Topics in Stereochemistry, Volume 3

TOPICS IN STEREOCHEMISTRY VOLUME 3 AN INTERSCIENCE SERIES ADVISORY BOARD STEPHEN J. ANGYAL, University of New Sou...

Author: Norman L. Allinger | Ernest L. Eliel

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TOPICS IN

STEREOCHEMISTRY

VOLUME

3

AN INTERSCIENCE SERIES

ADVISORY BOARD

STEPHEN J. ANGYAL, University of New South Wales, Sydney, Australia JOHN C. BAILAR, Jr., University of Illinois, Urbana, Illinois OTTO BASTIANSEN, University of Oslo, Oslo, Norway GIANCARLO BERTI, University of Pisa, Pisa, Italy DAVID GINSBURG, Technion, Israel Institute of Technology, Haifa, Israel WILLIAM KLYNE, Westfield College, University of London, London, England KURT MISLOW, Princeton University, Princeton, New Jersey SAN-ICHIRO MIZUSHIMA, Japan Academy, Tokyo,Japan GUY OURISSON, University of Strasbourg, Strasbourg, France GERHARD QU INKERT, Techrrische Hochschule Braunschweig, Braunschweig, Germany VLADO PRELOG, Eidgenossische Technische Hochschule, Zurich, Switzerland

JlRl SICHER, Institute for Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Prague, Czechoslovakia HANS WYNBERG, Uniuersity of Gronirtgen, Groningen, The Netherlands

TOPICS IN 0

STEREOCHEMISTRY EDITORS

ERNEST L. ELIEL Professor of Chemistry University of Notre Dame Notre Dame, Indiana

NORMAN L. ALLINGER Professor of Chemistry Wayne State University Detroit, Michigan

VOLUME

3

INTERSCIENCE PUBLISHERS A DIVISION OF JOHN WILEY & SONS

New York

-

London

*

Sydney

-

Toronto

Copyright 8 1968 by John Wiley & Sons, Inc. All rights reserved. No part of this book may be reproduced in any form, nor transmitted, nor translated into a machine language without the written permission of the publisher. Library of Congress Catalog Card Number 67-13943 Printed in the United States of America SBN 470 237473

INTRODUCTION TO THE SERIES During the last six years several texts in the areas of stereochemistry and conformational analysis have been published, including Stereochemistry of Carbon Compounds (Eliel, McGraw-Hill, 1962) and Conformational Analysis (Eliel,Allinger, Angyal, and Morrison, Interscience, 1965). While the writing of these books was stimulated by the high level of research activity in the area of stereochemistry, it has, in turn, spurred further activity. As a result, many of the details found in these texts are already inadequate or out of date, although the student of stereochemistry and conformational analysis may still learn the basic concepts of the subject from them. For both human and economic reasons, standard textbooks can be revised only at infrequent intervals. Yet the spate of periodical publications in the field of stereochemistry is such that it is an almost hopeless task for anyone to update himself by reading all the original literature. The present series is designed to bridge the resulting gap. If that were its only purpose, this series would have been called “Advances (or “Recent Advances”) in Stereochemistry.” It must be remembered, however, that the above-mentioned texts were themselves not treatises and did not aim at an exhaustive treatment of the field. Thus the present series has a second purpose, namely to deal in greater detail with some of the topics summarized in the standard texts. It is for this reason that we have selected the title Topics in Stereochemistry. The series is intended for the advanced student, the teacher, and the active researcher. A background of the basic knowledge in the field of stereochemistry is assumed. Each chapter is written by an expert in the field and, hopefully, covers its subject in depth. We have tried to choose topics of fundamental import, aimed primarily at an audience of organic chemists but involved frequently with fundamental principles of physical chemistry and molecular physics, and dealing also with certain stereochemical aspects of inorganic chemistry and, hopefully, biochemistry. It is our intention to bring out future volumes at approximately annual intervals. The Editors will welcome suggestions as to suitable topics. V

vi

INTRODUCTION

We are fortunate in having been able to secure the help of an international board of Editorial Advisors who have been of great assistance by suggesting topics and authors for several articles and by helping us avoid duplication of topics appearing in other, related monograph series, We are grateful to the Editorial Advisors for this assistance, but the Editors and Authors alone assume the responsibility for any shortcomings of Topics in Stereochemistry. N . L. Allinger E. L. Eliel

PREFACE The response of potential authors to our new series has been so good that we have decided to publish three volumes within the first two years instead of the originally contemplated two. Volume 3, like the two previous volumes, contains four articles on topics of current interest in the field of stereochemistry. The first article, a comprehensive treatment of the stereochemistry of phosphorus by M. J. Gallagher and I. D. Jenkins, documents our intent of having the series extend to elements other than carbon. To be sure, most of the examples in this chapter are organo-phosphorus compounds and therefore the chapter should be of considerable appeal to chemists with a wide variety of different backgrounds and interests. Phosphorus stereochemistry illustrates the important new phenomenon of pseudorotation (the term “ligand reorganization” suggested to one of the Editors by Professor Andre Dreiding would appear to be more appropriate, since “ pseudorotation ” has already been preempted for the type of puckering motion found in cyclopentane) which will undoubtedly prove to be of significance in other areas of stereochemistry as well. The second chapter deals with the computation of rotational barriers from NMR data. This has become an important area of conformational analysis with which every chemist should be at least somewhat familiar. In this chapter G. Binsch combines a thorough theoretical introduction with an extensive but very critical consideration of the existing experimental data. An important message to the many chemists of diverse background who nowadays measure barriers by NMR is that while faulty methodology and inadequate mathematics have frequently been used in this field, there is little extra effort involved in using accurate methods and an adequate mathematical treatment. The third chapter, by G. L. Closs, deals with the stereochemistry of addition of methylenes, carbenes and carbenoid species to olefins. This is a topic which was covered in a few sentences only six years ago and in which recent research has shown that matters are not quite as simple as had been assumed in the early hypotheses. This chapter, like the following one, should be of special interest to the reader who wishes vii

viii

PREFACE

to gain an insight into the stereochemistry of an important fundamental organic reaction. The stereochemistry of electrophilic addition to double bonds is another topic which only six years ago was covered in most textbooks in a few pages, the gist of which was that such addition usually involves bridged ion intermediates and proceeds in arlri stereochemical fashion. R. C. Fahey’s extensive treatment of the subject in the last chapter clearly shows that this point of view represents a vast oversimplification. There are now recognized to be several mechanisms of electrophilic addition (just as there have long been known to exist several mechanisms of nucleophilic displacement), and the stereochemistry may vary from extensive SJW addition through a stereochemically indiscriminate process to nearly complete anti addition. This chapter should be of special value to the teacher who has to cope with the subject of electrophilic addition in both elementary and advanced courses in chemistry. N . L. Allinger E. L. Eliel

June 1968

CONTENTS STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY l y M . J. Gallagher and I . D. Jenkins, School of Chemistry, The Unicersity of New South Wales, Kensington, N S W , . . Australia

1

THE STUDY OF INTRAMOLECULAR RATE PROCESSES BY DYNAMIC NUCLEAR MAGNETIC RESONANCE by Gerhard Binsch, Department of Chemistry and the Radiation Laboratory, University of Notre Dame, Notre Dame, . Indiana

97

STRUCTURES OF CARBENES AND THE STEREOCHEMISTRY OF CARBENE ADDITIONS TO OLEFINS by Gerhard L. Closs, Department of Chemistry, The University of Chicago, Chicago, Illinois . . 193 THE STEREOCHEMISTRY OF ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES by Robert C. Fahey, Department of Chemistry, University of California (San Diego), La Jolla, California . . 237 Author Index

.

. 343

Subject Index

.

.

Cumulative Index

.

367

. 379 ix

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

Stereochemical Aspects of Phosphorus Chemistry M . J . GALLAGHER and I . D . JENKINS School of Chemistry. The University of New South Wales. Kensington. NS W. Australia I . Introduction

. . . . . . . . . . . . . . . . .

I1. Physical Methods for Determining Stereochemistry

. . . . .

I11. P(I1) Compounds . . . . . . . . . . . . . . . IV . P(II1) Compounds . . . . . . . . . . . . . . . A . Chiral Acyclic Compounds . . . . . . . . . . . B. Stability of P(II1) Structures and Steric Consequences of their Reactions . . . . . . . . . . . . . . . . C . Acyclic Symmetrical Compounds . . . . . . . . . D. Cyclic Compounds . . . . . . . . . . . . . V. P(1V) Compounds . . . . . . . . . . . . . . . A . Introduction . . . . . . . . . . . . . . . B. Optical Isomerism . . . . . . . . . . . . . 1. Types of Resolvable Compounds . Methods of Resolution and Stability . . . . . . . . . . . . . . 2 . Reactions of Phosphonium Salts . . . . . . . . 3. Reactions of Phosphoryl and Thiophosphoryl Compounds . 4 . The Wittig and Related Reactions . . . . . . . . C . Geometrical Isomerism . . . . . . . . . . . . 1. Cyclic Compounds . . . . . . . . . . . . 2. Acyclic Compounds . . . . . . . . . . . . D . Conformational and Rotational Isomerism . . . . . . E. Steric Effects . . . . . . . . . . . . . . . F. Neighboring Group Participation . . . . . . . . . VI. P(V) Compounds . . . . . . . . . . . . . . . A . Structure and General Properties . . . . . . . . . B . P(V) Structures as Reaction Intermediates . . . . . . . VII . P(V1) Compounds . . . . . . . . . . . . . . . VIII . Addendum Added in Proof . . . . . . . . . . . . A General . . . . . . . . . . . . . . . . 1. Spectroscopic Methods . . . . . . . . . . . B . P(II1) Compounds . . . . . . . . . . . . . C . P(1V) Compounds . . . . . . . . . . . . . D . P(V) Compounds . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

.

1

11 15 19 25 25 26

26 29 31 38 44 44 41 51 56 59 61 61 68 76 79 79 79 80 82 85 86

2

M. J. GALLAGHER AND I. D. JENKINS

I. INTRODUCTION Stereochemistry and its influence on reaction pathways in carbon compounds have been the subjects of fruitful study for over a century. Until very recently, investigations relating to other elements have been spasmodic and largely directed toward the resolution of selected compounds. Thus, though Meisenheimer first reported the resolution of a phosphine oxide, R1R2R3P0,in 1911 (l), only a handful of such studies was reported in the subsequent forty years. However, with the realization of the importance of phosphates in metabolic processes and the discovery of the extreme biological activity of certain classes of organophosphorus compounds, an immense upsurge occurred in work relating to the chemistry of phosphorus and its derivatives. Stereochemical studies have been less common but have increased considerably in the last few years following the development of a useful general method for the resolution of phosphonium salts. The stage has now been reached where it seems worthwhile to review the subject as a whole and to note in particular the difficulties and peculiarities arising from the presence of an element of the second row of the periodic table. In this chapter, an attempt will be made to survey all aspects of stereochemistry concerned with compounds of phosphorus with the exception of condensed phosphates and metal complexes. The literature has been surveyed until the end of 1966. A comprehensive coverage is not intended and some topics which have been extensively covered elsewhere will be dealt with only briefly. A number of other reviews have appeared dealing with general aspects and reaction mechanisms ( 2 4 ) and optically active compounds (5,6), and, very recently, there has been a comprehensive review on structural features (7). Important papers which have appeared in the first ten months of 1967 are covered in the Addendum (Sect. VIII). The most notable feature of the chemistry of phosphorus, which is shared by most elements other than those in the first row of the periodic table, is multiple valence. Thus, stable compounds are known carrying 2-6 substituents attached to a central phosphorus atom. This greatly increases the difficulty of interpreting the stereochemical consequences of a reaction. In unfavorable cases, it is not uncommon to have as many as three possible transition states (or intermediates) for a given reaction, each having a different geometry. [See, for example, the discussion on P(V) compounds in Sect. VI.] For convenience, this chapter

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY

3

TABLE I

Bond Lengths and Bond Angles in Phosphorus Compounds Bond length,

A

Bond angles, degrees

/\

2.22

P-P

P-P-P = 106 (6-membered P(IV) ring)

/\

P-P-P = 95 (6-membered P(II1) ring)

A

P-P-P = 94-107 (5-membered P(II1) ring)

P-c

1.84

P=C

1.71

P=C P-H P-F

P-Cl P-Br P-I P(I V)-N P(II1)-N

k N

/\

C-P(1V)-C

+ 106

c-P(II1)-c

=

/\

/\

P=C=C 1.65 (Ph,P=C=C=O) (8) 1.54 1.42 1.53 (Me2PF3;P-Fradlal = 1.55; P-Fapical = 1.64) (9) 1.98 2.14 2.47 1.77 (NaHNH2P03) 1.69 (Me2NPC12)(10) + 1.88 (PhzP-N(Et)-PPhzEt (1 1) 1.49

/\

1.59 1.56

P-0-C

P-o-(P)a

1.61

P-0-P 100

P-S-(P) P=S

=

145.5

=

120 rfr 6

=

128; 0-P-0

I-)

P-O-(C)* P-0-( H)a

P=O

99

From 1.46 (&PO) to 1.54 (Po: -) 2.10 1.91

/\

/\

=

4

M. J. GALLAGHER AND I. D. JENKINS

will be divided into sections dealing with each of the possibilities, and compounds will be referred to as P(IV), P(VI), etc., without regard to the nature of the substituents or the type of bonding involved. Where convenient, these sections will be further subdivided along lines of acyclic and cyclic structures. A proper understanding of steric effects requires an accurate knowledge of bond lengths and bond angles. In Table I are recorded some average values of these parameters. For accurate data, the comprehensive review of Corbridge (7) should be consulted. Stereochemical effects deriving from the bulk of substituents (H. C. Brown’s F strain) will, in general, be less evident in phosphorus compounds than in the carbon or nitrogen analogs by virtue of the greater radius of the central atom and the greater length of the bonds. For these effects to become severe, it is usually necessary to have very bulky groups (e.g., t-butyl) present.

II. PHYSICAL METHODS FOR DETERMINING STEREOCHEMISTRY

1. 31P nuclear magnetic resonance ( N M R ) spectra. Although the chemical shifts of large numbers of P compounds of all types have been reported, very little use has been made of this information in the study of reaction mechanisms, and only a single assignment of the shifts in two stereoisomers has appeared. Katz et al. observed a difference of 65 ppm for two geometrical isomers of a P(II1) compound (see Sect. IV). This huge difference is probably atypical, since the structures involved are somewhat exceptional, but suggests that when sufficient data accumulate chemical shift differences may provide a valuable method for determining stereochemistry. Though peaks corresponding to diastereoisomers have been observed in a number of instances, no assignments have yet been made. 2. IH NMR spectra. A reasonable number of examples of olefins carrying P substituents has been examined, principally by Westheimer (12), Griffin (13,14), and their co-workers. Stereochemistry may be assigned with a fair degree of confidence on the basis of the large difference between the cis 3JpH(9-25cps) and trans 3JpH(30-50cps) coupsplitting across a double ling constants. This behavior parallels the 3JHH

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY

5

bond but the splittings are of considerably greater magnitude. The correlation is reasonably well established for P(IV) compounds but an insufficient number of P(II1) compounds have been examined to confirm it, though the detailed analysis of trivinylphosphine (1 5 ) supports the same behavior for this class. Unfortunately, the proton spectra are often quite complex and the vinyl proton signals sometimes overlap into the aromatic region. This is a disadvantage since phenyl groups are common substituents on phosphorus. The useful correlation between the 13C-H coupling constant and the per cent s character of the bond (16) suggests that a similar relationship may exist with 31P-H coupling, thus providing direct information concerning stereochemistry at phosphorus, particularly since many compounds with P-H bonds are known. The relationship is not a good one, however (1 7); changes in hybridization at phosphorus produce considerable changes in JPHbut much more work is necessary before any but the most qualitative conclusions can be drawn. In general, P(II1) compounds have relatively low coupling constants (170-240 cps) and P(1V) compounds considerably higher ones (350-700), but structural or stereochemical assignments cannot yet be based on the magnitude of the splitting. X-ray crystallography, electron diffraction, and microwave spectroscopy have been used to determine the structures of a wide variety of phosphorus compounds; reference 7 should be referred to for an extensive collection. Of course, such methods cannot be used for routine stereochemical determinations. Of particular importance however is the recent determination (18) of the absolute configuration of the P(IV) salt ( +)benzylmethylphenylpropylphosphonium bromide, 1 as S,which has enabled many stereochemical correlations to be made. Pr

I

,,Pt Ph” 1 “CH, CH,Ph

Br-

cis-trans Isomers of olefins may often be distinguished on the basis of melting point, that of the trans isomer being higher. Though insufficient examples are known to indicate a useful general trend, the same relationship does not seem to hold for many phosphorus compounds.

M. J. GALLAGHER AND I. D. JENKINS

6

Thus, cis- and trans-ethene-l,2-bisdiphenylphosphinehave the same melting point (19), and in the case of Iy2-diphenylethenediphenylphosphine, the cis isomer is solid and the trans isomer liquid (20). However, in those relatively few cases where assignments have been made to geometrical isomers the melting point of the trans oxides is higher than that of the cis (Table 11). If this relationship is general then it will be a useful one since oxides are readily obtained from phosphines and phosphonium salts by reactions of known stereochemistry.

TABLE I1

Melting points of Isomeric Phosphine Oxides (“C) Oxide PhZP(O)CH=CHP(O)Phz PhCH=CHP(O)PhZ PhCH=CPhP(O)Pha

PhZP(O)CH=CHCHa

Refs.

cis

trans

244 103 153

310 168 224

19 21,22 23

234

251

24

276

> 400

24

182

197

25

113-116

124-125

307

3. Optical Rotatory Dispersion. In a few instances this technique has been used for confirming the stereochemical consequence of reactions at phosphorus (26,27) and to support the assignment of absolute stereochemistry to phosphine oxides (28).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY

7

III. P(II) COMPOUNDS Very few compounds belonging to this class are known. Cyaninetype salts of general formula 2 may be obtained (29) as shown in eq. (1).

The molecule 2 is nearly planar, the dihedral angle between the two ring systems being 6" and the CPC angle 105". The structure has been determined by X-ray methods (30). A more interesting structure from the chemical viewpoint is 3 which is prepared in an analogous way (31) [eq. (211-

No details of the structure are available but the compound is monomeric and the NMR of the ring protons is in the region expected for aromatic protons. The chemistry and stereochemistry of this new class of compounds should prove most interesting. Reactive intermediates such as Ph,P- and Ph2P. have had their chemistry explored to a considerable extent but nothing is known of their stereochemistry. Nucleophilic displacement of halogen at unsaturated carbon by Ph2P- [eq. (3)] proceeds with retention of stereochemistry (19) and the radical, Ph2P., attacks alcohols [eq. (4)] without affecting the stereochemistry of the a-carbon atom (32). PhzP.

+ R*OH (+I

PhaPOR*

(+I

(4)

8

M. J. GALLAGHER AND I. D. JENKINS

IV. P(III) COMPOUNDS

A. Chiral Acyclic Compounds Despite earlier predictions to the contrary [good surveys of this early work have been given in the reviews of Mann (2) and McEwen (4)], it is now well established that P(I1I) compounds have a configurationally stable, pyramidal structure. Much of the progress in this field is due to the elegant work of Horner and his collaborators (5) who first succeeded in obtaining optically active phosphines. The path to these compounds is beset with difficulties. P(1V) compounds had been resolved over fifty years ago but numerous attempts to reduce them had always led to failure. Part of the reason lay in the stability of P(1V) compounds and the necessity for the use of forcing conditions or powerful reagents to reduce them. Thus, reduction of optically active phosphine oxides (33) or phosphonium salts with sodium (34) or with lithium aluminum hydride (35,36) at 0" invariably afforded racemic products. The first P(II1) compound to be resolved was the cyclic compound 4 by Campbell and Way (37) but, as these workers point out, this example is ambiguous since the molecule is in fact a bridged biphenyl and could

N-P

HI

exhibit asymmetry even if the P(II1) group were planar. Since no evidence could be found of diastereoisomerism the question remained unresolved. In 1959, McEwen and his colleagues (38) introduced the (-)-dibenzoylhydrogentartrate anion as a resolving agent for phosphonium salts, and optically active phosphonium salts became relatively readily available. Horner resolved a number of salts in this fashion and, using the recently developed (39) method of electrolytic reduction

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY

-

9

(cathodic fission), obtained a series of optically active phosphines (40) [eq. (511. RlR2R3kH2Ph ( + I or (-)

2.Z. Hf

+

RlR2R3P PhCH3 (+) or (-)

(5)

Earlier studies (39) had shown that the group removed in this process was that most stable as an anion, benzyl in the example. This made optically active phosphines accessible by a reasonably straightforward process since the appropriate benzylphosphonium salts are available conveniently by the method of Bailey et al. (41) [eq. (6)]. PCI3

+ PhCH,MgX

+ P(CH2Ph)3

I

R16(CH2Ph),XLiAlH,

+ R,X etc. RiR2RaPCHzPhX- t RlP(CH2Ph)a

(6)

Subsequently, McEwen and his collaborators (42) synthesized both enantiomers of benzylbutylmethylphosphine (5) by resolving the 2-cyanoethylphosphonium salt of this phosphine and decomposing it with sodium methoxide [eq. (7)] by the method of Grayson et al. (43). BuMePCH2Ph

CH,-CHCN NHICl

BuMePhCHakHzCH2CNC1-

I

1. Resolve 2. MeO-/MeOH

4,

BuMePCH2Ph

(+I and (-1 (5)

(7)

A less-clean method involves the reduction with trichlorosilane of optically active phosphine oxides (44). Optical purity of the product phosphine is not as high as by the methods using phosphonium salts but it usually exceeds 60%. If the reaction is carried out in the presence of triethylamine, the configuration of the resulting phosphine is inverted. The pathways shown in eqs. (8)-( 10) have been suggested.

M. J. GALLAGHER A N D I. D. JENKINS

10

In theory any reaction yielding a phosphine and not involving attack at the central phosphorus atom could be adapted to prepare optically active phosphines. Such reactions are not common, however, since phosphonium salts undergo elimination much less readily than their ammonium analogs. Horner has recently reported that allylarsonium salts are decomposed by cyanide ion to give arsine in high yield and with good optical purity (45). The reaction also works for phosphonium salts but its steric consequences have not been reported. It has been observed in these laboratories (46) that 2-cyanoethylphosphonium salts are decomposed smoothly to the corresponding phosphine in high yield by cyanide ion. Doubtless, other methods will be developed, but at the moment, the most general seems to be the cathodic fission of resolved benzyl- or allylphosphonium salts. An alternative synthesis for chiral phosphines involves the reaction of a phosphonous halide with a mixture of Grignard reagents [eq. (1 l)]. RiPCla

+ R2MgX + R3MgX

RiPRaRz

+ RiPR3R3 + RiRaR3P

(1 1)

The desired phosphine is formed in the highest yield and readily separated by distillation. The method seems simpler and less laborious than methods involving alternate quaternization and removal of preferred leaving groups. It should also provide easy access to chiral triarylphosphines not readily available by other methods [although one example has been reported (47)]. Table 111 records the optically active phosphines so far obtained.

TABLEI11

Optically Active Phosphines R1R2R3P RI Me Me Me Me 4-Methoxyphenyl Me

Rz Pr CHz=CHCHz Et PhCHz 1-Naphthyl Bu

R3 Ph Ph Ph Ph Ph PhCH2

+1.5 k 0.5

Ref. 40 40 40

f24 f 2

42

b I D

+ 18.4

-1Of

+ 45.8 + 2.9

1

5 47

Horner has also obtained an optically active diphosphine (8) and a

meso (9)diphosphine by cathodic fission of the bisphosphonium cations

6 (resolved) and 7 (meso),respectively, but no rotation of 8 was reported (48).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 11 CH,Ph

CH,Ph

I

I

.P+ H,C,"

1

\

Ph

H,C,"

CH,-H,C

I

/

CH,Ph

P.+

1

...

Ph CH, 2Br-

CH,Ph

I

Ph

I

I

,P;

CH,-H,C CH3

(7)

I CH,-H,C 1

I

(8)

(9)

,p\

Ph

P. / -. 'Ph CH,

/

P+ ,**. 'Ph CH, 2Br-

I

No examples of optically active P(II1) compounds other than phosphines (i.e,, compounds with three P-C bonds) have been reported.

B. Stability of P(II1) Structures and Steric Consequences of their Reactions

Optically active P(II1) compounds are relatively stable but they may be thermally racemized (49) with half-lives of 3-5 hr a t 130" and activation energies of ca. 30 kcal/mole (49). The mechanism of thermal racemization is unknown but is presumably analogous to the much more facile behavior of NR, compounds and involves oscillation of the P atom along an axis normal to the plane of the substituents. The process has been studied in another fashion using the diphosphine, PhMePPMePh, whose 31P NMR spectrum shows two peaks corresponding to the two expected diastereoisomers (50). These peaks coalesce at 180" and from a study of the rate (51) an EA of 26 f 2 kcal/mole was derived in fair agreement with the value obtained for monophosphines (49). This is reasonable, since only one inversion is required, but the possibility of a very rapid dissociation-recombination process cannot be excluded and must be given serious consideration in view of the labile nature of the P-P bond [eq. (12)]. RZPPR,

2RzP.

!12)

It should be noted that Fluck and Issleib (52) obtained no NMR evidence of stereoisomerism in the tetralkyldiphosphine EtBuPPBuEt. Thermal racemization also explains why Maier (50) always obtained the same 1 : 1 mixture of diastereoisomers when either meso or

M. J. GALLAGHER AND I. D. JENKINS

12

racemic compounds RIRzP(S)P(S)RIRz were reduced to the corresponding diphosphine by tributylphosphine at 170". Many reactions of phosphines involve the lone pair of electrons on the P atom and proceed with an expansion of valence from three to four, e.g., quaternization. Reactions of this type follow second-order kinetics and are free of side reactions, at least in the case of primary aliphatic halides. Retention of configuration at the P atom would seem a reasonable assumption. If an optically active phosphine and a benzyl or allyl halide are used, then the product phosphonium salt may be converted back to the starting phosphine without loss of optical activity, by cathodic fission [eq. (13)]. R1RaR3P

PhCHaX 2-,H+

+

RiRaRsPCHaPh X -

Hence, both forward and back reactions have the same steric result, either retention or inversion,if the reasonable assumption is made that neither is a multistep process. From the sequence of reactions shown in Figure 1 Horner et al. (53) concluded that both quaternization and cathodic fission proceed with retention. However, since the replacement of allyl by propyl (bottom line) must in any case involve inversion, regardless of the steric course of quaternization and cathodic fission, the reaction sequence does not, in fact, establish the stereochemical pathway. Horner and Winkler subsequently noted (57) this fact; hence, though it is apriori probable that quaternizationproceeds with retention, all stereochemicalassignmentsstemming from this assumption still await a rigorous proof. CH2Ph

I

,P\ H&"' Ph

I

CH,Ph

I .P+

RdNi/Ho

H3C'"

CH2CH=CH2 I

2,

I

H3C" Ph CH,CH= CH2

PrBr

H2CH,CHS

Pr I

,.p<

~

H,C"

I Ph

CHzCH=CH2 c.f. = cathodic fission

Figure 1

H,C'

3,

1 Ph

$1 (10) Pr P (->

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 13

When, subsequently, the absolute configuration of the phosphonium + salt (+)MePrPhPCH,Ph Br- was determined by X-ray diffraction, the absolute configuration of the phosphine (+)MePrPhP (10) followed as S if the assumption of retention during quaternization is accepted. Prior to this study two other methods had indicated the same result: Cervinka and Kriz from a study of the optical rotatory dispersion curve of (+)MeEtPhPO (28) and Horner and Winkler (54) from the absolute configuration of the ester PhCHCH3COOCH3 obtained by alkylation followed by cathodic fission of the optically active ylid (+)MePrPhP=CPhCOOCH,. The optical yield in the latter case was only 0.4% ; the configuration was inferred using the asymmetric induction principles of Prelog ( 5 5 ) and Cram (56). The availability of optically active P(II1) compounds and the knowledge of their absolute configuration has led to a tremendous increase in our understanding of the steric course of much of the chemistry of these highly reactive compounds. Figure 2 depicts the stereochemical changes which have so far been investigated. Of particular interest is the observation (58) that the stereochemical integrity of methylphosphines is preserved when they are converted into the carbanion R1R2PCH;. This is strong evidence for 2p,-3dn

Retention (5,28) Peroxy compounds, disulfides, phenylsulfinic acid

Episulfides, sulfur

R,R2R3PS Retention (42,152) Y

RiRzRJ'O(S) Retention (57,58,60,61) Inversion (60,61) Racemization (60,61,59)

14

M. J. GALLAGHER AND I. D. JENKINS

bonding since 2p,-3pn should lead to a planar species and hence racemization. Not surprisingly, many apparently simple reactions have been shown to be of considerable complexity. Denney has investigated the reaction of P(II1) compounds with hypochlorites, hydroperoxides, and peroxides in considerable detail and a very complex picture has emerged. These reactions are sensitive to minor structural changes and vary unpredictably with change in solvent. Some of these results are collected in Table IV. TABLE IV

Oxidation of (+)MePrPhP (60,61) Oxidant EtOOEt EtOOEt EtOOEt Me3COOCMe3 Me3COOCMe3 Me3COC1 Me3COCl

Solvent Benzene EtOH HaO.THF(1 :4)” Benzene Pentane Pentane CHaC12/MeOH

Steric result Racemization Racernization Inversion Retention Retention Racemization Inversion (72oJ,)

THF = tetrahydrofuran

A number of different mechanisms can be written to accommodate these results but much more information concerning these complex reactions is necessary before any useful generalizations can be made. It is obvious, however, that mechanisms operative in one solvent cannot be assumed to hold for any other, even closely related, system. The reaction of halogens with optically active phosphines is more amenable to interpretation since it has been shown (62) that in acetonitrile the compounds formed (R3PX2) are strong 1 : 1 electrolytes and + hence have the structure R3PX X-, in contrast to the As, Sb, and Bi analogs (63). Racemization accompanies formation of these compounds in aprotic solvents and inversion in the presence of water (57). Racemization could result from rapid S,Z-type displacements on +

R3PC1 or via a symmetrical R3PCI2 intermediate and inversion from +

attack by water on the R3PC1 cation formed with retention in the first

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 15

step of the reaction. The actual pathway will probably depend on the dielectric constant of the solvent. BrCN also brings about racemization and this cannot be explained by multiple SN2 displacements. There is good reason to believe, however, that a trigonal bipyramidal intermediate can spontaneously racemize without bond breaking (see Sect. VI), and there is no reason to invoke the more complex pathway suggested by Horner [eqs. (14) and ( I 5)].

+ BrCN d CN$RlRzR3 BrCNPRlR2R3Br (14) CNPRIRzRjBr + R 1 R 2 R 3 k NBr- h [Br2PRlRzR3CN]-R1R2R3kN RlR2R3P

I1

dl (CN)zPR1RaR3 BrzPRlRzR3 (15)

+

C. Acyclic Symmetrical Compounds

Very little information is available on the conformational analysis of acyclic P(II1) compounds and what has been done has led to some rather puzzling results. Tetraiododiphosphine, Pz14,has been shown to have the anti structure (11) in the crystalline state (64). Frankiss et al. (65) have assigned the same structure to this compound in solution in contrast to earlier results (66,67) claiming gauche forms though recently evidence has been advanced for complex equilibria [eq. (16)] in solution (68). The same structure has also been claimed for P&I, (69). Gauche structures 3PzI4

4PIz

+ &P4

(16)

have been suggested for P2H4 (70,71) and a full analysis of the lH resonance spectrum has shown that the two P atoms are magnetically nonequivalent (72). It is very difficult to see why this should be so since the energy barrier to rotation about the P-P bond should be very small. It is possible that there is some type of interaction between the two P nuclei as has been suggested for the cyclic polyphosphines, (RP), (see ref. 73 for a discussion), though a planar molecule would not, of course, account for the complexity of the lH spectrum.

(11)

Substitution of P(II1) compounds with bulky groups introduces steric effects of a moderate order. PCI3 cannot normally be mono- or

16

M. J. GALLAGHER AND I. D. JENKINS

disubstituted with Grignard reagents but t-BuPC1, and (t-Bu),PCI may be prepared in this way (74). These compounds appear to react normally though (t-Bu),PCl is markedly resistant to hydrolysis (75). 2,4,6-Tri-t-butylbenzenereacts with PC13 and AlCl, to give the corresponding phosphonous dichloride (76). Severe steric hindrance is apparent in this molecule and it hydrolyses with great difficulty to give in low yield the only well-characterized compound of phosphorus in which hydrogen and chlorine are bonded to the same P atom [eq. (17)]. 0

II

t-Bu

t - B u qPCI, t - B u H1O

VBU PC13/AICI.

t-Bu

+

/

t-Bu

t-Bu,@t-Bu H-P-CI (17) t -Bu

The molecule P(SiH3), is planar (77) but this is attributed to d,-d, bonding and not to steric effects and, indeed, P(SnMe,), is pyramidal (78). A number of failures to prepare tri-t-butyl phosphite were attributed to steric effects, but Mark and Van Wazer showed that the compound could be obtained in virtually quantitative yield in the usual way by reaction of the alcohol with PC13 in the presence of triethylamine (79). The reaction is more sluggish than with simpler alcohols but otherwise is unexceptional. Apart from a tendency to lose isobutene on mild heating (50") the ester displays no very unusual behavior. Di-t-butylphenylphosphine attacks a-haloketones preferentially at halogen (80), presumably because this is the less-hindered path. Less-hindered phosphines give less product arising from attack at halogen [eqs. (18) and (19)].

+ PhCOCHClPh PhMeBu'P + PhCOCHClPh (Bu')aPhP

-

Et.O/H,O

PhCOCHzPh (90%)

MeCN/H,O

PhCOCHzPh (23%)

(18)

(19)

These reactions of t-butyl compounds may only be attributed in part to steric effects with any degree of confidence, since it is not clear to what extent inductive effects are important. A further indication of weakened steric requirements in P(II1) compounds is the absence of B strain in their reactions with protons (81) or Lewis acids (82,83).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 17

The mechanism of the Michaelis-Arbuzov reaction is now well established (84) and proceeds as shown in eq. (20). (RO)sP

+ R X -+

(RO)$RX-

--f

RX

+ RP(0)(OR)2

(20)

The second step of this reaction involves attack at carbon by X- and it has been shown to proceed stereospecifically in a number of instances (85-89). Triisopropyl phosphite fails to undergo the normal Arbuzov reaction with isopropyl iodide although it does so with ethyl iodide. This has been attributed to steric hindrance in the transition state (90). The synthesis and stereochemistry of olefins bearing P(II1) substituents has been investigated by Aguiar and co-workers with some very interesting results. This class of compounds is important in that the stereochemistry of the various compounds formed has been assigned with considerable certainty. Thus cis and trans 1,Zdichloroethene react with lithium diphenylphosphide in tetrahydrofuran to form two distinct bis(dipheny1phosphine)-ethenes (19), one from each isomeric dihalide. The formation of two isomeric compounds precludes an addition4mination reaction, which would pass through a symmetrical intermediate, and it is only necessary to assume the same steric consequence of each displacement to assign the structures 12 and 13 to the products. CI 2Ph, PLi -k

2Ph2 PLi

H

w - +ph2pWH n nPPhz H C1 H

'LY + cn H

H

-

(21)

(12)

PhapWpPhz (22)

nH

H

(13)

These reactions proceed in good yield and apparently with complete stereospecificity. The compounds are not interconvertible thermally or photochemically and react with hydrogen peroxide and elemental sulfur to give the corresponding oxides and sulfides. (These reactions are believed to proceed with retention of configuration at P; see Sect. IV-A.) Heating with thiophosphoryl chloride affords the trans disulfide from either phosphine. Similarly, quaternization of either diphosphine

18

M. J. GALLAGHER AND I. D. JENKINS

gives the same bis-quaternary salt (46), presumably the trans isomer. The bis-quaternized cis isomer would be expected to be unstable as a + consequence of repulsive interactions between the two Ph2PR groups. cis (22) and trans (21) fl-Bromostyrenes react similarly with lithium diphenylphosphide but the products have in this case only been isolated as their oxides. Dehydrobromination of the phosphine oxide 14 should yield the trans product 15 and this reaction has been used to confirm the PhCHBrCH,P(O)Ph,

KOH +

(14)

'"WH

nP(0)Ph2

H

(15)

stereospecificity of the reaction. Lithium diphenylphosphide also adds stereospecifically to acetylenes (20,23). The reaction is subject to an unusual directing effect by amines. The results are summarized in Figure 3. It is interesting to note that sodium diphenylphosphide adds to diphenylacetylene to form only the (presumably) thermodynamically less stable cis isomer (19). Under forcing conditions, diphenylphosphine will add to phenylacetylene (23,91) to give what is now known to be the cis isomer 17. If the reaction is carried out in air, the trans oxide 16 results. All these stereochemical assignments rest on independent syntheses from lithium diphenylphosphide and the appropriate vinyl halide and are supported by NMR data. Another method of potential value in the synthesis of olefins carrying P(II1) substituents has been reported recently (92) and is shown in eq. (23). PhZPCHP(0)Pha

+ RCHO

d

Ph,PCH=CHR

(23)

This is essentially a Wittig reaction and should yield principally the trans isomer. The reaction is potentially as flexible as Aguiar's methods but its scope has not been fully explored and it may be subject to a considerable steric effect in view of the bulk of the Ph2P group.

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 19

ph2pWH

n Ph

phzpWph

n H

H

H

(18)

(17)

Ph2pWph

n H

Ph

(19)

1

Ph,PNa

PhCrCPh /h2PLi!RNH,

PhzpWH

n Ph

kzpLiiRzNH phzpWph

Ph

n

Ph

(20)

H

(19) Figure 3

D. Cyclic Compounds With the realization of the configurational stability of P(II1) compounds many cyclic systems incorporating P(II1) have been examined for evidence of stereoisomerism. In most cases it has been found, but unfortunately very few stereochemical assignments have been made and it is not yet possible to suggest any correlations of value in making such assignments. A great deal of fundamental work remains to be done in

20

M. J. GALLAGHER A N D I. D. JENKINS

this field. No optically active cyclic P(II1) compounds have been reported. Stereoisomers of P(II1) compounds were first obtained by Davis and Mann (24) in a study of the chemistry of the 5,10-diethyl-5,10-dihydrophosphanthren system (21 R = Et) synthesized as shown in eq. (24).

I

R

(21)

Two isomeric diphosphines were obtained, mp 52-53' and 96-97', as also were two bisquaternary salts by reaction of the crude product with benzyl iodide and two dioxides by saponification of these salts. The lower melting of the two dioxides had a dipole moment of 4.0 D and was hence assigned the cis configuration. There was insufficient material to measure the dipole moment of the higher melting dioxide which, if trans, should have a zero moment. Unfortunately, the higher-melting diphosphine was obtained in minute yield and no evidence of direct interconversion of isomers was obtained. The principal product of the reaction, the low-melting diphosphine, is considered to have the cis configuration since it could be oxidized to the cis dioxide with hydrogen peroxide. This reaction proceeds first to give a complex adduct of the dioxide with hydrogen peroxide and water and hence may not follow a simple steric path. Other evidence presented by these authors was: ease of reaction with 1,Zdibromoethane and o-xylylene dibromide to give new cyclic compounds, and coordination with one molecule of PdBr,. Since this supposed cis isomer may be converted into a bis-salt with benzyl iodide and this salt on saponification gives the cis dioxide, this may be taken as strong supporting evidence since saponification is known to proceed with inversion. It is necessary to assume, however, that the saponification of cyclic bis-salts will proceed by the same simple path as for monosalts, but this does not seem unreasonable. Davis and Mann also prepared the diphenyl analog of this phosphanthren (21; R = Ph) but found no evidence of stereoisomerism. The compound was isolated as its diquaternary salt with benzyl

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 21

bromide. Saponification of this gave a dioxide, mp > 400°, too slightly soluble for dipole moment measurements. On the other hand, reduction of the bis-salt to the P(II1) compound (21; R = Ph) with lithium aluminum hydride followed by oxidation with hydrogen peroxide gave an isomeric dioxide with p = 3.4 D, which was assigned the cis structure on this basis. Inversion of the trans to the cis isomer could easily have occurred during reduction with the complex hydride (Sect. IV-A). In both cases, (21; R = Et or Ph) the cis P(II1) appears to predominate, suggesting that it is the most stable. Mann and Davis (24,93) have discussed the stereochemistry of these systems in terms of a molecule folded about the axis of the two heteroatoms (P,P or As,As). Mislow et al. (94) have pointed out that the lowenergy barrier calculated for flexing of the molecule (ca. 7 kcal/mole) should lead to rapid equilibration (22 e 2 3 ) and that isomerism is solely a consequence of the pyramidal structure at the heteroatoms.

In reply, Mann has pointed out that such flexing is not possible in the cis isomer since the two R groups in 25 would severely interact, though he concludes from a study of molecular models (93) that the process is relatively facile for the trans isomer. The difference would seem to be one of degree rather than kind, but it may be possible to measure the relative proportions of the two forms from the chemical shift of R in the 'H NMR spectrum. A recent N M R study of 5-ethyl5,lO-dihydroanthracene indicates that either the flipping process is very slow in this molecule or that one isomer is strongly preferred (95). The only other assignments of stereochemistry to a P(II1) compound have been by Katz et al. (25). Dipotassium cyclooctatetraenide reacts with phenylphosphonous dichloride to give the phosphirane 26 stereospecifically. On warming, this rearranges to the bicyclo[4.2.1] phosphanonatriene 27 also stereospecifically, and the latter, with further heating or in the presence of acid, is converted irreversibly to the more stable isomer 28.

22

M. J. GALLAGHER AND I. D. JENKINS

p$

Ph

Ph

Ph

A&*& (27)

(26)

(28)

The stereochemistry of 26 has been tentatively assigned on the basis that this is the most feasible structure to rearrange to 27. The remaining diastereoisomers were differentiated on the basis of the difference in chemical shift of the olefinic protons which arises from the shielding influence of the benzene ring attached to phosphorus. The structures of all three compounds are supported by a detailed analysis of their lH NMR spectra. Derivatives were obtained corresponding to each isomer. The large difference in chemical shift between 27 and 28 has already been commented on (Sect. 11). The acid-catalyzed rearrangement 27 --f 28 is suggested to proceed via a P(V) intermediate (Sect. VI). In other cases, cyclic P(II1) stereoisomers have been detected but without assignment of geometry. Denney and Denney (96) using NMR as a probe have detected isomerism in cyclic phosphites of the type 29 and Goldwhite (97) has similarly shown the presence of isomers in the five-membered phosphites 30.

CL;

R

Me&-O

I

POCH,

>-x

Me& -0 (30)

(29)

Compounds of type 29 equilibrate rapidly in the presence of methanol but those of type 30 are thermally configurationally stable except for X = C1. In the latter instance equilibration is attributed to an exchange process rather than inversion since the rate of equilibration was shown to be concentration dependent. Isomer separation was not achieved for either 29 or 30. On the other hand, Quin et al. (98,99) have separated isomeric compounds of types 31 and 32 obtained as shown.

'M e P D ' "Et

I . 2.EtMgBr H,0

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 23 MePCI,

+ CH3CH=CHCH=CH2

+ Qcl / \ H3C C1

H3c

%-QCH3 I

CH3 (32)

In 32,there is a considerable difference (8 cps) between the 3JpH of the C-methyl group in the two isomers. No assignments were made in either class of compound. The cyclic polyphosphines, (PhP), (n = 5 and 6) have been examined by X-ray diffraction (100,101) and their structures accurately determined (33 and 34) as also has the unusual 1,2,3-triphosphaindane (35) obtained by Mann and Pragnell (102,103). Similar studies have been carried out on (CF3P), (n = 4 and 5 ) (104,105). It is surprising that no evidence of geometrical isomerism has been obtained for any of these compounds. The reason for their apparent preference for one structure may lie in the as yet not clearly understood nature of the P-P bonding in these compounds. Ph’

\pf

.P-P Ph”

a;; Ph

Ph

‘p-p.

I//

(33)

Ph

PhP -P ’p‘\/

Ph7

/Ph p\p,P-Ph

/ Ph

Ph

I

P----Ph

I

Ph

(2)

(35)

The compound ( B u ~ P forms )~ a stable monophosphonium salt with methyl iodide (106). Less-hindered members of this class of compounds suffer rupture of a P-P bond by subsequent attack of iodide ion under similar circumstances. Finally, mention must be made of P(II1) compounds of type 36 whose existence has been invoked to account for the greatly enhanced rate of alkaline hydrolysis of phosphoramidates with an N-H bond. A P(II1) intermediate of this type should be planar and hence should afford a racemic product. In fact, both reactions [eqs. (25) and (26)] proceed with inversion (107), contrary to an earlier observation (108), thus making the existence of 36 unlikely. It does not necessarily follow, however, that 36 must be planar [cf. the carbanions from

24

M. J. GALLAGHER AND I. D. JENKINS

methylphosphines (Sect. IVB)]. A similar intermediate has been invoked to explain the partial racemization of 37 during reaction with piperidine (109).

(37)

A number of polycyclic phosphines, esters, and amides containing one or two bridgehead P(II1) atoms are known (110-118), e.g., 38-41. The chemistry of these structures has not been extensively investigated though such investigations should be very informative particularly as regards geometry of transition states. Compounds of type 38 appear to be somewhat less reactive than their acyclic analogs, though their geometry would be expected to facilitate a P(II1) --t P(IV) change. The fused-ring system (40) is of interest since it displays none of the reactions of a phosphine even under forcing conditions. It is readily obtained by the action of phosphine on pyruvic acid in the presence of

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 25

x = CH,,NR,O

y = CH,, N R z = P,CR

(38)

MeN\p/

/

NMe

I

\

P---...NMe,.NMe.. _... -P

\

MeN”‘NMe

-I-------- . / ~

an acid catalyst. Adamantane-type structures are formed from pentane2,4-dione and phosphine which, though more reactive than 40 are less so than acyclic phosphines.

V. P(1V) COMPOUNDS A. Introduction Four-coordinated compounds form by far the largest group in phosphorus chemistry and only a limited treatment will be attempted here. The chemistry of condensed phosphates will be omitted and phosphonitrilic compounds will not be discussed as they have been reviewed elsewhere (7,119). P(1V) compounds invariably have a tetrahedral phosphorus atom and unlike P(V) compounds (Sect. VI) are stereochemically rigid. The four a-bonding orbitals are sp3 hybridized and these are associated with

26

M. J. GALLAGHER AND I. D. JENKINS

some T bonding involving the phosphorus d orbitals. The use of d orbitals has been discussed at length by Hudson (120), especially d,-p, bonding in phosphoryl compounds. For the purposes of this review, the P = 0 bond will be assumed to be best described as a double bond, perhaps with some 6-6 character (121,122).

B. Optical Isomerism

An understanding of the mechanism and stereochemistry of reactions in phosphorus chemistry is now rapidly emerging, mainly as a result of the considerable progress that has been made in recent years in the resolution of optically active P(1V) compounds. An important recent advance has been the determination of the absolute configuration of (+)-benzylmethylphenylpropylphosphonium bromide as S by X-ray analysis (Sect. IV). With this as reference, Homer et al. (123) have been able to assign the absolute configurations of benzylmethylphenylpropylarsonium and -ammonium salts using the quasi-racemate method. Also, ORD measurements with (+)-methylethylphenylamine N-oxide and (+)-methylethylphenylphosphine oxide support the S configuration for these compounds (28). Further evidence for the phosphine oxide assignment comes from the results of Homer’s asymmetric synthesis with an optically active Wittig reagent (54). 1. Types of Resolvable Compounds. Methods of Resolution and Stability Phosphonium salts are invariably resolved by salt formation with an optically active anion. D( -)- and L( +)-Dibenzoylhydrogentartrate anions have been used successfully since 1959 (Sect. IV). Other anions which have been used are (+)-camphorsulfonate (124) and I-menthoxyacetate (125). Optically active phosphonium salts may also be obtained by quaternization as this occurs stereospecifically and probably with retention of configuration (Sect. IV). Phosphine oxides are moderately basic substances and can also be resolved by salt formation with acids such as (+)-camphorsulfonic acid and (+)-bromocamphorsulfonic acid. Other methods of obtaining resolved phosphine oxides are by degradation of optically active phosphonium salts with aqueous alkali and by Wittig and related reactions. Phosphine sulfides are not sufficiently basic to be resolved in the same way as the corresponding oxides, and resolution appears to be

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 27

limited to those phosphine sulfides that contain an acidic or a basic substituent somewhere else in the molecule. Various thiophosphoryl compounds are easy to obtain, however, using the fairly readily available optically active alkylphosphonothioic acids, RP(0)(OR1)SH (126-128), which are obtained (129) by fractional crystallization of their quinine or brucine salts. A number of chiral phosphates, such as 42, have been prepared with some difficulty (130), but attempts to resolve them have been unsuccessful. p-02NCeH4CHzO

\p/

/ \

p-BrC6H4CHz0

0

OCHzCOOH

(42)

Some representative P(IV) compounds that have been resolved and their methods of resolution are shown in Table V. Optically active phosphonium salts, phosphine oxides, and phosphine sulfides are in general quite stable. For example, phosphonium salts can be treated with reagents such as phenyllithium to produce the corresponding ylid with retention of configuration. Treatment of the ylid with an aldehyde or ketone gives the phosphine oxide with a high degree of retention of configuration, a fact which lends support to a cyclic transition state for the Wittig reaction (26). Similarly, resolved phosphine oxides can undergo a Wittig-type reaction in which group exchange takes place [eq. (27)] with retention of configuration (26,139). ( +)-MePh(PhCHz)PO

+ PhN=CHPh

base

(+)-MePh(PhNH)PO + trans-PhCH=CHPh

(27)

Phosphine oxides are racemized by acid however; ( +)phenylmethylpropylphosphine oxide was racemized on standing for nine days in anhydrous dioxan saturated with hydrogen chloride. It also underwent racemization and oxygen exchange on standing (50-80 days) in l80enriched water saturated with hydrogen chloride (140). These processes probably involve initial protonation'of the phosphoryl oxygen followed by formation of a pentacoordinate intermediate which must (in the anhydrous case at least) undergo intramolecular racemization (see

M. J. GALLAGHER AND I. D. JENKINS

28

TABLE V

Some Resolved P(1V) Compounds Compound

Chiral reagent

MePh(PhCH2)P=0 MeOP(S)(OH)OCeH4NOa-p MeOP(S)(OH)NHCeHl + MeP(0)(MeO)-CeH4NMe3-p I -

Ref.

Camphorsulfonicacid and bromochamphorsulfonic acid Strychnine methiodide (on Agt Salt) Quinine

1,131 132 27

Silver dibenzoylhydrogentartrate

133

t

PhP(0)(OPh)NHCH2CH2NMesI- Silver camphorsulfonate RMeP(O)SCH,Ph a-(2,4,5,7-Tetranitro-9(R = 3-phenanthryl) fluorenylideneamino-oxy) propionic acid RIP(S)(OR)OH Quinine or brucine Quinine Et(EtO)P(Se)SH PhBuP(S)CeH40CH2COOH-p 1-Phenylethylamine

134 135 129,136 137 138

33

mp"

Silver menthoxyacetate

124

Silver bromocamphorsulfonate

123

hI-e H , O H - - P

RiRSR3R4P Xt

Silver dibenzoylhydrogentartrate

38

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 29

Sect. VI). In the aqueous case, a symmetrical intermediate of type 43 would give the same result. OH

I

Ra-T\R,

,/R1

OH

(43)

It is interesting to compare the ease of racemization of phosphine oxides with that of arsine oxides and sulfoxides. Methylethylphenylarsine oxide racemizes spontaneously in the presence of water, and sulfoxides racemize in dioxan/hydrogen chloride. (-)-Methylpropylphenylphosphine oxide, on the other hand, was stable in refluxing water for 8 hr, in 2N sodium hydroxide for 6 hr, and in 50% acetic acid for 1 hr. Racemization took place in acid anhydrides (2 hr in acetic anhydride at 140") probably through formation of a symmetrical diacyloxyphosphorane intermediate (141). With aqueous acid, the rate of racemization increased in the series perchloric acid < hydrogen bromide < hydrogen chloride (141); cf. rates of racemization of the +

arsonium salts; EtBu"Ph(PhCH,)As X-: C1-< B r - < I-. The perchlorate was stable (142). Resolved phosphoryl halides are much less optically stable than phosphonium salts and phosphine oxides and must normally be prepared just prior to use. Thus, isopropylmethylphosphonofluoridate, MeP(O)(OPr')F, racemizes in 20 hr at 25", although dilute (0.1M) solutions in acetone, ethyl acetate, and isopropanol are optically stable for several weeks (143). Similarly the half-life of racemization of ethyl ethylphosphonochloridate was found to be (144-146) about 4 hr (neat), 6 hr in dry acetone, and 4 days in dry benzene at room temperature. Traces of chloride ion brought about extremely rapid racemization. In contrast to this, the thiophosphoryl halides are optically stable and permit the synthesis of many optically active P(1V) compounds (126-128). 2. Reactions of Phosphonium Salts Reduction of phosphonium salts with lithium aluminum hydride leads to racemic phosphines (35,147,148). This could well be due to racemization of an intermediate phosphorane (44) rather than to the

30

M. J. GALLAGHER A N D I. D. JENKINS

formation of a symmetrical phosphorane (45) as has been previously suggested (4,149). Strong evidence for racemization of P(V) compounds is now available (Sect. VI) and, in fact, a phosphorane of the type 44 has recently been isolated (150). It would be interesting to know in this connection if phosphines are racemized by lithium aluminum

(44)

(45)

hydride, but this does not appear to have been studied. In contrast, cathodic reduction of phosphonium salts occurs stereospecifically and probably with predominant retention of configuration (Sect. IV). The decomposition of phosphonium hydroxides (and alkoxides) has been considered in some detail by McEwen (4).In summary: I. Nucleophilic displacement by hydroxide ion at phosphorus (the leaving group being that most stable as an anion) is 100% stereospecific and proceeds with inversion of configuration. 2. The reaction obeys third-order kinetics; first order with respect to phosphonium cation and second order with respect to hydroxide ion. 3. The mechanism usually put forward as best fitting the experimental data is as shown in eqs. (28)-(31). R46

+ OHR4PO-

R-

+ HZ0

fast

p RIPOH

slow fast

R3P0 RH

+ R-

+ OH-

(31)

The individual steps themselves are little understood and many assumptions have to be made in order to obtain the correct stereochemistry. The most fundamental ambiguity seems to be that surrounding the pentacoordinate intermediate. If indeed R,POH is formed, then it must be very shortlived, as it is difficult to see why intramolecular racemization should not occur prior to decomposition (Sect. Vl). Unlike the hydroxides, phosphonium alkoxides decompose to the

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 3 1

phosphine oxide with much racemization (149). The mode of decomposition does however vary with the phosphonium salt and with the conditions employed. For example, 2-cyanoethylphosphonium salts decompose stereospecifically to the phosphines with alkoxide ion (42), while n-alkyltriphenylphosphonium methoxides on heating in the absence of solvent yield n-alkyldiphenylphosphine, anisole, and small amounts of triphenylphosphine. With ethyltriphenylphosphonium salts, olefin formation is the major reaction (151). Benzylphosphonium salts react with alkoxide ions, RO -, in alcohol however, to give the phosphine oxide, toluene, and ether, ROR. The proposed mechanism to account for the products and stereochemistry is shown in eqs. (32)-(35). R'46 +

R',POR

RO-

+ OR-

R',POR + R'3POR

(32)

+ R'-

(33)

$ R13P(OR)2(symmetric)

(34)

R'IPOR

+ SN2displacement of OR- resulting in racemized

R1,60R; or R1360R

+ OR-

n o

R'SPOR OR-

R',PO

+ ROR

(35)

As in the phosphonium hydroxide mechanism R',POR should +

undergo rapid racemization, but if R13POR were to be formed by a direct SN2 displacement, i.e., combining steps (32) and (33), racemization could occur at this later stage as in eq. (34). Two recent results (I 52) which are worth mentioning in connection with these decomposition reactions are shown in eqs. (36) and (37). R36NR1R2X -

+ (+)MePrPhP-SMe

OH-

I - --+

OH-

R 3 P 0 (inversion)

(-)MePrPhP=O

(- 50% inversion)

(36) (37)

3. Reactions of Phosphoryl and Thiophosphoryl Compounds

Nucleophilic displacement reactions at phosphoryl and thiophosphoryl centers frequently occur with high stereospecificity and take place with inversion of configuration at phosphorus. A transition state (46), analogous to an SN2displacement at carbon, would seem to offer a fairly accurate interpretation of the experimental data. A pentacoordinate intermediate seems most unlikely, for, if an intermediate such

32

M. J. GALLAGHER AND I. D. JENKINS

as 47 were to be formed (in the hydrolysis of phosphoryl halides say), then even if (47) did not racemize by a rapid rearrangement of groups, it should undergo racemization by a fast proton-exchange reaction. 0-

0

N ........p ........X II8+

8-

6-

Cl-P

I

,R1

(47)

N- = nucleoDhile

X = leaving group (46)

The reactions shown in eqs. (38) and (39) have established beyond doubt that inversion of configuration at phosphorus occurs during nucleophilic displacement at phosphoryl(l53) and thiophosphoryl(l54) centers. In both cases, the rate of isotopic exchange was found to be exactly equal to the rate of inversion, i.e., half the rate of racemization. This means that each act of substitution involves an inversion of configuration at phosphorus. MeOH

+ MeOPhEtP(0)OMe + '*CH30+ Li3W + Et(EtO)P(S)3eCl + LiCl

PhEtP(0)01*CH3 Et(EtO)P(S)CI

,

(38)

(39)

Much of the work that has been done on nucleophilic displacements has been carried out on thiophosphoryl compounds, mainly because these are more readily obtainable, often from thiophosphoryl halides which are much more optically stable than the corresponding phosphoryl compounds. Optically active thiophosphoryl halides are easily prepared from the corresponding acid by treatment with a P(V) halide. This reaction has been shown (126,128) to be at least 98% stereospecific by the sequence outlined in Figure 4. The reaction is proposed as occurring with inversion of configuration at phosphorus, perhaps via an intermediate such as 48 formed by initial attack of PCls on oxygen. Inversion in the formation of the acid chloride would require a further inversion in the formation of the P-0-P linkage as the product must have the same configuration as the original thio-acid. Triphenylphosphorus dibromide reacts in an analogous way, i.e., with inversion, to give (0-ethy1)ethylphosphonobromidothioate of optical purity 2 94% [eq. (40>1* OHPhaPBr.

