheme 2). In order to demonstrate the formation of a complex 0

ll Enz :AMP-0-P-*0-P*O-0 I

"0

II

:X

* Enz :AMP-O-P-*O-

-0 XI

0

'

ll

-0

*O

II

p-X

*/ \*

-0

0-

jlscrarnbling

+o

*o

I1 II E m : AMP-O-PLO-P-*O-:X I - *oI '0 +

'0

T-

II Enz :AMP-O-P-+O-

*O

I1

Denotes that a bridge oxygen has been scrambled

Scheme 2 82

83

s4 a5

86

M. Kezdi, L. Kiss, 0. Bojan, T. Pave], and 0. Barzu, Analyt. Biochem., 1976, 76, 361. K. Kihara, H. Nomiyama, M. Yukuhiro, and J.-I. Mukai, Analyt. Biochem., 1976, 75, 672, B. R. Martin and H. P. Voorheis, Biochem. J., 1977, 161,555. K. A. Abraham, Biochem. J., 1977, 161, 615. C.F. Midelfort and I. A. Rose, J. B i d Chem., 1976, 251, 5881.

164

Organophosphorus Chemistry

[glutamine synthetase:ADP: P-XI, in which the terminal phosphate group of ATP becomes transferred reversibly to X (which is a nucleophilicgroup on the enzyme), a sample of ATP that is labelled with l 8 0 in the terminal bridging oxygen was prepared from adenylyl phosphoromorpholidate and 180-labelledphosphate, and it was then incubated with glutamine synthetase. The exchange was analysed by treating the reisolated ATP with acetyl-CoA synthetase (which interchanges the 8- and y-phosphates) and then using it as a substrate for glycerokinase, transferring the terminal phosphate to make dihydroxyacetonephosphate. Treatment of this with base afforded methylglyoxal and phosphoric acid, which was isolated, converted into trimethyl phosphate with diazomethane, and its l 8 0 content then analysed by mass spectrometry. The results indicated that isotopic scrambling between the terminal bridge and the p-phosphate non-bridge oxygens only took place when glutamine was present in the medium. Another elegant approach to the investigation of the stereochemical course of reaction in nucleotides involves the use of nucleoside phosphor~thioates.~~ Diastereoisomers of adenosine 5’-0-( l-thiotriphosphate) (50) have been isolated, and are arbitrarily designated A and B: the absolute configuration is not yet known. Diastereoisomer A is a substrate for DNA-dependent RNA-polymerase, and in the presence of UTP and poly[d(A-T)] as template, the alternating copolymer poly(aA-U), in which the 3’-hydroxy-group of each uridine residue bears a thiophosphate link, is formed. Successive treatments with pancreatic RNase and spleen phosphodiesterase yield exclusively the endo-isomer of uridine 2’,3’-O,O-phosphorothioate (51), a compound of known absolute configuration which is identifiable by its 3 1 P n.m.r. spectrum. No exo-isomer was detected. Since pancreatic RNase breaks phosphodiester links by an in-line mechanism, the internucleotide bond in poly(iA-U) was in the (R) configuration (52), and no racemization had occurred during

(5 ’-Ado)

S-qp-OwAde 1A1

-0

0, OH \

(5 2) 87

\

F. Eckstein, V. W. Armstrong, and H. Sternbach, Proc. Nut. Acad. Sci. U.S.A., 1976,73,2987.

Nucleotides and Nucleic Acids

165

polymerization. The question as to whether nucleophilic substitution at the Ephosphate by the 3’-hydroxy-group of the growing chain takes place directly, involving inversion at the phosphorus atom, or via a phosphorylated enzyme intermediate, with inversion and re-inversion at phosphorus, or by some other mechanism, and whether the mechanism involves ‘in-line’ or ‘adjacent’ displacements at phosphorus, with their stereochemical implications, remains open, and will probably have to await the determination of the absolute configuration of (50A) or (50B). Stereoisomer (50A) is also a substrate for phenylalanyl tRNA synthetase, and h.p.1.c. analysis shows that, during the pyrophosphate exchange reaction that is catalysed by this enzyme in the presence of phenylalanine, the configuration at the a-phosphorus atom is On the basis of this, and other observations, it has been suggested that the formation of 5’-phenylalanyl-AMP involves simple SNZ-type displacement of pyrophosphate by the amino-acid. Adenosine 5’-0-( 1-,2-, and 3-thiotriphosphates) have also been used to investigate the nature of the ATP-binding site in L-phenylalanine :t RNA ligase.* On treatment with DCC, ATP forms adenosine trimetaphosphate (53). Treatment of (53) with a nucleophile opens the ring to give the y-substituted ATP derivative,

providing a high-yield general method for preparing these analogues.9oSuch ATP analogues have been used to investigate the interaction of substrate analogues with DNA-dependent RNA polymerase from Escherichia coli,91 and y-substituted derivatives of GTP have been used to investigate the topology of the GTP-binding site of adenyl c y ~ l a s e . ~ ~ Treatment of thymidine 5’-phosphorodiamidate (54) with pyrophosphate in anhydrous DMF leads to the formation of P1-(thymidine-5’)-P1-aminotriphosphate (55) in good yield.g3The compound is sufficiently stable to be purified on DEAESephadex at low temperature. In acid, conversion into TTP is quantitative, but in ammonia, thymidine-5’-phosphoramidateand pyrophosphate are formed. Treatment with alkaline phosphatase cleaves (55) to the phosphoramidate. Nucleophilic attack takes place very easily: in anhydrous DMF at ambient temperature, (55) is in equilibrium with (56) and pyrophosphate. With a view to investigating its effect on the activity of thymidine kinase, 5-iOdO5’-amino-Z’,5’-dideoxyuridine5’-N-triphosphate (57) has been prepared by treating the amino-nucleoside with trimetaphosphate at pH 9.5.94Below pH 8, first-order 88

89 90

91 92 93

94

F. von der Haar, F. Cramer, F. Eckstein, and K.-W. Stahl, EuropeanJ. Biochem., 1977,76,263. J. Pimmer, E. Holler, and F. Eckstein, European J . Biochem., 1976, 67, 171. D.G. Knorre, V. A. Kurbatov, and V. V. Samukov, F.E.B.S. Letters, 1976, 70, 105. V. W. Armstrong and F. Eckstein, European J. Biochem., 1976, 70,33. T.Pfeuffer and F. Eckstein, F.E.B.S. Letters, 1976, 67,354. A. Simoncsits and J. Tomasz, Tetrahedron Letters, 1976, 3995. M. S. Chen, D. C. Ward, and W. H. Prusoff, J. Biol. Chern., 1976, 251, 4839.

166

Organophosphorus Chemistry 0

0

H

;

I1” I

~

~

o

~

T

0

0

I1 ~-0-P--0-P--0-P--0 Y II 0I 0I

II

NH, I

HO

pT Hi)

(54)

(55)

0

0

li (dThd:5‘)-O-P-O-PI

NH,

ll

I

/I II 0-P-O-P-O-(5’-dThd) 0

I

0-

0 ‘

0

I

NH2

(56)

hydrolysis to the nucleoside and trimetaphosphateis observed, but the compound is appreciably stabilized by the addition of magnesium ions. From the influence of these on the pH-rate profile, it appears that protonation of a secondary phosphate dissociation is the critical step in hydrolysis, and a novel mechanism (Scheme 3) has 0

0

I1

-O-,P-O-P-O-

I

0-

0

II

0 I I H P- N-

0-

0-

(57)

I

7.x

OH

0

II

167

Nucleotidcs and Nucleic Acids

been suggested for this. Thymidine kinase from E. coli is converted into an inactive dimer by (57). New chemical syntheses of guanosine 3’,5’-bis(pyrophosphate) (58) and the bis(methylenediphosphonate)analogue (59) have been reported.95 Attempts to couple phosphate groups directly to deoxyguanosine 3‘,5’-bisphosphate, using DCC, gave deoxyguanosine 3’,5’-pyrophosphate as the major product. A new ‘superactive’ phosphorylating agent was therefore devised, by treating CEP with DCC (to give condensed cyanoethyl phosphates) and then with mesitylenesulphonyl chloride. This mixture is capable of converting 2’-deoxyguanosine 3’,5’-bisphosphate directly into its 3’,5’-bispyrophosphate in 20 % yield. For (58), synthesis starts with 2’-U-(lmethoxyethy1)guanosine.Treatment with CEP and DCC, followed by alkali, affords 0

0

0

I I

0-p-0-

X

I o=p-oI (58) X = 0 ( 5 9 ) X = CH,

0-

the 3’,5’-bisphosphate, and this is treated as described above and subsequently deblocked to afford (58). Compound (59) is best prepared by straightforward treatment of 2’-0-1etrahydropyranylguanosinewith DCC and methylenediphosphonic acid, followed by deblocking with acid. While (58) accumulates in E. coli cells as part of the ‘stringent response’ to amino-acid starvation, it also accumulates in conditions of glucose exhaustion and of uncoupling of oxidative phosphorylation, apparently because the rate of degradation of the nucleotide is reduced.96The level of (58) is thus under at least a dual control system. Since ATP-phosphoribosyltransferase is syngergistically inhibited by (58) and histidine, the biosynthesis of histidine is thus coupled by (58) to the amino-acid levels and to the nutritional state of the ceILg7 Recent work on the role of ATP in muscle biochemistry has been summarized in a short review article.98Oxygen exchange in the myosin-ATP complex in the presence and absence of actin has been investigated by monitoring the incorporation of oxygen from H2l80;since the rate constants for formation and degradation of all intermediates thought to be involved in myosin-catalysedATP hydrolysis are known, the 95 96 97 98

G. N. I3ennett, G. R. Gough, and P. T. Gilham, Biochemistry, 1976, 15, 4623. H. A. de Boer, A. J. Bakker, W. J. Weyer, and M. Gruber, Biochim. Biophys. A d a , 1976,432, 361. D. P. Morton and S . M. Parsons, Biochem. Biophys. Res. Comm., 1977, 74, 172. H. White, Nature, 1977, 267, 754.

168

Organophosphorus Chemistry

measurement of the rate of incorporation of l80into inorganic phosphate gives information on the nature of binding of nucleotide and phosphate in [myosin,ATP] and [myosin,ADP,Pi] c o m p l e x e ~ .One ~ ~ phosphate oxygen is found to exchange rapidly, and two much more slowly than anticipated from the supposed kinetic scheme; it is therefore thought that the enzyme-bound phosphate is not free to rotate. Fluorescence quenching in l,Ns-etheno-ADP and -ATP has been used to follow F actin-myosin binding looand G actin-nucleotide association kinetics.lo1 X-Ray studies of the change in insect flight muscle on binding the imidophosphate (60)show that a structural alteration, thought to be the rotation of the myosin head, takes place in proportion to the amount of nucleotide bound.lo2 Guanosine triphosphate and its imidodiphosphate and methyleiiediphosphonate analogues have been used to investigate the polymerization of tubulin to form microtubules, the role and stoicheiometry of GTP hydrolysis during assembIy,103-106and phosphate exchange in tubulin-bound nucleotides.lo6 Guanosine 5’-cz,&methylenetriphosphate (63), like (61), causes persistent activation of adenylate cyclase, thus arguing against enzyme pyrophosphorylation by guanosine nucleotides as the activating Epinephrine and (61) activate adenylate cyclase synergistically;108 a model that has been proposed to account for this and other observations postulates that the hormone binding to the enzyme switches the enzyme from an inactive to an active form, and also provides the signal whereby bound GTP is h y d r o l y ~ e d When . ~ ~ ~ the nucleotide (61)-(63) is not hydrolysable by the enzyme, persistent activation occurs. Initial tests appear to support this Analogue 0

0

I1 II -o--P-x--P-Y--P-o I -0 -0

0

II

HO

O€I

(60) X = NH; Y = 0; B = Ade (61) X = NH; Y = 0 ;B = Gua (62) X = CH,; Y = 0; B = Gua (63) X = 0 ;Y = CH,; B =. Gua (64) X = NH; Y = 0 ; B = Hyp (65) X = 0; Y = CH,; B = Ade ( 6 6 ) X = CH,; Y = 0 ; B = Ade 99 K. K. Shukla and H. M. Levy, Biochemistry, 1977, 16, 132. loo S. C. Harvey, H. C. Cheung, and K . E. Thames, Arch. Biochem. Biophys., 1977, 179, 391. 1 0 1 F. Waechter and J. Engel, European J . Biochem., 1977, 74, 227. l02 103

104 105

106

107 108

R. S. Goody, J. B. Leigh, H. G . Mannherz, R. T. Tregear, and G. Rosenbaum, Nature, 1976,

262, 613.

J. W. H. Sutherland, Biochem. Biophys. Res. Comm., 1976, 72, 933. R. Weissenberg, W. J. Deery, and P. J. Dickinson, Biochemistry, 1976, 15, 4248. R. Maccioni and N. W. Seeds, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 462. B. Zeeberg, A. Hassid, and M. Caplow, J . Biol. Chem., 1977, 252, 2101. A. M. Spiegel, R. W. Downs, jun., and G . D. Aurbach, Biochem. Biophys. Res. Comm., 1977,

76, 758.

N. Sevilla, M. L. Steer, and A. Levitzki, Biochemistry, 1976, 15, 3493. A. Levitzki, Biochem. Biophys. Res. Comm., 1977, 74, 1154. N. SeviIla and A. Levitzki, F.E.B.S. Letters, 1977, 76, 129.

loo

110

169

Nucleotides and Nucleic Acids

(61) is as active as GTP in binding elongation factor T(EF-T) to the ribosomal A site in protein synthesis, but its inability to be hydrolysed is thought to prevent the release of EF-T and EF-G from the ribosome, preventing translocation and the formation of polypeptide.'ll The newly reported ITP analogue (64) is a potent inhibitor of beef heart mitochondria1 ATPase.l12 Many ATP analogues, including (50), (60),(65), and (66), have been tested as substrates for leucyl-tRNA synthetase from a strain of E. coli. While (50) and (60) were substrates for the enzyme, (65) and (66) were, not surprisingly, inhibitors. The presence of 6-amino- and 2'-hydroxygroups was found to be essential for substrate binding.l13Similar studies have been performed with GDP analogues to determine the structural requirements at the GDP-binding site of EF-Tu.l14 Among other studies with nucleotide analogues worthy of mention, the triphosphate of cordycepin (7)l18l2has been used to investigate the selective inhibition of chromatin-bound poly(A) polymerase in rat liver nuclei 116and the inhibition of DNA synthesisin toluene-treated E. coZi.12The diphosphate of (7) has been used, with other analogues, to define structural requirements in substrates for spinach chloroplast photophosphorylation.116While ara-CTP inhibits DNA synthesis in HeLa cell nuclei,l17 5-iodo-2'-deoxycytidine 5'-triphosphate, prepared by iodinating dCTP [using iodide and thallium(~r~)J, is a substrate for DNA polymerase I and also reverse transcripfase.lls Complementary DNA transcripts containing iodine can thus be prepared for radiolabelling or for labelling with heavy atoms. Similarly, 5-mercuriuridine 5'-triphosphate is a substrate for RNA polymerase (form A) from rat liver nuclei, allowing the introduction of heavy atoms into RNA.llS New fluorescent nucleotide analogues that are likely to be of value in binding studies and for testing defined dimensional changes in enzyme cofactors have been reported. The 5'triphosphate of (lo), prepared from the monophosphate by the phosphoromorpholidate method, is a substrate for several kinases.21 Treatment of 4-thiouridine 5'triphosphate or 6-thioguanosine 5'-triphosphate with (67) results in the formation of

SO,H NHCH,CH,NHCOCH,I I

I

the S-alkylated derivatives.120 Despite the bulk of the fluorescent group thus introduced, preliminary binding studies with glutamate dehydrogenase and RNA polymerase suggest that the analogue is indeed bound, and will function as an environT. Girbes, D. Vazquez, and J. Modolell, European J . Biochem., 1976, 67, 257. S. M. Schuster, R. J . Gertschen, and H. A. Lardy, J . Biol. Chem., 1976, 251, 6705. R. Marutzky, J. Flossdorf, and M.-R. Kula, Nucleic Acid. Res., 1976, 3, 2067. 114 A. Wittinghofer, R. Leberman, and W. F. Warren, F.E.B.S. Letters, 1977, 75, 241. 115 K. M. Rose, L. E. Bell, and S. T. Jacob, Biochim. Biophys. Acta, 1977, 475, 548. 116 K.-S. Boos, J. Lustorff, E. Schlimme, H. Hesse, and H. Strotmann, F.E.B.S. Letters, 1976,71, 111 112

l13

124.

117 118

119 120

E. Wist, H. Krokan, and H. Prydz, Biochemistry, 1976, 15, 3647. R. B. Bhalla, D. Geraci, M. J. Modak, W. Prensky, and S. L. Marcus, Biochem. Biophys. Res. Comm., 1976,72, 513. T. J. C. Beebee and P. H. W. Butterworth, European J . Biochem., 1976, 66, 543. P. Faerber and W. Vizethum, J. Carbohydrates Nucleosides Nucleotides, 1976, 3, 15.

170

Organophosphorus Chemistry

mental reporter group. Terbiumh) ions form highly fluorescent complexes with guanine nucleotides, and this may be used as a sensitive assay for GTP.121 A number of spectroscopic studies on metal-nucleotide complexes have been described, and for these the reader is advised to seek specific reviews. A study of the catalysis of ATP dephosphorylationby divalent transition-metal ions has shown that dephosphorylationis more rapid at metal :nucleotide ratios of 2: 1 than at 1 :1. Ratedependency studies suggest that the reactive complexes are dimers, and a stacked dimer model has been proposed in which a metal ion is co-ordinated to a- and /3phosphates of one molecule and to N-7 of the base of the second molecule with which the first is stacked, thus labilizing the y-phosphate for hydrolysis.122 P1,P4-Di(adenosine-5’)tetraphosphate has been detected in mammalian cells in concentrations which vary inversely with the doubling time.123The steady-state concentration of ATP is unaffected by the doubling time, however. Cell starvation or the inhibition of protein synthesis bypuromycin depressed the level of the tetraphosphate, and it has therefore been speculated that it behaves as a positive growth regulator (‘pleiotypic activator’). The tetraphosphate is readily prepared by treating adenosine 5’-phosphoromorpholidate with ATP. The analogous pentaphosphate is an effective inhibitor for carbamoyl phosphate ~ y n t h e t a s e . ~ ~ ~ Affinity Labelling.-Of a large number of 5-substituted-2’-deoxyuridine 5’-monophosphates prepared as potential inhibitors of thymidylate kinase,16-19 5-formyldUMP was found to be a potent non-competitive inhibitor of the enzyme from calf thymus, and 5-azidomethyl-dUMP irreversibly inactivated both this enzyme and the enzyme from Ehrlich ascites tumour cells. Protection by cofactor addition could only be demonstrated for the latter case, however.16 5-IodoacetamidomethyI-dUMP(68) irreversiblyinactivates the tumour enzyme more rapidly than the calf thymus enzyme, and protection could also be demonstrated in this case; it has therefore been claimed that (68) is isozyme-specific for the tumour enzyme.lS A large number of phosphonate analogues of AMP bearing oxygenated or acylaminomethylated substituents at C-6’ have been tested as potential inhibitors of IH,C-C--N(CH,)~NH

0

I1

I

II

-0-P-0

I

-0

AMP aminohydrolase from rabbit muscle. All were competitive inhibitors for the enzyme, and many were substrates: however, the a-L-tab-epimer of 5’-C-propionylaminomethyl-AMP was found to be a non-competitiveinhibitor, though it showed no A. D. B. Malcolm, Analyt. Biochem., 1977, 77, 532. H. Sigel and P. E. Amsler, J. Amer. Chem. Soc., 1976, 98, 7390. l Z 3E. Rapoport and P. C. Zamecnik, Proc. Nat. Acad. Sci. U.S.A., 1976, 73, 3984. la4 S. G. Powers, 0. W. Grifith, and A. Meister, J . Biol. Chem., 1977, 252, 3558. 121 122

Nucleotides and Nucleic Acids 171 substrate pr0~erties.I~~ N6-(6-Iodoacetamido-n-hexyl)-ATP(69) is an effective affinity label for adenylate kinase from rabbit muscle,126and 6-mercapto-9-B-~ribofuranosylpurine 5’-triphosphate (‘thioinosine triphosphate’) one for brain hexokinase.12’ In the latter case, covalent masking of an essential thiol is the critical step; activity can be restored with thiol reagents. Spectroscopic studies on periodate-oxidized ribonucleosides and ribonucleotides, which are used for affinity columns and for affinity labelling, inter alia, suggest that they exist in solution in hydrated and condensed forms, and not as the free dialdehydes (Scheme 4).12*Periodate-oxidized UDP has been used for affinity labelling of

OH

OH

R = H or PO,H,; B

= Ade, Gua, Cyt, or Ura

Scheme 4

galactosyltransferase from bovine ~ o l o s t r u r nThe . ~ ~inactivation ~ of the enzyme was reversible by nitrogenous bases but became irreversibleon reduction by borohydride, suggesting that Schiff bases are formed, and, on digestion with thermolysin, a polypeptide fragment containing the label linked to a lysine residue was isolated. 8-Azidoadenosine 3’,5’-monophosphate has been employed as a photoaffinity label for cyclic nucleotide binding However, 8-azidoadenosine derivatives are very rapidly reduced to the corresponding 8-aminoadenosine derivatives by 1,2- and 1 ,3-dithiols,131thus emphasizing that any results reported using these compounds for ‘affinity labelling’ should be considered circumspectly, especially when dithiols are known to be present in the reaction medium, and that future workers should perform appropriate controls. Methioninyl 8-azidoadenosine 5’-phosphate and two derivatives of tRNAfMetfrom E. coli bearing photolabile groups have recently been prepared, with a view to labelling methionyl-tRNA synthetase, and preliminary results are en~0uraging.l~~ The enzyme tRNA nucleotidyltransferase is capable of rebuilding the 3‘-CpCpA terminus on to a tRNA molecule in which this end is incomplete, using CTP and ATP as substrates; in fact, it will ‘repair’ a fragment as small as C P C , and ~ ~ will ~ also accept CTP and ATP analogues as substrates, allowing the construction of modified tRNA Thus, 2’-amino-2’-deoxy-CTP can be incorporated as the 3’125 126 127

128 129 130 131 132 133

134

A. Hampton, T. Sasaki, F. Perini, L. A. Slotin, and F. Kappler, J. Medicin. Chem., 1976, 19, 1029. A. Hampton, L. A. Slotin, and R. R. Chawla, J . Medicin. Chem., 1976, 19, 1279. B. Subbarao and U. W. Kenkare, Arch. Biochem. Biophys., 1977, 181, 19. F. Hansske and F. Cramer, Carbohydrate Res., 1977, 54, 75. J. T. Powell and K. Brew, Biochemistry, 1976, 15, 3499. K. Skare, J. L. Black, W. L. Pancoe, and B. E. Haley, Arch. Biochem. Biophys., 1977,180,409. I. L. Cartwright, D . W. Hutchinson, and V. W. Armstrong, Nucleic Acid Res., 1976, 3, 2331. R. Wetzel and D. Soll, Niicleic Acid Res., 1977, 4, 1681. P. Masiakowski and M. P. Deutscher, F.E.B.S. Letters, 1977, 77, 261. A. C. Chinault, J. W. Kozarich, S. M. Hecht, F. S. Schmidt, and R. M. Bock, Biochemistry, 1977, 16, 756.

172

Organophosphorus Chemistry

terminal nucleoside in tRNAPhe from bakers’ yeast, to give a -CPC.~-NH~ terminus. The 2’-amino-group may then be bromoacetylated or mercuriacetylated with the appropriate ester of N-hydroxysuccinimide, to afford tRNAPhe carrying terminal 2’-bromoacetamido- or 2’-mercuriacetamido-cytidylicacid. These molecules are effective affinity labels for tRNA nucleotidyltransferase, and probably block an essential sulphydryl group.135 Russian workers have explored the use of nitrogen mustards for constructing alkylating modifications of nucleic acids. Studies of the rate of ionization of the carbon-chlorine bond in (70) and analogous nucleotide derivatives indicate that

HO

OH

ionization is the rate-determining step in the alkylation of nucleosides and oligonucleotides using this The alkylating moiety has since been introduced into the 3’-terminal nucleotides of oligocytidylic acid 13’ and 5’-phosphorodeoxycytidylyl(3’ -+ 5’)deoxyguanylyl(3’+ 5’)adeno~inel~~ as the 2’,3’-0-{4-[N-(2-~hloroethyl)-Nmet hylamino]}benzylidenegroup. The trinucleotide binds to three GpC sequences in tRNA,v&lfrom bakers’ yeast with alkylation of adjacent n ~ c l e o t i d e s . ~ ~ ~

4 Oligo- and Poly-nucleotides Chemical Synthesis.4f the several new reviews of chemical synthesis of oligonucleotides, the most comprehensive is, fortunately, in English, and readily accessible.139 In the phosphotriester method of nucleotide ~ y n t h e s i s , l ~a~ nucleotide -l~~ chain consisting of sugar- and (where necessary) base-protected nucleoside units linked by 3’+5’ phosphate groups which are further fully esterified to phosphotriesters is elongated stepwise, and the fully protected, apolar products are separated by chromatography after each elongation cycle. In the final stages, all protecting groups are removed, to give the desired product. Refinements in methodology consist in finding sugar-, base-, and phosphate-protecting groups which can be quantitatively and selectively removed from the chain under conditions mild enough to cause no cleavage or transesterification at the internucleotide link, and in finding condensing 135 136

137 138 139

140 141

142

H. Sternbach, M. Sprinzl, J. B. Hobbs, and F. Cramer, European J. Biochem., 1976, 67, 215, N. I. Grineva, T. S. Lomakina, N. G. Tigeeva, and T. A. Chimitova, Bio-org. Khim., 1977, 3. 210. V. K. Rait, G. G. Karpova, and N. I. Grineva, Bio-org. Khim., 1977, 3, 31. N. I. Grineva, G. G. Karpova, L. M. Kuznetsova, T. V. Venkstern, and A. A. Bayer, Nucleic Acid. Res., 1977, 4, 1609. V. Amarnath and A. D. Broom, Chem. Rev., 1977, 77, 183. C. B. Reese, Phosphorus Sulphur, 1976, 1, 245. R. Arentzen and C. B. Reese, J.C.S. Perkin I , 1977, 445. E. Ohtsuka, T. Tanaka, and M. Ikehara, Chem. and Pharm. Bull. (Japan), 1976, 24, 2143; L.A. Alexandrova and J. Smrt, Coll. Czech. Chem. Comm., 1977, 42, 1595, 1686.

173

Nuc1eotide.r and Nucleic Acids

agents which effect phosphate esterification with maximum yield and minimal sidereactions. Laevuliriic acid has been introduced as a 5’-hydroxy-protecting group in the triester Esterscation is effected using DCC, and removal with hydrazine hydrate. The group is quite stable under the conditions usually used in the ‘triester’ method. Other workers have favoured trityloxyacetyl144 and other aryloxyacetyl1419 145 groups as base-labile protecting fuctions for the 5’-hydroxy-group. Mono- and di-methoxytrityl groups are frequently used as acid-labile protecting functions for 5’-hydroxy-groups. Blocking of the internucleotide bond by easily removable groups has received much attention. Phenyl 141and 2- 143 or 4-chloropheny1146s147 groups have been used, but removal by alkali gives an unacceptably high degree of internucleotide cleavage,141 and aqueous ammonia leads to the formation of phosphoramidates, even when using an acidic phenol such as 2-nitro4-t-butylphenol146 to protect the phosphate. Tribromomethyl146 and trichloroethyl 144 groups have been used, and are removed using a zinc/copper couple. However, yields are far from ideal. 8-Hydroxyquinoline has recently been introduced for this purpose, and is removed by anhydrous copper(r1) chloride. Probably the best prospects for clean removal of phosphate-protecting groups lie in the use of fluoride 145 The agents used to effectcondensation between phosphate and hydroxygroups show increasing complexity. The reagent TPS continues to find wide lp2 146 148 but 2,4,6-tri-isopropylbenzenesulphonyl-4(5)-nitroimidazolide (71) 143*14* and mesitylenesulphonyl-1,2,4-triazolide(72) 144 are described as giving 1439

1459

yo2

pri&S02-N -

A v /N

/=I

M e G S 0 2- N e N

Me

Pri

(73) R = Pri (74) R = Me

high yields and cleaner reactions, and tri-isopropylbenzene- (73) and mesitylenesulphonyltetrazoles (74), though decomposing on storage, offer high yields and short reaction times.147The use of benzenesulphonic acid as an alternative to acetic acid for removing mono- and di-methoxytrityl groups has been recommended;le7 less depurination is observed using this reagelit. 143

J. H. van Boom and P. M. J. Burgers, Tetrahedron Letters, 1976, 4875. S. Werstiuk and T. Neilson, Canad. J. Chem., 1976, 54, 2689. W. Adamiak, R. Arentzen, and C. B. Reese, Tetrahedron Letters, 1977, 1431. J. H. van Boom, P. M. J. Burgers, R. Crea, G. van der Marel, and G. Wille, Nucleic Acid Res., 1977, 4, 747. J. Stawinski, T. Hozumi, S. A. Narang, C. P. Bahl, and R. Wu, Nucleic Acid Res., 1977, 4, 353. H. Takaku, M. Kato, and T. Hata, J.C.S. Chem. Comm., 1977, 190.

14* E. I45 R. 146 147

148

174

Organophosphorus Chemistry

The internucleotide link is frequently introduced by coupling the 3’-phosphate of a protected nucleoside to the 5’-hydroxy-group of the 5’-terminal residue of the oligonucleotide chain that is being extended, and the resulting phosphodiester link is subsequently masked by further esterification with the desired protecting Alternatively, the monophosphate of the desired protecting group may be condensed sequentially with the 3’-hydroxy- and 5’-hydroxy-groups of the nucleoside and oligonucleotide which it is desired to 145 A related approach is to perform sequential coupling of the 3’- and 5’-hydroxy-groups to a reactive phosphorus compound which already contains the protecting group for the nucleotide link. For instance, methyl phosphorodichloridite has been used for this purpose.149 The phosphite triester thus formed is then oxidized to the phosphotriester with iodine, and the methyl group is finally removed, using thiophenol in the presence of base, a reaction which involves S Nattack ~ at the methyl group rather than attack at phosphorus. Alternative agents used for this approach have included 2-chlorophenyl phosphorod i ~ h l o r i d a t eand , ~ ~a~mixture of 4-chlorophenyl phosphorodichloridate with triethylamine and N-methylirnidaz~le.~~~ The chief advantage in this approach seems to be rapidity of synthesis. The yields reported are good, but this is frequently the case with oligothymidylates; the true test of an ‘improvement’ is its performance in preparing an oligonucleotide of mixed sequence. A mixture of phosphoryl chloride with imidazole gives rise to phosphoryl chloroimidazolides and phosphoryl tri-imidazolide, and these may be used to phosphorylate an oligonucleotide blocked at the 5’hydroxyl end to give the 3‘-terminal ~ h 0 s p h a t e .Another l~~ method for introducing a 3’-terminal phosphate into oligonucleotides has been devised for the triester synthesis: phosphate is initially attached to the 2‘-hydroxy-group of the 3’-terminal residue by treatment with diphenyl phosphorochloridate. After triester synthesis by the usual methods, unmasking of the terminal 3’-OH group and controlled treatment with ammonia gives the terminal 2’,3’-cyclic phosphate, which is opened with pancreatic ribonuclease to give the 3’-ph0sphate.l~~ While the method is effective, it is not clear why it offers any advantage over, say, initial introduction of phosphate at the 3’-hydroxy-group, using dibenzyl phosphorochloridate, and terminal hydrogenolytic demasking. Dianilidophosphorochloridate has been used to introduce a masked 5’-terminal phosphate into fully esterified TpT.lS4 The nature of intermediates produced on treating mono- and oligo-nucleotides with condensing agents has been investigated by pulsed 31Pn.ni.r. Treatment of 3’-O-acetylthymidylic acid with arylsulphonyl chlorides in pyridine gives a signal ascribed to the monomeric metaphosphate or its pyridinium adduct. In the presence of internucleotidic phosphodiester groups, evidence for the formation of trisubst ituted pyrophosphoryl groups was 0btai11ed.l~~ When DCC is used in the ‘phosphodiester’ W. Daub and E. E. van Tamelen, J . Amer. Chem. SOC.,1977,99, 3526. B. Juodka, W. B. Lunsford, and R. L. Letsinger, Bio-org. Khim., 1976, 2, 1318. 151 P. Cashion, K. Porter, T. Cadger, G . Sathe, T. Tranquilla, H. Notman, and E. Jay, Tetrahedron Letters, 1976, 3769. 152 N. F. Sergeeva, V. D. Smirnov, Z. A. Shabarova, M. A. Prokof’ev, V. F. Zarytova, A. V. Lebedev, and D . G . Knorre, Bio-org. Khim., 1976, 2, 1056. 153 J. H. van Boom, P. M. J. Burgers, and C. A. G . Haasnoot, Nucleic Acid Res., 1976, 3, 2731. * j 4 N. S. Bystrov, V. N. Dobrynin, M. N, Kolosov, and B. K. Chernov, Bio-org. Khim., 1976, 2, 1271. 155 D . G. Knorre and V. F. Zarytova, Nucleic Acid Res., 1976, 3, 2709; V. F. Zarytova, E. M. Ivanova, and A. V. Lebedev, Bio-org. Khim., 1976, 2, 1196. 149 G . 150

175

Nucleotides and Nucleic Acids

synthesis, excess DCC reacts with the internucleotidic links, thus protecting thern.ls5 The amount of DCC to be used for a condensation should therefore allow for this side-reaction. With large excesses of arylsulphonyl chlorides, internucleotidic links are thought to condense, to form tetrasubstituted pyrophosphate~.~~~ Though many papers have appeared during the past year concerned with the methodoIogy of the ‘triester’ synthesis, the ‘diester’ method has many adherents, as several impressive syntheses Diester methods invite the development of solid-phase techniques of oligonucleotide synthesis. In those newly reported, the residue which will form the 5’-terminal of the oligonucleotide is immobilized by attachment to the resin. This may be a polyacrylmorpholide resin treated with ethylenediamine and subsequently esterified with a derivative of trityl alcohol (75),15’ or else a partially hydrolysed poly(N,N-dimethylamidated resin) (76) 158 or a polyacrylamide resin with a 2hydroxyetbyl thioether in the spacer arm (77).159The 3’-hydroxy-group of the termi-

0

Ph

CHZ CH-CONHCHzCH2NHCOCH,01

I

(75) Polymer

1-0

-(5

‘-dThd)

Pll

I

-COO(5’-dT)

-CONMe,

nal nucleoside or nucleotide is linked to a 3’-0-(1-methoxyethyl)-158 or 3’-O-acetyl159 using TPS as condensing agent. Coupling deoxyribonucleoside 5’-pho~phate,l~~v yields are in the region of 80 %, which means that 20 % of the chains in each stage have not been elongated, but d a y become elongated in the next cycle of synthesis, thus giving rise to a ‘failure sequence’. These may be avoided by treating the preparation with acetic anhydride158or phenyl after each coupling stage, to block unreacted 3’-hydroxy-terminals as acetates or phenylurethanes, respectively. The 3‘-hydroxy-group of the ‘success sequence’ is unblocked with or base, 15s according to the nature of the masking group, and the next cycle of synthesis is commenced. Despite the sound concept of the technique for avoidance of failure sequences, it is still necessary to separate an oligonucleotide mixture by ion-exchange R. Padmanabhan, Biochemistry, 1977, 16, 1969; D. V. Goeddel, D. G . Yansura, and M. H. Caruthers, Biochemistry, 1977, 16, 1765; Y . A. Berlin, A. N. Vul’fson, M. N. Kolosov, V. G. Korobko, and S. A. Yakimov, Bio-org. Khim., 1977, 3, 22, and references therein. l F BC. 7 K. Warang, K . Blunfeldt, and K . E. Norris, Tetrahedron Letters, 1977, 1819. l r J 8 W. Hcidmann and H. KGster, Angrw. Chrin. Iiiternnt. Edn., 1976, 15, 547. M. J. Gait, and R. C. Sheppard, Nucleic Acid Res., 1977, 4, 1135.

156

176

Organophosphorus Chemistry

methods, following removal of the terminal from the resin; it would seem a useful idea to block failure sequences with a group which permits extraction with organic solvents or other specific methods of separation. Adenosine 5’-phosphorimidazolidate condenses in aqueous solution in the presence of divalent metal ions to form oligo(adeny1ic acid).160 Using divalent lead ions, as much as 57 % condensation to oligo(A) has been reported; studies on the diand tri-nucleotide with RNase T, show the internucleotide bonds to be mainly 2’+ 5’-linked. The metals most efficientin catalysing condensation occupy an intermediate position in the classification as hard and soft acids and bases, and it is thought that they may co-ordinate to both base and phosphate. On treatment of adenylyl(3’+5’)adenosine 2’,3’-monophosphate with propane1,3-diamine at low temperature for prolonged periods in the presence of poly(U), oligomerization takes place, giving products up to the decamer. The phosphodiester bonds introduced are exclusively of 2’+5’ linkage.161An attractive model has been put forward whereby oligonucleotidescontaining 3’+ 5’ links could have been formed under prebiotic conditions, as the result of a daily heating and cooling cycle.162 Using phosphotriester methods, the oligothymidylate [Tp(Et)]7T has been constructed, in which each internucleotide bond is esterified with the ethyl group. This forms a 1 : l complex with poly(dA) in neutral aqueous buffer, the stability of the duplex being independent of ionic strength. Co-chromatographyof the complex with poly(dA) on Sephadex at various temperatures allows the isolation of fractions of [Tp(Et)],T of differing binding affinity for poly(dA). These are thought to represent diastereoisomers of the phosphates in the oligonucleotide. The enthalpy of binding to poly(dA) was found to be more negative than that of (Tp),T, to the extent of 1.6 kcal per mole of base pairs, and the difference has been ascribed to the contribution of inter-strand electronic repulsion, and intra-strand electronic repulsion in (Tp) ,T, to the forces opposing destabilization of duplex formation. The entropy of binding was more negative for [Tp(Et)],T than for (Tp),T, possibly because of restriction of the rotational freedom of the ethyl groups on formation of the d ~ p 1 e x . l ~ ~ Enzymatic Synthesis.-Novel homopolynucleotides prepared by polymerization of the appropriate nucleoside 5’-diphosphate with polynucleotide phosphorylase include poly(2’-azido-2’-deoxyadenylic acid),13 poly(2’-amino-2’-deoxyadenylic aci~l),l6~ poly(2’-fluoro-2’-deoxycytidylicacid),14 poly(6-O-methylguanylic acid) and poly(6-O-ethylguanylic acid),l9~ 165 poly(3,N4-ethanocytidylic acid),20 and poly(8oxyadenylic acid).ls6 Poly(6-thioguanylic acid) is reportedly obtainable by treatment of poly(2-amino-6-chloropurinylicacid) with hydrogen sulphide at 60 “Cfor 3 days. All have been investigated for their ability to form stable self-structures by base stacking or complexing, or duplex and triplex structures with complementary homopolynucleotides. While enzymes from E. coli or Micrococcus Zuteus have been used for these preparations, the enzyme from the thermophilic bacterium Thermus thermophilus effects efficient polymerization of GDP at 70 “C, and may be a useful 160

H. Sawai, J. Amer. Chem. SOC.,1976, 98, 7037. Uesugi and M. Ikehara, Biochemistry, 1977, 16, 493. D. A. Usher, Science, 1977, 198, 311. R. C. Pless and P. 0. P. T’so, Biochemistry, 1977, 16, 1239. M. Ikehara, T. Fukui, and N. Kakiuchi, Nucleic Acid. Res., 1977, 4, 989. D. B. Ludlum, J. R. Mehta, and R. F. Steiner, Biochim. Biophys. Acta, 1977, 475, 197. J. 0. Folayan and D. W. Hutchinson, Biochim. Biophys. Acfa, 1977, 474, 329.

l61 S. 163

lo4 165

166

Nucleotides and Nucleic Acids

177

alternative if polymerization of nucleoside 5’-diphosphates is sluggish at lower temperatures with enzymes from other sources.167The stability of the duplexes formed by poly(4-thiouridylicacid) with poly(2-aminopurinylic acid) and poly(2,6-diaminopurinylic acid) has been investigated to elucidate the contribution of the thioketomoiety to base-pairing.16*Poly(4-thiouridylic acid) can act in place of mRNA in a protein-synthesizingsystem in citro, and it codes for phenylalanine. Upon irradiation at 330 nm it is photoactivated, and has been used as a photoaffinity label. With 70s ribosomes, ribosomal proteins and 16s RNA are labelled.16vThe duplex formed by mixing poly(2-thiocytidylicacid) with poly(1) is as effectivean interferon inducer as poly(I).poly(C), and is highly resistant to nucleases, and less toxic in rodents than poly(1). p01y(C).~~~ It may thus be the first analogue to offer real therapeutic advantage. In the presence of a suitable alternating copolymer as template, 5-thio- and 5’-methylmercurithio-derivativesof dUTP and dCTP are polymerized by DNA polymerase I, the methylmercurithionucleotidesbeing polymerized more readily than the thion~c1eotides.l~~ The mercurated substrates are potent inhibitors of other nucleases, however. Polymers containing the mercurated nucleotides are selectively retained on mercuriagarose by exchange of the methylmercury group. Polymers containing unblocked thiols tend to form disulphides unless stored with excess thiols. Partially 5-thiolated oligo(C) has been reported to inhibit DNA- and RNA-polymerases from various sources.172 A promising enzymic method for synthesizing oligoribonucleotides of defined sequence is to synthesize a short primer, the 5’-terminal of the desired sequence. by chemical methods, and then to use this as template for the addition of ‘single addition’ substrates (nucleoside 5’-diphosphates that are reversibly blocked at the 2’- or 3’-positiori, of which only one residue is added to the 3’-hydroxy-group of the template) by polynucleotide phosphorylase. Following addition, the 3’-terminal is unblocked and the next addition performed. Thus, 2’(3’)-O-dihydrocinnamoyIribonucleoside 5’-diphosphates are single-addition substrates for the enzyme from T. t h e r m o p h i l ~ sand , ~ ~2’-0-(2-nitrobenzyl) ~ ribonucleoside 5’-diphosphates are substrates for the enzyme from E. c 0 1 i . l ~In ~ the latter case, the protecting group is removed photolytically. 2’-Deoxyribonucleoside 5’-diphosphates are also substrates for the E. coli enzyme, and by juggling the concentration of sodium chloride in the reaction mixture, optimum conditions may be found whereby an oligodeoxyribonucleotide template is elongated by a single residue. This technique has been used to synthesize a t r i d e ~ a m e r Short . ~ ~ ~ tRNA sequence fragments have been prepared, using ribonucleases T, or A to attach guanosine 2’,3’-monophosphate or ribothymidine 2’,3’-monophosphale to the 5’-hydroxy-groups of nucleosides, and extending the resulting dinucleoside monophosphates at the 3’-end, using ribonucleoside 5’167 168 169 170 171 172 173 174

175

Y. Kikuchi, K. Hirai, F. Hishinuma, and K. Sakaguchi, Biochim. Biophys. Acta, 1977, 476, 287. C. Janiori and K.-H. Scheit, Biochim. Biophys. Acta, 1976, 432, 192. I. Fiser, K.-H. Scheit, and E. Kuechler, European J. Biochem., 1977, 74, 447. K. Reuss, K.-H. Scheit, and 0.Saiko, Nucleic Acid Rcs., 1976, 3, 2861, D. C. Livingston, R. M. K. Dale, and D. C. Ward, Biochim. Biophys. Acta, 1976, 454, 9. Y.K. Ho, M. P. Kung, and T. J. Bardos, Biochem. Biophys. Res. Comm., 1976,73,903. Y. Kikuchi, K. Hirai, K. Someno, and K. Sakaguchi, J . Bioclzem. (Japan), 1976, 80, 3 3 . M. Ikehara, S. Tanaka, T. Fukui, and E. Ohtsuka, Nucleic Acid. Res., 1976, 3, 3203. S. Gillam, F. Rottman, P. Jahnke, and M. Smith, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 96.

178

Organophosphorus Chemistry

diphosphates and polynucleotide pho~phorylase.~~~ Unfortunately, these last two methods are bedevilled by modest yields and the constraint of using small quantities, which tend to offset their convenience. If an oligoribonucleotide bearing a phosphate group at the 5’-terminal residue and a 2’-O-(l-methoxyethyl)or 3’-phosphate group at the 3’-terminal residue is incubated with another oligoribonucleotide with free hydroxy-groups at 5’- and 3’-terminals in the presence of T4 RNA ligase and ATP, the 5’-phosphate of the former is bound to the 3’-hydroxy-group of the latter to give the joined oligomer in yields of around 50%. The reaction intermediate consists of AMP linked to the 5’-phosphate of the substrate molecule forming a 5’+5’ pyrophosphate link.177-179 This technique seems likely to find wide application for joining defined-sequence olignucleotides to make larger oligomers. The oligomerization of oligo(dT) or oligo(A) by T4 polynucleotide ligase is a convenient method for generating a series of specific molecular weight markers for use in polyacrylamide gel electrophoresis.180Starting with the decamers, chain lengths up to 250 can be obtained. DNA Ligase from L cells will catalyse the joining of an oligodeoxyribonucleotidebearing a 5’-terminal phosphate to an oligoribonucleotide bearing a terminal 3’-hydroxy-group on a polydeoxyribonucleotide template, e.g. will link oligo[d(pA)] to oligo(A) on poly(dT), but will not effect the reverse ligation, i.e. oligo(pA) to oligo(dA).181 Elegant enzymatic tailoring has been used to construct a series of oligomers of form (dG)n.d(C12AmCz),where rn=1-6, x = 10, n=12+rn+x, and (dG)n.d(CloGmCz),where rn = 1-5, x = 10-30, n = 10 rn x, thus containing defined lengths of mismatched base pairs.la2These have been used to study the effect of the mismatch region on the normal co-operative melting transition and the susceptibility of the mismatch region to attack by single-strand-specifcnucleases. Sequencing.-A useful, comparative short review letter on the latest DNA sequencing techniques may be The Maxam-Gilbert technique of DNA sequencing has appeared in print, at long last!ls4 In this, DNA is treated with reagents which attack specific bases on the chain, Alkylation with dimethyl sulphate produces 7-methylguanineand 3-methyladenineresidues, and labilizes the glycosidic bonds attached to these bases. If the DNA is now heated, at pH 7, the alkylated bases are removed; if dilute acid is used, 3-methyladenineis removed preferentially. Treatment with alkali then cleaves the chains at the points of depurination. Hydrazine attacks thymidine and deoxycytidine residues, fragmenting the bases and leaving ribosyl hydrazones. Treatment with base leads to chain cleavage. In 2M-NaCl, attack on thymidine is suppressed, and the chain breaks only where deoxycytidine has been attached. One takes, therefore, a solution of a DNA fragment of about 100 nucleotides length and divides it into four portions, and treats each portion with

+ +

S. M. Zhenodarova, V. P. Klyagina, 0. A. Smolyaninova, M. I. Khabarova, E. G. Antonovich, and M. A. Prokof’yev, Nucleic Acid. Res., 1977, 4, 2099. 177 J. J. Sninsky, J. A. Last, and P. T. Gilham, Nucleic. Acid. Res., 1976, 3, 3157. 178 0. C. Uhlenbeck and V. Cameron, Nucleic Acid. Res., 1977, 4, 8 5 . 179 A. Sugino, T. J. Snopek, and N. R. Cozzarelli, J . Biol. Chem., 1977, 252, 1732. l a 0 J. H. van de Sande and B. W. Kalisch, Analyt. Biochem., 1976, 75, 509. lS1 E. Bedows, J. T. Wachsman, and R. I. Gumport, Biochemistry, 1977, 16, 223 I . 182 J. B. Dodgson and R. D. Wells, Biochemistry, 1977, 16, 2367, 2374. lA3 M. Szekdy, Nature, 1977, 267, 104. la4 A. M. Maxam and W. Gilbert, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 560.