Et(EtO)P(S)OH __t Et(EtO)P(S)Br [a]C = 13.9" [alga = +140.4"

+

Et(EtO)P(S)OH

[a]g3 =

$13.0"

(40)

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 33 S

PEt

OEt

I

PCI,

Et-P-OH

II

t

Et-P-C1

IIS

S [aIDao=

OEt

- 14.00'

[a]Dao

OEt

OEt

I

I I Et-P-0-P-Et II II S

[a]Dao

= -81 3 5 "

OEt

Et-P-0-P-Et

II

S

0 = $29.5"

[a]""

I

11

0 =

+28.75"

Figure 4

If hydrolysis occurs with inversion, then Ph,PBr, must also react with inversion (155). Some illustrative nucleophilic displacement reactions and their stereochemical result are shown in Table VI. On the strength of available data, it seems fairly safe to conclude that displacements at the phosphoryl center occur in an analogous fashion to displacements at the thiophosphoryl center so that the thiophosphoryl examples in Table VI can probably be taken as being applicable to phosphoryl compounds as well. It can be seen from Table VI that although inversion is the predominant mechanism, retention and racemization are also possible. Thus reaction (c) occurs with inversion but the closely related reaction (d) occurs with retention. This is possibly the result of an intramolecular mechanism operating in reaction (d) (146). The hydrolysis reaction (e) is shown as occurring with inversion. Further evidence for inversion during hydrolysis at the thiophosphoryl center is obtained from the Walden-type inversion cycle in Figure 5 (127). The reaction is 957, stereoselective. (The methoxide reaction establishes attack at the chiral phosphorus atom of the pyrophosphate.) The same conclusion

+

SO2Clz

I CHzCI

+ +

OH

(+I MeONH2

( -)-MeP(O)(OPr')OEt

NaOEt Aniline

(h) (+)-MeP(O)(OPr')F (i) MeOP(S)(NHC6HI1)

I

(+)-MeP(O)(OPrl)F

Picryl fluoride

(g) MeP(O)(OPrl)SNa

(-1

(MeO)P(S)(NHR)OH

NaOH

OH(0")

I

MeOP(S)(NHPh) I (-1 OH MeOP(S)(NHOMe)

(+)

(MeO)P(S)(NR2)OH

(-1

(+I

Et(EtO)P(O)CI

(-)

,,

Et(EtO)P(O)CI

( )-Et(EtO)P(S)OCHoPh ( )-Et(EtO)P(S)NHPh

Product

NaOH

(e) (MeO)P(S)(NR2)OC,H,NO2-p (HNR2 = morpholme)( ) (f) (MeO)P(S)(NHR)OC6H,NOz-p (R = cyclohexyl)(+)

(+I

I

I

CHa (d) Et(EtO)P(O)SCHz

(a) (-)-Et(EtO)P(S)CI

PhCH20Na PhCHzNHz so2c12

Nucleophile

(b) (-)-Et(EtO)P(S)CI (c) (+)-Et(EtO)P(O)SCH,

Electrophile

TABLEVI

Displacement Reactions a t P(1V)

Racemization

Inversion Inversion

27

143 27

143

107

Inversion Inversion

107

146

156 156 146

Ref.

Inversion

Retention

Inversion Inversion Inversion

Stereochemical result

5

8 2: B

.

U

F

5

ia

8

b

b

9

0

F

P

W

-

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 35 EtO \p/

S

( i ) NaH

/ \

Et [.ID

=

OEt

I

Et-P-0-P-OEt

(ii) (EtO),P(S)CI

OH -15.10"

OEt

S

= +30.65"

D I . [

I

1

OMe-

S

Et-P-OMe I

OEt

I

OEt

Et-P-0-P-OEt SII [a]D =

I

Sl +29.85"

OEt = f3.05"

OH-

S

II + (Et0)2P-O-

II

[.ID

I I

EtO Et'

[.ID

\pH

S

\OH = +12.9"

Figure 5

was reached by Green and Hudson (157) using a slightly different Walden inversion process. They claimed at least 99% inversion for hydrolysis at the thiophosphoryl center. The preparation of optically active Sarin [reaction (g)] was important not only from the chemical point of view (several other fluorinating agents gave racemic Sarin) but from the biological point of view also. It was found that (-)-Sarin reacted with acetylcholinesterase from bovine erythrocytes 2 4000 times as fast as (+)-Sarin. This marked difference in reactivity dropped to a factor of 2 for horse serum butyrylcholinesterase. There has been some doubt in the literature as to the mechanism of phosphorylation of thioic acids. It was known that 0-pyrophosphates resulted, but it was uncertain whether phosphorylation of the thiono form, R,P(S)OH, or thiolo form, R,P(O)SH, took place (the latter being followed by rearrangement). Michalski et al. (158) have shown by the sequence of reactions shown in Figure 6 that the reaction of (0-ethy1)ethylphosphonothioic acid (49) with a phosphoryl chloride in the presence of a tertiary base takes place by attack of the anion Et(EtO)P(S)O-, and not the alternative Et(EtO)P(O)S-. This sequence disproves the possibility of initial formation of the S-pyrophosphate followed by rearrangement to the more thermo-

36

M. J. GALLAGHER AND I. D. JENKINS 0

II

Et-P-SH

I

bEt EtO

\/

Et' EtzP(O)W&/

s

o

1

I--

+ (-149

'OH

(( -)49)

I Et-P-W -Et I I OEt Et (+I

EtaP(0)OMe

I

S

\

( f )Et(EtO)P(O)CI/Et,N

s

II Et-P(+)Et(EtO)P(O)Cl I

(+I

Et-P-WP-Et OEt

I

II I

WP-Et

OEt

s . 0 1I I

o

II I

OEt

OEt

loMe-

(+)Et(EtO)P(O)OMe

+ (+I49

Me.NH

(+)Et(EtO)P(0)NMe2 Figure 6

+ (-)49

dynamically stable 0-pyrophosphonothionate (3,120), i.e., P(0)-SP(0) P(0)-0-P(S). An interesting variation in the formation of pyrophosphates is provided by the reaction of phosphonothioic acids with dicyclohexylcarbodiimide (DCC)(159). Here again, the O-pyrophosphonothioate is obtained, presumably via the mechanism shown in Figure 7. When 49, DI.[ = -14.22', is treated with DCC in the presence of pyridine, the product 50 has a rotation of +27.58'; with 2,6-lutidine as base the rotation obtained was +33.60'. This, coupled with the fact that treatment of 50,DI.[ = +27.58, with NaSEt gave acid 49 with D I . [ = -12.84' (i.e., 9% optical retention) and Et(EtO)P(O)SEt of D I . [ = -1.57' (i.e., 2% optical retention) indicates involvement of

*

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 37 0

S

EtO

\p4

DCC Ligroin

/ \

Et

OH

I

I1

+?

I1 I

0-P-OEt

(-1

(49)

- 14.32"

S

I1 Et -P-0I

Eto\P/SEt / \o

OEt

(-1 0

II I

P -Et OEt

(+)

(->

-70.5"

Et

I

( i ) EtONa (ii)EtBr

Et

S

RNH=C-v-P-OEt NHR I Et I\-

I

(9)

+41.95"

(R = cyclohexyl)

( i ) EtSNa ( i i ) HCI

Et(EtO)P(S)OH -13.42"

+ Et(EtO)P(O)SEt

-33.57" (48% optically pure)

Figure 7

intermediate 51, formed by nucleophilic attack of the amine at phosphorus. Thus the phosphoryl portion of the product 50 can have either configuration, depending on whether or not attack by the second mole of thiophosphonate occurs on the initially formed DCC adduct or the EtO 0 \p/

R,N:

-4

+

II I

NHR +R,N-P-OEt Et

L - C '

(-)

0

\"HR

(+I (51)

0

S

OEt

OEt

I1 II Et-P-0-P-Et I I

M. J. GALLAGHER AND I. D. JENKINS

38

intermediate 51. With the sterically hindered 2,6-lutidine, formation of 51 is much less favorable. In contrast to phosphorylation, reaction with alkyl halides and phosgene appears to proceed by attack of the Et(EtO)P(O)S- anion and not Et(EtO)P(S)O-, i.e., S-alkylation occurs (144,145). Acetyl chloride gives the 0-acylation product and is thus analogous to phosphorylation. RX

+ COCl,

Et(EtO)P(S)SR f- Et(EtO)P(O)SNa (+)

Et(EtO)P(O)CI

(-1

(+)

The anomalous reaction with phosgene led to the suggestion (144) that this reaction proceeded by formation of the intermediate 52 followed by rearrangement, rather than by direct formation of the thermodynamically more stable 53. This seems unlikely however (4). EtO

EtO

S

\pH

\p/

Et

/-\

0-C-CI

I

Et

0

/-\

S-C-Cl

I

0 (52)

0 (53)

Phosphorylation, acylation, and alkylation of phosphonothioic acids can be interpreted in terms of Pearson’s concept of “hard” and “soft” acids and bases, the reactions being subject to kinetic control (120). For example, the alkylation reaction involves interaction of the soft acid (RX) with the soft sulfur atom (base). All three of these reactions lend support to the theme (160) that mutual polarizability of reactants is a very strong operative force in the reactions of phosphorus compounds. 4. The Wittig and Related Reactions

Most aspects of the Wittig reaction have been discussed at considerable length in recent review articles (161-165) and only a brief resume will be given here.

a. Stereochemistry at Phosphorus. The reaction is stereospecific and takes place with complete retention of configuration at phosphorus. Horner (26) has interrelated the Wittig olefination reaction with

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 39

-

cathodic reduction and oxidation as shown in eq. (41). This result was taken as good evidence for cis elimination in a four-membered ring + MeEtPh(PhCH,)PBr= -43.4"

Olefination with

67% MeEtPhP=O

benzaldehyde

(41)

I [a1546

= -19.1"

(i) Cathodic fission (retn) (ii) Oxidation with H.Oo (retn)

intermediate. A cis elimination was also proposed in the olefination reaction shown in eq. (42). MePhP(O)CH,Ph [a1646

+ PhCH=NPh

= +61.5"

(54)

KOBut

+MePhP(0)NHPh [ a ] 5 4 6=

-29.2'

+ PhCH=CHPh

+ MePhP(0)OH

(42)

(55)

Rotatory dispersion curves of 54 and 55 showed that both compounds belonged to the same steric series, i.e., the substitution of -NHPh for -CH,Ph occurred with retention of configuration, presumably via a cyclic intermediate of type 56 or 57. 0

II

TI

R,P-CHPh

R,P-CHPh

PhaCHPh

PhNd-CHPh

\I

(56)

I \I

(57)

The related, but more complex, reactions of optically active phosphorus ylids with styrene oxide (166) and benzonitrile (167) have been given adequate treatment by McEwen (4). Both of these reactions result in a phosphine oxide which is only partially optically active. This has been explained on the basis of competing pathways of different stereochemistry, some leading to inversion and others to retention of configuration. b. Stereochemistry of the Product Olefin. Stereospecific olefin formation is best discussed with reference to a mechanism. The mechanism (168,169) given in eq. (43) is fairly adaptable and allows a reasonable interpretation of the stereospecificity of the products obtained from more general reactions. Betaine formation has been shown to be reversible (169) and betaine dissociation occurs at a rate comparable to

M. J. GALLAGHER A N D I. D. JENKINS

40

that of elimination, hence allowing the formation of a predominant amount of the thermodynamically more stable trans olefin.

R,P=CHR'

+

(43)

R"CH0

(5W

(5W

From eq. (43) it can be seen that the cis olefin would be favored if the ratios kl/k3,k6/ks,and k6/klwere high. It might be expected therefore that a high percentage of cis olefin (i.e., approaching 50%) would be obtained by employing a very reactive (or nucleophilic) phosphorus ylid, provided betaine decomposition was fast (168). In general, this is found to be the case. Highly reactive Wittig reagents give mixtures of cis and trans isomers [very nucleophilic ylids and electrophilic aldehydes give high ratios, approaching unity, of cis-trans olefins (168,170)]. Stable ylids tend to give exclusively trans olefin, though many anomalies exist. For example, in the reaction of phthalic anhydride with acyl-ylids (Ph,P=CHCOR; R = NR2 or OR) the product 59 was cis, but for R = Me, the product was trans. R = Ph gave a 4:l trans:cis ratio (171).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 41

Similarly, the phosphole 60 is a stable isolable ylid being less reactive (and less stereoselective) than the triphenylphosphorusethoxycarbonylmethine ylid. With acetaldehyde and 60, the olefin obtained was 26% cis; with the ylid (Ph,P=CHCOOEt) it was only 8% cis (172). Probably specific bonding effects (dipolar and n-cloud interactions) are present in these particular examples (171,172). It seems likely that the geometry of ylids may be an important factor governing the initial nucleophilic attack by the ylid (173). The X-ray structure determinations (174) of several stable phosphorus ylids has shown that the major contributing resonance structure is the dipolar betaine (61; X = halogen). As X is varied from C1 to Br to I, the system becomes less planar but more basic (due to decreased carbanion stabilization). The decreased planarity would make steric factors much Ph3P

0

II

PhSP=C-C-Ph

I

X

++

X

\ / c=c / \

0-

Ph

(61)

more important for the iodo compound than for the chloro compound, so that despite the increased nucleophilicity of the iodo compound, it may be more stereospecific. Evidence of hindered rotation in stable triphenylphosphine alkylenes has recently been obtained by NMR (175). The compound Ph,P=CMe-COOMe was found to exist in chloroform in a 65 :35 ratio of rotamers 62 and 63, respectively. The rate of rotation was solvent dependent. 8+

8-

Ph3P Me

0

/

\ (62)

OMe

8+

Ph3P Me

OMe

/- -\ (63)

0 8-

The importance of factors such as hindered rotation and geometry of ylids is difficult to gauge at the present time but these factors could well be important in conjunction with solvent and Lewis base effects which are little understood. Lewis bases and polar solvents are said (161,176179) to increase the proportion of cis isomer in nonstabilized phosphorus ylid olefinations. In fact relative yields of close to 90% cis isomer have been reported (164) for some reactions employing aldehydes and excess ylid in a highly polar solvent and in the presence of

42

M. J. GALLAGHER A N D I. D. JENKINS

iodide ions. It is considered likely that halide salt impurities in reactive ylids are partly responsible for non-trans selective olefination of aldehydes (164), although a recent paper (180) contradicts this by claiming that alkylidenetriphenylphosphorus ylids tend in general toward cis olefination, the proportion of cis olefin being highest when the ylid is prepared in “salt-free” form. Lithium salts were found to favor the formation of trans isomers, the more so the larger the radius of the anion. The Lewis base effect has been interpreted in terms of a decreased orientation in attack by the ylid-base complex on the carbonyl compound, and the polarity effect in terms of solvent stabilization of the erythro betaine 58a, i.e., more equal energies of both betaines, 5& and 58d, due to solvation (161,179). In connection with the Lewis base catalysis (of cis olefin formation) it has been suggested that lithium salts affect the course of the reaction by forming an organolithium compound so that the ylid is no longer the reacting species (120,163,179). A recent, rather novel selective transolefin synthesis has employed a carbon-lithium bond in the betaine An analogy itself to bring about a stereospecificreaction (181) [eq. (a)]. was made between this result and the rapid rates of racemization of optically active organolithium compounds (182). + Ph,$-CHR X- + R’CHO + Ph3P-CHR X-

I

I

LiO-CHR‘

Li

PhLi

(44)

I

I

-

I

KOt-Bu

pure trans Olefin

The literature is also in a confused state regarding the effect of solvent and Lewis bases on stabilized ylid reactions. Some authors claim no effect (161,164,172,176,183) while others claim marked influence (179). Acid catalysis by benzoic acid has been found in several instances, specific hydrogen bonding being proposed in one case (1 84) and protonation of the carbonyl group in another (185).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 43 Ph,P4o Ph \c-H

I HO/C;;;.H

I

Ph

(64)

(65)

i

/G-B"

PhLi

PhLi

(cis)-PhCH=CHPh

( / r a m )-PhCH=CHPh

The phosphonate modification of the Wittig reaction is usually much more stereospecific leading to the trans isomer, with only trace amounts of the cis (164,186). It has been claimed (164,187) that solvent and Lewis bases have no effect on the stereochemistry and that only minor changes are produced by sterically and electronically different starting materials. The following examples show, however, that bases do affect phosphoryl activated olefination. Dihydrotestosterone reacts with diethyl ethoxycarbonylmethylphosphonatein an aprotic solvent in the presence of sodium hydride to give exclusively trans-3-ethoxycarbonylmethylene5-a-androstane-l7p-01, whereas addition of potassium-t-butoxide as Lewis base led to a preponderance of the cis isomer (188). A related observation has been made by Horner (1 39). Treatment of benzaldehyde with diphenylbenzylphosphine oxide and one mole of phenyllithium gave 90% threo-p-hydroxyphosphineoxide (64)and 5% erythro isomer (65). Treatment of the erythro isomer with phenyllithium gave cisstilbene, but potassium-tert-butoxide resulted in trans-stilbene. It is clear that an exhaustive study of the factors influencing product stereochemistry in the W h i g and related reactions is required. R'R2CHP(O)(NMeZ),

BuLi

- 78"

RRaCP(0)(NMe&

I

Li

(66) I

ASi02

4

(i) R3R4CO (ii) HaO

R'R2C=CR3R4 a R'R'C-CR3R4 benzene

I

(Me2N),P0 (67)

1

OH

M. J. GALLAGHER AND I. D. JENKINS

44

From the synthetic point of view, a recently developed variant of the phosphonate modification of the Wittig reaction should prove valuable. Corey and Kwiatkowski (189) have recently been able to obtain either pure cis olefin or pure trans olefin by employing a-lithio phosphonic acid bisamides of type 66. The stereospecificity of this reaction rests upon the isolation of the two diastereoisomers of 67 which, upon heating in benzene or toluene in the presence of silica gel undergo stereospecific (probably cis) elimination to give the respective olefin in high yield. The 8-hydroxyphosphondiamidates may also be synthesized by alternative means. Steric effects can affect the course of the Wittig reaction. Thus, although benzylidene groups a to the carbonyl in cyclohexanone do not prevent olefination (190), triphenylphosphine methylene will not attack acetomesitylene (191). Reaction does occur with benzalacetomesitylene, but conjugate addition takes place as shown in eq. (45). Conjugate addition is rare for phosphorus ylids and apparently only occurs when the carbonyl group is sterically hindered. PhCH=CHCOCeH11

+

4

+ PhaP=CHa

Ph3P-CH2-CH-CH-COCsHlI

I

Ph

-

A

+ CaH11CO-CH-CHPh

\/

(45)

CH2

C. Geometrical Isomerism Two types of geometrical isomerism are found in organophosphorus compounds : (a)that resulting from the configuration of phosphorus and (b) that arising from configuration of an atom attached either directly or indirectly to the phosphorus atom. The former type is restricted to cyclic and the latter to acyclic phosphorus compounds. Many examples of both of these types have appeared in recent years, mainly as a result of investigations using NMR. Since (a) and (b) involve quite different concepts, they will be treated separately. 1. Cyclic Compounds

From the point of view of phosphorus stereochemistry, cyclic compounds are much more important than the acyclic ones. The ring compounds provide information on the configurational stability of the

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 45

phosphorus atom not always obtainable using optically active P(1V) compounds. Denney and Denney (96)have separated cis and trans six-membered cyclic phosphates by gas chromatography. The phosphates were obtained by oxidation of the corresponding phosphites (see Sect. IV). No work was done however on the interconversion of the cis and trans isomers. Ramirez et al. (192,193) have observed a slow stereomutation at phosphorus, in chloroform solutions of the meso five-membered cyclic phosphate (68). Roughly equal amounts of the two isomers were formed. It was suggested that the stereomutation was catalyzed by traces of methanol but traces of acid may have been responsible as aged chloroform solutions were employed. A definite configurational assignment was not made in this case but on the basis of 31P-ring Me M e 0\

...:,””’

O””\

0

+ 0 ,O , ‘ COMe + M e 0P COMe

.--. COMe

(68) hydrogen coupling constants, Ramirez (193)suggests a smaller coupling constant for the cis isomer of ~~-4-acetyl-5-ethyl-2-methoxy-4-methyl-

2-oxo-l,3,2-dioxaphospholan(69).

COMe (69)

There is a surprisingly large difference between the coupling constants for the cis and trans isomers of 69 (4.4and 14 cps), as they appear to differ only in the configuration at phosphorus. Ramirez attributed this to a difference in the dihedral angle between phosphorus and the ring hydrogen, resulting from a strong dipole-dipole interaction in the cis isomer. This is not a completely convincing argument, for, although it

46

M. J. GALLAGHER A N D I. D. JENKINS

has recently been shown (194) that 3JpH depends on the dihedral angle between H-C and P-C, according to an approximate relation given by Karplus, a very large change in conformation would normally be required to bring about a difference in coupling constants of nearly 10 cps (see Sect. V-C-2). Possibly an equally important factor is the change in charge distribution with conformation (subsection D). A somewhat similar stereomutation has been observed for the cyclic phosphonate 70, but refluxing with dilute hydrochloric acid was necessary (88). The equilibration results in a 2 :1 mixture of trans :cis. The identical IR absorption frequencies for the phosphoryl groups in 70 and 72 are good evidence for a different configuration of groups about the 4 position.

ClCHa E t k a p / C H a P h

II

0 (72) ( / r a m )

The fact that the six-membered cyclic phosphonate (70) required refluxing with hydrochloric acid for stereomutation while the fivemembered cyclic phosphate (68) underwent stereomutation simply on standing, perhaps in the presence of trace amounts of acid, may be an important piece of information regarding the pentacoordinate transition state proposed for the acid hydrolysis of cyclic phosphate esters and also from the point of view of the stereochemical rigidity of cyclic P(V, compounds (see Sect. VI). Another more novel molecule which exhibits cis-trans isomerism is the phosphacyclobutane(73).Gas chromatography of this ester showed two peaks, but here again no work was done on the interconversion of

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 47

0 MeV,!-OMe

MeI

MMe

e

(73)

the two isomers ( I 95). This problem would be most interesting, as intermediates of type 71 in which both hydroxyls are apical, should be almost impossible to form because of the angular restrictions imposed by a four-membered ring. The acid from 73 is quite stable to boiling concentrated nitric acid and potassium hydroxide solutions. This stability was thought (1 17,118)to be indicative of freedom from internal strain in the molecule, but restricted rehybridization dependent upon the four-membered ring, or simple steric hindrance to attack would seem to be more likely explanations. Cyclic bisphosphine oxides and phosphonium salts also exhibit cis-trans isomerism as a result of configuration at phosphorus. These have already been dealt with (Sect. IV). 2. Acyclic Compounds Considerable data are now available on the characterization of various cis and trans alkenyl phosphorus compounds. There are in most cases quite distinct cis and trans phosphorus-proton coupling constants analogous to proton-proton couplings in alkenes. Table VII gives a number of examples of these. It can be seen that the trans couplings 3 J p H for vinylphosphorus compounds are in the range 30-50 cps whereas cis couplings are usually about 10-25 cps. In allylic compounds on the other hand, cis couplings are greater in magnitude than trans couplings. Unfortunately, little work has been done on the sign of the coupling constant in phosphorus compounds (17,197,200) so that the relative signs of these values are uncertain. Based upon the homoallylic compounds 74 and 75 (Table VII) and model compounds, such as y-dimethylallylphosphonate, it has been shown (198) that transoid 5 J p H coupling has a greater magnitude than cisoid 5JpH coupling in the system H-C--C-C-C-P. This is analogous to 5 J coupling ~ ~ (201). 8, y-Unsaturated phosphonates, such as 74 and 75, are obtained by a Stobbe-type condensation of diethyl 13-carbethoxyethylphosphonate

48

M. J. GALLAGHER AND I. D. JENKINS

TABLE VII

cis-trans Coupling Constants in Unsaturated P Compounds

3JpHcis, cps

Compound PhCH=CHP(O)Pha CHa=CClP(O)(OEt)a ClCH=CHP(O)(OEt)a CH3CH=CPh-P03Ha CHa=CPh--POaHa CHBr=CPh-P03Ha CHCl=CPh--P03Ha PhCH = CPh-POaHa PhCH=CH-P03Hz

MeO-CeH4-CH=CHP(0)(OEt)2

Cl-Ce H,-CH=CHP(

0)(0Et)a

NOa-CeH*-CH=CHP(O)(OEt)a

CH3(CH2)3CH=CHP(O)(OEt)a CHa=CCH3P(O)(OEt)2 + Ph3P-CH=CHa Br+ Ph3P-C(CH3)=CHa Br-

3JpHtrans, cps

Ref.

19.5 13.6 13.6 20 22 15 13 16 16 23.7 23.8 23.5 23.1 23.5

40.3 35.9 40.3 38 45

50.3

22 13 13 12 12 12 12 12 12 14 14 14 14 14

25

50

196

22

48

196

19

12

23

194

23.5

194

50

17

194

12 (continued)

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 49

TABLEVII (continued) Compound

3JpHcis, cps

3JpH trans, cps

9

v

Ref. 12

48.8

12

‘OEt

P(CH = CH3,

13.6

30.2

197

*JPH cis (MeO),P(O)OCMe=CH-C00Me 1.8 ( Me0)2P(0)OCH=CCl-H ( T ) 1.7

4JpHtrans 0.9 (f11.6 (1.2 and 3.2)

199 199 198

(CH3)2C=CH--P(O)(OEt)a

sJpHcis

5JpH trans

(CH3)2C=C(COOEt)

I

H,CP(O)(OEt)OH

4.1

5.8

198

4.4

5.6

198

4.2

5.4

198

(74)

CH3PhC=C(COOEt)

I

H2CP(O)(OEt)OH (75)

(CH3)2C=CH-CH2P(0)(OMe)2

with ketones (198). Approximately a 1 :1 ratio of cis :trans products is obtained. No base catalyzed isomerization was observed in the compounds studied although this type of isomerization [eq. (46)] has been reported (202). C-C=C-C-p-

I I I

H O

OH-

&

C-CH-C=C-p-

I 1

0

(46)

Vinyl phosphonates on the other hand are apparently produced stereospecifically by the Wadsworth-Emmons procedure, i.e., reaction of the carbonyl compound with tetraethylmethylene-bisphosphonatein the presence of base. The trans isomer is obtained (14). cis-Vinylphosphonates can be prepared by catalytic (Lindlar) reduction of the corresponding ethynylphosphonates (14).

M. J. GALLAGHER A N D I. D. JENKINS

50

Isomerization of vinyl phosphorus compounds has received some attention. Unlike the bis-phosphines, cis-l,2-vinylene-bis-diphenylphosphine oxide and sulfide may be converted to the trans isomers by refluxing in THF with phosphorus trichloride (19). The mechanism and generality of this isomerization are unknown. Presumably the C-C bond must lose at least some of its double bond character in order to undergo rotation. One can postulate an intermediate such as in eq. (47), but this is purely speculative.

H

/"

%=C PhzPf \'PPh,

"

-

H\

/

H

Ph,P 4c-c\pph,

l

0 p

(47)

I

0-

<Pa,

The partial conversion of trans vinylphosphonates to the cis isomers has been achieved by photoisomerization (14). Thus photolysis of diethyl trans-8-styrylphosphonate for 12 hr gave a 40 :60 cis :trans mixture. The isomerism considered so far has been due to the presence in the molecule of a C=C double bond. Interesting NMR data should also be obtainable from a study of molecules in which cis-trans isomerism is not dependent on a C=C double bond, i.e., molecules such as 76-78. &p(owEth

(76)

&

A

P(O)(OEt)z

(77)

(78)

P(O)(OEt)z

Diethyl 2-methyl- and 3-methylcyclohexylphosphonates76 and 77 are obtained as mixtures of cis-trans isomers which are separated by gas chromatography (203), and gas chromatography and PMR showed the presence of presumably endo and exo isomers in the norbornene compound (78). Unfortunately, attempted separation of 78 resulted in partial decomposition and the structures of the two isomers could not be assigned. No phosphorus-ring hydrogen coupling constants were reported for 76-78 but a study of similar systems by Benezra and Ourisson (194) has

STEREOCHEMICAL ASPECTS O F PHOSPHORUS CHEMISTRY 5 1

revealed an angular dependence of the spin-spin coupling constant, 3Jp H . For example in the phosphonate derivative 79, 3JpH is 12 cps, in 80 it is 35 cps while in 81 3JpH is approximately 0. The dihedral angles in 79, 80, and 81 are probably about 60, 180, and 90" respectively. In

(80)

(82)

compound 82, 3JpHi = 7 cps while 3JpH26 0.5 cps. It should be noted here that a dihedral angle of 180" does not always result in a large 3 J p H value. Thus in acetylenic compounds, P-C-C-H, 3Jp H can be quite small ( < 0.5 cps), smaller in fact than the coupling across two triple bonds (204). D. Conformational and Rotational Isomerism

The study of conformation in phosphorus chemistry is still in its infancy. The little work that has been done is almost wholly concerned with very simple molecules and the most probable rotational isomer or isomers present in solution. Nevertheless the importance of conformation has increased considerably in the last few years especially in relation to the anomalous rates of reaction of cyclic phosphate esters (Sect. Vl). As a result of molecular orbital calculations carried out on aliphatic phosphate esters (205) it has been suggested that very little energy is required to bring about small changes in conformation. These changes are considered to alter the 2p-3d orbital interaction sufficiently to result in large changes in charge distribution, i.e., nucleophilic attack at phosphorus is sensitive to the conformation of the ester groups about phosphorus. The charge distribution in cyclic esters is proposed as a

52

M. J. GALLAGHER AND I. D. JENKINS

possible explanation for their extremely rapid rates of hydrolysis (205). Some time ago Paddock (206) suggested similarly that a restricted P-0-C angle should not only cause direct ring strain but would also prevent back donation (by the ring oxygens) to phosphorus, thus causing it to become strongly electrophilic. Considering Jaffe's conclusion (207) that unequal radicals enter into effective competition for the d orbitals of the central atom, it is perhaps not unreasonable that small changes in conformation and alterations in bond angles should markedly influence electronic charge distribution. Useful information might be gained here from 13C NMR of certain phosphonate esters, owing to the dependence of 13C-H coupling constants on the electronegativity of attached groups (in this case 31P).Unfortunately, a correlation of the 31P chemical shift with electron density at phosphorus is not yet possible (17,208), although it has been reported (209) that five-membered cyclic phosphate esters show less electron shielding of the phosphorus nucleus than do sixmembered esters or acyclic phosphate triesters. This does offer some support for the above proposals of increased electrophilic character of the P atom in five-membered phosphates, and is consistent with decreased dZ-pnbonding in these esters. It is perhaps significant here that the recent structure determinations of methyl ethylene phosphate (210) and methyl pinacol phosphate (21 1) have shown that the cyclic P-0 bond lengths are equal to the exocyclic P-OMe bond length and these values do not differ significantly from those in triphenylphosphate (212). This in itself would seem to indicate no major difference in the n bonding involved in the cyclic or acyclic phosphates, but based on symmetry arguments it has been proposed (21 1) that in the cyclic case, only four d orbitals are available for n bonding whereas five are available in acyclic phosphates. The remaining d orbital in the cyclic phosphate is thought to facilitate nucleophilic attack at phosphorus. As pointed out in Section VI, other calculations (213) have placed more emphasis on angle bending and bond eclipsing as the important factors governing the total strain energy in cyclic phosphate esters. These calculations revealed that the actual value of the strain energy, and the variation of this value with changes in the ring OPO angle, were sensitive to the values of the force constants and bond eclipsing constants. For an OPO angle of 90" in the transition state, the energy of the ring strain was of the order of 10 kcal/mole lower than for an OPO angle of 120".

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 53

It is probably true to say that both (a) ring strain as a result of angle bending and bond eclipsing, and (b) the concept of configurationally and conformationally monitored electronic charge distribution, play a part in determining the hydrolysis rates of phosphate esters. (b) embraces d-orbital participation and stabilization as a function of hybridization and the arrangement of groups about the phosphorus atom. Rehybridization is an important factor affecting reactivity and is apparent in the observed difficulty of quaternization of certain bicyclic phosphines (Sect. IV). An attempt has been made to elucidate the conformations of phosphines, phosphine oxides, phosphates, and phosphites in benzene solution using dipole moments, molar Kerr constants, and refractivities (214,215). Results indicated that the phenyl rings in triphenylphosphine oxide and sulfide are rotated (in the same sense) through angles of 60" and 62" from a theoretical model in which the phenyl planes are parallel to the molecular symmetry axis. In triphenylphosphine itself, the groups are rotated through 62". These results compare favorably with those obtained by X-ray analysis of solid triphenylphosphine (216). There is evidence that rotation around P-C and P-0-C linkages is rapid, even in compounds such as tert-butylphenylphosphinyl chloride (217,218). Rotational isomerism has been observed in the NMR spectra of organophosphorus compounds as a doubling of the resonances (218). This doubling has been found to be essentially temperature invariant and has been interpreted (218) in terms of a very low energy difference (AH = 0), but a high energy barrier between, the two isomers (if in fact the doubling is actually due to two discrete rotational isomers). Thus, the observed (219) PMR spectrum of 0,O-diethylmethylphosphonothioate was found to agree with a calculated spectrum based on two sets of nonequivalent methylenic protons (the nonequivalence of the methylenic protons is due to their diastereoisomeric environments. For other examples and discussions of nonequivalence see ref. 220). In this particular case of the diethyl ester, an explanation based on unequal P-O(R) bond orders was offered rather than preferred ethoxy group orientiations about P-O(R) single bonds. A similar effect would be produced by employing the antibonding electrons of only one oxygen atom in "back-donation" type resonance stabilization (219). In view of the results obtained for monoesters and for compounds such as ButP(0)(F)NMe2 the argument based on unequal bond orders seems invalid.

54

M. J. GALLAGHER AND I. D. JENKINS

A study of N,N-dimethyl-tert-butylphosphonamide fluoridate, Bu'P(O)(F)NMe, (221) gave some quite unusual results. NMR (31P, l0F, and lH) spectra indicate two, presumably rotational, isomers in an approximately 3 : I ratio at room temperature. At 300", the ratio is 1 : 1. One isomer gave two sets of doublets for the NMe, group but the other isomer showed essentially no P-H or F-H coupling. Thinlayer chromatography also showed two components in a 3 : 1 ratio. This is certainly remarkable, as one would not expect rotational isomers of this type to be separable by chromatography [although rotational isomers of 2,4,6-tri-tert-butylbenzoic acid amides have been isolated in this way (222)]. The doubling of the phosphoryl (and thiophosphoryl) bands in the infrared spectra of phosphates and phosphonates has also been attributed to rotational isomerism involving the P-0-R groups (223228). Thus, the P=O band for phosphonates of the type HP(O)(OR), is a doublet, the relative intensities of the components varying with solvent (223). The lower frequency band was less intense in the liquid and absent in the solid, but it reappeared again in the gaseous phase (226). Low temperature IR spectra of (MeO),PO, (MeO),PS, (MeO),P(S)Me, and MeOP(O)Cl, in the solid, liquid, and gas phases indicate the presence of rotational isomers in these compounds. Crystallization stops the rotation and results in elimination of one isomer (226). Isomerism as a result of rotation around P-C bonds has also been observed (229). Raman and IR spectra of chloromethyl phosphonic dichloride (liquid) confirm the presence of two isomers; I R ofthe crystal showed only one form. Experiments with solvents of different polarity showed that the symmetrical form was present in the crystal, but the unsymmetrical form prevailed in the liquid state. Dialkylphosphinic chlorides (except the dimethyl compound) have been shown (230) to exhibit two P-C1 absorption bands as a result of P-C rotational isomerism. Rotational isomerism has been given some theoretical treatment (231-233). For example, of the three likely conformations (Fig. 8) for the dimethylphosphate anion, calculations suggest that only the conformation with C, symmetry is involved in solutions or crystals of barium dimethylphosphate (23 1). Favored conformations of molecules can lead to important stereochemical consequences. Kenyon and Westheimer (234) have shown that

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 55 Me

Me

O \ 0.- / ‘P

o--+/

‘

0

‘\

‘ 0

0

/

0-Me

O \ O - - - p/

OcMe

0‘

Me

\o G

Ca,

\

Me

Figure 8

1,2-dibromo-1-phenylpropylphosphonicacids decompose stereospecifically in aqueous base to 1-bromo-1-propenylbenzene, bromide ion, and a phosphorus moiety which behaves as the hypothetical monomeric metaphosphate ion [eqs. (48) and (49)]. The erythro isomer 83 gives the cis olefin and the threo isomer 84 gives the trans olefin as expected for a trans-oriented elimination. Br

Br

Ph-C-

I

Ph

I

NaOH

\

I

HaO

/

\H

\

/H

C-CH3-

I

P03Hz H (83) Br H Ph-C-

I C-CHs I

I

I

Br

Br

Ph >-

/CH3

C=C

/c=c\ Br

+ Br- + H2P0,

(48)

+ Br- + HaPo;

(49)

CH3

(84)

Swan (235) has shown that this stereospecificity is pH dependent, as erythro- 1,2-dibromo-2-phenylethylphosphonicacid (85) decomposes at pH 7 to the cis olefin but at pH 3.4 a mixture of cis and trans isomers is obtained.

- 0 H ‘7’ \’ -O\ / Ph

I/?

c

Br

>=./

Ph Cd,,NH2+

H

Br +

EtOP03-

(50)

‘H

B< ‘H

(85)

Swan has interpreted this to mean that the acid, which is present as the dianion at pH 7, exerts a sufficient dipolar repulsion toward the 2-bromine to hold the molecule in the conformation shown (85), which

56

M. J. GALLAGHER AND I. D. JENKINS

is favorable for a trans elimination of bromide and metaphosphate ions [eq. (SO)]. At lower pH the acid is only monoionized and presumably the weakened dipolar repulsion allows the conformation of the molecule to be determined more by other factors. The solvent probably plays an important role in conjunction with pH, as it would be expected that dipolar repulsive forces would be more effective in nonpolar solvents. This pH-solvent determined stereospecificity has also been observed for the analogous carboxylic acids. Thus, erythro- 1,2-dibrom0-2-phenylpropionicacid decomposes stereospecifically in ethanol to the cis olefin but in the more acidic solvent water, a mixture of cis and trans isomers is obtained. E. Steric Effects Although it is very difficult to separate steric from electronic effects, steric hindrance does seem to be an important factor in the reactions of P(1V) compounds. It has even been suggested that phosphorylation of cholinesterase may be subject to steric hindrance so that steric control could prove valuable in modifying the reactivity of certain types of organophosphorus compounds of biological interest (236). Bulky groups attached directly to phosphorus markedly reduce the rates of hydrolysis of various P(IV) halides and esters (237-240). For example diisopropylphosphiny1 chloride is hydrolyzed in aqueous acetone nearly 700 times as slowly as dipropylphosphinylchloride (238). This, together with the fact that the diisopropyl compound exhibits a lower energy of activation than the dipropyl compound is probably indicative of steric hindrance (120). As might be expected the effect of bulky substituents on reactivity is, in general, much more marked in phosphinyl than in phosphonyl compounds. Thus isopropyl isopropylphosphonochloridate is only hydrolyzed about 25 times as slowly as propyl propylphosphonochloridate. In nucleophilic displacement reactions such as those just cited, care must be taken before declaring a particular effect a result of steric hindrance as it cannot be assumed a priori that the nucleophile will attack at phosphorus itself. Westheimer et al. have shown (241) that in the solvolysis of tetrabenzyl pyrophosphate, catalysis by imidazole or N-methylimidazole occurs by nucleophilic attack at phosphorus, but with pyridine as base, attack occurs at carbon (242). It is suggested (241) that the transition state for attack by imidazole at a phosphorus

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 57

atom is stabilized by d,-p, overlap and that the more available lone pair on imidazole, as compared with pyridine, favors attack of the former at phosphorus. Similarly, 2,6-lutidine increases the rate of hydrolysis of diethylphosphonochloridate [which reacts rapidly with less basic amines such as aniline (243)l. 2,6-Lutidine is too sterically hindered to attack the phosphorus atom (241,244) of either compound, but can abstract a proton from the nitrogen atom of the phosphorodiamidic chloride and hence accelerate hydrolysis via a metaphosphatetype intermediate (see Sect. IV). There have been many reports in the literature of sterically hindered organophosphorus compounds and many more proposals of steric interference in reactions involving P(IV) compounds. Only a few representative examples can be dealt with here; a number of others are listed under ref. 245. One of the early examples of a sterically hindered organophosphorus compound is “ Boyd’s chloride ” 86 formed from triphenylcarbinol and phosphorus trichloride (246,247). The structure originally assigned to the compound was 87 as alcohols normally form phosphites with phosphorus trichloride. 0

II

PhaC-PCIz

Ph3C-O-PCIz

(86)

(87)

Compound 86 is not attacked by boiling water or aqueous sodium hydroxide and can be recrystallized from ethanol with little loss. Alcoholic potassium hydroxide gives triphenylmethylphosphonicacid. Steric hindrance is also thought (248) to account for the sluggish reactivity toward nucleophiles of the somewhat similar phosphinic chloride 88. 0

II 1

Ph2C-P-CI

1

CI Ph (88)

In the synthesis of sterically hindered phosphorus compounds, it is almost impossible to attach more than two highly branched groups to the phosphorus atom. Thus highly branched Grignard reagents react with phosphorus trichloride to give only the disubstituted product, while the reaction of r-BuPOC1, with t-BuMgC1 is very sluggish (249).

M. J. GALLAGHER A N D I. D . JENKINS

58

Similarly, the phosphoroamidic dichloride 89 reacts with only one mole of Grignard reagent 90 to give the highly hindered acid chloride 91. This was reported (250) as being difficult to hydrolyze and, in fact, it was claimed that the partially hydrolyzed product 92 could be steam distilled out of aqueous hydroxide solution. A model of 92 indicates considerable steric crowding but it seems unlikely that this factor alone could account for essentially complete loss of acidity. In general, branched chain alkylphosphonic acids give a fairly linear Taft plot (251) although deviations are observed with phosphinic acids such as Bu:P(O)OH (249). Et2N-POCI2

+ Me2CH-CMe2-MgCI

d

(90)

(89)

I

MeaCH-CMe2-P(0)(C1)NEtz (91)

MezCH-CMe2-P(0)(NEtz)OH (92)

1. HCI/ROH/H.O, 23 hr 2. NaOH 3. Steam distil

+ MezCH-CMe2P(0)(OH)2 (93)

The proposed sterically inhibited acidity of acid 92 contrasts with the observed (252) sterically increased (or assisted) acidity of the methylene protons in the phosphonium salts 94 and 95. Both of these salts undergo trans-ylidation with triphenylphosphine methylene [eqs. (51) and (52)]. This is unexpected on the basis of inductive effects, and, in fact, triphenylphosphine methylene is less basic than the corresponding ethylidene, isopropylidene or isobutylidene. +

Ph3P-CH2-SiMe31(94)

Ph3$-CH2-CMe31(95)

+ Ph3P=CHz + Ph3P=CH2

-

t

-

+ Ph3P-CHSiMe3 Ph3$-eHCMe3

+ + Ph3PMeI(51)

+ Me3bMeI- (52)

It is suggested (252) that the methylene protons in 94 and 95 are subject to severe steric crowding and that this results in C-H bond elongation and hence increased acidity of these protons. Compounds in which both a chlorine and a hydrogen atom are attached to the one phosphorus atom are usually unstable and lose hydrogen chloride very readily. However, the phosphinic chloride 96

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 59

is extremely stable to both hydrolysis and oxidation (76). The corresponding phosphinic anhydride 97 is also very stable as opposed to the phenyl analog which decomposes facilely to tetraphenylcyclotetraphosphine, phenylphosphine, and phenylphosphonic acid simply on standing at room temperature (253).

I

OH-/Fe(CN),'- 80-100 iZ2hr

KM"O,,OH-1

HOOC t-Bu

H

r-Bu

H

(97)

t-Bu

(98)

Steric hindrance does appear to be the main factor here but inductive effects could play an important part. For example, the stability toward oxidizing agents of secondary phosphine oxides increases markedly with increasing methyl substitution in the ring (254): (2,4,6-Me3CsHz)zPH0is oxidized in 30 min by alkaline ferricyanide at 80-90" (2,3,5,6-Me4C,H),PH0 is oxidized in 2 hr by alkaline ferricyanide at 80-90" (,Me5C&PH0 is only 14% oxidized in 17 hr by alkaline ferricyanide at 80-90"

F. Neighboring Group Participation Relatively few cases of neighboring group participation in the reactions of phosphorus compounds have been reported in the literature. The following examples are intended merely to illustrate these effects.

M. J. GALLAGHER AND I. D. JENKINS

60

In the hydrolysis of 2-hydroxy-2,2-dimethylethylcyclohexyl phosphate 98, the rate of formation of the'cyclohexyl phosphate is nearly 40 times the rate of formation of the glycol phosphate. For the isomeric 2-hydroxy-1,l-dimethylethyl cyclohexyl phosphate, glycol phosphate formation exceeds cyclohexylphosphate formation by a factor of nearly 3. This is explained by a mechanism for the hydrolysis of 98 involving epoxide formation (255). A somewhat different mechanism was invoked (256) to account for the alkaline hydrolysis rates of alkyl diethylphosphinates 99-101. Hydrogen bonding of the neighboring hydroxyl group to the phosphoryl oxygen was proposed to account for the increased rate in 100. 0

0

II

EtaPOCH2-CH3 (99)

k(mo1e -%ec - l) 0.573 x lo-'

0

I1

EtzP-O-CHa-CHa-OH (100)

4.42 x 10-4

II

Et~P-O-CHa-CH2-OMe (101)

2.25 x 10-4

It seems equally likely that participation by the neighboring oxygen atom as in 98 is responsible for these rate differences. p-Nitrophenyl phenacyl methylphosphonate(102) is hydrolyzed about 9O00 times as fast as ethyl p-nitrophenyl methylphosphonate (103). It has been suggested that the neighboring carbonyl group could enhance the rate in several ways, one possible intermediate being 104 (257). This intermediate should be considered in the light of results obtained with phosphoramidates. Hamer (258) found that the phosphoramidate 105 did not undergo an intramolecular rearrangement to phosphoramidate 106, although it did react with 1-naphthylamine to form the

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 61

N-1-naphthyl phosphoramidate. This was explained on the basis of entering and leaving groups being unable to occupy apical positions in a trigonal bipyramidal intermediate 107 for the compound 105.

'CH,-NHPh 105)

\I/

N+

0--P

I i0-

I\ 1

N+

OR

/I\

(107)

It is worth mentioning here that in the apparently analogous system 108, a (presumably) intramolecular rearrangement does occur in the nitrogen to oxygen phosphoryl migration (259). H

I

H

I

R-C-C-COOH

I

OH

I

NH

A,HCI/HzO

H

1

H

I

R-C-C-COOH

I

I

I

VI. P(V) COMPOUNDS A. Structure and General Properties This is the first class of compounds for which there is no accumulation of data obtained with other elements on which one may rely to provide analogies and working hypotheses. Compounds of this type have long been known (e.g., PX5; X = halogen) but only recently have they become available in sufficient variety to allow consideration of the stereochemical consequences of an atom carrying five substituents.

62

M. J. GALLAGHER A N D I. D . JENKINS

A P(V) molecule must utilize at least one of its 3d orbitals in bonding, and which of these is considered to hybridize with the 3s3p3 orbitals normally used determines the geometry of the resulting structure. The possible structures are shown in the diagrams 109-111. The stereo-

chemical consequences of each structure will differ in some respects from those of the other two and clearly, before any useful interpretation of reaction pathway is possible, the geometry of the reacting species must be known. Unfortunately, knowledge is at a very early stage in this complex field. The various possibilities have been the subject of a great deal of theoretical speculation particularly with regard to bond lengths and bond energies. Which result is obtained appears to depend on what approximations are made and on the relative importance attached to the various parameters involved in the calculations. A clear summary of the current state of this mild controversy has been given by Hudson (120). The principal fact which seems to emerge is that there is little energy difference between the possible structures but that the trigonal bipyramid formed from three sp2 bonds and two pd bonds is slightly favored. Indeed, all structure determinations made to date support this, but since many of these refer to the crystalline state it does not follow that the same structure is preserved in the liquid or gaseous phase. A good example is Pel, whose structure varies with solvent (260) and phase. Some electron diffraction studies of the vapor of PCI, and PF5 have given the same picture but here it may not be wise to extrapolate from structures involving strongly electronegative substituents to others forming weaker bonds. The discussion which follows must therefore be seen as liable to considerable revision in the future. Nevertheless, a recent review by Muetterties and Schunn (discussing pentacoordination in general) summarizes the structural work on these compounds and shows that, for monomeric species at least, the trigonal bipyramid is the structure most commonly found (261). Hence, we will adopt this structure as a working hypothesis. At present, insufficient data are available to allow an accurate assessment of the effects of substituents on stability. In general P(V)

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 63

’15.

Y

y b

X b

“/j

b ah z

x b

Y x.

Y

Fig. 9. Diastereomeric (+) forms of Pabxyz.

compounds seem to be reactive species, but since a considerable variety of them is now known and they are relatively stable, it no longer seems reasonable to consider them as transition states. This applies only to neutral species; the situation when a positive or negative charge is present is less clear. In the absence of evidence to the contrary it will be assumed that such compounds have appreciable lifetimes and cannot be considered as transition states. Optically active compounds have been used extensively in chemistry as powerful probes for the study of reaction mechanisms but it does not seem likely that they will be similarly useful for P(V) compounds. A trigonal bipyramidal structure Pabxyz, carrying five different substituents, is capable of existing in ten diastereoisomeric racemic forms (Fig. 9) presenting a synthetic problem of awe-inspiring complexity. Even a compound of the type Paabbx would have three symmetrical and one racemic forms. The situation is simplified somewhat by incorporating pairs of substituents in rings, which restricts the positions such substituents can take up to apical-radial and radial-radial. One such ring reduces the number of possibilities to nine, but two, which is the maximum, of course, brings it down to a manageable two (if the rings are identical) or three if they are nonidentical (Fig. 10).

C

& p p

6

-

C C Fig. 10. Isomeric forms of P(V) compounds with two cyclic substituents.

64

M. J. GALLAGHER A N D I. D. JENKINS

Wittig and his school have studied the synthesis of P(V) compounds carrying cyclic substituents but have been unable to detect any evidence of isomerism (262). This failure probably resides in a unique feature of these structures first suggested by Berry (263) and elaborated by Gillespie (264) and others (265). Since, in the radial plane, the substituents are separated by an angle of 120°, vibrations in this plane are accompanied by little interaction until the angle between any two substituents approaches go", when repulsive forces between the substituents and the bonds begin to assert themselves. Hence, the formation of a structure of the type 112a from a trigonal bipyramid 112 requires relatively little energy. The return vibration to the trigonal bipyramid can now occur in either of the planes defined by xyz or aby. Such a process,termed pseudorotation, may result in interconversion of diastereoisomers (112 + 113) and, in fact, all ten diastereoisomers shown in Figure 9 may be so interconverted. The rate of interconversion, while dependent on steric and electronic factors, is normally very rapid. An additional important stereochemical consequence is that an optically active species may racemize without bond breaking, a process never observed for tetrahedral or octahedral molecules. Five successive pseudorotations are required (112 .+ 113 .+ 114 + 115 + 116 + enantio 112) in each of which the uninvolved substituent (pivot) is different.

The process is also possible for cyclic substituents provided that the structure of the ring can accommodate the angular variations involved. In this case it should be slower since the energy barriers to the necessary

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 65 CH2 R

CHa

CHa

‘CH2 (117)

(118)

vibrations will be considerably higher. If both rings were four membered, vibrations of this type should be impossible and hence isomerism should be observable, e.g., in a compound such as 117. The difficulties attendant on the synthesis of such a structure are, however, formidable, although the structure of a trigonal bipyramidal P(V) compound 118 containing a four-membered ring has been reported (266). The experimental evidence on which the above hypothesis of interconvertible isomers rests is due almost entirely to NMR studies. A trigonal bipyramidal molecule, PR5, should have two magnetic environments corresponding to apical and radial substitution. In consequence, if such a species is configurationally stable, two peaks should be observed for the group R and they should be in the ratio of 3: 2. Since PH5 has not been prepared and is believed too unstable to exist [though R4PH compounds are known (151,267)], much of this work has been done with P-F compounds; it has been reviewed by Schmutzler (268). Structures PF5, RPF4, and R3PF2show only single fluorine resonances a t room temperature in accord with the concept of a very rapid positional averaging process. Intermolecular exchange is unlikely since splitting of the laFsignal by 31Pis observed. On the other hand, some structures of the type R2PF3show two kinds of lSFresonance in a 1 : 2 ratio. In the case of the amino compound, Et2NPF4, nonidentity of fluorine atoms is observed at low temperature and the activation energy for interchange of fluorines in this molecule has been estimated at ca. 13 kcal/mole. This should be compared with the value of ca. 7 kcal/mole calculated for PF3C12and PF3Br2(269). Diamino compounds (R2N)2PF3 show two different leFenvironments at room temperature (270). It is difficult to see why only the structures R2PF3should show apical and radial fluorines and not, for example, RPF4, although significant differences are found even between apparently analogous R2PF3 compounds. Thus the cyclic compound 119 shows two lgFresonances

66

M. J. GALLAGHER AND I. D. JENKINS

(119)

(120)

only at low temperatures in contrast to 120 which shows no sign of coalescence of its 'OF spectrum even at 100". This behavior has been attributed to steric effects and will be discussed below. A recent spectral study of PH2F3and PHFl (306) has led to similar conclusions: a trigonal bipyramidal structure with radial hydrogen atoms and undergoing rapid positional exchange without bond breaking. In structures where the substituents are less strongly electronegative a similar situation is found. A considerable number of pentaoxyphosphoranes (121,122) have been prepared and examined by Ramirez (271). No evidence has been reported of any differentiation between the

R

0,

/o

0, o ,

RO/p\I OR OR

RO/p\I OR OR

(121)

(122)

OR groups and though no results of low-temperature studies have appeared, the X-ray study (272) of the phosphorane from triisopropyl phosphite and phenanthrenequinone has yielded structure 123. Penta-p-tolylphosphorane shows only a single methyl peak in its

(123)

NMR spectrum down to -60". Other cyclic phosphoranes with five P-C bonds show some evidence of apical-radial substituents dependent on the bulk of the attached groups (273). Thus phosphoranes of type 124 show sharp singlets for the methyl resonances when R = phenyl or 2-naphthyl, a diffuse band for R = 2-biphenylyl, and

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 67

CH3

CH, (124)

doublets when R = 1-naphthyl or 9-anthryl. This implies a mixture of isomers or, perhaps, a very much slower rate of exchange. None of the above evidence rigorously excludes tetragonal pyramidal structures, but no simplification occurs on invoking such a type. A compound, Pabxyz, of this geometry would have fifteen possible diastereoisomeric racemic forms. The exchange process formulated above can be thought of as proceeding via such structures, in which case, if their lifetimes were appreciable, the possibility of obtaining an optically active P(V) compound would become impossibly remote. It has been suggested by Hellwinkel (273) that the tetragonal pyramidal form has the character of a transition state but the energy difference is probably too small to allow such a sharp distinction. Despite the great difficulties of obtaining stereochemically pure P(V) compounds, Hellwinkel has recently (274b) succeeded in obtaining an optically active penta-aryl phosphorane. Reaction of the resolved octahedral anion 125 with acid results in the formation of a mixture of three phosphoranes, one of which 127 retains the asymmetry of the anion and has [a],,k 94 k 1". The P(V) compound 127 can of course undergo the isomerization discussed above, but because of the restriction imposed by the rings such a process does not result in inversion (Fig. 11). Racemization is possible when both rings in the product phosphorane are identical and in fact 126 and 128 were also isolated and shown to be inactive. The papers describing this elegant work (274) also provide a clear and detailed discussion of more aspects of P(V) and P(V1) stereochemistry than is possible here, and they are recommended to anyone with an interest in this problem. The above discussion of P(V) stereochemistry applies equally to

68

M. J. GALLAGHER AND I. D. JENKINS

other atoms having five substituents. All will belong to that class of structures called by Muetterties (275) “stereochemically nonrigid.” B. P o Structures as Reaction Intermediates

Despite the stereochemical complexity of the P(V) system and the unlikelihood of obtaining stable isomeric forms useful in mechanistic studies, a knowledge of such structures has become of increasing importance in recent years in order to understand the reaction pathways of many P(II1) and P(1V) compounds. The first proposal concerning P(V) structures as reaction intermediates was made by Ingold and co-workers (276,277) over thirty years ago to account for the formation of an alkane and a phosphine oxide by pyrolysis of phosphonium hydroxides [eq. (53)], R,P+OH-

--f

RnPO

+ RH

(53)

which contrasted sharply with the almost exclusive elimination of the

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 69

corresponding ammonium salts to give an amine, olefin, and water [es. (5411. +

R3NCHzCHzR OH- ---+ R3N

+ RCH=CHz + HzO

(54)

The saponification of phosphonium salts has been the subject of considerable study; the departing group is that which is most stable as an anion (276); the kinetics are third order (278,279) (except where the departing group is a very good one, e.g., p-nitrobenzyl, when the kinetics are second order (280); and the reaction proceeds with 100% inversion at phosphorus (36). On this basis, McEwen has proposed the following mechanism (4): R,P+

OH-

R4POH (130)

OH-

R4PO(131)

-

R3P0

+ R-

(55)

There are, however, some objections to this. The intermediates 130 and 131 should spontaneously racemize on the basis of the arguments presented above unless their lifetimes were extremely short and there is no good ground for supposing this, at least in the case of 130. This difficulty may be overcome by supposing that the intermediate is P(V1) and not P(V) since in this case racemization would not be expected (see Sect. VII). The phosphorus atom in R4P+ is highly electrophilic and certainly strongly solvated in aqueous solution and hence attack at such a solvated cation could lead directly to an octahedral intermediate such as 132. Alternatively, the second molecule of hydroxide required by the kinetics could attack 130 to give [R4P(OH),]- as has been suggested by Wittig (262) and McEwen (278). This reaction can have the same steric result but it seems less likely since there is no reason why the P(V) center in 130 should be strongly electrophilic.

(132)

This reaction, because of its importance, would seem to merit further study.

70

M. J. GALLAGHER AND I. D. JENKINS

Phosphonium salts also react with alkoxides to yield phosphine oxides. The reaction is much more sluggish and is probably complex (15 1,281). Significantly it results in nearly complete racemization. A symmetrical intermediate has been invoked to account for the racemization but this is unnecessary since an initially formed P(V) compound of appreciable lifetime could easily racemize prior to subsequent reaction. The Wittig reaction (Sect. V) also proceeds stereospecifically with retention of configuration at phosphorus. The proposed intermediate 133 has many of the characteristics of a P(V) structure, and the retention

R3p-r +

6-CHR (133)

of configuration is also compatible with this since the four-membered ring should effectively block the autoracemization process. Much of the current interest in transition states (or intermediates) of this type stems from the work of Westheimer and his school on the hydrolysis of ethylene phosphate and related structures. This hydrolysis attracted attention since the observed rates were some 106-108times as great as for the acyclic analogs such as dimethyl phosphate. The heat of hydrolysis of methyl ethylene phosphate (134) is 7-9 kcal/mole greater than its acyclic analog 135 indicating the presence of strain in

the cyclic ester (282). It seems reasonable that the acceleration in rate is due to relief of this strain in the transition state or intermediate, and Khorana et al. have shown that the rate of hydrolysis of the corresponding six-membered cyclic ester 136 is unexceptional (283). Acid hydrolysis of ethylene hydrogen phosphate proceeds very largely by P-0 cleavage and is accompanied by exchange of oxygen with the aqueous medium at about 207, of the rate of hydrolysis (284), supporting the strained ground-state hypothesis since it indicates that collapse of the intermediate in the exchange process is less favorable than hydrolysis. Alkaline hydrolysis likewise occurs at a much greater

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 71

rate but no exchange of oxygen with solvent occurs. Subsequently it was found (285) that the enhanced hydrolysis of methyl ethylene phosphate proceeded with both ring opening and loss of methanol under acid conditions, but with exclusive ring opening in the presence of alkali. Cyclic phosphonates behave similarly (286). Strong support for the strained five-membered ring hypothesis was advanced by Usher, Dennis, and Westheimer (21 3) by detailed calculations of bond angles in methyl ethylene phosphate, which agreed closely with the concurrent X-ray work of Steitz and Lipscomb (210). Both approaches showed a ring angle of 99" at phosphorus, and hence considerable angular distortion from the anticipated tetrahedral structure. From this the relief from strain in a trigonal bipyramidal intermediate with a ring angle at phosphorus of 90" was calculated to be 3-6 kcal/mole which is sufficient to account for the rate increase. An angle in the ring of 120"would, on the contrary, introduce strain into the intermediate relative to the ground state. A recent structure determination on a six-membered cyclic phosphate (137) has shown (287) that the ring angle at phosphorus is 105.5" confirming the unstrained nature of the ground state in such species. Finally, the X-ray analysis of a pentaoxyphosphorane by Hamilton, LaPlaca, and Ramirez (272) showed that, in the solid state, the five-membered ring did indeed occupy CH,Br

& -/o

(kP,O

I

Br (137)

a radial-apical position and the ring angle at phosphorus was 90".In view of these studies the assignment of the structure 138 to the intermediate of acid hydrolysis must now be considered compelling.

(1%)

(139)

(140)

Haake and Westheimer also considered the possibility of a tetragonal pyramidal structure and the stereochemical consequences of the

12

M. J. GALLAGHER A N D I. D. JENKINS

phosphorus atom being chiral. Since there is evidence that the intramolecular flipping previously discussed occurs also with cyclic substituents, it does not seem probable that useful information will be obtained from the latter. Similar rate accelerations were observed (288) with other fivemembered cyclic systems but not with esters of cyclic phosphinic acids (139). Also, the cyclic phosphonic diester 140 underwent hydrolysis with almost exclusive ring opening (289) whereas methyl ethylene phosphate, gave both ring retention and ring opening. To account for these facts Dennis and Westheimer modified the original theory to include two further points: (a) there is an energy barrier to the occupation of an apical position by a carbon atom, or conversely, electronegative substituents favor apical positions (this is in agreement with theoretical expectations and the proposed structures of the fluorophosphoranes) ; (b) in the transition state pseudorotation occurred analogous to the autoisomerization of P(V) compounds discussed in Section VI-A. These, together with the original suggestion that the departing group left from an apical position (284), provide a rationale for the apparent exceptions. A trigonal bipyramidal intermediate of the cyclic phosphinic acid must have an apical carbon atom and the energy required to place it there is sufficient to offset the release of strain achieved in such a transition state. Similarly, in the case of the cyclic phosphonate, in order for the methoxyl group to take up an apical position prior to its expulsion "pseudorotation " must occur which would once again force a carbon atom into an apical position. It should be pointed out however that in the latter case the methoxyl group could occupy the apical position in the initial transition state formed by attack of water on the protonated ester, since this depends on which face or edge of the tetrahedron is attacked by the water molecule (140-142).

(141)

(14)

(142)

The first of the two modifications put forward by Dennis and Westheimer had been previously proposed for P(V) structures on theoretical (290,291) and spectroscopic grounds (9,270,292). Since the 3s orbital of phosphorus is concentrated in the radial bonds these are

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 73

the preferred sites for binding of electropositive groups. Such reasoning is also used to account for the single leF environment observed for R3PF2though this may be an oversimplification. In this context, it has been suggested (269) that the relatively strainfree 119 very rapidly isomerizes and hence shows only one fluorine EPFS

c P F 3

(119)

(120)

environment in its NMR spectrum as compared with 120 which shows two fluorine environments even at 100". However, it is difficult to see why acyclic RzPFBalso show apical and radial fluorine environments since these also should be strain free. An unrelated example of a rate acceleration attributed to relief of strain in an intermediate has been reported. The heterocyclic bis-salts 144 and 145 are known (293,294) to be decomposed by an excess of alkali into the phosphine-phosphine oxide 143. When the salts are in excess, different products (146,147), are formed which, on subsequent reaction with an excess of alkali, do not yield 143. The rate of this reaction is substantially greater than for acyclic monophosphonium salts. This is unexpected since the intermediate (either trigonal bipyramidal or octahedral) should be strained as a result of the angular distortion introduced into the ring. In this case it is suggested that relief of the strain arising from electrostatic repulsion between the two phosphonium centers is sufficient to overcome this. That the intermediate once formed is strained is shown by the preferential

14

M. J. GALLAGHER AND I. D. JENKINS

opening of the ring in the product, instead of the expected expulsion of a phenyl group (295). In sharp contrast to these results Aksnes and Berges have observed (296) that alkaline hydrolysis of the cyclic monophosphonium salts 148 proceeds with ring retention and expulsion of the phenyl group. The rate for the five-membered ring was 1300 times that for the six-membered one and the reaction obeyed third-order kinetics. Analysis of the data, however, showed that the difference occurred in the frequency factor and not in the activation energy as might be expected by analogy with Westheimer’s work on the cyclic phosphates.

(148)

A number of other reactions are known which very probably involve P(V) intermediates. Some of these have already been mentioned, e.g., the action of halogens or bromocyanogen with optically active P(II1) compounds (Sect. IV). The racemic phosphines obtained by reduction of P(IV) structures with lithium aluminum hydride suggests a P(V) complex such as 149.

‘\.PI -RB Ra ‘I AlH; Ri

H

(149)

In the case of phosphonium salts, racemization may occur in an initially formed RIPH compound which has been isolated in one instance (150). Optically active phosphine oxides are racemized by HBr or HC1 (140,141) in the presence or absence of water. It is interesting to note that HCl is more effective than HBr, suggesting that the more electronegative chlorine forms a more stable P(V) compound. Similarly, such oxides are rapidly racemized by acid anhydrides (141). Denney has reported that when (+)PhMePrP reacts with chloral and the product is hydrolyzed, racemic PhMePrPO is obtained, and he has attributed this behavior to a P(V) intermediate (297).

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 75

Unfortunately, too few precise data are available in this complex field, particularly as regards the stability of these P(V) structures. It cannot be doubted that neutral P(V) compounds are relatively stable, and if, as seems probable, positively charged P(V) compounds can exist for long enough to undergo pseudorotation or autoisomerization, then it would seem unwise to consider these as true transition states. On the other hand, P(V) species carrying a negative charge would seem to be much less stable. Thus alkaline hydrolysis of ethylene phosphate, though very rapid, proceeds without exchange of oxygen with the aqueous medium. Optically active phosphine oxides are not racemized by boiling aqueous alkali and many P(1V) compounds react with alkali without racemization. All this suggests that intermediates such as 150 are extremely short lived and should perhaps be considered as

(150)

true transition states. This extreme instability may lie in the fact that the occupation of an apical position by 0 - is energetically highly unfavorable, a not unreasonable supposition in the light of current concepts, some of which have been previously mentioned. If such species are truly transition states then the reaction of resolved P(1V) compounds with nucleophiles to give asymmetric products is not at variance with the trigonal bipyramidal intermediates suggested for such reactions (3). Aryl amines displace alkyl amines from P(IV) compounds [eq. (56)]. ArNHz

/OH /OH + AlkNHP=O + ArNHP=O ‘OR

(56)

‘OR

However suitably constructed molecules such as PhNHCH2CH2NHP(O)(OR)OH (105) give no evidence of intramolecular reaction though they should favor it. On this basis Hamer (258) has suggested that in the transition state both entering and leaving groups should be apical, this being the only simple requirement which forbids intramolecular reaction in 105. This

76

M. J. GALLAGHER AND I. D. JENKINS

is not in agreement with Westheimer’s views on the acid-catalyzed hydrolysis, but it is doubtful if the comparison can be carried too far since one reaction is done under acidic and the other under basic conditions, and this may well have a profound effect on the stability of the intermediate species. The intermolecular reaction proceeds probably by inversion and hence possibly by a transition state rather than an intermediate, and this is not necessarily the case in acid-catalyzed reactions.

VII. P(V1) COMPOUNDS Compounds of this type have been known for a considerable time, e.g., PF; . According to the Gillespie-Nyholm theory they should have octahedral geometry and this is true within experimental error for PF; (298). The complex anion 151 obtained by Hellwinkel (299) by the action of 2,2’-dilithiobiphenyl on phosphorus pentachloride has been resolved into enantiomers, strongly supporting an octahedral structure. Hellwinkel has also resolved a number of other such anions (274). The anion 152 formed by the disproportionation reaction shown in eq. (57) has a lDFspectrum compatible with this structure (300).

(151) 2MePF3NMe2 ---f [MePF(NMe2)2] [MePFJ+

(57)

(152)

Brown and Bladon (301) have obtained the only neutral P(V1) compounds known (153) by the action of PF6 on /3-diketones. Spectral data support the octahedral structure here also. Apart from this handful of substances, little is known about the chemistry or stereochemistry of P(V1). Gillespie has pointed out (264)

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 77

that octahedral structures should be stereochemically rigid since all the angles at the central atom are 90"and any appreciable distortion would be energetically expensive. This is confirmed (274d) by the stability of the anion 151. The stereospecific cleavage of these anions by acid has been mentioned in Section VI-A. P(V1) structures as intermediates or transition states have received little attention. It would be expected that the bulk of substituents should exert important steric effects when so large a number of ligands is attached to the central atom. This is borne out by the studies of Muetterties et al., on the adducts of PF5 with ethers (302). With diethyl ether an unstable adduct is formed but with the less-hindered tetrahydrofuran a distillable product is obtained. This should be compared with the minor steric effect observed in the saponification of phosphonium salts where a P(V) intermediate is believed to be involved (303). It seems likely that P(V) compounds in general will possess some Lewis acid character since PF, is quite a strong electron acceptor. By far the largest group of P(V) compounds known are the pentaoxyphosphoranes (such as 121 and 122) studied in detail by Ramirez (271). P(V1) structures should be important in the reactions of these compounds since the presence of five electronegative substituents should confer considerable Lewis acid character on the phosphorus atom and make it the preferred site of nucleophilic attack. The systematic chemistry of these compounds is in its infancy but two reactions have been examined in some detail (Fig. 12). The reaction with water is puzzling since ring retention is unexpected (see Sect. VI-B) and implies a considerable driving force which results in collapse of the intermediate or transition state to the thermodynamically less stable (compared with the ring-opened product) cyclic ester. If the reaction is sterically directed it is difficult to account for on the basis of an octahedral geometry in the intermediate. Alternatively, it is difficult to see why attack at oxygen or carbon should occur, and use of 180-labeled water results in a P=l80 ester, supporting attack at phosphorus by the water (271).

18

M. J. GALLAGHER AND I. D. JENKINS

The reaction of carbonyl compounds with the oxyphosphoranes

121 to afford saturated oxyphosphoranes has been suggested (304) to proceed as shown. A transition state (or intermediate) such as 154

Rl R2 R l C O W R ,

/o

P

\

(OR),

formed by initial coordination of the carbonyl oxygen with phosphorus would seem to be particularly favorable for such an electron shift. Nucleophilic ligand exchange by Ar,P [eq. (SS)] has also been observed (305). Ar6P

+ Ar'Li

-----, Ar,MP

+ ArLi

(58)

This reaction presumably proceeds via a P(V1) intermediate. It is considerably more sluggish than the reactions of the oxyphosphoranes, probably reflecting the lowered Lewis acid character of the phosphorus in this class of compound.

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 79

VIII. ADDENDUM ADDED IN PROOF This brief section has been written in order to incorporate the more important papers which have appeared in the first ten months of 1967.

A. General Horner has published an extensive review covering his work on optically active derivatives of the Group V elements (308) and Michalski has reviewed the work of the Polish school on optically active P(1V) compounds (309). The synthesis of olefins using phosphoryl activated reagents has also been reviewed (3 10). Muetterties has discussed relative stability toward intramolecular racemization in pentacoordinate species in general (31 1). The influence of d-orbital participation on structure and stereochemistry in phosphorus compounds-particularly on the transition state for SN2 displacement at P(1V)-has been considered (312). Methods of resolution have been reviewed (313). I. Spectroscopic Methods

Further work has been reported on the angular dependencies of various 31P-1H coupling constants, and these should prove invaluable in stereochemical assignments. Table VIII summarizes these values and

TABLE VIII Angular Dependence of 31P-1H Coupling Type P(II1)-0-C-H P(II1)-0-C-H P(IV)-0-C-H P( 1V)-0-C-H P(I V)-0-C-H P(IV)-0-C-H P( 1V)-C-C-H P(IV)-C-C-H P(IV)-C-C-H P(IV)-C-C-H

Approximate angle, degrees 30 180 60 60 180 180 30 60 90 180

J, CPS

Ref.

2.8 10.8 3 6.2 21 22.4

314 314 315 316 315 316 194 194 194 194

7 12 0 35

80

M. J. GALLAGHER AND I. D. JENKINS

for convenience, incorporates the values already recorded in Section V-C-2. The marked dependence of J on the dihedral angle supports the proposals of Ramirez that conformational changes accompany stereomutation in the cyclic phosphate ester 69 discussed in Section V-C-I. Gagnaire et al. (317) have observed two different 3JpHcouplings (9-9.6 and 1.2-1.8 cps) in monosubstituted 1,3,2-dioxaphospholans of type 155 which they attribute to different orientations of the protons with respect to the lone pair of electrons on phosphorus. RCH-0

IF

RCH-O

(155)

A similar reason is advanced for the AABBX-type spectrum observed (318) in the phospholan 156. Here the aJP(III)H couplings (25 and 6 cps) differ both in magnitude and sign and lead to the suggestion that the low values observed in acyclic systems may be time-averaged values arising from rapid rotation about the P-C bond. This suggestion contrasts sharply with the interpretation that steric compression increases the s character of the C-P bond (17).

H3cvcH I

Ph (156)

B. P(1II) Compounds The crowded tri-t-butylphosphine has been c-tained by Hoffmann and Schellenbeck (319) by the action of BdLi on BubPC1. The direct action of ButMgCl with PC13 leads to reduction as well as substitution. BdMgC1

+ PCla

4

BuP~CI+ B u~PH

The hindered tertiary phosphine reacts normally with methyl iodide and with sulfur, but fails to give a colored adduct with carbon disulfide, a reaction normally characteristic of trialkylphosphines. Stepwise replacement of ethoxy groups in P(OEt)3 with bulky alkoxy groups (e.g., But) produces a steady increase in the chemical shift of the phosphorus atom for the first two such replacetnents.

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 81

Introduction of the third such group, however, results in a large (10 ppm) negative shift. Mark and Van Wazer (320)have interpreted this as a sterically induced alteration in bond polarity and degree of 7r bonding. The calculated angular variation in each bond is ca. 0.25". No such effect occurs with P(IV) compounds. A new method, particularly suited for the resolution of triarylphosphines, has been developed by Wittig et al. (321).This incorporates the method of half quantities of Pope and Gibson (322) and involves partial conversion of the chiral phosphine to its hydroxymethyl salt by reaction with formaldehyde and an optically active acid such as camphorsulfonic. The phosphine is regenerated by treatment of the salt with triethylamine. 2Ar,P+ CHzO

1

+ HA* d A r 3 k H z 0 H A* + (-)Ar,P EhN

(

The optical purity of the products is uncertain, but the magnitude of the rotations (+ 8.7 and - 5.2)compares favorably with that of the previously reported triarylphosphine ( +2.9) prepared by cathodic fission (47). The method fails with alkyl- or aralkylphosphines. Shook and Quinn have reported full details of their work on 1,4-disubstituted4-phosphorinanols, including tentative assignments of stereochemistry based on differences in proton chemical shift values (323). The 31P spectrum of 1,4-dimethy1-4-phosphorinanol shows two peaks separated by 5.7 ppm; no interconversion of isomers is observed on heating. From a discussion of bond angles and interactions, a chair form for rhe ring is considered most likely. Tertiary acetylenic alcohols react readily with diphenylphosphinous chloride to give allenic phosphine oxides. A cyclic six-center transition state 157 has been proposed, and this is supported (324)by conversion of R( +)-phenylpropynol to an optically active product.

(157)

Stereospecificity in the reaction is also supported by a proton NMR study (325).

82

M. J. GALLAGHER AND I. D. JENKINS

C. P(1V) Compounds

A valuable new route to resolved phosphine oxides has been described by Korpiun and Mislow (326). Phosphinic esters of optically active menthol are readily separated into diastereoisomers whose isomeric purity can be very conveniently checked by proton NMR. Reaction of the esters with Grignard reagents occurs stereospecifically to yield enantiomeric phosphine oxides in good yield and high optical purity. The Grignard reaction is believed to proceed with inversion since the chirality of one of the esters has been determined by X-ray diffraction and that of the oxide by correlation. This assignment is almost certainly correct; however, an absolute proof requires an X-ray structural determination on a known optically active phosphine oxide. This is very desirable as it would establish beyond doubt many correlations and proposed stereochemical pathways.

S

II

Ph-P-0-P-Ph I

NEt,

i I

NEt2

-t 109" 1 0 . -

i 'PN

> Ph-P-Nd

I

NEt,

NEt,

+ 7.9"

T NEt,

- 9.3"

NEt, Figure 13

4-71.5"

-

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 83

A careful study of the proton NMR spectra of diastereoisomeric menthyl phosphinates shows significant differences and allows assignment of chirality at phosphorus; similarly the ORD curves of the separated menthyl methylphenylphosphinates show enantiomeric positive and negative Cotton effects corresponding to R and S configurations at phosphorus, respectively (327). The salt 158 has been resolved as its camphorsulfonate (328). The dimethylimidazolium group is readily replaced by nucleophiles. The reaction with the anion from 2-methylimidazole proceeds with 100% inversion at phosphorus and the action of alkali yields an optically active P-0-P compound. These transformations are shown in Figure 13. Hydrolysis of ethyl ethylphosphonothiochloridate with water in dimethylformamide proceeds with inversion as in the case of alkaline hydrolysis. The stereospecificity is much reduced and this is believed to be due to the hydrogen chloride formed. In the presence of aqueous imidazole or pyridine almost complete racemization occurs (329). a-Phenylethylamine is reported to be a very convenient resolving agent for derivatives of phosphonothioic acids (330). Wadsworth (33 1) has presented a simple proof that nucleophilic attack on cyclic phosphates proceeds with inversion (159-162). The CH,CI

CH,CI

CH,CI

84

M. J. GALLAGHER AND I. D. JENKINS

X-ray structure determination (332) of the cyclic phosphate 1-0x0-Iphenoxy-1,3,2-dioxaphosphorinanshows the molecule to be a somewhat flattened chair with the phosphoryl grouping equatorial. This distortion of the ring by phosphorus may be general since the previous study of a cyclic six-membered phosphate (287) also shows this feature. The effect is to lessen the distinction between axial and equatorial substituents at phosphorus. It should be compared with the considerable flattening observed in five-membered cyclic phosphates (210,211) which should also minimize confornational differences. It is interesting to note that the preferred orientation of the phosphoryl group is equatorial in both examples studied so far. Bartle, Edmundson, and Jones (316) have studied the NMR spectra of a considerable number of 1,3,2-dioxaphosphorinanderivatives and conclude on the basis of the chemical shift difference between axial and equatorial protons that the chair form is most likely. A detailed study of the factors influencing product stereochemistry in Wittig reactions has appeared (333). The Russian authors have examined the effect of varying solvent, substrate, ylid, time of reaction, and reactant ratio, as well as the influence of ions, on the steric course of the reaction and indicated the preferred conditions for obtaining a cis or trans olefin. The great variation in behavior between the unstabilized and semistabilized ylids, however, indicates that much more information must be acquired before any general guides to product stereochemistry in the Wittig reaction can be formulated. The bisWittig reagent 163, on the other hand, reacts nonstereospecificallyunder a wide range of conditions (334).

(163)

Benezra and Ourisson have studied the addition of the dimethyl phosphite anion to cholestan-3-one to give the a-hydroxyphosphonate (335). They conclude that the phosphonate group is equatorial on thermodynamic grounds since the reaction is reversible. Other ketosteroids react similarly, but no addition occurs when the keto group is in the 11, 17, or 20 position on the steroid nucleus. The contribution of the substituent (MeO),P(O) to the chemical shift of the C-19 methyl group is calculated to be zero in the a orientation and -2 cps in the 8.

STEREOCHEMICAL ASPECTS OF PHOSPHORUS CHEMISTRY 85

A number of transformations of the hydroxy-phosphonates are described. The reaction of dimethyl phosphonate with monocylic ketones has also been studied (336). trans-Ethene- 1 ,Zdiphosphonic acid has been synthesized (337) and its Diels-Alder reactions have been studied. The Arbuzov reaction between triethyl phosphite and /3-chlorocrotonic and -isocrotonic esters affords the corresponding trans and cis phosphonates (338). Geometrical isomers of 1,2,2-dioxaphosphorinans have been separated and tentative assignments made on the basis of the modified Auwers-Skita rule (339).

D. P(V) Compounds Low temperature (- 76") NMR spectra of 164 show the presence of one apical and two radial methoxyl substituents. No separation is observed in a pentaoxyphosphorane even at - IOO", thus substantiating Westheimer's arguments concerning the preferred radial orientation of the carbon substituent in such structures (340).

o&cocH3 CHP.. \ CH30

;rCHPh OCH3

(164)

Though five-membered cyclic phosphinic acids normally show no great acceleration of their rates of hydrolysis, presumably for the reasons discussed in Section VI, they may be compelled to do so if the relief of strain in going to a trigonal-bipyramidal transition state is great enough. Westheimer's group has observed this in the highly strained tricyclic structures 165 and 166. The hydrolysis of one of the ester groups (believed to be P*) is some lo5 times as great as that for analogous monocyclic systems (341). The X-ray structure determination of l-methyl-l-phenylphospholanium iodide shows a ring angle at phosphorus of 94.8" (340). Since a P(V) intermediate is believed to be involved in the hydrolysis of phosphonium salts, relief of steric strain in such an intermediate may also explain the enhanced rate of hydrolysis of these compounds

86

M. J. GALLAGHER AND I. D. JENKINS

(296). This enhanced rate is also observed with p-nitrobenzylphosphonium salts when the observed kinetics are second order rather than third (343). It seems reasonable that both reactions (i.e., with secondor third-order kinetics) proceed via a similar intermediate.

Acknowledgments The authors are indebted to many workers in. this field who informed them of work in progress at the time this review was written. I. D. Jenkins acknowledges financial support by the C.S.I.R.O. in the award of a Postgraduate Scholarship.

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Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

The Study of Intramolecular Rate Processes by Dynamic Nuclear Magnetic Resonance GERHARD BINSCH Department of Chemistry and the Radiation Laboratory* University of Notre Dame. Notre Dame. Indiana

I . Introduction . . . . . . . . . . . II . Scope . . . . . . . . . . . . . 111 Theory . . . . . . . . . . . . . A . Line-Shape Theories . . . . . . . 1 . Classical Line-Shape Theory . . . . 2. Quantum-Mechanical Line-Shape Theory B . Transient Techniques . . . . . . . C . Multiple Resonance Method . . . . . I V . Processing of the Data . . . . . . . . A . Experimental Procedures . . . . . . B. Determination of Rate Constants . . . . C . Calculation of Activation Parameters . . . D . Sources of Errors . . . . . . . . V Hindered Rotation . . . . . . . . . A . Substituted Ethanes . . . . . . . . B . Sterically Crowded Bonds . . . . . . C Amides. Thioamides. and Carbamates . D . Nitrosamines and Nitrites . . . . . . E . Aldehydes and Ketones . . . . . . F. Miscellaneous Hindered Rotations . . . VI . Inversion of Lone Electron Pairs . . . . . A . Open-Chain Derivatives of Ammonia . . . B. Cyclic Derivatives of Ammonia . . . . C . Derivatives of Imines . . . . . . . D Other Elements . . . . . . . . .

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VII. Ring Inversions . . . . . . . . . . . . . A. Cyclohexanes and Cyclohexenes . . . . . . . B. Six-Membered Heterocycles . . . . . . . . C. Seven-Membered Rings . . . . . . . . . D. Eight-Membered Rings . . . . . . . . . . E. Miscellaneous Ring Systems . . . . . . . . VIII. Valence Isomerizations and Intramolecular Rearrangements IX. Conclusion. . . . . . . . . . . . . . . X. Appendix . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .

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I. INTRODUCTION In the past two decades high-resolution nuclear magnetic resonance (NMR) has developed from an ancillary technique of the nuclear physicist into one of the chemist’s most valuable tools for probing the structure and stereochemistry of molecules. The positions of the resonance signals and their fine structure give detailed information about the bonding situation of magnetic nuclei and their spatial relationships. Since the energetics of pure spin problems can be treated exactly by quantum theory, NMR spectra can be fully analyzed in terms of resonance frequencies and intensities. The final aim is to obtain a set of parameters: the chemical shifts 6, and coupling constants Jlj. These parameters completely determine the energy levels of the nuclear spins in the external magnetic field H,, and therefore comprise the static information that can be extracted from an NMR experiment. In this review we will assume that the reader is familiar, at least in principle, with these static aspects of nuclear magnetic resonance. In addition to chemical shifts and coupling constants, NMR spectra are a function of certain time-dependent phenomena. There is, of course, the trivial case where a compound undergoes an irreversible chemical reaction while its NMR spectrum is being observed. By measuring the gradual disappearance of certain lines of the reactants and the appearance of the product spectra as a function of time, one may be able to calculate the rate constant for such a reaction. We shall not be concerned with this straightforward, though very useful, application of NMR; rather we shall be interested in those rate processes that occur in systems that already have reached a state of thermodynamic equilibrium, where, in other words, no net macroscopic change can be detected. If these processes are characterized by rate constants of a similar order of

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magnitude as the total spread (in cycles per second) of the NMR spectra of a certain magnetic isotope (typically 10-1 to lo5 sec-l), they may cause profound changes of the shape of NMR signals. It is common practice to speak of a characteristic “ NMR time scale,” inversely related to these rate constants. If the average lifetimes of a number of species in equilibrium exceed an upper limit, the NMR spectrum will show them as individual entities. Conversely, if the lifetimes are short with respect to the NMR time scale, one will obtain a single spectrum, in which the chemical shifts and, for intramolecular processes, also the coupling constants are statistically weighted averages of the corresponding values in the exchanging species, a feature which is especially valuable for conformational analysis. The characteristic phenomena that can be observed during the transition from one to the other extreme and their analysis constitute the realm of the method that we have chosen to call “dynamic nuclear magnetic resonance” (DNM R) . Following a number of early studies in the late 19503, DNMR has experienced a great upsurge of activity. The theory of this method has been refined, new experimental techniques have become available, and an ever-increasing number of publications deal with applications of DNMR, especially to problems in organic chemistry. The barrier heights of dynamic processes amenable to this technique conveniently extend just from the borderline (20-25 kcal/mole), where compounds become too unstable to be isolated chemically, down to activation energies of about 5-6 kcal/mole, below which another powerful tool, microwave spectroscopy, can be applied. Many rate processes of fundamental importance in chemistry happen to fall into this formerly almost inaccessible gap between the realm of rotational spectra and conventional kinetic techniques. Rate processes involving reversible intermolecular proton transfer, rotations around sterically crowded single bonds and single bonds with partial double character, inversion of lone electron pairs on nitrogen and phosphorus, inversion of carbocyclic and heterocyclic rings, and degenerate valence isomerizations and intramolecular rearrangements are among the more common examples. Many important qualitative conclusions can be drawn from the characteristic changes in the NMR spectra brought about by the variation of pH, magnetic field, or temperature. DNMR even led to the discovery of a new class of compounds, molecules with fluxional structures, of which bullvalene is perhaps the most striking example.

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II. SCOPE Basic information about the theory and applications of dynamic nuclear magnetic resonance can be found in practically every standard textbook on NMR (e.g., refs. I and 2). A number of review articles, covering more or less the whole area (3-5) or various aspects of it (6-8), have also been published. For the present review the literature was searched up to the end of 1966. It is hoped that not too many important contributions have been overlooked. References to papers appearingearly in 1967 have been included as they came to the attention of the author. Although the theory applies, with little modification, to intermolecular as well as intramolecular rate processes, only the latter will be discussed. Readers interested in the former will find a detailed account of such applications in the review by Loewenstein and Connor (3). As mentioned in the Introduction, characteristic changes in an NMR spectrum on variation of a parameter (in most cases the temperature) indicate the presence and nature of a rate process with an activation energy between 5 and 25 kcal/mole. The value of such qualitative information is undisputed. In principle, however, dynamic nuclear magnetic resonance is also capable of yielding quantitative data about rate constants and activation parameters. On the surface it would appear that such data are quite easily obtained. Without carrying out a detailed investigation, many workers have therefore been tempted to report values along with rather optimistic error limits. Unfortunately, this quantitative aspect of DNMR is fraught with difficultiesand pitfalls. Judging from the interesting case histories of the cyclohexane ring inversion and the hindered internal rotation in amides, it now appears that the vast majority of reported values may not stand up to careful scrutiny. It has been argued that accurate values are really not sufficiently interesting to warrant all the trouble of obtaining them. Whereas this may have been true some years back, we do not believe it to be a valid argument any more. In view of the present activity in this field, more and more numbers about related systems are becoming available. If there is to be any purpose in obtaining all these data, one eventually must be able to compare them and draw conclusions from such a comparison. With the quantitative unreliability of a rapidly accumulating body of data this is becoming an increasingly frustrating exercise. To explain the philosophy that was adopted in writing this review, it may suffice at this point to indicate the two main origins of difficulties

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in DNMR. One is inherent in the method itself and is related to the fact that dynamic parameters are much more susceptible to spurious effects, such as field inhomogeneities or saturation, than are line positions and intensities. The other one is due to the inadequate theoretical treatment of the experimental data. Although complete theories have been available for some time for all practically important cases, the use of approximate formulas of dubious validity is still very common. It was decided at the outset to make full treatment based on appropriate theory a prerequisite for considering a reported value as reliable. This may well turn out to be unfair to some investigators for whose results a detailed analysis might show that the approximations have not introduced a significant error. However, in the absence of such an analysis and in view of the rather desolate general situation, it was felt that there was no other choice. No attempt will be made to give a complete review of the theoretical work pertinent to DNMR. Interested readers are referred to the articles by Loewenstein and Connor (3) and by Johnson (8) for details and references. Only those theories that, in the author’s opinion, have proved to be of practical use are outlined in some detail. The formulas suitable for direct programming are given [eqs. (15), (19), (31), and (33)]. With the availability of modern computers the full treatment is just as easy to apply as the approximate formulas. For this reason, we will spend little effort or space to discuss approximations.

III. THEORY A. Line-Shape Theories The majority of dynamic studies by nuclear magnetic resonance have employed the line-shape method. Since the necessary measurements can easily be performed with standard NMR equipment, the line-shape method will probably remain the most important technique of DNMR. We will therefore discuss the underlying theory in somewhat greater detail. 1. Classical Line-Shape Theory It is a well-known fact that the spin of elementary particles does not have a classical analog and that the existence of discrete spin states in a magnetic field can only be explained by quantum theory. Nevertheless,

G . BINSCH

102

one finds that the resonance condition of a bare nucleus,

(Y/2n)Ho (1) relating the resonance frequency yo to the external magnetic field Ho and the gyromagnetic ratio y , does not contain Planck's constant h. This observation suggests (9) that it might be feasible to describe the resonance phenomenon itself by a classical picture. This view has indeed been adopted by Bloch in a celebrated paper (10). yo

=

a. The Bloch Equations. Bloch considers a nucleus with spin 111 = (h/27r)dZ(Z 1) and magnetic moment p = 71as a tiny gyroscope.

+

The forces it experiences in an external constant magnetic field in the z direction, H = (0,0, Ho},cause it to move in such a way that the rate of change is given by the torque with components

* dt

=

y [ p x HI

dpz - - y b x H l l - plyHx]= 0

dt Eqs. (3) immediately tell us that the nuclear dipole p precesses about the z axis with an angular frequency wo = yHo in a clockwise fashion (assuming y > 0), that is the vector wo points in the negative z direction (Fig. 1). This angular frequency, wo, is called the Larmor frequency and is related to the resonance frequency of eq. (1) by wo = 27rv0. In a sample containing a large number of identical nuclear dipoles, all will precess with wo, but their phases will be randomly distributed over a cone about z (Fig. 1). The resultant macroscopic magnetization will therefore only have a component in the z direction, M o = (0,0, Mo}. If we now disturb the system by a second magnetic field rotating in the xy plane with an angular frequency w in the neighborhood of wo and in the same sense as the precessional motion of the nuclei, H1= { H l cos wt, - H I sin wt, 0}, the x and y components of M will become different from zero. The quantitative description is again d-M(4) dt - Y[M x HI

RATE PROCESSES

103

Fig. 1. Classical precessional motion of nuclear magnetic dipoles in a magnetic field.

with H = { H , cos wl, - H , sin wt, Ho}. Instead of giving the components of eq. (4) in the coordinate system of Figure I , it is advantageous to refer them to a set of axes rotating clockwise about z with angular frequency W. In this rotating frame H1 is stationary, causing the time dependence of the right-hand side of eq. (4) to disappear. With H, coinciding with the rotating x axis, the components become*

%

=

(Wo

-

w)My

*In Bloch’s paper (10) and in most subsequent papers that made use of Bloch’s equations, all signs on the right-hand sides of eqs. ( 5 ) are reversed. This discrepancy is without consequences for the calculation of line shapes, since it only causes a phase shift by n.

G. BINSCH

104

NMR spectrometers are built in such a way that one can detect changes in the macroscopic magnetization in the xy plane, either by a receiver coil mounted perp.endicular to the transmitter coil or by an unbalance in the transmitter circuit itself. Eq. (5c) shows that the y magnetization is responsible for a change in M , and thus in the net nuclear Zeeman energy of the system. The out-of-phase component M y therefore corresponds to the absorption mode and M , describes the dispersion. Both effects can be expressed in a single equation if one defines the complex xy magnetization G by G = M,

+ iM,

(6)

so that eqs. (5a) and (5b) can be combined to read

dG - -- - i(wo - w)G dt

+ iyH,M,

The description of eqs. (5) is still incomplete, since it only takes cognizance of Ho and H, and ignores all other factors that might influence M. The combined action of such factors is referred to as relaxation. Bloch assumes that, whenever the system is perturbed, there will be mechanisms by which M can eventually return to its equilibrium value Mo = (0,0, Mo) by a first-order rate process. The complete Bloch equations then take the form

dG - -- -i(wo - w ) G dt dMz =

dt

+ i y H I M , - -G1 T2

(74

1 - y H I M , - T,(M, - Mo)

The longitudinal relaxation time TI is inversely related to the average first-order rate constant of the processes by which the spins can exchange their nuclear Zeeman energy with other degrees of freedom of a thermal bath or “lattice.” The transverse relaxation time T2 characterizes the rate by which G returns to its equilibrium value of zero. Obviously such a process does not involve exchange of energy with a bath, since it can be accomplished simply by a dephasing of the individual nuclear spins in the xy plane. Consequently, Tamay aptly be called the “ phase-memory time.”

b. Exchange between Two Sites. All classical line-shape theories may be based on suitably modified Bloch equations. We shall illustrate the

STUDY OF INTRAMOLECULAR RATE PROCESSES

105

principles by first treating the simplest possible case, the reversible exchange of a single uncoupled proton between two chemically shifted sites. The first detailed treatment of a similar problem was presented by Gutowsky, McCall, and Slichter (11) (GMS) and elaborated in later papers by Gutowsky and Saika (12) and Gutowsky and Holm (13). The equations and approximations derived in the last paper (13) are the most widely used in practical applications of DNMR. The GMS theory is, however, somewhat involved in that it uses a complicated averaging procedure. Fortunately, the same equations can be derived in a much simpler way that was first suggested by Hahn and Maxwell (14) and McConnell(l5) (HMM). The following derivation is closely akin to the HMM treatment. Consider a proton that can reside in two different environments A and B with chemical shifts vA = (WA/27r) and vB = (wB/27r) and that jumps back and forth between A and B. A jump from A to B results in a decrease of magnetization in site A and a jump from B to A results in an increase. A corresponding statement holds true for the change of magnetization in site B. HMM assume that both the forward and reverse reactions can be described by first-order rate laws with rate constants kA-. = ~ / T Aand kB,A = ~ / T B .The Bloch equations for the sites A and B may therefore be modified to read

dGA = dt

-[~(WA

dGB dt

-[i(Wg

_.-

-

W)

+ ~ / T ~ A ] G+AiyHlhf,$ - (~/TA)GA+ (I/TB)GB @a)

- W)

+ ~ / T ~ B ] G+BiyH1hft - (~/TB)GB+ (I/TA)GA (8b)

Since the system is supposed to be in equilibrium, the mean lifetimes in the sites A and B must have the same ratio as the corresponding fractional populations p TA/TB

= PA/PB

(9)

In addition it is convenient to introduce a new variable =

TAPB= TBPA

(10)

If one sweeps slowly enough through the resonance (“slow passage”), the magnetizations will manage to follow “isothermically,” that is, they

G . BINSCH

106

become stationary. It is also assumed that saturation is avoided by choosing a low Hl field. These experimental conditions imply

With eqs. (10) and (1 1) the modified Bloch equations become linear equations in GA and G B ~(wA- W)

"83

+ - + - GA + PA T2A

-GB

=

-ipAyHiM,

(12a)

and are easily solved. If one defines = -[2ri(vA - v) f l/T2A UB

=

-[2ri(YB - v) f l/TZB

+ pB/r]

+ PA/T]

C = yH1Mo

(134 (13b) (14)

where vA and vB are the chemical shifts in cps relative to some standard and where C may be taken as an arbitrary scaling factor, the total transverse magnetization G = GA + CB is given by

G = -iCT[2pApB - dPAaB f PB"A)l PAPB - r 2 a A a B

(1 5 )

Formula (15) [together with the definitions eqs. (13)] is directly suited for a complete line-shape calculation over the whole sweep range Y as a function of the parameters vA,Y ~ TaA, , TZB, pA,pB,and 7.TOobtain the computed spectrum in the absorption mode, it is only necessary to extract the imaginary part of the complex quantity G. This operation is performed automatically by modern computers. An example of a spectrum computed with eq. (15) is shown in Figure 2. In most practical applications, including those based on a complete line shape analysis, the GMS equations as given in the paper by Gutowsky and Holm (13) have been employed. Although these formulas look more formidable than our eq. (15), it is not difficult to show that they are in fact equivalent, except that in the GMS theory one usually makes the additional assumption of equal transverse relaxation times

STUDY OF INTRAMOLECULAR RATE PROGESSES

107

Fig. 2. Calculated line shapes [eq. (15)] for classical exchange between two sites with populations 0.3 and 0.7. The transverse relaxation times were taken to be the same in both sites.

for all sites (or one neglects the effects due to T2altogether). A great variety of approximate formulas has been derived from the GMS equations (1 1-1 3,16-24). These approximations have been of considerable importance in the past, but recent experience (25) shows that the errors introduced in them are much more serious than was thought

108

G . BINSCH

previously. A strong plea is therefore made to abandon their use. We will only mention one very approximate formula, not because we mean to encourage its use, but because it provides a rapid means to get a rough estimate of a rate constant at a single temperature, the so-called coalescence temperature, for classical exchange between two equally populated sites with a chemical shift difference Av. The coalescence temperature corresponds to the point at which the doublet lines just merge to a single broad line. kcosl = =Av/Z/Z

(16)

The prospective user should be warned, however, that this estimate may easily be inaccurate by several hundred per cent. c. Exchange between Many Sites. A particularly nice feature of the HMM equations is that they can easily be generalized for n sites. To see how this is done let us write eqs. (12) in a different way. Suppose the coefficients of the GIon the left-hand side of eqs. (12) are collected in a square matrix A, and the G,andp, are written as column vectors G and P, respectively. Also making use of eq. (14), eqs. (12) become

AG

=

-iCP

(17)

Multiplying from left with A-' gives G = -iCA-'P

(18)

Eventually, we will have to sum over all the GIto get the total magnetization G . This is easily accomplished by multiplying eq. (1 8) from the left with the transpose IT of an n-dimensional vector (i.e., a row vector) whose components are all equal to 1.

G

=

1TG

=

-jCITA-lp

(19)

Since computer routines for inverting complex matrices are available, the solution of eq. (19) presents no problems. In fact, Saunders (26) has written such a program based on a somewhat different but equivalent equation and applied it to the bullvalene valence isomerization. It remains to show how the A matrix is evaluated. By looking at eqs. (I 2) one verifies by inspection A = -2~i(W,3- vI) - T-'

+X

(20)

STUDY OF INTRAMOLECULAR RATE PROCESSES

109

where Wo and T are diagonal matrices with the chemical shifts (in cycles per second) and the relaxation times (in sec), respectively, I is the unit matrix, and X has elements xlj = kji

The k t j are the rate constants (in sec-') for jumps from site i to sitej. Since detailed balancing requires Plkt, = Prka (22) the spectrum depends on only n(n - 1)/2 independent rate parameters for a given set of populations. For the two-site problem we already took account of this feature by introducing the single variable T by eq. (10). But even for a many-site exchange process all possible rate ratios may become fixed automatically by the very nature of the problem. Bullvalene (26) happens to be a case in point. Here the k l j are simply given by q { j / T where the qlj specify the probability that a jump out of site i will terminate in sitej. Historically, equivalent equations were first derived by Sack (27) from Anderson's (28) stochastic theory of random Markovian modulation. The somewhat intuitive arguments used by Hahn and Maxwell (14) and McConnell (15) thus receive their justification by the detailed quantum-mechanical theory of exchange effects as developed by Anderson (28), Kubo and Tomita (29), Kubo (30,31) and Powles and Strange (32).

d. Exchange Involving First-Order Coupling. The classical treatment of the nuclear resonance phenomenon can only be rigorously justified for an ensemble of independent spins. Whenever nuclei in different magnetic environments are interacting by indirect spin-spin coupling, a quantum-mechanical theory is indicated. We would therefore suspect that our line-shape theories based on the Bloch equations break down in such situations. This is especially true for the strong-coupling case as encountered, for instance, in the exchange between the sites of an AB spin system. It may be argued, however, that a classical theory should still be a good approximation in the weak-coupling case. At an early date the classical GMS paper (11) was concerned with such an example. The method has since been extended by a number of authors (16,17,20,33-35), especially to the well-known collapse of multiplets in amines and alcohols. The Israel school has compiled a

110

G . BINSCH

catalog of exchange-broadened multiplets (36). Since essentially all these studies involve intermolecular reactions, we will not discuss them further. Complications due to first-order splittings may also arise in intramolecular exchange. An interesting case has been treated by Dahlqvist and Forsdn (37). If one modifies the chemical shifts by the appropriate combinations of coupling constants for the various spin states, or if one replaces the role of chemical shifts altogether by couplings and takes proper care of the intensity ratios in the multiplets, the methods discussed in Sections b and c can be applied in a straightforward manner. We shall not enter into details here, however, for the following reason. The excellent agreement between the experimental and computed spectra in the paper by Dahlqvist and Forsdn (37) certainly indicates that the classical model was a very good approximation in their case. But the conditions under which such a behavior may be expected with certainty have unfortunately not yet been subjected to a systematic scrutiny. In any event, there is reason to suspect (38,39) that the approximations will get progressively worse as exchange gets faster. For the general case, therefore, it seems safer to apply the quantummechanical treatment to be discussed in the next section. 2. Quantum-Mechanical Line-Shape Theory We start with a simple argument to show why a quantum-mechanical theory is really indispensable whenever exchange effects on line shapes are complicated by spin-spin coupling. To be specific, let us first consider an intramolecular exchange of two uncoupled protons 1 and 2. Immediately before exchange proton 1 shall have its spin in the CL orientation and proton 2 in the t9 orientation. We will label this “state” by a( I ) /3(2). Exchange permutes the nuclear coordinates and converts our system to the new and distinct state cr(2)/3(1). Each time such a change takes place it will alter the magnetization and we will be able to detect it by DNMR. Now, if there is spin-spin coupling between the nuclei, the two states discussed above lose part of their individuality due to a typical quantum-mechanical interaction. The degree of “mixing” increases with increasing ratio of the spin coupling constant J to the chemical shift difference Av, until finally, for Av = 0, the two states become completely indistinguishable. Consequently, there is a finite chance of finding the system in the same state after exchange as before. Exchanges of this type will therefore go undetected and the rate constant

111

STUDY OF INTRAMOLECULAR RATE PROCESSES

calculated by a classical theory does not correspond to the true rate constant of the molecular process. For strong coupling, that is, high J / A v ratios, and slow exchange this error must become very serious. For weak coupling and slow exchange, the quantum-mechanical correction may be so small as to be safely neglected. However, as exchange gets faster, even a small mixing coefficient must eventually produce an important effect due to a phenomenon that may be visualized as a “feedback” mechanism. In view of this it seems somewhat strange that a classical calculation becomes valid again for very fast exchange in the strong-coupling case. Rather than stretching our qualitative interpretation too far in trying to explain this also, we will now proceed to the quantitative formulation of the theory. A quantum-mechanical treatment of exchange effects in DNMR was first given by Kaplan (39,40) and further developed by Alexander (41-44), Johnson (49, and Newmark and Sederholm (46). All these theories are based on the density-matrix formalism (47), which is also highly suited for a refined discussion of Bloch’s phenomenological equations (48-50). In the following presentation we will follow a slightly different course ( 5 1). Consider a system of p identical coupled nuclei with spins undergoing exchange between n different magnetic environments. Each environment k shall be characterized by the state function $k. We wish to calculate the total transverse magnetization G = x k pkCk,where p k is the population of the spin system in the magnetic environment k. In the language of quantum mechanics each Gk corresponds to the expectation I,’ = hy ( I ; f il;). Note that in value of the operator hyI* = fiy order to be consistent with common N M R conventions, we have used the I operators in their abbreviated form from which the true operators are obtained from multiplication by h. Without loss of generality we may either work with I + or I - , and we will choose the minus sign (corresponding to spin flips from CY to /3). For convenience, we will henceforth drop Planck’s constant h whenever it occurs, so that the energy is expressed in frequency units. Thus we have

+

x,,

xfl

Gk

=

y(I-)

=

d$kl

I-

I#k>

(23)

Expanding # k into a complete set of orthonormal stationary spin basis functions c$~ =

2

#!i

I

ckih

(24)

G. BINSCH

112

eq. (23) becomes =$

2 (kl I-

l$j)

CkjCk:

1j

(25)

where the time dependence of Gk is now exclusively contained in the complex coefficients c. If one defines a density matrix pk for the kth magnetic environment by PFt = c k j c z (26) Eq. (25) can be written as G k = y ~ h ~ =ytr(I-P'0 P % (27) 1j

where Z,j denotes the matrix elements (+,I I and tr the trace. The calculation of G k becomes particularly simple if one chooses the spin product wave functions as basis # (41). The I- matrix then has only elements 0 or 1 and its evaluation is well known from static NMR. For an AB spin system with the basis a(l)a(2), a(1)8(2), p(l)a(2), 8(1)8(2) one obtains for instance 0 0 0 0 1 0 0 0

0 O1 O1 O0) It remains then to compute those off-diagonal matrix elements of the pk matrix that are needed to obtain the trace in eq. (27). For our AB example these are G k = y(d2 + O p! + Pf4 + p k ) (29) In the absence of relaxation and exchange, each pk (here interpreted as an operator) obeys the equation of motion (47,52) dpk-- 2rri[pk,.ekl = 2ai(pk*k

- i~kpk) (30) dt In analogy to the procedure we used in the classical case, this equation can be modified to read for the off-diagonal elements of pk in the presence of relaxation and exchange dPk - = 2ni[pk,*kl + dPk

(z)

dt

relax

=

2ni[pk,*']

Pk + -T2k

+

l(#k)

(klkp' - kklpl')

where the klkare the first-order rate constants of the processes by which the system switches from the magnetic environment 1 to the magnetic

STUDY OF INTRAMOLECULAR RATE PROCESSES

113

environment k . Under unsaturated steady-state conditions the left-hand sides of eq. (31) vanish, and one obtains a system of linear equations for the elements p&. These are the master equations for line shapes in DNMR and they can be programmed for a computer (51). For all J = 0 they automatically reduce to the classical equations. We briefly indicate how the commutator in eq. (31) is evaluated. In the frame rotating with angular frequency w = 2 r v the Hamiltonian (in sec-l) becomes where YE are the chemical shifts (cps) of the nuclei p in environment k , J,& the coupling constants (cps) between nuclei h and p in environment k , and H , is the strength of the rotating radiofrequency field. If one prefers not to use the completely general master equations [eqs. (31)], they can of course be broken down algebraically for special cases. For the convenience of the reader we will here reproduce the full line shape function for the case most frequently encountered in practice, the intramolecular exchange of an AB spin system. =

with

'{(A+

+

R, + F iF)(B, + iF) - Q,

+

(A-

+

+ +

1

RF iF)(B- iF) - Q-

(33)

- 2 ? 7 i ( v A ? 5/2) - 1/T2 - k ; V o = (YA + V g ) / 2 ; B , = - 2?7i(vg k J/2) - 1/T2 - k ; Q+ = ( + r i J + k)2; R , = - 27r(v0 k J ) + 2ik + i/T2; F = 2nv (34) A,

=

where k is the rate constant and C an adjustable scaling factor. An equivalent equation was derived by Alexander* (41), using a somewhat different approach, and a number of people (53-58) have written computer programs. The theoretical curves in Figure 3 show the general behavior of an A B system. A rough estimate of the rate constant at the coalescence point can be obtained (55) from

+

kcoal= V ~ / ( V A- Vg)' 6Jig/d? (35) Special equations for ABC spin systems exchanging between three different magnetic environments were derived and programmed by Newmark (46,59).

* Note, however, that eq. (57a) in Alexander's (41) paper contains two errors. The quantity 1 should be replaced by i in both denominators.

114

Fig. 3.

G. BINSCH

Calculated line shapes [eq. (33)] for intramolecular exchange between the sites of an AB spin system.

B. Transient Techniques The line-shape equations discussed in Section A only apply under unsaturated steady-state conditions, that is, for slow passage and low H I fields. If either of these requirements is not satisfied, the NMR spectra themselves become time dependent. These transient phenomena may sometimes also be exploited to obtain information about rate processes.

STUDY OF INTRAMOLECULAR RATE PROCESSES

115

Rapid passage spectra have occasionally been used to extend line shape measurements slightly beyond the fast- and slow-exchange limits (19,60,61) or to draw inferences from nonequilibrium magnetization transfer (62,63). Because of their limited applicability and inherent inaccuracy we are only mentioning these techniques in passing. By far the most important transient NMR method for studying rate effects makes use of strong and short radiofrequency pulses. Suppose a strong rf field H,, whose frequency satisfies the resonance condition, is switched on (at t = 0) for t, sec so that yHlt, = v/2. t , is so short that the system will have no time to relax during this “90” pulse,’’ and the total macroscopic magnetization Mo will therefore end up in the y direction of the rotating reference frame (Fig. 4u). After the rf field is switched off at t = t,, the y magnetization will start to decay, since the individual spins gradually lose their phase memory and “fan out” (Fig. 4b). Field inhomogeneities within the sample are the main cause for this dephasing. If after a time t, a second pulse of duration 2t, (180” pulse) is applied, the directions of all individual spins become reversed (Fig. 4c). Instead of fanning out they now move together and refocus 2t, t, to produce a strong signal, the so-called at t = t, + t , “echo” (Fig. 4 4 . The reader who wishes to learn more about spin echoes will find a commendably lucid presentation in the paper by Carr and Purcell (64). Not all of the original magnetization will be recovered in the echo signal, however. A certain amount of it is irretrievably lost, and this loss increases as t, gets longer. In the absence of exchange the decrease of the echo amplitude is mainly governed by the transverse relaxation as characterized by T2. An additional irreversible loss ensues if magnetization is transferred to another site in an exchange process. A quantitative analysis of the echo decay is therefore expected to yield numbers for the rate constants. Following a few scattered publications up to 1963 dealing with the theory of spin-echo methods and their applications to the study of rate phenomena (14,38,65-67), this technique has now developed into an elaborate tool for kinetic measurements, especially as a result of the systematic investigations by Gutowsky and his group (68-74) and the contributions by a number of other workers (32,75-79). The experimental procedure now being employed exclusively consists of a single 90” pulse followed by a whole sequence of equally spaced 180” pulses, referred to as a Carr-Purcell spin-echo (CPSE) pulse train. As one of the

+

+

G . BINSCH

116 Y

t”

I-

.V

1” V

V

f

Fig. 4. Classical motion of nuclear magnetic dipoles to produce a spin echo.

advantages of this modification all losses of phase memory due to diffusion through an inhomogeneous magnetic field are effectively eliminated, provided the pulse repetition rate is only fast enough. The CPSE train may actually be viewed as a “double-focusing” device. One also obtains a whole sequence of echoes in one experiment. By drawing a smooth curve through the echo maxima one can construct an “echo envelope,” and it is this echo envelope that contains the essential information of a CPSE experiment.

STUDY OF INTRAMOLECULAR RATE PROCESSES

117

Since the decay of the xy magnetization starts after the HI field has been switched off, we can describe it by a Bloch equation in which the driving term is omitted, provided, of course, that spin-spin coupling is absent . dG = [-2ni(v, - v) - - G dt T2

‘I

In the presence of exchange between two chemically shifted sites A and By we have to modify eq. (36) in the, by now, well-familiar way

‘1

1 5 = [-2ni(vB - V) - - - - GB + -GA dt T2B rB

TA

(37b)

These two coupled linear differential equations have to be integrated subject to the boundary conditions of the stepwise action of the 180” pulses. In other words, one has to choose the integration constants in such a way that the magnitude of the magnetization at the beginning of a pulse interval is just equal to the magnitude of the magnetization at the end of the preceding one. The only practical way to treat these equations is to solve them numerically by means of a computer. The generalization of eqs. (37) to n sites is obvious. In the presence of spinspin coupling one has to resort to the corresponding density matrix equations. It is even possible to treat the effects of finite pulse times 2t, numerically (76). Needless to say, the mathematics for the most general case gets rather involved. Nothing much would be gained for an understanding of the principles by going into all the details here, so we refer the interested reader to the original literature. It turns out that for zero coupling the echo envelope is independent of pulse separation in the absence of exchange, whereas this is no longer true if magnetization is lost due to transfer by a rate process. One can make use of this feature by plotting the decay constant versus pulse frequency. This not only gives the rate constants, but as an additional “ bonus” also gives the chemical-shift differences and “true” transverse relaxation times, a distinct advantage over the line shape method. We will discuss the respective merits and drawbacks of the various methods in more detail in Section IV. In closing we only want to mention that the decay envelope may become modulated in the presence of spin-spin coupling.