Nucleotides and Nucleic Acids 179 reagents as described above at concentrations calculated to give one statistical hit per chain. The DNA fragments from each portion are end-labelled with [Y-~~P]ATP, and then separated on polyacrylamide gels. Autoradiography then allows the sequence to be read by straightforward inspection (the ‘ladder’), and up to 100 residues can be sequenced in a single experiment. The other technique of similar power, Sanger’s ‘plus-and-minus’method, has been used to elucidate the complete 5375-nucleotide sequenceof $X 174 DNA;ls5a truly remarkable feat, and one which adds enormously to the knowledge of gene arrangement and control sites. The techniques of DNA sequencing are now so successful that it appears simplest to sequence RNA by preparing the complementary DNA (cDNA) by ‘copy synthesis’and sequence that, using the plus-and-minus method,lse or the ‘ribosubstitution’method,187or end-labelling, exonucleolyticdegradation, and mobility-shift analysis.188The last-named method is well suited for determining the nucleotide recognition sequence at a restriction endonuclease cleavage site,ls9 and is, of course, equally applicable to sequence analysis in RNA A dual-labelling procedure for sequencing picomole amounts of RNA fragments has been described, as follows: the 3’-terminus is tritiated by oxidation with periodate and subsequent reduction with borotritiide, and then the fragment is subjected to partial endonucleolytic digestion by the single-strand-specific S1 nuclease. The unlabelled fragments thus produced, bearing terminal cis-diols, are oxidized with periodate to dialdehydes, which remain at the origin on PEI-cellulose; the labelled oligonucleotides run on this support, and are separated according to chain length, labelled at the 5’-terminus with [y-32P]ATPand polynucleotide kinase, and each is then digested fully with S, nuclease. Determination of the identity of the 32Plabelled nucleotide from each chain gives the sequence.lgl Alternatively, separate limited treatment of the tritium-labelled RNA obtained as above with specific ribonucleases (TI, U2,and A) generates arrays of fragments of lengths corresponding to the distances of the specific cleavage sites from the labelled terminal which are separable, according to their size, on PEI-cellulose. Cleavages with RNase A may be distinguished as ‘uridine’ or ‘cytidine’ cleavages by mobility differences on PEIcellulose at pH 2.6. Collating the data for the three enzymes enables the sequence to be read, not unlike the ‘ladder’.lo2 Restriction-site mapping in DNA may be performed by end-labelling with polynucleotide kinase as above, and subsequent partial digestion with the restriction enzyme. An overlapping series of polynucleotides with a common labelled terminus is thus formed, and size analysis of these affords a restriction map.lg3Polynucleotide kinase may also be used to assay the number of 5’-phosphorylated termini in DNA generated as the result of the action of restriction endonuclease. In the presence of IS5 187

F. Sanger, G. M. Air, B. G . Barrell, N. L. Brown, A. R. Coulson, J. C. Fiddes, C. V. Hutchison, tert., P. M. Slocombe, and M. Smith, Nature, 1977, 265, 687. P. H. Hamlyn, S. Gillam, M. Smith, and C. Milstein, Nucleic Acid Res., 1977, 4, 1123. T. Sekiya, M. J. Gait, K. Norris, B. Ramamoorthy, and H. G. Khorana, J. Biol. Chem., 1976,

251,4481.

C.-P. D. ‘Tu, E. Jay, C. P. Bahl, and R. Wu, Analyt. Biochem., 1976, 74, 73. D. ‘Tu, R. Roychoudhury, and R. Wu, Biochem. Biophys. Res. Comm.,1976, 72, 325. Igo M. Fuke and H. Busch, Nucleic Acid Res., 1977, 4, 339. 19I R. C. Gupta, E. Randerath, and K. Randerath, Nucleic Acid Res., 1976, 3, 2895. Ig2 R. C. Gupta and K. Randerath, Nucleic Acid Res., 1977, 4, 1957. Ig3 H. 0. Smith and M. L. Birnstiel, Nucleic Acid Res., 1976, 3, 2387. lS8

la9 C.-P.

180

Organophosphorus Chemistry

ADP and [p3,P]ATP at pH 7, the unlabelled phosphate exchanges with the label under enzymic catalysis.194Otherwise, the termini generated on cleavage may first be dephosphorylated with alkaline phosphatase, before end-labelling. At pH 8.6 the exchange reaction is suppressed, and only the kinase reaction for determination of 5’-hydroxy termini takes ~1ace.l’~ Sequence determination of purine-rich RNA sequences is difficult, particularly when a cumulative run of guanosine residues occurs. However, if such sequences are treated with kethoxal the guanosine residues are modified, and adjacent cleavage by RNases T, and U, is abolished: RNase U,, which normally cleaves the chain adjacent to purine residues, therefore cleaves only after adenosine residues, greatly facilitating characteri~ation.~~~ Several reports on heavy-atom labelling of polynucleotides have appeared. In the presence of pyridine or 2,2’-bipyridyl, osmium tetroxide binds rapidIy to the 5,6double bond in uridine residues in poly(U) and the pyrimidine residues in DNA, while cytidine in poly(C) reacts more slowly, It is hoped to find conditions in which pyrimidines can be labelled selectively,and allow nucleic acid sequencing by electron microscopy.107Platinum(@-DMSO complexes bind to nucleic acid bases. At pH 7.5, each pyrimidine binds one platinum atom, and each purine two; at pH 6.0, each guanine binds only one. The comparison of electron micrographs obtained after platinum binding at different pH may therefore allow sequencing information to be obtained, conceivably even total sequencing,if complementary strand data are available.lD8Possibly the brightest prospect, however, is offered by platinum-terpyridyl complexes, which bind quantitatively to phosphorothioate residues in the alternating copolymer poly(zA-U), and form 1:l adducts with adenosine and uridine 5’phosphorothioates in which direct platinum-sulphur bonding appears to be involved.lSs Since nucleoside 5’-0-(1 -thiotriphosphates) are substrates for polymerizing enzymes, it may be possible to prepare polynucleotides of unknown sequence containing phosphorothioates by copy synthesis, and to use this reagent to sequence them. Analysis of the mass spectra of dinucleoside monophosphates shows that base fragments and others containing base-sugar and sugar-phosphate moieties occiir in patterns that are characteristic of the sequence.2ooFor instance, preferential formation of the 2’,3’-monophosphate of the 5’-terminal nucleoside occurs in diribonucleoside monophosphates. The construction of computerized pattern-recognition programs has been undertaken to extend the potential sequencing by mass spectrometry to tri- and tetra-nucleotides.201 Other Studies.-Studies on the alkylation of homopolynucleotides by a number of alkylating agents, some of which are potent carcinogens (e.g. ethylnitrosoguanidine, methyl- and ethyl-nitrosourea) indicate that an appreciable degree of alkylation takes L. Berkner and W. R. Folk, J. Biol. Chem., 1977, 252, 3176. W. D. Kroeker and M. Laskowski, Analyt. Biochem., 1977,79, 63. W. Min Jou and W. Fiers, F.E.B.S. Letters, 1976, 66, 77. lg7 C.-H. Chang, M. Beer, and L. G . Marzilli, Biochemistry, 1977, 16, 33. lg8R. F. Whiting and F. P. Ottensmeyer, Biochim. Biophys. Acta, 1977, 474, 334. lg9K. G. Strothkamp and S. J. Lippard, Proc. Nut. Acad. Sci. U.S.A., 1976, 73, 2536. 2oo J. L. Wiebers and J. A. Shapiro, Biochemistry, 1977,16,1044; D. R. Burgard, S. P. Perone, and J. L. Wiebers, ibid., p. 1051. 201 H.-R. Schulten and H. M. Schiebel, Nucleic Acid Res., 1976, 3, 2027 lg4K.

lg5 lg6

Nucleotides and Nucleic Acids

181

place on the phosphodiester link,202-204 particularly at lower pH values, around 5.0. At this pH, the phosphotriesters formed mainly lose alcohol to re-form the phosphodiester, but at higher pH, hydrolysis with chain scission takes place. Alkylation also proceeds at nucleophilic centres on the base and sugar moieties, and the modification likely to cause most damage in vivo has not been defined. Studies involving afiatoxin B1 and benzanthracene derivatives have tended to concentrate on the modification of the bases, to the exclusion of possible effects at the phosphate group, but there is good evidence that the latter should not be ignored.205 5 Analytical Techniques and Physical Methods

A review on spin-labelled nucleic acids has appeared.208Nucleoside triphosphates complex manganous ions strongly, and therefore in a reaction involving changing concentrations of nucleoside triphosphates in solution, the change in the concentration of free manganous ion in solution, which can be monitored by e.s.r., can be used to plot the course of the reaction.207The technique seems to rely on non-precipitation of manganous ph~sphate.~lP Fourier-transform n.m.r. studies on mono- and dinucleotides have been performed.208The pH-dependence of the chemical shifts allows the determination of the pK values of the phosphate dissociations: a 2’hydroxy-group has a marked effect on the secondary dissociation in 3’-mononucleotides. The temperature dependence of 31P chemical shifts in dinucleoside monophosphates and polyribonucleotides has been investigated to monitor changing phosphate ester torsional c ~ n f o r m a t i o nFrom ~ . ~ ~observations ~ of the phosphorusproton Nuclear Overhauser effects in ATP, it is thought that the triphosphate chain folds to allow the terminal phosphorus to interact with intramolecular (probably sugar) protons.a1o Raman spectroscopy has been used to investigate helix-coil transitions in poly(C) at varying pH 211 and poly[d(br6U-A)] at varying temperatures.212 DNA has been tagged with a fluorescent label by condensing acriflavin with the aldehyde groups generated by limited d e p ~ r i n a t i o n ,or ~ ~by ~ direct treatment with fluorescein mercuric acetate.214The former method appears more specific and diagnostically useful.

B. Singer, Nature, 1976, 264, 333. C.-J. Chang and C.-G. Lee, Arch. Biochem. Biophys., 1976, 176,801. 204 J. T. Kusmierek and B. Singer, Biochim. Biophys. Acta, 1976, 442,420. 205 M. Koreeda, P. D. Moore, H. Yagi, H. C. J. Yeh, and D. M. Jerina, J. Amer. Chem. Soc., 1976,98, 6720. 206 H. Dugas, Accounts Chem. Res., 1977, 10,47. 207 J. M. Backer and I. A. Slepnjova, Analyt. Biochem., 1977, 77, 413. 208 P. J. Cozzone and 0. Jardetzky, Biochemistry, 1976, 15, 4853, 4860. 209 D. G.Gorenstein, J. B. Findlay, R. K. Momii, B. A. Luxon, and D. Kar, Biochemistry, 1976, 15, 3796. 210 P. A. Hart, J. Amer. Chem. SOC.,1976, 98, 3735. 211 C. H. Chou and G. J. Thomas, jun., Biopolymers, 1977, 16,765. 212 L. Chinsky, P. Y.Turpin, M. Duquesne, and J. Brahms, Biochem. Biophys. Res. Comm., 1977, 75, 766. 213 J. W. Levinson, A. Desostoa, L. F. Liebes, and J. J. McCormick, Biochim. Biophys. Acta, 1976, 447,260. 214 S . Takeuchi and A. Maeda, Biochim. Biophys. Acta, 1976, 454, 309. 202

203

7

9

Ylides and Related Compounds BY

D. J. H. SMITH

1 Methylenephosphoranes Preparation and Stnrcture.-Dichloromethylenetrisdimethylaminophosphorane (1) can be prepared in situ from bromotrichloromethane and HMPT. The addition of (Me,N),P

+

BrCCl,

-

(Me,N),P=CCI,

+ (Me,N),+Br C1'

(1) p H 0

(Me,N),P-=O

Ph,P=CH,

+ P h , k H $ l C1'

__*.

+ RCH=CCL,

Ph,kH,Cl-

+ Ph,P=CHCl (2)

aldehydes gives high yields of 1,l-dichloroalkenes in a reaction in which the other products are water-so1uble.l Pure chloromethylenetriphenylphosphorane (2) has been isolated, using a transylidation reaction. The carbodiphosphorane (3) was unexpectedly obtained when the salt (4) was treated with methylenetrimethylphosphorane,presumably by rearrangement of the initially formed ~ l i d eThe . ~ phosphonium chloride ( 5 ) can be readily dechlorinated with HMPT to give bi~(triphenylphosphorany1idene)methane.~ A similar reaction with salt (6) gave an ylide which is thermally unstable and which dimerizes to give a water-soluble high-melting solid (7) that displays no ylide reactions.6 The addition of 3 mole equivalent of hydrogen chloride to a solution of the heterocumulene ylides (8) leads to the formation of cyclobutane-l,3-dione derivatives, which, when treated with base, give the bis-ylides (9). Compounds (9) react as expected with p-nitrobenzaldehyde, and can be oxidized with ozone to the cyclobutanetrione derivative (10) (Scheme 1).6 1

W . G. Salmond, Tetrahedron Letters, 1977, 1239.

8

A. Wohleben and H. Schmidbaur, Angew. Chem. Internat. Edn., 1977,16,417. R. AppeI, F. Knoll, H. Scholer, and H.-D. Wihler, Angew. Chem. Znternat. Edn., 1976,15,702. R. Appel, F. Knoll, and H.-D. Wihler, Angew. Chem. Internat. Edn., 1977, 16, 402. H. J. Bestmann, G.Schmid, D. Sandmeier, and L. Kisielowski, Angew. Chem. Internat. Edn., 1977, 16, 268.

a R. Appel and W. Morbach, Angew. Chem. Internat. Edn., 1977,16, 180. 4

5 6

182

Ylides and Related Compounds

Me

183

yMe

Ph,;’

+

‘iph,

I

I

[ Ph,P-C(C1)-PPh3]+C1-

+ (Me,N),P -+

Ph,P-C=PPh,

(5)

c1

I

[Ph,P==C(Cl)PPhJ+

c1-

(6)

+

(Me,N),P

-

+

Ph,P=CPPh,

-+

c1

(7)

Tris(dialky1amino)phosphines react with maleimide at room temperature to give stable crystalline ylides (1 l), which behave normally with benzaldehyde. Ph3i)

>c-c /x-

H \ Ph,P---C=C=X 4 HCl + +,C=C=XClPh, P (8) X := 0 or NPh

#-C

/X-

Ph,; ‘C=C

I I /c=c

-X

0/.”-c\o

\+

I I1

Ph, $ ‘C-C

/c-cI

PPh,

X

c1-

‘bh,

I

YX ‘hh,

ArCH

“c-c/x-

I II

/c-c\,+

X Reagents: i, base; ii,

7

03;

PPh,

iii, ArCHO

Scheme 1

A. N. Pudovik, E. S. Batyeva, Yu. N. (U.S.S.R.), 1975, 45, 2579.

Girfanova, and V. Z. Kondranina, J. Gen.

Chem.

Organophosphorus Chemistry

184

(11)

The electronic distribution and conformations of triphenylphosphinimines and phosphinazines have been discussed in terms of their 13Cand 31Pn.m.r. parametersS (see Chapter 11). Reactions.-AZdehydes. The condensation of optically active aldehydes with phosphonium salts containing a chiral p atom leads to alkenes with no racemization of the asymmetric centres [equation (l)].gThe same ylide is obtained when either (12) or

a

R1CH26Ph,+ R2CH0 R1CH=CHR2 R.and R2 are optically active

(11

(13) is treated with base.lo It may be the (2)-isomer, as shown, since the principal product on condensation with benzaldehyde is (14).

mC0,Me

I

'PPh,

$

A Wittig reaction with the ylide (15) has been used in a synthesis of (+)-lysergic acid.ll C0,Me

@

+ Ph3P<

PhCON

,

C0,Me

(15)

C0,Bu'

CO,But

_j.

\

/

PhCON

Condensation between p-anisaldehyde and (16) gave a 15:85 mixture of the (2)and (E)-isomers. The reaction with the corresponding diethyl phosphonate was T. A. Albright, W. J. Freeman, and E. E. Schweizer, J. Org. Chem., 1976, 41, 2716. P. Salvadori, S. Bertozzi, and R. Lazzaroni, Tetrahedron Letters, 1977, 195. lo R. N. Gedye, K. C. Westaway, P. Arora, R. Bisson, and A. H. Khalil, Canad. J. Chem., 1977,55, 1218. 11 V. W. Armstrong, S. Coulton, and R. Ramage, Tetrahedron Letters, 1976, 431 I . 8

185

YIides and Related Compounds

considerably more stereoselective, giving more than 98 % of the (E)-isomer.12The reaction of (16) with p-methoxyacetophenone produced a low yield of the stilbene, even under forcing conditions. A number of 1-(heteroaromatic)-ly3-butadienes(17) have been synthesized, using allylidenetriphenylphosphoraneand the appropriate aldehyde.ls

5-(2’,2’-Dibromoviny1)uracil (18), prepared using dibromomethylenetriphenylphosphorane, can be transformed into a biologically active acetylene derivative.l* Various hydroxylated stilbenes, e.g. (19), have been obtained as shown.ls

H

+. Ph,P=CBr2

A

OHN+H=cBr2 H (18)

A c O e = P P h ,

-

Me0

+

O

C

I

i

=

C

H

a

MeO(1 9 )

A number of 1-aryl-2-(3’-indolyl)ethylenes(20) have been prepared in good yield from indole-3-~arba1dehyde.l~ 2-Methyl-3-phthalimidopropanalcan be converted into (21), which is hydrazinolysed to the expected amine.I7 The compounds (22) are formed as shown, in moderate yields, as a mixture of cisand trans-isomers.l8 B. G. James, G. Pattenden, and L. Barlow, J.C.S. Perkin I , 1976, 1466. l a B. I. Rosen and W. P. Weber, Tetrahedron Letters, 1977, 151. 14 J. Perman, R. A. Sharma, and M. Bobek, Tetrahedron Letters, 1976, 2427. 1 5 L. Lonsky, W. Lonsky, K. Kratzl, and I. Falkehag, Monatsh., 1976, 107, 685. R. S . Tewari and K. C. Gupta, Indian J. Cltem., 1976, 14B, 419. l7 E. D. Bergmann and Y . Migron, Org. Prep. Proced. Internat., 1976, 8, 75 (Chem. Abs., 1976, 85, 62 587). l* U. Lachmann, H. G. Henning, and D. Gloyna, J. prukt. Chem., 1976,318,489 (Client. Abs., 1976, 85, 108 718). 12

186

Organophosphorus Chemistry

CHO

0 Ph,PCHPhP(OPh), + RCHO --+

I1

Ph,PC=CHR Ph

.

.

+ (PhO),P(O)OH

Ketones. Condensations between the phosphonium salt (23) and alkyl aryl ketones in the presence of methylsulphinylmethanide ion lead to mixtures of (2)-stilbenes and @)-styrenes in stereospecific reactions resulting from dichotomous ylide formation (Scheme 2). The authors have shown that this unusual behaviour is due to the

(23)

I

R

--% A

r

W

Reagents: i, MeSCH2-; ii, ArCOR

II

0

Scheme 2

presence of the ortho-methyl groups in (23).19 The reaction of chalcone with the ylide generated from (2-phenylethyl)triphenylphosphonium bromide gave (24) as trans,trans- and trans,cis-isomersin a ratio of 6: 1. However, the use of the reagent from diethyl (2-phenylethy1)phosphonategave predominantly the trans,cis-product (Scheme 3).20 A series of bicyclo-alkenes21 and strained methylene-bridged bicyclic alkenes, e.g. (29, 2 2 have been prepared, using intramolecular Wittig reactions (Scheme 4). 19 20

21

22

B. G . James and G . Pattenden, J.C.S. Perkin I, 1976, 1476. D. H. Hunter, S. K. Sim, and R. P. Steiner, Canad. J. Chem., 1977, 55, 1229. K. B. Becker, Helv. Chim. Acta, 1977, 60, 68. K. B. Becker, Helv. Chim. Acta, 1977, 60, 81.

187

Ylides and Related Compounds 1

6

1

7

(24)

1 0

Reagents: i,

It

PhNpPh7,; ii, ph/\/P(oEt)’ -

xo *

Scheme 3

(CH, )n

(CH,

Rr

(CH,), a

C

H

zh

- 3

or

n = 1,2, or 3 m - 3,4,or5

Reagents: i, Ph3P; ii, LiOEt-DMF; iii, ButO-

Scheme 4

Phenylcyclobutenediones (26) react with stabilized ylides to give the expected but (26; X=Br) also gave (27), as a result of a transylidation Wittig reaction.24 PPh, II

(26) X = B r o r O M e

I

CO, Me

(27)

Enolizable a-diketones react with stabilized ylides to form the expected products.26 The fist step of the reaction, however, is clearly different from the normal Wittig reaction, since an unidentified, more polar, intermediate, suggested to be the phosphonium salt (28), is rapidly formed. The keto-ester (29) reacts cleanly with methylenetriphenylphosphoraneto afford a high yield of the expected dienyl ether.26 23 24

25 26

H. Knorr, W. Ried, U. Knorr, P. Pustoslemsek, and G. Oremek, Arinalen, 1977, 545. U. Knorr, H. Knorr, W. Ried, and W. Schuckmann, Chem. Ber., 1976,109,3869. K. Inoue and K. Sakai, Tetrahedron Letters, 1976, 4107. P. M. Wege, R. D. Clark, and C. H. Heathcock, J. Org. Chem.. 1976.41 3144.

188

Organophosphorus Chemistry

+ Ph,P=CH,

ButO,C

--+

HDE

ButO,C

(29)

Several 2-vinylaziridines (30) have been prepared by treatment of the corresponding N-substituted 2-acylaziridines with phosphoranes.27Anti-inflammatory agents have been obtained from (31), which was synthesized using a Wittig reaction.28

'2;' -

H

N

+ Ph3P=CHR4

R'

+ MeS

R'

(3 0)

CH=PPh,

__t

(31)

Treatment of cyclopropyl methyl ketone with cycylpropylidenetriphenylphosphorane at room temperature gave the expected product, whereas (32) was obtained from reaction at 65 0C.29

Miscellaneous. Some rearrangements in steroids that are initiated by methylenetriphenylphosphorane have been reported.so Thus 170c-acetyl-A4-oestren-17~-01 gave (33) with a limited amount of ylide. The desired isopropenyl compound could be obtained by protecting the 17B-hydroxy-groupas the silyl ether. 27 28 29

30

D. Borel, Y. Gelas-Mialhe, and R. Vessiere, Canad. J. Chem., 1976, 54, 1582. R. J. Tull, R. F. Czaja, R. F. Shuman, and S. H. Pines, Ger. Offen. 2 462 380 (Chem. Abs., 1977, 86, 189 604).

N. A. Donskaya, T. V. Akhochinskaya, and Yu. S. Shabarov, Zhur. org. Khim., 1976,12, 1596 (Chem. Abs., 1976,85, 176 883). H. A. C. M. Keuss and J. Lakeman, Tetrahedron, 1976, 32, 1541.

189

Ylides and Related Compolcplds

+

(33)

Ph,P=CH,

The stabilized ylide (34) reacts with acyl chlorides to form the compounds ( 3 3 , which, when heated, decompose with loss of triphenylphosphine oxide to form Ph,P=CMCO,

Me

(34)

+

RC-CC0,Me

* 0II PPh, II

A R C Z C C 0 , M e + Ph,PO

KCOCl Ph,kH,CO,Me C1Ph,P=C=PPh,

+

ArCOCl

-+ ArC-Cf+

11

PPh, \-PPh,

+

c1-

Arc-C-PPh, A (36)

C1'

+

0

Ph,PO

methyl acetylenecarb~xylates.~~ In a similar way, bis(triphenylphosphorany1idene)methane reacts with aromatic acid chlorides to form salts which decompose on heating to produce arylethynylphosphonium salts (36).32 A study of the ligand properties of bis(trimethy1phosphoranylidene)methane (37) indicates that it has ambident character.33Thus, the reaction of (37) with [MeAuMe,P=C=PMe,

(37)

Me,P=CH,

+ 2Me-Au-PMe3

+ 2BuLi

+

-

[MeP(CH,),] Li,

(Me,P),C(AuMe),

Me,GeCI

+

2Me,P

Me,P==C(GeMe,), (3 8)

(PMe,)] liberated trimethylphosphine, whereas its reaction with trimethylgallium produced methane. The synthesis of ylides containing methyl-germanium, -tin, and -lead substituents, e.g. (38), has been described.34 Treatment of methylenetrimethylphosphorane with two equivalents of butyllithium, followed by bis(dimethylchlorosily1)methane (39), gave a mixture, as shown 31

32

33 34

H. J. Bestmann and C. Geismann, Annalen, 1977, 282. H. J. Bestmann and W. Kloeters, Angew. Chem. Znternat. Edn., 1977, 16, 45. H. Schmidbaur and 0. Gasser, Angew. Chem. Znternat. Edn., 1976, 15, 502. H. Schmidbaur, J. Eberlein, and W. Richter, Chem. Ber., 1977, 110, 677.

190

Organophosphorus Chemistry

in Scheme 5. However, the addition of (39) to the silylated ylide (40) afforded a thermally stable bicyclic ylide.36

Reagents: i, BuLi; ii, CHz(SiMe2Clz)z (39)

Scheme 5 Me, Me,P=C(SiMe,),

+ (39) -+

(40) Me2

-

The nature of the phosphonium salts obtained from the addition of ylides tofluoroalkenes depends upon whether or not the ylide has an a-hydrogen atom (Scheme6).38 ?h,P=CMe, Ph,P=CHMe

+ F,C=CFCI

+ F2C=CPhPF3

--+

Scheme 6

+

Ph,PC(Me),CF===CFCl FPh36C=C=CPhCF,

I Me

F-

Keto-ylides act as nucleophiles with triazolinediones. Subsequent proton transfer produces the ylides (41).37

(41) R’,RZ = Me or Ph

Cyano-substituted N-methoxypyridinium salts undergo ring cleavage with ethylcarboxymethylenetriphenylphosphorane in dipolar aprotic solvents to yield the alltrans ylides (42).38Cyclic monothiodicarboximides react with resonance-stabilized configuration and ylides to form the corresponding alkylidene lactams having a (2) small amounts (4-14 %) of the alkylidenethiolactams (43).39 35

36

37

38 39

H. Schmidbaur and M. Heinmann, Angew. Chem. Internat. Edn., 1976, 15, 367. D. J. Burton and T. M. Lee, J. Fluorine Chem., 1976, 8, 189. A. Hassnet, D. Tang, and J. Keogh, J. Org. Chem., 1976,41, 2102. J. Schnekenburger, D. Heber, and E. Heber-Brunschweiger, Tetrahedron, 1977, 33, 457. A. Gossauer, R.-P. Hinze, and H. Zilch, Angew. Chem. Internat. Edn., 1977, 16, 418.

GNR

Ylides and Related Compounds

191

+ Ph,P=CHCO,Et

---+M

c

o

(42)

= 2-, 3-, or 4-CN

AT)''

+

0

S

€1

~ PPh,

OMe C10,-

+ Ph,P=CHCO,Me

0

~

J-5+fT;,l

I

R

oR N

e

/ N

I

H. .o'

OMe

I

'o*'~ (43)

Iminophosphoranes are obtained from (44) and ylides (Scheme 7) by a rearrangement that is influenced by substituents and the reaction t e m p e r a t ~ r e . ~ ~ R,C-C(CN),

'.

N

ll

PPh,

I 1 CN Me

+

Ph,P=CCI,

\

(44) R = PhCH,

II

c1

PPh,

Scheme 7

The reaction of dibromides with the bis-ylide (45) gives cyclic phosphoranes that can be used in Wittig reactions.*l Only the 0-alkylated salts (46) are formed when acylmethylenetriphenylphosphoranesare treated with benzyl iodide at 20 "C.They rearrange to the C-alkylated salts on heating.42 The addition of Grignard reagents to a-(dipheny1phosphino)carbonyl compounds leads to alcoholates, which react with methyl iodide exclusively at phosphorus to yield betaines. Diphenylmethylphosphine is eliminated upon addition of strong base to yield isomerically pure alkenes (Scheme 8).43 40

C. Gadreau and A. Fouchaud, Tetrahedron, 1977, 33, 1273.

A. Hercouet and M. Le Corre, Tetrahedron, 1977, 33, 33. 4% N. A. Neomeganov, S. T. Berman, and 0. A. Reutov, Bull. Acad. 41

2737.

43

M. T. Keetz and F. Eibach, Annalen, 1977, 242.

Sci.

U.S.S.R., 1975, 24,

z

0rganophosphorus Chemistry

192 Ph,PCH,CR'

I1 0

0

II

Ph,PMe

+

R'MgX --+ Ph2PCHzCR'R2

I

OMgX

+ CHz=CR1R2 d-Ph,$CH2CR1R2

I

Me

I

dMgX

Reagents: i, MeI; ii KOBut Scheme 8 CH,, (CH2)
0

II

(CH )/cHzBr

*\

+ Ph,P==CHCCH=PPh,

CH,Br

+

__t

'

-

Ph,P=CHCOCH,fiPh,

(45)

+ PhCH,I

Ph,P=CHCOR

+ ,PPh, BrC 'COCH=PPh3

,OCH,Ph

\R1-

Ph,&-CH=C

(46)

Br-

I

CH, Ph Ph,$-CHCR

a

I'

2 Phosphoranes of Special Interest trans-Methyl chrysanthemate is obtained stereospecifically by simply mixing solutions of unsaturated aldehyde (47) and isopropylidenetriphenylphosphorane.44~ 46 A more general approach to chrysanthemic ester analogues is outlined in Scheme 9, C0;Me Me>PPh,

Me

+%0

H

- :<,

,CO,Me

+ 0

~

c9.

3

R4 R5?R2

,CO,Me R'

Scheme 9 44

45

M. J. Devos, L. Hevesi, P. Bayet, and A. Krief, Tetrahedron Letters, 1976, 391 1. A Krief and H. Laszlo. Beln. P. 827 651 (Chem. A h . . 1976, 85, 177 686).

193

Ylides and Related Compounds

in which the cyclopropyl function is obtained by the reaction of an ylide with a blocked unsaturated aldehyde. Treatment of tetraphenylcyclopentadienonewith ethylidenetriphenylphosphorane gave the spiroheptadiene (48)as a mixture of cis- and frans-is~mers.~~ Reactions of Ph

Ph

+ Ph,P=CHMe

> rO

Ph

Ph

Ph

_j

Ph (4 8)

methylene- or cyclopropylidene-triphenylphosphorane with the ketones (49) 4 7 and (50) have been successfully used in the synthesis of rotanes, e.g. (51).

0

& Br

Br

(49)

(5 1)

Hetero-analogues of methylenecyclobutane, e.g. (52), have been prepared by treatment of azetidinones or thiet-3-one with various y l i d e ~ . ~ ~

(52)

X = S or Ph,CHN

The phosphonium salt (53) is converted quantitatively (by potassium hydroxide) into an ylide, which reacts with aldehydes to yield keten dithioacetals5 0 (Scheme 10).

(5 3) Reagents: i, Ph3P; ii, KOH-EtOH; iii, RCHO

Scheme 10 46

47

48 49

50

W. Ried, H. Knorr, and H. Guercan, Annalen, 1976, 1415. L. Fitjer, Angew. Chem. Internat. Edn., 1976, 15, 762. L. Fitjer, Angew. Chem. Internat. Edn., 1976, 15, 763. G. Seitz and H. Hoffmann, Chem. Ztg., 1976, 100,440 (Chem. Abs., 1977, 86, 89 482). C. G. Kruse, N. L. J. M. Brockhof, A. Wijsman, and A. van der Gen, Tetrahedron Letters, 1977, 885.

194

Organophosphorus Chemistry

1,3-Benzodithiolyliurn tetrafluoroborate can be transformed into the phosphonium salt (54). Reaction with carbonyls, in the usual way, affords 1,4-benzodithiaf~lvenes.~~

2-Ethoxyallylidenetriphenylphosphorane(55) reacts smoothly with a variety of a/l-unsatwated ketones. Acid hydrolysis of the initial products affords cyclohexenones.68

Stabilized ylides, e.g. (56), are formed by the addition of (diethoxyviny1idene)triphenylphosphorane to acidic CH and NH compounds (Scheme 1l).63 H Ph,P=C=C(OEt),

+

1

CH,NO,

OEt

ph,p=C-C<-+

\OE t

-CH,NO,

It H EtOH + Ph,P=C---C=CHNO,

I

OEt H I .t- Ph,P=C-C-CH,NO,

I

OEt

OEt

(56)

Scheme 11

Treatment of salicylaldehyde with bis(triphenylphosphorany1idene)methane gave

a phosphonium phenolate, which, on heating, rearranged to the phosphorane (57).

64

Acyl-ylides, e.g. (58), prepared from ab-unsaturated acyl chlorides and ethoxycarbonylmethylenetriphenylphosphorane,undergo Michael addition reactions with 51 52

53 54

K. Ishikawa, K. Akiba, and N. Inamoto, Tetrahedron Letters, 1976, 3695. S. F. Martin and S. R. Desai, J. Org. Chem., 1977, 42, 1665. H. J. Bestmann, M. Ettlinger, and R. W. Saalfrank, Annalen, 1977, 276. H. J. Bestmann and W. Kloeters, Tetrahedron Letters, 1977, 79.

195

Ylides and Related Compounds

a variety of carbon nucleophiles. These adducts can be readily alkylated and the resulting acyl ylides converted into simple esters by heating in the presence of the desired alcohol containing one equivalent of hydrochloric acid. Such reactions have great potential as a 'one pot' conversion sequence, without the need to isolate the intermediates, as outlined in Scheme KLS5

+

C0,Et

PPh

PPh,

Reagents: i, MeLi; ii, BuI; iii, MeOH-H+

Scheme 12

Alkylidenephosphoranes react with phenylselenyl bromide to yield selenophosphoranes (59), which react normally with aldehydes.s6 However, with ketones, the corresponding 2-phenylseleno-derivatives,e.g. (60), are formed. 5 7 2Ph,P=CHR'

+ PhSeBr

-

Ph,P=CR'SePh

+ Ph,6CH,R1

Br-

(59)

(59) + R'CHO --+ R'CH=CR*SePh

K' = H o r Me R2 = alkyl or aryl (59) +

4

-

Ph,kHR' S e P h b

t

--+ Ph,P=CHR'

f-

+

b(60)

3 Selected Applications of Ylides in Synthesis Heterocycles.-Stabilized phosphoranes react as nucleophiles with azamethine ylides generated from suitably substituted aziridines or o x a z o l i n e ~The . ~ ~ resulting zwitterionic intermediates undergo intramolecular Wittig reactions to form 3pyrrolines (Scheme 13). The addition of two equivalents of an acylmethylenetriphenylphosphoraneto the hydroximoyl chlorides (61) results in a transylidation reaction, leading to the forma55 56 57 58

M. P. Cooke and R. Goswami, J. Amer. Chem. SOC.,1977,99, 642. N. Petragnani, R. Rodriques, and J. V. Comasseto, J. Organometallic Chem., 1976,114,281. N. Petragnani, J. V. Comasseto, R. Rodriques, and T. J. Brocksom, J, Organometallic Chem., 1977, 124, 1.

M. VauItier, R. Danion-Bougot, D. Danian, France, 1976, 1537.

J. Hamelin, and R, Carrie, Bull,

Soc. chim.

196

OrganophosphorusChemistry _j

t

Me),

PhC
- + Ph,kHCO,Me I

,CO,Me

Ph/CH~~f;Co,Me

Ph,P=CHCO,Me

t-l

Schemeil3

tion of acylisoxazoles, which, the authors have suggested, proceeds as shown in Scheme 14.69 02Ph,P=CHCOR1

+

R~COC-NOH

I

+

R' C=C-fiPh,

I

R~C-C=N-OH

+ R' COCH,;Ph,

C1-

II

c1

0

Ph, PO

+

R'C=CH

I

0

t

CCOR'

\J

f -

0- CCOR'

4

N

Scheme 14

Pteridines have been prepared by the treatment of the nitroso-uracil (62) with phenacylidenetriphenylphosphorane.6o 0

Me (62)

_+

+

Ar CCH-PPh,

II

0 59 80

M. I. Shevchuk, S. T. Shpak, and A. V. Dombrovskii, J. Gen. Chem. (U.S.S.R.), 1975, 45,

2571.

K. Senga, H. Kanazawa, and S. Nishigaki, J.C.S. Chem. Comm., 1976, 588.

Ylides and Related Compounds

197

The addition of amines to propadienyltriphenylphosphoniumbromide gives salts (63), which exist in either the enamine or imine form. The application of these salts

to the synthesis of quinolines by an intramolecular Wittig reaction with a suitably placed carbonyl or nitrile function (Scheme 15) has been extended.61

Ido 1 x,”,, *

o ; e P h 3 P = 0

Me

Scheme 15

Pheromones.-Polymer-bound aldehydes (64a) have been used, with free Wittig reagents, to produce sex attractants, on subsequent cleavage, as a mixture of cisand trans-alkenes.g2It is noteworthy that synthesis in the ‘reverse’ sense, i.e. the use

‘ @----o-, Ph

b-O(CH,),,CHO

+ Me(CH,), fiPh,

Y

n = 6 , 8 , or 9 rn = 4 0 r 3

Ph

Ph Ph

Yi

Ph

Ph

of a polymer-bound phosphonium salt (64b) with a free aldehyde, was highly stereospecific, leading to yields of more than 90 % of the cis-isomer. 61 63

E. E. Schweizer, S. D. V. Goff, and W. P. Murray, J. Org. Chem., 1977,42, 200. C. C. Leznoff, T. M. Fyler, and J. Weatherston, Canad. J. Chem., 1977,55, 1143.

198

Organophosphorus Chemistry

A general method for the stereospecific synthesis of conjugated (E,Z)-dienes has been reporteds3 and used to synthesize bombykol and its derivatives (Scheme 16).

Scheme 16

The use of ylides for the preparation of intermediates (65)64and (66),65useful in the stereoselective syntheses of disparlure, has been described.

h.rY-. THPO‘

BuLi

+ C,H,,fiPh3

. THPO” Ho\\ (65)

(66)

A ‘salt-free’ ylide has been used to obtain 95 % of the cis-product (67) in the synthesis of a constituent of the androgamete attractant of CutZeria rnuZt$da.66

(67)

Other intermediates for pheromone synthesisthat have been prepared using Wittig reactions include (68),67 (69),s8 and (70).s0 CH2=CH(CH,)SCH,C=CCH-CHCH(CH2)20H

MeCH=CHCH=CH(CH,),CO,H

(6 8)

(6%

H\ H,C=CH

,c=c

,(CH2)@H

‘ H

(70) H. J. Bestmann, 0. Vostrowsky, H. Paulus, W. Billmann, and W. Stransky, Tetrahedron Letters, 1977, 121. s4 K. Mori, T. Takigawa, and M. Matsui, Tetrahedron Letters, 1976, 3953. 66 H. J. Bestmann, 0. Vostrowsky, and W. Stransky, Chem. Ber., 1976,109,3375. 66 L. Jaenicke and W. Boland, Annulen, 1976, 1135. 67 V. M. Bulina, T. I. Kislitsyna, L. I. Ivanov, and Yu. B. Pyatnova, Khemoretseptsiyu Nusekomykh, 1975,2, 211 (Chem. Abs., 1976,85, 77 553). 68 L. Garanti, A. Marchesini, and U. M. Pagnoni, Gazzetfu, 1976, 106, 187 (Chem. Abs., 1976, 133

85, 123 260).

69

J. H. Babler and M. J. Martin, J. Org. Chem., 1977, 42, 1799.

Ylides and Related Compounds

199

Prostaglandins.-Much imagination has been used in devising syntheses of a variety of analogues, particularly those containing heteroatoms in the ring, of prostaglandins. However, ylides are still used to put on the side-chains. It has been found that, in the synthesis of the analogue (71), the use of potassium hydride in DMSO gave more

?+ \

p" I

OTHP

OTHP

(71)

YHO

0 MeN

(72) reproducible results than the more commonly used sodium hydride. 70 Similar reactions were used with (72)71and (73).7a In some instances the C , side-chain has been constructed using an ylide, for example with (74)73 and (75).74

4

-CO,R

CO,R

-

CHO (74)

(75)

An ylide generated from the phosphonium salt (76) with lithium di-isopropylamide has been used in the synthesis of the 9,ll-aza-analogue of prostaglandin endoperoxide PGH2.75

OTHP 70

7l

72

75 74

75

~THP

A. E. Greene, J. P. Depres, M. C. Meana, and P. Crabbe, Tetrahedron Letters, 1976, 3755. G. J. Lourens and J. M. Koekemoer, Ger. Offen. 2 618 861 (Chem. Abs., 1977, 86, 89 589). Hoeschst A.-G., Neth. Appl. 75 12 794 (Chem. A h . , 1977, 86, 89 596). Tanabe Seiyaka Co., Ltd., Japan Kokai 76 01 461 (Chem. A h . , 1976,85, 123 751). G. Ambrus, I. Barta, G. Cseh, P. Tolnay, and C. Mehesfalui, Hung. Teljes 11 745 (Chem. Abs., 1977, 86, 16 352). E. J. Corey, K. Narasaka, and M. Shibasaki, J. Amer. Chem. SOC.,1976,98,4617.

200

Organophosphorus Chemistry

Caroten0ids.-A number of excellent reviews on carotenoids have appeared, based on the main lectures given at the 4th International Symposium on Carotenoids, at Bade, Switzerland. They include reviews on new carotenoid structures,76 syntheses of carotenoids and related polyenes (includingnew routes to tunaxanthin and l ~ t e i n , ' ~ . ~ ~ reand various industrial syntheses of vitamin A and related c a r o t e n o i d ~Wittig actions have been used in the synthesis of a non-isoprenoid ether pigment,79including condensations with the phosphonium salts (77) and (78).

-+

MeoM+

Ph,kH,

CHO

I C Z C H

(77)

\

Me

a

M e o~ ( c H = C H ~ 4 ~ - C H H*&

M 1 0 M ~ ( C ~ = ~ ~ ~ 4 - ( ~ ~ C ) 2 C T H = C H C$. HPh,hCH,C-0 0

-

II

0

(78)

Me

0

The reaction of all-trans-,%ionylideneacetaldehyde with the phosphonium salt (79),using sodium hydride as base, gave a mixture of furanones as shown.80

76

77

78 79 80

S. Liaaen-Jensen, Pure Appl. Chem., 1976,47, 129. B. C. L. Weedon, Pure Appl. Chem., 1976,47, 161. F. Kienzle, Pure Appl. Chem., 1976, 47, 183. H. Achenbach and J. Witzke, Angew. Chem. Internat. Edn., 1977, 16, 191. J. F. Blount, R. J. L. Han, B. A. Pawson, R. G. Pitcher, and T. H. Williams, J. Org. Chem., 1976,41,4108.

201

Ylides and Related Compounds

Polyenes that are useful for treatment of tumours have been prepared from the unsaturated aldehyde (80).*l

Me0 C \

"

t

Other polyenes that have been synthesized using Wittig reactions include the sequiterpenes a- and /?-sinesal8 2 (8 1) and (82), cross-conjugated carotenals (83),8s and (84).84

Bollag, R. Rueegg, and G. Ryser, Ger. Offen. 2 542 612 (Chem. Abs., 1976,85, 32 639). M. Baumann, W. Hoffmann, and H. Pomrner, Annalen, 1976, 1626. J. E. Johansen and S. Liaaen-Jensen, Tetrahedron, 1977, 33, 381. A. K. Chopra, B. P. S. Khambay, H. Madden, G. P. Moss, and B. C. L. Weedon, J.C.S. Chem. Comm., 1977, 357.

~31 W. 82

83 84

Organophosphorus Chemistry

202

Non-benzenoid Aromatic Compounds.-The slow addition of lithium ethoxide in ethanol to a solution of reagents in DMF at -40 "C gave a small yield of the bicyclophane (85).

LiOEt

OHC

DMI', -40°C

CHO

CH, $Ph,

+

(85)

Lithium ethoxide appears to be the base of choice in condensations using bisylides, as shown in the formation of the metacyclophanediene(86).86 The trans,transq H 2 b p h 3

oHc9 LiOEt

(86)

benzannelated [13lannulene (87) is formed in a similar condensation reaction.87 However, if DBN is used as the base, a cis,trans-annulene (88) is obtained.

CH,fiPh3

85 86

87

+

Q

OHC

I

LiOEt

(88) H.-E. Hogberg, B. Thulin, and 0. Wennerstrom, Tetrahedron Letters, 1977, 93 1. B. Thulin and 0. Wennerstrom, Tetrahedron Letters, 1977, 929. A, Gamliel, I. Willner, and M. Rabinovitz, Synthesis, 1977, 410.

203

Ylides and Related Compounds

Benzo[l8]annulene has been synthesized from (89), which was formed as shown.88

(89)

The preparation that can be used to produce a number of helicene derivatives uses a Wittig reaction, as illustrated by the preparation of (W),followed by a photodehydrocyclization.*g

/

gCHO f

ph36>

-5iOEt 4

ph363 0+ i0 I Ph,;

{

CHO (91) WCO),

+

Fe(CO),

8%

LiOEt:

Ph,h

I

I

204

Organophosphorus Chemistry

The reactions of thiophen-2,3-dicarbaldehydewith a number of bis-ylides, including (92),91(93),92(94),9a and (95),93have been studied.

a

p

p

h

3

PPh,

(93)

(92)

cpph3 CPPh,

PPh,

PPh,

(94)

(95)

4 Selected Applications of Phosphonate Carbanions General.-The factors affectingthe &:trans ratios of alkenes obtained by the conB5 densation of anions generated from cyclic phosphonates have been Larger amounts of cis-alkenes are obtained, particularly when using phosphonate (96).

(96)

The regioselectivity of the addition of phosphorylated anions to @-unsaturated ketones has been studied in some detai1,96~97 and has been discussed in terms of perturbation theory. Most products arise from nucleophilic attack at the C=C bond. The condensation of phosphonates with aromatic aldehydes may be carried out in a two-phase system in the absence of a typical phase-transfer catalyst.9s Among those aldehydes and ketones used successfully in alkene syntheses with phosphonates are (97),99(98),’0° (99),lo1and (lOO).loa

A (97) , ,

ph

RQ-y N

Ac

(9 8) 91 92 93

94

f7JJy-J

/

CHO

(99)

Q< (100)

D. N. Nicolaides, Synthesis, 1976, 675. D. N. Nicolaides, Synthesis, 1977, 127. D. N. Nicolaides and C. N. Coutrakis, Synthesis, 1977, 268. B. Deschamps, J. P. Lampin, F. Mathey, and J. Seyden-Penne, Tetrahedron Letters, 1977, 1137.

100 101

E. Breuer and D. M. Bannet, Tetrahedron Letters, 1977, 1141. M. Cossentini, B. Deschamps, N. T.Anh, and J. Seyden-Penne, Tetrahedron, 1977,33,409. B. Deschamps and J. Seyden-Penne, Tetrahedron, 1977,33,413. M. Mikolajczyk, S. Grzejszczak, W. Midura, and A. Zatorski, Synthesis, 1976, 396. R. Y.Levina, U. 1. Sein, A. S. Kosmin, Z. A. Lysenko, and 1. G. Bolesov, Zhur. org. Khim., 1977,13,63 (Chem. Abs., 1977,86, 170 965). A. Buzas and C. Hbrisson, Synthesis, 1977, 129. M. Sunagawa, H. Sato, J. Katsube, and H. Yamamoto, Ger. Offen. 2 556 143 (Chem. Abs.,

102

J. M. Bastian and M. Marko, Experienfia, 1976, 32, 413 (Chem. Abs., 1976, 85, 62 892).

95 96

97 98

99

1976, 85, 62 865).

Ylides and Related Compounds

205

Metallated phenylphosphine oxides (101) react with aldehydes at room temperature to give trans-alkenes, with high se1e~tivity.l~~

(101)

The anions generated from geometrically pure allylic diphenylphosphine oxides,

e.g. (102), react with carbonyl compounds to afford conjugated dienes in which the

geometry of the original ally1 system is preserved.lo*

(102)

Conversion of aldehydes or ketones into the homologous aldehyde can be accomplished readily with the anion generated from the phosphine oxide (103). The procedure (Scheme 17) removes many of the problems associated with similar reactions using ylides.lo6 n

Reagents: i, PrizNLi; ii, R1COR2; iii, NaH-THF; iv, H30+

Scheme 17

One-carbon homologation of aldehydes or ketones to carboxylic acid derivatives108 has also been achieved (Scheme 18), using the phosphonate (104).lo7

Reagents: i, NaH; ii, ZnClz-AczO; iii, KOH; iv, HaO+

Scheme 18 M. Schlosser and B. T. Huynk, Chimia (Switr.), 1976,30,197 (Chem. A h . , 1976,85, 167 734). l o 4 B. Lythgoe, T. A. Moran, M. E. N. Nambudiry, and S . Ruston, J.C.S. Perkin I, 1976, 2386. lo5C. Earnshaw, C. J. Wallis, and S . Warren, J.C.S. Chem. Comm., 1977, 314. 106 S. E. Dinizo, R. W. Freerksen, W. E. Pabst, and D. S . Watt, J. Amer. Chem. SOC.,1977,99, 103

107

182. S. E. Dinizo, R.

W.Freerksen, W. E. Pabst, and D. S. Watt, J. Org. Chem., 1976,41, 2846.

206

Organophosphorus Chemistry

a-Alkoxybenzylphosphonates(105) react with carbonyl compounds in the presence of base to yield enol ethers.loB 0

11

,OR'

(Eto),PCH

P 'h

(105)

R2 + '>=o R3

- Rk21 R3

A general synthesis of keten dithioacetals, using (106), has been reported. The

carbanion can be generated by using conventional bases of by using phase-transfer 0

I1

(MeO),PCH(SR'), +

(106)

RZ

>O

+

P-(:

R2

R1

R

cataly~is.1~~ Excellent yields of dithioacetals are also obtained by the use of the phosphonates (107) and (108).61

II

0

(107)

(108)

The isomeric phosphonates (109) and (110) are rapidly equilibrated by base. Condensation of either isomer with aldehyde gives (1 11) as the main product.1°

(109)or(110) + RCHO

__f

RL \C

0

,

M

e

The preformed anion from (112) was treated with ethyl pyruvate to give (113) as a mixture of isomers.11oIsophorone oxide reacts with the anion generated from (114) to yield an epoxy-ester as a mixture of isomers.111 108

109

E. Schaumann and F.-F. Grabley, Annalen, 1977, 88. M. Mikolajczyk, S. Grzejszczak, A. Zatorski, and B. Mlotkowska, Tetrahedron Letters, 1976,

2731.