118

G. BINSCH

C. Multiple Resonance Method An elegant yet simple multiple-resonance method was recently discovered by ForsCn and Hoffman (80-82), applicable to rates that are too slow to lend themselves to quantitative measurement by the line-shape technique. As usual we start the discussion with the Bloch equations, this time focusing our attention on the z components of the macroscopic magnetizations. Suppose an exchange process takes place between two uncoupled, chemically shifted sites A and B. In the absence of radiofrequency fields the modified Bloch equations for the z components take the form dMf M," M : -- _ - M,A-Mt -(384 dt Tl A rA rB dM,B M f - Mt -M," M," - = dt TlB rB rA Since the system is in equilibrium, the left-hand sides of eqs. (38) vanish and by definition M," = M t , M," = M t . If at t = 0 we suddenly and selectively start to irradiate the B resonance with a strong radiofrequency field, M," will be annihilated (presumably after a very short transient period). This will disturb the equilibrium and cause a change in M$ described by

+-

+-

dM$ M," - - - -M $ - M t - dt TIA TA which on integration yields

(39)

Conversely, if one selectively irradiates the A resonance with a strong H, field, the change in M,B is described by equations analogous to eqs. (39) and (40) except that the label B takes the place of label A. Equation (40) can be exploited in a straightforward fashion. For t = co, that is, after the system has reached a new state of equilibrium, one obtains @ ( a ) / M t = rA/(TiA + 7A) (41) Taking the logarithm of eq. (40) yields

In [M,"(t)- Mf(co)]

=

- TIA

+ rA t + C

Tl A rA

STUDY OF INTRAMOLECULAR RATE PROCESSES

119

where the constant C is of no interest in this context. From the slope of a logarithmic plot [eq. (42)] and with eq. (41) both T A and T i A can be calculated. The “mirror-image” experiment affords T B and T i B in the same way. The results can be checked against the peak areas of an ordinary steady-state spectrum by means of eq. (9). Experimentally one uses the unsaturated slow-passage technique to record the spectrum of A while double-irradiating B and vice versa. Under these conditions the signal intensity is directly proportional to M,. To observe the gradual decrease from M : at t = 0 to M , as a function of time, ForsCn and Hoffman used a multiple-sweep recording device. If the spectrometer features a field-frequency lock system, it is easier to just “sit” on the A resonance while double-irradiating B (83). Several modifications of the basic procedure and an interesting application to a three-site problem are described in the papers by ForsCn and Hoffman (81,82). It should be evident that the method in this form is suitable only if the nuclei in the various sites show up as distinct, nonoverlapping signals. Although the density-matrix description of multiple resonance is highly developed (84,85), including relaxation phenomena (86), no applications to rate processes involving coupled spin systems or employing low-power levels have been reported as of this day. This area promises to become an active and exciting field of research in the near future. IV. PROCESSING OF THE DATA A. Experimental Procedures

As already mentioned, most DNMR rate determinations have been done by the line-shape method. The application of double-resonance and spin-echo techniques is limited to special cases (compare Sect. IV-D), and since pulse experiments furthermore require equipment which at present is available in only very few laboratories, we will merely point out a few facts that deserve to be kept in mind when recording slow-passage spectra. In virtually all cases the parameter to be varied is the temperature, and the necessary variable-temperature probe is now a standard accessory of commercial instruments. Curiously enough, the design of the inserts and the general procedure of achieving and measuring a certain

120

G. BINSCH

temperature in the sample have remained somewhat primitive until quite recently, and further improvements are still desirable. Since there will necessarily be temperature gradients within the probe (the more so the farther away from room temperature the measurement is to be performed) it is imperative to allow for complete equilibration before any readings are taken. Even so, the temperature one measures may not be the actual temperature in the sample, and the difference may itself be a function of the absolute temperature, thus introducing systematic errors. One should therefore frequently calibrate the readings under the actual conditions of the measurements, either against a second thermocouple in the interior of an NMR tube partially filled with a solvent or by making use of the peak separations in methanol or ethylene glycol as recommended by Varian (87). Since line shapes depend very critically on field inhomogeneities, the importance of high-quality spectra cannot be overemphasized. It is quite common for the magnetic field to deteriorate substantially each time the temperature is changed by an increment, but one may not become aware of this if one only looks at an exchange-broadened spectrum. It is necessary, therefore, to readjust the field-homogeneity controls of the spectrometer while observing a signal that is not affected by the exchange, for example, the peak of a standard. Under the slow-sweep conditions required to eliminate transient effects such as wiggles, the danger of saturation is also more pronounced than usual. Finally, excessive filtering of noise should be avoided since it may cause distortions also. With all these precautions the lines not broadened by exchange will be symmetrical, narrow, and very close to true Lorentzian lines. Otherwise the deviations from Lorentzian shape may be so significant as to render even the merits of a full line shape calculation illusory. The theory of exchange effects on NMR line shapes has now matured to such a stage that every spectrum can be calculated without major trouble provided the static parameters for all exchanging species are known. But there are of course many cases of such high complexity that the chemical shifts and coupling constants cannot be extracted. It is then necessary to simplify the problem experimentally. One of the most frequently employed methods consists in deuterating the molecule selectively so as to “insulate” a particularly simple proton spin system which still shows all the characteristic effects of the rate process of interest. The proton resonance is then observed while simultaneously

STUDY OF INTRAMOLECULAR RATE PROCESSES

121

irradiating the deuterium nuclei. Another very elegant device is to introduce fluorine atoms at certain points in the molecule and make use of 19F resonance to analyze the motions at the molecular level. This technique has been employed extensively by Roberts and his collaborators. Its particular advantages have recently been reviewed by Roberts himself (88). B. Determination of Rate Constants

In Section 111-C we already indicated how the mean lifetimes 7, and hence the rate constants k , = I/., are obtained from a logarithmic plot in those cases where the multiple-resonance method can be applied. In all other instances a simple and safe procedure is to compare, visually, computer-calculated plots of line shapes or echo envelopes with the experimental curves. For line shapes this gives the rate constants directly; for spin-echo data one has to construct another plot of the apparent decay constants versus pulse frequency. All other precomputer treatments based on certain approximations have become obsolete by now. For very simple spin systems a time-saving variation of the above procedure is sometimes feasible. One extracts a single spectral parameter such as a line separation, linewidth, peak-to-peak ratio, or peak-tovalley ratio from the computed line shapes and plots this parameter versus the rate constant. By measuring the same parameter in the experimental spectra one can read the corresponding rate constants directly from the theoretical plot (21-23,89). It should be noted, however, that this method is more susceptible to spurious effects than a direct comparison of the full line shapes (88). The ideal method is, of course, to feed the experimental spectra point by point into a computer and let it find the theoretical curve that represents the best least-squares fit. Programs of this type have been written for an AB exchange by Jon$:, Allerhand, and Gutowsky (57) and for a classical two-site exchange by van der Werf, Olijnsma, and Engberts (90). It is even possible to take account of significant deviations from Lorentzian line shape due to field inhomogeneities by a numerical convolution integral technique that generates any desired shape in the absence of exchange broadening (91). If one is careful in obtaining highquality spectra, however, the incorporation of such a refinement may not be necessary (83). It is then feasible to work with an “apparent”

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transverse relaxation time T i which is related to the widths W(in cps) a t half-height of the peaks not broadened by exchange by the simple formula T ; = l/vW (43) In general T2will be found to be slightly different for the time-averaged peaks in the fast-exchange limit and for the separate lines of the individual species in the slow-exchange limit, and some function must be chosen to join these two extremes, since Ta is not available experimentally in the intermediate region. The simplest device is of course a linear relationship (92) and this should be entirely satisfactory, since the detailed functional form is not critical for high-quality spectra. Sometimes it is not possible to obtain exactly the same field homogeneity at all temperatures. In that case an appropriate correction, obtainable, for instance, from the linewidths of a standard, should be superimposed on the functional form of T;. For two-site exchange problems the spectra are usually calculated as functions of a single rate parameter, often expressed in terms of T as in our eq. (15). To get the separate first-order (or pseudo-first-order for intermolecular processes) rate constants for the forward and back reactions, one must use eq. (10). In particular, for equal populations k is given by 1/(27)! It is perhaps worthwhile to mention that in Alexander’s (41-44) original formulas the variable T is directly equal to the inverse of the rate constant. We have avoided this inconsistency of notation by writing eqs. (31), (33), and (34) in terms of k.

C. Calculation of Activation Parameters In many applications of DNMR only a single rate constant, at the coalescence temperature, has been calculated or, rather, estimated. By means of the well-known Eyring equation (93)

k = K(k,T/h) exp (- AG*/RT) (44) this number may be converted to the free energy of activation, AG*, a t this temperature. Since no meaningful standard deviation can be attached to this value, since the calculation makes use of an approximate formula, and since the measurement is performed at a rather ill-defined point, it is somewhat difficult to judge how far this quantity might be off the true value. Its significance for comparison purposes is further limited by the fact that its temperature dependence is not known.

STUDY OF INTRAMOLECULAR RATE PROCESSES

123

If the rate constants have been obtained at a number of different temperatures, one may construct a linear Arrhenius plot Ink

=

- E , / R T -k In A

(45)

and extract the activation energy E, from the slope and the frequency factor A (commonly reported as log A ) from the intercept. An Arrhenius plot of course implies the tacit assumption that both E, and A are independent of temperature, which can only be an approximation. Experience has shown this approximation to be a good one. In general, it would mean taxing the accuracy of rate data beyond its limits to detect deviations from linearity with any degree of certainty. The modern literature seems to prefer enthalpies and entropies of activation in place of Arrhenius parameters. Substitution of AG*

=

AH* - TAS*

(46)

in eq. (44) gives k

=K

("J

exp ( - A H * / R T )exp ( A S * / R )

(47)

A H * and AS* could, in principle, be obtained from the Arrhenius parameters by A H * = E, - R T (48) AS*

=

R[ln

(eT) - 11

(49)

and this seems to be the method of calculation employed by many authors. However, with eqs. (48) and (49) one introduces a temperature dependence into A H * and AS*. This temperature dependence is really artificial, since it is based on the assumed temperature independence of E, and A . A more reasonable approach is to assume temperatureindependent A H * and AS* values and obtain them experimentally in a direct fashion. There are two ways to do this. One can make use of eq. (47) and plot In (k/T) versus I/T to give a straight line with the slope - A H * / R and the intercept In (Kk,/h) A S * / R , or one may calculate AC* from eq. (44) for each temperature and plot eq. (46). In the sections that follow it would have been desirable to convert all activation parameters to oneconsistent set of numbers, but the requiredinformation was unfortunately not available in many instances. Thus we have had to be content to report the numbers as they are given by the respective

+

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124

authors, but we have decided to delete all references to specific temperatures. The question of what to do about the somewhat mysterious transmission coefficient K still remains to be answered. The simplest way is to set it equal to 1 and thus dispose of this problem. In fact, there hardly seems to be a reasonable alternative. In their study of the internal rotation in substituted ethanes, Newmark and Sederholm (46) provisionally tried another extreme value, but reported that this led to disagreement with experiment. If exchange takes place between two unequally populated sites, the activation parameters of the forward reaction are of course different from those of the reverse path. Figure 5 illustrates their interrelation. AG stands for the free energy difference of the ground states at the same temperature to which AG$ refers and is given by AG = - RT In (pB/pA)= - RT In K

(50)

For exchange between n sites there will be n(n - 1)/2 pairwise relationships of this kind. Analogous diagrams can also be drawn for A H * and AS*and their ground-state counterparts. Since the equilibrium constant K is itself a function of temperature, the corresponding changes in the populations must be taken into account in line-shape calculations. It is sometimes possible to determine the thermodynamic functions from peak-area measurements at a series of temperatures below the slow-

A

L Y

B

Fig. 5. Relation between thermodynamic and kinetic parameters for an exchange between two unequally populated sites.

STUDY OF INTRAMOLECULAR RATE PROCESSES

125

exchange limit and extrapolate to the temperature region where broadened or collapsed spectra are obtained (94). Or one treats the populations as free parameters to be adjusted so as to give the correct line shape. Finally, it is clear that the NMR method for determining reaction rates will not be applicable at all when the ground-state energies differ vastly, because then one sees essentially only one species, and the line shapes do not respond to any exchange process that might still be going on.

D. Sources of Errors In this section we will restrict ourselves mainly to a discussion of the advantages and disadvantages of the various D N M R methods. Consistent with our policy not to treat approximate procedures at any length, we will not address ourselves to the complicated problem of evaluating in detail all the conceivable errors that have to be blamed on the use of approximate formulas. Allerhand, Gutowsky, Jondi, and Meinzer (25) published an excellent discussion of these aspects and we refer the interested reader to their paper. Here we only want to stress again their most important conclusion-that these errors have a tendency to be systematic in character. One may still obtain a satisfactory Arrhenius plot with small standard deviations, but such an agreement may be highly deceptive. The distinct advantages of the line-shape method are that it is the most versatile technique, applicable even to quite complicated cases, that the experiments are comparatively easy to perform with standard N M R equipment, and that the analysis of the data has by now become a rather straightforward task. Unfortunately, the significant information content of the measurements is limited to a rather narrow temperature range, usually between 20 and 60" in magnitude, and the sensitivity is not uniformly distributed over this range. The most pronounced changes in line shapes occur in the vicinity of the coalescence temperature. By applying a complete line-shape analysis to carefully measured spectra one may place a high degree of confidence on the calculated numbers in this region. The spectral changes diminish rapidly toward both extremes of the range, and unless the spectra are of high quality, errors will become appreciable. As long as they stay random and are taken with a lower weight in a least-squares analysis, this will only reduce the precision of the activation parameters. As already mentioned, approximate formulas are likely to make these errors systematic. It can

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G. BINSCH

be shown (70) that this feature most seriously affects the entropies of activation. It is therefore not surprising that ASt values have become a sore point in applications of DNMR. There is one further drawback that deserves comment. For line shape calculations one needs the chemical shifts (and possibly also the coupling constants) of the exchanging species. Naturally, these parameters can only be determined at the slow-exchange limit. If they change appreciably over the temperature range of the measurements but are assumed constant in the calculations, the rates calculated are incorrect. It seems that insufficient attention has been paid to this possibility in the literature. One can sometimes check and, if necessary, correct for such a temperature variation of the static parameters by recording the slow-exchange spectra at a number of different temperatures. With the spin-echo method it is not only possible to extend the measurements to faster rates than are accessible by the line shape method, but the total temperature range itself may cover as much as 100”. The chemical shifts and true transverse relaxation times are obtained simultaneously with the rate parameters, first-order couplings may frequently be safely neglected, and field inhomogeneities do not seem to be critical. All this sounds very promising. Nevertheless, as we shall explain in more detail in later sections, the practical results that have become known so far do not seem to live up to these expectations. This author does not feel competent enough to pinpoint really what might have gone wrong. There is also a serious limitation to the practical applicability of the spin-echo technique. The radiofrequency pulses are, at least at the present state of the art, “nonselective.” If the molecule, as is frequently the case, contains magnetic nuclei that do not take part in the exchanges, spin-echo rate measurements become difficult or even impossible to perform. Spin-echo experiments furthermore require special equipment, are quite a bit more tedious to carry out than lineshape measurements, and the mathematical analysis is considerably more involved. The multiple-resonance technique is particularly suited to extend line shape measurements to slower rates. Although the method is, at present, limited to these very slow rates and to rather simple spin systems, it is very simple to apply, both experimentally and theoretically, and has the appealing features of affording the rate constants for the forward and reverse exchange separately, even for more than two sites, and of being insensitive to field inhomogeneities.

STUDY OF INTRAMOLECULAR RATE PROCESSES

127

In the tables of the succeeding sections we will make use of the following abbreviations A B C D E F SE DR

Complete line-shape calculation, using accurate theory Complete line-shape calculation, using approximate theory Peak separation approximation Linewidth approximation Other approximate treatment at more than one temperature Number based on coalescence temperature only Spin echo Double resonance V. HINDERED ROTATION

For many applications of DNMR to be discussed in the following sections, hindered rotation about bonds may be one aspect of a more complicated motion of a molecule. In this Section we will discuss those cases for which internal rotation is the essential part of a rate process. A. Substituted Ethanes A huge body of literature has accumulated about hindered internal rotation about single bonds (95,96). Most of the numbers were obtained by the microwave technique. Compared to this activity, NMR investigations are almost nonexistent. It is true that the barriers of ethane-type molecules in which only one or two hydrogen atoms are replaced by bulkier groups are still outside the accessible range, but the NMR method should be ideally suited for heavily and especially asymmetrically substituted ethanes, for which the difficulties of a microwave study become insurmountable. Following some early studies by Phillips (6) and by Roberts and his group (97), there is only the work by Sederholm and co-workers (46,98,99), but this happens to be one of the most advanced applications of DNMR known to this day, both experimentally and theoretically. Figure 6 shows a schematic representation of an energy profile to be expected for this type of problem and Table I lists the results. In spite of the complexities of the systems (or rather, one is tempted to say, because of them), it was possible in all cases to arrive at an unambiguous assignment of the slow-exchange spectra to the various “frozen” conformers.

G . BINSCH

128

F

C

F

E

C

C

EA&D

Fig. 6. Typical free energy profile for the internal rotation in asymmetrically substituted ethanes.

The meso- and d,l isomers 1and 2 could actually be studied as a mixture. Peak-area measurements gave the free energy differences and complete line shape calculations, based on the classical equations for the unsplit systems 2 and 5 and on quantum-mechanical equations derived from Alexander’s theory (Sect. 111-B)for the A2, AB, A2B, ABX, and ABC systems of the other molecules, yielded the free energies of activation. Since the interconversion between conformers 2 and 3 of 5 does not change the magnetic environments of the two fluorine nuclei, the corresponding barrier does not affect the NMR spectrum. The exchangebroadened spectra do not respond to all rate constants with equal sensitivity, so that for some AG*values only lower limits could be stated. After it was found that the spectra of 4 could not be reproduced theoretically with K << 1, the transmission coefficient was chosen to be 1 in all cases. The AG* values turned out to be independent of temperature within the experimental errors, indicating that the activation entropies must be close to zero, This does not only seem to be a rather general phenomenon for all hindered rotations (uideinfru), but it is also a reasonable one. It would be very hard indeed to think of any good theoretical

F F F F C1 F F

C1 C1 F F C1 F F

B

Br Br Br Br F Br Br

C

Br Br Br Br F Br Br

D

F C1 C1 C1 C1 F C1

E C1 F F Cl C1 Br H

F 0 0 0 0 0 0 0

1

*

438 450 746 30 320 f 20 122 f 7 0 167 f 13

2

*

3

438 119 313 f 10 320 f 20 122 7 760 248 f 20

AG, cal/mole 12 10.1 f 2 10.6 f 2 8.8 10.8 f 9.65 f 7.7 f 2 7.8

AG* was found to be independent of temperature within experimental error. Unobservable.

1 2 3 4 5 6 7

Structure no. A

Compound

0.1 0.1 0.2

0.2 0.2

9.9 f 0.2 2 7.8

-b

212.0 1.0 2 10.6 f 0.2 2 8.8 212.0 f 0.5

*

23

AG*, kcal/rnolea

10.1 9.9 7.9 10.8 9.65 9.9 6.9

0.2 0.1 0.1 0.1 0.2 k 0.2

f f f f f

* 0.2

s?

.e

U

Free Energies and Free Energies of Activation for Substituted Ethanes as Defined in Figure 6

31

Y

TABLE I

C

STUDY OF INTRAMOLECULAR RATE PROCESSES 129

130

G. BINSCH

reason why the entropies of the activated states should be substantially different from those of the ground states. The problem of the origin of barriers around single bonds continues to have a great appeal to quantum chemists and has been, and still is, the subject of hot controversy. It is just barely possible that the preoccupation with the small barriers associated with carbon-hydrogen bonds has infected this discussion with an unfortunate bias. Whatever the importance of various contributions to the barrier in ethane itself may be, there can be no question that ordinary steric effects must play a dominant role in the compounds studied by Sederholm. Inspection of Table I reveals that the relative magnitudes of all free energies of activation can consistently be explained by this hypothesis.

B. Sterically Crowded Bonds A shrewd idea was employed to find the barrier to rotation in the tetra-substituted biphenyl derivative 8 (100). In one of the preferred nonplanar conformations of 8, the two hydrogen atoms of a CH,OAc group are in different chemical and magnetic environments ; they are “diastereotopic ” (101). They interchange their environments by rotation about the central pivot bond of the biphenyl system. By studying the gradual collapse of the AB spectrum on increase of the temperature, the barrier to racemization could be calculated to be 13 kcal/mole. A rather similar situation is encountered in compound 9 (102). Extreme steric crowding prevents the two benzene-to-neopentyl bonds from being coplanar in the conformation of lowest energy, again causing the methylene protons to become diastereotopic. A concerted rotation in a conrotatory fashion was suggested (102) to account for the change in the spectrum of the methylene hydrogens from an AB pattern at - 30” to a single line at 80”. A full line-shape analysis yielded an activation energy of 11.5 k 0.6 kcal/mole.

STUDY OF INTRAMOLECULAR RATE PROCESSES

131

Diastereotopic methylene protons are also found in the lowtemperature spectrum of trans-cyclodecene. By rotating the doublebond segment through the loop formed by the saturated hydrocarbon chain, the allylic methylene protons interchange their magnetic environments (actually, the details are a little more complicated). To study this process quantitatively, the hexadeuterio compound 10 was prepared (92). A complete line-shape analysis of the deuterium-decoupled DNMR spectra afforded an activation energy of 10.7 f 0.3 kcal/mole and a frequency factor of log A = 11.7 f 0.3. Shortening of the ring by one or two carbon atoms causes a dramatic increase in steric hindrance, reflected in the activation energies of 20 & 2 and 35.6 f 0.9 kcal/mole, respectively, as determined by Cope and co-workers (103,104) by conventional kinetic techniques.

Steric hindrance in triphenylmethyl carbonium ions causes these molecules to assume a propeller shape. An interesting DNMR study was reported (105,106) for a number of fluorine derivatives such as 11. The conformers l l a and l l b were found to be separated by an energy barrier of 9.1 kcal/mole.

G. BINSCH

132

C. Amides, Thiomides, and Carbamates Restricted rotation about the carbon-nitrogen bond in amides is the classical example of a rate process that can be studied by DNMR. Resonance theory describes the electronic structure of amides by a hybrid, 12a t)12b, suggesting a certain amount of double-bond charac-

R” (124

Rw

U2b)

ter for the carbon-nitrogen bond and a concomitant increase of the rotational barrier over that in “pure” single bonds. Since R’ and R” reside in different magnetic environments [R’ being more shielded than R (107)] in the fixed structure 12, but become time-averaged on rapid rotation, there is a chance to observe this rate process by DNMR. This prediction was first confirmed qualitatively by Phillips (108) for dimethylformamide and dimethylacetamide, and these two compounds also happen to be the first examples of an intramolecular rate process to be studied quantitatively by DNMR (13), being, as it were, the prelude to what became one of the most discouraging chapters in the history of dynamic nuclear magnetic resonance. Table I1 shows that the barrier for D M F alone has been determined over and over again, producing random numbers between the extremes 6.3 and 28.2 for the activation energy and 4.6 and 17.2 for the logarithm of the frequency factor. These results might easily induce an unprejudiced reader to lose all confidence in DNMR as a quantitative method. It is this author’s conviction that such a conclusion would be premature. DMFjust is an unusually tricky case in that the chemical-shift difference between the two methyl peaks is quite small (about 10 cps at 60 Mcps) and, furthermore, changes with concentration, solvent, and temperature, and the methyl peaks are split or broadened by long-range couplings to the formyl proton, causing the results to depend very critically on highquality spectra and on the shortcomings of approximate formulas and single-parameter methods. It is especially significant that none of these numbers has been obtained by the complete line-shape method. In one investigation (113) the authors have gone to great pains to eliminate instrumental sources of errors as carefully as possible, and in another

133

STUDY OF INTRAMOLECULAR RATE PROCESSES

TABLEI1

Arrhenius Activation Energies and Frequency Factors for the Internal Rotation in Dimethylformamide as Reported by Different Investigators Solvent Neat Neat Neat Neat Acetone-de CFC13

Hexamethyldisiloxane Formamide Neat Hexachloroethane Neat Neat Neat Neat

E,,, kcal/mole

Log A

7 f 3 9.6 f 1.5 18.3 f 0.7 15.9 f 2.0 16.8 f 2.0 11.3 & 2.0

3-7 6.5 10.8 f 0.4 16.8 f 2.0

9.4 f 1.0 26.3 f 2.6 18.7 f 0.9 6.3 f 0.3 26 28.2 f 2 22.0 27.4

15.5 f 1.5 11.8 f 0.6 4.60 f 0.01 16 17.2 13 16

Method" C

Reference

c, D, E

13 109 21 110 110 110

C E E C C, D, E C C, D, Eb C, D, EC

110 111 111 112 113 114 115 115

E C C C

"See p. 127 for key. bSpectrataken at 100 Mcps with simultaneous decoupling of the formyl proton. Formyl proton replaced by deuterium.

(1 15) the long-range coupling complication was removed by double resonance and deuteration, producing what may justly be considered the most reliable results. It is therefore all the more regrettable that the data were still analyzed by single-parameter methods. Table I11 gives another case for which spin-echo data are also available. Barrier measurements have been reported for formamide (1 16a), symmetrically (13,21,35,68, 78,109,111,113,116b, 1 17-121) and unsymmetrically (94,114,120,122124) substituted N,N-dialkylamides, N-vinyl-substituted amides (1 14), and thioamides (111,125-127). More often than not the data are extremely erratic, rendering any detailed interpretation a hazardous undertaking. There would be no point in reproducing them in this review. Many of the conclusions attempted must be viewed with utmost suspicion, such as whether protonation or complexation at oxygen results in an increase or decrease of the barrier (35,109,112,115), how and to what extent the electronic and steric factors of the substituents

G.BINSCH

134

TABLE 111

Activation Parameters for the Internal Rotation in Dimethylcarbamoyl Chloride Solvent Neat Neat Neat Neat Neat CCl4 CC14

E,, kcal/mole

16.9 f 0.5 14.0 k 0.9 8.6 f 1.7 9.7 f 0.5 7.3 f 0.5 17.7 f 0.9 6.8 ? 0.2

Log A

12.9 & 10.9 k 6.9 k 7.7 k 6.1 k 13.8 k 5.9

*

0.4 0.6 1.2 0.4 0.3 0.7 0.2

Method

Reference

A SE

125 68 68 68 21 125 116b

C E E A E

really change the barrier heights, and whether all the seeming inconsistencies should be blamed on association and solvent effects (1 10,112, 116b,118). The idea that the very low frequency factors are due to catalytic impurities (1 28) or low transmission coefficients (1 16b) does not seem well founded either. What this area desperately needs is a complete reinvestigation. There are only two publications in which carefully measured spectra have been analyzed by the complete lineshape method. Weil, Blum, Heiss, and Kidnaird (94) quantitatively studied the conformational interconversion of 13a and 13b, obtaining

02N-GN>’cH \;/ 0

O2N+N/

NO2

CH, NO2

U3a)

CH

0

’.‘CH, NO2

03b)

E, = 21.0 k 0.3 kcal/mole and log A = 14.3 k 0.2 for the forward exchange (a+ b) and E, = 19.2 ~t:0.3 kcal/mole and log A = 13.5 f 0.2 for the reverse (b + a). These numbers are particularly trustworthy, since the analysis of the peaks due to the two aromatic protons and those of the N-methyl resonances in the perdeuteroacetyl compound led to good agreement. The other study has been reported by Neuman, Roark, and Jonas (125), and their numbers for N,N-dimethylcarbamoyl chloride are quoted in Table 111. Typically enough, both investigations

STUDY OF INTRAMOLECULAR RATE PROCESSES

135

yielded “normal” frequency factors, that is activation entropies very close to zero. A spin-echo study (68), on the other hand, yielded a frequency factor of log A = 10.9 (TableIII),which appears to be too low. It may be that the spin-echo method, though in general more reliable than any approximate treatment of line shapes, still suffers from some small systematic error whose origin is not understood at this time. It is gratifying that these conclusions receive independent corroboration by a recent paper by Walter, Maerten, and Rose (129) who succeeded in actually isolating the rotational isomers of 14 (the more stable “trans” H-C

// N ‘’

S CH3

I

H-C

// N ‘’

S

CHaCeHs

I

CHaCeHs

CH3

(144

(14~

isomer 14a in pure form, the “cis” isomer 14b enriched to 75%). The kinetics of their interconversion could be studied by conventional techniques and yielded activation energies of 25.16 & 0.46 and 25.12 f 0.46 kcal/mole and normal frequency factors of log A = 14.16 and 14.33 for the forward and reverse reactions, respectively. This piece of work also seems to confirm the qualitative conclusion reached by a number of workers (1 11,125-127) that the barriers in thioamides are higher than those in amides, but at the same time shows that this difference has sometimes been grossly overestimated (1 11). Incidentally, stable amide conformers have also been isolated in pure form by Staab and Lauer (130) in a case (15) where a severe steric interaction raises the barrier by

136

G. BINSCH

an additional amount. A preliminary estimate of 30-32 kcal/mole for the free energy of activation is mentioned in this paper. Before proceeding, a general comment about these activation parameters is in order. It has been noticed by many authors that the free energies of activation found by different workers for the same compound are in much better agreement than the Arrhenius values, and that the numbers for AG* also do not show the sometimes completely unintelligible scatter encountered with E, and log A (or A H * and AS*). One may suspect that the errors in E, and log A partly cancel in AG*, and this is precisely what one concludes from an analysis of the systematic errors introduced by various approximations. Some authors have therefore advocated that only AG* values be used for purposes of comparison. This would mean, of course, that one is prepared to waive the potential capabilities of DNMR and that rate measurements a t more than one temperature become illusory. Furthermore, the conclusion that the AG* values are good enough for establishing general trends simply because they do not show a severe scatter does not in any way appear to be warranted. The typical amide barrier persists in vinylogous compounds such as 16 (131,132), but seems to become attenuated with increasing number of

(CH3)aN-CH=CH-CO-R

[

(R=H, CBHB) CH3-C <JQCF

intervening double bonds (133). Hindered rotation was also detected in acetamidinium chloride 17 (134). Barriers of heights similar to those in amides have been found in carbamates. The most clear-cut example seems to be 18 where the splitting of the methyl resonance into a doublet below -3" indicates hindered rotation around the carbon-nitrogen bond with a free energy of activation of about 16 kcal/mole (135). The same type of rate process causes the methylene hydrogens A and B in 19 to become nonequivalent at low temperatures (1 35). It was claimed that hindered rotation around the carbamate bond also accounts for the temperature dependence of the NMR spectra of compounds such as 20 (136), but there is evidence

STUDY OF INTRAMOLECULAR RATE PROCESSES

137

c6HSCH2\N/C02C’2H5

I

C,H,CH,’

N

\CO,C,H,

(21) H5

c6

H,COzC H

Ci\C02CH3

C6H5

(137-139) that slow inversion at the two nitrogen atoms provides an

alternative and possibly preferable explanation (cf. Sect. VI). Even more ambiguities arise in 21 and 22 and similar systems. The low-temperature spectrum of 21 indicates the presence of at least four conformers (140), and the great number of possibilities has so far prevented a detailed identification of the various interconversions. Compound 22 is characterized by two distinct rate processes. The one with the higher barrier [AG* z 19 kcal/mole (141)] was attributed to ring inversion (141) (cf. Sect. VII), and this interpretation has survived (135,142-144) subsequent criticism (145). There is still disagreement, however, as to whether the other rate process with a AG* value of about 15 kcal/mole represents the restricted rotation in the carbamate structure (135,136,141,144) or a nitrogen inversion (143). A barrier ( E , = 16 kcal/mole) was discovered in 23 (90), but was attributed to hindered rotation in the ester function, based on the observation that only the 0-methyl and not the N-methyl group showed splitting at low temperature. Independent evidence for this highly surprising conclusion seems desirable. Restricted rotation has also been found in thiocarbamates (1 27).

G. BINSCH

138

D. Nitrosamines and Nitrites Hindered internal rotation in dimethylnitrosamine 24 was inferred from its NMR spectrum by Looney, Phillips, and Reilly (146) as early CH3

\ / / N-N /

0

++

CH3

CH3 0” \e / N=N

/

CH3

(Ma)

Wb)

as 1957 and has since been studied a number of times (Table IV). The origin of the barrier in this molecule can be explained in the same way as for amides, and its height seems to be of a similar magnitude to that in amides. The high-field peak was originally attributed to the methyl group trans to the nitrogen-oxygen bond (l46,147), but arguments were presented later (149) in favor of the reverse assignment. Replacement of the hydrogen atoms by fluorine results in a dramatic decrease of the barrier to about 5 kcal(150). Since the electron-attracting fluorines are

TABLE IV

Activation Parameters for the Internal Rotation in Dimethylnitrosamine. The Measurements Were Taken on Neat Samples Unless Stated Otherwise E,, kcal/mole 23 25 k 5 10

1 8-40 a 21.9 f 1.6 22.9 k 1.7

Log A 12.8 11.2

AG*,kcal/mole 23

Method C E C

12.0 12.8 21.1d

E SE SE F

Reference 146 147 147 147 78 78 148

‘These studies were done in ethylene glycol solution as a function of concentration. The lowest value for E, was found for a molar solute-solvent ratio of 0.2, the highest for a ratio of 0.5. Spin-echo measurements “on resonance.” Spin-echo measurements “off resonance.” dValue obtained from the coalescence temperature in a 1WMcps spectrum of a gaseous sample.

STUDY OF INTRAMOLECULAR RATE PROCESSES

139

expected to destabilize the resonance contributor 24b, this observation can easily be rationalized. When the nitrosamine resonance is transmitted through a benzene nucleus as in 25,the rotation of the nitroso group is still restricted, but the barrier is substantially lowered. Approximate formulas derived from the classical theory of exchange were applied to the spin-coupled aromatic protons in 25a (151) to yield AH* = 11.2 i- 1.1 kcal/mole and A S = - 3 k 5 eu. A single-parameter method derived from Alexander’s equations was later used to analyze the AB system in 25b (89) and activation parameters AH* = 14.9 f 0.1 kcal/mole and AS* = 4.8 f 0.4 eu were obtained. K H

R

H

(25a) R (25b) R

=H .= D

The temperature dependence of the NMR spectra of alkyl nitrites is thought to arise from the conformational interconversion between the nonequivalent forms 26a and 26b (152). Various investigators (19,66, R-0

/N=o

(26a)

-7

/N=o

A

R

(26b)

153,154a) found barrier heights in the vicinity of 10 kcal/mole. As for the nitrosamines, the original assignments have had to be interchanged (149). Brown and Hollis (149) recently also questioned the intramolecular nature of the rate process observed in the NMR by pointing out that a dissociation-recombination mechanism may be operative. However, no definite proof for such an alternative has yet been reported.

E. Aldehydes and Ketones When a carbonyl group is attached to an aromatic nucleus, stabilization due to resonance between the constituent T systems can only become effective in a planar arrangement and must get lost by rotation

G. BINSCH

140

into a perpendicular conformation. The anisotropy of an aldehyde or acetyl group should make such systems suitable for an NMR study. This expectation was first verified by Anet and Ahmad (154b) for the compounds 27a, b, and c. From the coalescence temperatures they estimated free energies of activation of 7.9, 10.8, and 9.2 kcal/mole, respectively. The differences between these numbers are in qualitative agreement with the known electron-donating powers of the dimethylamino and methoxy substituents. These findings were later confirmed (155) for 27b and d and extended to 27e and f, the latter two compounds showing free energies of activation about 2 kcal lower than the corresponding aldehydes. R

R\'P

27a H 2713 (CH3)aN 2 7 ~ CH3O 27d CH30 27e (CH&N 27f CH30

:
R'

H

R'

R"

H

H H H H CH3 CHa

D

H D D

D

A brilliant and very careful DNMR study of the internal rotation in 2-furaldehyde (28) has been reported by Dahlqvist and ForsCn (37,156) and it deserves to be discussed in some detail. At room temperature the

(1)

(28)

(11)

aldehyde proton shows up as a doublet of doublets (Fig. 7 4 , the smaller splitting of 0.30cps being caused by the 4-proton and the larger splitting of 0.77 cps due to long-range interaction with proton 5. Figure 8a shows the room-temperature spectrum of the proton in position 3, split by coupling to protons 4 and 5 (3.70 and 0.80 cps, respectively). The slow-exchange spectra are shown in Figures 7d and 8d. The intense aldehyde-proton doublet at higher field arises from a stereospecific coupling to proton 5 (1.10 cps) and the weak from a stereospecific coupling to proton 4 (0.85 cps). The 3-proton gives rise to two double doublets of unequal intensities and splittings identical to the roomtemperature spectrum of Figure 8a. Dahlqvist and ForsCn were able to

STUDY OF INTRAMOLECULAR RATE PROCESSES 5 cps

jv~

Tt = = +30.5OC 1 0 - ~sec

(a)

141

JVL

t = -52.5”C T = 0.014 sec

(b)

t T

-

= 115.5’C = 8.0 sec

(d)

Fig. 7. Experimental and calculated DNMR spectra for the aldehyde proton of 2-furaldehyde. [By permission of K. I. Dahlqvist and S. Forsen, J. Phys. Chem., 69, 4062 (1965).]

identify the strong peaks in the “frozen” spectra with conformer I and the weak with conformer I1 (28). From peak-area measurements at low temperatures and by detailed balancing of the stereospecific couplings to give “effective” aldehyde coupling constants in the temperature interval -40 to +50°, the thermodynamic functions for I and I1 could be evaluated. With a computer program based on HMM equations modified by the proper combination of coupling constants, chemical shifts, and populations for the various spin states in both molecules, an excellent fit was obtained for the experimental spectra in the region of broadening, both for the aldehyde and for the 3-proton. Figures 76,7c, 8b, and 8 c show four convincing examples. Table V lists the values calculated for 216°K. The set of numbers obtained from the analysis of the aldehyde proton differs slightly from that calculated from the spectra of the ring proton in position 3. The difference is just outside the

G. BINSCH

142 5 cps

t = +30.5"C 1 0 - ~sec

(a

T=

(b,

t = -52.5'C r = 0.014 sec

10 cps

'

t = -71.5'C = 0.18 sec

bk

-

T

(C)

t=

T

- 115.5'C

= 8.0 sec

(d)

Fig. 8. Experimental and calculated DNMR spectra for the proton in position 3 of 2-furaldehyde. [By permission of K. I. Dahlqvist and S. Forsen, J. Phys. Chem.,

69, 4062 (1965).]

TABLE V Thermodynamic Data and Activation Parameters for the Interconversion of the Rotational Isomers I and I1 in 2-Furaldehyde at 216°K Parameters

CHO proton

H-3 proton

E,, (kcal/mole) E,,, (kcal/mole) A H (kcal/mole) A H $ (kcal/mole) AH!, (kcal/mole) A S (eu) AS€(eu) A s $ (eu) AG (kcal/mole) A C $ (kcal/mole) A C (kcal/mole)

12.17 k 0.17 11.12 f 0.17 1.05 k 0.05 11.74 k 0.17 10.69 f 0.17 2.17 k 0.18 3.77 f 0.09 1.60 f 0.20 0.58 k 0.04 10.93 k 0.20 10.35 k 0.20

11.68 f: 0.21 10.63 f 0.21 1.05 f 0.05 11.25 f 0.21 10.20 k 0.21 2.17 k 0.18 1.21 k 0.06 0.04 f 0.19 0.58 f 0.04 10.77 f 0.23 10.19 f 0.24

STUDY OF INTRAMOLECULAR RATE PROCESSES

143

standard deviations. It would be extremely interesting to know if this last minor discrepancy could be made to disappear by basing the computation on the quantum-mechanical equations [eqs. (3 l)]. F. Miscellaneous Hindered Rotations

Hindered rotation in tetrafluorohydrazine 29 has been detected by 'OF DNMR (157). At -155" a superposition of an A4 and AA'BB' splitting pattern (about equal intensities) was observed, indicating the

F

qF F

FF+

F

presence of the conformers 29a, 29b, 29c in a 1 :1 :2 ratio. From the behavior of the spectrum at higher temperatures a barrier of 4-7 kcal could be estimated. A qualitative study of pentadienyl-lithiums 30 and 31 (158) revealed hindered rotation around formal single bonds, the rotations about the inner bonds in the five-carbon framework presumably being faster than the rotations about the outer bonds.

L

Li

The conformational interconversion between the nonequivalent rotamers 32a and 32b of diazoketones has been investigated by Kaplan and Meloy (23,159).

The frozen spectra of the predominant isomers were attributed to the s-cis conformation 32a. Analysis of the line shapes of the diazo proton

G. BINSCH

144

by a single-parameter method yielded activation energies in the range 9.0-18.2 kcal/mole for a number of alkyl and alkoxy-substituted derivatives. The interaction between a free electron pair on an amino-nitrogen atom and a .rr-electron system is also sufficient to produce a substantial barrier to rotation, especially if the .rr system contains electron-attracting groups. In the cyanine dyes (33) the activation energy decreases from 17 to 10 to 7 kcal/mole as n increases from 1 to 2 to 3 (160). A great number R' @

(CH3)sN-[CH=CH-]nCH=N(CHa),

\

,C=C,

/

H

(33)

of enamines (34)with phenyl, nitro, ester, and cyano substituents (161) and dimethylamino derivatives of fulvenes (35) (161 ,162) have been studied. The rotation about the carbon-nitrogen bond in 35 can be as severely restricted as in amides if the fulvene nucleus is heavily loaded with aldehyde groups, whereas the corresponding barriers in the hydrazones (36) are lower by about 5 kcal/mole (161). A careful

investigation was reported for the picryl derivatives 37 and 38 (56). The numbers are the result of complete line-shape calculations of the AB spectra due to the aromatic protons. It was concluded that intramolecular hydrogen bonding to the nitro groups in the ortho position must play an important role in fixing a planar conformation. In a number of papers Siddall and co-workers (163-167) reported hindered rotation about the benzene-to-carbonyl bond in orthodisubstituted benzamides of the type 39 and about the benzene-tonitrogen bond in molecules such as 40. Their evidence rests on the

STUDY OF INTRAMOLECULAR RATE PROCESSES

0

N

,

H

VN\CH3 /D

0

N

,

NO,

H

TN\N(C6H,), /H NO,

(38)

(37) E.

145

E.

= 14.5 10.3 kcal 'mole log A = 15.1510.3

= 12.5 f 0.2 kcaljrnole log A = 10.8r0.1

observation that the methoxy protons in 39 give rise to four different signals in the low-temperature spectrum and the methylene protons of the N-ethyl group in 40 are nonequivalent. The barriers in both cases

(39)

(40)

seem to be substantial, 20 kcal/mole or more (165,166). Qualitative observations at much lower temperatures communicated later by the same group of workers (168) indicate much lower barriers in the metadisubstituted analogs of 39. In many cases described so far appreciable barriers to rotation about formal single bonds could be explained by invoking resonance contributors that cause such bonds to assume certain degrees of double-bond character. The opposite case is also conceivable where a certain amount of single-bond character in a formal double bond lowers the barrier so much that rotation becomes amenable to a DNMR study. Molecules 41 (169) and 42 (170) are pertinent examples. The resonance form 41b

CHO

c3H1

CHO

c3H1

G. BINSCH

146

reflects the well-known tendency for cyclic conjugated systems to assume a closed-shell electronic configuration (“Huckel’s rule”). Compared to that, 42b does not look so favorable, but here a steric interaction may raise the energy of the planar form and thus contribute to a lowering of the barrier to rotation about the pivot bond. The barrier heights were estimated to be about 20 kcal/mole for both molecules.

VI. INVERSION OF LONE ELECTRON PAIRS A. Open-Chain Derivatives of Ammonia It has been known for a long time that the two equivalent, pyramidal conformations 43a and 43b of ammonia are separated by a potential

1:)

,N\FH H

H

(43a)

(43b)

barrier of about 6 kcal/mole (cf., e.g., ref. 171). Ammonia is, however, an exceptional case in that to get from one conformation to the other it is not necessary to cross this barrier, since the small masses of the protons enable the molecule to “tunnel” through the potential hill. This quantum-mechanical effect causes a splitting of the vibrational levels, which can be measured by microwave spectroscopy, and the magnitude of this splitting provides an indirect means to calculate the above-cited number. If the hydrogen atoms in ammonia are replaced by heavy atoms or groups, tunneling becomes negligible and the classical picture of an “umbrella motion” associated with the inversion of the lone electron pair on nitrogen provides an adequate description. No examples of tri-

STUDY OF INTRAMOLECULAR RATE PROCESSES

147

alkylamines have become known so far where such a motion could be frozen on the NMR time scale at low temperatures, but with the help of an elegant trick Saunders and Yamada (53) succeeded in measuring the inversion rate in dibenzylmethylamine at room temperature. The benzyl protons in each of the pyramidal conformations are diastereotopic (101) and should therefore give rise to an AB pattern. Rapid inversion would cause the AB spectrum to collapse to a single line, since the protons exchange environments by such a process. Analogous statements hold true for the protonated species, except that the ammonium ions are configurationally stable. In the presence of an acid-base equilibrium, however, the following possibility can be envisioned, +

R3NH

R3N

+ H+

RaN*

+ H+

+ R3N*H

where the asterisks denote the inverted species. If protonation and deprotonation are much faster than inversion, the “apparent” rate constant k‘ calculated from the AB line shapes due to the benzyl protons in the ammonium ions is given by

k‘

=

k,,,[amine]/([amine]

+ [salt])

(51)

since inversion can occur only during the time spent as mine. Saunders and Yamada were able to show that the condition of very rapid acidbase equilibration was satisfied. By plotting k‘ versus the concentration ratio in eq. (51) for a number of measurements on solutions of different pH, kin, at room temperature was calculated to be (2 f 1) x lo5 sec-l. This corresponds to a free energy of activation of about 10 kcal/mole. The inversion barrier increases if one of the alkyl groups is replaced by an alkoxy group, presumably because the mutual repulsion of the lone electron pairs on oxygen and nitrogen destabilizes the transition state (172). Griffith and Roberts (172) examined the low-temperature spectrum of N-benzyl-O,N-dimethylhydroxylamine.Again making use of the diastereotopic benzyl protons, a complete line-shape fitting of the spectra recorded for n-hexane solutions yielded an activation energy of 12.9 f 0.3 kcal/mole and log A = 12.8 f 0.3. The barrier was found to decrease with increasing dielectric constant of the solvent. No evidence was obtained for measurable inversion barriers in a number of similar compounds containing electronegative substituents. It is not clear whether this failure is due to low barriers or to an accidental equivalence of the anisochronous (101) benzyl protons. A qualitative

G. BINSCH

148

observation indicating a substantial inversion barrier in tris(perfluor0propy1)-hydroxylamine has also been reported (173).

B. Cyclic Derivatives of Ammonia

In the process of inversion a trialkylamine has to pass from a pyramidal conformation with approximately sp3-hybridized bonds and tetrahedral angles through a planar transition state in which the free electron pair resides in a p orbital and the bonds to the substituents subtend angles of about 120". One would therefore expect a stronger destabilization of the transition state relative to the ground state and a concomitant higher inversion barrier for those cases in which the nitrogen atom is part of a strained ring system. This was first shown to be the case for 44 and 45 in a pioneering investigation by Bottini and

(44)

(45)

Roberts (174,175). The AA'BB' spectrum of the ring protons in 44 coalesces to a single line at 108 & 5" and the AB spectrum of the ringmethylene protons in 45 at -65 f 10". A great number of substituted aziridines have since been studied by DNMR (176183). Much of this work was done before the appropriate theories had been developed and the numbers estimated for the sometimes rather complex spin systems are therefore not likely to be very meaningful; we will not reproduce them here. Nevertheless,judging from the differences in the coalescence temperatures, it seems reasonably certain that all substituents on the nitrogen atom and in the aziridine ring that offer a possibility for delocalizingthe p electrons on the nitrogen in the planar transition state cause a substantial lowering of the barrier heights, a conclusion which is not unexpected. The size of an N-alkyl substituent, on the other hand, does not appear to have a significant influence on the barriers. This is in agreement with the observation that 2,2,3,3-tetramethylaziridine still shows two methyl signals at room temperature (in dry CCl,) (184). The claimed deuterium-isotope effect (1 84) in this compound, however, cannot be reconciled with theoretical expectations(185). Splitting of geminal

STUDY OF INTRAMOLECULAR RATE PROCESSES

149

nuclei into AB systems due to slow nitrogen inversion has also been observed in the oxaziridine 46 at room temperature (186) and in the

1

0 C

d

\

N-C(CH& (46)

CHZ-C

I

/

N-N

//

0

\

I

CBHI (47)

\

CF3 N-0

I

CeHs

I

CFa-CFa (48)

four-membered rings 47 (187) and 48 (188) 30-50"below room temperature. Nitrogen inversion in larger rings seems to be too fast to be detected by DNMR (175), except in derivatives of the type 49 (189,190) 0

Q where steric hindrance raises the inversion barrier by such an amount that the frozen conformers can still be seen in the NMR 100" above room temperature. Analysis of the AB line shapes of the a-methylene protons in 49 by a single-parameter method derived from Alexander's equations yielded (190) an activation energy of 23.0 f 1.0 kcal/mole and log A = 14.1 i-0.5. A surprisingly high resistance to nitrogen inversion is found in those ring systems that contain two directly bonded nitrogen atoms. Mannschreck, Radeglia, Grundemann, and Ohme (191) examined a series of substituted diaziridines 50 with R = H and CH3. In no case could a coalescence or even broadening of the peaks be accomplished in the accessible temperature range. This places a lower limit of about 23 kcal/mole on the free energies of activation. The fact that the ringmethylene protons in 51 give rise to a singlet but the ethyl resonances

G . BINSCH

150

(9)

(51)

show ABC3 spectra demonstrates a comparatively rigid trans arrangement of the alkyl groups on the two nitrogen atoms. This interesting “geminal nitrogen effect,” probably partly steric in origin, has been noticed in larger rings as well. The methyl and methylene resonances in 52 show splitting at low temperatures and collapse to singlets on rapid

(52)

(53)

(54)

(55)

simultaneous inversion at both nitrogens (192). From the coalescence temperatures a free energy of activation of 12 kcal/mole was estimated (192). Two groups of workers (137-139) have studied the bicyclic systems 53-55. The activation energies lie in the range 14-17 kcal/mole and are similar for corresponding compounds where R is methyl or carbomethoxy. This seems to indicate that the same type of rate process, a consecutive inversion at the two nitrogen atoms which converts the stable trans arrangement of the two R groups into its mirror image, is operative in both cases. In view of these observations the idea that the changes in the N M R spectra of 20 and 22, which we discussed in Section V, are due to restricted rotation in the carbamate structure is open for discussion.

C. Derivatives of Imines There are two possible pathways by which an imine-type molecule 56 may oscillate between the conformations a and b, either by inversion of the free electron pair (and R ) in the plane of the double bond or by

STUDY OF INTRAMOLECULAR RATE PROCESSES

151

rotation about the carbon-nitrogen bond. Although the first alternative appears more likely (193), the second has sometimes been preferred (194), but neither has thus far been proven beyond doubt. It is of course conceivable that either mechanism may be operative and that the details of the structure determine which will have the faster rate. The fact that we discuss these rate processes in Section VI only reflects the personal opinion of the author. Imines in which R is alkyl(195), alkoxy (193), or halogen ( I 93) have higher barriers than are accessible by DNMR, and the stereoisomers have frequently been isolated in pure form. Only in highly fluorinated derivatives such as 57 (150) and 58 (196) and for R = phenyl have temperature effects on NMR line shapes been noticed. CF3

\

/

CF(CF&

F

\

/CF(CF3)2

F /C=N

/C=N CF, (57)

(58)

CH,

\

/

CeHs

/C=N CH3 (59)

The two methyl peaks of 59 in quinoline solution coalesce at 140°, yielding a free energy of activation of about 21 kcal/mole (195). Curtin, Grubbs, and McCarty (193) studied a whole series of paru-substituted triarylimines and obtained activation energies between 17 and 20 kcal/mole. The barriers in para-substituted iminocarbonates 60 are only about 13 kcal/mole and depend very little on the nature of the substituent X (194).

D. Other Elements DNMR information about inversion barriers in elements other than nitrogen is very scarce. We are aware of only two papers in this field, one by Lambert and Mueller (197) about phosphorus inversion in diphosphines and the other by Abel, Bush, Hopton, and Jenkins (198) about a sulfur derivative. Inversion barriers in trivalent phosphorus compounds must be substantially higher than in the corresponding amines, since it has been

G.BINSCH

152

possible to prepare optically active phosphines (see Chapter 1). A “geminal phosphorus effect” in the diphosphines 61,presumably due R =CH,

(61a)

(61b) to the availability of low-lying d levels in phosphorus, brings the barrier down to where it can be studied by DNMR. A single inversion at either

phosphorus interconverts the meso and dl forms 61a and 61b. Lambert and Mueller were able to identify the changes in the spectra on variation of the temperature with this process and to derive an activation energy of 26.0 i-2.0 kcal/mole from a complete line shape fitting of the aromatic resonances in the deuterated compound 61. Sulfur inversion was invoked to explain the splitting of the methyl resonances in the platinum and palladium complexes 62 and 63 (198).

(62a)M = Pt (63a)M = Pd

(62b)M (63b)M

= Pt -

Pd

The cis and trans isomers a and b give rise to separate resonances of unequal intensities below 95” for 62 and below 40”for 63.The spectrum of 62 is actually further complicated by the presence of magnetic and nonmagnetic platinum isotopes. The spin-spin splitting in 62 due to loapt is preserved even after the separate resonances of a and b have collapsed, thus indicating that sulfur inversion and not breaking of the sulfur-metal bonds is responsible for the spectral changes. The inversion barriers have not yet been determined (the numbers tentatively suggested by the authors are certainly far too low). Detailed investigations of inversion processes in organometallics, especially Grignard reagents, have been carried out by two groups of investigators (1 99-204). Since the experimental evidence clearly demonstrates that inversion of the free electron pair in the corresponding carbanions is not the rate-determining step, but rather that one is

STUDY OF INTRAMOLECULAR RATE PROCESSES

153

dealing with a slow bond breaking or bimolecular mechanism, we are only mentioning these papers in passing.

VII. RING INVERSIONS A. Cyclohexanes and Cyclohexenes There is no single molecule in the whole domain of stereochemistry that plays as central a role as cyclohexane. This carbocyclic system not only serves as a unique model framework to demonstrate many basic concepts and to elucidate the intricate relationships between chemical reactivity and three-dimensional shape, but it also was the secret code par excellence to open the door to the quantitative era of conformational analysis. The accumulated body of thermodynamic data [for the most recent compilation see the article by Hirsch (205)] already allows a detailed evaluation of the factors contributing to conformational preferences (206). Much added insight would no doubt be gained by complementing these values by the corresponding kinetic parameters. There has been no lack of effort to obtain such information from DNMR measurements; in fact, more than 30 papers have been published dealing with cyclohexane and its derivatives alone. It may therefore be somewhat surprising when we hereby express the opinion that the kinetic aspect of cyclohexane stereochemistry has not yet developed far from infancy. Let us first discuss what one can deduce about the cyclohexane ring inversion from theoretical considerations. Semiempirical strain calculations by Hendrickson (207) indicate that a planar cyclohexane lies about 30 kcal/mole above the energy of the stable chair conformation. If the chair-chair interconversion had to proceed through a planar transition state, equatorial and axial conformers of monosubstituted cyclohexanes should exist as stable isomers at room temperature, which is clearly at variance with all experience. It is now generally agreed that the energetically cheapest pathway for the ring inversion crosses a half-chair or “cyclohexene-like” transition state and that the incipient motion continues to the metastable boat conformation (Fig. 9). The boat, about 6 kcal/mole above the chair, can alleviate a small portion of its strain (a kilocalorie or so) by distorting itself to a twist boat and this “pseudorotation” can continue around the ring with great ease, reflecting the contention that the conformers of the boat family are rather “floppy.”

154

G . BINSCH I

I

"Cyclohexenelike" barrier form

, w + H

(and 3 other

"Cyclohexenelike" barrier form

R

10

-.

m

1

++- 5

z

Chair ground state, R axial

a

a

'-

4 "twist-boat" forms

Chair ground state, R equatorial

H

R Reaction coordinate

Fig. 9. Reaction path for inversion of monosubstituted cyclohexanes. [By permission of F. A. Bovey, E. W. Anderson, F. P. Hood, and R. L. Kornegay, J. Chern. Phys., 40, 3099 (1964).]

The boat will eventually receive enough energy to cross the halfchair barrier again, thus either returning to the chair from which the whole sequence of events started or crossing over to the inverted chair. For cyclohexane itself the overall rate constant for the chair-chair interconversion, k,,, is therefore just one-half the rate constant of the chair-boat process, kcb.In monosubstituted cyclohexanes there will not only be a ground-state energy difference between the chair forms in which the substituent is equatorially or axially oriented, but one also obtains a number of nonequivalent boats, twist boats, and half-chairs, their energy differences being schematically indicated by dashed lines in Figure 9. As long as the DNMR spectra only respond to the net chairchair interconversion, as was the case in all investigations published so far, the (presumably small) differences in the activation energies connecting one of the chair conformations with the various boat forms must remain unobservable; one can calculate only a statistically weighted average. The extension of these general considerations to polysubstituted cyclohexanes is straightforward. As we shall see presently, most of the controversy in DNMR investigations of cyclohexanes has been centered around the activation

STUDY OF INTRAMOLECULAR RATE PROCESSES

155

entropies found by various workers. Before we discuss their results, we will attempt to guess the theoretical order of magnitude to be expected for such numbers from statistical mechanics. Since we are dealing with species of the same total mass, the translational partition function contributes nothing to the entropy difference. The rotational partition function is given by (208) QR = (8n2k,T/h2)3’2[(nZ,ZyZ,)1’2/u]

(52)

and contributes S& -

s,“= R In (Qh”clQ3

(53)

to the entropy difference between the half-chair (hc) and chair (c). Assuming reasonable structural parameters, the products of the three principal moments of inertia [(Z,, I,, Z, in eq. (52)] differ by such small amounts for the chair, half-chair, boat, and twist boat that their effect on the logarithm of the ratio in eq. (53) may be neglected (209). The quantity u in eq. (52) is the so-called “symmetry number” (208) and represents the number of possible arrangements of equivalent atoms that are related by rotational axes: uc = 6 , uhC= 2. The rotational contribution to the entropy of activation then turns out to be ASR* = R In (uc/uhc)= R In 3 (eu)

(54)

To obtain the total activation entropy, AS*, one has to add the vibrational contribution, ASv*, and take account of the fact that the half-chair is dissymmetric, the latter property introducing an additional probability factor of 2 [“entropy of mixing” (210)l. Thus, AS*

=

ASR* + R l n 2

+ ASv* = 3.6 + ASv*

(eu)

(55)

It may sometimes be easier and more instructive to derive the contribution corresponding to R In 6 = 3.6 in eq. (55) by the “directcount’’ approach (2 1 1) : there are 6 equivalent ways for the chair to get to the half-chair. It remains to estimate the vibrational partition functions. Their contribution to the total entropy of hydrocarbons is small in the first place, since at ordinary temperatures only the lowest vibrational levels are populated to any significant extent. For cyclohexane itself, for instance, this vibrational contribution only amounts to 9.3 eu (212). ASv between

G . BINSCH

156

isomers is therefore likely to be still smaller. It is known (213) that the twist boat form of trans-l,3-di-t-butylcyclohexanehas an entropy 5 eu higher than that of the chair. There is no contribution from symmetry, so this number provides an upper limit for the vibrational entropy difference between chair and boat. Although there can be little doubt that this is in fact a very generous estimate, since both the differences in the moments of inertia as well as restricted rotation of the axial t-butyl group in the chair conformation of this special compound are expected to contribute appreciably, the result is qualitatively in the expected direction, since the high flexibility of the twist boat will produce some rather low-lying vibrational levels. If one accepts the assumption that the flexibility of the half-chair is somewhere between that of the chair and that of the twist boat, the theoretical entropy of activation for the cyclohexane chair-to-boat conversion is bound within the limits +3.6

< AS:,, <

+8.6 eu

(56) For substituted cyclohexanes, of course, this range has to be modified according to the appropriate symmetry properties. Specifically, for monosubstituted and 1,l-disubstituted cyclohexanes one obtains 1.4 < ASlb < 6.4 eu on the average. The above consideration rests on the hypotheses of transition state theory and on the assumption of a transmission coefficient of unity. It may be argued that transition-state theory does not apply here. This objection would be very hard indeed to refute on theoretical grounds. But then the author believes that much more ironclad DNMR evidence than now exists is required to demand a revision of so widely accepted a concept. On the contrary, the recent high-quality work seems to confirm the validity of transition-state theory. Be that as it may, whenever DNMR yields entropies of activation differing vastly from those expected, we have good reason to be highly surprised, to say the least. At room temperature cyclohexane gives rise to a single sharp NMR signal. Below -70” this peak splits into two structured bands of equal intensity with a chemical-shift difference of about 0.5 ppm. The upfield resonance is due to the axial protons of the “frozen” chair conformation; the equatorial protons absorb a t lower fields. Table VI shows that there have been a few attempts to obtain the rate constants of the ring inversion from the line shapes of cyclohexane itself, but, since the spectra are very complicated as a consequence of spin-spin coupling, only an approximate treatment is possible. There are three ways to get around

STUDY OF INTRAMOLECULAR RATE PROCESSES

157

this difficulty and all of them have been applied in the case of cyclohexane (Table VI). ( I ) Use of the spin-echo technique. For a certain range of rates the influence of spin-spin coupling on the echo decay may be neglected. (2) Heavy deuteration and deuterium decoupling. Undecadeuterocyclohexane shows two sharp unsplit signals at the low-temperature limit. (3) Use of the fluorine-labeling method. Table VI reveals that the general error situation is very much better than in the case of the amides, for instance. In fact, the free energies of activation found by the various investigators all agree very closely. Unfortunately, this is not the case for the entropies of activation. In view of our previous discussion one is tempted to conclude that the negative values cannot be correct. This seems to be confirmed by the full line-shape analysis applied to the deuterium-decoupled spectra of undecadeuterocyclohexane by Bovey, Hood, Anderson, and Kornegay (22 I), by the investigation of 1,l-difluorocyclohexane by Roberts and his group (223), and especially by the recent, extremely careful highresolution and double-resonance work by Anet and Bourn (83). However, a spin-echo investigation of undecadeuterocyclohexane, in which rates could be determined over a temperature range of 123" (!), gave an entropy of activation of - 5.8 & 0.4 eu (70). The author of the present review does not have an explanation for this disconcerting discrepancy. Apart from the cases listed in Table VI, symmetrically 1,I-disubstituted (226) and I , 1,4,4-tetrasubstituted (223,226-229), monosubstituted (22, 230-234), and polysubstituted (223,229,23 1,232,235-240) cyclohexanes have also been studied by DNMR. The data obtained by Bovey and co-workers (22) for fluorocyclohexane by a complete line-shape analysis of its proton-decoupled fluorine spectrum may serve as a typical example. Peak-area measurements at low temperatures and the averaged shift at high temperatures yielded enthalpy and entropy differences of A H o = 471 f 50 cal/mole and A S o = 1.05 i-0.10 eu between the axial and equatorial chair forms (Fig. 9, R = F), and the following average activation parameters (at 218°K) AG& AG;,

= =

10.14 f 0.05 kcal/mole A H $ , = 9.87 f 0.10 kcal/mole A H : , = 9.40 f 0.10 kcaI/mole 9.90 f 0.05 kcal/mole AS:, = - 1.46 & 0.40 eu AS:, = -2.51 f 0.40eu

Solvent

C6H12 CS2 cs2 C6Hl2 cs2 C6H12 C6H12 -e C6H12 -e C6H12 cs2 cs2 C6H12 CeFiz CFC13, C&,CF3 CsF12 Neat, isopentane -e CsHDii cs2 C6HDii cs2 CsHDii cs2 CsHDii cs2 CsHioFz C6HioFz CFC13 cs2 GHioFz cs2 C6H10F2 CsHioFz Propene

Compound

10.5 11.3

9.5

A' SE 9.5 A,1 DR Bm 9.5 B" 9.1 SE" 9.8 SE" 9.9 A 10.9

-1.J

C, D D D SE SE D SE

F

Log A

AG* a, kcal/mole

9.7b Coalescence temperature 10.1 f. 0.1 10.3 10.3 10.7 f 0.5 11.7 10.3 9.9 f 0.2 12.1 10.5 f 0.6 10.3 10.2 f 0.1 11.6 10.3 10.3 rf: 0.1 12.4 9.4 f 0.3 12.0 9.4 f 0.1 12.7 9.5 f 0.1 12.6 9.7 f 0.4 13.8 f 0.4 9.5

E,, Method kcal/mole

AS, eu

Reference

- 1.1 +4.4 f 2

220,221 70 83 57 57 71 71 88,222,223

2.3k 61

72

214 215 216 1.0' 60 0.9' 217 218s 2.4 70 219 +1.4 k 1.0 -5.8 f 0.4 +2.8 k 0.5' - 1.9 - 3.6 - 0.6

at 40 Mcps f. 2" +4.9d f 0.2' -6.5 k k 0.2' -0.2 k +4.9 f 0.5 -5.8 f f 0.3 -10.7" f 0.2 -3.0 f 0.6 +2.9 rf: 10.5 0.5 9.1 f 0.1 10.8 f 0.1' 9.04 8.64 9.34 9.44 10.43

-71" 11.1 9.0 10.3 11.5 9.1 7.5 9.9 10.9

AH*, kcal/mole

Activation Parameters for the Cyclohexane Ring Inversion as Obtained from DNMR Measurements on Cyclohexane, Perfluorocyclohexane, Undecadeuterocyclohexane, and 1,l-Difluorocyclohexane. The Arrhenius parameters refer to the net chair-to-chair interconversion, the Eyring parameters have been converted to the chair-to-boat process unless indicated otherwise

TABLE VI

?

aAt -65". bValue for the chair-to-chair process. "Allerhand, Chen, and Gutowsky (70) later calculated a value of 5.9 kcal/mole from the data of ref. (216), but this calculation was based on a misunderstanding (224,225). dAssumed value. This value is based on the assumption of an unsymmetrical transition state; for the half-chair it would be + 3.6 eu. Solvent not specified. 'The data in ref. (60) were replotted in a different way to give the numbers in ref. 217. =As reported in Table I of this reference. The values AH* = 11.4 kcal/mole and A S * = 4.0eu are quoted as private communication on p. 116 of J. E. Leffler and E. Grunwald, Rates and Equilibria of Orgunic Reactions, Wiley, New York, 1963. hValue obtained from a plot of log k versus 1/T. The relation AS* = d(AG*)/dT yielded AS* = -9.7 eu. Although the author mentions a statistical factor of 2, we are not absolutely certain that these data refer to the chair-to-boat process. Measurements performed on deuterium-decoupled spectra. 'The rate constants were calculated "in the usual way," presumably by methods C and D. ref. 83 the authors mention that the slowexchange rates in ref. 61 shouldjbe corrected by a factor of 2. Because of the considerable scatter of the points in ref. 61, the activation parameters were not recalculated. 'Estimated errors, presumably including statistical as well as systematic deviations. Calculations based on least-squares computer fit on Alexander's AB equations. The proton-fluorine coupling was neglected. "Calculation based on the chemical-shift difference of 18.5 ppm found from the echo decay. OCalculation based on the chemical-shift difference of 15.64 ppm found in the low-temperature high-resolution spectrum.

!a

z

c U <

G . BINSCH

160

for the two different chair-to-chair processes were found to reproduce the observed line shapes. If there is one general conclusion that can be drawn from the DNMR studies of substituted cyclohexanes, it is that they all exhibit very similar barrier heights, rather close to those found in cyclohexane itself. This being so, any inferences one wishes to draw from the dynamic aspects of cyclohexane stereochemistry place high demands on the accuracy of the corresponding DNMR measurements and their mathematical analysis. These stringent requirements have so far been met by only very few studies in this field. It is likely that this situation will improve in the future, and the recent report by Jensen and Bushweller (241) about a successful isolation of the equatorial isomer of chlorocyclohexane in pure form at low temperature offers the possibility of checking and supplementing DNMR studies by conventional rate determinations. A half-chair analog of the transition state discussed for the cyclohexane ring inversion is thought to be the most stable conformation of cyclohexene. By following the spectral changes in the deuterated compound 64 down to - 170°, Anet and Haq (242) were able to estimate a free energy of activation AC* = 5.3 kcal/mole for the inversion 64a + 64b. A boat form is believed to be an intermediate in this process

(64)

(64b)

(65)

also and the transition state can be described by a conformation having 5 carbon atoms in a plane (half-boat). A similar value of AGI = 5.9 kcal/ mole was reported (243) for 4-bromocyclohexene. Curtin and coworkers (244) have interpreted the NMR spectra of compounds such as 65 in terms of restricted inversion between two rigid boat forms with nonequivalent methyl groups, characterized by an activation energy of about 16 kcal/mole. B. Six-Membered Heterocycles DNMR investigations have been reported for a great variety of heterocyclic analogs of cyclohexane. Line-shape measurements on these

STUDY OF INTRAMOLECULAR RATE PROCESSES

161

compounds are frequently much easier to perform than on cyclohexane itself, either because the heteroatoms “insulate” certain simple spin systems or because there are convenient synthetic routes for introducing deuterium atoms .or methyl groups at certain positions. The pertinent data are collected in Table VII.

I

K

(66)

(67) X = 0 (68) X = S (69) X = NR

(77)

(70) X = Y = NCH3 (73) + (71) X = Y = N(CH& (74) (72) X = 0, Y = NCH3 (75) (76)

X X X X

=Y = 0

= Y = NCH3

=Y =S = 0, Y = S

0 (784

Although it may be taken for granted that the chair form is the most stable conformation in all the heterocyclic compounds listed in Table VII, a conclusion which is, incidentally, strictly demanded in many cases by the N M R spectra, there will undoubtedly be substantial differences in geometry due to differences in bond lengths, bond angles, and repulsive properties of the free electron pairs as compared to the situation in the carbocyclic framework, and these factors must in turn affect the barrier heights to ring inversion. As is unfortunately too often the case in D N M R , the suspected unreliability of the numbers makes one reluctant to discuss many of the experimental results in detail. The two complete line shape investigations in this field consistently show that the activation energies in the nitrogen heterocycles 66 and 77 are somewhat higher than in cyclohexane, 14.5, 14.4, and 14.0 kcal/mole for 66 a, b, and c and 14.2, 12.1, 1 1.3, and 10.8 kcal/mole (in n-pentane) for 77a, b, c, and d, respectively, and that they decrease with increasing bulk of the substituents at the nitrogen atoms. An interesting aspect of these nitrogen heterocycles (except 71) is that in addition to ring inversion a nitrogen inversion process must also be involved. It can, however, be

73a

12

71

69a 69b 69c 70

68C

68b

68a

66a 66b 66c 66d 67

Compound

4,4,5,5-D4

3,3,5,5-D4 3,3,5,5-D4 3,3,5,5-D4 Perfluoro 3,3,6,6-Me4

~

14.5 f 0.5 14.4 14.0 6.1 f 1.5 11.7 18.5 16.1 f 1.2

E,, kcal/mole

13.3 f 0.3

11.5 16.1 3,3,6,6-Me4 ci~-4,5-(OAc)~ 12.0 Me 3,6-Ph2 Me 4,5-Me2 C02Et 4,5-Br2-4,5-Me2