M. Davidson and G. L. Kenyon, J. Org. Chem., 1977,42, 1030. N. Bensel, H. Marschall, and P. Weyerstahl, Tetrahedron Letters, 1976, 2293.

1l0 R.

111

207

Ylides and Related Compounds 0

II (EtO),PCH, P(0Et 1, + MeCCO, Et

a0

0

I1

(EtO), PCH=C,

-+

,Me \

C0,Et

(113)

0

II

+ (MeO),PCH,CO,Me

_ _ f

(114)

0.'

0 '

The effect of substituents and reaction conditions on the reaction of pyrroline N-oxides (1 15) with phosphonate anions has been discussed.lla~ 113 0

I

I

x

0-

(115)

H

The reaction of the dialdehyde (116) with phosphonate (117) gave an acyclic compound, whereas condensation with (1 18) afforded a cyclized 0

II

OHC(CH,),CHO + (EtO),PCHCO,Et I

-

OHC(CH,),CH-CCO,Et I I Me

C0,Et 45%

N-Substituted 2,4,5-trienamides (119) have been synthesized (being potential insecticides) from 4,4-dialkylbuta-2,3-dienalsand the appropriate phosphonate.lls MeEtC=C=CHCHO

+

(EtO), PCH,CONR' R2

It

_ _ f

MeE tC=C=CHCH=CHCONRI (119)

Rz

0 E. Breuer and S. Zbaida, J. Org. Chem., 1977, 42, 1904. D. St. C. Black and V. C. Davis, Austral. J. Chem., 1976, 29, 1735. N. P. Dormidontova, B. G. Kovalev, and A. P. Gulya, Zhur. org. Khim., 1976, 12, 319 (Chem. Abs., 1976, 85, 32 485). 115 P. D. Landor, S. R. Landor, and 0. Odyek, J.C.S. Perkin Z, 1977, 93.

112 113 114

208

Organophosphorus Chemistry

Similar reactions with hepta-2,3-dienal, however, resulted mainly in Michael addition at C-3 (Scheme 19).

n "3' 11

PrCH=C=CH-CH

\

a1

(Eto), P-CHCONH

Bu'

-

PrCH=C-CH=C

I

H-0-

CHCONHB~

I O=P( 0Et l2

__f

PrCH=YH2ao CHCONHBU~

1

O=P( OEt)z

Scheme 19

The epoxides (120) can be metallated specifically with lithium di-isopropylamide (Scheme 20).ll6

(120) Reagents: i, LiNPria; ii, Me1

Scheme 20

Natural Products.-The phosphonate anion (121) is still quite commonly used to put the standard C 8side-chain onto prostaglandins. Among those aldehydes used have been (122),'17 (123),73(124),7aand (125).?l

116 117

J. J. Eisch and J. E. Galle, J. Organometallic Chem., 1976, 121, C10. P. A. Grieco, C. S. Pogonowski, S. D. Burke, M. Nishizawa, M. Miyashita, Y. Masaki, C.-L. J. Wang, and G. Majetich, J. Amer. Chent. SOC.,1977, 99, 41 11.

209

Ylides and Related Compounds

A number of novel phosphonates have been used to construct prostaglandin analogues, among them (126),118(127),lls (128),lZ0and (129).121 0

II

(MeO ), PCHBrCO(CH, ), Me (1 26)

(127)

rPh

il

0

II

(MeO),PCH,COCqOAr

(MeO),PCH,CO

The condensation of (130) with the aldehyde (131) has been used in the synthesis of the antibiotic vermiculine, to give a diene ester with the desired trans-configuration.12a C0,Bu‘

I

CHO

0 f

OH

/

I1

(MeO),PCH,CO,But

-+

(130) I

OH

(131)

118

119 120

lZ1

122

C. Gandolfi, G. Doria, R. Pellegata, and M. M. Usardi, Ger. Offen. 2 537 406 (Chem. Abs., 1977, 86, 43 259). B. J. Broughton, M. P. L. Caton, E. C. J. Coffee, and P. J. Warren, Ger. Offen. 2 548 878 (Chem. Abs., 1976, 85, 108 345). K. B. Mallion, Ger. Offen. 2 556 104 (Chem. Abs., 1977, 86, 29 410). P. R. Marsham, Ger. Offen. 2 626 287 (Chem. Abs., 1977, 86, 155 250). Y. Fukuyama, C. L. Kirkemo, and J. D. White, J. Amer. Chent. SOC.,1977, 99, 646.

10

Phosphazenes BY R. KEAT

1 Introduction There have been few important advances in this area during the past year. The first crystal structure of a phosph(m)azene, But(Me3Si)NP=NBut, has been reported,l and the claim made last year, of the formation of a compound containing a phosphazene linkage which forms part of a four-membered ring, has been shown to be erroneous.2 The formation and properties of cyclophosphazenes * (mainly aminoderivatives) and the phosphazene polymers6* have been reviewed. The patent literature is the most important growth area, particularly where flameproofing applications are concerned. 3y

2 Synthesis of Acyclic Phosphazenes From Amines and Phosphorus(v) Halides.-Relatively few examples of this route to monophosphazenes have been reported, apparently because of the greater versatility of the azide route (see*below).Examples of the former route are those by which (l),' (2),8 and (3)v have been prepared. The slP chemical shifts of compounds (1) were linearly related to Hammett a-constants for the substituents R, and the novel compounds (2) presumably result from partial hydrolysis at some stage in the reaction. The synthesis of N-halogenoalkyl-phosphazenesRCC12N=PC13-,Phn (n =0, 1, or 2) has been reported in general terms only.l0 From Azides and Phosphorus(1n) Compounds.-Although phosphorus(zI1) compounds and azides generally undergo a ready reaction, two examples (4) and ( 5 ) of the class of azidophosphineshave recently been prepared. The bulky di-isopropylamino-groups in (4) confer thermal stability such that the compound can be distilled at reduced pressure.ll Compound (5) was identified l2 spectroscopically at low temperatures, S. Pohl, Angew. Chem. Internut. Edn., 1976, 15, 687. G. Schoning and 0. Glemser, Chem. Ber., 1976, 109, 2960. 3 R. A. Shaw, 2.Nuturforsch., 1976, 31b, 641. 4 S. S. Krishnamurthy, R. A. Shaw, and M. Woods, Current Sci., 1976, 45, 433. 5 H. R. Allcock, Science, 1976, 193, 1214. 6 H. R. Allcock, Angew. Chem. Internut. Edn., 1977,16, 147. 7 8. S. Kozlov, S. N. Gaidamaka, and R. Kh. Sadykov, J. Gen. Chem. (U.S.S.R.), 1976,46,552. 8 A. M. Islam, E. A. Hassan, E. H. Ibrahim, and A. E. Arifien, Egypt. J. Chem., 1974 (publ. 1976), 17, 561 (Chem. Abs., 1977, 86, 171543). 9 T.-P. Lin and 0. Glemser, Chem. Ber., 1976, 109, 3537. 10 V. P. Rudavskii, D. M. Zagnibeda, and E. E. Nizhikova, Khim. Tekhnol. (Kieu), 1976,23 (Chem. Abs., 1976, 85, 123472). 11 0. J. Scherer and W. Glassel, Chem.-Ztg., 1975, 99, 246 (Chem. Abs., 1975, 83, 78473). 1 2 H.-G. Horn, M. Gersemann, and U. Niemann, Chem.-Ztg., 1976,100, 197 (Chern. Abs., 1976, 85, 160238). 1 2

210

211

Phosphazenes CCl,PCl,

+

A

H,NC,H,R

CCl,Cl,P=NC,H,R (1) R = m-or p-H, Me, OMe, Hal, N-NPh, or NO,

(R’NPCI,),

+ H,NRZ

-HC’

* (2)

R1 = Ph or C,H,Me-p RZ = Ph, 0-,m-,or p-c6H4Me, or CH,Ph

(3)

(Pri,N),PC1

+ Me,SiN,

+ Me,SiCl

(Pri,N),PN,

c_f

(4)

(C,Fs),PBr

+ NaN,

(C,F,),PN,

__f

+ NaBr

(5)

on].

and by the formation of (C,F,),P-N=PPh3 when it reacted with triphenylphosphine. Interestingly, a mixture of cyclic phosphazenes (6; n= 3,4, or 5 ) is obtajned13from the reaction of chloro-phosphites with trimethylsilyl azide. a > P C l

+ Me,SiN,

-+

[

+ N2 + Me,SiCl

‘NP

n

( 6 ) n = 3,4, or 5

A series of N-trimethylsilylphosphazenes(7) have been obtained14by the azide route, and their n.m.r. properties examined in some detail. It was shown last year R,P

+ Me,SiN,

R,P=NSiMe,

+ N,

(7) R = OAlkor NEt,

that this type of reaction can also lead to diphosphazenes R3P=NPRz=NSiMes (R = NMe,). Work on the synthesis of diphosphazenes (8) of this type by the route shown in Scheme 1 now leads to the postulatels that an exchange process at the 13 14

15

D. Dahmann and H. Rose, Chem.-Ztg., 1976,100,340. E.-P. Flindt, H. Rose, and H. C. Marsmann, 2. anorg. Chem., 1977,430, 155. W. Wolfsberger and W. Hager, J. Organometallic Chem., 1976, 118, C65.

21 2

Organophosphorus Chemistry

+ Me,SiN, --+

R,P=NPR,

+ NL

R3P=N-PR,-NSiMe, (8) R = alkyl

Scheme 1

phosphazenyl-nitrogen, for example reaction (l), can account for the mixture of Me,P=NPMe,

+ Me,SiN3

* Me,P=NSiMe,

+

[Me,PN,]

(1)

products obtained. Under certain conditions, phenyl azides can also give unusual products (9), which are stable only at low temperatures.16 (MeO),(Me,SiO)P t PhN,

* (MeO),(Me,SiO)k---N=N-~Ph

It

(MeO),P(O)-N=N-NPhSiMe, (9)

The trimethylsilyl group is also labile in the products (10) and (11) of the reaction between dialkyl trimethylsilyl phosphites and azides R22P(0)N3.17N.m.r. spectroscopy has been used to show that the formation of (11) is favoured when R2 is a (RlO),(Me,SiO)P

+ RZ,P(0)N3 -+

(R'O),(Me,SiO)P=N-P(0)RZ,

(10)

I

(RIO),P(0) -N=P(OSiMe,) (11)

-

+ N,

RZ,

R' = alkyl RZ = alkyl, alkoxy, or Me,N

relatively good electron donor. In an analogous manner, the phosphazenyl group forms18at the electron-rich phosphorus atoms in (12) and (13). The synthesis of the

(R'O),P=N--P(O)

(NR2JZ

(1 2)

heat

(R'O),P(0)--N=-P(NRZz)z (OR' ) (13) R', Rz = alkyl

related compounds (14) by the azide route has also been described;l9 interest is centred on the potential herbicidal and defoliant activity of these compounds. (EtzN)nR'3-,,P=N-P(Z) (14)

16 17 18

19

(NR',),

R' = alkoxy or Ph Rz = Me or Et Z =OorS n = 0-3

R. D. Gareev, J. Gen. Chem. (U.S.S.R.), 1975, 45, 2511. M. I. Kabachnik, N. N. Zaslavskaya, V. A. Gilyarov, P. V. Petrovskii, and V. A. Svoren, Doklady Akad. Nauk. S.S.S.R., 1976, 228, 849. N. N. Zaslavskaya, V. A. Gilyarov, and M. I. Kabachnik, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1976, 675 (Chem. Abs., 1976,85,45909). N. N. Zaslavskaya, V. A. Gilyarov, and M. 1. Kabachnik, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1976,931 (Chem. Abs., 1976, 85, 78186).

21 3

Phosphazenes

Reactions of phenyl azide with a tautomeric mixture of (15) and (16) also leadaoto the phosphazenes (17) as intermediates, tentatively identified as such by n.m.r. spectroscopy. Intermediate (17) undergoes intramolecular addition of the N-H bond across the phosphazenyl linkage to form a phosphorane (18). Novel polymers (19), containinga1phosphazenyl side-groups, have been obtained by the azide route.

(1 7)

X = -CHz-CHz--

or -CMez-CMe2-;

(1 8) R = MeorPh; 2 = OorNMe

(19). R = OEt, NEt,, or Ph

As reported last year, the reaction of diazoalkanes with phosphorus(II1) compounds also leads to phosphazenes. This is typified by the formation of the phosphazene (20), which isomerizes when heated, to give (21).22The lH n.m.r. spectra of (20) (Mf?O)3P.+. CH2N,.

__fi

(Me.O),P=N-N=CH,

(MeO),P(O)NMeN=CH, (21)

(20)

(MeO),P=N “=C

(22)’

/H

‘ 3

(MeO),P(O).-N

/””

/H

\ N=c\H (23)

and (21) revealed that the =CHz protons were non-equivalent in each case; the spin coupling and chemical shift e 6 c t s are said to indicate that (20) and (21) adopt con20

21 22

M. Sanchez,J.-F. Brazier, D. Houalla, A. Munoz, and R. Wolf, J.C.S. Chem. Comm., 1976,730. G . L. Butova, E. S. Gubnitskaya, N. G. Feshchenko, and A. V. Kirsanov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 918. A. N. Pudovik and R. D. Gareev, J. Gen. Chem. (U.S.S.R.),1976,46,946. 8

214

Organophosphorus Chemistry

formations (22) and (23), respectively. The lH n.m.r., i.r., and U.V. spectra of the related phosphazenes (24) (R1, Rz, R3included alkoxy- and dialkylamino-groups, Me, and Ph), obtained by the reaction shown, gavez3information on the transmission of electronic effects through the P-N-N-C skeleton, and on the dynamic equilibrium which involves interchange of the mutual orientations of the C=O and C=N groups about the C-C bond. Other workersz4have explored the reactions of TDAP with diazo-compounds, and have obtained similar results, the compounds (25) being formed [Rl, R2included H, CO(alkyl), C02(alkyl),AsMe,, HgMe, SiMe,, and GeMe,]. R'R2R3P f N,CHCO,Me.

R' R2R3P=N-N=CHCO,Me

~ _ f

(24)

(Me,N),P

+

N2CR1R2 -+ (Me,N),P=N-N=CR1R2 (25)

By contrast, reactions with silyl phosphites do not give the phosphazenes (26), for the silyl group readily migrates to nitrogen, leaving (27).26The same tendency for migration of the silyl group has also been noted for intermediates derived from azides.l

(R'Q),POSiMe, + N2CR*R3-+

Me, SiO R10-P-N-N=CR2R3

[

R'O'

(26)

-1

1)

(R' O),P(O) NSiMe,N-=CR2R3 (27)

R' = Meor Et R2 = H o r P h R3 = CO,AIk, COMe, or Ph

Other Methods.-No new phosph(1Ir)azenes have been reported, but several unusual routes to phosph(v)azenes have appeared. In one case,z6migration of the silyl group from nitrogen to carbon in a Wittig reagent results in the formation of the phosphazene (28). Descriptions of further conventional examples of deprotonation of (Me,Si),N-;Me,

I"

Bu"Li

+ (Me,Si),N--P(=CH,)Me,

-

Me,SiN=PMe,CH,SiMe,

phosphonium salts to give phosphazenes have also appeared, compounds formed including (29) and (30). Compound (29), as its N-lithio-derivative,was employed27to 23

24

25 26

27

R. D. Gareev and A. N . Pudovik, J . Gen. Chem. (U.S.S.R.), 1976,46, 1424. P. Krommes and J. Lorberth, J. Organometallic Chem., 1977, 127, 19. R. D. Gareev and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.),3976, 46, 1670. J. C. Wilburn and R. H. Neilson, J.C.S. Chem. Comm., 1977, 308. 0. J. Scherer and G. Schnabl, Inorg. Chim. Acta, 1976, 19, L38.

21 5

Phosphazenes Me,kNHMe), I-

Me,(MeNH)P=NMe (29)

prepare complexes of stannic chloride, and (30), whose preparation is shown in Scheme 2, is the first example of an optically active monophosphazene.28The latter is MePhP(0) NHBd

S-(+I

--% MePhs(0Et) NHBd PF; S-(+I

MePhP(=NBu')OEt

s-(+I (30)

Reagents: i, EtsO+ PFs-; ii, KH

Scheme 2

hydrolysed in alkaline 50 % aqueous acetonitrile to R-(- )-MePhP(0)NHBut with complete inversion of configuration at phosphorus; this rules out the possibility of hydrolysis occurring by a route that involves cleavage of the C - 0 bond. The reactions of amino-phosphites with activated olefins,2aand with activated ketonesY3O provide a route to phosphazenes (31) and (32), respectively.

N' H

POEt

+ CH,=CHX

-+

a:x::;H H

(31) X = CN or C0,Me

(EtO),P-NHAr

+ MeCOCH2Cl

Et3N

*

(EtO),P-0-C(=CH,)Me

II

NAt

(32)

N-Chloro-amines can be employed to effect 31 the oxidation of phosphorus(II1) halides to phosphazenes (33). The first example of a phosphazenylphosphorane, (34), Bu'NClSiMe, + RPCl,

PhPF4 + (Me,Si),N-P(Z)F,

ButN=PCl,R (33) R = Cl,Me,Ph,PhO, Et,N, or ChPNMe + PhPF,=N-P(Z)F, + Me,SiF (34) Z = OC(CF,),C(CF,),O

has been On heating, (34) decomposes into the salt [(PhPF,=N),PZ]+ [F4PZ]- and a polymer, (NPFPh)n; these results may be contrasted with analogous reactions with phosphorus pentafluoride [reaction (2)]. PF5 + (Me,SI),NP(Z)F, 28 29

30

31 32

I_)

F,P(Z)

.t

(NPF,)

+ Me,SiF

(2)

K. E. DeBruin and L. L. Thomas, J.C.S. Chem. Comm., 1977, 33. M. A. Pudovik, T. A. Pestova, and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.), 1976, 46, 227. A. N. Pudovik, 8. S. Batyeva, and E. N. Ofitserov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 224. A. M. Pinchuk, L. P. Filonenko, and A. V. Kirsanov, Khim. Elementorg. Soedin., 1976, 98 (Chem. ,4bs., 1977, 86,43777). G.-V. Roschenthaler, J. Gibson, and R. Schmutzler, Chem. Ber., 1977, 110, 611.

216

OrganophosphorusChemistry 3 Properties of Acyclic Phosphazenes

Halogeno-derivatives.-N-Halogenoalkyl-phosphazenes (35) have been converted 34 into their aziridinyl derivatives (36) ; all phosphorus-halogen bonds are cleaved, but reaction only occurs at specific carbon atoms. 339

CCI,CCl,N=PCl,

(35)

+

NH(CH,),

+

Et,N --+ CCl,C[N(CH,),],N--P[N(CH,),]

+ Et,h

(36)

C1-

gives 36 bis(dialkoxyphosphiny1)amines (37), Alcoholysis of C13P=N-P(0)CI rather than alkoxyphosphazenes. At present, it is not clear whether this conflicts with the work of another who have found that the products of this type of reaction exist as a tautomeric equilibrium mixture involving the phosphazene (38) and the amide (39).

+ ROH

C13P=N-P(0)C1,

Cl,P=N-P(Z)Cl,

+ ROH

[(RO),P(O)],NH + HCl

(37) R = Me,Et, or Pr"

+ HOP(OR),=N-P(2)

(OR),

(3 8)

It

The rates of reorientation of PCI, and of CCI, groups of Cl,P=N-P(0)(CC13)2 in the solid state have been measured3' by n.q.r. spectroscopy. Amino-, Alkoxy-, Alkyl, and Aryl Derivatives-Recent developmentsin the synthesis and properties of phosph(m)azenes, all of which are P-amino-derivatives, have been reviewed,38unfortunately in a journal which is difficult to obtain. Interest in the phosph(rrr)azenes has centred around their reactions with various acid halides, as summarized in Scheme 3. Invariably, the product is a ring compound, ranging from R,N-P=NR

+ AJC1,

-

R N R,N-$-NR-~iCl,

--+

P''

/N'

\~icI,

+

RCI

R

(40) R = SiMe,

Scheme 3 33

34 35

36

37

38

V. S. Petrenko, A. I. Kutovoi, V. Ya. Semenii, and G. F . Solodushenko, Fiziol. Akt. Veshchestua, 1976, 8, 15 (Chem. Abs., 1977, 86, 170769). V. Ya. Semenii, G. F. Solodushenko, V. P. Kukhar, A. I. Kutovoi, and Z. P. Bulkina, Russ. P. 514845 (Chem. A h . , 1976, 85, 108508). L. Riesel, G. Pich, and C. Ruby, Z . anorg. Chem., 1977, 430, 227. A. A. Volodin, S. N. Zelenetskii, V. V. Kireev, and V. V. Korshak, Doklady Akad. Narrk. S.S.S.R., 1976, 227,355 (Chem. Abs., 1976, 85, 5130). V. A. Mokeeva, L. A. Kyuntsel', and G. R. Soifer, J. Struct. Chem., 1976, 17,317. E. Niecke and 0. J. Scherer, Nachr. Chem. Techn., 1975, 23, 395.

217

Phosphazenes R'

R'R*N--.P=NR'

+ AsC1,

__f

R'R2PC1-NR'

I AsCl,

' N

C1P ' N '

_+

+ R2C1

'AsC1

_.

R'

(41) R1 = But, R2 = SiMe, BdN, R,N-NMe-P=NBuf

(R =

+ AsC1,

SiMe,)

I

--+

As

,c1

/

,NMe

P-i-I'iJ MeN L N - P I c~N ' BU~

As

+

RC1

t

I

R' R'R2N-P=-NR' (43) R' = But R2 = SiMe,

+

+

MePC1, --+ MePP "'Cl

' N '

RZCI

R' (44)

R2 action of aminophosphines with N-acylhydrazines, even when alternative modes of cyclization appear to be possible.7* 3 Phosphonous and Phosphinous Acids and their Derivatives Continuing their investigation of the stereochemistry of tervalent phosphorus, Mikolajczyk and his co-worker have shown that optically active O-methyl ethylphenylphosphinite (112) and S-ethyl ethylphenylthiophosphinite (113) react with methyl-lithium and sodium methoxide with predominant inversion of configuration at phosphorus.76The absolute configuration of (113) was established by conversion into ethylmethylphenylphosphine sulphide, and the stereochemical course of the nucleophilic displacements was determined by conversion of the initial products into the corresponding oxide and sulphides, as shown in Scheme 9. The unstable acyldiarylphosphine oxides, although previously postulated to exist,7s have only now been prepared, by the reaction of secondary phosphine 72

73 74 75 76

42

43 44

45

H. Werner and T. N. Khac, Angew. Chem. Internat. Edn., 1977, 16, 324. W. Klaui, H. Neukomm, H. Werner, and G . Huttner, Chem. Ber., 1977, 110, 2283. A. Schmidpeter, J. Luber, H. Riedl, and M. Volz, Phosphorus and Sulphur, 1977, 3, 171. J. Omelanczuk and M. Mikolajczyk, J.C.S. Chem. Comm., 1976, 1025. D. J. H. Smith and S. Trippett, J.C.S. Perkin I , 1975, 963 and references therein, 1976, 15,.101.

0. J. Scherer and G. Schnabl, Chem. Ber., 1976, 109, 2996. U. Klingebiel, P. Werner, and A. Meller, Monatsh., 1976, 107, 939. R. Appel and M. Halstenburg, J. Organometallic Chem., 1976, 121, C47. R. Appel and M. Halstenburg, Angew. Chem. Internat. Edn., 1977, 16, 263.

21 8

Organuphosphorus Chemistry R

action of aminophosphines with N-acylhydrazines, even when alternative modes of cyclization appear to be possible.74 3 Phosphonous and Phosphinous Acids and their Derivatives Continuing their investigation of the stereochemistry of tervalent phosphorus, Mikolajczyk and his co-worker have shown that optically active O-methyl ethylphenylphosphinite (1 12) and S-ethyl ethylphenylthiophosphinite (1 13) react with methyl-lithium and sodium methoxide with predominant inversion of configuration at phosphorus.76The absolute configuration of (1 13) was established by conversion into ethylmethylphenylphosphine sulphide, and the stereochemical course of the nucleophilic displacements was determined by conversion of the initial products into the corresponding oxide and sulphides, as shown in Scheme 9. The unstable acyldiarylphosphine oxides, although previously postulated to exi~t,~G have only now been prepared, by the reaction of secondary phosphine 73 73 74

75 76

H. Werner and T. N. Khac, Angew. Chem. Inremat. Edn., 1977, 16, 324. W. Klaui, H. Neukomm, H. Werner, and G . Huttner, Chem. Ber., 1977, 110, 2283. A. Schmidpeter, J. Luber, H. Riedl, and M. Volz, Phosphorus and Sulphur, 1977, 3, 171. J. Omelanczuk and M. Mikolajczyk, J.C.S. Chem. Comm., 1976, 1025. D. J. H. Smith and S. Trippett, J.C.S. Perkin I , 1975, 963 and references therein,

NR',

Y

I

R'N~P-N=C=NR*

I

N RI2 (49)

which is the product of addition to S4N4, is less well defined:? and it is intensely blue. With ketones, the products of addition include cyclodiphosphazanes(51) and olefins (52)t8 but with sulphoxides the acyclic phosphazenes (53) are The positions of a number of tautomeric equilibria involving phosphazenes and phosphoramidateshave been investigated by lH n.m.r. spectros~opy.~~ Thus the ratio of [(54)] :[(%)I is 89 :11 at 28 "C in a-bromonaphthalene. Activation parameters for 48

47 48

49

R. Appel and M. Halstenburg, J . Organometallic Chem., 1976, 116, (213. R. Appel and M. Halstenburg, Angew. Chem. Internat. Edn., 1976, 15, 696. R. Appel and J. Halstenburg, Chem. Bcr., 1977, 110, 2374. P. K. G. Hodgson, R. Katz, and G . Zon, J. Organometallic Chem., 1976, 117, C63.

Phosphazenes

219 NR'

R',N-P(=NR'), R' = SiMe,

/CH2

MeCOR2 ----if R*,N-P-0-C II R2 = Me orPh NHR'

+

I

,N, R'

R'N\

,p\N,p\ R'NH Rl

ZR'

,NHR'

+ R'OC(=CH,)R' NR'

(5 2)

(53) R' = SiMe,; R2 = Me Or Ph

the interconversion of (54) and (55) were also obtained. The phosphazenes R1,(Me3SiO)P=N-P(0)R2, (R1= R2= alkoxy) showed only one 31Psignal at ambient

II

(PhO),P-N' (54)

' /

SiMe,

A

Ph

OSiMe,

I

(PhO),P=NPh (55)

temperatures, but an AB-type spectrum was obtained on cooling.50These observations indicate that the trimethylsilyl group exchanges rapidly (on the n.m.r. timescale) between the phosphoryl oxygen atoms at ambient temperatures, but that this can be stopped at ca. - 40 "C.The exchange process is slow at ambient temperatures when R1 is electron-supplying, e.g. NMe, or alkyl. New reactions of various phosphazenes with a wide range of electrophilic species continue to be reported. These include those of alkoxy-derivatives with dialkyl s ~ l p h a t e se.g. , ~ ~to give (56), or with sulphenyl chlorides, e.g. the reaction that produces (5'7) (see Scheme 4). With pyridine, compound (56) can be converted into two isomeric products (58) and (59). (€
--L[ (EtO),P=N==P(OEt),(SEt)]'

BPb-

(56)

(EtO),P=N-P(S)

(OEt),

6 [ (EtO),P---N==P(OEt),(SSPh)]'

Reagents : i, (EtO)aSOz--NaBPh4;ii, PhSCl-SbC15

SbC1;

( 5 7)

Scheme 4

50 51

M. I. Kabachnik, N. N. Zaslavskaya, V. A. Gilyarov, P. V. Petrovskii, and V. A. Svoren', Doklady Akad. Nauk. S.S.S.R.,1976, 228, 849. A. A. Khodak, V. A. Gilyarov, and M. I. Kabachnik, J. Gen. Chem. (U.S.S.R.),1976,46,1628.

0rganophosphorus Chemistry

220 (56)

(OEt) (SMe) + (EtO),(MeS)P =N-P(0)

(EtO),P=N-P(0)

(OEt),

(59)

( 5 8)

The reactions of phosphazenes (prepared in situ from aminophosphoniumsalts and triethylamine) with sulphur tetraftuoride have been further explored. An example is shown in reaction (3),62 where X is a bridging alkyl or aryl group. However, when X

+ SF, + EtsN * FzS=N-X-N=SF2

Ph,P-NH-X-NH-PPhJ

+

.t

Ph,PF,

Et,&HCl- (3)

is o-C,H4 in equation (3), the intermediate (60)undergoes a cyclhtion step to give (61). The reactions of certain diphosphazenes (62) with hydrogen fluoride are very dependent on the solvent F,S=N-X-NH$Ph,

Cl'

(60)

R

Me,FzP--PF2Me,

HF

N

4 Et,O

Me,P-PMe,

II

HI:

. CCI,F

[Me,FPNR], + Me,(CFCI,)P=NR

N

R

(62) R = SiMe,

Another example of a cleavage of the phosphazene linkage that is induced by hydrogen halide is provided6*by reactions of the type shown in Scheme 5.

Scheme 5

Cardodi-imides can be generated66 from chloroalkyl isocyanates and phosphazenes, e.g. as shown in reaction (4), and N-(trichloromethy1)dialkylamines [CC12= NR2]+C1- can be used to effect the replacement of trimethylsilyl groups in Nsilylphosphazenes.6sAn example is shown in reaction (9,and the same products can CI(C1,C)HC-NCO Ph,P=NSiMe, 52 53 54

6,

+

Ph,P=NPh

+ [CCI,=NMe,J+ C1-

Cl(Cl,C)HC-N=C=NPh __f

Ph,P=N-CCJNMe,

+ Ph,PO +Me,SiCl

(4) (5)

R. Appel, J.-R. Lundehn, and E. Lassmann, Chem. Ber., 1976, 109, 2442. R. Appel, R. Milker, and I. Ruppert, 2.anorg. Chem., 1977,429, 69. T. Hosogai, T. Nishida, and K. Itoi, Japan. Kokai 75 130745 (Chem. Abs., 1976, 85, 78200). V. I. Gorbatenko, V. N. Fetyukhin, and L. I. Samarai, Zhur. org. Khim., 1976,12,2472 (Chem. Abs., 1977, 86, 72081). V. P. Kukhar', V. I. Pasternak, M. V. Shevchenko, A. S. Shtepanek, and A. V. Kirsanov, J. Gen. Chem. (U.S.S.R.),1976,46,245.

221

Phosphazenes

also be obtained from aminophosphonium salts as shown in reaction (6), where R is an alkyl group. Ph3;NH, C1' + [CCl,=NR,]'

C1' -+

Ph,P=N-CC&NR,

+ 2HCl

(6)

Other N-chloroalkylphosphazenes(64;R2= CCl, or CF,; X=C1 or Br) have been synthesized6' from the compounds (63; R1=Me, Et, or Ph; R2=CC13or CF,). (R'02C),C=CR2-N=PPh3

(63)

-% R2CX2-N=PPh3

+ C&(CO,R'),

(64)

The compound Na+ [Me,SiN=PPh ,==NSiMe,]- undergoes a ready reaction with Me,PCl, to give Me3P=NPPh2N=PMea,68 and the intermediate Me,SiN= P(Ph,)N=PMe, can also be isolated if the reaction conditions are suitably chosen. Several new P-trialkyl- or -triaryl-phosphazenes, which form complexes with organometallic compounds, have been described.6BThus, R,P=NGeMe, (R= Me, Et, or Ph) (prepared by no less than three different routes, uiz. R,P+Me,GeN,, R,P=NH + Me,GeCl + base, and R,P=NGeCl, + MeLi) forms the complexes (65) on reaction with Me,Al,OEt,. Simple 1:1 adducts of N-siIylphosphazenes Me3P= N-SiMe,OSiMe,,Me,M (M = Al, Ga, or In) and Me,P=N-%Me,-N=PMe,,Me3M (M=Al, Ga, or In) have been prepared,60with nitrogen again forming a dative bond to M. A feature of the latter series is that there is fast exchange of the

Me,M molecules between the nitrogen atoms of the diphosphazene in solution at ambient temperatures. An analogous rapid proton transfer is encountered 61 in the lHn.m.r. spectrum of (66),andit proceeds by an intra- and an inter-molecularmechanism. This phosphazene (66) was obtained by the route shown in Scheme 6. ComMe,P+ Br-

A

Me,P=CH,

Reagents: i, NaNHa; ii, Me4P+ Br-

6 Me,P=NNa

& Me,P=N-Me,P=CH, (66)

Scheme 6

pound (66) forms the complexes (67) when it reacts with GaMe, and (68) with ZnEt, or CdMe,. Reactions with ammonium halides also provide a convenient route to the salts [Me3P==N=PMe3]+X- (X = C1, Br, or I). 67

58

59 60 81

N . D. Bodnarchuk and V. V. Momot, J. Gen. Chem. (U.S.S.R.), 1976,46, 1027. W. Wolfsberger and W. Hager, Z . anorg. Chem., 1976, 425, 169. W. Wolfsberger, 2.Naturforsch., 1977, 32b, 152. W. Wolfsberger, J. Organometallic Chem., 1976, 122, 5. H. Schmidbaur and H.-J. Fiiller, Angew. Chem. Internat. Edn., 1976, 15, 501.

Organophosphorus Chemistry

222 Me, P-CH, Nc \&Me, $. / Me, P-CH,

(6 7)

M (68) M = Zn or Cd

P-Triarylphosphazenes undergo 62 ortho-metallation reactions with PdClc2- salts, and leaving the complexes (69). The complex Ph3P=NH,SbC15 has been its i.r. and 31Pn.m.r. spectra have been discussed.

(69) Ar = C,H, Me-m, *Me-p,or OMe-p

Salts containing the cation Iph,P=-N.r=PPhJ+ (hereafter described as C+) are gaining wide acceptance in the preparation of anionic transition-metal species, and details of several crystal structures have appeared. There is now evidence64for the formation of ion pairs in the complex salt C+[Fe(CO)NO]-, with a N - 0 . * .C+ interaction that can determine the reactivity of the anion, for example in reactions with iodine. Associative effects have also been observeds5 in the species C+A(A- =BPh4-, HFe(CO),-, Co(CO),-, V(CO),-, or p-H[Cr(CO)&-) when in solution in THF. Of the physical properties of the acyclic phosphazenes, the electron-donor properties of HN=NH, H2C==NH, and H,P=NH have been compared by M.O. (PPDP/2) calcUlationsY6* and the relative basicities of Ph,P=NR (R =H or aryl) measured 13' by detection of the hydrogen bonding that occurs to propanol and chloroform by i.r. spectroscopy. The latter measurements show that the phosphazenes are stronger bases than the analogous ketimines Ph,C=NR. An interesting series of 13Cand 31P n.m.r. data on the phosphazenes Ph3P=NR [R=Ph, CPh,, SiMe,, COPh, Tos, N=CH2, N=CHC02Et, or N=C(CO,Me),] and some of their adducts have been compared with the results of CND0/2 calculations.6sEvidence was obtained for the dissociative process (7), e.g. for R = CO,Me, which moves to the right at higher Ph,P=N-N=CR, 69

63 64

65 66 67 68

* Ph3P + N,C&

(7)

H. Alper, J . Organometallic Chem., 1977, 127, 385. W. Buder and A. Schmidt, Spectrochim. Acta, 1976, 32A, 457. K. H. Pannell, Y . 4 . Chen, and K. L. Belknap, J.C.S. Chem. Comm., 1977, 362. M. Darensburg, H. Barros, and C. Borman, J. Amer. Chem. SOC.,1977, 99, 1647. N. N. Kharabaev, V. A. Kogan, 0. A. Osipov, and 1.-I. Zakharov, Teor. i eksp. Khim., 1976,12,

398 (Chem. A h . , 1976, 85, 130915). Yu. P. Egorov, E. V. Ryl'tsev, I. F. Tsymbal, and G . A. Kalyagin, Teor. i eksp. Khim., 1976,12, 336 (Chem. Abs., 1976,85,93639). T. A. Albright, W. J. Freeman, and E. E. Schweizer, J. Org. Chem., 1976, 41, 2716.

223

Phosphazenes

temperature. A further instalment of the continuing study of the electronic spectra of P-triarylphosphazenes R1R2R3P=NR4(R1-R4 = aryl) has appeared.6g 4 Synthesis of Cyclic Phosphazenes Compounds containing a phosphazene linkage which forms part of a four-membered ring are elusive. It has now been shown that (70), claimed 7 O as the first phosphazene of this type, is in fact a mixture of the six-membered ring systems (71) and (72) in

-

which X = Cl,3The compounds (71) and (72) may be produced as shown in reactions (8) and (9), where X is F or Cl. CX,CCL,N=PCl,

t NH,Cl

CX,CCI,N=PC1,

t NH,Cl

(71) t HCl

f

(72) t HC1

+ (CX,CN),

(NPCI,),

(8)

(9)

The reactions of N-chloroalkylphosphazeneswith hydroxylamine hydrochlorideto give (73) proceed in a similar manner.'l Derivatives of (73) were obtained by reactions with arylamines, with sodium aryloxides, and with acetic (or formic) acid. The latter is noteworthy in that the proton of the hydroxy-group in (74) does not migrate to nitrogen.

R

(73) R = CCl, or CF,

Another route to this type of cyclic phosphazene is provided72by the reaction shown in Scheme 7. Like (73), (75) is hydrolysed by acid to give a hydroxy-phosphazene. Publications dealing with improvements in the synthesis of N3P,Cl, and N,P,Cl are still appearing. For example, yields from the reaction between PC15 and NHICl I. Yurchenko, 0. M. Voitsekhovskaya, I. N. Zhmurova, and V. G. Yurchenko, J. Gen. Chem. (U.S.S.R.),1976, 46, 251. V. P. Kukhar', T. N. Kasheva, and E. S. Kozlov, J. Gen. Chem. (U.S.S.R.), 1973, 43, 741. V. P. Kukhar' and T. N. Kasheva, J. Gen. Chem. (U.S.S.R.), 1976, 46, 239. V. P. Kukhar' and A. P. Boiko, J. Gen. Chem. (U.S.S.R.),1976, 46, 2132.

139 R. 70

71 73

224

Organophosphorus Chemistry R1CH2CN + R2CCI,N=PCl,

-+ R ' C f C l , Rz\ N

+

HCL

c1 R' = H,C1, or alkyl (75) R2 = CCI, or CF, Scheme 7

are optimized by treatment of the crude cyclic products with calcium hydr~xide,?~ and new solvent-extraction procedures have been suggested. 76 Conditions for the optimization of cyclic products from the reaction between PC13, Clz, and NH3 have also been patented.76 749

5 Properties of Cyclic Phosphazenes Halogeno4erivatives.-The usefulness of t.1.c. has been adequately demonstrated77 for the analytical separation of bromocyclophosphazenes (NPBr& (n = 3-1 6). Compounds (76; X = Cl or F; Y = C1) have been fluorinated 78 by antimony triihoride to give (76; X = C1 or F; Y = F). The latter compounds undergo reactions with silyl-

amines (or lithiated amines), substitution occurringat the phosphorus atom as shown in Scheme 8. The use of a mixture of SbF, and SbC16for the partial fluorination of

,FP'

+

Me,SiNR1R2

._f

'PFNR1R2

'IJ (or LiNR1R2) GI (76) Y = F (R', R2included H, alkyl, and SiMe,)

yp

4-

(Me,Si),NR

+

R

+ Me,SiF (or LiF)

+ Me,SiF

(R = MeorEt) (76) Y = F Scheme 8

chlorocyclophosphazeneshas been recommended. Particularly good yields of the monofluorinated derivatives NsP3C16F,N4P4C17F,N6P6ClgF,and N6P6CIl1Fwere J. W. Fieldhouse, U.S.P. 3952086 (Chem. Abs., 1976, 85, 124604). M. L. Stayer, jun., T. A. Antkowiak, and M. S. Pritchard, Ger. Offen. 2627998 (Chem. Abs., 1977, 86, 140909) 75 C. R. Bergeron, Ger. Offen. 2549677 (Chern. Abs., 1976, 85,63952). 713 J. W. Hudson and T. F. Dominick, Ger. Offen. 2629932 (Chem. Abs., 1977,86, 142358). 77 V. Novobilskjr, 2. anorg. Chem., 1976, 427, 189. 7 8 G. Schoning and 0. Glemser, Chem. Ber., 1977, 110, 1148. 79 N. L. Paddock and D. J. Patmore, J.C.S. Dalton, 1976, 1029. 73

74

Phosphazenes

225

obtained, and their 19Fand 31Pn.m.r. parameters were reported. Adducts formed between N3P3CI6,or N4P4Cl and antimony pentachloride have been assignedE0 ionic formulations [N3P3Cl,]+[SbCI,]- and [N4P4CI7]+ [SbCI,]- in the solid state. These structures, and that of ~ J P 3 C 1 5 ][TaCl,]-, + were assigned on the basis of 36CI (as well as 1219123Sb) n.q.r. spectroscopic results. The sulphur-phosphorus heterocycle (77) undergoes reactions with KSCN, substitution occurring exclusively at the phosphorus atom. Compound (78) was obtained as a mixture of geometrical isomers, and these reacted with KSCN to produce the disubstituted heterocycle (79).

(78)

(77) (&-isomer)

(79)

Further details of the e.s.r. spectra of y-irradiated cyclophosphazenes have been published.s2The compounds N3P3C16,N4P4CIa, and N3P3C13(NMe,),form radical anions in which the extra electron is localized on a single phosphorus atom, but this was not the case with N3P,(NMe2), and N3P3Ph6. Amino-derivatives.-The cyclophosphazene N3P3(NH& undergoes a rapid reaction with f~rmaldehyde:~~ (80) was identified by its n.m.r. spectrum, but its isolation was N,P,(NHJ,

t HCHO

+ N3P3 (80)

precluded by rapid condensation reactions, which lead to polymeric materials. The efficiency of N3P3(NH2),as a fertilizer, compared with more conventional nitrogenand phosphorus-containing ones, has been The reactions of N3P3C16 with N-methylaniline to produce compounds (81) have been examined in detail,86 N,P,Cl,

+

NHMePh

N,P,Cl,-,(NMePh),

+

PhMeNH,' C1'

(81) n = 1 , 2 , 3 , o r 6

with the followingresults: compounds (81) were formed in which n was 1 ,2,3, and 6 ; a mixture of cis- and trans-isomers of (81 ; n = 2) was obtained; there were cis- and gem-isomers of (81 ; n = 3). The course of the reaction is different from that with other amines when n 3 3, particularly in the isolation of a cis- (rather than a trans-) 80

81

82 83 84

85

E. A. Kravchenko, B. V. Levin, S. I. Bananyarly, andT. A. Toktomatov, Koord. Khim., 1977,3, 374 (Chem. A h . , 1977, 86, 182280). E. Klei and J, C. van de Grampel, 2. Naturforsch., 1976, 31b, 1035. S. P. Mishra and M. C. R. Symons, J.C.S. Dalton, 1976, 1622. L. Meznek, J. Kabela, J. Novosad, and K. Dostal, 2.Chem., 1977, 17, 72. B. S. Chandrasekhar, G. Naggendrappa, B. V. Venkata Rao, S. S. Krishnamurthy, and A. R. Vasudeva Murthy, Current Res. (Bangalore), 1975, 5, 51. S. S. Krishnamurthy, M. N . Sudheendra Rao, A. R. Vasudeva Murthy, R. A. Shaw, and M. Woods, Indian J. Chem., 1976, MA, 823.

Organophosphorus Chemistry

226

trisamino-derivative (81 ; n = 3) and in the formation of gem-N,P,Cl,(NHPh)(NMePh),, which must involve the cleavage of an N - C bond. The cyclic compound N4P4(NH2)ahas been preparedss by the reaction of N4P,Cl 8 with liquid ammonia, and the kinetics of hydrolysis of the former compound have been studied. The replacement of chlorine atoms by ethylamino-groups in and the derivatives N4P4Cl8-n(NHEt), N4P4Cl follows a non-geminal [n= 1, 2 (two isomers), 3,4 (two isomers), or 81 have been isolated. Structures were assigned after studying the lH and ,lP n.m.r. spectra and by the preparation of mixed methoxy(ethy1amino)-or dimethylamino(ethy1amino)-derivatives.The novel squareplanar Pt2+ complexes (82; R=NHMe or NMe,) have been obtainedySaand they

(82)

show anti-cancer activity. In acid media, the salts [H2N4P4(NHMe)a]2+ IptC1J2- and [H2N4P4Me8l2+ EptClJ2- were also formed, and they too show similar activity, being the first charged platinum complexes to do so (see also Section 6). Full details 8 9 of the preparation of the bicyclic compounds (83 ;R =NHEt or NMea), which are produced in the reactions (10) and (ll), respectively, have been described. The

N4P4C18 3.

cHc'3= (83; R = NHEt)

+

(83; R = NHEt),HCl

-I-N4P4(NHEt),

(10)

NH,Et 2,6 -N4P4C16(NHEt), f

NHMe, 88

87 88

89

CHC1,

(83; R = NMeJ + N4P4(NMe,),(NHEt),

+

N4P4(NHMe,),(NHEt), ,2HCI

(1 1)

E. Kobayashi, Chem. Letters, 1976, 479; Bull. Chem. SOC.Japan, 1976, 49, 3524. S. S. Krishnamurthy, A. C. Sau, A. R. Vasudeva Murthy, R. Keat, R. A. Shaw, and M. Woods,

J.C.S. Dalton, 1976, 1405. H. R. Allcock, R. W. Allen, and J. P. O'Brien, J.C.S. Chem. Comm., 1976, 717. S. S. Krishnamurthy, A. C. Sau, A. R. Vasudeva Murthy, R. A. Shaw, M. Woods, and R. Keat, J . Chem. Res., 1977, (S)70; ( M ) 860.

227

Phosphazenes

lH and 31Pn.m.r. spectra of compounds (83 ; R = NMe, or NHEt) were reported and, unusually for cyclophosphazenes,large Eu(fod),-induced shifts in the lH (downfield) and 31P(upfield) n.m.r. spectra were detected, presumably because of N-tEu coordination by the bridging nitrogen atom. Brief information on the formation of anilino-derivatives from N3P3CI, and H2NCBH,R-p(R = H, NO2,NH2,etc.) in pyridine solution, and on the preparation 91 of structurally related compounds (84), which have applications as scorch inhibitors N,P,(NHPh),

+

RSCl

l-t,N f

N,P,(NPhSR), (84)

R = cyclohexyl

in rubber, has been published. The reaction between N3P3C16and salicyIamide is complex,gabut compounds (85) and (86) have been isolated, using triethylamine to QCN

QCN

remove the hydrogen chloride generated. The nature of these products indicated that nucleophilic attack at phosphorus occurs first by the oxygen of the carbonyl group and secondly by the nitrogen of the amido-group. Monophosphazenyl derivatives (87) of N3P3CI, and N,P,F, were prepared g3 by the reaction shown. In the fluoride series (X=F), further substitutionQ4is limited to N,P,X, + Me,SiN=PR,

---+ N,P,X,-N=PR, (87)

X = Clor F

+

Me,SiX

R = NMe,, Me, Ph, etc.

the replacement of two or three halogen atoms, depending on the bulkiness of the group R. Thus an extensive series of phosphazenyl derivatives were prepared by reactions of N3P3F6,N3P3FSPh,N3P3F4Ph2,and N3P3F6NMe2with Me,SiN=PR, (R = Me or Ph). Replacement of fluorine atoms probably occurs by a non-geminal route in these reactions. The gem-diamino-compounds (88) are the precursors of new spiro-compounds (89).96The compounds (89) can be protonated on the nitrogen atoms of the original S. K. Kakar, Textile Res. J., 1976, 46, 848 (Chem. Abs., 1977, 86, 30986). V. R. Sharma and J. A. Taylor, Ger. Offen. 2540018 (Chem. Abs., 1976, 85,47930). e2 E. J. Walsh and J. Smegal, Inorg. Chem., 1976, 15, 2565. 93 D. Dahmann, H. Rose, and R. A. Shaw, 2. Naturforsch., 1977, 32b, 236. g4 J. A. K. DuPlessis, H. Rose, and R. A. Shaw, 2. Naturforsch., 1976, 31b, 997, 95 A. Schmidpeter and H. Eiletz, Phosphorus, 1076, 6, 113.

90

91

228

Organophosphorus Chemistry

R2

(89) a; R’ = R2 = Meor Ph b; R’ = Me, R2 = Ph

(88)

phenyl-substituted phosphazene ring, and the =NH group can be metallated, or can be methylated by diazomethane. In an extensive surveys6of the 31P n.m.r. spectra of aminocyclophosphazenes, it was shown that the prediction of P N P coupling constants is more difficult than previously assumed, and 1H-{31P} INDOR results indicated that this coupling constant is generally positive. By contrast, the four-bond coupling JP-N-P-N-Pcan be positive or negative in phosphazenyl (R,P=N-) derivatives of cycfophosphazenes,s7 and may be related to the conformation of the phosphazenyl group in the solid state. Quantum calculations on a series of cyclophosphazenes,08and on the hypothetical species m3P3(NMe2)6H3]3+ and N3P3(NMe2)6,3BH3,9B support the Dewar-type P=N-P localized bonding scheme. The separation of isomeric forms of phenyl-, phenoxy-, and dimethylamino-substituted cyclotriphosphazatrienes and cyclotetraphosphazatetraenes by t.1.c. has been described.loO Alkoxy- and Aryloxy-derivatives.-The cyclophosphazene (90) undergoes lol the reactions with alcohols and with sodium alkoxides that are shown in Scheme 9. The

(93) Reagents: i, NaOR (R = alkyl); ii, ROH (R = alkyl, but not Me) Scheme 9

physical (36Cln.q.r., i.r.) and chemical properties of (91), in particular, were discussed, The ring system in (91; R=Et) is cleaved by water, as shown in reaction (12). A 96

97 98

99 100

101

R. Keat, R. A. Shaw, and M. Woods, J.C.S. Dalton, 1976, 1582. M. Biddlestone, R.Keat, H. Rose, D. S. Rycroft, and R. A. Shaw, 2.Naturforsch., 1976,31b,

1001.

J.-P. Faucher, J.-F. Labarre, and R. A. Shaw, 2. Nuturforsch., 1976, 31b, 677. J.-P. Faucher and J.-F. Labarre, Adv. Molecular Relaxation Processes, 1976, 8, 169. G. B. Kauffman, B. H. Gump, B. J. Stedjee, and R. A. Houghten, J. Chromatog., 1976,123,448. P. P. Kornuta, L. I. Derii, A. I. Kalenskaya, and V. I. Shevchenko,J. Gen. Chem. (U.S.S.R.), 1976,46, 1453.

229

Phosphazenes (91; R = Et)

Hzo:

EtCOCH(CN)Me + (EtO),P(O)OH

+

NH,Cl

(12)

thorough investigation into the course of the reaction of N,P,CI, with sodium trifluoroethoxide was reported last year (Vol. 8), and this has now been repeated for other fluoro-alkoxideslo2 NaORF [RF= CH2CF2CF2H, CH2(CF2),CF2H, or CH2(CF2)sCF2H].For RF= CH2CF2CF2H,a complete series of substitution pro(n= 1-6) were isolated by g.l.c., and 31Pn.m.r. spectroscopy ducts N3P3Cl,-n(OR~)n showed that for n = 2, 3, or 4, non-geminal products were obtained, as was the case when RF was CH2CF3,although in the latter case mixtures of non-geminal isomers were encountered. Several new spiro-alkoxy-cyclophosphazenes[94; X = CI or OMe, or X2= ORO, R = -(CH2)-2,3,or 4, -CHMeCH,-, -CClMeCHCI-, -CICH2CICH2-, -CC12CC12-,or -CHCI(CC12),-] have been isolated,lo3using a conventional preparative route (diol pyridine chlorophosphazene),and their mass spectra described.

+

+

(94)

(95)

More unusual alkoxy-derivatives of N,P,CI, are formed in the reactions with sodium salts of cellulose, which obey second-order kinetics,loaand in copolymers derived from arabinose,lo6the latter being hydrolysed by alkaline phosphatase. By contrast, (95) is not hydrolysed by this phosphatase. Relative basicity measurements,los obtained from the i.r. spectra of cyclophosphazenes mixed with phenol, show that fluoroalkoxy-derivatives N3P3(OR~), are more basic than N3P3C1,. Of the aryloxy-derivatives,a series of compounds N3P3C16(0C6H4R-p) (R = H, F, C1, Me, or OMe) have been obtainedlo7from reactions with the analogous sodium aryloxides. The trifluoroethoxy-anion CF3CH,0- is able to effect loSthe replacement of aryloxy-groups from N3P3(0Ar),, for example, to give the series N3P3(OAr)6-n(OCH,CF3), (Ar = C6H4N02-p;n = 1-5), and furthermore, the ease of replacement is in the order Ar = C,H&O,-O (or -p) > C6H4Cl-pSPh.Aniline, and the anions PhNH- or PhS-, can also be used to displace aryloxy-groups from N3P3(OAr),. Attack on the a-carbon atom of the aryloxy-group was also observed, particularly in DMF solutions, leading to aryl ethers and unidentified phosphorus-containing materials, e.g. as shown in reaction (13).

102 103

104

105 106

107

108

G. S. Gol'din, S. G. Federov, S. F. Zapuskalova, and A. D. Naumov, J. Gen. Chem. (U.S.S. R.), 1976, 46, 685. H. Rose and H. Specker, 2. anorg. Chem., 1976, 426, 275. Y.M. Won and H. C. Park, Sumyu. Konghak. Hoeji, 1976, 13, 66 (Chem. Abs., 1976, 85, 110289). I. Tabushi, H. Yamada, S. Arita, K. Yamamura, and S. Matsuo, J. Polymer Sci., Polymer Letters Edn., 1976, 14, 237. V. N. Prons, N. B. Zaitsev, M. P. Grinblat, and A. L. Klebanskii, J. Gen. Chem. (U.S.S.R.), 1976, 46,434. R. L. Dieck, J . Inorg. Nuclear Chem., 1976, 38, 2165. H. R. Allcock and L. A. Smeltz, J. Amer. Chem. Soc., 1976, 98, 4143.

0rganophosphorus Chemistry

230

Molecular motion and molecular separations in cyclophosphazene clathrates form the subject of an X-ray crystallographic and a wide-line lH n.m.r. study.looThe latter technique was used to assess the relative degree of molecular motion of benzene or p-xylene in the compounds (96) (see Section 8 for X-ray information).

R

/ \

0, /o N /p=N\,/o\ \p-N//

0 :

yR

>o

R

(96) R =

Alkyl and Aryl Derivatives.-No new routes to alkyl-substituted cyclophosphazenes have been described, although trimeric and tetrameric homologues can be interconverted on heating:l1° 3N4P4Mes

4N3P3Mes

AH =

+ 10.2kcal mol-1; AS = +

14.3 e.u.

The equilibration is accelerated by acids and inhibited by bases. In no case were substantial quantities of higher homologues or polymers obtained, and their absence was discussed in relation to interconversions between rings and polymers in halogenophosphazene, dimethylsiloxane, dimethylsilthiane, and polysulphur species. A route to the P-0-P-linked cyclophosphazenes (99) has been described,lll and is shown in Scheme 10. The reactions at the P-H bond of (97; R1= Me) with

(97) Reagents : i, Bra-pyridine

(99) a; R’ = Rz = Me b; R’ = OPh, Rz = Me Scheme 10

numerous reagents, including bromine, haloforms, olefins, thiocyanates, diols, ketones, CC1,-amines, CC1,-H,O, CC1,-MeOH, and sulphur, have been reported.l12 The S-N-P heterocycles (100) and (102) undergo preferential Friedel-Crafts 100

H. R. Allcock, R. W. Allen, E. C. Bissell, L. A. Smeltz, and M. Teeter, J. Amer. Chem. SOC., 1976,98,5120.

H. R. Allcock and D. B. Patterson, U.S.NTIS, A D Report 1976, AD-AO21932, Goo. Rep. Announce Index (U.S.), 1976, 76, 80 (Chem. Abs., 1976, 85, 124033). 111 A. Schmidpeter, K. Blanck, and J. Hogel, 2. Naturforsch., 1976, 31b, 1466. 112 A. Schmidpeter, K. Blanck, H. Eiletz, H. Smetana, and C. Weingand, Synth. React. Znorg. Metal-org. Chem., 1977, 7 , 1. 110

23 1

Phosphazenes

phenylation at the sulphur atom (Scheme 11).l13The geometrical isomers of (103) were further characterized as their dimethylamino-derivatives.

(100) X = Clor F

(103) cis- -itrans-isomers

cis-isomer Reagents: i, PhH-AlCls

Scheme 11

New arsenic-containing heterocycles (104) have been synthesized,l14using reaction

(14). In addition, a hydrochloride of (104; R1=R2=Ph) was isolated which contains [ (H,N)Ph,P-N-PPh,(NH,)]

+

R'R2AsCl,

C1 Et,N

~

P h 2II P H N y %

+

N\AgN

HC1

(14)

R'I/ \'R2

(104) a; R' = R2 = Ph b ; R1 = Ph, R2 = C1 c ; R' = R2 = Me

the P-NH-As grouping. Compound (104; R1=Ph, R2=Cl) was further characterized by the preparation of dimethylamino- and methoxy-derivatives. The 13Cn.m.r. spectra of the phenylfluorocyclophosphazenesN3P3F6-,Phn [n= 1,2 (three isomers), or 41 have been scrutinized,116and the shift of the para-carbon and the coupling constant ~ J P Chave C been related to the extent of electron withdrawal by the phosphazene ring. 6 Polymeric Phosphazenes This increasinglyimportant topic has been reviewed in general,6* l Xand 6 in terms of specific applications117of fluoroalkoxyphosphazenepolymers. A further series of catalysts for the polymerization of NsP3C16,including aluminium alkylslls and alkoxy-derivativesofN3P3CI6,llD has been proposed. Analysis of the non-polymer fractions soon after the initiation of polymerization of NaPaCI6 reveals 6s

113 114 115

116 117 118 119

J. B. van den Burg, B. de Ruiter, and J. C. van de Grampel, 2. Naturforsch., 1976,31b, 1216. D. B. Sowerby and R.J. Tillott, J.C.S. Dalton, 1977, 455. C. W. Allen, J. Organometallic Chem., 1977, 125, 215. B. R. Sant, Chem. Era, 1975, 11, 22. J. C. Vicic and K. A. Reynard, U.S. NTIS AD Report 1975, AD-A021001, Gov. Rep. Announce Index (US.), 1976, 76, 89 (Chem. Abs., 1976, 85, 47926). D. L. Snyder, M. L. Stayer, and J. W. Kang, Ger. Offen. 2637534 (Chem. Abs., 1977, 86, 140704). G. A. Ivanova, V. V. Korol'ko, and V. N. Prons, Russ. P. 531821 (Chem. Abs., 1977, 86, 17 326).

232

Organophosphorus Chemistry

that N,P,CI, is converted into N,P4CI,.120 An interesting new development is the conformational analysis of halogenopolyphosphazenes -(NPX2)n- (X = F, C1, or Br), using non-bonding intramolecularinteractions based on a Lennard-Jonespotential function and on a Coulombic term.121The results are informative122regarding the low glass-transition temperatures, the high chain flexibilities, and the conformational preferences of these molecules. Further details 123 of the temperature dependence of the torsional modulus of -(NPX,),(X = F, Cl, Br, or NCS) have appeared, and the application of (NPF& in chemical lasers has been the subject of a patent app1i~ation.l~~ Adverse viscosity characteristics of siliconepolymers can be reduced 125 by the addition of (NPC12)n. Several new fluoroalkoxyphosphazene polymers have been synthesizedl 2 ~ - l 2 O and the conformational properties of these compounds explored,130using the methods described in ref. 121. The properties of a fluoroalkoxyphosphazenerubber have been evaluated;131there are shortcomings in the processing and compounding of these rubbers, but some of these may be avoided by the addition of small proportions of silicone The properties of certain fluoroalkoxy-polymers at low temperatures can be improved by the incorporation of non-fluorinated a l k o x y - g r ~ u p sThermally .~~~ stable copolymers can be obtained134 by heating fluoroalkoxy-derivativesof N3P3C16with PhOSiMe, or with HCF2(CF2),CH20SiMe3.The physical properties of y-ray-crosslinked -[NP(OMe)2]n- and --[NP(OC6H4Et-p),In- have been The formation 136, 13' and p r ~ p e r t i e s ~of~ ~ aryloxyphosphazene --~~~ polymers have received less attention than the analogous fluoroalkoxy-polymers.141 Polymers have W. Sulkowski, V. V. Kireev, and V. V. Korshak, Vysokomol. Soedineniya, Ser. B, 1976,18,220 (Chem. Abs., 1976,84, 180701). 121 H. R. Allcock, R. W. Allen, and J. J. Meister, Macromolecules, 1976, 9, 950. 122 P. Calvert, Nature, 1977, 266, 497. 12s N. Buchholtz and H. Specker, 2.unorg. Chem., 1976,424, 296. 124 H. R. Lubowitz, U.S.P. 4003771 (Chem. Abs., 1977, 86, 98919). 125 J. Burkhardt and K. H. Wegehaupt, Ger. Offen. 2524041 (Chem. Abs., 1977, 86, 56333). 126 K. A. Reynard and A. H. Gerber, U.S.P. 4006125 (Chem. Abs., 1977, 86, 141392). 127 K. A. Reynard and S. H. Rose, U.S.P. 3948820 (Chem. Abs., 1976, 85,22283). 128 J. C. Vicic and R. W. Sicka, U.S.P. 3945966 (Chem. Abs., 1976, 85, 22610). 129 D. W. Carlson, E. O'Rourke, J. K. Valaitis, and A. G. Altenau, J. Polymer Sci., Polymer Chem. Edn., 1976, 14, 1379. 130 R. W. Allen and H. R. Allcock, Macromolecules, 1976, 9, 956. 131 P. Touchet and P. E. Patza, Elustomers Plust., 1977, 9, 3 (Chem. Abs., 1977, 86, 122648). 132 J. F. Witner and G. S. Kyker, Ger. Offen. 2614837 (Chem. Abs., 1977, 86, 6303). 133 T. C. Cheng, G. S. Kyker, and T. A. Antkowiak, U.S.P. 3972841 (Chem. Abs., 1976, 85, 120

144433).

134 135 136 137 138

139 140

141

G.S. Gol'din, S. G. Federov, and G. S. Nikitina, Vysokomol. Soedineniya, Ser. B, 1976, 18,

695 (Chem. Abs., 1976,85, 193 388).

J. E. Mark and C. U. Yu, J . Polymer Sci. Polymer Phys. Edn., 1977, 15, 371.

G. L. Hagnauer and B. R. Laliberte, J. Appl. Polymer Sci., 1976, 20, 3073. B. R. Laliberte and G. L. Hagnauer, U.S. NTIS A D Report 1976, AD-A027368, Gou. Rep. Announce Index (U.S.), 1976,76,96 (Chem. Abs., 1976, 86, 6010). K.A. Reynard and J. C. Vicic, U S . NTIS AD Report 1976 AD-A028872, Gou. Rep. Announce Index (U.S.), 1976, 76, 194 (Chem. A h . , 1977, 86, 56819). R. L. Dieck and L. Goldfarb, J. Polymer Sci., Polymer Chem. Edn., 1977, 15, 361. G. L.Hagnauer, B. R. Laliberte, R. E. Singler, S. J. Kalian, and E. R. Plumer, U.S. NTIS AD 1977,77,77 (Chem. Abs., 1977, Report 1976, AD-A032039, Goo. Rep. Announce Index (US.), 86, 122 160). G. S. Kyker, T. A. Antkowiak, and A. F. Halasa, U.S.P. 3970533 (Chem. Abs., 1976, 85, 125494).

Phosphazenes

233

been obtained142by the condensation of geminal and of non-geminal N3P3C12(OPh), with hydroquinone. The electrical conductivity of aminophosphazene polymers -[NP(NHR)&-(R =alkyl or Ph) is related to that of erni icon duct or^,^^^ and the characterization of a few arylaminophosphazene polymers has been 145 The methylaminoderivative [NP(NHMe)2 ] n forms square-planar platinum complexes on reaction with K,PtCl,. 7 Phosphazenes as Fire Retardants It is remarkable that the increase in activity in this area noted last year has been sustained, considering that phosphazenes are relatively expensive as fire retardants. Various aspects of this topic have been r e ~ i e w e d , ~ * including ~ - ~ ~ * the concept of N-P synergism14gin flame retardants. As usual, most interest centres on the propoxy- 150-163 and aryloxy-cyclophosphazenes164-178 and the flame resistance of M. Kajiwara, Sen’i Kako, 1976, 28, 440 (Chem. Abs., 1977, 86, 30344). M. Kajiwara and H. Saito, Polymer, 1976, 17, 1013. J. E. White, R. E. Singler, and S. A. Leone, Polymer Preprints Amer. Chem. SOC.,Div. Polymer Chem., 1975,16, 7 (Chem. Abs., 1977,86, 172118). 145 L. Busulini, M. Osellame, S. Lora, and G. Pezzin, Makromol. Chem., 1977, 178, 277. 146 J. Kuncicky, Horenie Org. Mater., 1975, 121 (Chem. Abs., 1976, 85, 47469). 147 P. A. Tatem and F. W. Williams, Fire Sax Combust. Mater. Internat. Symp., 1975,341 (Chem. Abs., 1976, 85, 143951). 148 M. Kajiwara, Sen? Kako, 1976,28,21, 138, 194,250, 312, 380, 504,675 (Chem. Abs., 1976,84, 181456; 85, 33757, 109869, 109237, 124917, 178231; 1977,86, 55984, 140727, respectively). 1 4 ~ 3C. V. Stevens and S. B. Sello, Proc. Symp. Text. Flammability, 1975,186 (Chem. Abs., 1976,85, 34538). l50 Ethyl Corporation, Japan. Kokai 76 70728 (Chem. Abs., 1976, 85, 194023). l 5 1 C. W. Lanier and J. T. F. Kao, U.S.P. 3974242 (Chem. Abs., 1976, 85, 144121). 152 Hoechst A.-G. Chemiefaser Lenzing A.-G., Neth. Appl. 7 5 09 847 (Chem. Abs., 1976, 85, 110050). l 5 3 J. W. Ager and T. M. Fekete, U.S.P. 3965219 (Chem. Abs., 1976, 85, 63704). 154 C. W. Lanier, J. T. F. Kao, and J. W. Hudson, Ger. Offen. 2458114 (Chem. Abs., 1976, 85, 64016). 155 B. R. Franko-Filipasic and J. F. Start, U.S.P. 3986882 (Chem. Abs., 1977, 86, 122898). 156 B. R. Franko-Filipasic, E. F. Orwoll, and J. F. Start, U.S.P. 3990900 (Chem. Abs., 1977, 86, 44673). 157 J. T. F. Kao, U.S.P. 4011089 (Chem. Abs., 1977, 86, 122869). 158 J. T. F. Kao, U.S. Publ. Pat. Appl. B 369221 (Chem. Abs., 1976, 84, 181560). 159 C. W. Lanier and J. T. F. Kao, U.S.P. 3974242 (Chem. Abs., 1976,85, 144121). 160 A. Kawai, K. Mimura, K. Kagawa, and T. Katsuyama, Japan. Kokai 76 17321 (Chem. Abs., 1976, 84, 181513). 1 6 1 J. Huepfl, M. Czermak, H. Tiechmann, and J. Paul, Ger. Offen. 2440074 (Chem. Abs., 1976, 85, 7219). 1 6 2 F. Siclari, P. P. Rossi, and R. Leoni, Ger. Offen. 2631 518 (Chem. Abs., 1977, 86, 107961). 163 C. R. Bergeron, U.S.P. 4017562 (Chem. Abs., 1977, 86, 172417). 164 T. Esaki, Japan. Kokai 76 91957 (Chem. Abs., 1976, 85, 193638). 165 J. E. Thompson, J. W. Wittman, and K. A. Reynard, Sci. Tech. Aerospace, Report, 1976, 14, Abs. N76-27424 (Chem. Abs., 1976, 85, 193391). 166 J. E. Thompson and R. W. Sicka, Ger. Offen. 2555348 (Chem. Abs., 1976, 85, 78992). l 6 7 E. J. Quinn and R. L. Dieck, J. Fire Flammability, 1976, 7, 5. 168 E. J. Quinn and R. L. Dieck, J. Fire Flammability, 1976, 7, 358. 169 T. Tsuji, T. Nishida, and S. Hikida, Japan. Kokai 76 151743; 76 151756 (Chem. Abs., 1977,86, 122849, 122850). 170 K. Hirakawa, T. Inoue, and T. Akasawa, Japan. Kokai 77 10377 (Chem. Abs., 1977, 86, 141578). 1 7 1 K. Hirakawa, T,Akasawa, M. Yano, and M. Mimno, Japan. Kokai 76 44155 (Chem. Abs., 1976, 85, 64650). 142 143 144

Organophosphorus Chemistry

234

rayon, although patents have appeared describingapplicationsof other a l k o ~ y - , ~ ~ ~ - ~ amino-,lsz-le4alkyl-,ls5and phenyl-cyclophosphazenes,186and of P-0-P-bridged cyc1ophosphazenes.l 8 Molecular Structures of Phosphazenes that have been Determined by

X-Ray Diffraction Methods

Compound

Comments

Me, Si

Fjrs t phosph(ii1)azene structure. C(Si)NPNC atoms coplanar; P-N 1.658(4) A; P=N 1.544(4) A; L NPN 104.9"

\ N-P-NBU~ /

But

[Ph,PNPPh,]+ [HOs,(CO),J-

NBut N(SiMe,), N,P3C1,-N=PPh3

Cation dimensions normal; P-N 1.55(2)A; 1.59(2)A; L PNP 144.5(10)" cis-Isomer ;forms monomer (Me,Si),NP(S)=NBuf in solution. P=N 1.529(2) A; P-N 1.662(2) A; L P=N-C 136.4(2)' Conformation of P-N-PPh, of especial interest; P=N,1.597(8) A; P-N 1.614(8)A; LPN-PC183"

Ref 1

188 189

190

T.Akasawa, K. Igi, M. Mizuno, K. Hirakawa, and M. Yano, Japan. Kokai 76 46400 (Chem. Abs., 1976,85, 125755). l 7 3 T. Akasawa, K. Igi, M. Mizuno, K. Hirakawa, and M. Yano, Japan. Kokai 76 47042 (Chem. Abs., 1976, 85, 64740). 174 T. Akasawa, M.Mizuno, M. Yano, K. Hirakawa, and K. Igi, Japan. Kokai 76 37 151 (Chem. Abs., 1976, 85, 64045). 175 T. Akasawa, M. Mizuno, M. Yano, K. Hirakawa, and K. Igi, Japan. Kokai 76 37149 (Chem. Abs., 1976, 85, 64046). 176 T. Akasawa, M. Mizuno, M. Yano, K. Hirakawa, and K. Igi, Japan. Kokai 76 34943 (Chem. Abs., 1976, 85, 34 577). 177 K. Hirakawa, T.Akasawa, M. Mizuno, and M. Yano, Japan. Kokai 76 47178 (Chem. Abs., 1976, 85, 79621). 178 Yu. V. Pokonova, I. A. Posadov, and V. A. Proskuryakov, Russ. P. 512221 (Chem. Abs., 1976, 85, 64099). 179 T. Esaki, Japan. Kokai 76 78813 (Chem. Abs., 1976,85, 144594). 180 G.S. Gol'din, S.G. Federov, and G. S, Nikitina, Russ. P. 525710 (Chem. Abs., 1977, 86, 17 609). 181 M. Yano, T. Akasawa, M. Mizuno, K. Hirakawa, and K. Igi, Japan. Kokai 76 34942 (Chem, Abs., 1976, 85, 34092). E. Kobayashi and T. Kanayama, Bull. Chem. SOC.Japan, 1977,50,307. 183 H. Maki, Japan. Kokai 76 21 000 (Chem. Abs., 1976,84, 165720). l e 4 A. Y. Garner, U.S.P. 3989702 (Chem. Abs., 1977, 86, 705). I85 R. M. Murch, U.S.P. 4002596 (Chem. Abs., 1977, 86, 73826). lS6T. Akasawa, M. Mizuno, K. Hirakawa, M. Yano, and K. Igi, Japan. Kokai 76 34938 (Chem. Abs., 1976, 85, 79540). 187 B. R. Franko-Filipasic, E. F. Orwoll, and V. C. Patel, U.S.P. 3994996 (Chem. Abs., 1977,86, 91 695). 188 C. R. Eady, J. J. Guy, B. F. G. Johnson, J. Lewis, M. C. Malatesta, and G. M. Sheldrick, J.C.S. Chem. Comm., 1976, 807. l g 9 S. Pohl, Chem. Ber., 1976, 109, 3122. IQ0 Y. S. Babu, T. S. Cameron, S. S. Krishnamurthy, H. Manohar, and R. A. Shaw, 2. Naturforsch., 1976, 31b, 999. 172

235

Phosphazenes Compound

Comments

C1, Ru(PEt, Ph),-N=PPhEt,

P-N

1.586(3)A; LPNRu 174.9(3j0. Bonding in this fragment is discussed

Ref. 191

F3 Me,P=N/

'Esi;'

Si\N=PMe,

geminal N,P,F4(NH,),

193 19* 195

196

197

1.623(4) A

192

Planar ring; for (H,N),P~-N=PBF, fragment, PA-N 1.597(5)A; PB-N 1.524(5) A; remaining P-N 1.564(5) A

193

Structure reexamined. P-N 1.59(2) A; L P-N-P 122(1)". Position of benzene in clathrate riot defined exactly because of the tumbling effect

109

Full paper ;for preliminary report see Vol. .8

194

Ni has square-planar arrangement of bonds. NAtom is co-ordinated to Ni. Nonplanar, with long adjacent bonds to P of 1.649, 1.635 A. Preparation described in ref. 195

194, 195

Dimer is formed by two H-bonds, P=O**.H-N

196

Ring has chair conformation. P-N 1.652(7) A; P-N 1.643(7) A

197

F.L.Phillips and A. C. Skapski, J.C.S. Dalton, 1976, 1448. W. S. Sheldrick and W. Wolfsberger, Z. Nuturforsch., 1977, 32b, 22. S. Pohl and B. Krebs, Chem. Ber., 1976, 109, 2622. F. R.Ahmed, Actu Cryst., 1976, B32, 3078. A. Schmidpeter, K.Blanck, and F. R. Ahmed, Angew. Chem. Internut. Edn., 1976,15,489. G . J. Bullen, P. E. Dann, M. L. Evans, M. B. Hursthouse, R. A. Shaw, K. Wait, M. Woods, and H. S. Yu, 2. Nuturforsch., 1976, 31b, 995. B. Nuber and M. L. Ziegler, Z . Nuturforsch., 1977, 32b, 134.

lS1

192

Planar (SIN), ring; P-N

Organophosphorus Chemistry

236 Compound F F-P

\ I“,

Ref.

Comments F P-N

\

\

Bridged at 2,4- rather than 2,6-positions. Ring has crown-saddle conformation

198

N,P,(NMe,),(NHEt) (NEt) [see structure (83)]

Full paper; salient features reported in Vol. 8

199

N,P,CL, (NMe,), (2, cis-4, cis-6, trans-8)

Ring has crown-saddle conformatiop. Wide variation of P-N bond lengths between 1.62 and 1.48(1) A

200

Non-planar (contrasted with N,P,Cll0); mean P-N 1.586(4) A

201

1.592(6) A

202

F

F

Mean P-N

Thermal behaviour of diffraction patterns studied

198 199 200

201 202

203

203

A. Gieren, B. Dederer, H. W. Roesky, and E. Janssen, Angew. Chern. Internat. Edn., 1976,15, 783. T. S. Cameron and Kh. Mannan, Acta Crust., 1977, B33, 443. M. J. Begley, T. J. King, and D. B. Sowerby, J.C.S. Dalton, 1977, 149. M. W. Dougill and B. Sheldrick, Acta Cryst., 1977, B33, 295. K. D. Gallicano, R. T. Oakley, N. L. Paddock, S.J. Rettig, and J. Trotter, Canad. J. Chem., 1977, 55, 304. C. R. Desper and N. S . Schneider, Macromolecules, 1976, 9,424.

Physical Methods BY J. C. TEBBY

The abbreviationsPIII,PIV,and PV refer to the co-ordination number of phosphorus, and the compounds mentioned in each subsection are usually dealt with in this order. A number of relevant theoretical and inorganic studies are included in this chapter. In the formulae, the letter R represents hydrogen, alkyl, or aryl; X represents electronegative substituents; Ch represents chalcogen (usually oxygen or sulphur); and Y and 2 are used to indicate a wide variety of substituents.

1 Nuclear Magnetic Resonance Spectroscopy Biological Applications.-Phosphorus-3 1 n.m.r. spectroscopy is becoming a valuable biological probe2 In addition to its use in the assay of phosphorus metabolites in living tissue,2 such as heart and other ~nuscle,~ it has revealed the presence of phosphorus compounds that were not previously known to be in muscle t i ~ s u eThe . ~ signal produced by inorganic phosphate appears to consist of numerous overlapping components, each depending on the unique environment of a phosphorus nucleus.6 The signals of ATP in normal and diseased muscle differ,$ and the 31Pspin relaxation times are significantly longer in malignant than in normal tissue.' Nucleotide equilibria in tumour cells have been studied.8Attention has also been focused on the phosphorus-containing components of bloods and on the binding of phosphate to haemoglobin.1° Phospholipids have been the subject of numerous reports, the ma-

1

R. E. Richards, Endeavour, 1975, 34, 118; s. J. Kohler, Diss. Abs. Internat (B), 1976, 37, 251. J. Dawson, D. G. Gadian, and D. R. Wilkie, J. Physiol., l976,258,82P; C. T . Burt, T. Glonek and M. Barany, Science. 1977, 195. 145. D. G. Gadian,- D. I. Hoult, GI K. Radda, P. J. Seeley, B. Chance, and C. Barlow, Proc. Nut. Acad. Sci. U.S.A., 1976,73, 4446; P. B. Garlick, G. K. Radda, P. J. Seeley, and B. Chance, Biochem. Biophys. Res. Comm., 1977, 74, 1256. C. T. Burt, T. Glonek, and M. Barany, Biochemistry, 1976, 15, 4850. P. J. Seeley, S. J. W. Busby, D. G. Gadian, G. K. Radda, and R. E. Richards, Biochem. SOC. Trans., 1976,4, 62. C. T. Burt, T. Glonek, and M. Barany, J. Biol. Chem., 1976,251, 2584. K. S. Zaner and R. Damadian, Science, 1975,189, 729. G. Navon, S. Ogawa, R. G. Shulman, and T. Yamane, Proc. Nut. Acad. Sci. U.S.A., 1977, 74, 87. R. J. Labotka, T. Glonek, M. A. Hruby, and G. R. Honig, Biochem. Med., 1976, 15, 311. E. T. Fossel and A. K. Solomon, Biochim. Biophys. Acta, 1976, 436, 505; B. Benko and S. Vuk-Pavlovic, Biochem. Biophys. Res. Comm., 1976, 71, 1303; W. E. Marshall, A. J. R. Costello, T. 0. Henderson, and A. 0. Machi, Biochim. Biophys. Acta, 1977, 490, 290.

237

Organophosphorus Chemistry

23 8

jority concerning 31Pchemical shift anisotropyl1 or praseodymium shift reagents.12 Complete resolution of the 13Cn.m.r. spectra of enriched phosphatidylcholine has been achieved, using an ytterbium shift reagent.13 Carbon-13 and proton relaxation times have also been usef~1.l~ Several 31Pn.m.r. studies of nucleotides and related compounds have appeared, mainly t o determine their c o n f o r m a t i ~ nand ~ ~ the dependence of conformation on pH,le but in one study, signals for two diastereoisomers were detected1' (see section on Non-equivalence; p. 248). The 13C spectra of AMP have also been analysed.l* Chemical Shifts and Shielding Effects.-Phosphorus-31. The sign convention used for expressing shifts in this Report is not the same as was used in earlier volumes. Positive chemical shifts are now downfield from 85 % phosphoric acid, and are given without the appellation p.p.m. Since both conventions are in use, it remains necessary to state the sign convention used in each paper published. BP of PI1 Compounds. A number of compounds of general formula X-P=Y have been prepared whose chemical shifts are very sensitive to the nature of the directly bonded atoms. Replacement of the carbon atoms in (l)lS by nitrogen caused an increase in values of dp from 150k 30 for (1) to 218 f 14 for (2),20 and to 326 for (3),21whereas replacement of carbon by phosphorus [as in (4)] gave a value of 8 , of -218.22 ,OSiMe,

/ RP=C\

CMe,

0

t

IR

R,NP=NR

R,P=P-P(OE

I1

t);

M. C. Uhing, Chem. and Phys. Lipids, 1975, 14, 303; J. Seelig and H. U. Gally, Biochemistry, 1976, 15, 5199; P. R. Cullis and B. De Kruyff, Biochim. Biophys. Acta, 1976, 436, 523; W. Niederberger and J. Seelig, J. Amer. Chem. SOC.,1976, 98, 3704; S. J. Kohler and M. P. Klein, Biochemistry, 1977, 16, 519. 1 2 K. Arnold, W. Gruender, R. Goeldner, and A. Hofmann, Z. phys. Chem. (Leipzig), 1975, 256, 522; A. Chrzeszczyk, A. Wishnia, and C. Springer, Chem. Abs., 1976, 86, 1374; P. W. Nolden and T. Ackermann, Biophys. Chem., 1976,4, 297; L. 0. Sillerud and R. E. Barnett, Biochim. Biophys. Acta, 1977, 465, 466. l3 B. Sears, W. C. Hutton, and T. E. Thompson, Biochemistry, 1976,15, 1635. 1 4 P. A. Kroon, M. Kainosho, and S. I. Chan, Biochim. Biophys. A d a , 1976, 433, 282; A. A. Ribeiro and E. A. Dennis, J. Colloid Interface Sci., 1976, 55, 94. 1 5 C. H. Lee,F. E. Evans, and R. H. Sarma, F.E.B.S. Letters, 1975,51,73; S . V. Zenin, Doklady Akad. Nauk S.S.S.R., 1975, 221, 1219; N. S. Kondon, F. Ezra, and S . S. Danyluk, F.E.B.S. Letters, 1975, 53, 213; F. E. Evans and R. H. Sarma, J. Amer. Chem. SOC.,1975, 97, 3215; C.-H. Lee, F. E. Evans, and R. H. Sarma, J. Biol. Chem., 1975,250, 1290. 1 6 K. Akasaka, A. Yamada, and H. Hatano, F.E.B.S. Letters, 1975,53, 339; P . J. Cozzone and 0.Jardetzky, Biochemistry, 1976,15,4853,4860; R. J. Labotka, T. Glonek, and T. C. Myers, J. Amer. Chem. SOC.,1976,98, 3699. 1 7 A. V. Lebedev and A. I. Rezvukhin, Izuest. sibirsk. Otdel. Akad. Nauk S.S.S.R., Ser. khim. Nauk, 1975, 149. 18 M. Morr, M.-R. Kula, and L. Ernst, Tetrahedron, 1975, 31, 1619. 19 G. Baker, 2.anorg. Chem., 1976,423,242. 20 J. Luber and A. Schmidpeter, Angew. Chem. Internat. Edn., 1976, 15, 111. 21 E. Niecke and R. Kroeher, Angew. Chem. Internat. Edn., 1976,15, 692. 22 D. Weber and E. Fluck, Z . anorg. Chem., 1976,424, 103. 11

Physical Methods

239

BP ofPII1 Compounds. Theoretical estimates of SP by CNDO/2 calculations required the inclusion of phosphorus d-orbitals and an adjustable parameter Zzif, which depends on the type of compound, e.g. phosphine or p h ~ s p h i t eThe . ~ ~chemical shifts of a series of cyano-compounds( 5 ; X,Y = ha1 or CN) agree with those predicted by Letcher and van Wazer’s quantum-mechanical interpretation.24 The sensitivity of BP to stereochemical changes often leads to quite large differences of chemical shift between various conformers or isomers, e.g. the axial conformer (6) has BP upfield

of the equatorial conformer,26and there is a difference of 10p.p.m. between the cis- and trans-isomers of the phosphine (7).26 Such differences can be used diagnostically. Thus the phosphorus resonances of the cis-isomers of the dioxaphospholan (8) appear downfield of those of the trans-isomer~.~~ However, there is an opposite trend for dioxaphosphorinans, which clearly shows the danger inherent in extrapolating an effect from one ring system to another. This particular difference is probably the result of a y-effect.28s29 The nature of the P-substituents can also be important ; thus, whilst the cis-isomers of the diazadiphosphetidines (9; Y = OR) give signals downfield of those of the trans-isomers,sothe trend is reversed for the di-t-butyl compounds (9; Y = The dependence of BP on bond angles enables the ring size of cyclopolyphosphines to be identified.32The chemical shift anisotro-

Pr R

23 24 25 26 27

28 29

30

31 32

\

Pr/p-p\

IPr Pr

M.Rajzmann and J. C. Simon, Org. Magn. Resonance, 1975, 7 , 334.

RP

/OH

‘Y

K. B. Dillon, M. G. C. Dillon, and T. C. Waddington, J. Inorg. Nuclear Chem., 1976, 38, 1149. S. I. Featherman and L. D. Quin, J. Amer. Chem. SOC.,1975, 97, 4349. K. Issleib, H. Winkelmann, and H. P. Abicht, Z. anorg. Chem., 1976,424,97. W. G. Bentrude and H.-W. Tan, J. Amer. Chem. Soc., 1976,98, 1850. H.-W. Tan and W. G. Bentrude, Tetrahedron Letters, 1975, 619. L. D. Quin, M. D. Gordon, and S. 0. Lee, Org. Magn. Resonance, 1974,6, 503. T. Kawashima and N. Inamoto, Bull. Chem. SOC.Japan, 1976, 49, 1924. 0. J. Scherer and G. Schnabl, Angew. Chem. Internat. Edn., 1976, 15, 772. M. Baudler, B. Carlsohn, W. Boehm, and G. Reuschenbach, Z. Nrrturforsch., 1976,31b, 558; M. Baudler, J. Hahn, H. Dietsch, and G. Furstenberg, ibid., p. 1305; L. R. Smith and J. L. Mills, J. Amer. Chem. SOC.,1976, 98, 3852.

240

Organophosphorus Chemistry

pies of the tetraphosphines (10; R=But or CF,) have also been determined.8s Changes in temperature can sometimes dramatically alter equilibria of tautomers or conformers. When this occurs, quite large changes of 6~may occur. Thus the phosphorus nucleus of the diphosphine (11) is shielded by 10.5 p.p.m. as the temperature is increased from - 50 to + 40 0C,34 and in the ester and amide derivatives of phosphonous acids (12; Y=OR or NR2) the nuclei are deshielded by 0.6 p.p.m. for each 10 "Crise.3s SP ofPIV Compounds.Phosphorus chemical shifts are generally insensitive to changes in solvent; however, the phosphorus nucleus of the oxide (13) is deshielded by 5-7 p.p.m. when the solvent is changed from chloroform to water.86The alkyl hypophosphites and thiono-analogues (14) have SP values of 15-18 and 4 1 4 2 , re0

I1

E t, PH (13) P s p e c t i ~ e l yThe . ~ ~ phosphorus-conjugated acetylenic bond consistently shifts C ~ upfield by 5-20 p.p.m.,38and the inclusion of the phosphorus atom in a five-membered ring has the opposite effect.39There can be little doubt that the latter effect is the cause of the signals' being at exceptionally low field, SP being 105-110 for the phospholen sulphides (15).40 On the other hand, very small rings, as in the phosphirans (16), produce a shielding effect.41 A quantum-mechanical interpretation of the n.m.r. parameters of 3- and 4-fluoro- or -chloro-phenylphosphines (17) and their

Ch

R / \

Z-NR (16)

(17)

chalcogenides indicates that n-bonding is largely responsible for the downfield shift of the chalcogenides, and that this is greater for the sulphides and ~ e l e n i d e sThe .~~ n-bonding concept contrasts with conclusions drawn from other theoretical studies 33 34 35

38 37

38 39

40

41 42

J. P. Albrand, A. Cogne, D. Gagnaire, and J. B. Robert, Mol. Phys., 1976, 31, 1021. S. Aime, R. K. Harris, E. M. McVicker, and M. Fild, J.C.S. Dalton, 1976, 2144. M. D. Gordon and L. D. Quin, J. Magn. Resonance, 1976,22, 149. L. D. Quin and C. E. Roser, J. Org. Chem., 1974, 39, 3423. N. B. Karlstedt, M. V. Proskurnina, and I. F. Lutsenko, J. Cen. Chem. (U.S.S.R.),1976,

46, 1942. H. J. Bestmann and W. Kloeters, Angew. Chem. Internat. Edn., 1977, 16,45; E. Fluck and W. Kazenwadel, 2. anorg. Chem., 1976, 424, 198; 2. Naturforsch., 1976, 31b, 172. F. Ramirez, J. F. Marecek, and H. Okazaki, J. Amer. Chem. SOC.,1976,98,5310; F. Ramirez, J. F. Marecek, and H. Tsuboi, Phosphorus, 1976, 6, 215; W. Winter, Tetrahedron Letters, 1975, 3913; M. A. Pudovik and A. N. Pudovik, Bull Acad. Sci. U.S.S.R., 1975, 24,880; M. El-Deek, G. D. MacDonell, S. D. Venkataramu, and K. D. Berlin, J. Org. Chem., 1976, 41, 1403; W. R . Purdum and K. D. Berlin, ibid., 1975, 40,2801. K. Moedritzer, 2. Naturforsch., 1976, 31b, 709. H. Quast, M. Heuschmann, and M. 0. Abdel-Rahman, Angew. Clzem. Internat. Edn., 1975, 15, 486; E. Niecke and W. Flick, Angew. Chem., 1975,87, 363. R . F. De Ketelaere and G. P. van der Kelen, J . Mol. Structure, 1975, 27, 25, 363.

241

Physical Methods

(see section on Carbon-13; p. 243) but it is in agreement with perturbation calculations based on reactivity studies.43The electronic distribution and conformation of iminotriphenylphosphoranesand hydrazino-analogues (18) have been discussed in the context of their 31Pand 13C n.m.r. parameters and relevant CND0/2 M.O. calculation^.^^ The chemical shifts of the iminophosphoranes (19)46and of the adducts (20)46correlate with Hammett substituent constants, and dp of the phosphonic esters (21) and phosphonyl fluorides (22) can be correlated with the log of the Ar,P=N-N-CR,

ArN=PCl$CI,

(19)

(1.8)

0

S-

+ I Bu,P-C=-NR (20)

II

YZPF (22)

(21)

sum of Taft substituent constants. The trends have been discussed in terms of varying d,-p interaction^.^' Mesomeric and inductive effects have been studied through the n.m.r. spectra of vinylphosphonates.4 8 The phosphonyl difluorides (23) have 6p and SF values which are shifted upfield as the electron-withdrawing power of Y increases. In this case also, SP correlates with substituent parameters of Y.49Steric effects on SP are often consistent within a given structural series. Thus, in a number of dioxaphosphorin chalcogenides, SP appears further downfield when the phosphoryl oxygen or sulphur atom occupies an axial orientation, as shown in (24).60* Ch

D".

II

0

Y

(23)

Se

1

(24)

II

(RO),PSeR (25)

The shielding effects of the trichloromethyl group have been compared with those of alkyl and aryl groups,62and the shielding effects of the dimethylamino-groups in tetra-azaphosphorineshave been compared with those of phenoxy-gro~ps.~~ Replacement of oxygen atoms by sulphur atoms generally causes dp of PIV compounds to shift downfield. Replacement of sulphur by selenium does not appear to cause a further shift; cf. BP 85-86 for the diselenophosphates (25)64and SP 94-99 for dithiophosphates. 43 44

45 46

47 48 49 50 51 52

63 54

B. Klabuhn, Tetrahedron, 1976, 32, 609. T. A. Albright, W. J. Freeman, and E. E. Schweizer, J. Org. Chem., 1976,41, 2716. E. S. Kozlov, S. N. Gaidamaka, and R. Kh. Sadykov, J. Gen. Chem. (U.S.S.R.), 1976,46,547. K. Akiba, T. Yoneyama, H. Hamada, and N. Inamoto, Bull. Chem. Soc. Japan, 1976,49,1970. E. T. Gainullina and M. K. Baranaev, Zhur. 8.z.Khim, 1976, 50, 1951. A. I. Razumov, S. V. Yalymova, and Yu. Yu. Samitov, Chem. Abs., 1975, 83, 96 170. L. L. Szafraniec, Org. Mugn. Resonance, 1974, 6, 565. M. Mikolajczyk, J. Krzywanski, and B. Ziemnicka, J. Org. Chem., 1977,42,190; R . D. Adamcik, L. L. Chang, and D. B. Denney, J.C.S. Chenz. Comm., 1974, 986. D. Bouchu and J. Dreux, Tetrahedron Letters, 1976, 3151. F. M. Kharrasova and V. D. Efimova, J. Gen. Chem. (U.S.S.R.), 1976,46,2150. J. P. Majoral, R. Kraemer, J. Navech, and F. Mathis, Tetrahedron Letters, 1975, 1481. N. I. Zemlyanskii, L. M. Dzikovskaya, V. V. Turkevich, and A. P. Vas'kiv, J . Gen. Chem. (U.S.S.R.), 1976, 46, 1447.

242

OrganophosphorusChemistry

of Pv Compounds. The chemical shifts of pentaco-ordinated phosphoranes, in general, vary remarkably little with variation of the atoms (if they are members of the first two Periods) which are bound to phosphorus.S6~ It was therefore of particular interest to find that the tricyclic phosphorane (26) has QP 31.6, far downfield of the usual region for P V compounds, and in the region for salts and It appears, therefore, that steric effects may have to be taken into account even when quite small structural changes are made. The presence of one five-membered ring QP

d /\

O+X

Et

OAr

X ( 2 6 ) X = CF,

0

(28)

(27)

does not usually cause excessive shifts, yet it is claimed that the hydroxyphosphoranes (27) are responsible for resonances at 6p 58-75, which is very close to those of the phospholen oxides (28).68The chemical shifts of the oxyphosphoranes (29) are relatively insensitive to changes in electron-donor power of the aryl substituents. Thus, changing Y from halogen to methyl shifts 8p downfield by 1.4 p.p.m.66 A

Ph (2%

\

(30)

transitory signal at dr -59.5 that was observed during the reaction of a phosphonium ylide with a phosphite-ozone adduct was attributed to the Wittig-intermediate G. G. Furin, T. V. Terent'eva, A. I. Rezvukhin, and G. G. Yakobson, J. Gen. Chem. (U.S.S.R.), 1975, 45, 1441; R. Appel and I. Ruppert, Chem. Ber., 1975, 108, 919; M. Fild, W. S. Sheldrick, and T. Stankiewicz, 2.anorg. Chem., 1975, 415, 43; J. V. Weiss and R. Schmutzler, J.C.S. Chem. Comm., 1976, 16, 643; H. B. Stegmann, H. V. Dumm, and K. B. Ulmsschneider, Tetrahedron Letters, 1976, 2007; M. F. Chasle-Pommeret, A. Foucaud, M. Leduc, and M. Hassairi, Tetrahedron, 1975, 31, 2775; T. Kh. Gazizov, Yu. I. Sudarev, and E. I. Gol'dfarb, J. Gen. Chem. (U.S.S.R.), 1976,46, 920; F. Ramirez, M. Nowakowski, and J. F. Marecek, J. Amer. Chem. SOC.,1976, 98, 4330; A. Skowronska, J. Mikolajczak, and J. Michalski, J.C.S. Chem. Comm., 1975,986; I. L. Knunyants, U. Utebaev, and E. M. Rokhlin, Bull. Acad. Sci U.S.S.R., 1976, 25, 853; M. Wilson, R. Burgada, and F. Mathis, Compt. rend., 1975, 280, C, 225; W. Stec, B. Uznanski, D. Houalla, and R. Wolf, ibid., 1975, 281, C, 727; W. Zeiss, Angew. Chem. Internat. Edn., 1976, 15, 555. 56 V. V. Vasil'ev, V. B. Lebedev, and N. A. Razumova, J. Gen. Chem. (U.S.S.R.), 1976,46,1690. 57 H. A. E. Aly, J. H. Barlow, D. R. Russell, D. J. H. Smith, M. Swindles, and S. Trippett, J.C.S. Chem. Comm., 1976,449. 58 N. A. Kurshakova, N. A. Razurnova, and A. A. Petrov, J. Gen. Chem. (U.S.S.R.), 1976,46, 1693; N. A. Kurshakova and N. A. Razumova, ibid., p. 1023. 66

Physical Methods

243

oxaphosphetan (30).69The chemical shifts of the related four-, five-, and six-coordinated species (31)-(33) showed regular upfield shifts.6o + Me,PF,

Me,PF,

Me, FF,

(31)

(32)

(33)

Carbon-13. The a-carbon resonance of phosphabenzene (34) appears at low field, possibly due to the diamagnetic anisotropy of the phosphorus atom.60The stereochemistry of the cyclohexylphosphine (35) was confidently assigned from its C-13 Ph

(34)

(35)

(36)

chemical shifts in combination with its proton spectra.61Quite pronounced differences in 6c are observed for the cis- and trans-isomers of heterocycles such as (36). As found for Q P , discussed ~ ~ above, the trends may be opposite in direction for fiveand six-membered rings.62The trend may also be reversed if there is a change in the axial or equatorial orientation of the substituents.28The shielding effects of phosphorus groups on the a-carbons of alkyl chains are quite large (15-30p.p.m.), although @-effectsare quite small (0-3 p.p.m.).29$6 3 The y-effects are also small (0.2-1.6 p.p.m.) along an aliphatic chain, e.g. (37),29but they are larger for diphosphine di~ulphides.~~ The deshielding @-effectby the PH2 group in the cyclohexyl compound (38; Y=H) is the largest (8.3 p.p.m.) of any phosphorus group so far

(37)

(38)

(3 9)

examined, although its a-effect is negligible.64Carbon-13 n.m.r. spectroscopy has been applied by a number of workers to the study of phosphonium ylides (39). The values of the chemical shift of the ylidic carbon atom (3.2-78 p.p.m.) are in the same region, but with a wider range than those of the corresponding s a l t ~ . ~ ~ - ~ ' However, for P-aryl compounds, the aryl C-1 atom is deshielded by 14 f2 p.p.m. in the ylides compared to the salts.66The 13Cn.m.r. spectra of the allylidenephosphorane (40) and its methyl derivatives have been recorded. Within the complex of peaks 59 60

61 62

63 64

6s 66 67

H. J. Bestmann and L. Kisielowski, Angew. Chem. Internat. Edn., 1976, 15, 298. M. Brownstein and R. Schmutzler, J.C.S. Chem. Comm., 1975, 278; A. J. Ashe, R. R. Sharp, and J. W. Tolan, J . Amer Chem. SOC.,1976,98, 5451. A. M. Aguiar, C. J. Morrow, J. D. Morrison, R. E. Burnett, W. F. Masler, and N. C. Bhacca, J. Org. Chem., 1976, 41, 1545. J. Martin and J. B. Robert, Org. Magn. Resonance, 1975, 7 , 76. R. B. King and J. C. Cloyd, jun., J.C.S. Perkin 11, 1975, 938. M. D. Gordon and L. D. Quin, J. Org. Chem., 1976,41, 1690. T. A. Albright. M. D. Gordon, W. J. Freeman, and E. E. Schweizer, J. Amer. Chem. Soc., 1976,98, 6%9:

M. Seno, S. Tsuchiya, H. Kise, and T. Asahara, Bull. Chem. SOC.Japan, 1975,48,2001. K . A. Ostoja Starzewski, and H. Tom Dieck, Phosphorus, 1976, 6, 177.