CMe3 F

Me

H

R

Other substituents

~~~

14.3

16.6 14.3 f 1.0

16.9 f 1.5 14.8 15.2

Log A

9.7 f 0.2

11.5

12.9 f 0.3

11.2 12.3 20.1 12.6

11.6

kcal/mole

AG*,

9.3 f 1.2

kcal/mole

AH*,

- 13.9 f 5.6

AS, eu

Ring Inversions of Saturated Six-Membered Heterocycles Studied by DNMR

TABLE VII

245,246 (A) 245,246 (A) 245,246 (A) 66 (D,SE) 247 (C) 248 (C,E) 24 (A") 249 (F) 250 (C) 248 (C,E) 250 (C) 137 (F) 137 (F) 136 (F) 251 (F) 252 (D,F) 227 (C) 251 (F) 236 (F)

Reference (method)

Et

i-Pr t-Bu

14.2 12.1 11.3 10.8 12.3 14.2

+

f 0.8 f 1.1 0.7 f 0.9

k 1.5

12.5 f 1.0

13.5 f 1.2

14.1 12.9 13.1 13.2 10.6

k 1.2 f 0.7 f 1.0 f 0.7 f 0.6

13.6 f 0.9

15.0 f 1.2

12.8 f 0.1 12.6 k 0.1 12.0 f 0.1 10.8 f 0.1 10.2 f 0.1

11.3 f 0.4 9.4 f 0.3 9.8 f 0.2 10.3

11.2

14.1 f 0.2

+

12.4 f 0.8 9.1 0.9

10.2 f 1.0 6.3

5.1

+ 0.7

9 2 4 4 + 5

6 + 5 -7

255 (C) 25513 (A)

58 (A) 58 (A) 58 (A)

253 (C,D) 236 (FA 253 (C,D) 236 (F) 24 (A") 253 (C,D) 253 (C,D) 254 (F) 236 (F) 236 (F) 236 (F) 24 (A") 255a 58 (A)

*Careful studies employing a modified single-parameter method which is probably equivalent to a full line-shape analysis.

77b 77c 77d 78 7%

Me

2,2-Mez 5,5-Me2 2,2,5,5-Me4

5,5-Mez

73c

73d 74 75a 75b 75c 76 772s

2,2-Mez

73b

G.BINSCH

164

deduced that the latter process is much faster than ring inversion. This becomes apparent from the observation that only th‘e signals of the ring protons in 70, for instance, but not the methyl resonances are affected by changes in the temperature. In view of the very small barrier in cyclohexene (Sect. A), it is rather surprising to find substantial activation energies to ring inversion in diaza analogs, of the order of 12 kcal/mole in substituted derivatives of 79 where R is alkyl (137,256), and about 20 kcal/mole in systems such as 80 (135,136,142-144).

(79)

(80)

As already mentioned in Section V, there has been some doubt (145) whether the barriers in derivatives of 80 were correctly attributed to ring inversion, but the objection could later be overcome (135,142-144). The reasons for the dramatic increase of the cyclohexene barrier on introduction of the two nitrogen atoms and for the difference between 79 and 80 do not seem to be well understood at this time. It appears questionable whether steric hindrance alone could account for the magnitude of the effect.

C. Seven-Membered Rings In contrast to the conceptually rather simple situation in cyclohexane, the number of conformational possibilities increases steeply with the insertion of additional methylene groups and so does the number of different modes of interconversion. There is consequently little hope of obtaining meaningful DNMR information from the parent hydrocarbons themselves; one has to resort to one of the labeling techniques discussed in Section IV-A. Another prominent feature of medium and large rings is a pronounced floppiness in many of the conformers; chances of freezing them out on the N M R time scale may therefore become rather slim. Cycloheptane happens to be such a case. Hendrickson’s (257) strain calculations indicate a twist chair with C, symmetry as the most stable conformation, but unlike cyclohexane, this cycloheptane twist chair can pseudorotate with great ease, crossing the barrier of a chair with C, symmetry to another twist chair on its itinerary. The

STUDY OF INTRAMOLECULAR RATE PROCESSES

165

pseudorotation alone is sufficient to average out all the different positions in cycloheptane, and since Henrickson's calculations suggest a barrier of only 2 kcal/mole to this motion, it is not surprising that no evidence for an exchange process could be found in 1,l-difluorocycloheptane down to - 180" (88). Roberts and co-workers (88,258) were, however, successful in slowing down the rate of pseudorotation by introducing substituents that aggravate the steric hindrance to conformational mobility and cause differences in the potential minima so that only a few preferred conformations have to be considered. The single fluorine resonance in the decoupled room-temperature spectrum of the derivative 81, for instance, splits into two singlets with an intensity ratio 74:26 below - 114"(258). This result has been rationalized

E h F

Br+=: Br H

F

Br

(814

(8W

in terms of a conformational equilibration between the twist-chair forms 81a and 81b. The authors feel that the activation parameters AH* = 9.8 f 0.3 kcal/mole and AS* = 15 f 3 eu are in better agreement with a chair-boat process rather than a pseudorotation. The degree of conformational freedom in the seven-membered ring diminishes by the introduction of a double bond. Models indicate that only the conformations 82a-c have to be considered.

Boat

Twist boat

(82b)

(823

A low-temperature NMR study of 5,5-difluorocycloheptene (258) revealed the exclusive presence of the chair conformation and yielded activation parameters for the chair-to-chair interconversion AH* = 7.4 f 0.1 kcal/mole and AS* = -0.2 k 2 eu. The same conclusion was reached and similar activation parameters estimated for the hetero system 83 (259), whereas the corresponding oxygen analog seems to

166

G . BINSCH

CH.

(83) R (84) R

-

H

CH,

(85) X - CD,, R -= H (86) X = CH,, R == CH, (87) X = S, R -= H (88) X S, : R -- CH, (89) X = 0, R - CH,

(90)

show an appreciably lower activation energy (259). Chair-to-chair inversion barriers 2-4 kcal/mole higher were found in the benzo systems 85-88 (24,259,260). The most likely mechanism for these conformational interconversions (261) can schematically be represented as follows (the asterisks indicate the inverted species) : (twist boat)

(chair)+(boat)

z'

I\L

r\L

/I

- (boat)*+(chair)*

(twist boat)*

Although the conformers of the boat family are ordinarily too high in energy to be detected by NMR, quite a few exceptions have been reported. The low-temperature spectrum of 84 shows 3 methyl signals, indicating an equilibrium mixture of chair and twist-boat conformers in the ratio 2: 1 (259). The ring-methylene protons of 89 give rise to an AB pattern below -76", but the methyl singlet remains unchanged down to - 127" (259). This could mean that only the twist-boat form is present and that pseudorotation has been frozen out. Compound 90 provides an even more interesting case (261). Its spectrum at +165" consists of 3 singlets for the aromatic, methyl, and methylene protons, respectively. By cooling to room temperature this pattern changes to 2 methyl peaks, 2 aromatic peaks, and an AB and Az pattern for the methylene protons. On further cooling the Az peak splits into a second AB pattern. Obviously the chair-twist boat-chair process is frozen out first (AGt = 19.8 kcal/mole) and eventually also the pseudorotation (AG* = 11.5 kcal/mole). Still a different mechanism seems to operate in the tetramethylbenzocycloheptene 91 (262), which is thought to exist as a mixture of chair and boat conformers and exhibits two distinct rate processes with activation enthalpies of 12.6 and 9.3 kcal/mole and

STUDY OF INTRAMOLECULAR RATE PROCESSES

167

activation entropies of - 1 and - 10 eu, respectively. Space limitations, unfortunately, do not permit a detailed discussion of the many intricacies of this highly intriguing case. Conformational rate processes in 1,3-~ycloheptadieneshave so far only been studied in the dibenzo hetero systems 92 and 93, or, to express it in more familiar terms, in singly and doubly bridged biphenyls (55,263-265).

(92)

(93)

(94)

The well-known deviation from coplanarity in the stable conformation of biphenyls causes the aliphatic methylene protons to become diastereotopic (94) and to split into AB systems as soon as the rotation about the biphenyl pivot bond and the concomitant ring inversion of the 1,3cycloheptadienyl system become slow on the N M R time scale. Kurland, Rubin, and Wise (55) applied a complete line shape analysis to the compounds 92 with R = H and Y = 0 and S and obtained activation energies of 9.2 i- 1.O and 16.1 f 0.3 kcal/mole, respectively. N M R investigations have shown that cycloheptatriene exists as a mixture of rapidly equilibrating boat conformations. Line broadening in the low-temperature NMR of a derivative was first noticed by Conrow and co-workers (266), and cycloheptatriene itself has subsequently been studied by Anet (267) and Jensen and Smith (268). A free energy of activation of about 6 kcal/mole was estimated from the coalescence temperature of the geminal-proton AB spectrum. AG* rises to 15 kcal/ mole in the dibenzo derivative 95 (269), and the collapse of the methoxy

NHC,H,

168

G. BINSCH

protons in 96 cannot be achieved in the accessible temperature range (269). Aza analogs such as 97 also show higher inversion barriers than cycloheptatriene itself (270). Free energies of activation for a number of 7,12-dihydropleiadenes 98 were reported (271-274) to be in the vicinity of 13.5 kcal/mole.

D. Eight-Membered Rings Although several DNMR attacks have been launched at unraveling the conformational multifariousness of cyclooctane, the final word has probably not yet been spoken. It is usual to partition the various conformations into five generic families : crown, chair, tub, boat-chair, and saddle. Hendrickson's (275) and Wiberg's (276) strain calculations can serve as a guide for the relative energies of the parent forms as well as their twisted 'variants. Some of these conformations are depicted in Figure 10. The first quantitative DNMR study was performed on pentadecadeuterocyclooctane (277). The deuterium-decoupled proton resonance changes from a singlet at room temperature to two equally intense signals at - 135". The spectral changes have been attributed to a rate process with an activation energy of 7.7 kcal/mole. Although this result is perfectly consistent with a crown conformation and a rate process corresponding to crown inversion, it does not rigorously exclude the possibility of a rapidly equilibrating mixture of conformations at the low-temperature limit. On the basis of later studies on selectively deuterated (278) and alkyl-substituted (279) cyclooctanes and on perfluorocyclooctane (280), the exclusiue presence of the crown could actually be ruled out. The low-temperature results are believed to be in concordance with a rapidly equilibrating mixture of crown, stretch crown, twist crown, boat-chair, and twist boat-chair forms, but not

0

-

N

e

c

3

Fig. 10. Cyclooctane conformations. The symbols in parentheses refer to the symmetry point groups to which these conformations belong.

I-

170

G . BINSCH

with the tub and twist tub. A similar conclusion was reached for a heterocyclic analog (281), except that the line shapes yielded a free energy of activation of about 14.5 kcal/mole. Glazer and Roberts (282a), on the other hand, have found two rate processes with distinct activation energies in a number of fluorine-labeled cyclooctanes and tentatively suggested twist tub forms to account for their observations. It now appears (282b) that the way to reconcile all results is to have the twist tub be favored for perfluoro- and 1,1,2,2-tetrafluorocyclooctane and the boat-chair for all the other compounds studied. Qualitative DNMR observations are available for a number of unsaturated eight-membered rings (283,284), and a quantitative study of cyclooctatrienone (285) yielded an activation energy of 11.9 f 0.5 kcal/ mole for ring inversion. A rate process in cyclooctatetraene could be inferred from the temperature dependence of its 13C satellite spectrum (286) and from DNMR measurements on fluoro- (287) and alkoxy-substituted (288) cyclooctatetraenes. Our detailed knowledge about the dynamic properties of cyclooctatetraene stems from an ingenious paper by Anet, Bourn, and Lin (289). The deuterium-decoupled NMR spectrum of the selectively deuterated cyclooctatetraenyl dimethylcarbinol of Figure 11 shows singlets for the methyl protons and the ring proton above +41". By gradually lowering the temperature one first observes a splitting of the olefinic resonance into two equally intense peaks, and this is eventually followed by a splitting of the methyl singlet as well. Line shape analysis showed that two distinct rate processes with free energies of activation of 17. I and 14.7 kcal/moIe were responsible for the spectra1 changes. Figure 11 provides the rationale for these observations. The different environments of the ring proton in A and B versus C and D can be interchanged by a "bond-shift " process crossing a planar transition state F with equalized carbon-carbon bond lengths. A second process involves ring inversion of the tub-shaped cyclooctatetraene system, presumably crossing a planar transition state (E or G) with fixed single and double bonds. Such a motion interchanges the environments of the methyl groups that happen to be diastereotopic in the tub forms and can therefore be attributed to the lower barrier. This result implies that the fully delocalized form F must be slightly less stable than E or G in which the w electrons are clustered in certain regions of space, and this is precisely what one concludes from molecular orbital theory (290,291): F does not have a closed-shell ground state and hence suffers a pseudo-

STUDY OF INTRAMOLECULAR RATE PROCESSES

171

Fig. 11. Dynamic pathways for cyclooctatetraenyldimethylcarbinol. All unmarked positions are deuterated.

Jahn-Teller distortion to a less symmetric and energetically more favorable nuclear configuration.

E. Miscellaneous Ring Systems The NMR spectrum of cis,cis,cis-l,4,7-~yclononatriene 99, for which decoupling experiments (292) indicate a crown 99a as the most stable

& (Wa)

&

6 inverted crown

(99W

conformation, was found to change with temperature (293-295). Activation parameters were obtained very approximately and therefore may not lend themselves even to qualitative conclusions. One group of workers (295) postulated a planar transition state from a strongly negative entropy of activation, but this evidence should be taken with a grain of salt. It appears more likely that the saddle form 99b is an intermediate in the inversion of the crown (293,294).

G. BINSCH

172

[2.2]Metacyclophanes 100 are known (296) to exist in a nonplanar chairlike conformation and the AA'BB' spectrum of their aliphatic protons remains unaltered up to 200" (297). It is interesting that the free

@ @ @ @ \

\ I

\

\

(loo)

(101)

( 102)

(103)

energy of activation decreases to about 17 kcal/mole in 101 and about 15 kcallmole in 102 (298). Since the substituents on the aromatic systems that point toward the "inside" of the central ten-membered ring must somehow pass one another in the course of inversion, this result demonstrates the substantially lower compressional energies of two electron pairs on oxygen and nitrogen as compared to the carbonhydrogen bonds in 100. Enlargement of the ring by one methylene group as in 103 also introduces a higher flexibility; the free energy of activation was estimated to be around 20 kcal/mole (299). The methyl protons of the isopropyl groups in tri-o-thymodide 104 were found to be anisochronous at room temperature and to collapse at + 103" (300). An activation energy of 22.2 kcal/mole and a frequency

I

(CHd, (104)

H

H

(105)

factor log A = 13.5 were reported. Models indicate that the molecule can exist in a propeller and a helix conformation, and the observed rate process presumably corresponds to the interconversion between them and their enantiomers. Temperature-dependent NMR spectra

STUDY OF INTRAMOLECULAR RATE PROCESSES

173

have been noticed for annulenes (301). In the [18]annulene 105, for instance, there are 6 inner and 12 outer hydrogen atoms and by a series of rotations and bond shifts (roughly speaking) the two types of protons can interchange their magnetic environments. Qualitative DNMR evidence for dynamic processes of this type was obtained for [14]- (302), [161- (303), [181- (302,304,305), and [24]annulenes (306), but no numbers have as yet been reported. Whereas the cyclohexane ring inversion is blocked by the annelation of a second cyclohexane ring in a trans fashion, cis-decalin is expected to exhibit conformational mobility. The two enantiomeric chair-chair forms 106a and 106b should be capable of interconversion in a manner

(106a) R H (107a) R = F 1

(1Mb)R (10%) R

=H =F

that Roberts has colloquially called the “gearshift mechanism” (307). More detailed strain calculations by Gerig and Roberts (308) indicate that the most likely pathway successively passes chair-twist boat and twist boat-twist boat intermediates. Since the inversion barrier for each chair is likely to be of the same order of magnitude as in cyclohexane itself, but the chair-twist boat should lie some 3 to 6 kcal/mole above the chair-chair, the overall activation energy for the decalin ring inversion should be somewhat higher than that of cyclohexane. However, the first studies of decalin (60,215) seemed to indicate a barrier too low to be detected by DNMR, although a very slight change in the spectrum was later noticed around -20” (232). In view of the work published since then it is now clear that the failure to see pronounced line shape changes in decalin itself has to be attributed to an accidental near-equivalence of all the different protons in the frozen conformers. Gerig and Roberts (308) have examined the fluorine DNMR spectra of 2,2-difluorodecalin and a number of substituted derivatives. The two frozen conformers 107a and 10% are not related by symmetry any more and should thus be present in unequal amounts. The DNMR spectra

G.BINSCH

174

have then to be described by the exchange of one AB system with a second, different AB (disregarding hydrogen-fluorine coupling). Gerig and Roberts (308) have programmed the quantum-mechanical line-shape equations for such a process and obtained, for instance, an activation energy of 13.4 5 0.8 kcal/mole and an activation entropy of 2 f 3 eu for the conversion of the dominant (74%) conformer of 107 (in which the methylene positions adjacent to the CF2 group were deuterated) to the less favored conformation. Activation parameters have also been reported for the substituted decalin 108 (309), the deuterated molecule 109 (224), and for derivatives such as 110 (310), where R and R' were

(109)

(100)

(IW

C02CH3, Br, and CN. In 110 the ring inversion can be studied via the AB spectra of the exocyclic methylene protons. Full line-shape analyses yielded activation energies that are substantially higher than for decalins, where none or only one of the bridgehead positions are substituted, between 18.0 and 20.6 kcal/mole for the various groups R and R. An interesting case of a ring inversion in the heterocyclic analog 111 of decalin has recently been reported (192). In this molecule an overall HN-N-NH

I

l

HNwN-NH (111)

l (112)

interconversion between two stable conformers with trans ring juncture is actually possible, since this process can be accompanied by a nitrogen inversion and is therefore not prohibited as in trans-decalin itself. The NMR evidence is in concordance with such an interpretation. A AG* value of 16.6 kcal/mole was estimated from the coalescence temperature of the AB methylene spectrum. In compound 112, on the other hand, the singlet of the aliphatic protons at 32" splits into two AB patterns with equal intensities at lower temperatures (256). This clearly indicates a cis ring juncture at the two nitrogen atoms and a rate process that involves ring inversion as well as nitrogen inversion.

STUDY OF INTRAMOLECULAR RATE PROCESSES

175

VIII. VALENCE ISOMERIZATIONS AND INTRAMOLECULAR REARRANGEMENTS Dynamic nuclear magnetic resonance has become an irreplaceable tool for the detection and identification of certain reversible intramolecular processes that have sometimes been apostrophized by the bold paradox "no-mechanism no-reaction reactions." The idea of a general class of molecules with fluxional structures was first conceived in a highly imaginative paper by Doering and Roth (31 1) and the ensuing research activity culminated shortly thereafter in the synthesis of bullvalene (cf. refs. 312 and 313). 3,CHomotropilidene 113 is an example (311) for which DNM R demonstrated a rapid degenerate Cope rearrangement

(113a)

(113b)

(114)

(115)

113a + 113b. At 180" the spectrum of 113 consists of four groups of multiplets in the intensity ratio 1 :2: 1 :1 expected for the time-averaged environments. At -50" one observes the more complex pattern of the frozen valence structure. The remarkable feature (3 11) about bullvalene 114 is that all positions can eventually become equalized by a random sequence of degenerate Cope rearrangements, thus giving rise to a single line in the fast-exchange limit. Saunders (26) has analyzed the bullvalene DNMR spectra by means of a computer program based on the equations of Section 111-A-I-c and obtained E, = 1 1.8 -t 1.O kcal/mole and log A = 12.3. A spin-echo study (73) produced similar values (€, = 12.8 k 0.1 kcal/mole, log A = 12.9), but the rearrangement was found to be retarded in the silver-ion complex (E, = 15.1 _+ 0.8 kcal/mole). Timedependent NMR spectra were also observed in many derivatives of bullvalene (314,3 15) and the activation energy for the barbaralone (115) valence isomerization was estimated to 8.1 kcal/mole (3 16). Rapid equilibration between cycloheptatriene-norcaradiene valence isomers was detected by DNMR in the 7-cyano-7-trifluoromethyl derivative (31 7) and quantitative studies have been done on the systems 116 (318-321) and 117 (322-324), the former yielding activation energies of about 9 kcal/mole, the latter about 16 kcal/mole. In both systems the values vary only slightly with the nature of R or X and Y.

176

0: =aR;*;> =y $& G . BINSCH

X

x

(116a)

(116b)

x

o

(117a)

o

X

(117b)

Recently, several groups of workers (325-329) have communicated interesting temperature effects on the NMR spectra of cyclooctatetraene metal carbonyl complexes. The original disagreement as to the interpretation of the observations has now been resolved (330-332) for the irontricarbonyl derivatives. Apparently the metal is complexed to two adjacent double bonds in the frozen structures and the temperature effects can be explained by stepwise migrations and bond shifts around the ring. Interesting DNMR studies have yielded rates for intramolecular hydride shifts in a number of carbonium ions, such as in the protonated form of hexamethylbenzene (333,334) and in the 2-norbornyl cation (335,336). In the latter molecule the 3,2-hydride shift is much slower than the 6,2-hydride shift. A quantitative analysis of the line shapes afforded E, = 10.8 +_ 0.6 kcal/mole and log A = 12.3 for the 3,2-process (334). Fast intramolecular rearrangements have also been inferred from temperature-dependent NMR spectra in the heptamethylbenzenonium ion (337,338) and in allylic Grignard reagents (339). IX. CONCLUSION

In this article we have attempted to convey an impression of the wide range of applicability of DNMR methods for the study of intramolecular rate processes in chemistry. Special emphasis has been attached to pointing out the various difficulties and their possible influence on the accuracy of the reported numbers. There will no doubt be many more cases in the future where qualitative DNMR information will prove extremely valuable. It is believed, however, that the importance of accurate rate determinations will become more generally recognized. If this article contributes to convincing prospective users that quantitative DNMR studies can actually be carried out and reliable values obtained without major difficulty, then it will have served its intended purpose.

STUDY OF INTRAMOLECULAR RATE PROCESSES

X. APPENDIX

177

Here we reproduce two simple computer programs for the calculation of line shapes. Program CLATUX (pp. 178-179) applies to the classical exchange betweentwo uncoupled sites, programQUABEX (pp. 180-1 81) computes NMR line shapes for the intramolecular exchange between the sites of an AB spin system. The programs are written in FORTRAN IV and make use of the plotting routines available in the UNIVAC 1107 system equipped with a CALCOMP plotter. Users with a different computer configuration may have to substitute their own plotting routines. The input to the programs is explained in the comment statements. Line-shape computer programs for more complicated exchange problems have been mentioned on pp. 108, 110, 113, 128, and 174 and programs featuring direct least-squares fitting on p. 121. A general program based on the master equations [eqs. (31)] is available from the Quantum Chemistry Program Exchange, University of Indiana, Bloomington, Indiana.

Acknowledgments I am deeply indebted to Professor E. L. Eliel (University of Notre Dame), Dr. R. Knorr (Universitat Miinchen), Professor J. B. Lambert (Northwestern University), Dr. W. von Philipsborn (Universitat Zurich), Professor J. D. Roberts (California Institute of Technology), and Professor M. Saunders (Yale University) for their constructivecriticisms of the manuscript and to Mr. F. R. Harrell of the Notre Dame Chemistry and Physics Library for his cheerful cooperation in providing me with photostatic copies of close to four thousand journal pages. Acknowledgment is made to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research.

G . BINSCH

178

Program Clatux C C C C

C

C

C C

C

C C

C C C C

C C C

C C

c

C C C

PROGRAM CLATUX MMH LINESHAPES FOri CLASSICAL TWO-SITF

EXCHANGE

ORDERIN6 OF DATA DECK 1. NRUN ( 1 3 ) NRUN HUN NUYRER 2. TEXT (12A6) 3. N T A U , F R A ~ F K ~ I ~ T ~ A P T ~ H , P A , P( IRl ,~ e 4 F 1 0 . 0 ) NTAU NUMBER OF TAU VALUES CHEMSHIFT A (CPS) FRA FRO CHEMSHIFT Y (CPS) RELAX T I Y E A (SEC) T2A RELAX T I Y E R (SEC) T2H PA POPULATION A PR POPULATION R 4. F R l ~ F R 2 ~ S C A L E ~ H E I G H(T4 F 1 0 . 0 ) FR1 LEFT PLOT FREOUENCY (CPS) NIGHT PLOT FIqEBUENCY (CPS) FR2 SCALE HORIZONTAL SCALE (MM/CPS) HEIbHT HEIGHT OF HIGHEST PEAK (MY) 5 . NEXT SET OF CARDS EXCHANGE VARIABLE TAU ( F 1 0 . 0 ) ~ ONF PER C A I 4 0 6. NEXT PROBLEM FOLLOWS, REPEAT 1 THRU 5 7. AFTER LAST PROBLEM BLANK CARD

=

=

= =

= = = =

= =

=

COMPLEX IM,AA,AB,FREQeALPHAA~ALPHAB,~UM,DENOM,S DIMENSION Y(SOOO)eTEXT(12) PI=3.14159 DEl.1S=20b. IY=CMPLX(O.tl.)

xx=1 ./DEWS 1 READ ( 5 0 1 0 0 1 ) 4RUN 1 0 0 1 FORMAT (13) I F (FIRUN) 2e2e.3 2 STOP 3 READ ( 5 e 1 0 0 2 ) T E X T 1 0 0 2 FORYAT (12Ab) tIEAD (5e1003) NTPUe FHA, FRHe T2A 7 T2de PA, PH 1 0 0 3 FORYAT ( I l U e 6 F l U . U ) HEAS (5,1004) FRI,FR2,5CALE,HEIGHT 1 0 0 4 FORYAT ( 4 F l O . O ) WRITE ( 6 1 1 0 0 5 ) NRUNeTEXT 1uos FORYAT ( l H l I 3 e Z U X 1 2 A 6 / / / / ) rJi7ITE ( b e l U 0 6 ) F R A ~ F R H e T 2 A e T 2 R , P A ~ P H ~ F R l , F R 2 , S C I \ L E e H F I G t i T 1 U 0 6 FOHYAT ( 2 5 r i GENtRAL IIUPJT P A R A M E T E R S / / / / l O X 1 6 H C H ~ M I C ~ L S H I F T A l 4 X l lH=FH.3rbH CPS/lOXlbHCtiCYICAL SHIFT 914Xlkl=FA.3,4H CPS/lOX17HRELAXA LTIOV TIME A13XlH=FH*3e4H SEC/lOXl7H?ELAXATION TIME 913XlH=FR,3e4H 3ScC/lOX12HPOPULATIOrJ AlHX1H=F8.3/1OX12tiPOPULATION HlRXtH=FR.3/10#.1 49HLEFT PLOT F ~ E ( ~ U E N C Y l l X l H = F R . 3 e 4 t iCPS/lOX20HRIGHT PLOT FRFOUEPICYl MY/CPS/lOX~HHFItHT24Xl~=F 5UXlti=FM.3e4H Ct’S/lOX5HSCALE2SXlH=FR.3,7H 6 8 . 3 ~ 3 H MM////22H TAU VALUES I N SECONDS////) XYAX=SCALE*(FHZ-FH1)/25.4 IJPO I NT=DENS*XMAX S T t P = ( F H 2 - F H l )/NPOINT DO 5 1 K=lv,\ITAU READ ( S e l U O 7 ) TAU 1 0 0 7 FORYAT ( F 1 0 . 0 ) WRIrF (6,1008) TAU i o o a FOHYAT ( 2 u x ~ i 0 . 5 )

STUDY OF INTRAMOLECULAR RATE PROCESSES

y=-xx FRZFH1-STEP A 1 / T 2 A -P / T A 11 A A =-2. P I I M F I< AB=-2.*PI*IM*FRH-I./T~~-~A/TAU UO 1 0 I = l ~ N P O I o I T FR=FR+STEP FHEO=2.*PI*IM*FR ALPHAA=AA+FREO ALPYAS=AR+FREO (PA*ALPtiAR+Pn*ALPHAA N U Y = - I l J l * T A U * ( ? a *PA*1'13-TAU* DEIIIOM=PA*PL3-TAU**2*ALPtiAb C A L P H A R G=NUM/DEVOY Y(I)=AIYAG(G) YYAXZY (1) Y Y I W Y (1) DO 11 I = 2 P J P O I I 4 T I F (YuAX.bT.Y(I)) b9 T O 1 2 YYAXZY ( I ) IF IYYIN.LT.Y(I)) L O TO 1 1 YYIl4=Y ( I I CONJTINUE F A C T O R = t I E I G H T / (25.4*( Y I ~ A X - Y Y I N ) 1 DO 1 3 I = l r f J P O I ' I T Y(I II ) - Y Y I I J ) * F A C T O H + O . 5 CALL PLGTS(nU~,010,XMAX,YYIO,O,MES) 30 1 4 1=1v I P O I i J T

* * *

1(1

12 11 15

x=x+xx

-

14 C A L L P L O T ( X v Y ( 1 ) r L ) CALL PLDT(Oe0,-4) 51 COFITINUE GO T O 1 END

.

n

11

179

180

G . BINSCH

Program Quabex C C C C C

C C C C C C C C C C C C C

C C

C C C

C

PROGRAM QUABEX NMH LINESHAPES FOR QUANTUM-YECHANICAL AB EXCHANGE

INTRAMOLECULAR

OHDERING O F DATA DECK 1. NRUN 1 1 3 ) NRUN HUN NUMBER 2. TEXT (12A6) 3. NRC,FRA,FRB,AJ,T2 (110,4F10.0) NRC NUMBER OF RATE CONSTANTS CHEMSHIFT A ICPS) FRA FHB CHEMSHIFT B (CPS) AJ COUPLING CONSTANT (CPS) T2 RELAX TIME ISEC) 4. FRl,FR2*SCALE,HEIGHT (4F10.0) FR1 LEFT PLOT FREQUENCY I C P S ) FR2 RIGHT PLOT FREQUENCY (CPS) HORIZONTAL SCALE (MMICPS) SCALE HEIGHT HEIGHT OF HIGHEST PEAK ( M M ) 5 . NEXT SET OF NRC CARDS RATE CONSTANT RC IFlO.O), ONE PER CARD 6. NEXT PROBLEM FOLLOWS, REPEAT 1 THRU 5 7. AFTER LAST PROBLEM BLANK CARD

=

= = = =

=

=

=

COMPLEX IMIG COMPLEX A l 2 ) ~ B l 2 ) ~ Q l 2 ) ~ R l 2 ) DIMENSION Y ( 5 0 0 0 ) , T E X T l 1 2 ) TUPI=2.+3.14159 DENS=200. IM=CMPLXlO.,l.) XX=l./DENS 1 HEAD 15,1001) NRUN 1 0 0 1 FOHMAT 1 1 3 ) I F INRUN) 2 ~ 2 ~ 3 2 STOP 3 READ 15,1002) TEXT 1 0 0 2 FORMAT 112A6) HEAD ( 5 , 1 0 0 3 ) NRCtFRA,FRB,AJ,TE 1 0 0 3 FORMAT (110,4FlO.U) READ 15,1001)) F R ~ P F R ~ , S C A L E , H E I G H T 1 0 0 4 FORMAT 11)FlO.O) WRITE ( 6 ~ 1 0 0 5 )NRUNPTEXT 1 0 0 5 FORMAT I l H l I 3 ~ 2 0 X 1 2 A b / / / / ) WRITE 16,1006) FRA,FHBtAJ*T2oFRloFRZ*SCALE,HEIGHT 1 0 0 b FOHMAT 12% GENERAL INPUT PARAMETERS////lOXl6HCHEMICAL S H I F T A14X1 lH=F8.3,1)H CPS/lOX16HCHEMICAL SHIFT BlYXlH=FB.J,4H CPS/lOX17HCOUPLI 2NG CONSTANTlJXlH=FB.St1)H CPS/10XlSHRELAXATION T I M E l 5 X l H = F 8 . 3 ~ 4 t i SE 3C/lOX19HLEFT PLOT FREQUENCYllXlH=FB.J,4H CPS/lOXEOHRIGHT PLOT FREQ 4UENCYlOXlH=F8.3,1)H CPS/lOX5HSCALE25XlH=F8.3,7H MM/CPS/10XbHHEIGHT2 S ~ X ~ H = F B . ~ VMM////2bH JH HATE CONSTANTS I N l l / S E C ) / / / / )

XHAX=SCALE*(FR2-FH1)/25.4

NPOINT=DENS*XMAX STEP=IFR2-FRl)/NPOINT FRO=IFRA+FHB)/Z. DO 5 1 K Z l t N R C READ 1 5 , 1 0 0 7 ) RC 1 0 0 7 FORMAT lF1O.U) WHITE 16,1008) RC

STUDY OF INTRAMOLECULAR RATE PROCESSES

1 0 0 8 F O R M A T llOXF20.5)

x=-xx

V

FH=FRl-STEP DO 4 I = 1 ~ 2 AJ=-AJ A(I)=-IM*TUPI*lFRA+AJ/2.)-l./T2-RC BlI)=-IM*TUPI*lFRBtAJ/2.)-l./T2-RC QlII=lIM*TUPI*AJ/2.tRC)**2 R~I)=-TUPl*lFHOtAJ)+2.*IM*RCtIM/T2 DO 1 0 I = l # N P O I N T FH=FRtSTEP FREQ=TUPI*FR G=CMPLXlU.tO.) DO 5 J = 1 v 2

5 G~GtlRlJ~tFREQ~/llAlJ~+IM*FREQ~*l~

1 0 Y(I)=AIMAGlG) YMAXZY I1 1 YMIN=YIl) 00 11 I=2iNPOINT IF IYMAX.GT.Yl1)) GO T O 1 2 YMAXZY I I ) 1 2 IF I Y M I N ~ L T ~ Y I I )GO ) TO 1 1 YMINZY I I ) 11 CONTINUE FACTOR=HEIGHT/l25.9*lYMAX-YMIN)) DO 13 I=lvNPOINT 1 3 YlI)=(YlI)-YMIN)*FACTOR+O.5 CALL PLDTS(BUF~O#O#XMAXvYYIO,O,MES) DO 14 I = l # N P O I N T

x=x+xx

19 C A L L P L O T I X v Y l I ) # 2 )

CALL PLOTlOvO#-9) 51 CONTINUE G O TO 1 END

181

182

G. BINSCH

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STUDY OF INTRAMOLECULAR RATE PROCESSES

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304. I. C. Calder, P. J. Garrat, and F. Sondheimer, Chem. Commun., 1967, 41. 305. I. C. Calder, P. J. Garrat, H. C. Longuet-Higgins, F. Sondheimer, and R. Wolovsky, J. Chem. SOC.( C ) ,1967, 1041. 306. I. C. Calder and F. Sondheimer, Chem. Commun., 1966, 904. 307. J. D. Roberts, private communication. 308. J. T. Gerig and J. D. Roberts, J. Am. Chem. SOC.,88, 2791 (1966). 309. F. G. Riddell and M. J. T. Robinson, Chem. Commun., 1965, 227. 310. J. Altman, H. Gilboa, D. Ginsburg, and A. Loewenstein, TetrahedronLetters, 1967, 1329. 311. W. v. E. Doering and W. R. Roth, Tetrahedron, 19, 715 (1963). 312. G. Schroder, J. F. M. Oth, and R. Merenyi, Angew. Chem., 77, 774 (1965); Angew. Chem. Intern. Ed. Engl., 4, 752 (1965). 313. G. Schroder and J. F. M. Oth, Angew. Chem., 79,458 (1967); Angew. Chem. Intern. Ed. Engl., 6, 414 (1967). 314. R. Merenyi, J. F. M. Oth, and G. Schroder, Chem. Ber., 97, 3150 (1964). 315. J. F. M. Oth, R. Merenyi, G. Engel, and G. Schroder, Tetrahedron Letters, 1966, 3377; G. Schroder, R. Mertnyi, and J. F. M. Oth, Tetrahedron Letters, 1964, 773. 316. J. B. Lambert, Tetrahedron Letters, 1963, 1901. 317. E. Ciganek, J. Am. Chem. SOC.,87, 1149 (1965). 318. E. Vogel, W. A. Boll, and H. Gunther, Tetrahedron Letters, 1965, 609. 319. H. Giinther, Tetrahedron Letters, 1965, 4085. 320. H. Gunther, R. Schubart, and E. Vogel, Z. Naturforsch., 22b, 25 (1967). 321. E. Vogel and H. Gunther, Angew. Chem., 79,429 (1967); Angew. Chem. Intern. Ed. Engl., 6, 385 (1967). 322. P. Diehl, H. A. Christ, and F. B. Mallory, Helu. Chim. Acta, 45, 504 (1962). 323. G. Englert, Z. Elektrochem., 65, 854 (1961). 324. F. B. Mallory, S. L. Manatt, and C. S . Wood, J. Am. Chem. SOC.,87, 5433 (1965). 325. F. A. Cotton, A. Davison, and J. W. Faller, J. Am. Chem. SOC.,88, 4507 (1966). 326. F. A. Cotton, J. W. Faller, and A. Musco, J. Am. Chem. SOC.,88, 4506 (1966). 327. C. E. Keller, B. A. Shoulders, and R. Pettit, J. Am. Chem. SOC., 88, 4760 (1966). 328. C. G. Kreiter, A. Maasbol, F. A. L. Anet, H. D. Kaesz, and S. Winstein, J. Am. Chem. SOC.,88, 3444 (1966). 329. M. 1. Bruce, M. Cooke, M. Green, and F. G. A. Stone, Chem. Commun., 1967, 523. 330. F. A. L. Anet, H. D. Kaesz, A. Maasbol, and S. Winstein, J. Am. Chem. SOC., 89, 2489 (1967). 331. F. A. L. Anet, J. Am. Chem. SOC.,89, 2491 (1967). 332. F. A. L. Anet, paper presented at the 20th National Organic Chemistry Symposium, American Chemical Society, Burlington, Vermont, June 1967. 34, 165, 201 333. C. MacLean and E. L. Mackor, Discussions Faraday SOC., (1 962).

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334. E. L. Mackor and C. MacLean, Pure Appl. Chem., 8, 393 (1964). 335. M. Saunders, P. von R. Schleyer, and G. A. Olah, J. Am. Chem. Soc., 86, 5680 (1964). 336. F. R. Jensen and B. H. Beck, Tetrahedron Letters, 1966, 4287. 337. V. A. Koptyug, V. G . Shubin, and A. I. Rezvukhin, Bull. Acad. Sci. USSR Dlu. Chem. Sci., 1965, 192. 338. M. Saunders in Magnetic Resonance in Biological Systems, A. Ehrenberg, B. G . Malmstrom, and T. Vanngard, Eds., Pergamon Press, Oxford, 1967, p. 85. 339. G . M. Whitesides, J. F. Nordlander, and J. D. Roberts, Discussions Faraday Soc., 34, 189 (1962).

Structures of Carbenes and the Stereochemistry of Carbene Additions to Olefins GERHARD L. CLOSS Department of Chemistry, The University of Chicago, Chicago, Illinois

I . Introduction . . . . . . . . . . . . . . . . . 193 Electron Configurations and Geometrical Structures of Carbenes. . 194 A. Methylene . . . . . . . . . . . . . . . . 194 B. Derivatives of Methylene . . . . . . . . . . . . 198 111. Stereochemistry of Carbene Additions to Olefins . . . . . . 203 A. Theoretical Considerations . . . . . . . . . . . 204 B. Methylene . . . . . . . . . . . . . . . . 210 C . Methylene Derivatives. . . . . . . . . . . . . 219 References . . . . . . . . . . . . . . . . . 231 11.

I. INTRODUCTION The last fifteen years have witnessed an ever-increasing level of research activity in carbene (methylene, divalent carbon compound) chemistry. Several excellent reviews have recently been published on the subject (1-6) and it should be stated at the outset that this chapter, as its title implies, is limited to the stereochemical aspects of the field. As in so many other areas of physical organic chemistry, however, the study of the stereochemical course of carbene reactions has served as a major tool to gain insight into the reaction mechanism. Consequently, it has been found advantageous to consider reaction mechanisms in greater detail than might appear necessary for the mere discussion of the stereochemical results. But only in this way has it been found possible to integrate the stereochemistry into a consistent framework of carbene chemistry. 193

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

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194

Considerable evidence has been accumulated over the last few years indicating that many of the reactions initially thought to proceed through divalent carbon compounds actually involve intermediates which may be called “complexed” carbenes and which have a valency greater than two ( 4 3 . Inasmuch as the observed chemistry of such “carbenoids” is in many aspects very similar to that of free divalent carbon compounds, a discussion of their stereochemical behavior will be included in this review. 11. ELECTRON CONFIGURATIONS AND GEOMETRICAL STRUCTURES OF CARBENES A. Methylene The symmetry of the simplest carbene, methylene, is represented by either point group C,, or Dm,,,depending on whether the molecule has a bent or a linear structure. Before discussing experimental evidence bearing on this question, it will be useful to give a qualitative description of the electron configurations associated with these geometries.

90

I35

H-C-H

Fig. 1.

I80

Bond Angle

Modified Walsh diagram of methylene (7-9).

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195

Orbital correlation diagrams, in which the one-electron energies of molecular orbitals are plotted as a function of geometrical parameters, have first been constructed by Walsh (7,8) and are helpful in predicting the most stable molecular geometry. Figure 1 is a modified (9) Walsh diagram for methylene. Neglecting the totally symmetric 1s orbital on carbon (la,), a linear combination of the valence atomic orbitals on carbon and hydrogen will yield for a bent structure three molecular orbitals of symmetry, a,, two of b2, and one of b,. Consideration of bonding and antibonding interactions leads to an ordering of the oneelectron energies of these orbitals as shown in the diagram. In the 90"-geometry two orbitals, 2al and lb2, are strongly C-H bonding, while orbital 3a, is weakly bonding and lb, is nonbonding. The orbitals 4a, and 2b2 have antibonding character. Figure 2 shows qualitatively the atomic orbitals contributing to the formation of molecular orbitals at this bond angle. Placing six valence electrons into the lowest orbitals gives the electron configuration for this geometry as 2 4 16; 3a: with a wavefunction symmetry of ,Al. Widening of the valence angle decreases the bonding character of 2a, slightly because of decreasing hybridization between the 2s and 2p, orbital on carbon. Symmetry considerations require that at 180" this orbital transform according to the fully symmetric representation 2ug, and only the 2s atomic orbital

Fig. 2. Symmetries of molecular orbitals of methylene in bent and linear configurations.

196

G . L. CLOSS

on carbon has this symmetry. The bonding character of the 1b2 orbital will improve with greater bond angles because of better overlap between the hydrogen 1s and the carbon 2p, orbitals. In the linear configuration this orbital becomes la, and has reached its lowest oneelectron energy. The rise in energy of the 3al orbital with increasing bond angle can be attributed to decreasing s-p hybridization because it correlates with the doubly degenerate IT, orbital which has no s character at all. No change in energy is expected for the 16, orbital which remains a pure p orbital over all bond angles. Similar qualitative arguments can be advanced for the behavior of the less important antibonding orbitals, 4al and 2bz, as a function of valence angle. The electron configuration in the linear geometry will then be 2 4 la: lw:, and application of Hund's rule to the doubly degenerate orbital IT, leads to a molecular wavefunction of 3X;. While there can be little doubt that the linear geometry of methylene should have a triplet multiplicity in its lowest energy state and while it is highly likely that the bent configuration will be a singlet state, there is room for discussion of which multiplicity may be expected for the true ground state of the molecule. This question can be resolved theoretically only with quantitative calculations and many attempts to do this have been reported (9-1 5). Unfortunately, very often the necessary drastic assumptions inherent in these calculations make the quantitative results highly suspect. However, backed up by experimental data to be discussed below, a semiquantitative picture emerges as shown in Figure 3 (12,14). The energy of the lowest singlet state shows a minimum

Fig. 3.

Energies of electronic states of rnethylene as function of bond angle 4.

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197

not far from a bond angle of 100" with a continuous rise for larger angles. The triplet state energy has a minimum at or close to 180" but the curve is rather insensitive to angle changes between 180 and 150". Only at substantially smaller angles does the energy increase significantly. Furthermore, the triplet state should be the true ground state although the energy difference between the minima of the two curves is rather uncertain. Estimates range from 0.3 to 0.6 eV. These theoretical considerations should be compared with experimental evidence relating to the structure of methylene. The most convincing information was obtained by flash photolysis spectroscopy in the pioneering studies by Herzberg and collaborators (16-18). These authors were able to obtain the absorption spectrum of methylene on flash photolysis of diazomethane at low pressure using a high-resolution spectrograph. Isotopic substitution of both hydrogen and carbon established beyond a doubt that methylene was the carrier of the spectra. A detailed analysis of rotational and vibrational fine structure of the spectra yielded extensive structural information. In summary, the results show that there are two states of methylene, a metastable state absorbing fairly strongly in the red region of the visible spectrum and weakly in the near ultraviolet, and the true ground state of methylene giving rise to a spectrum in the vacuum ultraviolet region. It appears that the metastable state is produced first and then decays to the ground state. The decay process is accelerated on collision with inert molecules such as nitrogen. The stereochemical structure of the metastable state as deduced from the fine structure of the spectrum shows it to be highly bent with a bond angle of 102" and a C-H bond length of 1.1 A. In contrast, the ground state appears to be linear or nearly linear with a C-H bond length of 1 .O A. Although the triplet splitting in the spectrum of the ground state molecule was not observed, it seems a safe assumption that the molecule has the expected 3C; configuration while the metastable species almost certainly should be identified as the 'Al state of methylene. From the observed transitions it is possible to reach some conclusions on the energy and geometry of the upper states which are indicated in Figure 4. Included in the figure are correlations between the corresponding electron configurations for the linear and bent geometries. However, since no transitions with intersystem crossing were observed and since the Rydberg limit is known only for the triplet manifold, the interesting question of the energy difference between singlet and triplet states remains unanswered.

198

G . L. CLOSS

bent

linear

Fig. 4. Observed transitions in the absorption spectrum of methylene (17,18).

B. Derivatives of Methylene The structures of substituted methylenes have been investigated in recent years by several techniques. Several mono- and dihalocarbenes were investigated by emission and absorption spectroscopy using electrical discharge or flash-photolysis techniques to generate the methylenes from polyhalomethane precursors. Halomethylenes for which spectra have been obtained so far are CF2 (19-21), CHCl(22), CHF(23). All appear to have highly bent structures with bond angles ranging from 102 to 110". The spectra are consistent with a l A electron configuration which most likely is the ground state for these molecules. Electronic excitation (24,27) and absorption spectra (2.5-27) have been obtained in the condensed phase for several arylmethylenes and for fluorenylidene ; however, little unambiguous structural information is available from these data. Most information on the structure of polyatomic methylene derivatives comes from electron spin resonance (ESR) studies. This technique is, of course, limited to methylenes with triplet ground states or at least to molecules in which the triplet state can be thermally populated. All ESR studies reported so far make use of the matrix isolation technique in which methylene derivatives are produced in low concentrations in an inert matrix usually at very low temperatures. The purpose of the matrix is to prevent the highly reactive molecules from reacting with

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199

themselves or with the methylene precursor. Furthermore, to obtain information on the dipole-dipole interaction of the unpaired electrons in the triplet state the molecules must be prevented from rapid rotation. Both crystalline (28,29) and glassy (30,3 1,33) matrices have been used leading to spectra from oriented and randomly distributed methylenes, respectively. In most cases the methylenes were generated from the corresponding diazo compounds by photolysis at liquid nitrogen temperature. Usually the methylenes were found to be stable under these conditions and spectra can be obtained many hours after irradiation has been ceased. Structural information can be deduced from the spectra in several complimentary ways. By fitting the experimental spectrum to the triplet state spin Hamiltonian, for S = 1, the zero-field splitting parameters D/hc and Ejhc can be extracted. These parameters describe the separation of the three energy levels when no external field is present. Each energy level corresponds to a principal magnetic axis in the molecule as its energy will not change with the external magnetic field when the field is parallel to that axis. D is defined as the difference between the z level and the mean of the other two. The separation of the latter pair is 2E. It follows that a molecule with three different axes should exhibit a finite E, while this quantity will vanish for molecules with two identical axes. For example, the E value for triplet methylene should be zero for the linear geometry, but should have a finite value for all other valence angles. Although the magnitudes of D and E depend on the electron distribution, it has been shown that there is a fairly good correlation between the ratio of the two parameters and the bond angle on the methylene carbon (32). Additional structural information is available from hyperfine splitting data which are a measure of the interaction of the electron spin with the nuclear magnetic moment either of the methylene carbon, when C-13 has been substituted at this position (28,29,34), or of suitably located protons (34). Most recently, electron nuclear double resonance (ENDOR) experiments have been carried out on methylene derivatives and have proven to constitute the most powerful technique for obtaining hyperfine interaction data (35,36). Since the isotropic component of the hyperfine interaction depends predictably on the hybridization of the atomic orbitals on carbon, information on the geometry of the molecule can be deduced from these parameters.

200

G . L. CLOSS

The most thoroughly studied molecules are the arylmethylenes, such as diphenylmethylene (1) (28-3 1,33,34,36), phenylmethylene (2) (33,34), and fluorenylidene (3) (29,33-35), all of which have triplet ground states. The common feature of the structure of these methylene derivatives is the nonlinear bond angle on the methylenic carbon. Angles of 140-1 55 have been estimated for phenylmethylene and diphenylmethylene. This result is somewhat unexpected in view of the fact that triplet mcthylene is linear or very nearly linear. The results obtained for

fluorenylidene, indenylidene (4), and cyclopentadienylidene (5) (37) require the assumption of bent bonds on the methylenic carbon. In all three cases the analysis of fine structure and hyperfine structure data leads to interorbital angles much larger than the internuclear angles compatible with a five-membered ring structure. A study of perfluoroalkylmethylenes (38) gives some information on the dependence of the bond angle on alkyl substitution. If one extrapolates the angles measured for bis-trifluoromethylmethylene (6) (140' ) and trifluoromethylniethylene (7)(160 ) to the unsubstituted system, a linear geometry is indicated for methylene. Unfortunately, so far no simple alkyl-substituted methyle m have been reported, but it is likely that the bond angle for these derivatives does not deviate very much from linearity. A series of propargylene derivatives with the general structure .. R-(C-C),--CH[/? H, CH,; / I = 2, R = CH,. (CH;j),C] 1, R have been examined by ESR, and in all cases E,'/K-was found to be zero within the experimental error (39). Symmetry considerations lead t o linear structures as the only ones compatible with the experimental data.

CARBENES AND CARBENE ADDITION TO OLEFINS

201

Besides the central bond angle, another structural parameter of interest in the arylmethylenes is the dihedral angle between the plane defined by the bonds on the methylenic carbon and the aryl plane. Assuming a planar structure for fluorenylidene this angle is, of course, O", but it can have finite values in phenylmethylene and diphenylmethylene. Experimental evidence on this question, however, is still very sparse. The ESR spectra of I - and 2-naphthylmethylenes (8 and 9) gave evidence for the existence of two geometrical isomers in each system (40). The data have been interpreted in terms of syn and anti structures (8a and 8b; 9a and 9b) which can be expected to have different zero-

9

field splittings. Of course, if the observed spectral differences are caused by conformational differences, the dihedral angle may have any value except 90". Considerably more information has recently become available from ENDOR studies on diphenylmethylene in a I , I-diphenylethylene crystalline host (36). A complete analysis of the isotropic and anisotropic hyperfine interactions gave the geometry of the molecule. As Figure 5 shows diphenylmethylene has a C , symmetry with a central carbon bond angle of 151". The dihedral angles between the phenyl planes and the plane defined by the sigma bonds on the methylene carbon are 34".It should be pointed out that although these values are quite precise, they may not necessarily represent the potential energy minimum of the isolated molecule because the packing forces of the host crystal may have some distorting influence on the geometry. On the other hand, the fine structure parameters, D and E, obtained in this

202

G . L. CLOSS

Fig. 5. The structure of diphenylmethylene as determined by ENDOR in a 1,l-diphenylethylene host crystal. Bond angle Q = 151" and dihedral angle 0 = 34" (36).

host are very close to those determined for diphenylmethylene in a variety of glasses (34). This may be taken as an indication that the packing distortions are not very severe. Application of the ENDOR method to the conformational analysis of other methylenes, in particular, methylenes with hydrogen substituents on the divalent carbon, should be very rewarding. Electron delocalization in arylmethylenes will be a function of the molecular conformation. The two unpaired electrons in the triplet ground state are in two separate orbitals and will be delocalized to a different extent. For example, in planar fluorenylidine one electron moves in a 7r orbital which extends over the whole carbon skeleton, while the second unpaired electron is confined to an orbital lying in the u plane and which is essentially localized on the divalent carbon atom. Spin density measurements by ENDOR technique confirm this simple model (35). A planar diphenylmethylene would show a similar partition of the unpaired electrons into an essentially localized electron and a highly delocalized one. Rotation of the phenyl planes out of the molecular plane will have the effect of diminishing delocalization of the 7r electron while at the same time increasing that of the u electron. The experimentally found dihedral angle of the phenyl groups of 34" is large enough to cause an electron delocalization somewhat different from that of the planar model. However, delocalization in fluorenylidene and diphenylmethylene is different in one other important aspect-the 7r electron of the diphenylmethylene is part of an odd and alternant hydrocarbon T system, while fluorenylidene must be classified as a nonalternant hydrocarbon. This difference in electronic configurations may

CARBENES AND CARBENE ADDITION TO OLEFINS

203

be partly responsible for the rather different chemical behavior of the two species and should contribute to the notable differences in the electronic spectra (25). 111. STEREOCHEMISTRY OF CARBENE ADDITIONS TO OLEFINS

Ever since Doering and Hoffmann reported that dihalocarbenes add to olefins to give cyclopropanes in good yields (41), the reaction of carbenes with carbon-carbon multiple bonds has been the subject of intensive investigation. The study of the stereochemistry of this process has yielded valuable information on the structure and spin multiplicities of a variety of methylenes. Stereochemical observations on cyclopropane formation have been used to distinguish free carbenes from the complexed counterparts (carbenoids). Also, the study of the steric course of methylene additions to olefins in the gas phase has been a valuable tool in the chemistry of “hot” molecules and the associated problem of unimolecular reaction rate theory. Finally, the great synthetic value of the reaction is a stimulus to much additional research. The stereochemical problems associated with the addition of methylenes to double bonds fall into two categories. The first involves the degree of stereospeciJciry of the addition as exemplified in eq. (1).

b

I

/

Olefins lacking a symmetry axis along the carbon-carbon double bond can form two adducts with a symmetrical methylene. The reaction is called stereospecific if the geometrical relationships of the substituents in the cyclopropane correspond to those in the olefin reactant. This stereochemical course is also referred to as a cis addition. A trans

G . L. CLOSS

204

addition would then lead to a cyclopropane in which the relationships of the substituents relative to the ring plane are opposite to the configuration of the olefin. A nonstereospecijic addition is defined as a reaction in which both cis-addition and trans-addition products are formed. If the methylene derivative is unsymmetrical and the olefin also lacks a center of symmetry, a further stereochemical problem arises because the maximum number of diastereorners formed will now be four. As shown in eq. (2), two arise by a cis addition and two from trans addition. Of course, the maximum number of cyclopropanes formed

6

will be smaller in reactions with more symmetrical olefins. Sometimes, the ability of an unsymmetrical methylene to discriminate between the two possible cis-addition routes has been referred to as the stereoselectivity (42) of the methylene. A. Theoretical Considerations It is rather obvious that a one-step addition of a carbene to a double bond will give the stereospecific cis-addition product. Just as obvious is the fact that the trans-addition product is hard to visualize as arising from a one-step reaction. Therefore, the formation of products with the latter stereochemistry is usually attributed to the intermediacy of a species with more or less free rotation around the carbon-carbon bond corresponding to the double bond in the olefin reactant. An intermediate meeting this requirement is a trimethylene diradical as shown in eq. (3) or its dipolar counterparts. Unless the rotamer equilibrium in this intermediate is strongly displaced to one side, through the intervention of strong nonbonded interactions, such a reaction scheme may lead to a nonstereospecific addition. Therefore, in an operational sense,

CARBENES AND CARBENE ADDITION TO OLEFINS

205

stereospecific addition has become synonymous with a one-step mechanism, while lack of stereospecificity is usually taken as evidence for a reaction intermediate. This inference, however, may not always be correct in cases of stereospecific additions, because it is easily possible that conformational or stereoelectronic effects will lead to a stereospecific closure of a trimethylene intermediate. Nevertheless, it is advantageous first to examine some theoretical principles which may hopefully lead to a better understanding of the stereochemistry of carbene reactions with olefins. b

b

A puioui, different results may be expected for additions of methylenes with different spin multiplicities. Reactions of singlet state carbenes should be simpler and will be considered first. Cyclopropane formation can be viewed as a cycloaddition reaction and therefore may be examined in the light of orbital symmetry correlations which have been very successful in predicting stereochemical results in other cycloadditions (43-46). To construct an orbital correlation diagram it must be recalled that singlet methylene has C,, symmetry in its low-energy conformation with a bond angle of 102". The symmetry of the orbital wavefunction 'Al is the product of the symmetries of the occupied orbitals: 2 4 lbz 3 4 . Considering a concerted reaction with ethylene, the first two orbitals 2al and lb, may be neglected since they are essentially C-H bonding only and do not participate directly in the reaction. Similarly, it is permissible to neglect their antibonding counterparts 4al and 26,. The only orbitals of importance in the ethylene molecule are the bonding and the antibonding 7r orbitals. The reaction path with the highest symmetry is the one in which a C,, symmetry is assumed at all points of the reaction coordinate. Classification of the orbitals of reactants and product in this point group gives the correlation diagram of Figure 6, in which the low-energy l A l state correlates with an excited state of cyclopropane. Based on symmetry considerations, one should therefore expect a transition state of lower symmetry to be more favorable. For example, the conformation of the transition state shown by

G . L. CLOSS

206

HH

\I

C2H4

n!*bl--

__---- u /-

-b,

u.0,

Fig. 6. Orbital correlation diagram for the addition of methylene to ethylene.

C,, symmetry of the reactants is assumed along the entire reaction coordinate.

(For simplicity, the cyclopropane orbitals have been considered to transform with C,, symmetry although the proper point group for this molecule would be Dab. The diagram is not changed by this simplification.)

10 has as the only symmetry element a plane of symmetry, and all participating orbitals in reactants and products are symmetrical with reference to this plane, making this reaction symmetry allowed. It may

(10)

be pointed out here that a transition state as pictured by 10 has been postulated for many carbene additions, but that it has been derived from a totally different line of thought. It has been recognized very early in the study of carbene additions to olefins that the carbene reagent exhibits electrophilic character, meaning that electron density has been shifted from the olefin to the carbene carbon atom in the transition state. Since the only low-energy orbital able to accept additional electrons

CARBENES AND CARBENE ADDITION TO OLEFINS

207

is the 16, orbital, it was postulated that the most efficient overlap would occur in a transition state resembling 10 (42,47,48). Another interesting consequence of a transition state having lower symmetry than C, is that in a concerted reaction the two cyclopropane bonds must be made to a different extent i n the transition state. Clearly, the two bonds cannot be equivalent because there is no symmetry operation which will transform one into the other. This postulate is also supported experimentally by relative rate studies which show that an unsymmetrical transition state is required to explain the observation that carbenes usually react faster with isobutylene than with 2-butene (42,47-49). It is worth noting that a transition state with C,, symmetry can be expected for the reaction of an olefin with a hypothetical methylene in which the relative energies of the 3a1 and 16, orbitals are interchanged. The low-energy singlet state of such a carbene would have the electron configuration 2 4 162 16:. Reaction of this state with an olefin gives a correlation with the ground state of cyclopropane. However, no methylene with this electron configuration has as yet been reported. While the theoretical discussion of singlet methylene addition rules out a reaction path with CZvsymmetry, it places no other restrictions on the process and even leaves open the possibility of a two-step reaction. In contrast, two powerful arguments can be advanced to demonstrate that the addition of triplet methylene to double bonds is a two-step reaction with all its stereochemical consequences. The first, and more widely accepted, argument rests on the principle of conservation of spin angular momentum during the reactive collision. The second restriction arises from orbital considerations similar to those advanced for the addition of singlet methylene. As originally conceived by Skell and Woodworth (50) the prediction of a nonstereospecific, two-step addition of triplet methylene is summarized in eq. (4). Their mechanism has as its basic assumption the postulate that the transfer of spin angular momentum is much slower than any other molecular process. If this assumption is correct, triplet methylene will react with an olefin to give as the initial product a species with the spin of 1. The simplest molecule meeting this requirement is a trimethylene diradical in its triplet state. The second assumption involves the lifetime of this species relative to the lifetime of a specific conformation (rotamer). Again it is assumed that spin angular momentum transfer is slower than rotamer equilibration with the effect of an overall nonstereospecific cyclopropane formation. Before commenting

208

G. L. CLOSS

in detail on this hypothesis it should be stated that the principle of this argument has been experimentally confirmed and has provided a theoretical explanation of the stereochemistry of many methylene additions. Nevertheless, the chain of reasoning is open to criticism and perhaps needs some modification. The first assumption, postulating the initial formation of a molecule in a triplet state, is backed up by the fact that in most organic molecules spin angular momentum is only very weakly coupled with orbital momentum, and therefore spin relaxation is expected to be slow on the time scale of molecular collisions (51). This argument, however, is based on considerations of the ground state of organic molecules and cannot necessarily be extended to the activated complex in which the nature of bonding may be obscure. Identification of the initially formed triplet state as the trimethylene diradical is justifiable because it is hard to conceive of a triplet intermediate with a lower energy. For example, a triplet state of cyclopropane in which the three-membered ring is preserved and which would presumably show no free rotation, can be expected to be of much higher energy than the postulated intermediate. The weakest link in the chain of reasoning appears to be the postulate of slow spin relaxation in the trimethylene diradical compared to rotamer equilibration. It is generally accepted that the probability of

CARBENES AND CARBENE ADDITION TO OLEFINS

209

intersystem crossing increases with a decreasing energy gap between two states of different multiplicity. Clearly, the energy separation between the singlet and triplet states of the trimethylene diradical cannot be large because of a small electron exchange interaction. Therefore spin relaxation in this system should be fast, although it is admittedly difficult to place this event on the time scale of intramolecular rotation. On the other hand, there is some evidence that ring closure of a trimethylene diradical requires a finite activation energy (52) and that, although some steric preference may be expected (53), this step will not be completely stereospecific even for the singlet state of this intermediate. It is therefore an open question whether nonstereospecific addition should be attributed to slow intersystem crossing in the trimethylene diradical or whether the intermediacy of a diradical by itself leads to nonstereospecific addition regardless of its spin state. Recently, a second argument has been advanced for a two-step nonstereospecific addition of triplet methylene to olefins (53). Without taking recourse to the principle of conservation of spin angular momentum, consideration of the orbital component of the wavefunction alone predicts that an adiabatic one-step process cannot lead to a ground-state cyclopropane. The orbital wavefunction of a triplet methylene belongs to the irreducible representation B, or C;, depending on whether it has a bent or linear geometry, respectively. Combination of these states of low symmetry with the totally symmetric state of an olefin correlates with wavefunctions which are not totally symmetric. This rules out all ground-state molecules with closed shells as the initial reaction products. Again, the trimethylene diradical is a suitable intermediate and the stereochemical consequences are the same as discussed above. Naturally, an experiment deciding whether orbital or spin correlation is the deciding factor for nonstereospecific carbene additions will be hard, if not impossible, to design. Finally, still another mode of nonstereospecific carbene addition to olefins can be envisioned. This process involves the initial stereospecific addition to form a cyclopropane in its electronic ground state but carrying a large excess vibrational and rotational energy. If vibrational relaxation is slow because of a low collision frequency with other molecules, as may occur in the gas phase, it is possible that one of the carbon-carbon bonds will break and a trimethylene diradical might be formed as a secondary product. Scrambling of the stereochemistry can then occur by intramolecular rotation in the diradical before vibrational

210

G . L. CLOSS

relaxation will permit ring closure (54). A thermochemical consideration as shown in eq. ( 5 ) makes this process appear very likely because CH2 +80

+ H2C=CH2 + 12.5

-

CHz

/ \

H2C-CH2

+ 12.7

AH = -79.8 kcal/mole (5)

of the high heat of formation of methylene (- 80 kcal/mole). With most olefins the reaction will be exothermic by 80 kcal/mole, while the activation energy of cyclopropane isomerization is known to be only 64 kcal/mole. Unless vibrational relaxation is very fast, as in highpressure gas phase reactions or in reactions in the condensed phase, the addition of methylene to olefins should always be nonstereospecific. Of course, this mechanism depends on a large heat of formation of the methylene participating in the reaction and more stable carbenes may show stereospecific behavior in the gas phase even at low pressures. It is worth pointing out that the argument presented here is not affected by the recently discovered stereoselective ring closure of the trimethylene diradical in its singlet state (55). The reason for this is that the 64 kcal/ mole of cyclopropane isomerization energy must not only include the energy for bond breaking in cyclopropane, but also the rotational barrier in the diradical. B. Methylene

The first systematic study of the stereochemistry of the addition of methylene to olefins in the gas phase was carried out by Frey (56,57). When diazomethane was photolyzed in the presence of either cis- or trans-2-butene, cis- and trans- 1,2-dimethylcyclopropaneswere among the reaction products together with several isomeric pentenes. It was found that the product ratios were strongly dependent on the total pressure of the system and, to a minor extent, on the wavelength of the incident light. For mechanistic considerations two observations were of importance: (a) the yield of cyclopropanes increases with rising total pressure and (6) the cyclopropane formation is more stereospecific at higher pressures. For example, in the reaction with trans-Zbutene the yield of trans-dimethylcyclopropane rises from virtually zero to an asymptotic value of 50% at the high-pressure limit, while cis-dimethylcyclopropane goes through a maximum of approximately 7”/, at 10 mm and declines at higher pressure. The stereospecificity of the

CARBENES AND CARBENE ADDITION TO OLEFINS

211

0

:n: I 0

a tre $*

I

I

I

I

-

4358 A

95-

3660 A

-

a9

I

I

100

200

I 300

I 400

Pressure ( m m 1

Fig. 7. The stereospecificity of the addition of rnethylene to cis-2-butene as a function of total pressure.

reaction as expressed by the ratio of trans-dimethylcyclopropaneversus total cyclopropane products is shown in Figure 7. Similar results were obtained for the reaction with cis-2-butene. The observations were rationalized in terms of the reaction scheme 1 which assumes initial stereospecific addition to the olefinic double bond in competition with the two possible C-H insertion reactions. Because of the high exothermicity of the primary addition process, however, the initial cyclic adduct is vibrationally highly excited and contains enough energy to rearrange to the isomeric cyclopropane and to the thermodynamically more stable pentenes. Deactivating collisions with other molecules, in this case mostly 2-butenes, compete with rearrangements more favorably at higher pressures and are responsible for preserving the initial adducts. The reduced stereospecificity of the reactions induced by light with shorter wavelength (cf. Fig. 7) is attributed to excess vibrational energy of the methylene carried over to the initial adduct. Thus, at constant pressure comparison of stereospecificity of cyclopropane formation is a measure of the excess energy of the reacting methylene. A detailed kinetic analysis based on steady-state assumptions led to a ratio of 0.33 for k,/k - ,. This number represents the equilibrium constant of the excited cis- and trans-dimethylcyclopropanes and reflects the additional nonbonded interactions between the two methyl groups in the cis isomer. Because of this steric effect the reaction with cis-2-butene should be considerably less stereospecific than with the trans-Zbutene. Experimental observations in this and many other nonstereospecific addition reactions are in agreemept with this conclusion. Also, it is

G. L. CLOSS

212

/

CH3 1 k ,b

<

it

C

H

3

(CH&C=CHCH3*

cF

/

H

‘CJ%

& ,c=c \

H*

kr

CH$H,CH= CHCH, (CH&C=CHCH, CHsCHZ(CH3)C=CH, Scheme I

found that the geometrical isomerization of the cyclopropanes proceeds considerably faster than structural rearrangement to the pentenes, a finding which again derives independent support from thermochemical studies on the dimethylcyclopropanes (58,59). Finally, it should be pointed out that within the pressure range investigated the addition never becomes completely stereospecific. Similar observations were made in the photolysis of diazomethane or ketene in the presence of cis-3-hexene. Even above the high-pressure limit where presumably all hot molecules are rapidly deactivated, some trans-diethylcyclopropane was among the reaction products (60). Also, in the photolysis of diazirine cyclopropane formation was not completely stereospecific at high pressures (6 1). This small portion of nonstereospecific reaction has been attributed to a fraction of triplet methylene participating in the reaction (60).

213

CARBENES AND CARBENE ADDITION TO OLEFINS

TABLE I

Products of Reaction of Methylene with cis-2-Butene as Function of Argon Pressurea

1600 850 356b 314 300 134 69 15.3 7.6

27.1 24.0 3.6 22.1 20.8 18.0 16.3 10.6 9.5

28.1 28.4 50.9 30.7 31.1 33.3 35.4 41.4 44.3

16.5 12.7 0.9 10.7 11.1 8.8 7.8 3.6 2.4

17.0 19.1 27.7 21.8 22.4 24.9 26.4 29.9 30.4

10.5 9.2 1.8 8.2 7.5 6.6 5.8 2.9 1.9

4.0 6.6 15.0 6.3 6.9 8.4 8.4 11.4 12.9

"Total pressures in range of 2100-3200 mm. bIndicatespresence of 4 mm of oxygen.

The stereochemistry of methylene additions to olefins in the gas phase changes drastically when the reaction is carried out at high pressure of inert gas, such as nitrogen or argon, and with the olefin accounting only for a small fraction of the total pressure (62,63). Under those conditions cyclopropane formation may show little stereospecificity even though the total pressure of 2100-3200 mm is considerably above the high-pressure limit required for immediate collisional deactivation of initially formed hot molecules. Table I summarizes the data obtained in the photolysis of diazomethane in the presence of variable ratios of argon and cis-2-butene. Although the olefinic products of the reaction are only indirectly connected with the stereochemistry of the addition step, they have been included because they provide additional evidence for the proposed reaction mechanism. The data are consistent with the hypothesis that methylene is initially formed in a singlet state, presumably the spectroscopically identified 'Al state. Upon many collisions with inert molecules intersystem crossing will occur leading to the true ground state, 3C;. At high argon/2-butene ratios most of the methylene will be in the ground state before a collision with 2-butene occurs and, consequently, the predominant fraction of

214

G . L. CLOSS

the reaction products is thought to arise from triplet methylene. The nonstereospecific cyclopropane formation is then attributed to the twostep addition mechanism involving a trimethylene diradical as outlined in detail in the previous section. This hypothesis receives considerable support from an examination of the olefinic products, which may be formed either by a direct one-step insertion reaction or through rearrangements of some primary unstable product. With cis-2-butene as the starting material, only cis-Zpentene and 3-methyl-2-butene can be formed by direct insertion, and at high butene pressures they constitute the major fraction of the isomeric pentenes. 3-Methyl-1-butene and trans-2-pentene, on the other hand, become major reaction products only at high argon/butene ratios. The latter products are thought to arise from the same intermediate as trans-dimethylcyclopropane. 1,CHydrogen and 1,2-methyl migration from the initial trimethylene diradical will account for the formation of these products [eq. (6)]. An alternative pathway involves the hydrogen abstraction by methylene from the methyl group, thus forming a radical pair which on recombination would yield the pentenes. H

HZC=CH-CH(CHa)

H2C H ‘

*CH2

\cH\

c=c/H

Additional strong support for a triplet methylene mechanism is provided by the drastic change of the stereochemical results by small amounts of oxygen. The increased stereospecificity of cyclopropane formation in the presence of oxygen is attributed to selective scavenging of triplet methylene by oxygen, leaving only singlet methylene as the precursor of the observed products. More recently, this mechanistic scheme has received additional support from a set of experiments demonstrating very clearly that two independent mechanisms must be responsible for nonstereospecific cyclopropane formation in the gas phase (64). It was shown that the yield of the trans addition product goes through a minimum when the partial pressures of the olefin and the methylene precursor are kept

CARBENES AND CARBENE ADDITION TO OLEFINS

215

constant while varying the pressure of the inert gas. The pressure at which this minimum occurs was shown to be a function of the nature of the inert gas. For example, with tetrafluoromethane the smallest fraction of trans addition to cis-Zbutene occurs at approximately 100 mm, while a much more shallow minimum at 500 mm can be observed when helium serves as the inert gas. These observations are very strong evidence for the formation of the trans addition product by two different mechanisms. At the low-pressure side of the minimum the rearrangement of the hot adduct predominates, while most of the nonstereospecific reaction path at the high-pressure side is due to triplet methylene which is formed by slow relaxation from the excited singlet state. Furthermore, the experiment demonstrates very clearly the different efficiencies of various gases in collisional deactivation. It appears that a molecule with a large number of internal degrees of freedom is much more effective than a single atom. Results very similar to those of the high-pressure reaction were observed in the mercury-atom photosensitized decomposition of ketene (65). Reactions with both cis- and trans-Zbutene were found to be nonstereospecific. Since mercury-atom photosensitization is well known to involve energy transfer from metastable mercury atoms in a triplet state it is postulated that methylene arises from the triplet state of ketene. Because of the conservation of spin angular momentum, the methylene should be formed in its triplet state and the stereochemistry of the addition reaction should reflect the pure triplet reaction path. A comparison of Tables I and I1 shows that the product ratios in the two entirely different experiments are very similar indeed. TABLE I1

Products from Mercury-Photosensitized Decomposition of Diazomethane in the Presence of 2-Butenes

cis-2-Butene trans-2-Butene

24.6 13.5

31.3 51.9

12.3 18.7

19.3 5.6

8.1 6.8

3.7 2.8

216

G . L. CLOSS

The facts that the ratio of cis- to trans-dimethylcyclopropane in the photosensitized experiment with cis-Zbutene (0.44) differs from the ratio found in the reaction with trans-Zbutene (0.21) and that still another ratio (0.51) is observed in the high-pressure limit of the inert gas experiments deserve some further comment. It is possible that none of the conditions is producing a pure triplet methylene reaction path and that in each case a parallel stereospecific reaction involving singlet methylene is responsible for part of the product formation. This explanation is reasonable for both reaction types if one assumes that incomplete filtering will allow some ketene to be photolyzed by an unsensitized route and that the high-pressure limit for singlet-triplet conversion has not been reached in the experiments with diazomethane. The other explanation is based on the relative velocities of conformational changes in the hypothetical trimethylene diradical and the ring closure rates of cis- and trans-dimethylcyclopropane.If the rate of the former process is not very much faster than ring closure it is possible that a “memory” effect can be observed, leading to a greater proportion of the cyclopropane with the corresponding geometry of the starting olefin. An examination of the nature of the conformational changes required for complete loss of stereospecificity reveals that the barrier must be small. If it is assumed that torsional interactions are the only contributors to the rotational barrier in the diradical, it is hard to see how this value can exceed 3 kcal/mole. It is more difficult to put a lower limit on the activation energy of ring closure, although a value of 8 kcal/mole has been estimated for the closure of the unsubstituted trimethylene diradical(52). Assuming that this value is correct and that it can be used as a lower limit for the dimethyl-substituted diradical, it is difficult to see how a memory effect can be carried over in the twostep addition reaction. Therefore, it is likely that a reaction proceeding completely through triplet methylene has not yet been observed. The stereochemistry of methylene addition reactions in the condensed phase is completely consistent with the hypotheses developed from the vapor phase reactions. For example, it is readily seen that hot-molecule rearrangements are extremely unlikely in the condensed phase if one extrapolates the observed pressure dependence of these rearrangements to the very high collision frequencies expected for the liquid state. Under those conditions collisional deactivation will be orders of magnitude faster than even the more readily occurring rearrangements. Consequently, any nonstereospecific addition in the liquid phase must be

CARBENES AND CARBENE ADDITION TO OLEFINS

217

attributed to an initial two-step reaction. In fact, methylene, when generated by direct photolysis from diazomethane in the liquid phase, adds to olefins with complete retention of configuration (66,67). This observation is generally interpreted by assigning a singlet state to the reacting methylene and by the assumption of a reaction rate which is faster than intersystem crossing to the ground state. Because of the very high reactivity of singlet methylene, it is very difficult to produce methylene in its triplet ground state in the liquid phase. The benzophenone-photosensitized decomposition of diazomethane has been reported to give triplet methylene in solution (68). In the presence of cis-2-butene the reaction was found to give 1,2dimethylcyclopropane with some loss of stereospecificity. Unfortunately, the trapping with trans-Zbutene does not show the equivalent stereochemistry, but instead produces almost entirely trans- 1,2-dimethylcyclopropane. Furthermore, cyclopropane formation in the photosensitization experiment accounts only for a small fraction of the total products. A complication in the interpretation of the photosensitized decomposition of diazomethane and many similar reactions is the possibility that the triplet state of diazomethane is relatively long lived and may undergo reactions by itself. At least no evidence exists ruling out a two- or threestep nonstereospecific cyclopropane formation involving the addition of triplet diazomethane as the first step. Loss of nitrogen and ring closure either in a concerted reaction or in two separate steps would complete the product formation [eq. (7)].

218

G . L. CLOSS

Photolysis of methylene iodide dissolved in olefins gives cyclopropanes in modest yield. Within the limit of detection ( 5 % ) this reaction was found to be stereospecific (69). However, there is some question as to whether the cyclopropanes are formed by addition of free methylene or whether some other intermediate, such as an excited methylene iodide or iodomethyl radical, is involved in the methylene transfer reaction. If methylene is indeed the precursor, the results must be interpreted in terms of a singlet methylene as the reacting species, although one might expect that the presence of methylene iodide and iodine in solution would considerably enhance spin relaxation. Finally, a number of methylene transfer reactions have been observed which in all likelihood do not involve free methylene as a reaction intermediate. The best studied of these is the Simmons-Smith reaction, in which iodomethylzinc compounds have been identified as the reactive species (70-72). Presumably the same methylene transfer reagent is generated in the reaction of diazomethane with zinc iodide (73,74). In both reations cyclopropane formation occurs with complete stereospecificity. The Simmons-Smith reaction is just one example of a variety of cr-eliminations which transfer methylene to a double bond via an organometallic reagent. In all cases cyclopropanes are formed with complete stereospecificity (75-77). T o account for the high specificity of these reactions two schemes differing in the number of steps required for ring formation have been proposed. The first, and more commonly accepted mechanism involves a one-step reaction with a bridged transition state as shown in eq. (8) (70-73). Both the stereochemistry and the

observed electrophilic behavior of the organometallic reagent are easily accounted for in this proposal. In contrast, the suggestion of a two-step reaction with an organometallic intermediate, as shown in eq. (9), suffers from the requirement of complete configurational stability for

CARBENES AND CARBENE ADDITION TO OLEFINS

219

this intermediate. Furthermore, nucleophilic reactivity sequences would be expected for this reaction scheme. Recently, additional evidence against eq. (9) has been reported (78).

C. Methylene Derivatives As discussed in the previous section, nonstereospecific addition of methylene to olefins has been attributed to either conservation of spin angular momentum in reactions involving the triplet state of methylene, or to rearrangements of cyclopropanes carrying excess vibrational energy. The latter cause of diminished stereospecificity is a direct consequence of the high heat of formation of methylene. Almost any substituent other than hydrogen can be expected to stabilize the open shell of the divalent carbon by some form of electron delocalization, and, as measured by the usual criteria of reactivity, methylene must be considered to be the least stable of the known divalent carbon compounds. As a result the hot-molecule mechanism for nonstereospecific additions in the gas phase should be much less important for derivatives of methylene. Unfortunately, very few data of low-pressure gas phase addition reactions have been reported for substituted methylenes, but the few available results are in agreement with this prediction. Thus, monofluoro- and monochlorocarbene generated in the gas phase through dehydrohalogenation of highly excited dihalomethane molecules added to olefins without subsequent rearrangements (79,80). The dihalomethane molecules were excited through hot-atom substitution of tritium for hydrogen, and the carbenes thus created were actually isotopically labeled. The total pressure of the system was unfortunately quite high (750 mm), and it is possible that collisional deactivation is partly responsible for the observed stereospecificity in the additions to 2-butene. The results were unchanged by the presence of oxygen, indicating singlet states for the reacting species. The stereochemistry of carbene additions in the condensed phase has been studied in great detail. The wealth of data can be summarized by stating that nonstereospecific addition has been observed only for those divalent carbon molecules which very likely have a triplet ground state. The converse conclusion that all carbenes with triplet ground states should add to olefins with loss of stereospecificity, however, is not warranted on the basis of experimental observations. The most

220

G . L. CLOSS

important violation of this postulate is the addition of methylene itself as discussed in the previous section. A further factor of uncertainty in predicting the stereochemistry of the addition reaction arises from the possibility that many reactions may bypass the free carbene and may instead proceed through a complexed species or carbenoid which exhibits an entirely different stereochemical behavior than the corresponding free carbene. The above problem is particularly severe in cyclopropane syntheses via heterolytic a-eliminations. Without exception reactions belonging to this general category (Scheme 2) form cyclopropanes by stereospecific cis additions. Without additional experimental information, the stereospecificity may be attributed to any one of four causes: (a) the reaction proceeds through a free carbene having a singlet ground state, (b) a free carbene with a triplet ground state is formed but spin relaxation is slow compared to the addition rate, (c) a triplet carbene is a reaction intermediate but internal rotation in the trimethylene diradical is slow compared to ring closure, and (d) the reaction does not form a

YM R

\c=c/ / \

\

R

/c:

Scheme 2

free carbene but the carbenoid [eq. (9)] transfers the substituted methylene directly to the olefin. Distinction of mechanism d from the remaining three is sometimes possible by generating the formally identical carbene by a different method, preferably one which has ample precedent to yield free

CARBENES A N D CARBENE ADDITION TO OLEFINS

221

carbenes. Photolysis of diazoalkanes or diazirines can be expected to fall in this category. For example, the reaction of methylene chloride with alkyllithium and olefins gives chlorocyclopropanes by stereospecific cis addition (81-82). However, the general reactivity of the intermediate in this reaction was found to differ substantially from that of the intermediate formed in the photolysis of chlorodiazomethane (83-84). I t was concluded that chlorocarbene is the intermediate in the photolysis while the a-elimination proceeds through the carbenoid dichloromethyllithium (85). The free chlorocarbene, as well as bromocarbene, is also stereospecific in its addition reaction. When combined with spectroscopic evidence (22), this result makes it very probable that monohalocarbenes react from a singlet ground state. Dihalomethylene groups have been transferred to olefins by many different methods. In all cases the reactions were found to be completely stereospecific. While it is likely that in some a-eliminations on polyhalomethanes free dihalomethylenes are not involved (86-88), others almost certainly proceed through the free carbenes (89-92). Again, it is highly probable that the singlet state is the ground state of dihalomethylenes and that the stereospecificity is due to a one-step addition mechanism. The behavior of many arylmethylenes is stereochemically more interesting. It was recognized quite early that diphenylmethylene produced by photolysis from diphenyldiazomethane adds to 2-butenes with partial loss of stereospecificity (93-94). On the other hand, the diphenylmethylene group was transferred to the same olefins with complete specificity in the a-elimination of diphenyldibromomethane with alkyllithium (94). It was concluded that in the latter reaction bromodiphenylmethyllithium was the reactive intermediate, whereas photolysis of diphenyldiazomethane gave diphenylcarbene in its triplet ground state. Subsequent electron spin resonance studies seemed to confirm the interpretation by proving the triplet multiplicity for the ground state of this molecule (28,30,33). Similar observations were made for phenylmethylene which when generated from phenyldiazomethane is not completely stereospecific in its addition reactions (95). Again, the transfer of the same group via a-elimination of benzal bromide with alkyllithium is completely stereospecific (42). The interpretation given for diphenylmethylene can be invoked in this system as well, since ESR data established a triplet ground state for phenylmethylene (34). However, an interesting problem remains : The loss of stereospecificity

222

G . L. CLOSS

in the photolytically induced additions is relatively small. For example, in the reaction of phenylmethylene generated from phenyldiazomethane with cis- and trans-Zbutene the trans addition products do not amount to more than 3 and 1%, respectively. Several hypotheses can be advanced to account for the results. The most attractive explanations call either for slow spin relaxation with the major fraction of the addition proceeding through the singlet state or for a very fast ring closure allowing only incomplete rotamer equilibration in the intermediate trimethylene diradical. A study of the stereochemistry of fluorenylidene (3) generated by photolysis from 9-diazofluorene shed some light on this problem (96,97). With cis-Zbutene as the solvent, cis-dimethylspiro-[cyclopropane1,9‘fluorene] (11) and its trans isomer (12) are formed in a ratio of 1.95, while irradiation in trans-Zbutene gives the same products in a ratio of 0.06. This large “memory” effect becomes much smaller when the reaction mixture is diluted with hexafluorobenzene as an inert solvent. At the highest dilution, when the solution was approximately 0.1M in olefin, the corresponding ratios were 0.25 and 0.14. These observations are completely compatible with a mechanism involving stereospecific addition of a metastable singlet fluorenylidene and a competing addition from the triplet ground state occurring with complete loss of stereospecificity (Scheme 3). The dilution effect results from the different concentration dependence of two competing reactions. The decay of the metastable state is unimolecular and, therefore, concentration independent, while the stereospecific addition rate is first order in olefin concentration. Although a common ratio of the two isomeric products has not been reached in the experiments with cis- and trans-Zbutene, there is no compelling evidence for an incomplete rotamer equilibration of the trimethylene diradical. It is more likely that even at the highdilution limit of the experiments a fraction of the reaction still proceeds through the singlet state. Extrapolation of the available data to infinite dilution suggests a common product ratio of approximately 0.16. Experiments in the presence of oxygen lend further support to the idea of a triplet state precursor in the nonstereospecific addition by showing a somewhat greater specificity (97). Scavenging of the paramagnetic species by oxygen results in a correspondingly greater proportion of the singlet-state reaction. A similar interpretation was offered for increased stereospecificity in the presence of butadiene, which is thought to have a greater reactivity toward the triplet state.

CARBENES AND CARBENE ADDITION TO OLEFINS

223

\ Scheme 3

The success of the dilution experiments depends very much on the relative rates of singlet-state decay and the addition rate of the metastable state to the olefin. Although nothing is known about the rates of intersystem crossing for carbenes in the condensed phase, it is selfevident that the more reactive the singlet state, the less chance there is for obtaining the triplet state by dilution. Dicyanocarbene generated from dicyanodiazomethane behaves in a similar manner to fluorenylidene. I t is known to have a triplet ground state from ESR studies (98) and adds to olefins in high concentration with partial loss of stereospecificity (99). On dilution with cyclohexane the ratio of cis- to trans- 1,2-dimethyl-3,3-dicyanocyclopropane reaches 0.43 regardless of whether cis- or trans-Zbutene is the reactant. Dilution experiments with dicarbomethoxymethylene (100) and cyclopentadienylidene (101,102) were only partially successful inasmuch as only minor deviations from the high stereospecificity of the addition reactions were observed at very high dilution. No loss of stereospecificity

G. L. CLOSS

224

at all was observed on lowering olefin concentrations in the photolysis of diazomethane (68). This is in agreement with the expectation that high reactivity of the singlet state will compete successfully with thermal singlet-triplet conversion. A different behavior is observed in the photolysis of diaryldiazomethanes in the presence of olefins (103). First of all, the major reaction path with cis- and trans-Zbutene is hydrogen abstraction from the allylic positions, followed by recombination of the radical fragments. Cyclopropanes account for no more than 10% of the total hydrocarbon products. At -10" with cis-Zbutene as the trapping olefin, cis- and (13 and 14) are formed in trans- 1,2-dirnethyl-3,3-diphenylcyclopropane a ratio of 3.2, while the corresponding ratio with trans-Zbutene is only 0.04. The stereospecificity increases at lower temperature; for example, at - 66" the product ratio obtained from cis-Zbutene is 9.0. At a given temperature the product ratio is independent of the olefin concentration over a range of 150-fold dilution with cyclohexane. With hexafluorobenzene as the diluent the reaction becomes somewhat more specific. Similarly, the presence of oxygen does not change the isomer ratio although the total yield of cyclic and acyclic hydrocarbons is greatly diminished and approaches zero for high oxygen concentration. All these observations are most consistent with a mechanistic scheme as outlined in Scheme 4. It is postulated that intersystem crossing is much faster than any other reaction in the system. Furthermore, it is assumed that the reverse crossing is also very fast so that both electronic con-

c \

/

.C

/

c

7

Scheme 4

\

/

c\

J-

CARBENES AND CARBENE ADDITION TO OLEFINS

225

figurations are effectively in equilibrium. Since diphenylmethylene is known to have a triplet ground state, k, must be larger than k - , . The fraction of stereospecific singlet-state addition will then be determined by this equilibrium and by the relative rates of the singlet (kaJ and triplet (kat)addition steps. The observed product ratios and the fact that k, > k - , requires that singlet-state addition is much faster than triplet addition (kas>> kaJ.The temperature dependence is easily explained if the difference in the free energies of activation for the two addition reactions is larger than the free energy difference between the two electronic states. Provided this scheme is correct, diphenylmethylene differs from fluorenylidene either by undergoing intersystem crossing much more effectively or by a considerably reduced efficiency in olefin additions, or by a combination of both effects. Steric arguments can be advanced for the slower addition rates because the twisting of the phenyl groups should result in a much better shielding of the divalent carbon atom (36). This assertion receives support from the fact that the triplet state of diphenylmethylene undergoes predominantly the sterically less demanding hydrogen abstraction, while fluorenylidene appears to have a preference for addition even in its triplet state. The related systems dibenzo[a,d]cycloheptenylidene (15) and tribenzo[a,c,e]cycloheptenylidene(16), when generated from the corresponding diazocompounds, add stereospecifically to the 2-butenes,

(15)

(16)

although ESR studies have shown them to have triplet ground states (104,105). Presumably this is due either to slow spin relaxation or to unusually high addition rates. Methylenes with alkynyl substituents have been reported to add to olefins with partial loss of stereospecificity (106-108). The simplest member of this group, propargylene (17), has been generated by photolysis from the corresponding diazo compound and shows a stereochemical behavior very similar to that of fluorenylidene. Addition to cis- and trans-2-butenes is not stereospecific, but different product

G . L. CLOSS

226

ratios are obtained from the isomeric olefins. Spin relaxation rates appear to be of the same order of magnitude as addition rates, and triplet scavenging experiments with butadiene increase the stereospecificity. Labeling at C-1 in the diazo compound and examination of the labeled position in the trans addition product revealed that carbons 1 and 3 have equal reactivity in the triplet state. This finding is in agreement with the results from ESR experiments which showed that propargylene in the triplet ground state is a linear molecule and probably should be represented as a resonance hybrid of the two canonical structures [eq. (loa)]. In contrast, no scrambling of label was found in

..

+-+ 3H-C-CrC-H

3H-C~C-C-H (17a)

'H-CEX-C (174

(17W

'H

.. \

\

C-C-C-H

Uoa)

(lob)

'H

the product which was formed by stereospecific cis addition and presumably had the singlet state as a direct precursor. A possible interpretation of this result consistent with the theory on the electronic structures of methylenes, assigns a bent structure to the singlet state of propargylene with a rather high barrier for the configurational interchange of carbons 1 and 3 [eq. (lob)]. The discussion on the stereospecificity of the addition of methylene derivatives to olefins can be summarized with a few general statements based on the experimental observations reported so far: (a) All carbenes known to have a singlet ground state add to olefins in a completely stereospecific cis addition. This category includes all known carbenoids in which the divalent carbon atom is complexed to some other molecule. (b) Stereospecific frans addition has never been observed. (c) In the condensed phase all nonstereospecific additions can be interpreted by a two-step mechanism involving a triplet carbene. ( d ) In solution there is no evidence for a mechanism based on rearrangements of hot cyclopropanes. (e) There is no evidence for a two-step mechanism in which stereospecificity is partially preserved by ring closure of the intermediate trimethylene diradical occurring faster than rotamer equilibration. (f) Carbenes with triplet ground states may add stereospecifically to olefins by reacting from metastable states. The stereoselectivity, as defined at the beginning of this chapter

CARBENES A N D CARBENE ADDITION TO OLEFINS

227

(p. 204), of carbene and carbenoid reactions has been studied for several systems. The two different adducts obtained from the stereospecific reaction of a monosubstituted carbene with olefins lacking both a center of symmetry and a twofold symmetry axis along the carboncarbon double bond have been referred to as syn-anti or as endo-exo pairs. The syn or endo configuration is assigned to the cyclopropane in which the carbene substituent has a cis relationship to the larger number of alkyl substituents (42). Obviously, a further definition is needed when both methylene hydrogens are substituted by different groups. The stereoselectivity of all four halocarbenes has been studied. Reactions which presumably yield free halocarbenes show little or no stereoselectivity at all. The syn and anti adducts to cis-2-butene of fluorocarbene (80), chlorocarbene (83,84), and bromocarbene (84) are formed in equal amounts. Iodocarbene, generated by photolysis of iodoform (109) adds to cyclohexene with a small preference (1.5 : 1) for the formation of the anti isomer. These observations suggest transition states for the addition with virtually nonexistent nonbonding interactions between the halogen atom and the alkyl groups. Only with the very large iodine atom steric repulsion becomes a noticeable factor in the syn addition mode. Different results were obtained when the chloromethylene group was transferred to olefins by reaction with methylene chloride and alkyllithiums. In the reaction with cis-2-butene, for example, the syn and anti isomers of I -chloro-2,3-dimethylcyclopropanewere formed in a ratio of 5.5 (81.1 lo). Similar ratios were observed for other olefins, and in all cases formation of the syn isomers predominated. The different stereoselectivities of chlorocarbene generated from chlorodiazomethane and of the intermediate produced in this a-elimination led to the suggestion that the alkyllithium induced reaction bypasses the free carbene and should be formulated as a reaction of dichloromethyllithium (1 lo). It should be pointed out here that at present it is not known which of the two cyclopropane configurations corresponds to the thermodynamically more stable isomer. A priori one might reason that the cis relationship of the chlorine atom and the alkyl groups might give rise to nonbonded repulsion. However, it is known that cis-I-chloropropene is slightly more stable than its trans isomer, and in many respects a cyclopropane ring resembles a double bond. The only unsymmetrical dihalocarbene for which the stereoselectivity has been reported is fluorochlorocarbene generated from sym-

228

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tetrachlorofluoroacetone and potassium tert-butoxide (1 1 1). With cis-Zbutene as a trapping olefin the two 1-chloro-l-fluoro-cis-2,3-dimethylcyclopropanes were formed in a ratio of 3 : 1 in favor ofthat isomer in which chlorine is syn to the alkyl groups [eq. (1 I)] (1 12). Whether this reaction involves a free carbene or whether the intermediate should be

Cl

formulated as a carbenoid is not known with certainty, although extrapolation from other dihalocarbenes strongly suggest a free carbene intermediate. Assuming a free carbene, the observation of some stereoselectivity should be compared with the results of the corresponding monohalocarbenes which showed no selectivity at all. A reasonable explanation for this trend is found in the generally greater selectivity in reactions of dihalocarbenes reflecting the stabilizing effect of halogen on the divalent carbon atom. The bond distances of the incipient cyclopropane bonds in the transition state must be somewhat shorter in dihalocarbene additions and nonbonded interactions, whether attractive or repulsive, will be more severe than in monohalocarbene reactions. The stereoselectivity of arylcarbene reactions has been studied in detail for both the free carbene and the carbenoid system (42). Phenylcarbene and several ring-substituted phenylcarbenes were generated by photolysis from the corresponding diazo compounds and the stereoselectivities were determined for additions to 1-butene, cis-2-butene, and 2-methyl-2-butene. Since the reactions were in all cases more than 96% stereospecific, it was assumed that by far the major fraction of the additions proceeded through the singlet state. The related carbenoid systems were generated from benzal bromides and alkyllithiums. The results of the additions to cis-Zbutene are displayed graphically in Figure 8 where line I connects syn-anti isomer ratios obtained in carbene additions and line I1 connects the ratios in the carbenoid systems. The

CARBENES A N D CARBENE ADDITION TO OLEFINS

229

, m-CI

p-GI

H

p-CH3

p-CH30

..

Fig. 8. syn-anri Isomer ratios obtained from the addition of X-c6H*-c-H (I) and X-c6H4-cHLiBr (11) to cis-2-butene (42).

stereoselectivities of the carbene reactions are small, but the slight preference is in favor of syn addition. Similarly, the syn adducts are preferred in the additions of the carbenoids and the selectivity is generally larger. The substituent effects are small in the free carbene reactions and become noticeable only for substituents with negative u. In the carbenoid reactions substituent effects are somewhat larger, and both substituents with negative and positive u increase the selectivity. Equilibration experiments showed that the predominantly formed syn isomers are the thermodynamically less stable products. For example, the free energy difference between the two I-phenyl-cis-2,3-dimethylcyclopropanes is 3.5 kcal/mole (1 13). The stereoselectivity of phenylmethylene transfer can be increased by using metal-halide catalyzed decompositions of phenyldiazomethane. The syn-anti isomer ratio obtained for addition to cis-Zbutene rises to 25 when phenyldiazomethane is decomposed with zinc iodide (1 14). Other zinc, magnesium, and lithium salts give values which lie between this extreme and those shown in Figure 8. The syn directive powers of the phenyl group and of the halogen atoms are placed in competition with each other in the reactions of phenylhalocarbenes. These methylene derivatives are easily generated from benzal halides and strong bases, such as potassium tert-butoxide (1 15) or alkyllithiums ( I 16). An uncertainty exists as to whether free carbenes are generated in these systems or whether they belong to the

230

G . L. CLOSS

category of carbenoid reactions. Both phenylchlorocarbene (1 17) and phenylbromocarbene (1 18) add stereospecifically to cis-2-butene, with the predominant formation of the isomer in which the halogen has the syn orientation. Phenylchlorocarbene is somewhat more selective than phenylbromocarbene with syn-anti isomer ratios of 3.0 and 1.4, respectively. The stereoselectivity of various alkoxycarbenes and phenoxycarbene has been examined and was found to depend not only on the nature of the carbene substituents, but also on the steric requirements of the acceptor olefin. Since the carbenes are generated by or-eliminations on a-haloethers with alkyllithiums, it is not known whether really free carbenes are intermediates. Cyclohexene and cyclopentene react with phenoxy- and various alkoxycarbenes with predominant formation of the anti (exo) isomers (1 19-122). Phenoxycarbene adds to cis-Zbutene in the same manner (1 19), while alkoxycarbenes react with this olefin with preference for the syn configuration (121,122). The phenylthioand phenylselenocarbenes show a predominant syn stereoselectivity (123-125). Carboethoxycarbene generated by photolysis from ethyl diazoacetate adds to cyclohexene with predominant formation of the anti product (126). The stereoselectivity is very much increased in the coppercatalyzed decomposition of the diazoacetate where an anti-syn isomer ratio of 17 has been obtained. Rationalization of the observed stereoselectivities in terms of a consistent model for the transition state of the addition reactions has been attempted (42,110). However, the predictive value of such a model is only modest because of a delicate balance of a number of opposing effects. First of all, in all reactions known to proceed through free carbenes the stereoselectivity is not very large. The interpretation of the selectivities of carbenoid reactions in which some large selectivities have been observed is complicated by the lack of knowledge of the detailed structure of the carbenoid. For example, there is good reason to believe that some lithium-containing carbenoids are dimeric or polymeric species (127), the steric requirements of which are very hard to assess. Nevertheless, some positive statements on the origin of stereoselectivities can be made. Since the stereoselectivity arises from secondary or nonbonded interactions in the transition state, it should be strongly dependent on the distance of the interacting groups. The transition state for cyclopropane formation will become “tighter’’ and resemble

CARBENES A N D CARBENE ADDITION TO OLEFINS

231

products more, the less reactive the carbene-olefin system is. Consequently, stereoselectivities should be at their maximum with the least reactive carbenes and olefins of low electrophilicity. This conclusion is generally supported by the available data. Furthermore, a surprisingly large number of carbene and carbenoid reactions show a preference for the formation of the presumably thermodynamically less stable syn isomer, suggesting a transition state with attractive interaction between the carbene substituent and the alkyl groups. The nature of the attractive forces is unknown at present, although the results may be explained by assuming strong London interactions between the polarizable carbene substituent and the alkyl groups. Another possible explanation is based on the known electrophilic behavior of most carbenes and carbenoids. In a transition state for an electrophilic addition the olefinic carbon atoms will be depleted of some electron density, and the .tabilizing influence of the alkyl groups must be attributed to their ability to accept part of this electron deficiency. This leads to a mechanism for attraction between the polarizable carbene substituent and the alkyl groups in the transition state for syn addition (18). Opposing these attractive forces will be nonbonded repulsive interactions which will be particularly severe if either the alkyl groups on the olefin or the carbene

substituent are unusually large. Since neither the attractive nor the repulsive forces can be predicted quantitatively and since the geometry of the transition states are not well defined, it is at present almost impossible to predict the stereoselectivity of carbene additions reliably. References 1. J. Hine, Divalent Carbon, Ronald Press, New York, 1964. 2. W. Kirmse, Carbene Chemistry, Academic Press, New York, 1964. 3. H. M . Frey, in Progress in Reaction Kinetics, Vol. 2, G . Porter, Ed., Pergamon Press, Oxford, 1964, 13 1-1 64.

232

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4. W. Kirmse, Angew. Chem., 77, 1 (1965);Angew. Chem. Intern. Ed. Engl., 4,1 (1965). 5. W.B. DeMore and S. W. Benson, in Aduances in Photochemistry, Vol. 2, W. A. Noyes, Jr., G. S. Hammond, and J. N. Pitts, Jr., Eds., Interscience, New York, 1964,pp. 219-262. 6. G.Kobrich, Angew. Chem., 79, 15 (1967); Angew. Chem. Intern. Ed. Engl., 6,41 (1967). 7. A. D. Walsh, J. Chem. SOC.,1953,2260. 8. G. Herzberg, Molecular Spectra and Molecular Structure, I l l . Electronic Spectra and Electronic Structure of Polyatomic Molecules, Van Nostrand, New York, 1966, 316. 9. S. D. Peyerimhoff, R. J. Buenker, and L. C. Allen, J. Chem. Phys., 45, 734 (1966). 10. J. M. Foster and S . F. Boys, Reo. Mod. Phys., 32, 305 (1960). 11. A. Padgett and M. Krauss, J. Chem. Phys., 32, 189 (1960). 12. P.C. H. Jordan and H. C. Longuet-Higgins, Mol. Phys., 5, 121 (1962). 13. G.W.King and G. L. Malli, Can. J. Chem., 39, 1652 (1961). 14. R.N. Dixon, Mol. Phys., 8, 201 (1964). 15. R.Hoffmann, G.D. Zeiss and G. W. Van Dine, J. Am. Chem. SOC.,90,1485 (1 968). 16. G.Herzberg and J. Shoosmith, Nature, 183, 1801 (1959). 17. G.Herzberg, Proc. Roy. SOC.(London), A262, 291 (1961). 18. G.Herzberg and J. W. C. Johns, Proc. Roy. SOC.(London),A295, 107(1967). 19. P. Venkateswarlu, Phys. Rev., 77, 79, 676 (1950). 20. R.K. Laird, E. B. Andrews, and R. F. Barrow, Trans. Faraduy SOC.,46,803 (1950). 21. D. E. Milligan, D. E. Mann, M. E. Jusk, and R. A. Mitsch, J. Chem. Phys., 41,1199 (1964). 22. A. J. Merer and D. N. Travis, Can. J. Phys., 44,525 (1966). 23. A. J. Merer and D. N. Travis, Can. J . Phys., 44,1541 (1966). 24. W.A. Gibbons and A. M. Trozzolo, J. Am. Chem. SOC.,88, 172 (1966). 25. 0.L. Closs, C. A. Hutchison, Jr., and B. Kohler, J. Chem. Phys., 44,413 (1966). 26. I. Moritani, S. Murihashi, N. Nishino, K. Kumura, and H. Tsubimora, Tetrahedron Letters, 4, 373 (1966). 27. A. M. Trozzolo and W. A. Gibbons, J. Am. Chem. SOC.,89, 239 (1967). 28. R.W. Brandon, G. L. Closs, and C. A. Hutchison, Jr., J. Chem. Phys., 37, 1878 (1962). 29. R. W.Brandon, G. L. Closs, C. E. Davoust, C. A. Hutchison, Jr., B. E. Kohler, and R. Silbey, J. Chem. Phys., 43, 2006 (1965). 30. R. W. Murray, A. M. Trozzolo, E. Wasserman, and W. A. Yager, J. Am. Chem. SOC.,84,3213 (1962). 31. E. Wasserman, L. C. Snyder, and W. A. Yager, J. Chem. Phys., 41, 1763 (1 964). 32. J. Higuchi, J. Chem. Phys., 39, 1339 (1963);38, 1237 (1963). 33. A. M. Trozzoio, R. W.Murray, and E. Wasserman, J. Am. Chem. SOC.,84, 4990 (1 962).

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34. E. Wasserman, A. M. Trozzolo, W. A. Yager, and R. W. Murray, J. Chem. Phys., 40, 2408 (1964). 35. C. A. Hutchison, Jr., and G. A. Pearson, J. Chem. Phys., 43, 2545 (1965). 36. C. A. Hutchison, Jr., and B. Kohler, private communication. 37. E. Wasserman, L. Barash, A. M. Trozzolo, R. W. Murray, and W. A. Yager, J . Am. Chem. Soc.. 86, 2304 (1964). 38. E. Wasserman, L. Barash, and W. A. Yager, J. Am. Chem. Soc., 87, 4974 ( I 965). 39. R. A. Bernheim, R. J. Kempf, J. V. Gramas, and P. S. Skell, J. Chem. Phys., 43, 196 ( I 965). 40. A. M. Trozzolo, E. Wasserman, and W. A. Yager, J. Am. Chem. Soc., 87, I29 ( I 965). 41. W. v. E. Doering and A. K. Hoffmann, J. Am. Chem. SOC.,76, 6162 (1954). 42. G. L. Closs and R. A. Moss, J. Am. Chem. SOC.,86, 4042 (1964). 43. R. B. Woodward and R. Hoffmann, J. Am. Chem. Soc., 87, 395, 2046 ( 1965). 44. H. C. Longuet-Higgins and W. E. Abramson, J. Am. Chem. SOC.,87, 2045 ( I 965). 45. R. B. Woodward and R. Hoffmann, J. Am. Chem. Soc., 87,251 I , 4388,4389 ( 1965). 46. R. Hoffmann and R. B. Woodward. Accounts Chem. Res., 1, 17 (1968). 47. W. v. E. Doering and W. A. Henderson, Jr., J. Am. Chem. Soc., 80, 5274 ( I 958). 48. P. S. Skell and A. Y. Garner, J. Am. Chem. SOC.,78, 5430 (1956). 49. H. D. Hartzler, J . Am. Chem. Soc., 83, 4997 (1961). 50. P. S. Skell and R. C. Woodworth, J. Am. Chem. Soc., 78, 4496 (1956). 5 1 . K. J. Laidler, Chemical Kinetics, McGraw-Hill, New York, 1950, 386. 5 2 . S. W. Benson, J. Chem. Phys., 34, 521 (1961). 53. R. Hoffmann, Trms. N. Y. Acud. Sci., Ser. !I, 28, 475 (1966). 54. Cf. W. B. More and S. W. Benson, Advances in Photochemistry, Vol. 2, W. A. Noyes, Jr., G. S. Hammond, and J. N. Pitts, Jr., Eds., Interscience, New York, 1964, 255-258. 5 5 . R. J. Crawford and A. Mishra, J. Am. Chem. SOC.,88, 3963 (1966). 56. H. M. Frey, Proc. Roy. SOC.(London), A250, 409 (1959). 57. H. M. Frey, Proc. Roy. Soc.(London), A251, 575 (1959). 58. M. C. Flowers and H. M. Frey, J. Chem. Soc., 1961, 5550. 59. M. C. Flowers and H. M. Frey, Proc. Roy. SOC.(London), A260,424 (1961). 60. H. M. Frey, Chem. Commun., 1965, 260. 61. H. M. Frey and I. D. R. Stevens, Proc. Chem. Soc., 1962, 79. 62. F. A. L. Anet, R. F. W. Bader, and A. M. Vander Auwers, J. Am. Chem. Soc., 82, 3217 (1960). 63. H. M. Frey, J. Am. Chem. Soc., 82, 5947 (1960). 64. R. F. Bader and J. I. Generosa, Can. J. Chem., 43, 1631 (1965). 65. F. J. Duncan and R. J. Cvetanovic, J. Am. Chem. SOC.,84, 3593 (1962). 66. P. S. Skell and R. C. Woodworth, J. Am. Chem. Soc., 78,4496, 6437 (1956); 81, 3383 (1959). 67. W. v. E. Doering and P. LaFlamme, J. Am. Chem. SOC.,78,5447 (1956).

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68. K. R. Kopecky, G. S . Hammond, and P. A. Leermakers, J. Am. Chem. Sor., 83, 2397 (1961); 84, 1015 (1962). 69. D. C. Blomstrom, K. Herbig, and H. E. Simmons, J. Org. Chem., 30, 959 ( 1965). 70. H. E. Simmons and R. D. Smith, J . Am. Chem. Sor., 80, 5323 (1958); 81, 4256 (1959). 71. E. P. Blanchard and H. E. Simmons, J. Am. Cliern. SOC.,86, 1337 (1964). 72. H. E. Simmons, E. P. Blanchard, and R. D. Smith, J. Am. Chern. Sor., 86, 1347 (1964). 73. G. Wittig and K. Schwarzenbach, Ann. Chem., 650, I (1962). 74. G. Wittig and F. Wingler, Ann. Chem., 650, 18 (1962); Chern. Ber., 97, 2139, 2146 (1964). 75. L. Friedman and J. G. Berger, J . Am. Chem. Sor., 83, 492 (1961). 76. H. Hoberg, Ann. Chem., 656, I (1962). 77. W. v. E. Doering and W. Roth, Tetrahedron, 19, 715 (1963). 78. W. Kirmse and B. v. Wedel, Angew. Chem., 75, 672 (1963); Angew. Chem. Intern. Ed. Engl., 2, 481 (1962). 79. Y. N. Tang and F. S . Rowland, J . Am. Chem. Soc., 87, 1625 (1965). 80. Y. N. Tang and F. S. Rowland, J. Am. Chern. Sor., 88, 626 (1966). 81. G. L. Closs and L. E. Closs, J . Am. Client. SOC.,81, 4996 (1959); 82, 5723 (1960). 82. G. L. Closs and G. M. Schwartz, J. Am. Chem. Sor., 82, 5729 (1960). 83. G. L. Closs and J. J. Coyle, J . Am. Chem. Soc., 84, 4350 (1962). 84. G. L. Closs and J. J. Coyle, J. Am. Chem. Soc., 87, 4270 (1965). 85. G. Kobrich and H. R. Merkle, Chem. Ber., 99, 1782 (1966). 86. W. T. Miller, Jr. and D. M. Whalen, J . Am. G e m . Sor., 86, 2089 (1964). 87. G. Kobrich, K. Flory, and R. H. Fischer, Chom. Bey., 99, 1793 (1966). 88. D. F. Hoeg, D. I. Lusk, and A. C. Crumblisa, J . Am. Cheni. Sor., 87, 4147 ( I 965). 89. D. Seyferth and J. M. Burlitch, J. Am. Chem. Sor., 86, 2730 (1964). 90. D. Seyferth, J. Yick-Pui Mui, and J. M. Burlitch, ./. Am. Chem. SOC.,89, 4953 (1967). 91. L. D. Wescott and P. S. Skell, J. Am. Chem. Sor., 87, 1721 (1965). 92. R. A. Mitsch, J. Heterocycl. Chem., 1, 59 (1964). 93. R. M. Etter, H. S. Skovronek, and P. S . Skell, J . Am. Chern. Sor., 81, 1008 (1 959). 94. G. L. Closs and L. E. Closs, Angew. Cliem., 74, 431 (1962); Angew. Chern. Intern. Ed. Engl., 1, 334 (1962). 95. C. D. Gutsche, G. L. Bachman, and R. S. Coffey, Tetrahedron, 18,617 (1962). 96. M. Jones, Jr. and K. R. Rettig,J. Am. Chem. SOC.,87,4013 (1965). 97. M. Jones, Jr. and K. R. Rettig,J. Am. Chem. Soc., 87, 4015 (1965). 98. E. Wasserman, L. Barash, and W. A. Yager, J. Am. Chem. SOL-.,87, 2075 (1965). 99. E. Ciganek, J. An]. Chem. Sor.. 88, 1979 (1966). 100. M. Jones, Jr., A. Kulczycki, Jr., and K. F. Hummel, Tetrahedron Letters, 1967, 183. 101. R. A. Moss, Chem. Commun., 1965, 622.

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102. R. A. Moss, private communication. 103. G. L. CIoss and L. E. Closs, unpublished results. 104. S. I. Murahashi, I. Moritani, and M. Nishino, J. Am. Chem. SOC.,89, 1257 (1967). 105. I. Moritani, S. I. Murahashi, M. Nishino, Y. Yamamoto, K. Itoh, and N. Mataga, J . Am. Chem. SOC.,89, 1259 (1967). 106. P. S. Skell and J. Klebe, J. Am. Chem. SOC.,82, 247 (1960). 107. P. S. Skell and J. Klebe, paper presented at 141st Meeting, American Chemical Society, Washington, D.C., 1962. 108. J. V. Gramas, Ph.D. Thesis, The Pennsylvania State University, 1965. 109. T. Marolewski and N. C. Yang, Chem. Commicn., 1967, 1225. 110. G. L. Closs, R. A. Moss and J. J. Coyle, J . Am. Chem. SOC.,84, 33 (1962). 1 1 1. B. Farah and S. Horensky, J. Org. Chem., 28, 2494 (1963). 112. R. A. Moss and R. Gerstl, Tetrahedron, 23, 2549 (1967). 113. G . L. Closs and D. Schober, unpublished results. 114. S. H. Goh and G. L. Closs, unpublished results. 115. S. M. McElvain and P. L. Weyna, J . Am. Chem. SOC.,81, 2586 (1959). 116. R. A. Moss, J . Org. Chem., 27, 2683 (1962). 117. G . L. Closs and J. J. Coyle, J . Org. Chem., 31, 2759 (1966). I 18. R. A. Moss and R. Gerstl, Tetrahedron, 22, 2637 (1966). 119. U. Schollkopf, A. Lerch, and J. Paust, Chem. Ber., 96, 2266 (1963). 120. U. Schollkopf and W. Pitteroff, Chem. Ber., 97, 636 (1964). 121. U. Schollkopf and J. Paust, Chern. Ber., 98, 2221 (1965). 122. U. Schollkopf, J. Paust, A. At-Azrak, and H. Schumacher, Chem. Ber., 99, 3391 (1966). 123. U. Schollkopf, G. J. Lehmann, J. Paust, and H.D. Hartz, Chem. Ber., 97, 1527 (1964). 124. U. Schollkopf and G. J. Lehmann, Tetrahedron Letters, 1962, 165. 125. U. Schollkopf and H. Kuppers, Tetrahedron Letters, 1963, 105. 126. P. S . Skell and R. M. Etter, Proc. Chem. SOC.,1961, 443. 127. G . L. Closs and C. H. Lin, unpublished results.

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

The Stereochemistry of Electrophilic Additions to Olefins and Acetylenes ROBERT C. FAHEY Department of Chemistry. University of California (San Diego). La Jolla. California

I . Introduction I1. Acids . .

. .

I11 IV

V.

VI VII VlII

. . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Addition to Olefins . . . . . . . . . . . I . General Considerations . . . . . . . . 2 . Arenes and Dienes . . . . . . . . . . 3. Nonconjugated Olefins . . . . . . . . 4 . Bicyclic Olefins . . . . . . . . . . . 5 . a.&Unsaturated Carbonyl Compounds . . . . B. Addition to Acetylenes . . . . . . . . . . Fluorine . . . . . . . . . . . . . . . Chlorine . . . . . . . . . . . . . . . A . Addition to Olefins . . . . . . . . . . . 1 . General Considerations . . . . . . . . 2 . Arenes and Polyenes . . . . . . . . . 3 . Nonconjugated Olefins . . . . . . . . 4 . Bicyclic Olefins . . . . . . . . . . . B. Addition to Acetylenes . . . . . . . . . . Bromine . . . . . . . . . . . . . . . A . Addition to Olefins . . . . . . . . . . . I . General Considerations . . . . . . . . 2. Arenes and Polyenes . . . . . . . . . 3 . Nonconjugated Olefins and a&Unsaturated Acids 4 . Bicyclic Olefins . . . . . . . . . . . B. Addition to Acetylenes . . . . . . . . . . Iodine . . . . . . . . . . . . . . . . Peracids . . . . . . . . . . . . . . . . Sulfenyl Halides . . . . . . . . . . . . . A . Addition to Olefins . . . . . . . . . . . B.

Addition to Acetylenes

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238 242 242 242 244 246 250 256 258 263 265 265 265 266 273 277 279 280 280 280 283 286 288 291 292 294 299 299 304

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IX. Electrophilic Nitrogen . . . A. Introduction . . . . . B. Dinitrogen Pentoxide . . C. Acetyl Nitrate . . . . D. Nitrosyl Halides . . . . X. Mercuric Salts . . . . . . A. Addition to Olefins . . . B. Addition to Acetylenes . . XI. Some Comments and Conclusions References . . . . . .

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306 306 306 307 311 3 14 314 324 326 330

I. INTRODUCTION

Electrophilic additions to olefins and acetylenes are usually characterized as involving the reaction of a reagent XY with the unsaturated compound via a transition state having net positive charge at the olefinic or acetylenic carbon, as evidenced by the effect of substituents upon the rate of reaction. This review covers reactions involving acids, halogens, halogen compounds, sulfenyl halides, electron-deficient nitrogen compounds, peracids, and mercuric salts as electrophilic reagents. All of these reagents are thought to be capable of initiating electrophilic attack at an unsaturated carbon, and a significant amount is now known about the stereochemistry of the adducts formed when these reagents react with olefins and with acetylenes, though in the latter case the information is less extensive. As early as 1912 it was believed that acids and halogens add to olefins according to the “Principle of trans addition” (1) and this view persisted for many years.* With the aid of modern instrumentation, many exceptions to this rule have been found. The stereochemistry of electrophilic addition is now recognized to depend upon the nature of the reagent, *Editor’s note: In accordance with common usage, the terms “cis addition” and “trans addition” will be employed in this chapter, even though “syn addition” (or “syn-periplanar addition”) and “anti addition” (or “anti-periplanar addition”) would be more descriptive as regards the torsional angles of the bonds formed by the incoming atoms or groups. As will be explained in the sequel, the stereochemistry of the addition must not be confused with that of the starting olefins (which may often exist as cis and trans stereoisomers) or that of the adducts (which, if cyclic or olefinic, may also exhibit cis-trans isomerism). The terms “syn addition” and “anfi addition” may be recommended for future adoption, as they distinguish the steric course of the addition process from the stereochemistry of the educts and adducts.

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

239

the structure of the olefin or acetylene, and the reaction conditions. Many of the observed variations in the steric course of additions can be understood in terms of modern mechanistic concepts. This review is an attempt to describe what is presently known about the stereochemistry of electrophilic additions and to outline what are believed to be the mechanisms involved. If the products of an electrophilic addition are obtained under conditions of kinetic control, then the mechanism of addition dictates the steric course of the reaction. Aside from the stereochemistry, there are two fundamental questions which we must answer in order to specify the mechanism for electrophilic addition of a given reagent, X + Y - , to an olefin or acetylene. Are the C-X and C-Y bonds both formed in the rate-limiting step, or is the C-X bond formed in a slow step followed by rapid formation of the C-Y bond? Do the species X + and Yderive from a single reagent molecule, XY, or from separate molecular species? The possible answers to these questions lead to three limiting mechanisms for electrophilic addition. The mechanisms will be outlined for olefins, the extension to acetylenes being obvious. The simplest mechanism which we can write for addition of the reagent XY to an olefin or acetylene is a molecular addition proceeding via a cyclic transition state and leading exclusively to cis adduct. Here both bonds are formed in the slow step and the transition state is

\ c=c/ +XY* / \

I

6 +

Molecular addition

cis

composed of olefin and XY. This is probably the mechanism involved in most nonradical gas-phase reactions, and these have been quantitatively described in terms of an electrostatic model by Benson (2). By far the most important mechanism for electrophilic addition in the liquid phase is stepwise addition via a carbonium ion intermediate. Here, rate-limiting reaction of an olefin, E, with XY gives a cationic intermediate which rapidly collapses to products. The importance of cationic intermediates in electrophilic additions appears to have been

R. C. FAHEY

240

hinted at by Francis in 1925 (3) and was discussed in detail in the 1930’s by Robinson (4), Ingold ( 9 , Whitmore (6), and Bartlett (7) for various E

+ XY % EX+ + Y - % EXY AdE2mechanism

addition reactions. Mechanisms of this type are conveniently classified as A d ~ 2(addition, electrophilic, bimolecular) using the notation of Ingold (8). Addition via the Ad&? mechanism can lead to either cis or trans adducts depending upon the structure of the intermediate EX+. If the cation has an open structure (l), a mixture of cis and trans adducts is generally expected (9). However, ion-pairing phenomena can cause preferential formation of cis adduct (lo), and electronic, steric or, conformational effects can cause attack at one or the other side of the carbonium p orbital of 1 to be favored. Alternatively, the intermediate

can have a bridged, or onium ion, structure (2) of the type first postulated by Roberts and Kimball (11) for X = Br and later formulated as a 7r complex (3) by Dewar (1 2). The bridged ion (or r complex), by analogy with nucleophilic displacement reactions, is presumed to be opened stereospecifically to trans adduct (1 1). Finally, a mechanism must be considered in which the C-X and C-Y bonds are both formed in the transition state, but in which X + and Y- are derived from separate molecular species. Since this type of mechanism is termolecular in the sense that the transition state is composed of three distinct reactants, it is conveniently denoted as an AdE3 mechanism (8). Addition can, in principle, occur either cis, via a E

+ XY’+ X’Y slow EXY + X J ++ Y’AdE3 mechanism

transition state resembling 4, or trans, via a transition state resembling 5. In this mechanism XY’ can be replaced by X + and X’Y by Y - . Mechanisms of this type have, in general, received less attention than the AdE2 mechanism, but several examples of A d ~ 3additions are now known.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

241

a+ x,----ya-

8

(4)

The A d ~ 3mechanism is taken here to include mechanisms in which onium ions (2) or 7~ complexes (3) are formed rapidly and reversibly, and in which the slow step of the reaction is nucleophilic attack on 2 or 3. This type of mechanism involves a transition state which closely resembles 5 and, since it is generally difficult to prove that reversible formation of T complexes or onium ions is a necessary step in such mechanisms, it has been found expedient not to treat this type of mechanism separately but to consider it as an Ad,3 trans addition. These three mechanisms represent limiting cases and other factors may play an important role in any given reaction. Many electrophilic reagents form molecular complexes (6) with olefins and acetylenes (13), and such complexes are probably formed rapidly and reversibly under the conditions of many electrophilic additions. In weakly dissociating E---XY (6)

[EX+Y-]

(7)

solvents, ion pairs (7) are likely to play an important role in AdE2 additions. These and other considerations may complicate the description of any given electrophilic addition, but the limiting mechanisms can still be retained as useful initial models for understanding the stereochemistry of electrophilic additions. Knowledge of the stereochemical course of a given electrophilic addition is not sufficient to specify the mechanism. Evidence on the rate of reaction as a function of structure is needed to show that the addition is electrophilic and to characterize the structure of the transition state. The observed rate law can provide information as to whether the addition is bimolecular or termolecular. Especially important is information on the formation of structurally rearranged products, since this provides the best evidence for a discrete cationic intermediate. It is beyond the scope of this review to survey all the kinetic, rate and product data accumulated for electrophilic additions. Fortunately, the subject has been reviewed in detail quite recently by de la Mare and

242

R. C. FAHEY

Bolton (14) and, by frequent reference to their excellent survey, an outline of the nonstereochemical results applicable to the various electrophilic additions can be given in the following sections. Each different type of electrophilic reagent is covered in a separate section and some comparisons of the various electrophilic reagents are made in Section XI. Since the emphasis of this review is on the stereochemistry of addition, it is found convenient and concise to refer to the products of addition as cis or trans adducts of the olefin or acetylene undergoing reaction. In most cases, this should cause no confusion, but with cis and trans isomeric olefins this practice may be somewhat misleading. Thus, the cis adduct from cis-2-butene is identical with the trans adduct of trans-Zbutene and, in the tables comparing the stereochemistry of addition to these olefins, the same compound will appear under two different headings.

11. ACIDS

A. Addition to Olefins 1. General Considerations

Olefins are weakly basic and form hydrogen bonded molecular complexes with acids. Evidence for both I : 1 (15,16) and 1 :2 (16) complexes of olefins with hydrogen halides has been obtained. Brown and Brady (17) have shown that the solubility of hydrogen chloride in solutions of olefins in toluene depends on olefin structure increasing in the order: RCH=CH, < RCH=CHR < RZC=CHZ < RZC=CHR

indicating that the stability of the molecular complex increases in the same order. The ionization potential of the alkene decreases along this series (1 8). Hydrogen halides and other strong acids add to olefins directly, while weaker acids-water, alcohols, carboxylic acids-add to olefins under catalysis by stronger acids. These additions are not strongly exothermic, the acid-catalyzed addition of water often being reversible by relatively minor changes in reaction conditions. Hydrogen halide addition, exothermic by 15-20 kcal/mole (2,19), is reversed in the presence of strong base. Because of the reversibility of acid additions one might

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

243

expect that the mechanism and stereochemistry of addition are closely related to that of elimination. In this regard, it is worth noting that the AdE2 and AdE3 mechanisms for acid additions correspond closely to the reverse of the El and E2 mechanisms of elimination (20). Most acids favor a polar mechanism in their addition to olefins, but facile radical additions can occur with hydrogen bromide, mercaptans, thioacids, and bisulfites (21-23). Kinetic studies have not, in general, distinguished between bimolecular and termolecular mechanisms for addition. The hydration of olefins (24) is first order in the olefin concentration and first order in acid concentration at low acid concentrations. In highly acidic media, the value of log k,,, increases linearly with - Ho. Various authors have suggested that the transition state for hydration may contain one or more water molecules in addition to the proton and the olefin, but the evidence is not entirely conclusive (25-29). General acid catalysis could not be demonstrated in the hydration of isobutene (30), but has been found for the hydration of p-methoxy-emethylstyrene (3 I). Acidcatalyzed addition of alcohols (32) and carboxylic acids (33,34) show kinetic behavior similar to that of the hydration reaction. The kinetics of hydrogen halide additions to olefins are more complex. In nonpolar solvents, fourth-order kinetics-first order in olefin and third order in hydrogen halide-are observed and trace amounts of water have a large catalytic effect (35,36). In nitromethane, hydrogen chloride addition is first order in olefin and second order in acid (37,38). Chloride salt inhibits the reaction by combining with the acid to form the less acidic hydrogen bichloride ion. Similar third-order kinetics are reported for hydrogen bromide addition in acetic acid, but in this case bromide salts accelerate the reaction by contributing to the rate law a third-order term involving olefin, acid, and lithium bromide (39). The latter type of kinetic behavior is indicative of an Ad,3 mechanism [es. (111. rate = k,[E][HBr]'

+ kj[EI[HBr][LiBr]

(1)

The variation in rate with olefin structure demonstrates that acid addition proceeds via an electrophilic mechanism for all but the most deactivated olefins. Thus, the rate of acid addition varies with structure in the order

244

R. C. FAHEY

and Markownikov addition is observed in all cases (24,33). Studies of substituted styrenes (29,3 1,34) and substituted or-methylstyrenes (29,40) have shown that log k , d d plots linearly with u+, giving p values ranging from about - 3 to - 5. This shows that substantial positive charge is present at the benzylic carbon in the transition state for addition to styrenes. Studies of the effect of substituents on the rate of addition of trifluoroacetic acid to alkenes show that the addition is electrophilic (41,42). There are numerous examples of structural rearrangement accompanying acid additions to olefins (24,43,44). These prove that addition can occur via a cationic intermediate. It has been demonstrated in a variety of systems that little or no proton exchange accompanies addition (28,3 1,38,40,45-48), showing that an open cation (8) is not reversibly formed.

(8)

The foregoing results of kinetic, rate, and product studies strongly favor an Ad,2 mechanism for acid additions, but the limited kinetic results for hydrogen halide additions suggest that an Ad,3 mechanism may also be of importance. In considering the stereochemistry of acid additions, olefins have been divided into four groups. Dienes and arenes, capable of forming resonance-stabilized cations, undergo addition by an AdE2 mechanism and this class of olefin is considered first. Nonconjugated olefins undergo addition via AdE2 and Ad,3 trans addition mechanisms and are considered second. Bicyclic olefins, which appear to undergo addition through both A d ~ 2and molecular cis addition mechanisms, are considered next. Finally, a,P-unsaturated carbonyl compounds, which can protonate either at carbon or at oxygen, are discussed. 2. Arenes and Dienes Unfortunately there have been no studies of the stereochemistry of hydration of arenes or dienes. The available data on the stereochemistry of acid additions to these systems comes from studies of hydrogen halide additions. The results are collected in Table I and show that

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

245

TABLEI

The Stereochemistry of Acid Additions to Arenes and Dienes ~~

~~

Compound Acenaphthalene Indene cis-1-Phenylpropene rrans-1-Phenylpropene Cyclohexad iene

~

Conditions

Adduct

DBr, CHzClz DBr, DOAc DCI, CHzClz DBr, CHaClz DBr, CHzCla DCl, CHSN02 DBr, CHzClz DCI, CHaNOz DBr, pentane

yocis Addition

yotrans Addition

DBr 90 10 DBr 75 25 DCl 85 15 20 80 DBr 85 15 DBr -65 -35 DCI 85 15 DBr -65 -35 DCl 12.5 1,2-DBr 33.5 1,4-DBr 54

Ref. 47 47 47 10 48 38 48 38 50

addition follows a preferential cis course, but tends to be more nonstereospecific in the more polar solvents. The observed stereochemistry of addition is consistent with an Ad,2type mechanism involving rate-limiting formation of a carboniumhalide ion pair 9 which collapses to cis adduct or rearranges to ion pair 10 which collapses to trans adduct (49). In aprotic solvents the halide ion formed in the slow step is probably solvated by one or more molecules of hydrogen halide.

(9)

cis

(10)

trans

Hammond and Warkentin (50) found that cyclohexadiene adds deuterium bromide to give nearly equal amounts of 1,2- and 1,Cadduct

R. C. FAHEY

246

(Table I). The 1,Zadduct was found to be mainly cis, and IR analysis suggested that the 1,Cadduct was also primarily cis. They were reluctant to conclude that 1 ,Zcis-addition was the kinetically controlled result and ascribed this product to a secondary rearrangement. They considered that the primary reaction involved 1 ,2-truns- and 1,Ccisaddition, a result which would accord with the recent prediction by Fukui (5 I), based on molecular orbital considerations, that 1,2-trunsand 1 ,Ccis-addition are favored modes for addition to dienes. Nevertheless, predominant 1,2-cis- and 1 ,Ccis-addition is the observed result and can now be viewed as the logical consequence of an Ad,2 mechanism involving an allylic cation-bromide ion pair (11) as the main product-forming intermediate. It is expected that polar solvents should

favor less stereospecific addition and that the hydration of arenes and dienes should be a nonstereospecific process. 3. Nonconjugated Olefins The stereochemistry of acid addition has been determined for a number of cyclic alkenes. Some of the results are summarized in Table 11. TABLEI1 The Stereochemistry of Acid Additions to Alkenes Alkene 1,2-Dimethyl cyclohexene

1,2-Dimethylcyclopentene Cyclohexene Cyclohexene-1,3,3-d3

Conditions

Adduct

yotrans yocis

HN03, HzO HBr, HOAc HBr, pentane HCI, pentane

Hz0 HBr HBr HCI

-50

100 100 292

-50 0 0 <8

DBr, HOAc, 10" DBr, HOAc, 60" HBr, HOAc, 15"

DBr DBr HBr HOAc HBr HOAc

76 24 287 28 271 322

24 76 <4 <1 <5 <2

HBr, HOAc, 60"

Ref. 52

54

54 55

39 39 56 56

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

247

The hydration of 1,2-dimethylcyclohexene was studied by Collins and Hammond (52) and found to be nonstereospecific. This result would provide strong evidence for an open carbonium ion 12 as the product-forming intermediate, but the possibility of prior isomerization

(12)

(13)

of the starting olefin discussed by Hammond (52) requires that the conclusion remain tentative. Wolfe and Campbell (53) attempted to determine the stereochemistry of D,O addition to cyclohexene-3,3,6,6d4 (13) but found deuterium scrambling in the product, and this precluded an analysis of the steric course of addition. Considering the substantial amount of effort which has been devoted to rate and kinetic studies of olefin hydration, it is surprising that the stereochemistry of the reaction has received so little attention. The stereochemistry of hydrogen halide addition to cyclic alkenes has received more attention. In contrast to the hydration reaction, Hammond and Nevitt (54) found that hydrogen bromide adds trans to 1,2-dimethyIcyclohexene (14). They further demonstrated that 14-16, all of which would formally give the same classical carbonium ion (17),

(15)

(14)

(16)

(17)

react with hydrogen bromide to give different product mixtures. They concluded that the addition proceeded either via a T complex (18) or by way of an Ad,3 mechanism involving a transition state resembling 19.

‘c /

i2 \

(18)

H---- C1(HCl), \ C d \i /

/; (HCI),H----CI (19)

Smirnov-Zamkov and Piskovitina (39) reported that cyclohexene adds deuterium bromide in acetic acid to give a mixture of bromides

248

R. C. FAHEY

with the cis adduct becoming favored at higher temperatures (Table 11). Later studies (56) of the hydrobromination of cyclohexene-1,3,3-d3 in acetic acid showed that the hydrogen bromide and acetic acid adducts are formed quite predominantly trans with little or no effect of temperature. The predominant trans addition was confirmed by Wolfe and Campbell (57) who examined deuterium bromide addition to cyclohexene-3,3,6,6-d4(13). The reason for the conflicting results is not clear, but it is evident that cyclohexenes can add hydrogen bromide quite predominantly trans. Recent studies of the hydrochlorination of cyclohexene in acetic acid serve to clarify the mechanism leading to trans addition. Cyclohexene reacts slowly with hydrogen chloride in acetic acid to yield a mixture of chloride and acetate, the amount of chloride increasing with the acid concentration (58,59). The stereochemistry of the reaction was studied using cyclohexene-1,3,3-d3. It was shown that, while the acetate is always formed by very predominant trans addition, the chloride is formed as a mixture of cis and trans adducts with the trans isomer being more favored at higher HCl concentrations. Addition of tetramethylammonium chloride to the reaction mixture produces a rate enhancement which is too large to be attributed to a normal salt effect and which is associated almost entirely with an increase in the rate of trans hydrochloride formation. These results show that nucleophilic attack by chloride does occur in the rate-limiting step leading to trans adduct. Since chloride salts produce no reaction in the absence of HCl, both the C-H and C-CI bonds must be formed in the transition state and an AdE3 trans addition mechanism must be involved. The overall reaction leading to chloride might be represented by an AdE2 open carbonium ion mechanism [eq. (2)], which gives mainly cis hydrochloride, competing with an AdE3 trans addition mechanism [eq. ( 3 ~ It is not entirely clear how acetate is formed in this reaction. Attack by acetic acid on ion pair 20 could yield the acetate of trans addition or it might be formed via an A d ~ 3mechanism involving a transition state such as 21 [eq. (4)]. These studies demonstrate that Ad,3 trans addition and AdE2 addition via an open carbonium ion are competitive processes in the hydrochlorination of cyclohexene in acetic acid. It is obvious that small changes in olefin structure or reaction conditions can cause one or the other of these mechanisms to dominate the reaction.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

\ / C=C / \

C1 H

+ HCI + slow

I (20)

\

/

C=C

/

\

249

(2)

I cis

+ HCI + R+CI- + trans

\ / C=C / \

+ HCI + HOAC +

(4)

AcOH

(21)

AcO

trans

In view of the results with hydrogen chloride, it now seems probable that hydrogen bromide adds trans to cyclohexene primarily via an AdE3 mechanism. Thus, hydrogen bromide is a stronger acid than hydrogen chloride which should favor both AdE2 and AdE3 addition, but hydrogen bromide is also a better nucleophile than hydrogen chloride which would specifically favor the A d ~ mechanism. 3 Since the balance between AdE2 and AdE3 addition is close with hydrogen chloride, the A d ~ 3 mechanism could easily become dominant with hydrogen bromide. The observed kinetics [eq. (l)] are entirely consistent with this view. The trans additions to the 1,2-dimethylcycloalkenesmay also occur via an Ad,3 mechanism, but these olefins can form more stabilized cations than cyclohexene which may favor the AdE2 process. No clear decision between the two mechanisms is possible from the available results. There is still no evidence which requires a protonium ion (18) as an intermediate in acid additions, but rapid reversible formation of a protonium ion, as proposed by Taft (45) has not been ruled out in additions to nonconjugated olefins. No results on the stereochemistry of acid additions to acyclic nonconjugated olefins have been reported. While it seems unlikely that acyclic olefins would give substantially different results from those found for cyclic alkenes, studies of such systems could prove fruitful in further delineating the balance between the various competing mechanisms.

250

R. C. FAHEY

4. Bicyclic Olejins

Bicyclic olefins, and especially norbornene derivatives, are considered separately for two reasons. First, nonclassical cations can be formed in the norbonyl system and the structure of these cations can control the stereochemistry of the products formed from them (44,60,61). Second, as pointed out by Cristol(62), E2 elimination of norbornyl compounds occurs preferentially cis-exo (63-65) and it is possible that the factors which cause this process to be favored over trans elimination might also play an important role in the addition reactions to norbornene derivatives. Cristol and co-workers have studied the acid-catalyzed additions of water, methanol, acetic acid, and formic acid to endo-trimethylenenorbornene (22) (62,66,67). The addition of methanol leads to a mixture of

ethers 23 and 24, the latter being shown with deuteromethanol to be the product of exo-cis addition (66). Since em-trimethylenenorbornene (25) undergoes addition to give a different mixture of 23 and 24, they concluded that cation 26 cannot be the common, sole product-forming intermediate in both reactions. Two competing paths or two different product-forming intermediates are required to explain the results; they considered that the results could be accommodated in terms of the

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

251

classical cations 27 and 28, o r by a mechanism involving 26 in competition with molecular cis addition. The stereochemistry of hydrogen halide addition to norbornene has been studied by several workers and their results are summarized in Table 111. The results obtained by Kwart and Nyce (68) indicate that TABLE 111

Hydrogen Halide Addition to Norbornene Products, yo

A Olefin

(29)

(31)

Conditions DBr, D 2 0

Ref. 51

68

14 12

46 38

65 65

34

6

69

46-49

60"

HBr, H20 HCI, pentane

50 40

nearly equal amounts of 29 and rearranged product are formed with deuterium bromide. They assumed, but did not show, that the rearranged product is 30 and considered that the results were consistent with reaction via the symmetrical intermediate 32, which should give equal amounts of 29 and 30. Later, Stille, Sonnenberg, and Kinstle (65) found that norbornene-2,3-d2 added both hydrogen bromide and hydrogen chloride to yield more 29 than 30. Moreover, substantial amounts of 31 were also formed. To account for the high ratio of 29 to 30, they suggested that some other mechanism, possibly molecular cis

R. C . FAHEY

252

addition, must be competing with an ionic process involving 32 and 2,6-hydride shifted isomers.

More recently, Brown and Liu (69) obtained similar results with norbornene and deuterium chloride, but found less of the hydride shifted product 31. These authors argue that the results are best explained in terms of classical carbonium ion intermediates like 33 and ,D

(34)

(33)

34 (69-71). Brown and Liu (70) also found that apobornylene (35) with deuterium chloride gave primarily the cis-exo adduct (36)and only 10%

(35)

(36)

(37)

of the rearranged product (37). The latter result is especially surprising since the gem-dimethyl group should provide considerable steric hindrance to exo attack at the double bond. A similar preference for cis-exo addition has been observed in the oxymercuration of related norbornene derivatives (cf. Sect. X-A), but epoxidation of apobornylene occurs mainly by endo attack (Sect. V11). Exactly why hydrogen halides and mercuric salts favor cis-exo addition to apobornylene is not yet clear. These results with norbornene may be contrasted with those of Cristol and Caple (72) with benzonorbornadiene (38). Deuterium chloride addition to 38 yields equal amounts of 40 and 41, as would be expected from the nonclassical ion 39.

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

253

It should be noted that in none of these studies of hydrogen halide additions to norbornene derivatikes was it explicitly demonstrated that the observed product composition is the kinetically controlled composition. The catalyzed and uncatalyzed addition of CD,COOD to benzonorbornadiene was also studied by Cristol and Caple (72), but here unequal amounts of the adducts 42 and 43 were found. More 43 (-42%) was found for the acid-catalyzed addition than for the uncatalyzed reaction ,D

(43)

(27%), and in the latter reaction the amount of rearrangement is further reduced to 8Y0 if the acetic acid solvent is made less polar by dilution with cyclohexane. Again, the results are consistent either with classical cations as the product-forming species or with molecular cis addition competing with Ad,2 addition via a nonclassical ion. The catalyzed and uncatalyzed addition of DOAc to norbornadiene (44) is even more complex, as shown by the work of Cristol, Morrill, and Sanchez (73-75). The products include the 1,Zadduct (45), the rerearranged adduct (46), and nortricyclyl acetate (47). The product D

254

R. C. FAHEY

composition is a sensitive function of the reaction conditions with acid catalysis, polar solvents, and high temperature favoring 46 and 47 over 45. The effect of increasing hydrocarbon content of the solvent on the product composition shows that, in a pure hydrocarbon solvent, 45, would be the sole product. The authors compare the results obtained from addition experiments with those obtained from the acetolysis of 48 (76), both reactions potentially involving the same nonclassical ion

(49), and conclude that the same species cannot be involved in both reactions as a precursor of 46 and 47 since the observed ratio of 46 to 47 is different in the two reactions. The results can be accommodated in terms of the classical ions 50-52 or in terms of a molecular cis addition competing with an ionic process involving more than one nonclassical ion-pair species, the distinction being in the degree of solvent separation of the gegenion ion from the cation 49.

While the detailed description of the mechanism of acid additions to norbornene derivatives cannot as yet be decided with certainty, it is evident that the preference for exo-cis addition cannot be ascribed entirely to the formation of nonclassical ions. Schleyer has suggested (77) that this preference may arise from torsional effects (78). In the author’s opinion, molecular cis addition must be an important mechanism in these reactions. If only classical cations were involved, the amount of rearrangement accompanying addition should depend upon the lifetime of the cation and this in turn should depend on the nucleophilicity of the counterion. On this basis one would predict that acetic acid addition should lead to more rearrangement than hydrogen chloride addition, acetate ion being less nucleophilic than chloride ion, but the results suggest that the opposite is true. On the other hand,

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

255

molecular addition of acetic acid is an especially favorable process since the transition state can assume a six-membered cyclic structure (53), whereas molecular addition of HCI must involve either a fourcenter transition state (54) or a six-center transition state (55) with two molecules of HCI. Relative to the formation of a carbonium ion inter-

mediate, formation of 53 is likely to be more favorable than formation of 54 or 55, explaining why acetic acid addition gives less rearrangement than addition of halogen acids. The only other bicyclic alkene which has been studied is bicyclo[3.1.0]-hexene-2 (56). Freeman, Grostic, and Raymond (79) have shown that the acid-catalyzed addition of deuteromethanol to 56 gives the cis adduct 57 along with an isomer of undetermined stereochemistry at deuterium (58). Similarly, deuterium chloride addition to 56 was shown

(57)

(56)

(58)

by these authors (80) to give a 2:l mixture of 59 and 60 as the main products. They suggest that the direction of addition indicates that the 56

CHCI, DC"

@

transition state has delocalized character. While the preferential cis addition of hydrogen chloride might be rationalized in terms of ion pairs, they argue that ion-pairing phenomena cannot account for the cis addition of methanol and conclude that the addition has four-center character.

R. C. FAHEY

256

5. a$- Unsaturated Carbonyl Compounds

For the hydration of a,&unsaturated carbonyl compounds, there is considerable evidence for an initial 1,Caddition of water initiated by protonation on the carbonyl oxygen (81), but Noyce and students (82) have noted that protonation at the olefinic carbon is also possible for compounds such as ArCH=CHCOOH. Little is known about the stereochemistry of electrophilic hydration of these compounds, but it is well known that the enzymatic hydration of fumaric acid follows a stereospecific trans course (83). The stereochemistry of hydrogen halide addition has been studied with a number of a,p-unsaturated carbonyl compounds. Early studies with tiglic acid (61) and angelic acid (62) indicated that hydrogen iodide addition (84,85) gives primarily the trans adducts of 61 and 62, H H

/

\ (61)

\

c=c/CH3

COOH

but that hydrogen bromide addition (86) yields the same bromide from both 61 and 62. Lutz and Wilder (87) found that both the cis and the trans isomer of 63 reacted with hydrogen chloride in chloroform to give the meso isomer of 65 but, with ether as solvent, they gave the same PhCOCH =C(CI)COPh

[PhCOCH(CI)C(CI)=C(OH)Ph] 4

PhCOCH(Cl)CH(CI)COPh 4 and meso (65)

+

Poh'

Ph

(66)

mixture of dl and meso isomers. In ethanol, 66 is also formed and was claimed not to be a secondary product derived from 65. The authors conclude that 65 and 66 derive from the 1,Cadduct 64 as an unstable intermediate. The significance of this early work is somewhat uncertain, since the hydrogen halide adducts are known to isomerize under acid conditions. This has been demonstrated in a number of cases by Vaughan and coworkers (88-91), who have also shown that there is a definite preference for trans addition of hydrogen halides to olefinic acids.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

257

The addition of hydrogen bromide to 67 (88,89), 68 (89,90), 69 (90), 70 (90) and 71 (91) and the addition of hydrogen chloride to 67 (89)

CrcooH and 68 (89) have been shown by Vaughan et al. to occur largely or completely trans under conditions of kinetic control. It has been argued (92) that these additions proceed via the ],Cadducts (72) with steric factors favoring ketonization to the trans adduct, 73. However, as