244

0rganophosphorus Chemistry

associated with the spz-hybridizedcarbons, the a-signal is at highest field, followed by the y-signal and the almost normal /?-signal.The shifts correlate with the CNDO computed partial charges on carbon, with a slope of 240 p.p.m. per unit charge.gs Thus it appears that the charge on carbon and the related l / r 3 dependence on the paramagnetic term (i.e. the radius of the p,-orbital) are responsible for the shifts. It H the ylidic carbon of several ylides varied little as is interesting to note that ~ J Cfor /

H

the phenyl groups on phosphorus were replaced by methyl groups; 6 9 the 150 Hz coupling corresponds to sp2 hybridization. Further, the inclusion of d-sets in ab initiu calculations based on the ylide (41) had no dramatic effect on the carbonporbital, which is distorted far into the bonding region of the phosphorus atom.7o Thus the effect of the d-orbitals appears to be one of polarization rather than the formation of a n-bond.71The shorter P-C bond is attributed to coulombic forces and to the deformation of the H.O.M.O. into the bonding region.70The aryl substituent effects on 6c-a of benzoyl-stabilized ylides (42) correlate with ornin the sense that electron-withdrawingsubstituentscause deshielding. The carbonyl carbon atoms correlate in the reverse manner, and the extent of the shift is twice that of the ylidic carbon and greater than in the corresponding acetophenone.7 2 The deshielding of the axial methyl resonance in the phosphorinol sulphide (43) has been attributed to steric compre~sion,~~ whereas the deshielding of the p-carbon in the phospholen sulphides (44)has been attributed to polarization of the n-electrons towards the phosCh

(43)

(44)

(45 1

phorus atom. 7 4 Carbon-13 n.m.r. studies of methylene-bridged phosphonyl compounds 7 6 and aryl-substituted fluorophosphazenes7 6 have also been reported. Fluorine-19. Further work on the use of 6~ for estimating electronic effects has been reported. Both fluorophenylphosphines and their chalcogenides (45) gave positive 68 139

7O 71 72

73 74

75 76

K. A. Ostoja Starzewski, H. Tom Dieck, and H. Bock, J. Amer. Chem. SOC.,1976,98, 8486. K. A. Ostoja Starzewski and M. Feigel, J, Organometallic Chem., 1975, 93, C20. H. Lischka, J. Amer. Chem. SOC.,1977, 99, 353. D. A. Bochvar, N. P. Gambaryan, and L. M. Epshtein, Uspekhi Khim., 1976, 45, 1316. P. Froeyen and D. G. Morris, Acta Chem. Scand. (B), 1976,30, 790. L. D. Quiii, A. T. McPhail, S. 0. Lee, and K. D. Onan, Tetrahedron Letters, 1974, 3473. C. Symes, jun., and L. D. Quin, J. Org. Chem., 1976, 41, 1548. W. Althoff, M. Fild, and H. P. Rieck, 2. Naturforsch., 1976, 31b, 153. C. W. Allen, J. Organometallic Chem., 1977, 125, 215.

Physical Methods

245

01values for the phosphorus groups. The phosphoryl groups had mesomeric accepting properties which increased in the order PSe < PS < PO.77 The resonance and inductive interactionsof the phosphinimino-group have been similarly investigated.7 8

Oxygen-I7 and Nitrogen-15. The pulsed Fourier-transform n.m.r. technique is providing a probe into the changes of environment of oxygen and nitrogen nuclei. For phosphoryl and PN compounds in particular, the data promise to provide information which will help clarify the information obtained from other nuclei.79 Hydrogen-I. Proton chemical shifts and kinetic evidence indicate that there is a P. -0interaction in ortho-anisyl-phosphines(46).80 The downfield shift of NH or OH resonances when they are hydrogen-bonded is frequently used to identify isomers such as (47).81However, when hydrogen-bonding is present in both isomers,

-

Me

(46)

(47)

(48)

and the magnetic anisotropies of the basic sites differ, the most strongly hydrogenbonded isomer does not always give a proton signal at lowest field; thus although the trans-enol (48) has OH 14.6, compared to 13.3 for the cis-enol, the latter predominates in most Equilibria and Shift Reagents.-Tautomeric mixtures have been observed in phosphorus n.m.r. spectra. The thiophosphonite (49) contains 40 % of the phosphite tautomer (50),83and a sample of the anhydride (51) contains the phosphoryl com-

pound (52).84 It has also been shown that the j3-formyl salt (53), in chloroform solution, contains both cis- and trans-enol t a u t o m e r ~and , ~ ~ that the dihydrazides (54) 77 78 79 80

81 82

83 84

85

9

R. F. De Ketelaere and G. P. van der Kelen, J. Mol. Structure, 1975, 27, 33. S. Yolles and J. H. R. Woodland, J. Organometallic Chem., 1975, 93, 297. G. A. Gray and T. A. Albright, J. Amer. Chem. SOC.,1976, 98, 3857; G. Grossmann, M. Gruner, and G. Seifert, 2. Chem., 1976, 16, 362. W. E. McEwan, J. E. Fountaine, D. N. Schulz, and W. I. Shiau, J. Org. Chem., 1976,41, 1684. G. Baccolini and P. E. Todesco, Tetrahedron Letters, 1976, 1891 ;J. Y . Merour, T. T. Nguyen, and P. Chabrier, Compt. rend., 1975, 280, C , 473. A. N. Pudovik and R. D. Gareev, J. Gen. Chem. (U.S.S.R.), 1976, 46, 456. E, E. Nifant’ev, A. I. Zavalisbina, and S. F. Sorokina, J. Gen. Chem. (U.S.S.R.), 1976,46,469. V. L. Foss, Yu. A. Veits, N. V. Lukashev, and I. F. Lutsenko, J . Organometallic Chem., 1976,121, C27. N. A. Nesmeyanov, S. T. Berman, and 0. A. Reutov, Bull. Acac!. Sci. U . S . S . R . , 1976, 25, 223.

246

Organophosphorus Chemistry

are extensively in the iminol form.8s The change of 8~ upon addition of sulphuric acid to phosphoryl and thiophosphoryl compounds gave titration curves which showed a good correlation of basicity constant with substituent constants if the

0

ll P I ~ , ~ H , C HxO RP(CH,CONHNHJ, (5 3)

(54)

Me

I

(RO),P=O,H,O (55)

Y,P S--H

.

**

S

(56)

compounds were considered in two groups; (a) oxides and thiolic compounds, and (6) compounds possessing POR and POH groups.87Equilibria involving hydrates (55) 8 8 and dimers (56) 8 9 have been followed, using 8H20 and BSH, respectively. A study of the shifts produced by europium and praseodymium reagents on a series of ethoxy and ethyl phosphinous and phosphoryl compounds showed that the phosphorus shifts of the phosphines and phosphoryl compounds differed from the proton and carbon shifts in that they were dominated by contact interactions. Large pseudocontact phosphorus shifts for triethyl phosphite indicate that there is little direct P - .La interaction.OOShift reagents have been used in the stereochemical assignments of some bicyclic oxides such as (57) O1 and the conformational analysis of dioxaphosphorinans (58) O 2 and dithiaphosphorinans (59).ss The conformational

equilibria of the former were sometimes altered by the presence of the lanthanide. Shift reagents have been used to detect diastereotopic groups in a-aminophosphonic esters 9 4 and to assist studies of phosphatidyl~holines.~~ Pseudorotation.-Ab initio calculations on the hypothetical phosphorane (60) indicated that the relative tendency of ligand Y to occupy an apical site is OR> R > 0-, 86

87 88 89

91 92

93 94

95

A. I. Razumov, T. V. Zykova, R. L. Yafarova, R. K. Ismagilov, and N. A. Zhikhareva, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1687. N. K. Skvortsov, G. F. Tereshchenko, B. I. Ionin, and A. A. Petrov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 518. G. P. Savoskina and E. N. Sventitskii, Zhur. strukt. Khim., 1975, 16, 306. V. K. Pogorelyi, I. I. Kukhtenko, and T. F. Divnich, Teor. i eksp. Khim., 1975, 11, 242. T. A. Gerken and W. M. Ritchey, J. Magn. Resonance, 1976,24, 155. Y. Kashman and 0. Awerbouch, Tetrahedron, 1975, 31, 45, 53; 0. Awerbouch and Y . Kashman, ibid., p. 33. P. Finocchiaro, A. Recca, and W. G. Bentrude, Chimicae Industria, 1976,58,45 1 ;P. Finocchiaro, A. Recca, W. G. Bentrude, H. W. Tan, and K. C. Yee, J. Amer. Chem. SOC.,1976,98,3537; L. L. Chang and D. B. Denney, J. Org. Chem., 1977,42,782; A. J. Dale, Acta Chem. Scand. (R), 1976,30,255. B. E. Maryanoff and R. 0. Hutchins, J. Org. Chem., 1977, 42, 1022. V. A. Bidzilya, N. K. Davidenko, and L. P. Golovkova, Ukrain. khim. Z h u . , 1976,42, 1150. B. Dekrui-iff, P. R. Cullis, and G. K. Radda, Biuchim. Biuphys. Acta, 1975, 406, 6 ; K. K. Yabusaki and M. A. Wells. Biochemistry, 1975, 14, 162.

247

Physical Methods

c ’ :,

and that the phosphoryl oxygen’s apical preference is not altered by the presence of bulky substituent~.~~ Experimental measurements on the phosphoranes (61) showed H

I

“-pH

Me-P

OAr ,OAr

I I \OAr

H

OAr

(6 0)

(61)

Z

1 /OMe I OMe

OMe

(62)

that intense steric crowding, as in (61 ; Ar = 2,6-dimethylphenyl), slows ligand reorganization.97 Variable-temperature n.m.r. spectra of some trimethoxyphosphoranes (62) exhibit some remarkable differences of Tc.g8 Pseudorotation barriers of some bicyclic oxyphosphoranes 99 and caged polycyclic phosphoranes, e.g. (63),loo have been reported. In the caged compounds, the presence of one or more fivemembered rings inhibited pseudorotation. Pseudorotation of a number of di- and

F3cMcF3 s s

B

F

‘P’

tri-fluorophosphoraneshas also been investigated.l0lPlo2When an amino-substituent was present, as in (64), 13C n.m.r. showed that P-N bond rotation was not an important factor.lo2 Restricted Rotation.-The PN compounds (65), in which the phosphorus atom bears electronegative substituents (X=ha1 or CF,) and the nitrogen atom bulky groups (Y = But or SiMe,), exhibit rotational hindrance about the P-N bond at room temperature.lo3Four-co-ordinate compounds (66) and (67) exhibit lower barrier~.~*41 lo5 The possibility that n-u* directional z-bonding also contributes to restricted rotation has been discussed.lo4Cyclophosphamide has been studied,lo6and evidence for C. A. Deakyne and L. C. Allen, J. Amer. Chem. Sac., 1976,98,4076. I. Szele, S. J. Kubisen, jun., and F. H. Westheimer, J. Amer. Chem. SOC.,1976, 98, 3533. 98 B. A. Arbuzov, A. A. Musina, A. V. Aganov, R. M. Aminova, N. A. Polezhaeva, and Yu. Yu. Samitov, Doklady Akud. Nauk S.S.S.R., 1976,228, 865. 99 G. Buono and J. R. Llinas, Tetrahedron Letters, 1976, 749; R. Boigegrain and B. Castro, Tetrahedron, 1976, 32, 1283; D. Bernard and R. Burgada, ibid., 1975,31, 797. 100 B. S. Campbell, N. J. De’ath, D. B. Denney, D. Z. Denney, I. S. Kipnis, and T. B. Min, J. Amer. Chem. SOC.,1976,90, 2924. 101 J. A. Gibson, G. V. Roeschenthaler, and R. Schmutzler, J.C.S. Dalton, 1975,918; J. G . Riess and D. U. Robert, Bull. SOC.chim. France, 1975, 425. 102 J. A. Gibson and G. V. Roeschenthaler, J.C.S. Dalton, 1976, 1440. 103 0.J. Scherer and N. Kuhn, Chem. Ber., 1975, 108, 2478; R. H. Neilson, R. C.-Y. Lee, and A. H. Cowley, J, Amer. Chem. SOC.,1975,97, 5302. 104 J. Burdon, J. C. Hotchkiss, and W. B. Jennings, J.C.S. Perkin IZ, 1976, 1052. 105 J. Martin and J. B. Robert, Tetrahedron Letters, 1976, 2475. 106 W. Egan and G. Zon, Tetrahedron Letters, 1976, 813. 96 97

9*

Organophosphorus Chemistry

248

restricted rotation about the P-0 bond in steroidal phosphorofluoridates (68) has been presented.lo Non-equivalence, Configuration,and Medium Effects.-Extensive studies of the n.m.r. spectra of epimers in solution have been published by the Moscow chemists. Following observations on compounds such as the valine derivative (69), that the signals 0

\\ s

Me-P’

/

COVat

\I

EtO

obtained from a mixture of enantiomers are at different positions from those of separate enantiomers at the same concentration,loBthe role of hydrogen-bonding and the interaction of the two chiral centres was recognized.loBMore recently, the concept of Statistically Controlled Associate Diastereomerism has been developed to explain the phenomenon.11oThe effect can be observed in compounds containing only one asymmetric centre if strongly hydrogen-bonded associates are present; thus the lH n.m.r. spectrum of the optically active but optically impure amides (70; Y=Ph, CGH4NO2, or H) shows distinct signals for the P-methyl groups in the (A)-

OY

(70)

0-

(71)

and (9-enantiomers even without the addition of any optically active substanCes.111 The 31Pspectra of trisubstituted pyrophosphates (71) appear as two AB spin systems 107

108

109

110

111

G. H. Cooper and R. A. Chittenden, Org. Magn. Resonance, 1974, 6, 563. M. I. Kabachnik, T. A. Mastryukova, E. I. Fedin, A. E. Shipov, M. S. Vaisberg, P. V. Petrovskii, and L. L. Morozov, Bull. Acad. Sci. U.S.S.R., 1975, 24, 537, 1418; E. I. Fedin, L. L. Morozov, P. V. Petrovskii, M. S. Vaisberg, A. E. Shipov, T. A. Mastryukova, and M. I. Kabachnik, Doklady Akad. Nauk S.S.S.R., 1974,219, 1181. M. I. Kabachnik, T. A. Mastryukova, E. I. Fedin, A. E. Fedin, A. E. Shipov, M. S. Vaisberg, P. V. Petrovskii, and L. L. Morozov, Bull. Acad. Sci. U.S.S.R., 1975, 24, 537. M. I. Kabachnik, E. I. Fedin, L. L. Morozov, M. S. Vaisberg, P. V. Petrovskii, A. E. Shipov, and T. A. Mastryukova, Bull. Acad. Sci. U.S.S.R., 1976, 25, 58; M. I. Kabachnik, T. A. Mastryukova, E. I. Fedin, M. S. Vaisberg, L. L. Morozov, P. V. Petrovskii, and A. E. Shipov, Tetrahedron, 1976,32, 1719. M. J. P. Harger, J.C.S. Chem. Comm., 1976, 555.

Physical Methods

249

when one of the groups bound to phosphorus is optically active.l12 The apical fluorine atoms in fluorophosphoranes (72) can become non-equivalent not only by restricted rotation about a P-NHR bond113 but also by the presence of a chiral

(73

(73)

group, as in (73).11* The effects can be combined, to give four apical fluorine resonances.l16The diastereomers of the oxyphosphorane (74) 116and of the diphosphonate (75)117were observed directly in their 31Pn.m.r. spectra. They were unequally

0

Me-P-

/I

0

II

As-P-Me

I

l

Ph

Me0

l

OMe

populated for the oxyphosphorane. The chiral structure of the tris-chelate complex (76) was reflected in the presence of two sharp methyl doublets in its lH n.m.r. spectr um.l1

Ph

\

/p-p\

H

/Ph H

A chiral solvent, (+)- or (-)-1-phenylethanolamine, was used in order to distinguish the dl- and meso-forms of the diphosphine (77). The high-field signal was split into two resonances, showing it to be due to the dZ-form.llS The non-equivalence of the methoxy protons in chlorophos in various solvents and at different temperatures 112 113

114 115 116

117 118

119

V. F. Zarytova, D. G. Knorre, A. V. Lebedev, A. S. Levina, and A. I. Rezvakhin, Izuest. sibirsk. Otdel. Akad. Nauk S.S.S.R., Ser. khim. Nauk, 1975, 139. A. V. Fokin, G. I. Drozd, and M. A. Landau, Zhur. strukt. Khim., 1976, 17, 385. D. U. Robert, D. J. Costa, and J. G. Rims, J.C.S. Chem. Comm., 1975, 29; Org. Magn. Resonance, 1975,7, 291. M. Sanchez and A. H. Cowley, J.C.S. Chem. Comm., 1976, 690. J. I. G. Cadogan, R. S. Strathdee, and N. J. Tweddle, J.C.S. Chem. Comm., 1976, 891. K. M. Abraham and J. R. van Wazer, J. Organometallic Chem., 1976, 113, 265, D. Hellwinkel and W. Krapp, Phosphorus, 1976, 6, 91. J. P. Albrand and J. B, Robert, J.C.S. Chem. Comm., 1976, 876.

250

Organophosphorus Chemistry

has been studied.lZOHowever, the appearance of extra methylene resonances for hydroxymethyl compounds in carboxylic acid solvents such as TFAA was due to ester formation.121 Phosphorus-31 chemical shift anisotropies for trimethylphosphine, its oxide, and its sulphide were & 6, + 210, and + 127 p.p.m., respectively. n-Bonding will provide a cylindrical mobile electron cloud which can circulate freely when the C,,symmetry axis is parallel to the magnetic field, but which is hindered when it is perpendicular. Thus olI- oI should be positive, as is observed for the oxide and sulphide, and the smaller value for the sulphide compared to the oxide could reflect reduced nbonding. Spin-Spin Coupling.-Relationships have been derived between the PC bond length of vinylphosphorus compounds and J(HC=CH)c$s or trans.123 JPPand JPM.The larger negative value of ~JPP (-214 Hz) for the df-diphosphine (78) compared to the meso-form (79) (- 135.2 Hz), although differences in chemical shift are small, has been attributed to the preferential population of the conformers shown in (78) and (79),124and, as previously to J becoming more

(78)

(79)

negative as the lone-pairs are eclipsed. The PIII-PIII coupling constants are usually temperature-sensitive. This is especially noticeable for the very high vicinal coupling constant (80 Hz at 30 "Cand 167 Hz at - 50 "C)for a quasi-cyclic tetraphosphine.lZ6 There have been further examples of configurational assignments, e.g. for the dioxaphosphorinan (80), which are based on the magnitude of lJpse.12' The PSe couplings (ca. 230 Hz) for a number of selenophosphites (81) have also been recorded.lZ8The extremely wide range of the values of PNP coupling constants (- 35 to + 446 Hz)

K. V. Nikonorov, E. A. Gurylev, T. A. Zyablikova, and I. D. Temyachev, Bull. Acad. Sci. U.S.S.R., 1976, 25, 1341. 121 J. C. Tebby, Phosphorus, 1976, 6, 253. 122 J. D. Kennedy and W. McFarlane, J.C.S. Chem. Comm., 1976, 666. 123 S. V. Yalymova, Yu. Yu. Samitov, and A. Sh. Agishev, Zhur. strukt. Khim., 1975, 16, 991. 124 J. P. Albrand, J. B. Robert, and H. Goldwhite, Tetrahedron Letters, 1976, 949. 1 2 5 'Organophosphorus Chemistry', ed. S. Trippett (Specialist Periodical Reports), The Chemical Society, London; (a) Vol. 8, Ch. 12; (b) Vol. 7, Ch. 12. 126 M. Baudler and D. Koch, Z . anorg. Chem., 1976,425,227. 127 A. Okruszek and W. J. Stec, Z . Naturforsch., 1976, 31b, 354; W. J. Stec, R. Kinas, and A. Okruszek, ibid, p. 393. Iz8 L. Maier, Helu. Clrim. Acta, 1976, 59, 252. 120

25 1

Physical Methods

for diphosphinoamines has been attributed to changes of conformation; the geometry (82) is believed to produce large positive values.12eWhen one or more of the phosphorus atoms is tetraco-ordinated, the PNP coupling constant is usually less than 85 H d 3 *The phosphinimine (83) is an exception, and has J p ~ p 110Hz.131The trends for cyclic P-N-P compounds have also been discussed.132 JPF,JPO, and JPN.The apical trifluoromethyl groups of fluorophosphoranes exhibit relatively small 2 J p values ~ ~ (34-88 Hz) compared to equatorial groups (108-134 H z ) . ~Several ~ ~ P-15N coupling constants have been determined, and found to change in sign upon co-ordinati~n.~~, 134 Some PJ4N and P--170couplings 136 have also been recorded. JPC.The direct P-C coupling constant to the methylene carbon of the phosphiran (84; n = 1) was much larger (- 39.7 Hz) than those (+ 0.6 to - 17 Hz) for the phosphines (84; n = 3-6) with larger rings; note the rare positive sign for a PII1compound. However, the direct P-C(pheny1) couplings were all in the region -12 to - 39 Hz. The corresponding salts all had ~ J PinCthe region 46-53 H Z .The ~ ~cis~ 7 9 y

and trans-phosphines (85) and (86) also possess ~ J P values C which, although smaller, show a greater stereodependence than those of the corresponding 0 ~ i d e s . It l ~has ~ C be quite large, e.g. 169 Hz for diethyl phosphonates been found that ~ J Pcan (87),13$and even 220 Hz for dimethyl diazophosphonates (88).139The effect of substituting chlorine groups on phosphorus is usually to increase the coupling constants; isC only + 75 and + 104 Hz for the methylphosphonyl dichlorides (89; however, ~ J P 0

129

130

131 132

133 134 135 136 137

138

139

0

Ch

II (E tO),PCHY Z.

(M eO),PCN,

MePC&

(87)

(88)

(8 9)

I1

R

I1

R. J. Cross, T. H. Green, and R. Keat, J.C.S. Dulton, 1976, 1424. W. Wolfsberger and W. Hager, Z . anorg. Chem., 1976, 425, 169; M. A. Pudovik and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.), 1976, 46, 219; N. P. Grechkin, 1. A. Nuretdinov, and L. K. Nikonorova, ibid., p. 1703. W. Wolfsberger and W. Hager, J. Organometallic Cliem., 1976, 118, C65. R. K. Harris and M. I. M. Wazeer, J.C.S. Dalton, 1976, 302; 0. J. Scherer and G . Schnabl, 2. Naturforsch., 1976, 31b, 1462; R. Keat, R. A, Shaw, and M. Woods, J.C.S. Dalton, 1976, 1582; M . Biddlestone, R. Keat, H. Rose, D. S. Rycroft, and R. A. Shaw, Z. Naturforsch., 1976, 31b, 1001 ; G . Bulloch and R. Keat, J.C.S. Dalton, 1976, 1 1 13. K. I. The and R. G. Cavell, Znorg. Chem., 1976, 15, 2518. D. E. J. Arnold and D. W. H. Rankin, J.C.S. Dalton, 1976, 1130. W. J. Stec, A. Konopka, and B. Uznanski, J.C.S. Chem. Comm., 1974, 923. G. A. Gray, S. E. Cremer, and K. L. Marsi, J. Amer. Chem. SOC.,1976, 98, 2109. C. Symmes, jun., and L. D. Quin, Tetrahedron Letters, 1976, 1853; J. Org. Chem., 1976, 41, 238. N. Gakis, H. Heimgartner, and H. Schrnid, Helu. Chim. Acta, 1975, 58, 748; V. E. Bel'skii, L. A. Kudryavtseva, and A. M. Kurguzova, Bull. Acad. Sci. U.S.S.R.,1975,24, 958. P. A. Bartlett and K. P. Long, J. Amer. Chem. SOC.,1977, 99, 1267.

252

Organophosphorus Chemistry

Ch=S) and (89; Ch=0).l4O Coupling constants have also been reported for a variety of ylides and phosphonium derivatives.141 The spectra of some polycyclic phosphine sulphides showed that 2 J increases ~ ~ with an increase in ring Strong steric control of the vicinal coupling constants was observed for the cyclohexylphosphine (38 ; Y = H), 3.fPH being 9 Hz for the brans-isomer shown but only 2 Hz for the cis-isomer, in which the phosphino-group is axial.s4The difference was even larger for the dithiaphosphorinan (go), Jpscc(av) being 23.5 Hz when R is equatorial and 0.5 Hz when R is a ~ i a 1 . A l ~further ~ example is the different PNCC

(90)

(91)

coupling constants involving the non-equivalent methyl groups in the phosphine (91).144The variation of JPCCC according to the Karplus relationship has been used to determine the stereochemistry of the oxides (92)145and (93).146 0

II

Ph,PCHRCHRCOR

Y

(92)

(93)

JPH.The n.m.r. parameters of protons directly bonded to phosphorus in 550 compounds have been classified according to ~JPH, the lowest being 122 Hz for F2PHand the highest 11 15 Hz for F4PH.14' The almost doubled magnitude (642 Hz) of ~JPH fother diprotonated diphosphine (94) compared to other protonated triarylphos-

140 141

142

143 144

145 146

147

V. 1. Zakharov, Yu. V. Belov, Yu. L. Kleiman, N. V. Morkovin, and B. I. lonin, J. Gen. Chem. (U.S.S.R.),1976,46, 1391. R. Appel, F. Knoll, and H. Veltmann, Angew. Chem. Internat. Edn., 1976, 15, 315; R. Appel and W. Morbach, ibid., 1977, 16, 180; H. Schmidbaur, J. Eberlein, and W. Richter, Chem. Ber., 1977, 110, 677; H. Schmidbaur, H. J. Fueller, and F. H. Koehler, J. Organometallic Chem., 1975, 99, 353; M. S. Hussain and H. Schmidbaur, 2.Naturforsch., 1976, 31b, 721. Y.Kashman, I. Wagenstein, and A. Rudi, Tetrahedron, 1976, 32, 2427. J. Martin, J. B. Robert, and C, Taieb, J. Phys. Chent., 1976, 80, 2417. A. H. Cowley, M. Cushner, M. Fild, and J. A. Gibson, Znorg. Chem., 1975, 14, 1851. C. A. Kingsbury and D. Thoennes, Tetrahedron Letters, 1976, 3037. Y.Kashman and A. Rudi, Tetrahedron Letters, 1976, 2819. J. F. Brazier, D. Houalla, M. Koenig. and R. Wolf, Topics Phosphorus Chem., 1976, 8, 99.

Physical Methods

253

phines has been attributed to the increase in positive charge brought about by the second protonated On the other hand, JPH decreases for protonated phosphites (95) as alkoxy-groups are replaced by thioalkyl groups.149 JPC,H.The spectra of the phosphinates (96) can be rationalized in terms of JPCH being the least negative when the proton is trans to the phosphoryl group,lK0as 126 The predicted by M.O. LCAO calculations for phosphorus acids and coupling constants for a number of phosphorins l K 2and substituted vinyl compoundslK3have been recorded. The geminal coupling to the vinyl a-proton has not been used for stereochemical assignments; in fact the vicinal coupling constants of

(97)

1,2-vinylene compounds (97 ; R = H), and hence their stereochemistries, have been estimated, using the assumption that JPCHremained in the range of values 20+4 H Z . ' ~Evidence ~ for this assumption was obtained from the unsymmetrical compounds. However, the geminal coupling constant can vary more widely than this, e.g. 11 Hz for the cis-phosphonate (98) but 20.5 Hz for the 2,4dinitrophenylhydrazide of its truns-i~omer.~~~ The PCH couplings for a number of P V phosphoranes were in the range 12-26 The stereochemical dependence of the vicinal P-H coupling constant across a double bond also applies to P V phosphoranes; the oxyphosphorane (99) has J(trans)

0 0 3

C\O,Me ,COW

0-P,

c,=c

(99)

148 149 150 161 152 153

154 155 156

'H

No

(HO),P \ CH,-C

Ha\ /c-Hb

\

CO,H

(1 00)

L. J. Van de Griend, J. G. Verkade, C. Jongsma, and F. Bickelhaupt, Phosphorus, 1976,6,13 1. G. A. Olah and C. W. McFarland, J. Org. Chem., 1975,40,2582. R. D. Gareev, Yu. Yu. Samitov, and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.),1976,46, 1881. R. K. Safiullin, R. M. Aminova, and Yu. Yu. Samitov, Zhur. strukt. Khini., 1975, 16, 42. A. Naaktgeboren, J. Meijer, P. Vermeer, and L. Brandsma, Rec. Trav. cliim., 1975, 94, 92; M. S . Chattha, Chem. and Ind., 1976, 484. G. Haegele, W. Kuchen, and H. Keck, 2.Naturforsch., 1976, 31b, 1326; D. Gloyna, K. G. Berndt, H. Koeppal, and H. G. Henning, J. prakt. Chem., 1976, 318, 327. H. Christol, H. J. Cristau, and J. P. Joubert, Bull. SOC.chim. France, 1974, 2975; A. N. Pudovik and G. E. Vershinina, J. Gen. Chem. (U.S.S.R.), 1976, 46, 2385. A. J. Rudinskas and T. L. Hullar, J. Org. Chem., 1976, 41, 2411. W. Althoff, M. Fild, H. Koop, and R. Schmutzler, J.C.S. Chem. Comm., 1975, 468; H. Germa and R. Burgada, BuZl. SOC.chim. France, 1975, 2607; C . Laurenco and R. Burgada. Tetrahedron, 1976,32,2089; V. V. Vasil'ev, N. A. Razumova, and L. V. Dogadaeva, J. Gen. Chem. (U.S.S.R.), 1976, 46, 461; P. Savignac, B. Richard, Y. Leroux, and R. Burgada, J. Organometallic Chem., 1975, 93, 331; D. J. Scharf, J. Org. Chem., 1976, 41, 28; A. Schmidpeter and J. Luber, C k m . Ber., 1975, 108, 820.

254

Organophosphorus Chemistry

45.9 Hz and its cis-isomer has J(cis) 22 Hz.15' The stereochemistry of the acrylic derivative (100) was assigned from the vicinal 13C-H coupling constant, and the cis-coupling 4JPHa was larger than the trans-coupling 4JPHb.15s This trend, which is the same as that deduced earlier,169has been used for stereochemical assignments; thus the isomeric dichlorides which possessed values of *JPCH3 of 2.9-8.3 Hz were assigned the ( E ) geometry (101), whilst those showing 4JPCH3 of 0-2.5 Hz were assigned the (2)geometry.lsOThe PNNCH coupling constants of the phosphinimine (102) were assigned in the opposite manner because the authors worked on the basis

that Ha resonates to low field of Hb.lal In contrast, the four-bond couplings through saturated bonds are usually largest when the bonds possess a W configuration.la2 JPXCH and JPCXH. The vicinal couplings such as JPOCH continue to find use in the conformational analysis of The spectra of the oxathiaphospholans (103) showed that JPSCH varies with steric change to a greater magnitude than JPOCH.1a4 Values of cis- and trans-PCNH couplings of 3 and 19 Hz were observed

in the 14Nspin-decoupled spectra of the thiaformamides (104) in chloroform solution.la5 Long-range couplings ( 6 J 1.3-2.3 ~ ~ Hz) for iminothiazolines (105) have been described.ls6 Relaxation, C.I.D.N.P., and N.q.r. Studies.-The spin-lattice relaxation of diphosphines and diphosphine sulphides occurs by competing dipolar and spin-rotation 157

15s 159

160 161

162

163

164

165

166

R. Burgada, Compt. rend., 1976,282, C, 849. R. M. Davidson and G. L. Kenyon, J. Org. Chem., 1977,42, 1030. D. Danien and R. Carrie, Bull. Sac. chim. France, 1972, 1130. V. V. Moskva, T. Sh. Sitdikova, A. I. Razumov, T. V. Zykova, and R . A. Salakhutdinov,

J. Gen. Chem. (U.S.S.R.), 1976, 46, 1938. A. N. Pudovik and R. D. Gareev, J. Gen. Chem. (U.S.S.R.), 1976, 46, 946. G. A. Dilbeck, D. L. Morris, and K. D. Berlin, J. Org. Chem., 1975, 40, 1150. K. L. Marsi, J. Org. Chem., 1975,40, 1779; A. Hassner and J. E. Galle, ibid., 1976,41, 2273; R. Arshinova, R. Kraemer, J. P. Majoral, and J. Navech, Org. Magn. Resonance, 1975, 7 , 309; E. N. Ofitserov, T. A. Zyablikova, E. S. Batyeva, and A. N. Pudovik, Bull. Acad. Sci. U.S.S.R.,1976, 25, 1325; A. C. Guimaraes and J. B. Robert, Tetrahedron Letters, 1976,473; M. Revel, J. Roussel, J. Navech, and F. Mathis, Org. Mugn. Resonance, 1976, 8, 399; C. Roca, R. Kraemer, J. P. Majoral, and J. Navech, ibid., 1976, 8, 407. S. Nakayama, M. Yoshifuji, R. 0. Kazaki, and N. Inamoto, Bull. Chem. SOC.Japan, 1975, 48,3733. 0. Dahl and S. A. Laursen, Org. Magn. Resonance, 1976, 8, 1 . C. K. Tseng and A. Mihailovski, Org. Magn. Resonance, 1974, 6, 494.

255

Physical Methods

mechanisms, the relative importance depending on temperature and size of the substituents on phosphorus.ls7 Some lH and 13Crelaxation parameters and deuterium quadrupole splittings have been used to study phosphatidy1cholines.Iss Further C.I.D.N.P. studies of the oxidation of phosphites have been based on 31Pn.m.r. spectra.ls9 N.q.r. spectroscopy, which is one of the most sensitive methods for investigating molecular dynamics in crystals, has been used to study the phosphinimines (106; Y = C3C15or Poc&&) and chlorophosphoranes (1O7).l7O Structural studies by 36Cl

n.q.r. spectroscopy on the phosphazene (1O8)l7l and on chlorophosphorane-phosphonium salt equilibria172have also been reported.

2 Electron Spin Resonance Spectroscopy The e.s.r. spectra of ts and n radicals and radical ions that had been reported up to 1974 have been reviewed.173The similarity of a(P) of the PI1 amide radical (109) with values for other phosphino radicals indicated that they might have comparable

asi=(yJ N

(TmaN),+ (109)

Me

/

Me

(110)

structures, with the odd electron in a 3p,-orbital and bond angles of 95-100 O . I 7 * On the other hand, the phosphacyanine (110) had a very high a(P), 63.8 G,which 167

168

169

170

171 172

173 174

R. K. Harris and E. M. McVicker, J.C.S. Faradaj, ZI, 1976, 72, 12. R. M. Riddle, T. J. Williams, T. A. Bryson, R. B. Dunlap, R. R. Fisher, and P. D. Ellis, J. Amer. Chem. Soc., 1976,98,4286; A. A. Ribeiro and E. A. Dennis, Biochemistry, 1975,14, 3746; R. E. London, C. E. Hildebrand, E. S. Olson, and N. A. Matwiyoff, ibid., 1976, 15, 5480; B. Sears, W. C. Hutton, and T. E. Thompson, Biochem. Biophys. Res. Comm., 1974, 60, 1141; G. W. Stockton and I. C. P. Smith, Chem. and Phys. Lipids,1976, 17, 251. D. G.Pobedimskii, V. A. Kurbatov, E. P. Gol’dfarb, and A. L. Buchachenko, Bull. Acad. Sci. U.S.S.R., 1976,25,981; A. D. Pershin, D. G. Pobedimskii, V. A. Kurbatov, and A. L. Buchachenko, ibid., 1975,24, 506; D. G. Pobedimskii, A. D. Pershin, Sh. A. Nasybullin, and A. L. Buchachenko, ibid., 1976, 25, 68. V. A. Mokeeva, I. A. Kyun’tsel, and G. B. Soifer, Zhur. strukr. Khim., 1976, 17, 366; V. A. Mokeeva, I. A. Kyun’tsel, and G. B. Soifer, Zhur. fir. Khim., 1975, 49, 1020;V .A. Mokeeva, I. V. Izmest’ev, I. A. Kyun’tsel, and G. B. Soifer, V. sb. Radiospektroskopiya, 1975, 52, 59, (Chem. Abs., 1977, 86, 24 144, 24 145). P.P. Kornuta, L. I. Derii, A. I. Kalenskaya, and V. 1. Shevchenko, J. Gen. Chem. (U.S.S.R.), 1976,46, 1453. K. B. Dillon, R. J. Lynch, R. N. Reeve, and T. C. Waddington, J.C.S. Dalton, 1976, 1243. P. Schipper, E. H. J. M. Jansen, and H. M. Buck, Topics Phosphorus Chem., 1977, 9 , 407. M. J. S. Gyane, A. Hudson, M. F. Lappert, P. P. Power, and H. Goldwhite, J.C.S. Chem Comm., 1976, 623.

256

Organophosphorus Chemistry

The spectra of radical ions (111)176and may be due to twisting of the (1 12)177have been reported. Nucleotide phosphates have been studied by e.s.r. after either irradiation with X-rays,178co-ordination with Mn2+,179 or spin labelling with But

(1 11)

(112)

(113)

nitroxide.ls0A number of other nitroxide spin-labelled compounds have also been studied.lE1The thiyl radicals (113) gave no detectable e m . signals, possibly due to relaxation broadening, but their presence was established by trapping with nitromethane aci-anion.la2The fact that cyclization of unsaturated phosphoranyl radicals (114), for which a(P)= 860-900 G, to give the phosphetan (115) had occurred was RO,I

X

0-CH,

0-CH,

,Po

RO,I 1 ,P-CH-eH,

!

CH-CH,

I

X I

OR

OR

(1 14)

(115)

established by showing that a(P) had decreased to 180-200 G.le3y-Irradiation of cyclic phosphazenes gave radical ions in which the odd electron is confined to a single phosphorus atom possessing a t.b.p. c o n f i g u r a t i ~ nE.s.r. . ~ ~ ~spectroscopy has shown that X-ray irradiation of methylenediphosphonic acid produces a wide range of ~adica1s.l~~ The wide difference in pseudorotational barriers between P V phosphoranes and related phosphoranyl radicals has produced a burst of interest in variabletemperature e.s.r. spectra. Lineshape analysis of the spectra of the radical (116) showed equivalent methyl groups above -30 "C, whether R was ethyl, t-butyl, or t-penty1.lE6The aminophosphoranyl radicals (1 17) have amino-groups which are

OR (116) 175

176 177 178 179 180 181

183 184

185 186

NMe, (117)

z (118)

H.Oehling, F. Baer, and K. Dimroth, Tetrahedron Letters, 1976, 1329.

D. Griller, K. Dimroth, T. M. Fyles, and K. U. Ingold, J . Amer. Chem. SOC., 1975,97, 5526. A. G. Evans, J. C. Evans, and D. Sheppard, J.C.S. Perkin ZZ, 1976, 1 166. J. N. Herak, D. Krilov, and C. A. McDowell, J . Magn. Resonance, 1976, 23, 1. J. M. Backer and I. A. Slepneva, Analyt. Biochem., 1977, 77, 413. E. M. Gause and J. R. Rowlands, Spectroscopy Letters, 1976, 9, 237. A. V. Il'yasov, Ya. A. Levin, A. Sh. Mukhtarov, and M. S. Skorobogatova, Bull. Acacl. Sci. U.S.S.R., 1975, 24, 1545; A. Sh. Mukhtarov, A. V. Il'yasov, and Ya. A. Levin, Teor. i eksp. Khim., 1976, 12, 831; G. Sosnovsky and G. Karas, Phosphorus, 1976, 6, 123. G. Brunton, B. C. Gilbert, and R. J. Mawby, J.C.S. Perkin I I , 1976, 6 , 650. A. G. Davies and M. J. Parrott, J.C.S. Perkin ZZ, 1976, 9, 1066. S. P. Mishra and M. C. R. Symons, J.C.S. Dalton, 1976, 1622. M. Geoffroy, L. Ginet, and E. A. Lucken, Mol. Phys., 1976, 31, 745. J. W. Cooper and B. P. Roberts, J.C.S. Perkin II, 1976, 808.

257

Physical Methods

characterized by high a(N) values (ca. 12.6 G) when they occupy apical sites, and which have similar apicophilicities to a l k o x y - g r o ~ p s .On ~ ~ ~the other hand, the phosphate group appears to be more apicophilic than alkoxy-groups.ls8It has also been found that five- and six-membered rings which incorporate two P-N bonds, e.g. (1 18), resemble dioxaphospholan rings in that they bridge apical-equatorial positions and that the barrier to pseudorotation is higher for endocyclicligands than for acyclic ligands.lE7Several ethoxyfluorophosphoranyl radicals (119) were found to undergo rapid p s e u d o r o t a t i ~ n .Unrestricted ~~~ Hartree-Fock calculations on fluorophosphoranyl radicals F4P- , FBHP-,and FzHzP indicated large spin densities solely for the 3p,-orbitals of apical fluorine atoms, and also indicated that barriers to pseudorotation are higher by > 13 kcal mol-l than in the corresponding phosphoranes.lso Similar calculations were used to determine the factors which control the stereochemical change from t.b.p. to tetrahedral when oxygen functions are re-

-

€3.

H

placed by phenyl groups,1Q1and to show that d-orbitals must be included in order to calculate accurately the spin densities of n-ligand complexes of PIV compounds.1D2 Certainmonohalogeno-radicalsarealso believed to have a tetrahedral a on figuration.^^^ Changes in a(P) and a(N) of the tetrahedral nitrotetra-aryl radicals (120) have been attributed to a variation of conjugation.lg4The PH radical (121) has a(H)= 182 G, which is very large and corresponds to a 1s spin density of O.36.lg5The anion radicals produced by electrochemical reduction of p-nitrophenylphosphonic acid and its esters have been studied.lg6The factors which control the hyperfine splitting constants of H2P-,FzP-,HIP., and F4P. have been estimated by the ab initio U.H.F. method.

3 Vibrational and Rotational Spectroscopy Band Assignments and Structure Elucidation.-The conjugated A 2-phospholenscan be distinguished from A3-phospholensby the low frequency (ca. 2225 cm-l) of their P-H stretching vibrations.198The i.r. and Raman spectra of the chloride (122) R. W. Dennis and B. P. Roberts, J.C.S. Perkin 11, 1975, 140. A. G. Davies, M. J. Parrott, B. P. Roberts, and A. Skowronska, J.C.S. Perkin ZI, 1976, 1154. 189 1. H. Elson, M. J . Parrott, and B. P. Roberts, J.C.S. Chem. Comm., 1975, 586. lQo J. M. Howell and J. F. Olsen, J. Amer. Chem. Soc., 1976, 98, 7119. Igl V. V. Pen’kovskii, Chem. Abs., 1976, 85, 192 037. 1 g 2 3. M. F. van Dijk, J. F. M. Pennings, and H. M. Buck, J. Amer. Chem. Soc., 1975,97, 4836. lg3 M. C. R . Symons, Chem. Phys. Letters, 1976,40, 226. l g 4 R. D. Rieke, C. K. White, and C. M. Milliren, J. Amer. Chem. Suc., 1976, 98, 6872. l g 5 K. Nishikida and F. Williams, J. Amer. Chem. Soc., 1975, 97, 5462. Ig6 A. Sh. Mukhtarov, A. V. Il’yasov, Ya. A. Levin, A. A. Vafina, and S. S. Krokhina, Zhur. strukt. Khim., 1976, 17, 76. 197 A. Hudson and R. F. Treweek, Chem. Phys. Letters, 1976, 39, 248. 198 A. 0. Vizel, V. K. Krupnov, L. I. Zyryanova, and B. A. Arbuzov, J. Gen. Chem. (U.S.S.R.), 1976,46, 1536. lE8

10

258

Organophosphorus Chemistry

indicate the presence of a non-centrosymmetric dimer in the crystalline state.lg9 Corrections have been made to the Raman low-frequency assignments of tris(tri0

(122) (123) (124) fluoromethy1)phosphine.2oo The final locations of le0labels in the phosphorinan (123) and amidophosphate (124) were established by the shift by 30-40 cm-1 of The phosphoryl bands in the the appropriate PO band to lower frequency.201,z0a Raman spectra have been used as a mechanistic probe to follow the transfer of phosphate from ATP in a model The vibrational spectra of dioxaphospholans (125) have been assigned.204The site of methylation of the thioamide (126) was

(125)

(126)

(127)

followed by the change in Y(PS).~O~ The v(PN) band of the aminotriphenylphosphonium azide (127) and its deuterium analogues appeared in the region 889-938 cm-l, and at 1153 [v(PNH)] and 1036 cm-l [v(PND)] for the corresponding iminophosphoranes. 206 Stereochemistry.-The multiplicity of bands which arise from conformational effects have been analysed and correlated with those obtained by other spectroscopic technique~.~ Raman ~' spectra and torsional barriers at 14 and 190 K have been reported for trimethylphosphine (128), its chalcogenides, and the deuterium analogues.208 Rotational barriers have been calculated from the microwave and vibrational spectra of the difluoride (129).z09Restricted rotation about the P-N bonds of aminophos-

0

199 200

201 202

203 204

205

206 207 208

II

Me,P

MePF,

R,PNMe,

Me,CHPH,

(128)

(129)

(130)

(131)

J. R. Durig and J. E. Saunders, J. Mol. Structure, 1975, 27, 403. C.J. Marsden and L. S. Bartell, Znorg. Chem., 1976, 15, 2713. Zh. M. Ivanova, E. A. Suvalova, and I. E. Boldeskul, J. Gen. Chem. (U.S.S.R.), 1976,46,1647. Yu. G. Gololobov, I. E. Boldeskul, and T. I. Sarana, J. Gen. Chem. (U.S.S.R.), 1976,46, 1248. A. Lewis, N. Nelson, and E. Racker, Biochemistry, 1975, 14, 1532. K. R. Shagidullin, I. Kh. Shakirov, A. Kh. Plyamovatyi, L. I. Gurarii, and E. T. Mukmenev, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1017. J. Boedeker and P. Koeckritz, J. Organometallic Chem., 1976, 111, 65. W. Buder and A. Schmidt, Spectrochim. Acta, 1976, 32A,457. J. Goubeau, Pure Appl. Chem., 1975,44, 393. H. Rojhantalab, J. W. Nibler, and G. J. Wilkins, Spectrochim. A m , 1976, 32A, 519. J. R. Durig, K. S. Kalasinsky, and V. F. Kalasinsky, J. Mol. Structure, 1976,34,9.

Physical Methods

259

phines (1 30; R = Et or Ph) and their chalcogenides has also been studied.21oAnalyses of the v(PH) region of isopropylphosphine(131) and its deuterium analogue showed the presence of both gauche and trans conformers in the fluid phases.211Variabletemperature vibrational spectroscopy has also been used for the conformational analysis of various PI11 chlorides.212The conformational equilibria of thio- and seleno-pho~phinates,~~~ methylpho~phonates,~~~~ phosphonamidate~,~~~ phosp h o n t h i o a t e ~ ,dioxaphosphorinans,216 ~~~ and trialkyl phosphates 217 have also been tackled by vibrational spectroscopy. Bonding.-The intramolecular interactions in di-para-substituted arylphosphines (132) were estimated from the intensities of the y s ring-stretching band near 1600 cm-l. The PH, and PR2 groups appear to be weak electron donors, whereas PAr,, PC&,and P(OEt), are electron acceptors.218 Force constants have been calculated for dimethylsilylphosphine219 and aminomethylphosphonic acid.220There is still a keen interest in the study of hydrogen-bonding. Phosphoryl compounds are the most commonly studied,221substituent effects and correlations with Taft constants being the main area of interest.222Basicities of p h o s p h a z e n e ~the , ~ ~sites ~ of protona0

2Lo

211 212

213

214 a15

216 217

219

220

z21

222

223

A. N. Pudovik, 1. Ya. Kuramshin, N. R. Safiullina, A. A. Muratova, N. P. Morozova, and E. G. Yarkova, J. Gen. Chem. (U.S.S.R.), 1976,46, 764. J. R. Durig and A. W. Cox, jun., J. Phys. Chem., 1976, 80, 2493. A. I. Fishman, A. B. Remisov, 1. Ya. Kuramshin, and I. S. Pominov, Spectruchim. Ac fa, 1976, 32A, 651 ; D. F. Fazliev, R. R. Shagidullin, N. A. Chadaeva, N. A. Makarova, and E. T. Mukmenev, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1776; R . R. Shagidullin, D. F. Fazliev, L. I. Gurarii, and E. T. Mukmenev, ibid., 1975, 45, 1235. I. I. Vandyukova, R. R. Shagidullin, and I. A. Nuretdinov, Zzwst. Akad. Nauk. S.S.S.R., 1976, 1390. P. M. Zavlin, L. A. Ashkinazi, B. I. Ionin, and Ya. L. Iganatovich, J. Gen. Chem. (U.S.S.R.), 1976, 46, 2503; L. A. Ashkinazi, P. M. Zavlin, V. hl. Shek, and B. I. Ionin, ibid., p. 1015. L. A. Ashkinazi, P. M. Zavlin, and B. I. Ionin, J. Gen. Chern. (U.S.S.R.), 1976, 46, 921. E. I. Matrosov, A. A. Kryuchkov, and E. E. Nifant’ev. Bull. Acad. Sci. U.S.S.R., 1975, 24, 2473. 0. A. Kaevskii, A. N. Vereshchagin, Yu. A. Donskaya, A. G. Abul’khanov, and Ya. A. Levin, Bull. Acad. Sci. U.S.S.R., 1976, 25, 1889. M. I. Kabachnik, I. G. Malakhov, E. N. Tsvetkov, K. F. Johnson, A. R. Katritzky, A. J. Sparrow, and R. D. Topsom, Austral. J. Chem., 1975, 28, 755. R. Demuth, 2. anorg. Chem., 1976,424, 13. C. Garrigou-Lagrange and C. Destrade, Compt. rend., 1975, 280, C, 969. E. I. Matrosov and M. I. Kabachnik, Doklady Akad. Nauk. S.S.S.R., 1977, 232, 89; C . Madic, J. C. Saey, and L. Mangane-Le Desert, J. Inorg. Nuclear Chem., 1975,37, 1599; N. M. Turkevich, D. D. Lutsevich, and A. F. Mynka, Izoest. V.U.Z. Khim. i khim. Tekhnol., 1976, 19, 396. A. A. Shvets, E. G. Amarskii, 0. A. Osipov, and L. V. Goncharova, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1654; R . R. Shagidullin, L. Kh. Ashrafullina, and V. E. Bel’skii, Bull. Acad. Sci. U.S.S.R., 1976, 25, 778; I. P. Lipatova, Z. Z. Kurzhunova, and F. M. Kharrasova, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1251; V. E. Bel’skii, R. F. Bakeeva, L. A. Kudryavtseva, A. M. Kurguzova, and B. E. Ivanov, ibid., 1975,45, 2568. V. Prons, N. B. Zaitsev, M. P. Grinblat, and A. L. Klebanskii, J. Gen. Chem. (U.S.S.R.), 1976,46, 434.

260

Organophosphorus Chemistry

and the keto-enol tion of triphenyl phosphite 224 and aminobenzylphosphonates,225 equilibria of P-keto-phosphonates (133) 226 have also been studied. The difference in basicity between axial and equatorial phosphoryl groups, which controls the site of alkylation of cyclic has been investigated, using i.r. studies of hydrogen-bonded associates of the dioxaphosphorinans (1 34). 228 4 Electronic Spectroscopy Absorption.-It has been argued that U.V. evidence for p,, conjugation in arylphosp h i n e ~ isl ~invalid ~ ~ because the Kerr data show that the aryl rings do not have the required c ~ n f o r m a t i o nThe . ~ ~U.V. ~ absorption maxima of some cyclic arylphosphines (135; R = M e or Ph) and their oxides have been compared with their ionization potentials.230 The spectra of o-anisylphosphines(1 36) contain extra solvent-indepen-

Me

I

dent bands at 284 and 287.5 nni which are absent from those of the para-orientated isomers. The bands are part of the evidence for an intramolecularinteraction between the oxygen atom and the phosphorus d - ~ r b i t a l sThere . ~ ~ ~have been several reports on the spectra of conjugated ylides and phosphinimines,232 and some highly coloured compounds have been obtained.233 Theoretical M.O. calculations have been used to predict absorption frequencies of merocyanins and phosphocyanins.234 Intensely coloured compounds have also been produced by the diazotization of arylphosphine The U.V. spectra of spirocyclic phosphonium salts have been compared with those of the corresponding nitrogen and arsenic

224 225 226

227 228

229 230

231 232

23s 234

235

236

I. S. Akhmetzhanov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 575. G. Zuchi, G. Morait, and F. Chiraleu, Rev. Chim. (Rounzania), 1976, 27, 791. A. 1. Razumov, V. V. Moskva, M. P. Sokolov, and Z. Ya. Sazonova, J. Gen. Chem. (U.S.S.R.), 1976,46, 1936. A. P. Hong, J. B. Lee, and J. G. Verkade, J. Amer. Chem. SOC.,1976, 98, 6547. E. I. Matrosov, E. E. Nifant’ev, A. A. Kryuchkov, and M. I. Kabachnik, Bull. Acad. Sci. U.S.S.R., 1976, 25, 512. I. P. Romin and E. N. Gur’yanova, J. Gen. Chem. (U.S.S.R.), 1976, 46, 445. A. N. Smirnov, L. A. Yagodina, V. M. Orlov, A. 1. Bokanov, and B. I. Stepanov, f. Gen. Chem. (U.S.S.R.), 1976, 46, 435. W. E. McEwen, W.-I. Shiau, Y.-I. Yeh, D. N. Schulz, R. U. Pagilagan, J. B. Levy, C. Symrnes, G. 0. Nelson, and I. Granoth, J. Amer. Chem. SOC.,1975, 97, 1787. R. D. Gareev and A. N. Pudovik, J. Gen. Chem. (U.S.S.R.), 1976,46, 1424; R. I. Yurchenko, 0. M. Voitsekhovskaya, I. N. Zhmurova, and V. G. Yurchenko, ibid., p. 251 ; I. N. Zhmurova, 0. M. Voitsekhovskaya, R. I. Yurchenko, and A. V. Kirsanov, ibid., p. 229. I. V. Megera and M. I. Shevchuk, J. Gen. Chem. (U.S.S.R.), 1976, 46, 2135. N. Mishra, L. N. Patnaik, and M. K. Rout, Indian J. Chem., 1976, 14A, 56, 334. W. Kormachev, T. V. Vasil’eva, B. I. Bryantsev, and V. A. Kuktin, J . Gen. Chem. (U.S.S.R.), 1976, 46, 1244; K. A. Petrov, V. A. Chauzov, T. S. Erokhina, and L. P. Chernobrovkina, ibid., p. 491. D. Hellwinkel and H.-J. Wilfinger, Phosphorus, 1976, 6, 151.

Physical Methods

261

Photoelectron.-New information on the binding energies of phosphorus has been The orbital sequence and angular dependence of the band intensities for phospliabenzene (137)238and the nature of the lone pair of electrons of 2phosphanaphthalene (138) 2 3 9 have been studied. The p.e. spectra of phosphines and

(137) (138) the effects of substituents have been reviewed.2 4 0 The spectra of trifluoromethylphosphines 241 and of vinyl-, allyl, phenyl-, and benzyl-phosphines242 indicate the presence of P-C n-hyperconjugation. The ionization potentials of aryldicyclohexyl(139), and their oxides 2 4 4 have been measured, and p h o s p h i n e ~pyrrylphosphines ,~~~ 246 ~~ It7has been concluded that the that of phosphole (140) has been c a l c ~ l a t e d . ~

(139) (140) p.e. data in phospholes can be interpreted in terms of an aromatic ring, and that the non-planarity is due to 0 The nature of the bonding in the phosphorins (141),247 in a wide range of reactive and stabilized phosphonium ylides ( 1 4 2 ) y ~6S, z 4 8 and also in various chalcogenides2 4 9 has been studied, and there has

0 I

PhO H l Y

(141) 237 238

239 240

341 242

213 214

2 15 2.16

“47

2 18

249

R,P==CHY

(142)

I

0(143)

W. C . Lineberger, I.E.E.E. Truns. h‘urleur Sci., 1976, NS23, 934 (Chem. Abs., 1976, 84, 169 934). A. J . Ashe, F. Burger, M. Y. El-Sheik, E. Heilbronner, J. P. Maier, and J. F. Muller, Helo. Chiin. Acta, 1976, 59, 1944; M . H. Palmer, R. H. Findlay, W. Moyes, a nd A. J. Gaskell, J.C.S. Perkin ZZ, 1975, 841. W. Schaefer, A. Schweig, H. Vermeer, F. Bickelhaupt, and H. D. Graaf, J. Electron Spectroscopy Reloted Phenomena, 1975, 6, 9 I . H. Bock, Pure Appl. Chem., 1975, 44, 343. S. Elbel, H. Tom Dieck, and R. Demuth, Z. Nolur/brsch., 1976, 31b, 1472. H. Schmidt, A. Schweig, F. Mathey, and G. Mueller, Tctralzcdron, 1975, 31, 1287. H. Goetz, F. Marschner, 14. Juds, and H. Pohle, Phospirorus, 1976, 6, 137. F. Marschner, H. Kessel, and H. Goetz, Phosphorus, 1976, 6, 135. W. Von Niessen, L. S. Cederbaum, and G. H. F. Diercksen, J. Anier. Chem. Soc., 1976, 98, 2056. N. D. Epiotis and W. Cherry, J. Anicr. Clrrni. Soc., 1976, 98, 4365. W. Schaefer, A. Schweig, K. Dimroth, and €4. Kanter, J . Amcr. Chenz. SOC.,1976, 98, 4410. K. 51. A. Ostoja Starzewski and W. Richter, Chem. Ber., 1976, 109, 473; A. J. Dale, Phosphorus, 1976, 6 , 8 1. E. Fluck and D. Weber, Piire Appl. Cliem., 1975,44, 373; S . Elbel and H. tom Dieck, J.C.S. Drdton, 1976, 1762; W. B. Perry, T. F. Schaaf, and W. L. Jolly, J. Ampr. Chem. SOC.,1975,97, 4899; V. V. Zverev, F. 1. Vilesov, V. 1. Vovna, S. N. Lopatin, a nd Yu. P. Kitaev, Bid/. Acud. Sci. U.S.S.R., 1975, 24,961.

262

OrganophosphorusChemistry

been a theoretical study of the electronic structures of phosphorinone (143) and its isomers.2 5 0 5 Rotation The optically active triarylphosphine ( l a ) , [a]436=- 6.36 0,251 and the phospholan (145), [o(]D= +22.53 0 , 2 5 2 have been prepared. Nucleoside phosphates have been studied by ~ . d . ~ ~ ~

Ph-P

9

de Dco2H (144)

lP*-

Ph

(145)

6 Diffraction X-Ray.-A crystallographic study has shown that the phosphimine (146) has a NPN bond angle of 104.9 0 . 2 5 4 This remarkable feature indicates that the P-N bonds retain a large proportion of p-character, as in phosphines, with the lone-pair of

electrons being highins-character. It has been shown that steric hindrance in the phosphine (147) increases the CPC bond angles to 107-111 O, compared to 103 O for triphenylphosphine.2 5 5 The molecular structures of two tryptycene-type phosphines (148) and (149) 2 5 6 and of the phenoxaphosphine (150) 2 5 7 have been determined. The heterocyclic ring of the latter compound has a slightly boat-shaped conformation. The PNC and PCC bond angles of ylides and iminophosphoranes have been rationalized in terms of non-bonding interactions. The deformation of the endocyclic bond angle a of the phenyl ring in (151) has been found to depend on the a-electronwithdrawing or -releasing properties of the group Y and on the extent of conjugation 250 251 252

253

254 255 256

257

E. V. Borisov and E;. A. Kornienko, Zhur. .fiz. Khim., 1976, 50, 1566. R. Luckenbach, 2. Naturforsch., 1976, 31b, 1 1 35. K. L. Marsi and H. Tuinstra, J . Org. Clzem., 1975, 40, 1843. L. V. Karabashyan, A. M. Kritsyn, S. N. Mikhailov, and V. L. Florent'ev, Mol. Biol. (Moscow). 1976, 10, 367; J. Lavayre, M. Ptak, and M. Leng, Biochem. Biophys. Res. Comm., 1975, 65, 1355; M. Boublik, D. Grunberger, and Y. Lapidot, ibid., 1975, 62, 883. S. Pohl, Angew. Chem. Internat. Edn., 1976, 15, 687. A. N. Sobolev, L. A. Chetkina, I. P. Romm, and E. N. Gur'yanova, Zhur. strukt. Khim., 1976, 17, 103. D. Schomburg and W. S. Sheldrick, Act0 Cryst, 1976, B32, 1021 ; 1975, B31,2427. F. G. Mann, I. T. Millar, H. M. Powell, and D. J. Watkin, J.C.S. Perkin ZI, 1976, 1383.

263

Physical Methods

ph\

of Y with the phenyl ring. The relationship oc=3.33~+ 111.4 has been derived.a58 The mean values of o! are 118.5 for PII1compounds, 119.8 for phosphonium salts, and 119.4 for phosphonium ylides, which gives electronegativity values k)of 2.5 for the salts and 2.4 for the y l i d e ~Structures . ~ ~ ~ have been established of a mercuric complex of an ylide,260of the thiolate betaine (152),2s1 of triphenylphosphine oxide,262of the phosphocin (153),263and of the oxides (154),264(155), and (156).266 The phosphinamide (157) was found to possess a short P-N bond and a distorted O

O

O

c-NO

(1 52)

sMe

I

258

259 260

261 262

263 264

26s

(153) Me

/

G. Glidewell, J . fnorg. Nitclear Chem., 1976, 38, 669. A. Domenicano, A. Vaciago, and C. A. Coulson, Acta Cryst., 1975, B31, 1630. N. L. Holy, N. C. Baenziger, R . M. Flynn, and D. C. Swenson, J . Amer. C h ~ m SOC., . 1976, 98,7823. G . Bombieri, E. Forsellini, U. Chiacchio, P. Fiandaca, G. Purrello, E. Foresti, and R. Graziani, J.C.S. Perkin If, 1976, 1404. G. Ruban and V. Zabel, Cryst. Struct. Cumm., 1976, 5 , 671. W. Winter, Z . Naturfursch., 1976, 31b, 1 1 16. W. J. Seifert, 0. Schaffer, and K. Dimroth, Angew. Chem. fnternat. Edn., 1976, 15, 238. F. Allen, 0. Kennard, L. Nassimbeni, R . Shepherd, and S. Warren, J.C.S. Perkin ZI, 1974, 1530.

264

Organophosphorus Chemistry

trigonal arrangement of groups about the nitrogen atom. 266 The hydrogen-bonded dimeric structure (158) is forced to be out of plane by the t-butyl groups.267Inter-

(157)

(158)

(159)

molecular hydrogen-bonding causes phenylphosphonic acid to crystallize in puckered layers.268Strain in the bicyclic phosphonate (159) produces some very short C-C bonds and a torsional angle around one double bond of 29°.2G9The eightmembered ring of the phosphonate (160) assumes the crown symmetry 0

(160)

The crystal structures of glycylaminomethylphosphonic and of methane-, ethane-, and propane-diphosphonic have been determined. The unit cell of the last acid contains two molecules, with different conformations. The molecular structures of the constrained phosphite (161), the phosphate (162), and the thiophosphate (163) have been The nitrogen in the last compound is very nearly trigonal planar, and the large P--N distance (313 pm) shows that there is little P . .N interaction. The phosphazene (164) adopts a novel conformation,274 0

266

267 268

269

270

271

Mazhar-U1-Haque and C. N. Caughlan, J.C.S. Perkin I f , 1976, 1101. M. E. Druyan, A. H. Reis, jun., E. Gebert, S. W. Peterson, G. W. Mason, and D. F. Peppard, J. Ainer. Chem. Soc., 1976, 98, 4801. T. J. R. Weakley, Acta Cryst., 1976, E32, 2889. R. Hoge and G. Maas, Acta Cryst., 1976, B32, 3339. A. E. Kalinin, V. G. Andrianov, and Yu. T. Struchkov, Z h r . strukt. Khim., 1975, 16, 1041. M. Cotrait, M. Avignon, J. Prigent, and C. Garrigon-Lagrange, J. Mo!. Structure, 1976,

32, 45. S. W. Peterson, E. Gebert, A. H. Reis, jun., M. E. Druyan, G. W. Mason, and D. F. Peppard, J. Phys. Chem., 1977, 81, 466; E. Gebert, A. H. Reis, jun., M. E. Druyan, S. W. Peterson, G. W. Mason, and D. F. Peppard, ibid., p. 471. 273 J. C. Clardy, D. S. Milbrath, and J. G. Verkade, J. Amer. Chem. SOC.,1977, 99, 631; D. S. Milbrath, J. P. Springer, J. C. Clardy, and J. G. Verkade, ibid., 1976, 98, 4593. 274 Y.S. Babu, T. S. Cameron, S. S. Krishnamurphy, H. Manohar, and R. A. Shaw, Z. Naturforsch., 1976, 31b, 999. 273

265

Physical Methods

c1

O (165)

Ph,P (164)

+

-

and each ring of the pyrophosphate (165) has a flattened chair conformation, with the phosphoryl oxygen occupying an equatorial position.275On the other hand, the thione (166) has an open envelope conformation.276The molecular structures of

(166)

the insecticides bromophos (167) 2 7 7 and azinphos-methyl (168),278of the antitumour drug (169),279and of a number of nucleotides 2 8 0 have also been reported. n

OOH

Cl

Cl (167)

(168)

(169)

The molecular electrostatic potential of dimethyl phosphate has been investigated by the ab initiu method.281The stereochemistry of the polycyclic oxyphosphoranes (170) 2 8 2 and (171) 283 has been established and the crystallographic data of cyclic enediol and acyl phosphoryl derivatives have been reviewed.284 2i5 276 277 278

279 280

281 182

283 284

D. S. Cook and R. F. M. White, J.C.S. Dalton, 1976, 2212. M. W. Wieczorek and J. Karolak-Wojciechowska, Cryst. Struct. Comm., 1976, 5, 739. R. G.Baughman and R. A. Jacobson, J. Agric. Food Chem., 1976,24, 1036. W. J. Rohrbaugh, E. K. Meyers, and R. A. Jacobson, J. Agric. Food Chem., 1976, 24, 713. A. Camerman, H. W. Smith, and N. Camerman, Biochem. Biophys. Res. Comm., 1975, 65, 828. 9. M. Rosenberg, N. C . Seeman, R. 0. Day, and A. Rich, Biochem. Biophys. Res. Comm., 1976, 69, 979; S. B. Zimmerman, J. Mol. Biol., 1976, 106, 663; S. Neidle, W. KuehIbrandt, and A. Achari, Actu Cryst., 1976, B32, 1850; H. Sternglanz, E. Subramanian, J. C. Lacey, and C . E. Bugg, Biochemistry, 1976, 15, 4797; M. E. Druyan, M. Sparagana, and S . W. Peterson, J. Cyclic Nucleotide Res., 1976, 2, 373; D. W. Young, P. Tollin, and H. R. Wilson, Naturvz, 1974, 248, 513. H. Berthod and A. Pullman, Chem. Phys. Letters, 1975, 32, 233. T. Saegusa, S . Kobayashi, and Y . Kimura, J.C.S. Chem. Comm., 1976,443. A. Schmidpeter, D. Schomburg, W. S. Sheldrick, and J. El. Weinmaier, Angew. Chem. Internat. Edn., 1976, 15,781. F. Ramirez and 1. Ugi, Phosphorus and Sulphur, 1976, 213, 231.

266

Organophosphorus Chemistry

(170)

0

Electron.-Electron diffraction has shown that the acylphosphine (172) has larger bond angles than trimetliylphosphine.285 Chloromethylphosphonyl dichloride (173 ; Me

\

0

/O

M e/p-c\ (172)

Me

I/

RPCl,

0

Il

(CH,=CH),PCl (174)

(173)

R = CH2Cl) adopts two conformations in the vapour phase,286whereas the vinyl compounds (173; R=vinyl) and (174) have P-0 and C--C bonds close to cisgeometry in the principal conformers of both The spectra of the dichlorides (175) and (176) are in best agreement with [gauche]:[transoid]conformer F S

II

MeOPCL,

MeSPCI,

(175)

(176)

-

F (177)

ratios of 4: 1 2 8 8 and 3 :7,289respectively. The amino-groups of the difluorophosphorane (177) have been estimated to have a torsional angle of 70.1 The effects of temperature, hydration, and surface pressure on the structure of phospholipid single bi-layers have also been studied.291 7 Dipole Moments, Conductance, and Vultammetry The dipole moment of the lone pair on phosphorus has been calculated to be 0.54 D, which is based on the effective charges in PH3 and PF3.292 This figure is nearly half that of an earlier estimate based on data for t h i o p h ~ s p h i t eThe . ~ ~partial ~~ moment of the lone pair is found to dominate the dipole moment of triarylphosphines (178). 285 286

287 288

289 290

291 292

L. S. Khaikin, L. G. Andrutskaya, and L. V. Vilkov, Vestnik. Moskov. Univ., Khim., 1976, 17, 123. E. Vanja, M. Kolonits, I. Hargittai, and S. Szoke, J. Mol. Structure, 1976, 35, 235. V. A. Naumov and S. A. Shaidulin, Zhur. strukt. Khim., 1976, 17, 304. V. M. Bezzubov and V. A. Naumov, Zfiur. strukt. Khim., 1976,17, 98. V. A. Naumov and V. M. Bezzubov, Doklady Akad. Nauk S.S.S.R., 1976, 228, 888. H. Oberhammer and R. Schmutzler, J.C.S. Dalton, 1976, 1454. S. W. Hui, M. Cowden, D. Papahadjopoulos, and D. F. Parsons, Biochim. Biophys. Acta, 1975, 382,265. L. Maiis and G . N. Fainshtein. Latv. P.S.R. Zinat. Akad. Vrstis. Kim. Ser.. 1976. 364.

267

Physical Methods

As the CPC bond angles increase from go", the negative contribution from the ligands slowly decreases, whilst the positive contribution from the lone pair rapidly increases, reaching a maximum at 101.5" that corresponds to sp hybridization of the lone pair.293The calculated dipole moments for phosphabenzene (1.87 D on an sp basis and 0.99 D on an spd basis) are above and below the experimental value of OAr

I

(178)

(179)

(180)

1.5 D. The calculations confirm that the negative end of the dipole is towards phosdipole moments of phosphole (1.9 D) and pyrrole p h o r ~125a ~ .The ~ ~calculated ~ ~ (2.0 D) are similar, and, unlike furan, the positive ends of the dipoles are towards the h e t e r o a t o m ~Dipole . ~ ~ ~ moments have been used, in combination with results from other methods of study, to estimate the preferred conformations of the dichloThe use ride (179),294of the phosphites (180),295and of triarylphosphine of dipole moments to aid stereochemical studies of P I V compounds has been reviewed. 297 Additive polarizability parameters should not be used in the calculations, and it has been recommended that data should be obtained from model compounds containing identical environments for the phosphorus atoms.298 The sensitivity of bond moments to structural changes has been studied; perfluoroalkyl groups lower the phosphoryl bond moment, and the P-N bond moment is very sensitive to the valence state of the phosphorus atom.299The conformational analyses of phosphonates,300p h o s p h ~ n a m i d e ssilyl , ~ ~ ~phosphates,302and a number of dioxaphosphorinans (181) 304 have been reported. The P-Se bond moment has been estimated to be 1.24D.304The zwitterionic structure (182) was identified by its high dipole 30s9

M. P. Warchol, E. N. Dicarlo, C. A. Maryanoff, and K. Mislow, Tetrahedron Letters, 1975, 11, 917. 294 R. P. Arshinova, J. Faucher, M. Graffeuil, J. F. Labarre, and C . Leibovici, Acta Chim. Acad. Sci. Hung., 1976, 90, 207. 295 R. P. Arshinova, S. G. Vul'fson, S. D. Ibragimova, E. T. Mukmenev, and B. A.Arbuzov, Bull. Acad. Sci. U.S.S.R., 1976, 25, 1202. 296 S. B. Bulgarevich, E. G. Amarskii, A. A. Shvets, and 0. A. Osipov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1661. 297 B. A. Arbuzov, R. P. Arshinova, and 0. A. Raevskii, Chern. Abs., 1975, 83, 77 843. 298 B. A. Arbuzov and R. P. Arshinova, Doklady Akad. Nairk S.S.S.R., 1976, 227, 1361. 29Q S. I. Vdovenko, V. Ya. Semenii, Yu. P. Egorov, Yu. Ya. Borovikov, and V. N. Zavatskii, J. Gen. Chem. (U.S.S.R.), 1976, 46, 2491. 30° E. A. Ishmaeva, A. N. Vereshchagin, and F. M. Kharrasova, J. Gen. Chem. (U.S.S.R.), 1976, 46, 278; 0. A. Samarina, E. A. Ishmaeva, and N. G. Khusainova, ibid., p. 1708. 301 L. A. Ashkinazi, P. hf. Zavlin, V, M. Shek, B. I. Ionin, and Ya. L. Ignatovich, J. Gen. Chem. (U.S.S.R.), 1976, 46, 1699. 302 Yu. V. Kolodyazhnyi, V. G. Tkalenko, A. P. Sadiinenko, N. A. Kardanov, and 0. A. Osipov, J. Gen. Chem. (U.S.S.R.), 1975, 45, 738. a03 E. A. Ishmaeva, V. V. Ovchinnikov, R. A. Cherkasov, and A. B. Remizov, J. Gen. Chem. (U.S.S.R.), 1975,45,931; E. A. Ishmaeva, V. V. Ovchinnikov, R. A. Cherkasov, A. B. Remizov, A. N. Pudovik, and A. A. Musina, Chem. Abs., 1976, 85, 93 679; K. Faegri, jun., T. Gramstad, and K. Tjessem, J. Mol. Structure, 1976, 32, 37. 504 E. A. Ishmaeva, M. Mikolajczyk, A. B. Remizov, and A. N. Pudovik, Dokludy Akad. Nauk S.S.S.R.,1975, 223, 351. 293

Organophosphorus Chemistry

268

moment,305and the trends observed for a series of phosphoryl compounds and their di- and tri-thia-analogues were interpreted in terms of a pdn interaction which decreases in the order RO > RNH > RS.306 and reduction potentials 308 of Reports have been published on salts, and on the electrochemical oxidation of triarylphosphines 309 and diphosphonic acids.31e 8 Mass Spectrometry Mass spectral studies of organophosphorus compounds, published up to 1973, have been reviewed,311 as have the problems involved in the use of mass spectral data for the detection of p h o s p h i n i d e n e ~ However, .~~~ peaks corresponding to the phosphinidene (183) were the most intense peaks in the spectra of the phenylenediamine compounds (184) and their sulphides.31 A considerable amount of work has been carried Me

Me

(183)

Me

Me (184)

out on a wide variety of phosphines, including a c y l p h o ~ p h i n e s .Bridged ~~~ ions, such as (185) from o-tolylphosphines, are believed to be formed when the aryl rings bear ortho-substit~ents.~~~, 315 The presence of a second functional group may also produce some unusual migrations. Migrations of oxygen, hydroxy-groups, and diphosphino-groups have been postulated in order to explain the spectra of acyL316 and o-anisyl-diphenylphosphines. 231 Also, migration of phenyl from oxygen to 305 306

307

308 809 ti0 311 a12

313 314

a15 816

L. Maijs and 0. Lukevics, Latv. P.S.R. Zinat. Akad. Vestis, Kim. Ser., 1976, 590. P. M. Zavlin, V. M. Shek, A. N. D’yakonov, and V. M. Al’bitskaya, Chem. Abs., 1976, 85, 123 123.

V. M. Tsentovskii, V. P. Barabanov, V. S. Tsentovskaya, and L. I. Kashirskaya, J. Gcn. Chem. (U.S.S.R.), 1976, 46, 1472. L. Horner and J. Roeder, Phosphorus, 1976, 6, 147; Y.Nagao and L. Horner, ibid., p. 139. Yu. M. Kargin, E. V. Nikitin, G. V. Romanov, 0. V. Parakin, B. S. Mironov, and A. N. Pudovik, Doklady Akad. Nauk S.S.S.R., 1976,226, 1101. J. H. Wagenknecht, J. Electrochem. SOC., 1976, 123, 620. I. Granoth, Topics Phosphorus Cheivt., 1976, 8, 41. U. Schmidt, Angew. Cfiem.Internat. Edn., 1975, 87, 523. 0. S. Anisimova, A. I. Bokanov, E. N. Karpova, and B. I. Stepanov, J. Gen. Chem. (U.S.S.R.), 1976, 46, 807. R. G. Kostyanovsky, A. P. Pleshkova, V. N. Voznesensky, and Yu. I. Elnatanov, Org. Mass Spectrometry, 1976, 11, 237; K. Henrick, M. Mickiewicz, N. Roberts, E. Shewchuk, and S. B. Wild, Austral. J. Chem., 1975, 28, 1473; D. H. Lemmon and J. A. Jackson, J. Fluoriae Chem., 1976, 8, 23. K. Henrick, M. Mickiewicz, and S. B. Wild, Austral. J. Chem., 1975, 28, 1455. J. Martens, K. Praefcke, H. Schwarz, and H. Simon, Phosphorus, 1976, 6, 247.

Physical Methods

269

carbon has been postulated in order to explain the spectra of the phosphonylstabilized ylide (1 8Q317 The hydrogen rearrangements of cyclic phosphine oxides 318 and cyclic have been studied by deuterium labelling. The mass spectra of unsymmetrical d i s u l ~ h i d e sdialkylphosphonyl ,~~~ a z i d e ~phosphinyl ,~~~ and unsaturated phosphonates 3 2 3 have also been studied. Further details have been published of the spectra of steroidal phosphinic esters.324 G.c.-mass spectral analysis has been applied to cyclophosphamide3 2 5 and other pesticides,32sand, after derivatization, to aminoalkylphosphonic acids 3 2 7 and p h o ~ p h a z e n e s . ~ ~ ~ Field desorption mass spectrometry has been successfully applied to mono- and bis-alkyl- and -alkenyl-triphenylphosphoniumsalts (187). The phosphonium cation gave rise to the base peaks.32g There has been keen interest in ion-molecule reactions. Cyclotron resonance spectroscopy showed that methylpho~phines,~~~ the fluorides (188; ie = 1 or 2),331 Ph,{R X-

Me,PF3-,

(187)

(188)

Me,P=CH, (18%

and the ylide (189) 332 give ions which contain two or three phosphorus atoms. The formation of phosphonium ions in a field source from PI11 compounds and alkylating agents has been de~cribed.”~ The chemical ionization spectra of triphenylphosphine with isobutane showed M + 1, M+C4H9,and M-Ph peaks.334

L. Toekes and G. H. Jones, Org. Mass Spcctronietry, 1975, 10, 241. sl* G. L. Kenyon, D. H. Eargle, jun., and C. W. Koch, J. Org. Chem., 1976, 41, 2417.

317

319 Z2O

321 522

323

324 325

326 327 328

329 330

331 339

333

334

A. Murai and M. Kainosho, Org. Mass Spectrometry, 1976, 11, 175. J . Koketsu, K. Ohashi, and Y. Ishii, Chubu Kogyo Daigaku Kiyo, 1975, 11A, 85. H. F. Schroeder and J. Mueller, Z. anorg. Chem., 1975,418,247. B. N. Laskorin, V. V. Yakshin, and L. I. Sokal’skaya, J. Gen. Chem. (U.S.S.R.), 1976, 46,

2434. G. Peiffer and E. M. Gaydou, Org. Mass Spectrometry, 1975, 10, 122. K. Jacob, W. Vogt, M. Knedel, and W. Schaefer, Biomed. Mass Spectrometry, 1976, 3, 64. C. Pantarotto, A. Martini, G. Belvedere, M. G. Donelli, and A. Frigerio, Cancer Treat. Rep., 1976,60, 493. H. J. Stan, B. Abraham, L. Behla, and M. Kellert, Mitteilrtngsbl. G.D.C.H.-Pachgruppe Lebensmittelchem. Gerichtl. Chem., 1976, 30, 146. M. L. Reuppel, L. A. Suba, and J. T. Marvel, Biomed. Mass Spectrometry, 1976, 3, 28. R. Vilceanu and P. Schulz, Phosphorus, 1976, 6, 231. G. W. Wood, J. M. Mclntosh, and P.-Y. Lau, J. Org. Chem., 1975, 40, 636. K. P. Wanczek, 2. Naturforsch., 1975, 30a, 329; K. P. Wanczek and Z. C. Profous, Internat. J. Mass Spectrometry Zon Phys., 1975, 17, 23. K. P. Wanczek and G. V. Roeschenthaler, Dynamics Mass Spectrometry, 1976, 4, 163. 0. R. Hartmann, K. P. Wanczek, and H. Hartmann, 2. Nuturforsch., 1976, 31a, 630. V. B. Labintsev, Yu. K. Gusev, N. N. Grishin, V. N. Chistokletov, and A. A. Petrov, Zhur. org. Khim., 1976, 12, 1597. F. Kober, Chem.-Ztg., 1976, 100, 235.

270

Organophosphorus Chemistry

9 PKa and Thermochemical Studies Their deviation from The PKa values of phosphine oxides have been Hammett base b e h a ~ i o u rtheir , ~ ~ ~HO dependencies,336and their sites of protonation 337 have been studied. The acidifying effects of p h o ~ p h o r y l p, ~h~o~~ p h i n y l , ~ ~ ~ and thiophosphinyl groups 340 have been studied. Ionization constants have been used to examine substituent effects in alkanephosphonic acids 341 and phosphinylcarboxylic structural correlations in various phosphorus and solThe linear free-energy vent effects on the properties of thiophosphorus relationships, which are based mainly on PKa data, have been analysed and rt-

Thermogravimetric analysis has been used to study the thermolysis of phosphine the phosphinylimine (190),347 and the anhydrides of some phosphonic

and to follow the formation of p y r o p h o ~ p h a t e s ,other ~ ~ ~ mixed anhyd r i d e ~and , ~ ~indolylpho~phonates.~~~ ~ Triphenylphosphine oxide (heat of combustion = - 35 796.6 k 14.3 J g-l) has been recommended as a reference substance for organophosphorus compounds.352

E. I. Matrosov, E. N. Tsvetkov, Z. N. Mironova, R. A. Malevannaya, and M. I. Kabachnik, Bull. Acad. Sci. U.S.S.R., 1975, 24, 1231. 336 A. Piekos-Maron and T. A. Modro, Phosphorus, 1976, 6, 129. 337 M. I. Kabachnik, E. I. Matrosov, T. Ya. Medved, and N. P. Nesterova, Doklady Akad. Nauk S.S.S.R., 1976, 230, 1347. 338 E. S . Petrov, E. N. Tsvetkov, M. I. Terekhova, R. A. Malevannaya, A. 1. Shatenshtein, and M. I. Kabachnik Bull. Acad. Sci. U.S.S.R., 1976, 25, 517. 339 E. S. Petrov, E. N. Tsvetkov, S. P. Mesyants, A. N. Shatenshtein, and M. I. Kabachnik, Bull. Acad, Sci. U.S.S.R.,1976,25, 762. 340 J. Boedeker and H. Zaertner, J. prakt. Chem., 1976, 318, 149. 341 A.J. Kresge and Y. C. Tang, J. Org. Chem., 1977,42,757; P. C . Schulz and A. L. M. LeLong, Rev. Latinoamer. Quim., 1976, 7 , 9. 343 E. N. Tsvetkov, R. A. Malevannaya, and M. I. Kabachnik, J. Gen. Chem. (U.S.S.R.), 1975, 45, 706. 343 V. A. Baranskii, B. I. Istomin, and A. V. Kalabina, Reakts. spos. org. Soedinenii, 1976,13,263. 344 A. G. Kozachenko, A. B. Uryupin, L. L. Spivak, A. Grigor'eva, E. I. Matrosov, M. I. Kabachnik, and T. A. Mastryukova, Bull. Acad. Sci. U.S.S.R.,1976, 25, 1561. 345 B. I. Istomin, V. A. Baranskii, A. D. Lobanov, and E. F. Grechkin, Reakts. spos. org. Socdincnii, 1975, 12, 69; V. A. Baranskii and B. I. Istomin, ibid., p. 83; M. I. Kabachnik, Khim. Primen. Fosfororg. Soedinenii, 1974, 257, (Chem. Abs., 1975, 83, 77 844). 346 K. Moedritzer, Thermochim. Acra, 1976, 16, 173. 347 E. Kameyama, S. Inokuma, and T. Kawamura, Bull. Chem. SOC.Japan, 1976, 49, 1439. 348 0. N. Grishina, N. A. Andreev, and E. E. Sidorova, J. Gen. Chem. (U.S.S.R.), 1976,46, 1458. 3*9 M. A. Ruveda, E. N. Zerba, R. Podesta, and S. A. de Licastro, Tetrahedron, 1975, 31, 885. 35@ V. N. Eliseenkov, N. A. Samatova, and N. P. Anoshina, J. Gen. Chem. (U.S.S.R.), 1976, 46, 23. 351 A. 1. Razumov, P. A. Gurevich, R. I. Tarasova, and S. Yu. Baigil'dina, J. Gat. Ckrm. (U.S.S.R.), 1976,46, 33. 3J2 A. J. Head and D. Harrop, Con$ Int. Thermodyn. Chim., 1975, 19. 335

27 1

Physical Methods

10 Chromatography G.1.c.-Most reports have concerned the analysis of pesticides353and efforts to increase the sensitivity and selectivity of The gas-chromatographic physical behaviour of bis(2-ethylhexyl) phosphate has also been Reports T.1.c.-The separation of phosphonic acid derivatives has been on the application of t.1.c. to the analysis and separation of nucleotides 3 5 7 and other biologically important phosphates 3 5 8 abound. Enzymatic reagents have been used to develop chromatograms of phosphate esters which inhibit cholinesterase. Clean, sharp-edged spots against a dark background are obtained. 3 5 9 Paper Chromatography.-Solvent systems have been developed for the separation of trichloromethyl- phenyl-, and pentafluorophenyl-phosphonic and -phosphinic Phosphoramidates and their hydrolysis products have been chromatographed, using triethylamine as a Silica gel on glass-fibre sheets may be used to separate inositol from its phosphate 3 6 2 and to analyse phosphatide glyceryl ethers. H.p.1.c.-Methods have been devised for the separation of deoxyribonucleoside triof phosphatidylcholine from ~ p h i n g o m y e l i n ,and ~ ~ ~of phospholipids.3 6 6 0

II

(EtO), PSC€I,CH, SEt (191)

Column Chromatography.-Thiophosphates 353

354

355 456

357

558

356 360

361 362

363 a64

a66

such as (191) have been purified on

Y. Aoki, M. Takeda, and M. Uchiyama, Eisei Kugaku, 1976, 22, 81; T. Lipowska, S. J. Kubacki, and H. GOSZCZ, Pr. Inst. Lab. Badaw. Przem. Spozyw., 1975, 25, 395; G. F. Ernst and M. J. P. T. Anderegg, J. Assoc. Ofic. Analyt. Chemists, 1976, 59, 1185; W. Krijgsman and C. G . Van de Kamp, Mcded. Fac. Landbouwwet., Rijksuniv. Gent, 1976,41, 1423. S. Hasinski, Chem. analit. (Warsaw), 1975, 20, 1135; Y. Takimoto and J. Miyamoto, Nippon Noyaku Gakkaishi, 1976, 1, 193; N. Mellor, J. Chromatog., 1976. 123, 396; R. B. Dehew, Chem. Abs., 1976, 85, 86 799; V. V. Brazhnikov and E. B. Shmidel, J. Chromatog., 1976, 122, 527. L. L. Borin and V. I. Serov, Zhur. Jir. Khim., 1975, 49, 8 10. R. J. Maile, jun. and G. J. Fischesser, J. Chromatog., 1977, 132, 366. W. Kreis, A. Greenspan, T. Woodcock, and C. Gordon, J. Chromatog. Sci., 1976, 14, 33 1 ; E. R. Sargent and P. F. Agris, J. Chromatog., 1976, 123, 490; A. A. White, ibid., 1975, 104, 184; G. Volckaert, W. Min Jou, and W. Fiers, Anal-vt. Biochem., 1976,72,433; R. C . Gupta, E. Randerath, and K. Randerath, Nucleic Acids Res., 1976, 3, 2915. J. Zadrozinska, Rocz. Panstw. Zakl. Hig., 1976,27, 391 ; R. D. Petukhov, Veterinariya (Moscow), 1976, 101 ; C. K. Hong and I. Yamane, Nippon Dojo-Hiryogaky Zasshi, 1976,47, 122; N. Salen, jun., L. G. Abood, and W. Hoss, Analyt. Biochem., 1976,76,407; J. H. M. Poorthuis, P. J. Yazaki, and K. Y. Hostetler, J. Lipid Res., 1976, 17, 433; A. Di Muccio and M. Delise, Riv. SOC.Ital. Sci. Aliment., 1976, 5, 77. P. Ambrosetti, A. Bolla, and B. Chialo, Chromatographia, 1976, 9, 633; H. Dumitrescu, Z. Barduta, and D. Dumitrescu, Chem. Abs., 1976, 85, 121 884. A. N. Bogushevskii and N. I. Gabov, Zhur. analit. Khim., 1976, 31, 582. H. Kuehne, H. A. Lehmann, and W. Toepelmann, Z. Chem., 1976,16,23. M. Hokin-Neaverson and K. Sadeghian, J. Chromatog., 1976, 120, 502. M. H. Hack and F. M. Helmy, J. Chromatog., 1975, 107, 155. H. J. Breter and R. K. Zahn, Z. Naturforsch., 1976,31c, 551. F. B. Jungalwala, J. E. Evans, and R. H. McCluer, Biochem. J., 1976, 155, 55. R. H. McCluer and F. B. Jungalwala, Adu. Exp. Med. Biol., 1976, 68.

272

Organophosphorus Chemistry

silica gel,367and condensed phosphates separated using ion-exchange resin.368The analysis of a range of biologically important phosphates has been achieved,369using affinity micelle formation,371and microcolumn

J. Jarv and A. Aaviksaar, Chern. Abs., 1975, 85, 77 559. D. Lucansky, Chem. prumysl., 1976,26, 514. H. Jensen, F. Habault, A. M. Lacoste, and A. Cassaigne, J. Chromatog., 1977, 132, 556; J. X. Khym, ibid., 1976, 124, 415; I. M. Koshkina, L. A. Remizova, and I. A. Favorskaya, Vestnik. Leningrad Uniu., Fiz., Khim.,1976, 2, 135; S. T. Thompson, R. Cass, and E. Stellwagen, Analyt. Biochem., 1976,72, 293. 370 A. K. Sinha and R. W. Colman, European J. Biochem., 1977, 73, 367. a71 A. K. Sen Gupta, Fette, Seifen, Anstrichm., 1976, 78, 11 1. 371 V. P. Demushkin, Yu. G. Plyashkevich, and N. M. Shalina, Bioorg. Khim., 1975, 1, 1728. 367

368 3159

Author Index Aaviksaar, A., 272 Ababnin, B. E., 74 Abbott, S. J., 143 Abdel-Rahman, M. O., 240 Abdullaev, N. D., 44 Abel, E. W., 48 Abicht, H. P., 6, 15, 239 Abita, J. P., 146 Abood, L. G., 271 Abraham, B., 269 Abraham, K. A., 163 Abraham, K. M., 56, 249 Abul'khanov, A. G., 82,259 Achari, A., 265 Achenbach, H. 200 Achiwa, K., 7 Ackermann, T., 238 Adamcik, R. D., 241 Adamiak, R. W., 155, 173 Aganov, A. V., 247 Ager, J. W., 233 -4gishev, A. Sh., 250 Agris, P, F., 271 Aguiar, A. M., 23, 90, 243 Ahlberg, P., 43 Ahlers, W., 17 Ahmed, F. R., 235 Aida, T., 14 Aime, S., 240 Air, G. M., 179 Akasaka, K., 238 Akasawa, T., 233, 234 Akeson, A., 148 Akhmedov, Sh. T., 81 Akhmetzhanov, I. S., 260 Akhochinskaya, T. V., 188 Akiba, K., 9, 194, 241 Aklyan, Z. A., 23 Aksnes, G., 21 Albery, W. J., 141 AI'bitskaya, V. M., 268 Albrand, J. P., 240, 249, 256 Albright, T. A., 184, 222 241, 243, 245 Aleev, T. I., 113 Alexandrova, L. A., 157,172 Aliev, R. Z., 53 Allcock, H. R., 43, 210, 226, 229,230, 232 Allen, C. W., 231, 244 Allen, D. W., 8, 24, 28, 128 Allen, F., 263 Allen, G. W., 148 Allen, L. B., 153 Allen, L. C., 33, 77, 247 Allen, R. W., 226,230, 232 Allison, W. S., 141 Almasi, L., 101 Alper, H., 222 Altenau, A. G., 232 Althoff, W., 244, 253 Alunni, S., 12

Aly, H. A. E., 242 Amarnath, V., 152, 172 Amarskii, E. G., 78,259,267 Ambrosetti. P.. 271 Ambrus, GI, 199 Ames, B. N., 150 Aminova, R. M., 247,253 Amornraksa, K., 28 Amsler, P. E., 170 Anar'eva, L. G., 124 Anderegg, M. J. P. T., 271 Anderson, A. G., 51 Andreev, N. A., 124, 270 Andreo, L. S., 141 Andriamizaka, J. D., 16 Andrianov, V. G., 264 Andrutskaya, L. G., 266 Anh, N. T., 204 Anisimova, 0.S., 268 Anushina, N. P., 270 Antczak, S., 31 Antkowiak, T. A,, 224, 232 Antonovich, E. G., 178 Aoki, Y., 271 Appel, R., 9, 11, 12, 35, 48, 55, 57, 65, 182, 217, 218, 220,282 Aranda, G., 40 Arbuzov, B. A., 43, 53, 56, 69, 96, 111, 126, 247, 257, 267 Arentzen, R., 172, 173 Argyle, J. C., 147 Arifien, A. E., 210 Arita, S., 229 Armitage. I. M.. 139 Armstroig, V. ., 154, 164, 165, 171, 184 Arnold, D. E. J., 57, 60,281 Arnold, K., 238 Arora, P., 184 Arshinova, R. P., 254, 267 Asahara. T.. 243 Asako, T., 149 Ashe, A. J., 28, 29, 243, 261 Ashkinazi, L. A., 259, 267 Ashour, A. L. E., 143 Ashrafullina, L. Kh., 259 Aurbach, G. D., 168 Avetisyan, A. A., 84 Avigon, M., 264 Awerbouch, O., 246 Babaeva, T. A., 81 Babler, J. H., 51, 198 Baboulhe, M., 108 Babu, Y. S., 234, 264 Baccolini, G., 109, 245 Baciocchi, E., 12 Backer, J. M., 181, 256 Baenziger, N. C., 263 Baer, F., 256

273

Bauerlein, E., 141 Bahl, C. P., 173, 179 Baigl'dina, S. Yu, 101, 270 Bakeeva. R. F.. 259 Bakker, A. J., 167 Baldwin, J. E., 17 Balitskii, Yu. V., 105 Bananyarly, S. I., 225 Bannet, D. M., 204 Barabanov, V. P., 268 Baranaev, M. K., 241 Baranskii, V. A., 270 Bhrany, M., 130, 237 Baraze, A., 115, 123 Barciszewska, M. Z., 155 Barden, R. E., 134 Bardos, T. J., 177 Barduta, Z., 271 Barfknecht, R. L., 152, 153 Barlow, C., 130, 237 Barlow, J. H., 32, 242 Barlow, L., 21, 185 Barnett, R. E., 238 Barrell, B. G., 179 Barrio, J. R., 153 Barros, H., 222 Barry, S., 161 Barta, I., 199 Bartell, L. S., 258 Bartlett, P. A., 251 Barycki, J., 16, 72 Barzu, O., 163 Bastian, J. M., 204 Battioni, J.-P., 76 Batyeva, E. S., 84, 85, 183, 215,254 Baudler, M., 8, 239, 250 Baughman, R. G., 265 Baughn, R. L., 135 Baumann, M., 201 Bayardina, E. V., 113, 114 Bayer, M., 158, 172 Bayet, P., 192 Beaucage, S. L., 102, 155 Beavo, J. A., 160 Bechtel, P. J., 160 Bechodsheimer, H. H., 112 Beck, H. P., 16 Beck, W., 3 Becker, G., 16, 58, 238 Becker, H., 5 Becker, K. B., 186 Bedows, E., 178 Beebee, T. J. C., 169 Beer, M., 180 Begley, M. J., 236 Behla, L., 269 Belbeoch, A,, 108 Belkin, Yu. V., 96 Belknap, K. L., 222 Bell, L: E., 169 Bellotti, V., 86

Author Index

274 Belov, Yu. V., 252 Bel’skii, F. I., 79 Bel’skii, V. E., 251, 259 Belvedere, G., 269 Benb, J., 3 Benitez, L. V., 141 Benko, B., 237 Benkovic, S. J., 136, 154 Bennett, G. N., 167 Bennett, M. A., 7 Bensel, N., 206 Bentrude, W. G., 239, 246 Berdnikov, E. A., 10 Berg, U., 9 Bergeron, C. R., 224, 233 Bergmann, E. D., 185 Berkman, Z. A., 79 Berkner, K. L., 180 Berlan, J., 76 Berlin, K. D., 1, 16, 18, 72, 240, 254 Berlin, Y. A., 175 Berman, S. T., 26, 191, 245 Bernard, D., 247 Berndt, K. G., 253 Berthod, H., 265 Bertina, L. E., 79 Bertoli, E., 141 Bertozzi, S., 184 Bezzubov, V. M., 266 Bestmann, H. J., 18, 46, 182,189,194,198,240,243 Bhacca, N. C., 243 Bhalla, R. B., 169 Bhatawdekar, S. S., 115 Biala, E., 155 Bickelhaupt, F., 253, 261 Biddlestone, M., 251, 228 Bidzilya, V. A., 246 Billmann, W., 198 Binh, S. K., 25 Birnstiel, M. L., 179 Bissel, E. R., 118 Bissell, E. C., 230 Bisson, R., 184 Bittner, S., 14 Bjorray, M., 19 Black, D. S. C., 207 Black, J. L., 171 Blanck, K., 230, 235 Blandin, M., 152 Blaszcak, L., 119 Blound, J. F., 200 Blum, A., 150 Blum, J., 121 Bobek, M., 185 Bobkova, R. C., 92 Bochuar, D. A., 244 Bock, H., 244,261 Bock, R. M., 171 Bodnarchuk, N. D., 221 Boedeker, J., 126,258,270 Boehm, W., 239 Bohnel, B., 120 Bottcher, W., 4 Bogdanov, N. N., 110, 116, 125 Boggaram, V., 161 Bogushevskii, A. N., 271 Boguslawski, S., 153 Boigegrain, R., 247 Boiko, A. P., 223 Bojan, O., 163 Bokanov, A. I., 260, 268

Boland, W., 198 Boldeskul, I. E., 111, 122, 126, 258 Bolesov, I. G., 204 Bolla, A., 271 Bollag, W., 201 Bombieri, G., 263 Bondavalli, F., 118 Bone, S. A., 31, 32, 36, 42 BOOS,K.-S., 169 Boparai, A. S., 148 Bore], D., 188 Borisov, E. V., 262 Borisova, E. E., 82 Borir, L. L., 271 Borkent, G., 123 Borman, C., 222 Borovikov, Yu. Ya., 267 Rose, A. K., 13, 118 Boublik, M., 262 Bouchu, D., 241 Boudreau, J. A., 121 Boyer, M., 15 Boyer, P. D., 141 Brack, A., 3 Bradbury, E., 152 Bradshaw, T. K., 152 Brady, R. F., jun., 144 Brahms, J., 181 Bramblett, J. D., 17, 37 Brand, M. D., 130 Brandsma, L., 253 Braun, R. W., 61 Braverman, J. B. S.. 67 Bravo, P., 19 Brazhnikov, V. V., 271 Brazier, J.-F., 42, 213, 252 Bredikhina, Z. A., 125 Brencsan. A.. 19 Brennecke, L’., 81, 127 Breter, H. J., 271 Brett, C. T., 137 Breuer, E., 204, 207 Brevet, A., 143 Brew, K., 171 Brierley, J., 3 1, 35 Brison, O., 160 Brockhof, N. L. J. M., 193 Brocksom, T. J., 195 Brodelius, P., 161 Bronnyi, 0. V., 48 Broom, A. D., 152, 172 Broughton, B. J., 209 Brown, C., 52, 92, 120 Brown, D. H., 69 Brown, H. S., 156 Brown, N. L., 179 Brownbridge, P., 81 Brownstein, M., 243 Brunfeldt, K., 175 Brunton, G., 256 Bryantsev, B. I., 260 Bryson, T. A., 132, 255 Buchachenko, A. L., 255 Buchholtz, N., 232 Buck, H. M., 127, 255,257 Budarin, L. I., 111 Buder, W., 222, 258 Buerger, F., 261 Bugg, C. E., 265 Bugge, B., 137 Bu Cong, C., 31, 116 Bulgarevich, S. B., 267 B u l b , V. M., 198

Bulkina, Z. P., 216 Bullen, G. J., 235 Bulloch, G., 101, 251 Bunn, H. F., 135 Bunton, C. A., 116 Buono, G., 247 Burdon, J., 247 Burgada, R., 39, 242, 247, 253, 254 Burgard, D. R., 180 Burger, K., 45 Burgers, P. M. J., 173, 174 Burke, S. D., 208 Burkhardt. J.. 232 Burnaeva, ’L. ‘A., 105, 106 Burnett, M. G., 9 Burnett, R. E., 243 Burns, F. B., 70 Burt, C. T., 130, 237 Burdon, D. J., 190 Burzynska, H., 14 Busby, S. J. W., 135, 237 Busch, H., 179 Buss, J. E., 130 Busulini, L., 233 Butova, G. L., 213 Butterworth, P. H. W., 169 Buttlaire, D. H., 145 Buyer, P. D., 141 Buzas, A., 204 Bychkova, T. I., 125 Byistro, V. K., 75 Bystrov, N. S., 174 Cadger, T., 174 Cadogan, J. 1. G., 27,43,249 Calvert. P.. 232 Camerman, A., 265 Camerman, N., 265 Cameron, T. S., 234,236,264 Cameron, V., 178 Campbell, B. S., 40, 247 Campbell, P., 157 Cannon, P., 115 Caplow, M., 168 Carlsohn, B., 239 Carlson, D. W., 232 Carrico, R. J., 161 Carrie, R., 254 Cartwright, 1. L., 171 Caruthers, M. H., 175 Carver, M., 141 Cashion, P., 174 Caspi, E., 12, 91 Cass, R., 272 Cassaigne, A., 272 Castelijns, A. M. C. F., 127 Castro, B., 19, 247 Caton, M. P. L.,209 Caughlan, C. N., 70, 86,264 Cavell, R. G., 34, 62, 251 Cayzergues, P., 123 Cederbaum, L. S., 261 Cehovic, G., 158 Cerletti, N., 157 Chabrier, P., 245 Chadaeva, N. A., 259 Chambers, J., 137 Chambon, P., 160 Chan, J. L. W., 127 Chan, S. I., 238 Chance, B., 130,237 Chandrasekhar, B. S., 225

275

Author Index Chang, C.-H., 180 Chang, C.-J., 181 Chang, L. L., 33, 88,97, 241, 246 Chang, N., 146 Charalambous, J., 15 Charlton, J. R., 8 Charon, D., 135 Chasle-Pommeret, M. F., 242 Chattha, M. S., 81, 253 Chauzov, V. A., 72, 84, 110, 116, 125, 260 Chawla, R. R., 171 Chemiefaser Lenzing A.-G., 233 Chen, K.-C., 72 Chen, M. S., 165 Chen, Y.-S., 222 Cheng, T. C., 232 Cherkasov, R. A., 46, 113, 119, 125,267 Chernobrovkina, L. P., 260 Chernov, B. K., 174 Cherry, W., 26, 261 Chetkina, L. A., 262 Chettur, G., 154 Cheung, H. C., 168 Chiacchio, U., 263 Chialo, B., 271 Chimitova, T. A., 172 Chinault, A. C., 171 Ching Yee Cheng, 102 Chinsky, L., 181 Chiraleu, F., 260 Chiranjur, C., 102 Chistokletov, V. N., 19, 269 Chittenden, R. A., 248 Chiusoli, G. P., 86 Chizhou, U. M., 126 Chopra, A. K., 201 Chou, C. H., 181 Choudhury, P., 8 Chow, K.-K., 3 Christau, H.-J., 18 Christol, H., 18, 253 Chrzeszczyk, A., 238 Chung-Yi Lee, R., 34 Chuprakova, K. G., 54, 112 Clardy, J. C., 98, 264 Clark, R. D., 187 Clark, V. M., 139 Cloyd, J. C., 243 Cnauk, T., 81 Coates, H., 112 Coates, R. M., 148 Coffee, E. C. J., 209 Cogne, A., 240 Cohen, G. H., 139 Cohen, P., 146 Cohn, M., 145 Colman, R. W., 161, 272 Comasseto, J. V., 195 Cometti, G., 86 Conant, J. B., 67 Cong, C. B., 95 Conradi, R. A., 148 Cook, 0. S., 265 Cooke, M. P., 195 Cooper, G. H., 248 Cooper, J. W., 256 Corallo, M., 51 Corey, E. J., 199 Co-Sarno, M. E., 20, 70 Cossendini, M., 204

Costa, D. J., 249 Costello, A. J. R. 237 Costisella, B., 67, 81, 127 Cotrait, M., 264 Coulson, A. R., 179 Coulson, C. A., 263 Coulton, S., 128, 184 Couret, C., 16, 58, 59 Coutrakis, C. N., 204 Cowden, M., 266 Cowley, A. H., 34,57,61,62, 247, 249,252 Cox, A. W., jun, 259 Cozzarelli, N. R., 178 Cozzone, P. J., 181, 238 Crabbe, P., 199 Cradock, S., 58 Cramer, F., 165, 171, 172 Crea, R., 173 Cremer, S. E., 20, 78, 251 Cremlyn, R. J. W., 101, 102, 124 Cristau, H. J., 253 Cross, R. J., 69, 251 Cseh, G., 199 Cullen, W. R., 2, 7 Cullis, P. R., 238, 246 Cushley, R. J., 138 Cushner, M., 252 Czaja, R. F., 188 Czermak, M., 233 Dactrozzo, E., 45 Dahl, O., 6, 254 Dahmann, D., 21 1, 227 Dale, A. J., 246, 261 Dale, R. M. K., 177 Damadian, R., 237 Dangyan, M. T., 84 Danion-Bougot, R., 195 Danion, D., 195, 254 Dann, P. E., 235 Danyluk, S. S., 238 Darensburg, M., 222 Dattagupta, J. K., 154 Daub, G. W., I74 David, S., 40 Davidenko, N. K., 246 Davidson, A. H., 75 Davidson, R. M., 206,254 Davjes, A. G., 256, 257 Davies, D. R., 139 Davis, A. R., 7 Davis, V. C., 207 77, 247 247 de Boer, H. A.,’ 167 De Bruin, K. E., 128, 215 Dederer, B., 236 Deery, W. J., 168 de Gier, J., 139 Deiters, J. A., 4, 33 De Jersey, J., 147 De Ketelaere, R. F., 240,245 De Kruijff, B., 246 De Kruyff, B., 238 De la Mater, M. R.,123 de Leeuw, S. A. J., 127

de Licastro, S. A., 270 Delise, M., 271 de Maine, M. M., 136 Demel, R. A., 139 Demushkin, V. P., 272 Demuth, R., 58, 259, 261 Denisov, D. A., 79 Denisova, T. V., 126 Denney, D. B., 33, 40, 47, 87, 88, 97, 241, 246,247 Denney, D. Z,, 33, 40, 47, 87, 88, 247 Dennis, E. A., 238, 255 Dennis, R. W., 257 Denton, D. A., 79 Depres, J. P., 199 Derii, L. I., 228, 255 De Ruiter, B., 231 Desai, S. R., 194 Deschamps, B., 74, 204 Deshayes, H., 123 Desostoa, A., 181 Desper, C. R., 236 De Stefano, N. J., 3 Destrade, C., 259 Desvages, G., 143 Deutscher, M. P., 171 De Voe Goff, S., 23 Devos, M. J., 192 DeVries, R. A., 90 Dewhurst, B. B., 102 Dianova, E. N., 126 Dicarlo, E. N., 267 Dickinson, P. J., 168 Dickstein, J. I., 22 Dieck, R. L., 229, 232,233 Diercksen, G. H. F., 261 Dierdorf, D. S., 62 Dietsch, H., 239 Dilbeck, G. A., 254 Dillon, K. B., 56, 60, 239, 255 Dillon, M. G. C., 56, 239 Dills, W. L. jun., 160 Dimroth, K., 29, 256, 261, 263 Di Muccio, A., 271 Dinizo, S. E., 125, 205 Dirlam, J. P., 89 Divnich, T. F., 246 Dmitriev, V. I., 64 Dmitrieva, G. V., 55 Dmitrieva, N. V., 107 Doak, G. O., 61,62 Dobrynin, V. N., 174 Dodd, G. H., 103, 137 Dodgson, J. B., 178 Dogadaeva, L. V., 44,253 Dogadina, A. V., 50, 107 Dolzhnikova, E. N., 125 Dombrovskii, A. V., 196 Domenicano, A., 263 Dominick, T. F., 224 Donelli, M. G., 269 Donskaya, N. A., 188 Donskaya, Yu. A., 259 Doria, G., 209 Dormidontova, N. P., 207 Dormoy, J.-R., 19 Dose, K., 161 Dostal, K., 120, 225 Dougill, M. W., 236 Dourtoglou, B., 19 Dowle, M. D., 14

276 Downs, R. W. jun., 168 Drach, B. S., 111 Dreux, J., 241 Drocourt, J. L., 152 Drozd, G. I., 249 Druyan, M. E., 264, 265 Duax, W. L., 12, 91 Dubois, J.-E., 123 Dudman, N. P. B., 147 Dugas, H., 181 Dumitrescu, D., 272 Dumitrescu, H., 271 Dumm, H. V., 242 Du Mont, W-W., 7, 11, 15 Dunaway-Mariano, D., 151 Duncan, G. S., 152 Dunlap, R. B., 132, 255 Du Plessis, J. A. K., 227 Duquesne, M., 181 Durig, J. R., 258, 259 Dutasta, J. P., 98 Duyckaerts, G., 79 Dvoinishnikova, T. A., 113 D’Yakonov, A. N., 268 Dyer, R. L., 113 Dzhandzhapanyan, A. N., 84 Dzhemilev, U. M., 123 Dzikovskaya, L. M., 120, 24 1 Eady, C. R., 234 Ealick, S. E., 16, 72 Eargle, D. H., 78, 269 Earnshaw, C., 205 Eberlein. J.. 189. 252 Ebert, H.-D., 66, 100 Ebsworth, E. A. V., 58 Eckstein, F., 154, 164, 165 Edelheid, E. B., 152 Edelman, M. S., 153 Edmonds, M., 161 Efimova, V. D., 241 Efanov, V. A., 50, 107 Egami, F., 159 Egan, W., 247 Egberts, E., 160 Egorov, Yu. P., 222, 267 Eibach, F., 15, 191 Eigenbrot, C. W., 79 Eiletz, H., 227, 230 Einhellig, K., 45 Einstein, F. W. B., 7 Eisch, J. J., 208 Elbein, A. D., 137 Elbel, S., 261 El-Deek, M., 1, 18, 240 Elion, G. B., 152 Eliseenkov, V. N., 270 Ellis, P. D., 132, 255 El’natanov, Yu. I., 6, 268 El-Sheik, M. Y., 261 Elson, I. H., 257 Empsall, H. D., 2, 6 Endres, W., 25, 70 Engel, R., 80, 101, 138, 147 Engelhardt, U., 104 Engels, J., 158, 168 Enlow, W. P., 5 Endres, W., 1 Entwistle, D. W., 102, 155 Epiotis, N. D., 26, 261 Epshtein, L. M., 244 Epstein, J., 115 Erickson, D., 51

Author Index Ernst, G. F., 271 Ernst, L., 238 Erokhina, T. S., 72, 260 Esaki, T., 233, 234 Escudik, J., 16, 58, 59 Esperas, S., 19 Eto, M., 162 Ettlinger, M., 194 Evangelidou-Tsolis, E., 103 Evans, A. G., 73, 256 Evans, F. E., 238 Evans, J. C., 73, 256 Evans, J. E.. 271 Evans; M. L., 235 Evin, G., 19 Ezra, F., 238 Faegri, K., jun., 267 Faerber, P., 169 Fainshtein, G. N., 266 Falk, L. C., 40 Falkehag, I., 185 Farkas, W. G., 134 Farmer, P. B., 105 Faskhutdinova, T. A., 105 Faucher, J.-P., 228, 267 Favorskaya, 1. A., 272 Fazliev, D. F., 259 Featherman, S. I., 239 Federov, S. G., 229,232,234 Fedin, E. I., 248 Fedor, M., 19 Fedorova, G. K., 124 Fedorovich, I. S., 103, 125 Fedyukhin, V. N., 220 Feigel, M., 244 Fekete, T. M., 237 Felcht, U., 115 Feldman, K., 135 Fenzelau, C., 104 Feshchenko, N. G., 57, 213 Fiandaca, P., 263 Fiddes, J. C., 179 Fieldhouse, J. W., 224 Fiers, W., 180, 271 Fild, M., 240, 242, 244, 252, 341

LJJ

Filippov, E. A., 79 Filonenko, L. P., 215 Findlay, J. B., 147, 181 Findlav. R. H.. 261 Finocihiaro, P:, 246 Finzenhagen, M., 17 Fischer, H., 74 Fischer, R. R., 132, 2515 Fischesser, G. J., 271 Fiser, I., 177 Fishbein, R., 136 Fisher, S., 3 Fishman, A. I., 259 Fitjer, L., 193 Fitzgerald, A., 70 Fleming, I., 75 Flexser, L. A., 134 Flick, W., 240 Flindt, E.-P., 21 1 Florent’ev, V. L., 153, 262 Flossdorf, J., 156, 169 Flowers, W. T., 14, 89 Fluck, E., 10, 126, 238t, 240, 261 Flynn, R. M., 263 Fokin, A. V., 48, 53, 249 Folayan, J. O., 176

Folk, W. R., 180 Foresti, E., 263 Forrest, B. J., 138 Forrest, G., 158 Forsee, W. T., 137 Forsellini, E., 263 FOSS, V. L., 56, 69, 245 Fossel, E. T., 237 Foster, A. B., 105 Foucaud, A., 12, 191, 242 Fountaine, J. E., 8, 245 FrafFeuil. M., 267 Frank, A., 93, 217 Franko-Filapasic, B. R., 233, 234 Frazer, M. G., 118 Frazer, V. S., 118 Frearson, M. J., 124 Freeman, W. J., 184, 222, 241, 243 Freenor, F. J., 51 Freerksen. R. W.. 205 Frey, P. A., 146 Frey, W. A., 136 Fridland, S. V., 50, 107 Friedmann, 0. M., 104 Friedrich, P., 5, 93, 217 Frigerio. A.. 269 Frigrs, W., 180 Froehler, M., 45 Froeyen, P., 244 Fryer, R. I., 122 Fueller, H.-J., 221, 252 Fuke, M., 179 Fukui, K., 64, 73 Fukui, T., 152, 176, 177 Fukuyama, Y., 209 Furin, G. G., 242 Furness, R. A., 134 Furstenberg, G., 239 Furthmayr, H., 139 Furtsch, T. A., 62 Furukawa, N., 14 Furusawa, K., 131, 162 Fusco, R., 65 Fuzhenkova, A. V., 43 Fyler, T. M., 197, 256 ’

Gabhe, S. Y., 123 Gabov, N. I., 271 Gadian, D. G., 130, 135,237 Gadreau. C.. 12. 191 Gagnaire, D:, 240 Gaidamaka, S.N., 210, 241 Gainullina, E. T., 241 Gait, M. J., 175, 179 Gajda, T., 102 Gakis, N., 251 Galkin, V. I., 46 Gallagher, M. J., 26, 78 Galle, J. E., 121, 208, 254 Gallicano, K. D., 236 Gallien. P.. 104 Gallo, R.,9 Gally, H. U., 138, 238 Galpin, I. J., 25 Gambaryan, N. P., 13, 244 Gamliel, A., 202 Gandolfi, C., 209 Garanti, L., 198 Gareev, R. D., 45, 82, 105, 111. 125. 212. 213. 214, 245; 253,’254, 260 Garhck, P. B., 130, 237

Author Index Garner, A. Y., 234 Garrigou-Lagrange, C., 259, 264 Garriques, B., 42, 94 Gaskell, A. J., 261 Gasser, O., 189 Gassner, M., 146 Gatilov, Yu. F., 74 Gause, E. M., 256 Gaydou, E., 269 Gazizov, T. Kh., 44, 108,242 Gebert, E., 264 Gedye, R. N., 184 Geisler, K., 1 I , 48, 57 Geismann, C., 189 Gelas-Mialhe, Y., 188 Gensler, A., 203 Geoffroy, G. L., 79 GeoKroy, M., 256 Georgoulis, C., 123 Geraci, D., 169 Gerber, A. H., 232 Gerken, T. A., 246 Germa, H., 253 Gersemann, M., 49, 210 Gertschen, R. J., 169 Geurts van Kessel, W. S. M., 139 Giao, N.-B., 158 Gibbs, D. E., 86, 154 Gibson, J. A., 32, 34, 39, 58, 60, 62, 215, 247, 252 Gieren, A., 236 Gilbert, B. C., 256 Gilbert, W., 178 Gilham, P. T., 167, 178 Gilje, J. W., 61 Gilkerson, W. R., 78 GI11, G. N., 160 Gillam, S., 177, 179 Gillespie, D. G.. 4 Gilyaiov; V. A.,.43,212.2 19 Ginet, L., .256 Giniyatullin, R. Kh., 113 Girbes, T., 169 Girfanova, Yu. N., 183 Glassel, W., 93, 210,217 Glaser. S.. 86 Glemser, O., 210, 224 Glidewell, G., 263 Glonek, T., 130, 237, 238 Gloyna, D., 75, 185, 253 Glukhikh, V. I., 63, 107 Goeddel, D. V., 175 Goeldner, R., 238 Goetz, H., 3, 261 Goetze, A. M., 138 Goff, S. D. V., 197 Gol’dfarb, E. I., 44, 124, 242 Gol’dfarb, E. P., 255 Goldfarb, L., 232 Gol’din, G. S., 229, 232,234 Golding, B. T., 103, 137 Goldman, E. J., 153 Goldstein, J. A., 110 Goldwhite, H., 250, 255 Gololobov, Yu. G., 2, 105, 111, 122, 126, 258 Golovkova, L. P., 246 Goncharova L. V., 78,259 Goody, R. S., 168 Goranskaya, T. P., 90 Gorbatenko, V. I., 220 Gordon, C., 271

277 Gordon, M. D., 239, 240, 243

Gordon, P. F., 25 Gore, M. G., 161 Gorenstein, D. G., 116, 147, 181

Goryunov, E. I., 102 Gossauer, A., 190 Goswami, R., 195 GOSZCZ, H., 271 Goth, H., 45 Goubeau, J., 258 Gough, G. R., 167 Gozman, I. P., 124 Graaf, H. D., 261 Grabley, F.-F., 80, 206 Graddon, D. P., 26, 78 Gramstad, T., 267 Granoth, I., 260, 268 Granzow, A., 24 Grapov, A. F., 107 Grauk, T., 127 Graves, D. J., 134 Gray, G. A., 78, 245, 251 Gray, G. R., 135 Grayson, J. I., 75 Graziani, R., 263 Grechkin, E. F., 63, 64, 107, 270,281 Green, T., 251 Greene, A. E., 199 Greenspan, A., 271 Grez, M., 161 Grieco, P. A., 208 Griffin, C. E., 125 Griffin, J. A., 137 Griffith, 0. W., 170 Griffiths, D. E., 130, 141 Griffiths, R. W., 112 Grigor’eva, A., 270 Griller, D., 256 Grim, S. O., 78 Grinberg, S:, 14 Grinblat, M. P., 229, 259 Grineva, N. I., 172 Grishin, N. N., 269 Grishina, 0. N., 124, 270 Grisolia. S.. 144 Gross, H., 67, 81, 127 Grossmann, G., 245 Grubbs, R. H., 2, 90 Gruber, M., 167 Gruender, W., 238 Grunberger, D., 262 Gruner, C., 8 Gruner, M., 245 Grynkiewicz, G., 14 Grzeskowiak, K., 155 Grzejszczak, S., 80, 204, 206 Gubnitskaya, E. S., 106, 120, 213 Guenther, E., 84 Guercan, H., 193 Guy, J. J., 234 Guilbert, C. C., 133 Guimaraes, A. C., 98,254 Gulya, A. P., 207 Gumenyuk, A. V., 19 Gump, B. H., 228 Gumport, R. I., 152, 178 Gupta, K. C., 185 Gupta, R. C., 179, 271 Gurarii, L. I., 65, 258, 259 Gurevich, P. A,, 101, 270

Guryanova, E. N., 77, 260, 262 Gurylev, E. A., 250 Guschlbauer, W., 152 Guseeva, T. A., 82 Gusev, Yu. K., 269 Guseva, F. F., 113, 119 Gutter, B., 150 Gynane, M. J., 255 Haake, P., 108, 148 Haasnoot, C. A. G., 174 Habault, F., 272 Hack, hi. H., 271 Hackett, P. B., 160 Hadzi, D., 78 Haegele, G., 253 Hager, W., 211, 221, 251 Hagnauer, G. L., 232 Hahn, J., 239 Hahn, W. E., 160 Halasa, A. F., 232 Haley, B. E., 171 Haley, B. W., 134 Hall, C. D., 17, 37, 87, 113 Hall, C. R., 98, 114 Halstenberg, M., 35,217,218 Hamada, H., 9, 241 Hamada, Y.,118 Hamana, H., 29 Hamelin, J., 195 Hamlyn, P. H., 179 Hammond, P. J., 17, 37 Hampton, A., 17 Hamsen, A., 17 Han, R. J. L., 200 Haney, D. N., 135 Hannig, R., 126 Hansske, F., 171 Hanstein, W. G., 141 Harada, J., 148 Harada, M., 105 Harger, M. J. P., 129, 248 Hargittai, I., 266 Hargreaves, W. R., 138 Harnisch, H., 1 Harris, R. K., 32, 240, 251, 255

Harrop, D., 270 Hart, P. A., 181 Hartmann, H., 269 Hartmann, 0. R., 269 Harvey, S. C., 168 Hasegawa, S., 139 Hashimoto, S., 148 Hasinski, S., 271 Hassairi, M., 242 Hassan, E. A., 210 Hassid, A., 168 Hassner, A., 121, 190, 254 Hata, T., 131, 162, 173 Hatano, H., 238 Hax, W. M. A., 139 Hayashi, T., 3, 6 Hazlett, J. D., 7 Head, A. J., 270 Heath, E. C., 137 Heathcock, C. H., 187 Heatley, P., 24 Heber, D., 190 Heber-Brunschweiger, E., 190 Hechenbleikner, I., 5 Hecht, S. M., 171

Author Index

278 Heidmann, W., 175 Heifetz, A., 137 Heilbronner, E., 261 Heimgartner, H., 251 Meinmann, M., 190 Held, J., 7 Hellwinkel, D., 31, 36, 47, 249,260 Helmreich, E. J. M., 135 Helmy, F. M., 271 Hemmerich, P., 134 Hemmes P., 158 HendersAn, T. O., 237 Hendrix, J. W., 139 Hengstenberg, W., 146 Henning, H.-G., 75, 185,253 Henrick, K., 268 Herak, J. N., 256 Hercouet, A., 191 Herisson, C., 204 Herscovics, A., 137 Herweg, G., 17 Hesse, B., 104 Hesse, H., 169 Hesson, D. P., 17 HetflejS, J., 3 Heuschmann, M., 240 Hevesi, L., 192 Hewitson, B., 121 Hewitt, D. G., 111 Hietkamp, S., 2 Hikida, S., 233 Hildebrand, C. E., 255 Hinze, R.-P., 190 Hiraga, K., 149 Hirai, K., 177 Hirakawa, K., 233, 234 Hishinuma, F., 177 Ho, Y. K., 177 Hobbs, J. B., 172 Hochleitner, R., 96 Hochleitner, R. H., 66 Hock, B., 161 Hodgson, P. K. G., 81, 122, 218 Hoechst A.-G., 233 Hockel, M., 161 Hogel, J., 230 Hojeberg, B., 161 Hoene, R., 65 Hoeschst A.-G., 199 Hoffmann, H., 193 Hoffmann, M., 83, 109, 127, 179

Hoffmann, R., 77 Hoffmann, W., 201 Hofmann, A., 238 Hofmeister, P., 28 Hoftiezer. J.. 158 Hogberg,’H.-E., 202 Hoge, R., 264 Hohorst, H. J., 104, 105 Hohndorf, W.-D., 25 Hokin-Neaverson, M., 271 Holdy, K. E., 160 Holl. P.. 37 Hollkr, E., 165 Holmes, R. R., 33 Holt, G., 14, 89 Holy, N. L., 253 Honda, H., 79 Hong, A. P., 116, 260 Hong, C. K., 271 Honig, G. R.. 237

Honig, M. L., 90, 108 Honjo, M., 157 Hopkinson, M. J., 8 Horiki, K., 15 Horisaki, M., 107 Horn, H.-G., 49,210 Horner, L., 21, 25, 72, 114, 268 Hosogai, T., 220 HOSS,W., 271 Hossey, R. E., 67 Hostetler, K. Y., 271 Hotchkiss, J. C., 247 Houalla, D., 42,213,242,252 Houghden, R. A., 228 Hoult, D. I., 130, 237 Hounshell, W. D., 23, 90 Howell, J. M., 77, 257 Hoyano, J., 3 Hozumi, T., 173 Hruby, M.A., 237 Huang, T. S., 146 Hudson, A., 255, 257 Hudson, J. W., 224, 233 Hudson, R. F., 52,92, 121 Huepfl, J., 233 Huet-Rose, R., 153 Huet-Rose, R. A., 152 Hiittner, G., 217 Huffmann, J. H., 153 Hughes, A. N., 28 Hui, S. W., 266 Hull, W. E., 135 Hulla F. W., 161 Hulla;, T. L.,253 Hung, P., 19 Hunter, D. H., 186 Huntley, B. G., 128 Hursthouse, M. B., 235 Hussain, M. S., 252 Hutchins, R. O., 246 Hutchinson, D. W., 139, 147, 152, 171, 176 Hutchison, C. V., 179 Hutley, B. G., 8, 24 Huttner, G., 5, 93, 99 Hutton, W. C., 238, 255 Huynk, B. T., 205 Hyams, R. L., 141 Ibragimova, S. D., 267 Ibrahim, E. H., 210 Iemura, S., 148 Igi, I., 234 Igi, K., 234 Ignatova, N. P., 92 Ignatovich, Ya. L., 259, 267 Iio, M., 162 Ikeda. 1.. 121 Ikeda; Y;, 2, 3 Ikehara, M., 152, 157, 172, 176, 177 Tl’yasov, A. V., 256, 257 Inamoto, N., 9, 34, 123, 194, 239. 241. 254 Inch, T. D:, 98, 114 Indzhikyan, M. G., 23 Ingold, K. U., 256 Inokawa, H., 107 Inokawa, S., 107 Inokuma, S., 270 Inoue, K., 187 Inoue, T., 233 Jnoue, Y.,157

Ioannou, P. V., 103, 137 Ioffe, S. T., 102 Ionin, B. I., 50, 107, 246, 252,259,267 Ionov; L. B., 9 Ishii, Y.,269 Ishikawa, K., 194 Ishmaeva, E. A., 267 Islam, A. M., 210 Ismagilov, R. K., 246 Ismagilova, N. M., 54, 69 Tsmailov, V. M., 81, 124 Issleib, K., 3,4, 5,6, 15, 126, 219

Istomin, B. I., 270 Itoi, K., 220 Ittah, Y., 121 Ivanov, B. E., 259 Ivanov, L. I., 198 Ivanova, E. M., 174 Ivanova, G. A., 231 Ivanova, Zh. M., 111, 126, 258 Iwahori, S., 79 Iwate, T., 105 Izawa, Y.,73 Izmest’ev, I. V., 255 Jackson, J. A., 2, 268 Jacob, K., 269 Jacob, S. T., 169 Jacobson, R. A., 265 Jacobsson, K., 161 Jaenicke, L.,198 Jahnke, P., 177 James B. G., 21, 185, 186 Jankokki, A., 103 Janion, C., 177 Jansen, E. H. J. M., 255 Janssen, E., 236 Jardetzky, O., 181, 238 Jarman, M., 105 Jarv, J., 272 Jarvis, B. B., 12, 90 Jasperse, J. L., 20 Jay, E., 174, 179 Jeanloz, R. W., 137 Jenkins, J. M., 15 Jennings, W. B., 247 Jensen, H., 272 Jerina, D. M., 181 Johansen, J. E., 201 Johansson, C.-J., 161 Johnson, B. F. G., 234 Johnson, D., 162 Johnson, D. K., 3 Johnson, I., 3 Johnson, K. F., 259 Johnson, P. E., 143 Johnson, R. N., 7 Johnson, S. L., 132, 133 Jolly, W. L., 261 Jones, G. H., 269 Jongsma, C., 253 Jordan, F., 158 Joubert, J. P., 253 Juds, H., 261 Jungalwala, F. B., 271 Juodka, B., 155, 174 Jutzi, P., 1 Kabachnik, M. I., 72, 77, 79, 102,212,219,248,259, 260, 270

279

Author Index Kabachnik, M. M., 49 Kabachnik, M. P., 43 Kabakoff, D. S., 161 Kabela, J., 120, 225 Kadziauskiene, K., 155 Kagawa, K., 233 Kainosho, M., 238, 269 Kajiwara, M., 233 Kakar, S. K., 227 Kakimoto, T., 133 Kakiuchi, N., 152, 176 Kalabina, A. V., 64, 270 Kalasinsky. K. S., 258 Kalasinsky, V. F., 258 Kal'chenko, V. I., 119 Kalenskaya, A. I., 228, 255 Kalian, S. J., 232 Kalinchuk, N. A., 159 Kalinin, A. E., 264 Kalisch, B. W., 178 Kalyagin, G. A., 11 I , 222 Kametaka, M., 139 Kameyama, E., 270 Kampf, A., 152 Kanamaru, H., 25 Kanayama, T., 234 Kanazawa, H., 196 Kang, J. W., 231 Kanne, D. B., 20 Kanstein, C. B., 160 Kanter, H., 29, 261 Kao, J. T. F., 233 Kaplan, N. O., 161 Kappler, F., 171 Kar, D., 116, 181 Karabashyan, L. V., 262 Karabua, Z. K., 79 Karas, G., 256 Karataeva, F. Kh., 125 Karayannis, N. M., 79 Kardanov, N. A., 267 Kargin, Yu, M., 268 Karlstedt, N. B., 90, 240 Karolak-Wojciechowska, J., 265 Karpova, E. N., 268 Karpova, G. G., 172 Kasai, Y.,118 Kasheva, T. N., 223 Kashina, N. V., 113, 125 Kashirskaya, L. I., 268 Kashman, Y., 50, 67, 246,

Katsuyama; Y.; 105 Katz, R., 122, 218 Kauffman, G. B., 228 Kauffmann, T., 17, 74 Kaufman, S., 146 Kavas, G., 106 Kawamura, T., 270 Kawashima, T., 34, 123, 239 Kayalar, C., 141 Kazaki, R. O., 254 Kazarin, S. V., 54, 69 Kazenwadel, W., 10, 240 Kazior, R. J., 33, 88 Kearns, D. R., 151 Keat, R., 101, 226, 228, 251

Keck, H., 253 Keddedy, E. R., 51 Keeler, E. K., 157 Keihl, R., 141 Kellert, M., 269 Kemp, G., 30 Kenkare, V. W., 171 Kennard, O., 263 Kennedy, E. R., 95 Kennedy, J. D., 250 Kensett, M. J., 15 Kenyon, G. L., 78,206,254, 3 69

Keogh, J., 190 Kessel, H., 3, 261 Keuss, H. A. C. M., 188 Kezdi. M.. 163 Khabarova, M. I., 178 Khac, T. N., 99 Khachatryan, R. A., 23 Khaikin, L. S., 266 Khairullin, V. K., 53, 5 5 Khalil, A. H., 184 Khalil, F. Y., 21 Khammatova, Z. M., 126 Khambay, B. P. S., 201 Kharabaev, N. N., 222 Kharlampidi, Kh. E., 112 Kharrasova, F. M., 241, 259, 267 Khaskin, B. A., 113, 120 Khattak, I., 101, 102 Khodak, A. A., 219 Khorana, H. G., 179 Khusainova, N. G., 125, 126, 267 Khusnutdinov, R. I., 123 Khym, J. X., 272 Kibardina, L. K., 112 Kida, M., 149 Kienzle, F., 200 Kierzek, R., 155 Kihara, K., 163 Kikuchi, Y., 177 Killedar, A. V., 115 Kim, T. V., 126 Kimura, Y., 38, 86, 265 Kinas, R., 105, 250 King, R. B., 5 , 243 King, T. J., 236 Kingsbury, C. A., 55,77,252 Kinoshita, M., 118, 150 Kiorpes, T. C., 137 Kipnis, I. S., 40, 247 Kireev, V. V., 216, 232 Kirkemo, C. L., 209 Kirsanov, A. V., 213, 215, 220, 260 Kirzner, V. N., 2, 48 Kise, H., 243 Kisielowski. L..182, 243 Kislitsyna, T. I:, 198 Kiss, L., 163 Kitaev, Yu, P., 261 Kitagawa, Y., 148 Klabuhn, B., 241 Klakbk, A., 31, 43, 47, 116 Klassen. G. R.. 134 Klavi, I@ 99 , ., Klebanskii, A. L., 229, 259 Klei, E., 225 Kleiman, Yu, L. 252 Klein, M. P., 138, 238 Klingebiel, U., 217

Kloeters, W., 18, 46, 189 194,240 Kluger, R., 127 Klyagina, V. P., 178 Knedel, M., 269 Kneidl, F., 28 Knoll, F., 11, 182, 252 Knorr, H., 187, 193 Knorr, U., 187 Knorre, D. G., 165, 174, 249 Knowles, J. R., 141, 143 Knunyants, I. L., 13, 34, 82, 242 Kobayashi, E., 226, 234 Kobayashi, S., 38, 86, 265 Kobayashi, Y., 29, 129 Kober, F., 269 Koberstein, R., 131 Koch, C. W., 78,269 Koch, D., 250 Kocheshkov, K. A., 77 Kochetkov, N. N., 159 Kochmann, W., 84 Kodomaro, M., 123 Koeckritz, P., 126, 258 Koehler, F. H., 252 Koekemoer, J. M., 199 Kolle, U., 5 Koenig, M., 42, 43, 47, 94, 95, 252 Koeppal, H., 253 Koerner, T. A. W. jun., 143 Koster, H., 175 Kogan, V. A., 222 Kohler, S. J., 138, 237, 238 Koizumi, T., 129 Koketsu, J., 269 Kolobushkina, L. I., 153 Kolodii, Ya. I., 120 Kolodyazhnyi, 0.I., 50 Kolodyazhnyi, Yu. V., 267 Kolomiets, A. F., 48, 53 Kolonits, 266 Kolosov, M. N., 174, 175 Kondon, N. S., 238 Kondranina, V. Z., 183 Konieczny, M., 106 Konijn, T. M., 158 Konopka, A., 25 I Konovalova, I. V., 37, 105, 106, 113, 166 Koop, H., 253 Koosha, K., 76 Koreeda, M., 181 Kormachev, W., 266 Kornitnko, E. A., 262 Kornilov M. Yu., 105 Kornuta,'P. P., 228, 255 Korobko, V. G., 175 Korol'ko, V. V., 231 Korshak, V. V., 216,232 Koshkina, 1. M., 272 Kosinskaya, I. M., 119 Kosmin, A. S., 204 Kosminskaya, G. A., 113 Kossykh, V. G., 79 Kostina, V. G., 57 Kostyanovsky, R. G., 6,268 Kovalenko, V. I., 44 Kovalev, B. G., 207 Kovaleva, T.V., 57 Kow, R., 148 Kozachenko, A. G., 270 Kozarich, J. W., 171

Author Index

280 Kozhushko, €3. N., 19 Koziara, A., 121 Kozlov, 8. S., 210, 223, 241 Kozlov, I. A,, 141 Kozlov, L. M., 82 Kozlova, T. F., 107 Kraemer, R., 104,241, 254 Krapp, W., 31, 36,47,249 Kraszewski, A., 155 Kratzl, K., 185 Kravchenko, E. A., 225 Krawczyk, E., 40, 88 Krebs, B., 235 Krebs, E. G., 146, 160 Krech, F., 4 Kreis, W., 271 Kresge, A. J., 270 Krichevskii, L. A., 75 Krief, A., 192 Krijgsman, W., 271 Krilov, D., 256 Krishnamurthy, S. S., 210, 225, 226,234, 264 Kritzyn, A. M., 153, 262 Krivosheeva I. A., 126 Kroeher, R.,’92, 217, 238 Kroeker, W. D., 180 Krokan, H., 169 Krokhina, S. S., 257 Krolovets, A. A., 48, 53 Krommes, P., 214 Kroon, P. A., 238 Kroth, H.-J., 11, 15 Kroto, H. W., 8 Kruglyak, Yu. L., 91 Krupnov, V. K., 53, 69, 257 Kruse, C. G., 193 Kryuchkov, A. A., 259,260 Krzywanski, J., 96, 241 Kubacki, S. J., 271 Kubisen, S. J., 33, 247 Kuchen, W., 253 Kudryavtseva, L. A., 251, 259 Kuechler, E., 177 Kuehne, H., 120, 271 Kuehlbrandt, W., 265 Kugel, R. L., 43 Kuhn, N., 247 Kukhar, V. P., 12, 50, 216, 220, 223 Kukhtenko, I. I., 246 Kuktin, V. A,, 260 Kula, M.-R., 156, 169, 238 Kumada, M., 6 Kumadaki, I., 29 Kuncicky, J., 233 Kung, M. P., 177 Kunieda, T., 85 Kunitskaya, L. A., 9 Kunz, H., 25 Kuramshin, I. Ya., 259 Kurbatov, V. A., 165, 255 Kurguzova, A. M., 251, 259 Kornev, V. I., 9 Kurshakova, N. A., 37, 242 Kurzhunova, Z. Z., 259 Kusmierek, J. T., 181 Kusov, Y. Y., 159 Kutovoi, A. I., 216 Kutyrev, G. A,, 113 Kuzina, I. G., 37 Kuznetsova, L. M., 172 Kyba, E. P., 18

Kyker, G. S., 232 Kyun’tsel, I. A., 216, 255 Laarhoven, W. H., 203 Labarre, J.-F., 228, 267 Labintsev, V. B., 269 Labotka, R. J., 237, 238 Lacey, J. C., 265 Lachmann, U., 75, 185 Lacoste, A. M., 272 Laczi, J., 19 Lakeman, J., 188 Lal, B., 13, 118 Laliberte, B. R., 232 Lambert, J. B., 13, 59 Lamed, R., 161 Lampin, J.-P., 27, 74, 204 Landau, M. A., 91, 249 Landers, A. G., 57 Landor, P. D., 207 Landor, S. R., 207 Langohr, M. F., 139 Lanier, C. W., 233 Lanyi, K.. 19 Lapidot, Y., 262 Lapin, A. A., 72, 11 1 Lappert, M. F., 255 Lardy, H. A., 141, 169 Larubin, A. I., 79 Laskorin, B. N., 79, 269 Laskowski, M., 186 Lassmann, E., 220 Last, J. A., 178 Laszlo, H., 192 Lau, E. P., 134 Lau, P.-Y., 269 Lavayre, J., 262 Laurenco, C., 39, 253 Laursen, S. A., 254 Lavient’ev, A. N., 49 Laver, M., 161 Lazarus, L. H., 161, 166 Lazzaroni, R., 184 Lebedev, A. V., 174,238,249 Lebedev, V. B., 242 Leberman, R., 169 Le Corre, M., 37, 191 Le Dong Khai, 124 Leduc, M., 242 Lee, C.-G., 181 Lee, C. H., 238 Lee, C.-Y., 160, 161 Lee, J. B., 116, 260 Lee, R. C.-Y., 57,247 Lee, S. C., 148 Lee, S. L., 146 Lee, S. O., 239, 244 Lee, T. M., 190 Lee, Y.-G., 116 Legin, G. Ya., 51, 67 Le Gras, P. G., 113 Le Guern, D., 12 Lehle, L., 137 Lehlinger, A. L., 130 Lehmann, H. A., 126,271 Leibovici, C., 267 Leibovskaya, G. A., 91 Leigh, J. B., 168 Leloir, L. F., 137 LeLong, A. L. M., 270 Lem, C.-H., 127 Lemmen, P., 102 Lemmon, D. H., 2,268 Le Moing, M. A., 12

Leng, M., 262 Leonard, N. J., 153 Leone, S. A,, 233 Leoni, R., 233 LCpine, M. C., 40 Leroux, Y., 253 Lesiak, K., 85, 109, 139 Lesiecki, H., 66, 100 Lesniowski, Z. J., 152 Letsinger, R. L., 174 Levason, W., 3 Levjn, B. V.,225 Levm. I. W., 139 Levin; Ya. A., 110, 124 Levin, Ya. Y.,256, 257, 259 Levjna, A. S.,249 Levina, R. Y., 204 Levinson. J. W.. 181 Levitzki, A., 168 Levy, H. M., 168 Levy, J. B., 260 Lewellyn, M. E., 119 Lewis, A,, 258 Lewis, J., 234 Lewis, J. E., 57 Lewis, N. J., 123 Ley, D. A., 148 Leznoff, C . C., 197 Liaaen-Jensen, S., 200, 201 Liddlefield, L. B., 61, 62 Liebes, L. F., 181 Lin, T.-P., 210 Lindner, E., 66, 100 Lindquist, R. N., 144 Lineberger, W. C., 261 Ling, C.-F., 47 Liorber, B. G., 126 Lipatova, I. P., 259 Lippard, S . J., 180 Lipuwska, T., 271 Lischka, H., 244 Lisin, A. F., 126 Livingston, D. C., 177 Llina, J. R., 247 Llort, F. M., 20 Lobanov, A. D., 270 Lobanov, D. P., 111 Loewen, P. C., 134 Loewengart, H., 6 Loginova, E. I., 114 Loginova, G. M., 45, 82, 111 Loibner, H., 13 Lomakina, T. S., 172 London, R. E., 255 Long, K. P., 251 Longobardi, L., 118 Lonsky, L., 185 Lonsky, W., 185 Lopatin, S. N., 261 Lopez, V., 144 Lopusinski, A., 126 Lora, S., 233 Loran, J. S., 116, 127, 128 Lorberth, J., 214 Lourens, G. J., 199 Louw, R., 123 Lovasz, P., 19 Lowe, C. R., 160, 161 Loznikova, N. M., 119 Luber, J., 32, 44, 62, 92, 99, 238,253 Lubowltz H. R., 232 Luby, L. >.,143, 161 Lucansky, D., 272

28 1

Author Index Lucken, E. A., 256 Luckenbach, R., 1, 8, 17, 21, 25, 70, 112, 262 Ludlum, D. B., 153, 176 Luckoff, M., 29 Liistorff, J., 169 Lukashev, N. V., 245 Lukevics, O., 268 Lukszo, J., 110 Lundehn, J.-R., 220 Lunsford, W. B., 174 Lur’e, E. P., 34, 82 Lushchits, I. G., 113 Lutsenko, A. I., 13, 26 Lutsenko, 1. F., 2, 48, 49, 56, 69, 90, 91, 240, 245 Lutsevich, D. D., 259 Luxon, B. A., 181 Luzukina, L. A., 50 Lynch, M. W., 57 Lynch, R. J., 60, 255 Lysenko, Z. A., 204 Lythgoe, B., 74, 205 Maas, G., 264 MciZneny, M., 116 McAulifFe, C. A., 3 McBain, J. B., 147 Maccioni, R., 168 McCluer, R. H., 271 McCormick, J. J., 181 MacCoss, M., 162 McCoy, E. C., 150 Macdonell, G. D., 1 , 240 McDowell, C. A., 256 McEwen, W. E., 8, 245, 260 McFarland, C. W., 253 Mcfarland, J. W.. 89 McFarlane, W., 250 Mach, W., 29 Machesi, V. T., 139 Machi, A. O., 237 Mclntosh, J. M., 269 McKenna. C.. 116 Mctean, R,A., 48 McLennan, 0. J., 9 Macomber, R. S., 51, 95 McPhail, A. T., 244 MacPhee, J. A., 123 McVicker, E. M., 240, 255 Madan, P. B., 122 Madden, H., 201 Madic, C., 259 Maeda, A., 181 Markl, G., 7, 28 Maier, J. P., 261 Maier, L., 56, 250 Maijs, L., 266, 268 Maile, R. J., jun., 271 Majetich, G., 208 Majewski, P. J., 21 Majoral, J. P., 104, 241, 254 Makaiyama, T., 15 Makarova, N. A., 259 Makhmutov, S. F., 53 Maki, H., 234 Malakhov, I. G., 259 Malatesta, M. C., 234 Malcolm, A. D. B., 170 Malenko, D. M., 2 Malevannaya, R. A., 72, 77, 270 Mallion, K. B., 209 Mammano, N. J., 57

Mancini, V., 12 Mangane-Le Desert, L., 259 Manhas, M. S., 13, 118 Mann, F. G., 262 Mannan, Kh., 236 Mannervik, B., 161 Mannherz, H. G., 168 Manohar, H., 234, 264 Mansour, T. E., 144 Marchesini, A., 198 Marcus, C. J., 136 Marcus, S. L., 169 Marecek, J. F., 40, 84, 102, 103, 116, 117, 137,240,242 Margulis, B. Ya., 10 Marien, B. A., 12, 90 Mark, J. E., 232 Markiewicz, W. T., 155 Marko, M., 204 Maron, A., 52, 92 Marschall, H., 206 Marschner, F., 261 Marsden, C. J., 258 Marshall, J. A., 119 Marshall, W. E., 237 Marsham, P. K., 209 Marsi. K. L.. 20. 70. 78. 87. 251; 254, 262 ’ ‘ ’ Marsmann, €3. C., 21 1 Martell, A. E., 139 Martens, J., 268 Martensen, T. M., 144 Martin, B. R., 163 Martin, J., 98, 243, 247, 252 Martin. M. J.. 198 Martin; S. F.,’194 Martini, A., 269 Martynov, 1. V., 91 Marutzky, R., 156, 169 Marvel, J. T., 269 Maryanoff, B. E., 246 Maryanoff, C. A., 267 Marzilli, L. G., 180 Masaki, M., 64, 73 Masaki, Y., 208 Mash, E. A., 147 Masiakowski, P., 171 Maslennikov, I. G., 49 Nlasler, W. F., 5 , 243 Mason, G. W., 264 Mason, R., 2 Mastalerz, P., 127 Mastryukova, T. A., 248,270 Masushige, S., 137 Mathey, F., 26, 27, 74, 108, 204, 261 Mathis, F., 104,241,242,254 Mato, J. M., 158 Matrosov, E. I., 259, 260, 270 Matschiner, H., 104, 108 Matsui, M., 198 Matsumoto, H., 6 Matsumoto, S., 105 Matsuo, S., 229 Matthes, D., 7 Matwiyoff, N. A., 255 Maurer, W., 146 Mawby, R. J., 256 Maxam, A. M., 178 Maxwell, F., 160 Maxwell, I. H., 160 Mazhar-U1-Haque, 264 Meana, M. C., 199

Medved, T. Ya., 79, 270 Medvedeva, M. D., 112 Megera, 1. V., 260 Mehesfalui, C., 199 Mehta, J. R., 153, 176 Meijer, J., 253 . Meissner, U. E., 203 Meister, A., 144, 170 Meister, J. J., 232 Meller, A., 217 Mellor, M. T. J., 24, 128 Mellor, N., 271 Mel’nichuk, E. A., 57 Mel’nik, S. Y., 155 Mel’nik, Ya. I., 120 Mel’nikov, N. N., 113, 1 167 Mengel, R., 152 Menn, J. J., 147 Mentzer, E., 2 Menzel, H., 3 Merour, J. Y., 245 Merrem, H. J., 104 Mertes, M. P., 152, 153 Meskenaite, V., 155 Messer, K., 156 Mesyants, S. P., 270 Metzger, J., 9 Meyers, E. K., 265 Meznek, L., 120,225 Mhala, M. M., 115 Michalski, J., 40, 88, 101, 126, 242 Mickiewicz, M., 268 Midelfort, C. F., 163 Midura, W., 204 Miftakhova, A. Kh., 69 Migron, Y., 185 Mikhailov, S. N., 153, 262 Mikhailova, W. V., 106 Mihailcvski, A., 254 Mjkhailyuchenko, N. K., 83 Miki, M., 121 Mikolajczak, J., 242 Mikolajczyk, M., 18, 80, 96,99,204, 206, 241, 267 Mikulski, C. M., 79 Milbrath, D. S., 98, 264 Mildakhmetov, Z . M., 75 Milicev. S.. 78 Milker,‘R.; 11, 35, 220 Millar, I. T., 262 Miller, J. A., 37, 50, 5 5 , 66, 67. 94 Mill&, S. I., 22 Millington, D., 69 Milliren, C. M., 257 Millis, A. J. T., 158 Mills, J. L., 239 Milnes, D. R., 124 Milstein, C., 179 Milstein, S., 146 Mimura, K., 233 Min, T. B., 40, 247 Min, W., 180 Minato, H., 105 Min Jou, W., 271 Mironov, B. S., 268 Mironova, Z. N., 270 Mishra, N., 260 Mishra, S. P., 225, 256 Mislow, K., 267 Mitchell, P., 130 Mitschler, A., 26

Author Index

282 Miura, K., 162 Miyake, N., 6 M iyamoto, J., 271 M iyashita, M., 208 Miyazaki, T., 152 M izukami, F., 2 M izuno, K., 152 Mizuno, M.,233, 234 M izuno, Y., 156 M izutani, M., 14 Mlotkowska, B., 206 M odak, M. J., 169 M odolell, J., 169 M odro, T. A., 270 M oedritzer, K., 240, 270 M offatt, J. G., 153 M ojski, M., 79 M okeeva, V. A., 216,255 M okva, V. V., 124 M ollin, J., 120 Momii, R. K., 181 Momot, V. V., 221 M onson, R. S., 123 M ontenarh, M., 9 M oore, G. A., 128 M oore, G. Y., 43 M oore, P. D., 181 M orait, G., 260 Mloran, T. A., 74, 205 M orbach, W., 182,252 M orel, G., 12 M loreland, C. G., 61, 62 M lori, K., 198 iMorkovin, N. V., 252 M orozov, L. L.,102,248 M !orozova, N. P., 259 M orr, M., 238 M orris, D. G., 244 M !orris, D. L., 254 M orris, J., 49, 67 M orrison, J. D., 243 M [orrow, C. J., 243 M orton, D. P., 167 M ‘osbach, K.. 161 Mosbo, J. A.; 97 Moskva, V. V., 63, 254, 260 Moss, G. P., 201 Moyes, W., 261 Mueller, G., 261 Miiller. H.-D.. 5 Mueller, J., 269 Miiller, N., 1, 70 Muetterties, E. L., 77 Muhlrad, A., 161 Mukai, J.-I., 163 Mukaiyama, T., 80, 162 Mukhtarov, A. Sh., 256,257 Mukmenev, E. T., 65, 258, 259, 267 Muller, J. F., 261 Mulliez, M., 112 Mulvihill, S. J., 138 Munoz, A., 31, 42, 47, 94, 95, 116, 213 Murahashi, S. I., 25 Murai, A,, 269 Murai, R., 79 Muratov, S. S.. 110 Muratova, A. A., 259 Murav’ev, I. V., 103, 125 Murch, R. M., 234 Murphy, M. J., 153 Murray, W. P., 23, 197 Musebach .R., 40

Mushika, Y., 133 Musina, A. A., 125, 247, 267 Myasoedov, B. F., 79 Myers, K. R., 160 Myers, T. C., 238 Myles, A., 104 Mynka, A. F., 259 MYSOV,E. I., 13, 34, 82 Naaktgeboren, A., 253 Nadler, D., 1 Nagao, Y., 25, 268 Nagasaki, T., 105 Naggendrappa, G., 225 Nagyvary, J., 152 Naka, T., 157 Nakagawa, I., 162 Nakatsukasa, Y.,107 Nakayama, S., 254 Nakazato, H., 161 Nambvdiry, M. E. N., 74,205 Nand, P., 115 Narang, C. K., 175 Narang, S. A., 173 Narasaka, K., 199 Narindrasorasak, S., 162 Nassimbeni, L., 263 Nasybullin, Sh. A., 255 Naumov, A. D., 229 Naumov, V. A., 266 Navech, J., 104, 241,254 Navon, G., 237 Naylor, R. A., 127, 128 Nedorezova, T. P., 155 Negrebetskii, V. V., 92 Neidlein, R., 40 Neidle, S., 265 Neilson, R. H., 24, 214, 247 Neilson, T., 173 Neimysheva, A. A., 110 Nelson, G. O., 260 Nelson, N., 258 Nelson, S. M., 91 Nesmeyanov, N. A., 26, 191, 245,270 Neukomm, H., 99 Neumayr, K., 45 Newland, G. L., 111 Nguyen, T. T., 245 Nibler, J. W., 258 Nicolaides, D. N., 204 Niecke, E., 92, 216, 217, 238, 240 Niederberger, W., 238 Niemann, U., 49,210 Niessing, J., 161 Nifant’ev, E. E., 245, 259, 260 Niitsu, M., 79 Nikitin, E. V., 268 Nikitina, G. S., 232, 234 Nikolotova, Z. I., 79 Nikonorov. K. V.. 250 Nikonorova, L. K’., 251 Nirnmo, G. A., 146 Ning, R. Y., 122 Ninomiya, K., 118 Nishida, T., 220, 233 Nishigaki, S., 196 Nishikida, K., 257 Nishizawa, M., 208 Nivard, R. J. F., 203 Nixon, J. F., 8

Nizhnikova, E. E.. 2 10 No, B. I., 52 Nolden, P. W., 238 Nomiyama, H., 163 Noriyuki, N., 133 Norris, K., 179 Norris, K. E., 175 Norrish. H. K.. 75 Notman, H., 174 Novikova, N. K., 106 Novikova, 2.S., 2,48,49,91 Novobilsky. V., 224 Novosad, J., 225 Novruzov, S. A., 124 Nowakowski, M., 40, 116, 117, 242 Nozaki. H.. 148 Nu, Y.,’ 85 ‘ Nuber, B., 235 Nuretdinov, 1. A., 113, 114, 25 I , 259 Nuretdinova, 0. N., 113, 119. 124 Nurtdinov, S. Kh., 54, 69 Oades, A. C., 28 Oae, S., 14 Oakley, R. T., 236 Oberhammer, H., 61, 266 O’Brien, J. P., 226 Odyek, O., 207 Oehling. H.. 256 Ofitserg;, E: N., 84, 85, 251, 254 Ofitserova, E. Kh., 37 Ogasawara, N., 157 Ogata, I., 2, 3 Ogata, T., 107 Ogata, Y.,14 Ogawa, S., 131, 237 Ogilvie, K. K., 102, 158 Ohashi, K., 269 Ohkita, T., 123 Ohsawa, A., 29 Ohtsuka, E., 172, 177 Okahara, M., 21 Okazaki, H., 102, 103, 117, 240 Okruszek, A., 250 O’Kuhn, S., 119 Okutani, T., 149 Olah, G. A., 253 Oleinik, D. M., 155 Oliver, J. E., 64 Olsen, J. F., 257 Olson, E. S., 255 Omelanczuk, J., 18, 99 Omogbai, F., 14, 89 Omote, K., 123 Omura, H., 102 Onan, K. D., 244 Oplatka, A., 161 Oppenheimer, L., 158 Orernek, G., 187 Orgel, L. E., 154 Orlov, V. M., 260 Orlovskii, V. V., 86 ORourke, E., 232 Orr, G. A,, 143 Ortiz de Montellano, P. R., 148 Orwoll. E. F., 233, 234 Osaki, S., 152 Osellame, M., 233

283

Author Index Oshima, T., 159 Osipov, 0. A., 78, 222, 259, 267 Ostoja Starzewski, K. A., 243, 244, 261 Oswald, T., 9 Ottensmeyer, F. P., 180 Ovchinnikov, V. V., 46, 113, 119, 267 Owen, G. R., 153 Owen, N. E. T., 51 Ozawa, K., 118, 121 Pabst, W. E.. 205 Paddock, N. L., 224, 236 Padlan, E. A., 139 Padmanabhan. R.. 175 Pagilagan, R. U., 260 Pagnoni, U. M., 198 Pakulski, M., 40, 88 Paliichuk, Yu. A, 19 Palmer, M. H., 26, 261 Pancoe, W. L., 171 Pankiewicz, K., 105 Pannell, K. H., 222 Pantarotto, C., 269 Papahadjopoulos, D., 266 Papasathopoulos, D. S., 144 Parakin, 0. V., 268 Parg, A., 21, 72, 114 Park, H. C., 229 Parodi, A. J., 137 Parrett, F. W., 48 Parrott, M. J., 256, 257 Parsons, D. F., 266 Parsons, S. M., 167 Partis, M. D., 141 Pashinkin, A. P., 44 Pasternak, V. I., 220 Pastukhova, L V . , 72,84,110 Patel, V. C., 234 Patmore, D. J., 224 Patnaik, L. N., 260 Pattenden, G., 21, 185, 186 Patterson, D. B., 230 Patza, P. E., 232 Paul, J., 233 Paulsen, H., 84, 135 Paulus, H., 198 Pavel, T., 163 Pawson, B. A., 200 Pawson, D., 2 Pearce, A., 75 Pearson, D. E., 118 Pedersen, E. B., 123 Peiffer, G., 269 Pellegata, R., 209 Penczek, S., 118 Pen’kovskii, V. V., 257 Pensionerova, 6. A., 63, 107 Pennings, J. F. M., 257 Peppard, D. F., 264 Pepperman, A. B., 72 Perini, F., 171 Perks, M., 91 Perman, J., 185 Perone, S. P., 180 Perry, W. B., 261 Pershin, A. D., 255 Pesotskaya, G. V., 50 Pestova, T. A., 112, 215 Peter, G., 104, 105 Pete, J. P., 123

Peterson, H., 19 Peterson, L . K., 3 Peterson, S. W., 264, 265 Petragnani, N., 195 Petrenko, V. S., 216 Petrov, A. A., 19, 50, 83, 107, 246, 269 Petrov, E. S., 77, 270 Petrov, K. A., 72, 84, 110, 124, 125, 126, 260 Petrov, M. L., 83 Petrova, 6. S., 125 Petrovskii, P. V., 13,26,212, 219.248 Petukhov, R. D., 271 Pczzin, G., 233 Pfeuffer, T., 165 Phjlljps, F. L., 235 Phisithkul. S.. 28 Picavet, J.’P.,’96 Pich, G., 216 Pieke, R. D., 257 Piekos-Maron, A., 270 Pietrasanda, Y.,51 Pimmer, J., 165 Pinchuk, A. M., 215 Pines, S. H., 188 Pinnavaia, T. S., 139 Pisanenko, N. P., 119 Pisareva, S. A., 79 Pitcher, R. G., 200 Pleshkova, A. P., 268 Pless, R. C., 176 Plumer, E. R., 232 Plyamovatyi, A. Kh., 258 Plyashkevich, Yu. G., 272 Pobedimskii, D. G., 255 Podesta, R., 270 Pogonowski, C. S., 208 Pogorelyi, V. K., 246 Pohl, S., 92, 210, 234, 235, 262 Pohle, H., 261 Pokonova, Yu. V., 234 Polezhaeva, N. A., 96, 111, 247 Pollak, A., 135 Pominov, 1. S., 259 Pommer, H., 201 Pondant, M., 79 Poorthuis, J. H. M., 271 Portella, C., 123 Porter, K., 174 Portulas, J., 10 Posadov, I. A., 234 Potter, M., 139 Poulin, D. D., 62 Poulos, C. P., 14, 89 Poulter, C. D., 147 Powell, H. M., 262 Powell, J. T., 171 Power, P. P., 255 Powers, S. 6., 144, 170 Pradel, L.-A., 143 Praefcke, K., 268 Pramanik, B. N., 13, 118 Prensky, W., 169 Preobrazhenskaya, M. N., 155 Prignet, J., 264 Pritchard, M. S., 224 Prival, M. J., 150 Profous, Z. C., 269 Prokof’ev, M. A., 174, 178

Prons, V. N., 229, 231,259 Proskurnina, M. V., 90, 240 Proskuryakov, V. A., 234 Prusoff, W. H., 165 Prydz, H., 169 Ptak, M., 262 Pudovik, A. N., 30, 37, 44, 45, 69, 72, 82, 84, 85, 94, 105, 106, 108, 111, 112, 113, 119, 125, 126, 183, 213, 214, 215, 240, 245, 250, 251, 253, 254, 259, 260, 267, 268 Pudovik, M. A., 30, 46, 94, 112, 215,240, 251 Pujol, L., 15 Pullman, A., 265 Purdum, W. R., 1,240 Purrello, G., 263 Pustoslemsek, P., 187 Pyatnova, Yu. B., 198 Pytlewski, L. L., 79 Pyzhova, Z. I., 79 Quast, H., 240 Quilliam, M. A., 155 Quin, L. D., 13, 49, 67, 239, 240, 243, 244, 251 Quinn, E. J., 233 Raaberg, S. B., 57 Rabinovitz, M., 202 Rabinowitz, R., 147 Rachbn, J., 83, 109, 127, 139 Racker, E., 130, 258 Radda, G. K., 130, 135,237, 246 Raevskii, 0. A., 259, 267 Rait, V. K., 172 Rajzmann, M., 239 Raksha, M. A., 124 Ramadoss, C. S., 143, 161 Ramage, R., 25, 128, 184 Ramamoorthy, B., 179 Ramirez, F., 40, 84, 86, 101, 102, 103, 116, 117, 137, 240, 242, 265 Randerath, E., 179, 271 Randerath, K., 179, 271 Ranieri, R. L., 125 Rankin. D. W. H.. 57. 58. 60,251 Rao, B. D. N., 145 Rao, K. V., 102 Rapoport, E., 170 Rasch, D., 84, 135 Razumov, A. I., 63, 101, 124, 126, 241, 246, 254, 260. 270 Razumova, N. A., 37, 44, 242, 253 Recca, A., 246 Rechnitz, G. A., 144 Record, K. A. F., 52, 92 Redmore, D., 83, 108 Redoules, G., 16, 58, 59 Reed, B. C., 147 Reese, C. B., 172, 173 Reetz, M. T., 15, 191 Reeve, R. N., 60, 255 Regitz, M., 101, 115 Rehkop, D. M., 145 Reichert, K. H., 65 Reid, W., 193 .

I

Author Index

284 Reinhart, G. D., 141 Reis, A. H., 264 Remisov, A. B., 259 Remizov, A. B., 267 Remizova, L. A., 272 Rettig, S. J., 236 Reuschenbach, G., 239 Reuss, K., 177 Reuther, W., 19 Reutov, 0. A., 26, 191, 245 Reutrakul, V., 28 Revankar, G. R., 153 Revel, M.,254 Reyes, W., 6 Reynard, K. A., 231, 232, 233 Rezvukhin, A. I., 238, 242, 249 Rheingold, A. L., 8, 57 Ribeiro, A. A., 238, 255 Ricci, J. S., jun., 84 Ricco, A, 19 Rich, A., 265 Richard, B., 253 Richards, J. H., 138 Richards, R. E., 135, 237 Richman, J. E., 32, 61 Richtarski, G., 127 Richter, C., 108 Richter, W., 189, 252, 261 Riddle, R. M., 255 Rideout, J. L., 152 Riechel, T. L., 144 Rieck, H. P., 244 Ried, W., 187 Riedl, H., 99 Riesel, L., 216 Riess, J. G., 247, 249 Rilling, H. C., 147 Rishi, S., 118 Risi, S., 161 Ritchey, W. M., 246 Rizpolozhenskii, N. I., 56 Robert, D. U., 247, 249 Robert, J. B., 98, 240, 243, 247, 249, 250,252, 254 Roberts, B. P., 256, 257 Roberts, N., 268 Robinet, G., 60 Robins, R. K., 153 Roca, C., 254 Rodewald, G., 7 Rodionova, L. M., 79 Rodriques, R., 195 Roder, J., 25, 268 Rosch, L., 4, 58 Roschenthaler, G.-V., 8, 32, 34, 39, 58, 60, 63, 247, 269 Roesky, H. W., 9, 85, 236 Roethling, T., 84 Rogers, G. N., 136 Rohrbaugh, W. J., 265 Rojhantalab, H., 258 Rokhlin, E. M., 34, 82, 242 Roland, G., 79 Romanov. G. V.. 72. 111. 268 Romm, 1. P., 77, 260, 262 ROOS,J. P., 123 Rose, H., 21 1 ,227, 228,229, I

251

R&; I. A., 130, 163 Rose, K. M., 169 Rose, S. H., 232

_

I

Rosenbaum, G., 168 Rosenberg, J. M., 265 Rosen, B. I., 185 Rosen, 0. M., 130 Rosenkranz, H. S., 150 Roser, C. E., 240 Rosing, J., 141 Rossi, P. P., 233 Rosso, G. C., 137 Roth, W.-D., 4 5 Rottman, F., 177 Roussel, J., 254 Roustan, C., 143 Rout, M. K., 266 Rowlands, J. R., 256 Rowley, A. G., 27 Roychoudhury, R., 179 Rozanelskaya, N. A., 77 Rozen, A. M., 79 Rozhkova, N. K., 44 Rozinov, V. G., 63, 107 Ruban, G., 77, 263 Rubio, V., 144 Ruby, C., 216 Rudavskii, V. P., 210 Rudi, A., 50, 67, 252 Rudikoff, S., 139 Rudinskas, A. J., 253 Rudnitskaya, L.-S., 48 Riichardt, C., 123 Rueegg, R., 201 Rueppel, M. L., 269 Riiterjans, H., 146 Ruppert, I., 11, 35, 220, 242 RUSS,P., 104, 120, 216 Russell, D. R., 32, 242 Russell, P. J. jun., 161 Ruston, S., 74, 205 Ruvede, M. A., 270 Ryan, J., 136 Rycroft, D. S., 228, 281 Rydstrom, J., 161 Rylatti, D. B., 146 Ryl’tsev, E. V., 222 Ryser, G., 201 Saalfrank, R. W., 194 Sobanov, A. A., 69 Sabherwal, T. H., 48 Sabirova, K. G., 54 Sadechian, K., 271 Sadykov, R. Kh., 210, 241 Saegusa, T., 38, 86, 265 Saenger, W., 154 Saey, J. C., 259 Safiullin, R. K., 253 Safiullina, N. R., 259 Safronova, 2. V., 13 Sagina, E. I., 12 Saito, H., 233 Saito, O., 177 Sakaguchi, K., 177 Sakai, K., 187 Sakai, L. J., 160 Sakhibullina, V. G., 111 Salakhutdinov, R. A., 50, 63, 107, 254 Saleske, H., 1 Salishchev, V. G., 83 Salmond, W. G., 182 Saltykova, L. I., 91 Salvadori, P., 184 Samarai, L. I., 220 Samarina, 0. A., 267

Samatova, N. A., 270 Samitov, Yu. Yu, 125, 126, 241, 247, 250,253 Samukov, V. V., 165 Sanchez, M., 31, 34, 42, 61, 94, 116,213, 249 Shnchez-Ferrando, F., 10 Shnchez-Pardo, J., 10 Sandmeier, D., 182 Sanger, F., 179 Sanin, P. I., 155 Sannicolo, F., 65 Sant, B. R., 231 Santaniello, E., 12, 9 Sapozhkov, Yu. N., 119 Sarana, T. I., 122, 258 Sargent, E. R., 271 Sarin, V., 80, 147 Sarma, R. H., 238 Sartori, P., 66, 96 Sasaki, T., 171 Sasnauskiene, S., 155 Satek, L. C., 78 Satgk, J., 16, 58, 59 Sathe, G., 174 Sato, H., 204 Sato, M., 156 Sato, T., 79 Sau, A. C., 226 Saunders, B. B., 19 Saunders, J. E., 258 Savage, W. J., 58 Saveant, J. M., 25 Savignac, P., 108, 253 Savoskina, G. P., 246 Sawai. H.. 176 Sazonova;Z. Ya., 260 Schaaf, T. F., 261 Schafer, W., 26, 29, 261, 269 Schaffer, O., 263 Scharf, D. J., 253 Schaumann. E.. 80. 206 Scheit, K.-H., 177 ’ Schenone, P., 118 Scherer, 0. J., 90, 93, 94, 210, 214, 216, 217, 239, 247, 251 Schiebel, H. M., 186 Schiemenz, G. P., 17 Schipper, P., 255 Schlak, O., 32 Schlimnie, E., 169 Schlosser, M., 205 Schmid, G., 182 Schmidbaur, H., 33, 37, 182, 189, 190, 221,252 Schmid-Fritsche, W., 4, 58 Schmidpeter, A., 32, 44, 62, 92, 99, 227, 230, 235, 238, 253. 265 Schmidt, A., 222, 258 Schmidt, F. S., 171 Schmidt, H., 251, 261 Schmidt, M. F. G., 137 Schmidt, U., 268 Schmutzler. R.. 32. 34 39, 51. 58. 60. 61. 215. 242. 243, 247, 253, 266 Schnable. G.. 90, 93, 94, 217, 239, 241, 251 . Schneider, N. S., 236 Schnekenburger, J., 190 Schnuster, S. M., 141 Scholer, H., 11 I,

’

285

Author Index Schoning, G., 210, 224 Scholer, H., 48, 182 Scholtissek. C.. 137 Schomburg, D’., 31, 32, 62, 762, 265 Schrecker, O., 146 Schroder-Nielson, M., 79 Schroeder, H. F., 269 Schuckmann, W., 187 Schulten, H.-R., 180 Schulz, D. N., 8, 245, 260 Schulz, H., 17 Schulz, P. C., 269, 270 Schumann, H., 4, 7, 11, 58 Schuster, S. M., 169 Schutzbach, J. S., 137 Schwarz, H., 268 Schwarz, R. T., 137 Schweie. A.. 26. 29. 261 Schweizer, E. E., ‘23, 184, 197, 222, 241, 243 Scofield, R. E., 160 Scola-Nagelschneider, G., 134 Scopes, D. I. C., 153 Scopes, R. K., 161 Scott, G., 17, 37 Scott, R. J., 27 Sears, B., 238, 255 Seeds, N. W., 168 Seeley, P. J., 130, 135, 237 Seelig, J., 138, 238 Seeman, N. C., 265 Segal, D. M., 139 Seifert, W. J., 263 Seifert, Z., 245 Sein, U. 1.. 204 Seitz, G., 193 Sekine, M., 131, 162 Sekine, T., 79 Sekiya, T., 179 Sello, S. B., 233 Selve, C., 19 Semashko, Z. T., 106, 120 Semenii, V. Ya, 216, 267 Semeriva, M., 143 Senga, K., 196 Sen Gupta, A. K., 272 Seno, M., 243 Sergeeva, N. F., 174 Serov, V. I., 271 Sevilla, N., 168 Seyden-Penne, J., 74, 204 Shabarov, Y. S., 188 Shabarova, Z. A., 174 Shaffer, P. J., 152 Shagidullin, R. R.,258, 259 Shahak, I., 121 Shaidulin, S. A., 266 Shakhaliev, Sh. M., 6 Shakirov, I. Kh., 258 Shalina, N. M., 272 Shapeleva, E. S., 155 Shapiro, D. L., 139 Shapiro, J. A., 180 Shapiro, R., 156 Sharma, R. A., lS5 Sharma, V. R.,227 Sharp, R. R., 243 Shatenshtein, A. I., 77, 270

Shchukareva, T. M., 50 Sheik, A. R., 26, 78 Shek, V. M., 259, 267, 26% Sheldrick, B., 236 Sheldrick, G. M., 234 Sheldrick, W. S., 32, 62,235, 242, 262, 265 Shenke, R. J., 126 Shepherd, R., 81, 263 Shemard. D.. 73. 256 Sheppard; R.’C.,’175 Shermergorn, I. M., 82 Shev, K. R. R., 146 Shevchenko, M. V., 220 Shevchenko, V. I., 228, 255 Shevchuk, M. I., 196, 260 Shewchuck, E., 268 Shiau, W. I., 8, 245, 260 Shibaev, V. N., 49, 159 Shibasaki, M., 199 Shmidel, E. B., 271 Shimotohno, K., 162 Shiori, T., I18 Shipov, A. E., 248 Shiratori, O., 105 Shishkin, V. E., 52 Shokol, V. A., 19, 83 Shpak, S. T., 196 Shtepanek, A. S., 11 1, 220 Shukla, K. K., 168 Shulman, R. G., 131, 237 Shuman, R. F., 188 Shuets, A. A., 78, 259, 267 Shvetsova-Shilovskava. K. D., 119 Shvetsov-Shilovskii, N. I., 92 Sicka, R. W., 232, 233 Siclari, F., 233 Siddall, T. H., 72 Sidiropoulos, G., 9, 85 Sidorova. E. E.. 124. 270 Sidwell, R. W.,’153 ’ Sigel, H., 170 Sillerud, L. O., 238 Sim, S. K., 186 Simmons, N. P. C., 8 Simon, J. C., 239 Simon, M., 268 Simoncsits, A., 165 Singer, B., 181 Singler, R. E., 232, 233 Sinha, A. K., 161, 272 Sinyavskaya, E. I., 79 Sitdikova, Y.Sh., 63, 254 Skapski, A. C., 235 Skare, K., 171 Skorobogatova, M. S., 110, 256 Skorobogatova, S. Ya., 91 Skorovarov, D. I., 79 Skowronska, A., 40, 88, 242, 257 Skrzypazysnki, 2, 126 Skulachev, V. P., 141 Skvortsov, N. K., 246 Slepnjova, I. A., 181, 256 Sliwa, H., 96 Slocombe, P M., 179 Slotin, L. A., 171 Sluboski, B. C., 122 Smegal, J., 227 Smeltz, L. A., 229, 230 Smetana, H., 230 Smirnov, A. N., 260

Smirnov, E. V., 110 Smirnov, V. A., 111 Smirnov, V. D., 174 Smith, D. J. H., 66, 99, 242 Smith, G. D., 70, 86 Smith, H. O., 179 Smith, H. W., 265 Smith, 1. C. P., 255 Smith, L. R., 239 Smith, M., 177, 179 Smith, T. W., 28, 29 Smolyaninova, 0. A., 178 Smrt, J., 157, 172 Sninsky, J. J., 178 Snopek, T. J., 178 Snowden, R. L., 75 Snfatkova, E. V., 49 Snyder, D. L., 231 Sobczak, A., 126 Sobolev, A. N., 262 Sochilin, E. G., 49 Sodimenko, A. P., 267 Sohr, H., 104 Soifer, G. B., 216, 255 Sokal’skaya, L. I., 269 Sokalskii, M. A., 91 Sokolov. M. P., 260

,69 216 Someno, ’K., 177 Songstad, J., 8, 19 Sonnett, P. E., 64 Sonoda; A., 25 Soroka, M., 127 Sorokina, S. F., 245 Sosnovsky, G., 106,118,120, 256 Sowerby, D. B., 23 1 , 236 Sparagana, M., 265 Sparrow, A. J., 259 Specker, H., 229, 232 Spiegel, A. M., 168 Spiker, R. C. jun., 139 Spinger, C., 238 Spivak, L. L., 270 Sprangers, W. J. J. M., 123 Springer, J. P., 98, 264 Springs, B., 108 Sprinzl, M., 172 Spronk, A. M., 146 Staab, H. A., 203 Stahl, K.-W., 165 Stan, H. J., 269 Stanacev, N. Z., 138 Stankiewiez, T., 242 Starke, R., 39, 60 Start, J. F., 233 Starzemska, H., 127 Stawinski, J., 173 Stayer, M. L., jun., 224, 231 Stec, W. J., 8 5 , 105, 109, 126,139,152,242,250,257 Stedjee, B. J., 228 Steer, M. L., 168 Stegmann, H. B., 242 Stehlik, D., 146 Steiner, R. F., 176 Steiner, R. P., 186 Stellwagen, E., 272 Stepanov, B. I., 260, 268

286 Stepanov, I. A., 19 Stephenson, L. M., 40 Stern, P., 86 Sternbach, H., 164, 172 Sternglanz, H., 265 Stevens, C. V., 233 Stevens, T., 144 Stewart, D., 37, 55,66,67,94 Stocks, R. C., 13 Stockton, G. W., 255 Storm, D. R., 136 Striihle, 6,28 Stransky, W., 198 Strathdee, R.-S.,43, 249 Stringer, M. B., 203 Strothkamp, K. G., 180 Strotmann, H., 169 Struchkov, Yu. T., 264 Struck, R. F., 105 Striiver, W., 11 Strukov, 0. G., 11I Stufkens, D. J., 2 Stuhne-Sakalec, L., 138 Stull, J. T., 130 Sturtz, G., 108 SU,S.-C., H., 2 Suba, L. A., 269 Subbarao, B., 171 Subramanian, E., 265 Sudarev, Yu. I., 44,108, 242 Sudheendra Rao, M. N., 225 Sudol, M., 85 Sugimae, T., 150 Sugino, A., 178 Suhadolnik, R. I., 152 Sulewska, A., 104 Sulkowski, W., 232 Sun, H., 13, 59 Sun, M. S., 48 Sunagawa, M., 204 Sutherland, J. W. H., 168 Suvalova, E. A., 111, 126, 258 Sventitskii, E. N., 246 Svoren, V. A., 212, 219 Swenson, D. C., 263 Swidler, R., 115 Swindles, M., 242 Symmes, C., 49, 67, 244, 251, 260 Symons, M. C. R., 225, 256, 257 Szab6, L., 135 Szafraniec, L. L., 241 Szekely, M., 178 Szele, I., 33, 247 Szewczyk, J., 126 Szoke, S., 266 Tabushi, I., 229 Taguchi, Y., 133 Taieb, C., 252 Takaku, H., 173 Takeda, M., 271 Takei, H., 80 Takemizawa, A., 105 Takeo, K., 65 Takeuchi, S., 181 Takigawa, T., 198 Takimato, Y., 271 Takizawa, T., 85 Tamanoi, F., 159 Tamao, K., 6 Tamari, M., 139

Author Index Tamm, C., 157 Tan, H.-W., 239, 246 Tanabe, T., 118, 150 Tanaka, M., 2, 3 Tanaka, S., 177 Tanaka, T., 172 Tang, D., 190 Tang, Y. C., 270 Tanigawa, Y., 25 Tantasheva, F. R., 10 Tarasova, R. I., 270 Tarzivolova. T. A.. 126 Tatem, P. A., 233 ’ Taylor, J. A., 227 Tebby, J. C., 112, 250 Teeter, M., 230 Telyatnik, A. I., 111 Temnikova, G. S., 106 Temyachev, 1. D., 250 Terekhova, M. I., 77, 270 Terent’eva, S. A,, 30, 94 Terent’eva, T. V., 242 Tereshchenko, G. F., 246 Ter-Gabrielyan, E. G., 13 Tewari, R. S., 185 Thames, K. E., 168 Thang, M. N., 152 Thavard, D., 27 The, K. I., 34, 62, 251 Theriault, N., 102, 155 Thiem, J., 84, 135 Thoennes, D., 55,77, 252 Thomas, G. J., jun., 181 Thomas, L. L., 215 Thompson, E. A., 155 Thompson, J. E., 233 Thompson, S. T., 272 Thompson, T. E., 238, 255 Thomson, C. J., 57 Thorausch, P., 4, 6 Thorpe, W. D., 25 Thorstenson, T., 8 Thulin, B., 202 Ticozzi, C., 19 Tiechmann, H., 233 Tigeeva, N. G., 172 Tijssen, P. A. T., 123 Tikhonina, N. A., 43 Tilhard, H.-J., 17 Tilichenko, M. N., 54, 112 Tillott, R. J., 231 Timokhin, B. V., 64 Timoshina, T. V., 126 Tipson, R. S., 144 Tirodkar, R. B., 65 Tjessem, K., 267 Tkalenko, V. G., 267 Tochino, Y., 105 Todesco, P. E., 109, 245 Toekes, L., 269 Toepelmann, W., 120, 271 Toktomatov, T. A., 225 Tolan, J. W., 243 Tollin, P., 265 Tolman, R. L., 153 Tolnay, P., 199 Tolstikov, G. A., 123 Tomasz, J., 105 tom Dieck, H., 243,244,261 Tomioka, H.,73 Tomkins, 1. B., 7 Tomlinson, A. J., 62 Topsom, R. D., 259 Tordo, P., 15

Torgasheva, N. A., 113, 126 Toriyama, N., 73 Toropova, V. F., 69 Toscano, D. G., 136 Touchet, P., 232 Townsend, J. M., 6 Tranquilla, T., 174 Traub, P., 160 Tregear, R. T., 168 Treshchalina, L. V., 126 Treweek, R. F., 257 Trippett, S., 30, 31, 32, 35, 36, 42, 66, 99, 242 Trivedi, B. C., 20 Trondlin, F., 123 Trommer, W. E., 131 Tropp, B. E., 80, 138, 147 Trotter, J., 236 Tseng, C. K., 254 Tsentovskaya, V. S., 268 Tsentovskii, V. M., 268 Tsivunin, V. S., 54, 69 T’so, P. 0. P., 176 Tsuboi, H., 84, 102, 103, 117, 240 Tsuchiva. S.. 243 Tsuji, T.,’ 233 Tsvetkov, E. N., 72, 77, 125, 259,270 Tsymbal, 1. F., 222 Tu, C.-P. D. 179 Tuazon, P. T., 132 Tudrii, G. A., 43 Tuinstra. H.. 262 Tull, R. J., 188 Turcant, A., 37 Turchin, K. F., 155 Turco, S. J., 137 Turkevich, V. V., 120, 241, 259 Turpin, P. Y., 181 Turtle, B. L., 6 Tweddle, N. J., 43, 249 Tyhach, R. J., 138 Tyka, R., 110 Tzschach, A., 7 Uchida, T., 159 Uchiyania, M., 271 Uematsu, T., 152 Uesugi, S., 157, 176 Ugi, I., 101, 102, 165 Uhing, M. C., 238 Uhlenbeck, 0. C., 178 Ulmsschneider, K. B., 242 Uryupin, A. B., 270 Usardi, M. M., 209 Usgaonkar, R. N., 65 Usher, D. A., 176 Utebaev, Y., 34, 82, 242 Uyeda, K., 143, 161 Uznanski, B., 242, 251 Vaciago, A., 263 Vafina, A. A., 257 Vahrenhorst, A., 17 Vaisberg, M. S., 248 Vajna de Pava, O., 19 Valaitis, J. K., 232 Valentine, D. H., 6 Vallejos, R. H., 141 Van Aartsen, J. J., 123 van Boom, J. H., 173, 174

287

Author Index Van De Grampel, J. C., 225, 23 1 Vande Griend, L. J., 253 Van de Kamp, C. G., 271 Van Den Burg, J. B., 231 van der Gen, A., 193 Van der Helm, D., 16, 72 Van der Kelen, G. P., 240, 245 van der Marel, G., 173 van de Sande, J. H., 178 Van Dijk, J. M. F., 257 Van Duuren, B. L., 6 Vandyukova, I. I., 259 Van Etten, R. L., 145 Vanja, E.,.266 Van Swieten, A. P., 123 van Tamelen, E. E., 148,174 Van Thoai. N.. 143 Van Waze;. J.’R., 56. 249 Vasilenko, G. I., 74 . Vasil’ev, A. F., 92 Vasil’ev, V. V., 44,242, 253 Vasil’eva, T. V., 260 Vas’kiv, A. P., 120, 241 Vass, G., 40 Vasudeva Murthv. ., A. R.. 225, 226 Vaultier, M., 195 Vazquez, D., 169 Vdovenko, S. J., 267 Veits, Yu. A,, 56, 69, 245 Veltmann, H., I I, 252 l’enanzi, L. M., 3 Venkatardmu, S. D., 1, 18, 240 Venkata Rao, B. V., 225 Venkatesan, S., 161 Venkstern, T. V., 172 Vereshchagin, A. N., 259,267 Verheyden, J. P. H., 153 Verkade, J. G., 98, 116, 253, 260,264 Vermeer, H., 261 Vermeer, P., 253 Vershinina. G. E.. 253 Vessiere, R., 188 Veveika, F., 120 Vicic, J. C., 231, 232 Vigalok, 1. V., 107 Vila. F.. 15 Vilceanu, R., 269 Vilesov, F. I., 261 Vilkov, L. U., 266 Vinogradova, V. S., 111 Vinokurov, A . I., 113 Vizel, A. O., 53, 69, 257 Vizethum, W., 169 Vogt, W., 269 Voitsekhovskaya, 0. M., 223, 260 Volckaert, G., 271 Voll, R. J., 143 Volodin, A. A., 216 Volodin, I. I., 79 Volz, M., 99 Voncken, W. G., 127 Von der Haar, F., 165 Von Niessen, W., 261 Voorheis, H. P., 163 Vordermaier, G., 66, 100 Vostrowsky, O., 198 Vovna. V. I., 261 Vovsi, B. A., 86 ’

Voznesensky, V. N., 268 Vrieze, K., 2 Vuk-Pavlovic, S., 237 Vul’fson, A. N., 175 Vul’fson, S. G., 267 Vysotskii, V. I., 54, 112 Wachsman, J. T., 178 Waddington, T. C., 56, 60, 239.255 Waechcr, F., 168 Wagenknecht, J. H., 127,268 Wagenstein, I., 252 Wagner, T., 104 Wait, K., 235 Wakselman, M., 112 Walk, R.-A., 161 Walker, B. J., 4, 9, 91, 98 Walker, W. S., 61 Wallis, C. J., 205 Walsh, E. J., 227 Walton, G. M., 166 Wanczek, K. P., 269 Wang, C.-L. S., 208 Wang, J. H., 130, 134 Warchol, M. P., 267 Ward, D. C., 165, 177 Warren, C. D., 137 Warren, P. J., 209 Warren, S., 75, 81, 205, 263 Warren, W. F., 169 Washburn, L. C., 118 Washburn, W. N., 148 Wasielewski, C., 83, 109, 126, 139 Wassef, M. K., 139 Watanabe, H., 79 Watkin, D. J., 262 Watt, D. S., 125, 205 Waymack, P. P., 145 Wazeer, M. I. M., 32, 251 Weakley, T. J. R., 264 Weatherston, J., 197 Weber, D., 238, 261 Weber, W. P., 185 Weedon, B. C. L., 200, 201 Weeks, C. M., 12, 91 Wege, D., 203 Wege, P. M., 187 Wegehaupt. K. H., 232 Weichmann, H., 7 Wed, E. D., 90, 108 Weingand, C., 230 Weinmaier, J. H., 32, 265 Weiss, J.-V., 51, 242 Weiss, R., 26 Weissenberg, R., 168 Weitl, F., 20 Wells, M. A., 246 Wells, R. D., 178 Wennerstrom, O., 202 Wenzel, H. R., 131 Wermuth, B., 160 Werner, H., 99 Werner, P., 217 Werner, R. P., 160 Werstiuk, E. S., 173 West, B. F., 144 West, C. A., 148 Westaway, K. C., 184 Westheimer, F. H., 33, 110, 247 Westmore, J. B., 155 Wetzel, R., 171

Weyer, W. J., 167 Weyerstahl, P., 206 Whipple, A. P., 158 White, A. A., 271 White, C. K., 257 White, H., 167 White, J. D., 209 White, J. E., 233 White, M. W., 35 White, R. F. M., 265 Whitesides, G. M.. 135 Whiting, R. F., 180 Whittle, P. J., 32, 36, 42 Wiebers, J. L., 180 Wieczorek, M. W., 265 Wiedner, H., 152 Wieland, T., 141 Wiewiorowski, M., 155 Wihler, H.-D., 11, 65, 182 Wijsman, A., 193 Wilburn, J. C., 24, 214 Wild, S. B., 268 Wilfinger, H.-J., 260 Wilkie, D. R., 237 Wilkins, G. J., 258 Wilkowska, E., 127 Wille, G., 173 Williams, A., 116, 127, 128 Williams, F., 257 Williams, F. W., 233 Williams, G. A., 2 Williams, J. C. jun., 23, 90 Williams, T. H.,200 Williams, T. J., 132, 255 Willms, L., 11, 12, 65 Willner, I., 202 Wilson, H. R., 265 Wilson, M., 242 Wilson, N. H., 27 Winkelmann, H., 6, 239 Winkler, J., 119 Winter, W., 5 , 28, 240, 263 Wishnia, A., 238 Wist, E., 169 Witner, J. F., 232 Wittinghofer, A., 169 Wittman, J. W., 233 Witzke, J., 200 Wobke, B., 7 Wohleben, A., 182 Wolberg, G., 152 Wold. F., 160 Wolf,’G.; 137 Wolf, R., 42, 43, 47, 94, 95, 213, 242, 252 Wolfsberger, W., 211, 221, 235. 251 Woltermann, A., 74 Won, Y.M., 229 Wong, L. J., 130, 146 Wood, G. W., 269 Wood, H. G., 146 Woodcock, T., 271 Woodland, J. H. R., 245 Woods, M., 210, 225, 226, 228,235, 251 Wu, A. W., 2, 7 Wu, R., 179 Wu, W., 173 Yabusaki. K. K.. 246 Yafarova; R. L.,‘246 Yagi, H., 181 Yagimima, T., 121

Author Index Yagodina, L. A., 260 Yakimov, S. A., 175 Yakobson, G. G., 242 Yakshin, V. V., 269 Yalymova, S. V., 241, 250 Yamada, A,, 238 Yamada, H., 229 Yamada, S., 118 Yamaguchi, K., 105 Yamaji, N., 157 Yamamoto, H., 6, 148, 204 Yamamura, K., 229 Yamanaka, H., 84 Yamane, l., 271 Yamane, T., 131, 237 Yamashita, M., 14, 107 Yamatake, M., 79 Yamauchi, K., 118, 150 Yano, E., 157 Yano, J., 157 Yano, K., 162 Yano, M., 233, 234 Yansura, D. G., 175 Yarkova, E. G., 259 Yatsimirskii, K. B., 79, 111 Yazaki, P. J., 271 Yee, K. C., 246 Yeh, H. C. J., 181 Yeh, Y.-I., 260 Yeung, K. K., 161 Yokoyama, T., 38, 86, 118 Yolles, S., 245 Yoneyama, T., 241 Yoshida, H., 107, 146 Yoshida, Z., 19 Yoshifuji, M., 254

Yoshii, E., 129 Yoshioka, K., 149 Younathan, E. S., 143 Young, D. W., 265 Yu, C. U., 232 Yu, H. S., 235 Yuase, Y., 157 Yudina, K. S., 79 Yudina, T. V., 37 Yukhno, Yu. M., 52 Yukuhiro, M., 163 Yuldasheva, L. S., 106 Yurchenko, R. I., 223, 260 Yurchenko, V. G., 223, 260 Yusupov, M. M., 44 Zabel, V., 77, 263 Zadrozinska, J., 271 Zaertner, H., 270 Zagnibeda, D. M., 210 Zahn, R. K., 271 Zaitsev, N. B., 229, 259 Zakharov, I.-I., 222 Zakharov, L. S., 102 Zakharov, V. I., 19, 252 Zalkin, A., 57 Zamecnik, P. C., 170 Zaner, K. S., 237 Zapuskalova, S. F., 229 Zaret, E. H., 118, 120 Zarytova, V. F., 174, 249 Zaslavskaya, N. N., 212,219 Zatorski, A., 80, 204, 206 Zavalishina, A. I., 245 Zavatskii, V. N., 267 Zavlin, P. M., 259, 267, 268

Zbaida, S., 207 Zbiral, E., 13 Zdorova, S. N., 2, 48 Zeeberg, B., 108 Zeifman, Yu. V., 13 Zeiss, W 34, 93, 242 Zelenetskh, S. N., 216 Zemlyanskii, N. I., 120, 241 Zenin, S. V., 238 Zeniya, Y., 79 Zerba, E. N., 270 Zerner, B., 147 Zhenodarova, S. M., 178 Zbikhareva. N. A.. 126. 246 Zhmurova, 1. N., 223, 260 Ziegler, J.-C., 19 Ziegler, M. L., 235 Zielinski. W. S.. 152. 155 Ziemnika, B., 96, 241 Zilch, H., 190 Zimin, M. G., 69, 113 Zimmerman, S. B., 265 Zimmerman, T. P., 152 Zolotareva, L. A., 120 Zon, G., 122,218,247 Zschunke, A., 104 Zuchi, G., 260 Zverev, V. V., 261 Zvereva, M. A., 56 Zwierzak, A., 102, 104, 121 Zyablikova, T. A., 250, 254 Zykova, T. V., 54, 63, 124, 126,246, 254 Zyryanova, L. I., 53, 69, 257