Vaughan et al. point out (89), this mechanism is unlikely for addition to 67, since the I ,Cadduct 74 should show little steric preference in the ketonization process.

It should be added that there is no conclusive evidence for 1,4addition of hydrogen halides to olefinic acids and that 1,Zaddition via an Ad,3 trans addition mechanism should be considered as a possible alternative to the 1,Caddition process.

R. C. FAHEY

258

B. Addition to Acetylenes

The behavior of acetylenes with acids is generally similar to that of olefins. Acetylenes form complexes with hydrogen halides (16,93) and will add hydrogen halides to yield vinyl halide adducts. With hydrogen bromide, addition by both polar and free-radical (94-97) mechanisms is possible. The Markownikov addition of hydrogen chloride and bromide to acetylene and alkyl acetylenes has been estimated by Benson and Haugen (98) to be exothermic by 18-26 kcal, 3-8 kcal more exothermic than addition to the corresponding olefins (2). Acid-catalyzed hydration of acetylenes gives an enol which rapidly rearranges to the ketone as shown: H+ + HzO + -CH=C

-C=C-

/OH

fast

---+ -CH2-C0-

\ Ketones are frequently major products in the acid-catalyzed reaction of carboxylic acids with acetylenes, the intermediate vinyl acetates undergoing further reaction under acidic conditions (99-101).

The rate of hydration of acetylenic ethers and thioethers has been shown to be first order in acetylene and first order in acid at low acid concentrations (102-106). At high acid concentrations the rate is linear in -Ho with near unit slope for hydration of acetylenic thioethers (103). The reaction is faster in H,O than in D20and is subject to general acid catalysis (103-1 06). Electron-donating substituents accelerate the rate (103-106) and evidence has been obtained for anchimeric assistance by the hydroxyl group (107). The results support an Ad,2 mechanism involving the relatively stable vinyl cations 75 and 76 as intermediates. H

\

R

/

+

H

CS-0-R (75)

R

\

+

/c=c-s-R (76)

Evidence for the formation of vinyl cations from various precursors has been recently reviewed by Richey and Richey (1 08). The rates of hydration of substituted phenylacetylenes (77) (109,110) and phenylpropiolic acids (78) (1 10) correlate with O + with p z - 5 ,

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

259

and the hydration of phenylacetylene is faster in H,O than in D 2 0 (1 lo), the indicated mechanism again being rate-limiting protonation at carbon to form a vinyl cation.

Similar results and conclusions have been arrived at from studies of the addition of trifluoroacetic acid to alkynes by Peterson and Duddey ( 1 1 I). For 5-chloro-I-pentyne they show that chlorine participation leads to a rate acceleration and that the major product is 80. The cyclic chloronium ion (79) was suggested as an intermediate. Preliminary

(79)

(80)

evidence for fluorine participation in the addition of trifluoroacetic acid to 5-fluoro-I-pentyne has been obtained by Peterson and Bopp (1 12). Thus, there is good evidence that hydration and trifluoroacetic acid additions proceed via an Ad,2 mechanism. It is of interest to note that, contrary to the view that acetylenes undergo electrophilic addition less readily than olefins ( 1 13), acid additions to acetylenes occur at rates which are comparable to (and sometimes even faster than) those for the corresponding olefins (l05,110,111). The stereochemistry of hydration cannot be studied, since the enol adduct rapidly ketonizes, but Peterson and Duddey (1 11) have determined the stereochemistry of trifluoroacetic acid addition to 3-hexyne. They find the addition to be nonstereospecific, as expected if a vinyl cation (81) is the intermediate.

L=

H

CF,COOH

-7

L.1

CF3CO0

VH

x-A+T

(81)

WH

-

50%

CF3COO N

50y0

Hydrogen halide additions to acetylenes, like additions to olefins, occur by both AdE2 and Ad,3 mechanisms. The hydrochlorination of

R. C . FAHEY

260

1-phenylpropyne in acetic acid in the absence of chloride salts occurs primarily by an AdE2 mechanism (101,114). The reaction is first order in acetylene and the rate correlates with the equivalent of - Ho with a slope of about 1.5. The major product of addition is the cis adduct (82), but some trans adduct (83) and the acetates 84 and 85 are also formed. Under the reaction conditions the acetates are converted to propiophenone, but they can be detected in low concentration by VPC and their steady-state concentrations measured. Knowing the rate at which each acetate is converted to ketone under the reaction conditions, the amount of 84 and 85 formed in the primary addition process can be determined. The product composition varies only slightly with the HC1 concentration, the trans adduct increasing slightly at the expense of cis adduct with increasing acid concentration. Ph PhCrCCH3

HCI __t

HOAc

Ph

\ /'='\ c1

\

c1

H

(82) 70%

Ph

\

+ [Aco,C=C\H

/CH3

]

(84) 5%

Ph

+

\

/

H

CH3 (83) 17%

/

H

-+

[Aco,C=C\cH]

PhCOCHaCH3

(85) 8%

These results are quite consistent with those obtained for hydration and trifluoroacetic acid addition. The preferential cis addition logically results from an AdE2 mechanism involving an ion pair (86) as the intermediate formed in the slow step.

[

C1-

(86)

H

Ph

\ H /c=c\

7' CH,

(87)

In the presence of tetramethylammonium chloride, the hydrochlorination of 1-phenylpropyne is accelerated (1 15). The increased rate is associated in part with formation of the trans adduct (83), but a new product (87) is also formed. The enhanced formation of 83 and the induced formation of 87 are considered to result from AdE3 addition promoted by the chloride salt and involving the transition states 88 and

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

Ph

261

H C1-

89. Since there is less positive charge at carbon in the A d ~ 3transition state, the phenyl group is less effective in controlling the direction of addition. Even in the presence of chloride salt, 82 remains the main product so that the AdE2 mechanism dominates the reaction. In the hydrochlorination of 3-hexyne in acetic acid, just the opposite is true (1 14,116). The main products at 25" are the trans adduct (90) and 3-hexanone, less than 1% of the cis adduct (91) being formed. The ratio

of 90 to ketone increases markedly with HCI concentration and chloride salts specifically accelerate the formation of 90. Here A d ~ 3trans addition via a transition state resembling 92 dominates the reaction, but an AdE2mechanism leading to cis adduct (91) is almost competitive. Thus, when the reaction temperature is increased from 25 to 80°, 91 increases to 597, of the total product, Just as high temperatures favor El over E2 elimination, high temperatures should favor AdE2 over AdE3 ,H C1-

\8+

R+ a-,.c=c (92)

't

\

addition. It is also expected that steric effects will be much more important for AdE3addition than for AdE2 addition, but there is as yet no definitive evidence with which to illustrate this. Hydrogen chloride (1 15) and hydrogen bromide (1 17) have been observed to add trans to 2-butyne, very probably via an AdE3 mechanism. Hunziker, Meyer, and Giinthard (1 18) have shown that deuterium halide addition to propyne, catalyzed by mercuric salts, takes place with trans stereospecificity. This may also involve an AdE3 addition,

R. C. FAHEY

262

but mercuric halide addition followed by electrophilic displacement of mercury cannot be excluded. Similarly, hydrogen bromide has been CH3C-CH

+ HgX,

-

CH,

\

CH3

DX

/HgX

\

d

X /c=c\H

X

/

D

+ HgXz

/c=c\H

found by Drefahl and Zimmer (119) to add trans to PhC-CPh and p-NO,PhC=CPh in acetic acid as solvent. If the observed trans adducts are actually the kinetically controlled products in these additions, an A d ~ 3mechanism may be involved. Fairly extensive studies of hydrogen bromide addition to phenylpropiolic acid have been made by Michael and Shadinger (120) and by Kasiwagi (121). The addition can be either homolytic or ionic and the products of ionic addition are easily isomerized. Kasiwagi concludes that ionic addition in nitrobenzene gives comparable amounts of cis and trans adducts. However, addition of hydrogen bromide to tetrolic

-

Ph

PhCrC-COOH

HBr

\

PhNOz

Br

/'='\

/

COOH

Ph

H

Br

+

\

/

/c=c\

H COOH

acid (93), in nitromethane or in aqueous solution, yields the trans adduct (94) (120). Since these results are qualitatively similar to those CHa CH3CrCCOOH

\

HBr

Br

(93)

/H

/c=c\

COOH

(94)

found for the hydrochlorination of 1-phenylpropyne and 3-hexyne, it is tempting to conclude that they result from competing AdE2 and AdE3 mechanisms, but more quantitative results and evidence from rate studies are needed to support the stereochemical studies. Addition of hydrogen halides to acetylene dicarboxylic acid and its esters appears to be initiated by nucleophilic attack. These additions have been extensively studied by Dvorko and co-workers (1 22-124) who have shown that addition can be initiated by hydrogen halides or by lithium halides and that CH,OOCC-CCOOCH, reacts faster than HCrCCOOCH,, PhCsCCOOCH,, or P h C k C H .

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

263

III. FLUORINE Molecular fluorine, because of its low bond dissociation energy, usually undergoes reactions with organic compounds via homolytic mechanisms (125). Fluorine additions to olefins have been achieved in varying yields with a variety of fluorine compounds, such as lead tetrafluoride (126), but these appear to involve radical processes (127). However, Merritt (1 28-1 30) has recently studied the reaction of molecular fluorine with olefins at low temperature and obtained results which indicate an electrophilic mechanism for the reaction. The fluorination if 1,l-diphenylethylene gives both addition and substitution products, the latter reacting further to form a trifluoride (129a). The stereochemistry of addition to a number of arenes has been PhZC=CHz

Fz

- 7EQ

PhzCFCHzF 15%

+ Ph&=CHF + PhzCFCHF, 78%

8%

determined and the results are presented in Table IV. In general, these additions tend to be nonstereospecific, but cis difluorides are formed preferentially. With acenaphthylene and the I-phenylpropenes, small amounts of trifluoride are formed, indicating that some substitution occurs with these olefins but much less than with 1,l-diphenylethylene. The fluorination of A4-cholesten-3-one yields the cis-4,5-difluoride in 60-70"/, yield (1 30). The general similarity between these reactions and those of chlorine (Sect. IV) suggests that fluorine is reacting via a carbonium ion intermediate. The general preference for cis addition appears consistent with the formation of a carbonium-fluoride ion pair which collapses mainly, but not completely, to cis difluoride [eq. (5)]. Alternatively, a carbonium

\ / C=C / \

+ Fa

F-

'\\+

F

/

C-C-----t

4

\

cis

trans

ion process may be in competition with a molecular cis addition, as proposed by Merritt (129b). Because fluorine is a poor neighboring

a

_

85 85

85

85

85

32 43 46 20 95 85

7

N

- 85

N

N

N

With fluorine in the presence of Molecular Sieve to scavenge hydrogen fluoride.

_

CClaF, -78" CC12F2, - 145" CH30H, -78"

cis-1-Phenylpropene

~

1,ZdiF 1,2-diF 1,2-diF 1,2-diF 1,ZdiF 1,2-diF 1,2-diF 1,ZdiF 1,ZdiF 1-CH30-2-F 1,2-diF 1,ZdiF

CC13F, -78" CCISF, -78" CC13F, -78" CC13F, -120" CCISF, -78" CCISF, - 78" CClsF, - 126" CClzF2, - 145" CH30H, -78"

Indene 2-Methylindene Acenaphthylene 1-Methylacenaphthylene cis-Stilbene trans-1-Phenylpropene

1-CH3O-2-F

Adduct

Conditions

Olefin

Yield,

Stereochemistry of Fluorine Addition to Olefins"

TABLEIV

77

-

25 78 79 38 25

44

100 83 69 73 71

100 35

N

N

N

addn.

7, cis ~~

-

N

25 22 21 12 25

I

17 31 27 29

-

23

65

addn.

yo trans

129b 129b 129b

128 129a 129b 129b 129b 129b

128 128 128

Ref.

13.e

cl

7

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

265

group, formation of a bridged fluoronium ion in these reactions is not to be expected. NMR studies indicate that /3-fluorocarbonium ions have an open classical carbonium ion structure (131).

IV. CHLORINE A. Addition to Olefins

1. General Considerations Chlorine reacts with olefins by both homolytic and heterolytic pathways, the addition to ethylene being exothermic by nearly 44 kcal (19). Evidence for the formation of olefin-chlorine complexes comes from thermographic studies (132) and from studies of charge-transfer absorption spectra (133). It has generally been considered that liquidphase olefin chlorination in the absence of light is a heterolytic process, but Poutsma (134-136) has recenty shown for linear alkenes that spontaneous initiation of radical addition can occur in the dark reaction in nonpolar media. However, for trialkylethylenes, arenes, or linear alkenes under oxygen, the ionic reaction dominates. Hypochlorous acid and its derivatives also serve as electrophilic chlorinating agents, but with hypochlorous acid itself more than one electrophilic species is involved (137). Spontaneous initiation of radicalchain chlorination has been observed with tert-butyl hypochlorite (1 38). Chlorination with iodobenzene dichloride has been shown by Tanner and Gidley (139) to occur by both ionic and radical pathways. Since in earlier work it was not always clear which mechanism dominated, studies involving iodobenzene dichloride as the chlorinating agent will not be covered here. The most thorough studies of the rates and kinetics of chlorine additions to olefins are those of Robertson and co-workers, and their results have been surveyed by de la Mare and Bolton (137). The reaction is first order in both olefin and chlorine, showing that the addition is bimolecular, and the rate of addition increases steadily with increasing electron availability from the alkene substituents over a wide range of structure, demonstrating the electrophilic character of the reaction. The formation of rearranged products in the chlorination of a variety of olefins demonstrates that carbonium ions are formed as intermediates.

R. C. FAHEY

266

The chlorination of tert-butylethylene gives 10% of the rearranged product 95 (140) while trans-di-tert-butylethylene gives 46% of an CHZ=C

/CH3

\ /CH-cHnC' CH3 (95)

analogous rearranged product (1 41). Rearranged products have also been observed in the chlorination of dibenzobicyclo[2.2.2]octadiene (142), norbornene (136), and benzonorbornadiene (143). The addition of hypochlorous acid to allylic halides results in products involving halogen migration (144,145), and the reaction of 96 with tert-butyl hypochlorite gives the rearranged ketone 97 (146). In all cases, a car0

/,

CH3

(%I

(97)

bonium ion intermediate is required to explain the products, but the structure of the carbonium ion formed in olefin chlorination varies with olefin structure, as evidenced by the stereochemistry of addition and the structure of the substitution products which accompany addition. Olefins capable of forming stabilized cations undergo addition via an Ad,2 open ion mechanism while alkenes which cannot form stabilized cations add via an AdE2 bridged ion mechanism.

2. Arenes and Polyenes The chlorination of aromatic compounds is formally similar to chlorine addition to olefins, the preference for substitution over addition reflecting the resonance stabilization of the substitution product (147). Under appropriate conditions addition products are formed in electrophilic chlorination of polycyclic aromatics, as de la Mare and co-workers have amply demonstrated (148-1 50). The chlorination of biphenyl, as well as substituted biphenyls, in acetic acid yields tetrachloride adducts (148). Similarly, naphthalene gives a tetrachloride

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

267

(98) by what appears to be a 1,Zcis-addition followed by a second, rapid 3,4-cis-addition of chlorine (149).

The chlorination of phenanthrene in acetic acid gives mainly the 9,lO-adducts with cis dichloride predominating (1 50,151). The product

268

R. C. FAHEY

distribution is accommodated by assuming that an ion-pair intermediate, 100, is initially formed and collapses to 99 and 102, loses a proton to solvent to form 103 or isomerizes to ion pair 101 which is a precursor of 103, 104, and, possibly, a small amount of cis-9-acetoxy- 10-chlorophenanthrene (150). A slightly different scheme, in which the firstformed intermediate gives exclusively cis dichloride, is favored by de la Mare (150). These addition products are to some extent unstable to the reaction conditions, undergoing elimination to form 9-chlorophenanthrene. Similar preferences for cis-dichloride formation have been observed in other conjugated cyclic systems. Cristol and co-workers have shown that the chlorination of acenaphthylene in benzene gives a 27y0 yield of the cis dichloride (I 52). The chlorination of indene (1 53) gives a 71% yield of cis dichloride in carbon tetrachloride and 457, in methylene chloride, the remaining product being trans dichloride. A 65% yield of cis dichloride 105 is obtained from the chlorination of tetraphenyl-pdioxadiene in benzene (1 53).

Acyclic arenes undergo nonstereospecific addition with chlorine in a number of cases. Cristol and Bly ( I 54) have isolated 30 and 42y0 of the meso- (trans adduct) and df-dichloride (cis adduct), respectively, from the chlorination of trans-stilbene in benzene. Buckles and Knaack (155) obtain similar results for trans-stilbene with chlorine, but find that cisstilbene gives 92y0 of the cis adduct. Since the stability of the products was not checked in any of these experiments with stilbene, there is some uncertainty as to the extent of kinetic control achieved. However, in the presence of aluminum chloride, where thermodynamic control is probable, both isomers of stilbene afford greater than 95Y0 of the meso dichloride (1 55), suggesting that the df-dichloride obtained with transstilbene does derive from kinetically controlled cis addition. A detailed study of the chlorination of cis- and trans-l-phenylpropene (156) has provided insight into the details of addition to acyclic arenes. The reaction gives 2-chloro-trans and 2-chloro-cis-l-phenylpropeneby a substitution process and the isomeric dichlorides (106) by addition. In nucleophilic solvents, the mixed adducts (107) are also formed. The

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES 269 Ph H

\ ,c=c

/H \

Ph or

CH3

\ //C=C,

,CH3

H

H

CL

(SOHf c1

H

,c=c

\

CH,

H

(106b)

H

,c=c

‘CI

+

Ph

0s

H

(107b)

product compositions, determined under conditions of kinetic control, are given in Table V. Since carbonium ions are formed as ion pairs in nonpolar media and since the product distribution for the chlorination of I-pheaylpropene is little affected by the presence of hydrogen chloride, the chloride ion which collapses with the carbonium ion to form dichloride must derive from the chlorine molecule initiating the reaction. The initial attack by chlorine on rrans-l-phenylpropene yields the ion pair lO8a while ion pair 109d is formed initially from cis-l-phenylpropene. It is evident that 2-chloro-cis-1-phenylpropene can only be formed by proton loss from 108c or 109c and that 2 chloro-trans- l-phenylpropene must derive from either 108f or 109f. Since both of these products are formed (Table V), the intermediate cation must survive long enough to undergo rotation about the C,-C, bond. The data of Table V show that there is a preference for cis over trans addition of chlorine and a tendency for the mixed adduct to be formed by trans addition. These preferences are consistent with ion-pairing phenomenon. It is also clear that the product distribution obtained from trans-l-phenylpropene is, in all cases studied, substantially different from that obtained from cis- l-phenylpropene, even in the relatively

CHzCl2 HOAc CHSOH

cc4

CCl4 CH2C1, HOAc CHBOH

Solvent

.

62 62 49 9

55 27 9

38

106a

14 8

29 22

46 28 39 8

106b

yo Dichloride CH3

CI H

0.8

From cis-1-phenylpropene 5 10 6

4 6 1 0.2

CH3

CI

\ / c=c / \

Ph

From trans- 1-phenylpropene 0.8 15 2 15 0.6 6 <0.1 0.5

H

\ c=c/ / \

Ph

Products from the Chlorination of 1-Phenylpropene (1 56)

TABLE V

16 23

14 59

-

7 17

20 65

-

-

107b

-

-

107a

yo 2-Cl-3-OS

z

?X

7d

.n

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES 271

c1c1

c1H

-& I

Ph

I

H

H

CH3

(108a)

(108c)

CI -

c1-

CH3 Ph

pyYc:3

Ph

c1

H

Cl

(108d)

(108f) H

Ph& H H

c1-

Ph CH,

CH3

c1-

C1

(109a)

c1polar solvent methanol. This shows that the intermediates derived from the two isomeric olefins never become completely equivalent prior to the product-forming stage. Any attempt to account in detail for the observed product distributions is complicated by the fact that interconversion of 108 and 109, conformational equilibration within 108 and 109, and collapse to product are all occurring at comparable rates, so that the actual product composition is determined by a complex balance between many competing processes.

R. C. FAHEY

212

Similar results were obtained by Cabaleiro and Johnson (157) in a study of the chlorination of methyl trans-cinnamate in acetic acid. They found the addition to be nonstereospecific, but cis dichloride and truns-chloroacetate were preferentially formed. It would be expected that conjugated dienes and polyenes, which are also capable of forming resonance-stabilized carbonium ions, should add chlorine in a similar fashion to arenes. The stereochemistry of addition to 1,Zdienes does not seem to have been studied, but it is worth noting that Poutsma (1 58) has recently reinvestigated the addition to 1,3-butadiene finding that earlier studies involved largely radical additions, but that the kinetically controlled products of ionic addition are 3,4-dichloro-l -butene (%yo)and trans-1,4-dichloro-2-butene (457,). No more than 27, of cis-1,4-dichloro-2-buteneis formed in the ionic chlorination, confirming the earlier conclusion of Mislow and Hellman (159) that 1,Caddition to cis-butadiene is not a preferred reaction path. Huisgen and co-workers (1 60) have shown that cyclooctatetraene adds chlorine cis in polar, as well as in nonpolar, solvents. In this case, the preference for cis addition is determined not by ion-pairing phenomenon but by the structural features of the intermediate ion (110) which is presumably formed from a molecular complex. As Huisgen (160b) points out, in the homotropylium ion (110) T overlap at the 1 and 7 positions is greatest below the ring, and chloride attack is thus favored from the side of the C-8 bridge to yield cis dichloride 111.

csh, )p

h,;..o --

C1

__f

.-.

.--

:+

(110)

c1 CI

H

L_f

--

(111)

The chlorination of p-dioxene (112), which can proceed via the highly stabilized carbonium ion (113), has been shown by Summerbell and Lunk (161) to yield a mixture containing 60% cis and 407, trans dichloride when the reaction is carried out in carbon tetrachloride at - 15".

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

273

3. Nonconjugated Olejins For olefins which are not capable of forming resonance-stabilized cations, chlorine addition occurs via an Ad,2 mechanism involving a bridged chloronium ion intermediate (114) as was first proposed by Lucas and Gould (162) and amplified by Winstein and Lucas (163). \

/

C=C

/

\

+ CI,

slow

\

/

C1 /+\

C-C (114)

/ \

fast

CI- --+

products

Three lines of evidence can now be outlined to support this mechanism for addition. First, Poutsma (140) has found that the relative rate of olefin chlorination increases equally with alkyl substitution at either olefinic carbon atom, showing that, at the transition state, positive RC H=C Hz Relative rate =

I

RsC=CHz RCH=CHR

RzCzCHR

50

104

RzC=CRZ 4 x 105

charge can be distributed equally over both carbons as in the n-complex structure 115, rather than being localized on one carbon as in the ucomplex structure 116 (140). Transition state 115 is the logical precursor of a chloronium ion (114), while 116 is not (cf. 164). CI 6I

CI

y1---c1s-

Secondly, the addition of chlorine to linear alkenes occurs with high trans stereospecificity. This was first recognized by Lucas and Gould (162) for the chlorination of the 2-butenes under nonpolar conditions and provided the basis for postulation of the chloronium ion intermediate. Poutsma (135) has since shown that under similar conditions radical chlorination of the 2-butenes obtains and gives trans dichloride as a main, but not exclusive, product. Nevertheless, it has been shown that, when the reaction is ionic, addition occurs with greater than 99% trans stereospecificity (1 35,141,156,165). Representative data are summarized in Table VI.

214

R. C. FAHEY

TABLEVI

The Stereochemistry of Alkene Chlorination trans Addition product, yo Olefin

Solvent

2-Butene trans

Neat HOAc cis Neat cis HOAc Cyclohexene Neat Di-tert-butylethylene trans cc14 cis cc14 2-Pentene trans HOAc trans CH30H trans CFBCOOH cis HOAc cis CF3COOH trans

a

-

Di-Cl 2-C1-3-OR 3-Cl-2-OR 98 14 97 54 80

-

24

yo

Ref.

2"

135 156 135 156 134

2" 3" 3" 20b

43

54 100 76 16 91 53 83

Other product,

46"

-

10 35 4

12 7

13 49 5 32 10

141 141 165 165 165 165 165

3-Chloro-1-butene. 3-Chlorocyclohexene.

4-Chloro-2,3,5,5-tetramethyl-l-hexene.

3-Chloro-1-pentene.

Further examples of predominant trans addition include chlorine addition to 1,Ccyclohexadiene, which gives a tetrachloride by two successive trans additions (153), and addition to cholest-2-ene, which gives primarily 2fl,3a-dichloride by diaxial trans addition (1 66), both reactions in carbon tetrachloride as solvent. Stereospecific trans addition obtains not only for dichloride formation, in reactive but for formation of the mixed adducts -CHCl-CHORsolvents. This has been demonstrated for chlorination of the 2-butenes in acetic acid (Table VI) and water (167); the 2-pentenes in acetic acid, methanol, and trifluoroacetic acid (Table Vl) ; the 2-pentenes in ethanol, tert-butanol, and formic acid (165); and cis-di-tert-butylethylene in methanol (141). The chlorination of the 2-butenes with rert-butyl hypochlorite in aqueous media gives the 3-chloro-2-butanols from stereospecific trans addition (1 62) ; the addition of hypochlorous acid

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

275

to cyclohexene (1 68) and oleic acid (169) yields chlorohydrins by trans addition. Thus, there can be little doubt that the chlorination of alkenes follows a stereospecific trans course, as expected if a chloronium ion intermediate is involved. The third line of evidence supporting the intermediacy of a chloronium ion involves the nature of the substitution products formed. The substitution products are always allylic rather than vinylic chlorides. In addition to the examples in Table VI, isobutylene, trimethylethylene, and tetramethylethylene give large amounts of substitution product with chlorine (136). The increase in the amount of substitution product CH3

\ /

C=CHz

CH3’ CH3 CH3

\

/CH3

/c=c\

-

CHz

\\

Clz

/

CH3’ CHz

Clz

---+

H

C-CHZCI

87Yo

\\ C-CHCICH3 /

CH3

85%

CH3 CH3

\

/CH3

/c=c\

CH3

CH2 Clz

+ CH3

+ (CH3)2CCICH,CI c1

CI

I I + CHa-C-C-CH3 I I

CH3 H 15%

c1

c1

I I C-CCI(CH3)z + CHa-C-C-CH3 I I /

\\

99.7y0

CH3 CHj 0.3YO

with methyl substitution at the double bond probably results primarily from steric retardation of the step leading to dichloride. Taft (170) attributed the preference for allylic chloride formation to an unusual inductive effect of chlorine in a classical cation (117), but a more probable explanation is that given by de la Mare and Salama (171).

They argue that in the bridged ion (118) proton loss to form a vinyl chloride is not a favorable stereoelectronic process, whereas the methyl

R. C. FAHEY

216

group can assume a geometry favorable for proton loss to form the allylic chloride. Recent NMR studies by Olah and Bollinger (131) indicate that, while the tetramethylethylene and trimethylethylene chloronium ions have a bridged structure, the 1,l-dimethylethylene chloronium ion has an open structure (117). This appears to contradict the conclusion that the formation of allylic chloride from isobutylene requires a bridged structure; however, the chlorination is carried out under conditions which are quite different from those of the NMR studies. Alternatives have been suggested to the Ad,2 chloronium ion mechanism for olefin chlorination. Williams (172) has proposed a mechanism involving attack on an olefin-chlorine complex having the structure 119 or 120 (cf. 173). Such a mechanism would require that, for chlorina-

c1

(119)

c1

(120)

tion in hydroxylic solvents, the dichloride-to-mixed-adduct ratio increase with the chloride ion concentration. But, for the chlorination of linear alkenes in acetic acid, this ratio is quite insensitive to the presence of hydrogen chloride ( I 56) and changes significantly only in the presence of lithium chloride at high concentrations (165). Thus, this mechanism is of minor importance in the chlorination of linear alkenes, although it might be important for addition to less reactive olefins. It is perhaps worth noting that the chloronium ions formed from alkenes are quite reactive species and will attack ethers (174,175), nitriles (175) and benzene (175) to form various products. Hence, for preparing dichlorides from alkenes by ionic chlorination the use of nonreactive solvents saturated with oxygen (to suppress radical addition) is preferable. Exceptions to stereospecific trans chlorination via the Ad,2 bridged ion mechanism can be anticipated if the intermediate ion can rearrange to a more stable form before proceeding to product. An example, provided by the studies of Tarbell and Bartlett (176), is the aqueous chlorination of the disodium salt of dimethylmaleic acid (121). An intermediate lactone (122) is formed and opens in acid to 123, corresponding to overall cis addition of hypochlorous acid. While the stereo-

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

277

chemistry was not rigorously proven, the disodium salt of dimethylfumaric acid yields an isomeric lactone and chlorohydrin by a similar sequence, and there seems little doubt that the stereochemistry is as shown. De la Mare (137) has obtained nonstereochemical evidence on the addition of hypohalous acids to allylic compounds, CH2=CHCH2G, which shows that the initially formed chloronium ion (124) can

/?

CI

I\

CH2-CH-CHZG

ClCH2-CH-CH2

(124)

(125)

rearrange to an isomeric cation (125) before forming products. These results suggest that, when neighboring group participation is involved, cis addition products can be formed. Allene reacts with chlorine to give 2,3-dichloro-l-propene and propargyl chloride ( I 77), but the stereochemistry of chlorine addition to allenes has not been studied.

4. Bicyclic Olefins The ionic chlorination of norbornene has been studied by Poutsma (1 36) and that of benzonorbornadiene by Cristol and Nachtigall (143).

Under nitrogen, norbornene undergoes spontaneous radical addition, but addition to benzonorbornadiene is predominantly ionic. Norbornene yields (136) only a small amount of the trans-dichloride (127) expected from the chloronium ion (126). The main products-nortricyclyl chloride (131) and rearranged dichloride (128)-are those expected from a nonclassical ion (129), as is the small amount of cis dichloride (130) formed. This result suggests that, in the norbornene system, participation by the C,-C, bond is competitive with 2,3chlorine bridging. Similar results have been obtained by Tanner and

R. C. FAHEY

278

65% (131)

Gidley (139) with iodobenzene dichloride as the chlorinating agent and using oxygen to suppress the radical reaction. In the chlorination of benzonorbornadiene (143), however, no transdichloride is observed; the products are solely those expected from the Cl*-O,

cc'4 +

c1

/

dC1 Q

7

x.....

I : : : :

(132)

nonclassical cation (132). Here, chlorine bridging does not compete with formation of the nonclassical ion.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

279

B. Addition to Acetylenes Very little is known about either the stereochemistry or the mechanism of the ionic chlorine addition to acetylenes. Leitch (178,179) has studied the vapor-phase chlorination of propyne, l-butyne, 2-butyne, and 1-pentyne and finds that trans dichlorides and tetrachlorides are formed, but these reactions cannot involve ionic additions. Poutsma (180) has shown that neat 1-butyne does not react with chlorine in the dark by either an ionic or a spontaneously initiated radical mechanism, but photoinitiation produces a rapid radical reaction. Similarly, neither tolane (18 1) nor 1-phenylpropyne (182) undergoes homogeneous reaction with chlorine in carbon tetrachloride. The first serious effort to study the ionic chlorination of acetylenes was made by Hennion and co-workers (183-186) in the late 1930's. They showed that addition of chlorine to l-hexyne in a variety of reactive solvents yields chlorinated products, including the dichloro ketone (133) expected from ionic addition involving the solvent. The dichloride

isolated was predominantly cis under some conditions and predominantly trans under others. The results support chlorination via an ionic mechanism, but uncertainties exist as to whether the products observed are those resulting from kinetic control. The trifluoroacetic acid catalyzed chlorination of tolane in benzene is reported to give 83% cis and 17y0trans dichloride (181). Phenylacetylene reacts rapidly with chlorine under oxygen in methylene chloride to give roughly equal amounts of 135, 136, and 137, all of which are reasonably expected to result from an intermediate vinyl cationchloride ion pair (134) (182).

2 80

R. C. FAHEY

(134) Ph

\

/

c1/c=c\

c1

CI

\

/

H + Ph /c=c\H

(135)

(136)

c1

+ PhC-CCI (137)

V. BROMINE A. Addition to Olefins

I. General Considerations Bromine, like chlorine, forms complexes with olefins. Evidence for such complex formation derives from spectral observations (1 87-1 89) and from thermographic studies at low temperatures (190). The addition of bromine to olefins is exothermic by about 30 kcal (19), almost 15 kcal less exothermic than the addition of chlorine. Bromine reacts with olefins to form dibromides and, in hydroxylic solvents, mixed addition products. Olefins possessing substituents which

\ / Bra \ / \ / C=C e CBr-CBr+ CBr-COS+ HBr / \ / \ / \ can serve as nucleophiles can also undergo bromination with neighboring-group participation to yield cyclic products (I 9 1). Bromine, N-bromoamides, and hypobromites are common brominating agents and bromination with these reagents can occur by either ionic or homolytic (192) pathways. Spontaneous initiation of radical bromination has been observed by Walling, Heaton, and Tanner (138) with tert-butyl hypobromite. Bromination differs from chlorination in several important ways. The kinetic form for bromination is more complex than for chlorination. Bromination is less often accompanied by the formation of rearranged products or by the formation of substitution products. The formation of dibromide by bromination in hydroxylic solvents is very much dependent upon the bromide ion concentration; whereas for chlorination in the

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

281

same solvent dichloride formation is less sensitive to the chloride ion concentration. Because of these differences, the case for an AdE2 mechanism as the dominant mode of addition is not as strong for bromination as for chlorination. Considerable attention has been given to studies of the kinetics and rates of bromine addition to olefins, the subject being thoroughly reviewed by de la Mare and Bolton (193). The most important kinetic forms are given by -d[Brz]/dt = k2[E][Br2]

+ k3[El[BrZl2+ kj[EIIBrzl[Br-]

where E represents olefin. For bromination in hydroxylic media the first and third terms are most important. For bromination in nonpolar solvents, where bromide ion is normally not present and not formed in the reaction, the first and second terms are dominant. For the bromination of certain a,P-unsaturated carbonyl compounds, pronounced acid catalysis has been observed. For all but the most deactivated olefins, the effect of substitutents upon the rate of addition points to an electrophilic mechanism. Early studies by Robertson and co-workers (193) established that, for bromine addition to substituted ethylenes in acetic acid, both k , and k3 increase with increasing electron-donating ability of the substituent. A similar situation holds for the values of kz and k; measured by Bell and students (194,195) for bromination in aqueous solution. Dubois (196) has made extensive linear free energy correlations of koZbSwith olefin structure for bromination in methanol containing sodium bromide, kgbs being some undetermined composite of k , and kj. With substituted styrenes (197) and cinnamic acids (198), log k , for bromination in acetic acid correlates with 0 , giving a negative value for p. The best evidence for stepwise addition via a cationic intermediate would come from the observation of Wagner-Meerwein rearrangement accompanying addition, but such rearrangements are less common for bromination than for chlorination. Thus, tert-butylethylene, which undergoes some rearrangement upon reaction with chlorine, has been shown by Puterbaugh and Newman (199) to react with bromine in methanol to give roughly equal amounts of unrearranged dibromide and f-BuCHBr-CH,0CH3. Rearranged products are, however, found in the bromination of a variety of norbornene derivatives in nonpolar media (Sect. V-A-4). The results point to an electrophilic mechanism, but the distinction between an Ad,2 and an AdE3 mechanism is not entirely clear. In

R. C. FAHEY

282

principle, these mechanisms might be distinguished from kinetic and product studies in hydroxylic solvents. Thus, if only an A d ~ mechanism 3 were involved, the rate of mixed adduct formation,

\ / C=C / \

\ / CBr-COS + HBr / \ should be given by kz[E][Brz]and the rate of dibromide formation,

+ Bra + SOH

ka

--f

-

\ / C=C + Bra + Br- k& \CBr-CBr/ + Br/ \ / \ by k~tEItBr,ltBr-l. Bell et al. (194,195) have determined k,, kj, and the dibromide to bromohydrin ratio for bromination of a variety of olefins in aqueous solution and conclude that an A d ~ 3mechanism is not the dominant mode of addition for the more reactive olefins, but may be so for diethyl fumarate and less reactive olefins, as Kanyaev (200) has suggested. The available data on the bromination of stilbene in methanol appear incompatible with the A d ~ 3mechanism (7). On the other hand, it is also difficult to understand the kinetic results purely in terms of an A d ~ 2mechanism. Specifically, it is difficult to rationalize the apparent bromide catalysis. Because of the equilibrium Br- + Br, = Br,, with equilibrium constant K, the term in the rate law involving kj[E][Br,][Br-] can also be written kjK-'[E][Br;]. Tribromide ion might then be considered as a potentially electrophilic species in an AdE2 mechanism, but the observed values of kjK-l are often comparable to or larger than those for k,, and it is difficult to understand how tribromide ion can be more electrophilic than bromine itself. It seems probable that an AdE2mechanism is involved with alkenes and more reactive olefins, but it is difficult to exclude the possibility of a competing A d ~ 3mechanism. The tendency for bromine to add trans to olefins is widely recognized and is generally considered to result from the formation of an intermediate bromonium ion (138), as first postulated by Roberts and Kimball (I 1). The NMR studies by Olah and Bollinger (131) provide direct evidence for the existence of bridged bromine cations.

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

283

The steric course for bromination, like that of chlorination, depends upon the structure of the olefin. Olefins which can form highly stabilized cations are less prone to form bromine bridged cations, but, since bromine is a better bridging atom than chlorine, the tendency toward trans addition is more pronounced with bromine than with chlorine.

2. Arenes and Polyenes The stereochemistry of the bromination of cis- and trans-stilbene has been the subject of a number of studies by Buckles and co-workers (201-204) and, more recently, by Heublein (205). The addition of bromine chloride, either from N-bromacetamide and hydrogen chloride (201) or from mixtures of bromine and chlorine (202), to trans-stilbene gives a 50-70y0 yield of the trans adduct, while cis-stilbene gives similar amounts of trans adduct accompanied by 5-15oJ, of the cis-addition product. Bromine addition to both cis- and trans-stilbene occurs predominantly, though not exclusively, trans in nonpolar solvents, but is less stereospecific in more polar media (203,205). In the presence of bromide salts, the preference for trans addition is restored (203). Similarly, bromine addition to cis- or trans-1-phenylpropene in methylene chloride or in carbon tetrachloride is preferentially trans, but 15-30y0 of cis adduct is also formed (206). Bromine addition to p-methoxy-trans-1-phenylpropene in carbon tetrachloride is nonstereospecific (206). A possible representation of the mechanism in nonpolar solvents, where addition is second order in bromine, has been given by Buckles (204) and is outlined in eqs. (6)-( 10). Here, the initial step is assumed to E E--Br2

+ Brz + Brz

[EBr+ Br,] [EBr+ B r i ] E-Br2

+ Br; + Brg

-----f

E-Brz [EBr+ Br:]

--+EBrz + Bra d

EBrz

+ Brz + Br:

-+ EBrz + Br;

(6)

(7) (8)

(9) (10)

be rapid reversible complex formation, which is followed by bromineassisted ionization to the ion pair [EBr+ Br;]. The ion pair can then undergo unimolecular decomposition to product [(eq. (8)] or be intercepted by Br; to give product [eq. (9)]. In the presence of tribromide ion (added bromide salt), the complex E-Br, can be attacked by Br; to give dibromide directly. Which of the eqs. (7)-(10) is (are) rate determining is unclear.

R. C. FAHEY

284

The intermediate ion must be close in structure to an open cation (139) to allow for the occurrence of cis addition in the product-forming step of eq. (8). The interaction of the bromine with the carbonium center is presumed to be more important in the less polar solvents (205). If the aryl group in 139 is para-methoxyphenyl, the stabilization of the positive charge is sufficient to make bromine bridging unimportant.

%,+&Br

'

H

(139)

R

'€I

The recent studies of Norman and Thomas (207) are quite relevant to the foregoing discussion. They found that bromination of 140 (Ar = Ph) in carbon tetrachloride gave comparable amounts of dibromide (141) and rearranged substitution product (142). However, with 140 PhzArCCH=CHz (140)

Bra

CCI4

PhzArCCHBrCHzBr

+ PhzC=CArCHaBr

(141)

(142)

(Ar = p-MeO-C,H,) the reaction occurred 25-fold faster than with 140 (Ar = Ph) and gave only rearranged product (142). This indicates that the slow step of the reaction involves a phenonium ion structure (143) when Ar = p-MeO-c6H4, suggesting that this species is more stable than the bromonium ion (144).

6

PhzC-CHCH,Br (143)

7\

Ph,( p-MeO-CsH4)CCH -CH, (144)

Acenaphthylene gives a 50% yield of trans dibromide (145) with bromine in petroleum ether ( I 52), and cyclopentadiene gives a mixture of cis-3,5- and rrans-3,4,dibromocyclopentene (146 and 147), the former predominating (208). In cyclic systems, the formation of cis vicinal dibromides is likely to be unfavorable, even if bromine bridging is absent, since steric interaction between the two bulky bromine atoms disfavors the cis adduct, but the formation of a bromonium ion in these systems cannot be ruled

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

Br

285

11'

Br

(145)

out. Bromination of 148 and related compounds in carbon tetrachloride can occur via the highly stabilized oxonium ions 149 and 150, and this reaction yields significant amounts of the cis adduct (151) along with the trans dibromide (152) (209).

<:>O*q->+qF>b Br

H

(148)

Ejr Ejr (151)

H Br (152)

Limited studies of the bromination of arenes in hydroxylic media indicate that the mixed adducts are formed by trans addition. Thus, the bromination of trans-stilbene or indene with N-bromosuccinimide in aqueous dimethysulfoxide gives good yields of the trans bromohydrins (210). The bromination of phenanthrene gives the 9,lO-dibromide along with 9-bromophenanthrene (21 1,212). The reaction has been studied with methanol as solvent by van der Linde and Havinga (212) who have shown that trans-9,lO-dibromo- and trans-9-bromo-10methoxy-9,lO-dihydrophenanthreneare the primary products, but that no dibromide is formed until phenanthrene has been one-fourth converted to the mixed adduct with accompanying formation of hydrogen bromide. Thus, the bromide ion serving as a nucleophile in the formation of dibromide comes not from the bromine molecule initiating attack, but from the hydrogen bromide present in solution. This is consistent with either an AdE2 or an Ad,3 trans addition mechanism. These can, in principle, be distinguished by a combination of rate and

R. C. FAHEY

286

product studies, but, as we have seen (Sect. V-A-1) from Bell's work (194,195), even the results of such combined studies can fail to provide a fully satisfactory account of the mechanism. Hatch, Gardner, and Gilbert (213) have found that bromine adds to butadiene to give equal amounts of 3,4-dibromo-l-butene and trans1,4-dibromo-2-butene, showing that bromine, like chlorine, does not add preferentially via a cyclic transition state.

(154)

(153)

Bromine addition to cyclooctatetraene has been studied at low temperature by Huisgen and Boche (214). The primary product is the cis-dibromide (153), presumably formed from cation 154, by analogy with chlorine addition to cyclooctatetraene (Sect. IV-A-2).

3. Nonconjugated Olefins and a$- Unsaturated Acids It is well known that the addition of bromine to nonconjugated alkenes in nonpolar solvents gives high yields of the trans adducts. Young, Dillon, and Lucas (85,215) were able to isolate in 95% yields the trans adducts from cis- and trans-Zbutene upon addition of bromine to the neat olefin at -15". Similarly, Winstein (216) has shown that cyclohexene adds bromine predominantly trans. More recently Stevens and Valicenti (217) have demonstrated that bromine-82 addition to 1bromocyclohexene in chloroform is at least 99% trans stereospecific. Eliel and Haber (2 18) find that 4-tert-butylcyclohexene adds bromine to give the trans dibromides (155 and 156) with the diaxial isomer (156) predominating. Barton et al. (219-221) have shown that trans

t-Bu

t-Bu

(155)

(156)

Br

diaxial attack is the favored mode for bromine addition in cyclohexene ring systems, based on studies of the cholestenes and related compounds, and a similar preference has been found by Hageman and Havinga

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES 287

(222) for bromine chloride additions to a variety of cyclohexene derivatives. Most of these studies have been carried out in nonpolar media and one might worry that these are radical rather than ionic additions. However, the reaction rate increases markedly as the solvent is made more polar (204,223), which indicates that an ionic mechanism is involved. In nonpolar solvents and in the absence of bromide ion, an Ad,3 mechanism seems highly improbable so that the trans stereospecificity of addition under these conditions is good evidence for the bromonium ion mechanism. The rate term involving second-order dependence on bromine undoubtedly dominates the reaction under these conditions so that the mechanism is best expressed thus:

r

1

Br

Bromination in hydroxylic solvents yields mixed adducts by trans addition. Thus, Winstein and Lucas (163) were able to prepare the trans bromohydrin of cis-2-butene by bromination with N-bromoacetamide in water containing acetic acid. Cyclohexene, with N-bromosuccinimide in aqueous dimethyl sulfoxide, gives the trans bromohydrin in 78% yield (207). Bromination of the cis or trans acids, CH,(CHJ,CH -CH(CH,),COOH (n = 7 or I I), with N-bromosuccinimide in acetic acid has been shown by Juvtscheff (224,225) to yield bromo acetates by trans addition. Steroids form mixed adducts by trans addition with a variety of brominating reagents (226). Hassner, Levy, and Gault (227) have shown that addition of olefins to solutions of bromine and silver perchlorate in acetonitrile leads to a nitrilium ion (157) which hydrolyzes with base to the amide (158) or

2”RF N G CCH,

R

(157)

NHCOCH,

(158)

can be converted to a tetrazole by treatment with sodium azide. The addition takes place trans providing a novel method for the stereospecific introduction of nitrogen into organic compounds.

R. C. FAHEY

288

Waters and Caserio (228a) have found that addition of bromine to (-)-1,3-dimethylalIene in methanol gives 80% trans- and 20y0 cis-3bromo-4-methoxy-2-pentene.By establishing the absolute configuration of the major product, they demonstrated that it is formed by trans addition to the double bond. Berti and Marsili (228b) have recently shown that bromination of alkenes in the presence of Cinchona alkaloids leads to dibromides having optical activity. It has long been known that fumaric acid and maleic acid add bromine trans (229,230). This example is often used to illustrate the bromonium ion mechanism, but may not be the best choice in view of the possible intervention of an Ad,3 mechanism or nucleophilic mechanism with deactivated olefins (194,2OO,231). Bromine adds predominantly trans to the disodium salt of fumaric acid in the presence of sodium bromide, but the disodium salt of maleic acid gives primarily cis adduct (232). The latter observation has been attributed (11) to destabilization of the bromonium ion (159), as a result of repulsion between the carboxylate groups, causing isomerization to the isomeric

H ----ic

4

-0oc

(159)

\COO-

Br

COO-

’,..C-/ + \c,#”

- ooc4

(160)

H’

bromonium ion (160) to occur before collapse to product. However, the diethyl esters of fumaric and maleic acid also undergo trans and cis addition of bromine, respectively, suggesting that some other factor may be involved (195). 4. Bicyclic Olefins

That bromination of norbornene (161) with N-bromosuccinimide or bromine gives 3-bromonortricyclene (164) was shown by Roberts and co-workers (233) and confirmed by Kwart and Kaplan (234). The latter investigators showed that 163 and 166 are also primary products. Hydrogen bromide produced in the reaction adds to norbornene, giving norbornyl bromide, and also isomerizes the initial products, but these reactions are suppressed in the presence of pyridine. Dibromide 163 can be viewed as arising from the bromonium ion (162) and dibromides 164 and 166 from the cation 165.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

289

With exo-trimethylene-2-norbornene(167), bromination in pyridine gives 90% of unrearranged trans dibromide (168), the remaining products being those related to 164 and 166 (235). Similarly, bromination

d a (167)

4 :& Br

(168)

0

(169)

of the exo anhydride (169) gives mainly trans dibromide (236a); but the endo anhydride (170) gives 67% of the cis adduct (172) probably via an intermediate resembling (171) (236b). The endo acid (173) reacts with bromine to form the lactone (174) (237). Bromine addition to benzonorbornadiene (175) (238,239) and its derivatives (240) gives 85-90% yields of the rearranged dibromide (177), suggesting that 176 is more stabilized relative to the corresponding bromonium ion, than is 165. Cristol and Jarvis (241) found that

R. C. FAHEY

290

addition of bromine to 7-chlorodibenzobicyclo[2.2.2]octatriene (178) in ethyl acetate gives rearranged products 179 and 180, but 180 may arise by secondary isomerization of 179.

&

&>&+&

(178)

c1

c1

Br

(179)

(180)

Winstein (242) reports that norbornadiene gives a mixture of dibromides with bromine in nonpolar solvents. The products can be viewed as arising from the intermediate nonclassical ion (184); attack from the top at C-1 yields 181 while attack at the upper and lower side of C-5 gives 182 and 183, respectively. The products can, of

J & / . l & 3 r + B r &

- 25% (181)

+Br&

Cd -25% (182)

s + - - . .._* -....i s + *. aa*.....

'J,,,'

(184)

*

50% (183)

+

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

291

course, also be viewed as rising from classical ions. The possible toxicity of these dibromides should be noted (242). Farnum and Snyder (243) find that the tricyclic diene (185) and related compounds give varying yields of cis dibromides (186), along with other products, upon bromination in chloroform. Here, steric hindrance to trans addition forces the reaction to take a less favorable course. Br

B. Addition to Acetylenes Limited studies by Robertson and co-workers indicate that bromine additions to acetylenes (1 13a) in acetic acid follow kinetics similar to those found for olefins, but that acetylenes are 100- to 50,000-fold less reactive than the corresponding olefins. The bromination of symmetrically substituted stilbenes and tolanes in bromobenzene solution follows third-order kinetics, second order in bromine and first order in unsaturated substrate (244). Whereas electrondonating substituents accelerate and electron-withdrawing substituents retard the rate of addition to stilbene, both types of substituent accelerate addition to tolane. Here, bromine addition cannot be exclusively electrophilic in character. Bergel’son (245) has studied bromine addition to a variety of acetylenes under conditions for homolytic addition and also in polar media. He finds that both cis and trans adducts are formed in the radical process and that trans adducts appear to be favored in polar solvents. Acetylene dicarboxylic acid adds bromine in acetic acid to yield a mixture of adducts (246). Owing to the lack of definitive evidence for an electrophilic mechanism and the lack of quantitative stereochemical data under conditions of known kinetic control, very little can be concluded at the present time about the nature of electrophilic addition of bromine to acetylenes. Further studies in this area would obviously be of value.

292

R. C . FAHEY

VI. IODINE

Iodine and iodine chloride are known to form complexes with olefins and other unsaturated hydrocarbons (247-249) and iodination of olefins and acetylenes in solution can occur by either ionic or radical pathways (250-255). The addition of iodine to ethylene (256) or acetylene (257) is exothermic by only about 10 kcal. Since addition is accompanied by an unfavorable entropy change, AG for addition is usually small and equilibrium is established before complete conversion of the olefin or acetylene to diiodide (252,253,258).

\ / \ / C=C + I a e CI4I / \ / \ Kinetic studies indicate that iodine addition to olefins and acetylenes follows the rate law -4Ialldt = k3[El[Iala

+ kr[El[IaF

and limited studies of the rate of addition as a function of olefin structure suggest an electrophilic mechanism (259). The fourth-order kinetic term is most important in nonpolar solvents and has been interpreted in terms of iodine polymers. Iodination of olefinic alcohols, CH2=CH(CH2),0H, in aqueous solution leads to cyclic ethers. The rate of reaction is greatest for n = 3, suggesting that the reaction proceeds with neighboring-group participation via a transition state resembling 187 (260). Similar reactions with olefinic acids and their anions yield lactones (261,262).

(187) Tanner and Brownlee (263) have shown that addition of iodine to 188 in nonpolar media gives 190 as the sole product. The rearranged benzylic cation 189 is presumed to be the product-forming intermediate. The reaction of (- )-1,3-dimethylallene with iodine in methanol yields (- )-trans-3-iodo-4-methoxy-2-penteneby trans addition and as a minor product (228a). also gives cis-3-iodo-4-methoxy-2-pentene

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES 293

The stereochemistry of iodine addition to olefins has received little attention, but the addition of other iodine compounds has been shown by a number of workers to occur with trans stereospecificity. Heublein (264) has shown that iodine chloride adds to trans-stilbene in a stereospecific trans fashion and that the rate of reaction is first order in stilbene and first order in iodine chloride. Bowers et al. (265) find that iodine fluoride adds trans to cyclohexene and to various steroids (191).

1

(191)

The addition of iodine isocyanate to olefins has been investigated by Hassner and students (266) and by Drefahl et al. (267). Stereospecific trans addition is observed with a wide variety of arenes (266b,267a) and alkenes (266,267). Gebelein and Swern (268) have shown that the relative rates of INCO addition to various olefins follow a pattern similar to that for bromine addition. Fowler, Hassner, and Levy (269) have made a thorough survey of the addition of iodine azide to olefins and find that arenes, alkenes, and a,P-unsaturated carbonyl compounds all react smoothly to yield 1,2-trans-adducts. The simplest interpretation of these results is that addition occurs via an intermediate iodonium ion (192). Strong evidence for iodonium ions X-

as intermediates in organic reactions has been provided by studies of neighboring-group participation in displacement reactions (270), and

294

R. C. FAHEY

direct evidence for the existence and the bridged structure of these ions has been obtained from NMR studies (131). It is not entirely clear, however, whether the formation of 192 or some subsequent step is rate limiting (265). The iodination of acetylenes has been less thoroughly studied. The reaction of INCO with 3-hexyne is nearly 100-fold slower than with trans-3-hexene (268), showing that the iodonium ion (193) is less easily formed from the iodination of acetylenes than is the corresponding ion (192) from olefins. X(193)

Evidence has been obtained by Miller and Noyes (257) which indicates that iodine addition to acetylene in methanol occurs by an AdE3 trans addition mechanism. From studies of the rate and equilibrium of iodide-catalyzed elimination of 1,2-diiodoethylene, they could infer the mechanism of the addition reaction from the principle of microscopic reversibility. They conclude that the transition state for elimination, and therefore for addition, resembles 194. Since trans-l,2-diiodoethylene 8-

T

(194)

eliminates much faster than the less stable cis-l,2-diiodoethylene, it follows that trans addition must occur faster than cis addition. In accord with this conclusion, the addition of iodine to acetylene in aqueous potassium iodide has been observed to give a high yield of the trans diiodide (271). Iodine addition to olefins should, under appropriate conditions, also occur by an AdE3 trans addition mechanism, but evidence for this is lacking.

VII. PERACIDS Olefins react with peracids to form epoxides by an addition process which differs from the others considered in this review in that a single

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

295

atom becomes fixed across the double bond (272). The epoxide has the same configuration as the reacting olefin so that the stereochemistry of epoxidation involves a simple 1,Zcis-addition (272). 0

II

\

/

0

\ / \ / RCOOH+ C=C --+ C-C +RCOOH / \ / \ The rate of reaction is usually first order in both olefin and peracid (273) and is faster in polar than in nonpolar solvents (274). The variation of rate with structure follows the same trend as that for chlorination and bromination, but the magnitude of the variation is smaller. Thus, relative rates of epoxidation in the alkene series (275) are CH,=CH, 1

CH3CHzCHa 22

CHaCH=CHCH3 -500

(CH3)2CSHa -500

and correlation of epoxidation rates for ring-substituted styrenes (276) and stilbenes (277) with u + gives p values of about - 1.2. The reaction is considered to occur by a molecular cis addition involving a cyclic transition complex (195) as was first proposed by Bartlett (278). This is consistent with the view that peracids form

intramolecular hydrogen bonds (196) (279) and also with the fact that epoxidation is slower in ether solvent, which can form intermolecular hydrogen bonds with the peracid, than in hydrocarbon media, where intramolecular hydrogen bonding remains intact (274). An alternative mechanism has recently been proposed (280a), but subsequent studies (280b,280c) raise serious questions as to its validity. For certain cyclic alkenes, epoxidation can give stereoisomerically different products depending upon which side of the double bond undergoes attack. The effect of substituents upon the direction of attack has been the subject of considerable study by Henbest and co-workers

R. C. FAHEY

296

(28 1). In cyclohexene, a 3-methoxy or 3-acetoxy substituent directs attack trans, but in cyclohex-2-en01 hydrogen bonding stabilizes the

transition state (197) for cis epoxide formation and the cis epoxide is the major product (281a). A similar preference for cis epoxide formation

R

RCOOH

,

(197)

has been observed by Goodman, Winstein, and Boschan with 3-benzamidocyclohexene (282). In the steroid series (198), the hydroxyl group and the methyl group are seen to have opposing effects (281a). The effect of the methyl group

RCOaH

H CHS HO

H CH,

H

H H OH OH

66:34 1535

1OO:O

33:67 0: loo

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

297

is considered to be steric in origin and is larger in 4-methylcyclopentene (283) than in 4-methylcyclohexene (284). Rickborn and Lwo (284)

21~73

cis: trans epoxide

46 :54

60:40

find that 4-tert-butylcyclohexene gives a slight excess of cis epoxide and conclude that the tert-butyl group must distort the cyclohexene ring so as to favor cis epoxidation. Polar substituents can effect the cis:trans epoxide ratio, even when removed by one, two, or three rings from the alkene; the magnitude of the effect is solvent dependent, being more pronounced in nonpolar than in polar media (281). The expoxidation of norbornene gives mainly exo epoxide (285), the exo:endo ratio being 94:6 (286). A similar preference for exo epoxide

RC03H>

& &$ +

0 formation occurs in 201 (287), 202 (287), and 203 (288), but epoxidation

(201)

HO

(202)

(203)

(204)

of apobornylene (204) gives mainly endo epoxide (289). The endo hydrogens at C-5 and C-6 hinder endo attack in norbornene causing exo epoxide to form preferentially, but the C-7 gem dimethyl group in 204 provides an even greater steric hindrance to exo attack and here the endo epoxide predominates. Epoxides are readily opened by acids and, since epoxidations are 0

\ / + CX-COH \ / \

\ / \ / F I X

/

C-C

R. C. FAHEY

298

frequently carried out under acidic conditions, it often happens that the epoxide is not the isolated product. The stereochemistry of epoxide ring opening can be complicated (290); while the epoxides of most alkenes open in a stereospecific trans fashion, epoxides of arenes sometimes open nonstereospecifically or even with cis stereospecificity (290c,291). Rearranged products are sometimes found in epoxidations when the expected epoxide is highly strained. Thus, peracid reactions with methylenecycloalkanes often yield aldehydes (292), as does the oxidation

C

C=CH,

RCOiH

CH-CHO

of norbornadiene (293), but it is not clear if these are primary products or secondary products formed from an intermediate epoxide.

Acetylenes react with peracids at about 1/1OOO the rate of olefins (294). Oxirenes (205) are not isolated, but the products formed (207, 208, and related compounds) suggest that 205 is an unstable intermediate in the reaction (295,296). The formation of 1 ,Zdiketones has been RC-CR-

RCOIH

[

R--C-R

RzCO

] [

/O\

I

d

/O\ R-C-C-R

\o/

I

]

RCOCOR 0

II + RzCH-C-OH

interpreted (296) in terms of further oxidation of 205 to 206 followed by rearrangement,

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

299

VIII. SULFENYL HALIDES A. Addition to Olefins

A substantial amount is known about the addition of sulfenyl halides to olefins, largely through the studies of N. Kharasch and students, and the subject has been reviewed by Kharasch (297). Most of the sulfenyl halide additions studied have been found to occur by ionic mechanisms, but free-radical additions can occur and are especially favorable for sulfenyl halides with strong electron-withdrawing groups, e.g., CC1,SCl (297,298). It had been generally thought that addition of sulfenyl halides to olefins proceeds mainly according to Markownikov’s rule. Thus, Kharasch and Buess (299) found that 2,4-dinitrobenzenesulfenyl chloride reacted with propylene to give primarily the Markownikov product [eq. (12)]. However, more recent studies by Mueller and RSCl

+ CHaCHECHa

C1 --f

I

SR

I

CH3CH-CHa

SR

I

C1

+ CHaCH-CHaI

R = 2,4-di-NOa-Ph R = Ph: initial rearranged

65%

15%

32%

68% 15%

R = CH3: initial rearranged

15% 8870

85%

85%

(12)

12%

Butler (300) with benzenesulfenyl chloride and methanesulfenyl chloride show that the initial products are primarily those of antiMarkownikov addition and that rearrangement to a mixture rich in the Markownikov adduct occurs at ambient temperature. Addition to styrene was found to follow Markownikov’s rule in all cases studied (299,300a,301a). It is clear that the product distribution varies with the structure of the sulfenyl halide, as well as with the structure of the olefin; recent studies by Thaller, Butler, and Mueller serve to clarify the factors involved (300b-300d). While 1,Zadducts are normally obtained in high yield, substitution can be important in some cases. Traynham and Baird (292a) found that 2,4-dinitrobenzenesulfenylchloride reacts quantitatively with 209 to give 210 and substitution products have been found in the reaction of p-methoxystyrene (301b), phenyl vinyl ether (302), and 1,l-diphenylethylene (303) with sulfenyl halides.

300

c3"-(--J

R. C. FAHEY

CH,-SAr

Skeletal rearrangements are quite rare in these reactions. Under conditions of kinetic control, tert-butylethylene reacts with 2,4-dinitrobenzenesulfenyl chloride at 25" to give 1,Zadducts and no products involving methyl migration, although the latter were formed a t higher temperatures under conditions of thermodynamic control (304). Sulfenyl halides, like halogens, react with suitable olefinic acids to give lactones (305). The rate of sulfenyl chloride addition is first order in olefin and first order in sulfenyl halide (301b,306), but Campbell and Hogg (307) have shown that in nonpolar solvents the rate law can appear to be more complex owing to solvation phenomenon associated with the reactants and products. The rate is much faster in polar than in nonpolar solvents, as is illustrated by the relative rates of 2,4-dinitrobenzenesulfenyl chloride addition to cyclohexene (306b) Solvent Relative Rate

CCl4 1

CHCI, 600

(CH2CI)Z 1400

HOAC 140

PhNOa 3000

The variation in rate of addition with structure establishes the electrophilic character of the reaction. Correlation of log k2 with u for 2,4dinitrobenzenesulfenyl chloride addition to para-substituted styrenes gives p = -2.2 (301b). Kwart and Miller (308) have correlated the rates of 4-mOnO- and 4,5-disubstituted cyclohexenes with the inductive substituent constants, u,, and found P I = -2.88. The effect of alkyl substitution on the rate of addition to ethylene does not appear to have been studied. For addition of 4-substituted 2-nitrobenzenesulfenyl chlorides to cyclohexene, Brown and Hogg (309) find that log k2 correlates with U + and p + = -0.714. These results show that there is significantly more positive charge at both the sulfur and the olefinic carbon in the transition state than in the ground state. The reaction is considered to proceed by an AdE2 mechanism involving an episulfonium ion intermediate (211) (299). Strong support for this view comes from the studies of Pettitt and Helmkamp (310) who were able to prepare stable episulfonium salts (212) from the reaction of alkanesulfenyl 2,4,6-trinitrobenzenesulfonateswith cyclooctene

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

\ / C S / \

R S

+ RSCl + \C-C/ + \ /

(211)

/ C1\

*

\

301

/ \

CSR-CCI

/

in ether. As expected for reaction via a bridged ion (211), the additions show a high degree of trans stereospecificity.

L

R = Me,Et,n-Pr,n-Bu (212)

Arenes appear to add sulfenyl halides trans, although truly quantitative evidence for this is not yet available. Thus, Cram (311) has demonstrated that cis- and trans-2-phenyl-2-butene each add 2,4-dinitrobenzenesulfenyl chloride in fair yield to give the different Markownikov adducts resulting from trans addition. Addition of the same reagent to

Ph

SAr

wcH3 Y

AH CH3

H

ArSCI>

Ph

I c1

cis-stilbene gives an adduct in . V S O ~yield ~ which has a lower melting point than the adduct from trans-stilbene, suggesting that trans

302

R. C. FAHEY

addition occurred with both olefins (312). The adduct (213) of acenaphthylene with methanesulfenyl chloride has been shown by NMR to have the trans configuration (300d).

(213)

Havlik and Kharasch (313) have shown that sulfenyl halide addition to the 2-butenes and to cyclohexene occurs trans. A quantitative study of the reaction between the 2-butenes and p-chlorobenzenesulfenyl chloride has been made by Schmid and Csizmadia (314). Using 1,1,2,2tetrachloroethane as solvent, they demonstrated that the additions to cis- and trans-Zbutene are trans stereospecific to the extent of 2 99.95 and 2 99.5y0, respectively; no change with temperature occurred from - 30 to 146°C. This study leaves little doubt as to the stereospecificity of addition to symmetrical alkenes. The stereochemistry of sulfenyl halide additions to bicyclic systems has received substantial attention and the subject. has been reviewed by Brindell and Cristol (3 15). Addition of PhSCl(300d), p-Me-C,H,SCl (316,317), p-NO,-C,H,SCl (318), and o-NO,-C,H,SCl (318) to norbornene gives high yields of the 1,2-trans adducts (214) and little or no 215 or 216. With 2,4-dinitrobenzenesulfenylbromide and chloride,

,c1

however, up to 13% of 215 is formed, but again none of the rearranged product (216) was found (317). The failure of these reactions to yield significant amounts of rearranged product contrasts with the reactions of norbornene with acids and halogens, and is considered to result from the special stability of the cyclic sulfonium ion intermediate (217) which does not readily rearrange to the nonclassical ion (218).

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

303

In contrast to the finding by Brown (289) that apobornylene undergoes epoxidation by endo attack, benzenesulfenyl chloride with apobornylene yields 85% of the 1,2-truns adduct resulting from exo attack (300d). Cristol et al. have shown that norbornadiene also reacts with p Me-C6H4SCl to give primarily the 1,2-truns adduct derived from an exo episulfonium ion (3 16). Dibenzobicyclo[2,2,2]octatriene (220), on the other hand, gives mainly rearranged acetate (219) in acetic acid as solvent (319), but gives the unrearranged trans adduct (221) in carbon tetrachloride (316) or ethyl acetate (241) as solvent. Cristol and Jarvis

(241) consider that collapse of the intermediate ion pair 222 to 221 is rapid in aprotic media, but that solvation by acetic acid reduces the nucleophilicity of the chloride ion, allowing 222 to rearrange to the benzylic cation (223) which then collapses to 219. The reaction of 224

(222)

(223)

(224)

with benzenesulfenyl chloride is much slower than that of 220, and rearranged product is formed even in aprotic solvents (241). The presence of the chlorine at the olefinic carbon apparently destabilizes the intermediate episulfonium ion and facilitates the rearrangement process.

304

R. C . FAHEY

B. Addition to Acetylenes Sulfenyl halides form 1:1 adducts with acetylenes in much the same way as with olefins, but there are some complicating features in the reaction. Whereas styrene adds sulfenyl halides predominantly in the Markownikov sense, phenylacetylene gives a mixture of adducts which varies with solvent and 1-alkynes give predominantly the antiMarkownikov product (see Table VII). Addition to monosubstituted tolanes does give product compositions consistent with an electrophilic addition (Table VII). Kharasch and Yiannios (320) have established that the rate of addition of 2,4-dinitrobenzenesulfenylchloride to phenylacetylene and to 3hexyne in acetic acid is first order in both acetylene and sulfenyl halide. Phenylacetylene reacts at about 1/100 the rate of styrene and 3-hexyne at about 1/10 the rate of cyclohexene. The activation parameters for addition to phenylacetylene were found to be: E, = 24.3 f 1.3 kcal/ mole, AS* = -3.3 & 4 eu. Kharasch and Assong (326) found that 2,4-dinitrobenzenesulfenyl chloride reacts with acetylene only in the presence of aluminum chloride as catalyst, whereas 2-butyne reacts without catalysis and diethyl acetylene dicarboxylate does not react even with catalysis. These observations support an electrophilic mechanism for the addition. Additions in aprotic solvents are reported to follow a second-order rate law, but the reactions exhibit a number of unusual features (325). Addition of para-toluenesulfenyl chloride to tolane or 1-hexyne is faster in chloroform than in ethyl acetate. In chloroform as solvent, tolane and I-hexyne react at the same rate, but in ethyl acetate 1-hexyne reacts nearly 100 times as fast as tolane. Finally, for addition to tolane in chloroform as solvent, E, = 3.1 kcal/mol and AS* = -53 eu. These observations, plus the predominant anti-Markownikov addition in these solvents, are suggestive of a homolytic reaction, but other explanations are possible. The stereochemistry of the acetylene-sulfenyl halide adducts, although usually assumed to be trans, has been established in only a few cases. Truce and Boudakian (327) have shown that the adduct of paratoluenesulfenyl chloride with acetylene, obtained in ethyl acetate as solvent, has the trans configuration, and Montanari and Negrini (328a) have established the trans configuration for the adduct formed from benzenesulfenyl chloride and chloroacetylene in ethyl acetate.

HOAc PhH HOAc CHC13 EtOAc EtOAc CHC13 EtOAc EtOAc EtOAc

Solvent

R

-40

-80

Major Major <5

85

65

Major 20

-

\

c=c

/ c1

R'

/

\

R"S

* truns Addition has generally been assumed but not always proven for these additions.

CMeO-csH4 3-CI-CpH4 4-Cl-csH4

H Ph Ph Ph

4-Me-csH4 Et 4-Me-csH4 4-Me-CsH4 4-Me-CsH4

H

Et

n-Bu

2,4-Di-N02-C6H3 Ph 4-Me-CsH4

R"

H H H

R'

Ph Ph Ph

R

TABLE VII Orientation in Sulfenyl Halide Addition to Acetylenes"

R

/

\

c1

-

Minor -60

> 95

-

80 35 15

Major

\

c=c

R'

SR"

/

320 321 322 322 322 323 324 325 325 325

Ref.

P

W

ELECTROPHILLC ADDITIONS TO OLEFINS AND ACETYLENES v, 0

305

306

R. C. FAHEY

Recently, Schmid and Heinola (328b) have examined the addition of 2,4-dinitrobenzenesulfenylchloride to 1-phenylpropyne in chloroform. They found the reaction to be first order in each reactant and to yield a mixture of trans addition products corresponding to 94% attack by sulfur at the 2-position and 6y0 at the 1-position of 1-phenylpropyne. An episulfonium ion analogous to those proposed for addition to olefins was suggested as an intermediate. It seems probable that an electrophilic addition of sulfenyl halides to acetylenes does occur, but further studies of the kinetically controlled product orientation and stereochemistry, as well as additional rate data, are needed in order to establish the details of the reaction mechanism. IX. ELECTROPHILIC NITROGEN

A. Introduction Various inorganic reagents containing nitro or nitroso groups undergo addition reactions with olefins. These include Nz04,Nz05, NO,CI, NOCl, and AcONO,, but not all of these reagents react via polar mechanisms. That dinitrogen tetroxide, N,Or, reacts with olefins by a freeradical mechanism has been clearly demonstrated and the evidence has been reviewed by Shechter (329). Nitryl chloride, NO,Cl, adds to alkenes in the Markownikov sense, as would be expected from an electrophilic addition involving attack by NO: (330), but additions to RCHrCH2

+ NOaCl

RCHClCHaNOa

methyl acrylate (331) and to cyclohexene (332) have been found to give complex mixtures of products of the type expected from homolytic reactions (329). While it seems probable that nitryl chloride can undergo electrophilic addition to olefins, definite evidence for such a mechanism is not yet available. On the other hand, there is reasonable evidence that addition of dinitrogen pentoxide, acetyl nitrate, and nitrosyl chloride can occur by an electrophilic mechanism; these reactions are discussed separately in the following sections. B. Dinitrogen Pentoxide Stevens and Emmons (333) have studied the reaction of N,O, with a variety of alkenes in methylene chloride solution and find the reaction

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

307

to be rapid and exothermic. The reaction with propylene gives the 1,2adduct expected from Markownikov addition, along with substitution products. Addition of tetraethyl ammonium nitrate to the reaction CHaCH=CHZ

N205

CHzClz

CH3 \ CH-CHZNOZ

/

+ CI&CH=CHNOz

OZNO

+ CHz=CHCHzNOZ

mixture does not lower the rate of reaction or change the product composition, indicating that Nz05, rather than NO: is the effective nitrating agent. Similar results are obtained with other alkenes; camphene was found to give a rearranged product. The stereochemistry of addition has been studied with cis- and trans2-butene (333), cyclohexene (333), and cis- and trans-stilbene (334). In each case, the 1,2-adduct isolated was found to be the cis addition product. Stevens and Emmons (333) explained these results in terms of a concerted cis addition via a transition state such as 225. However, it is difficult to account for the substitution products in terms of a strictly

(225)

(226)

concerted process. An alternative explanation is that a tight ion pair (226) is formed as an intermediate; the ion pair could collapse preferentially to cis adduct or lose a proton to form substitution products. Further investigation of this reaction may serve to define the mechanism involved more clearly. C. Acetyl Nitrate Acetyl nitrate is a reagent frequently used to effect nitration of aromatic systems and it is therefore not surprising to find that it also nitrates olefins. The reaction of acetyl nitrate with a variety of olefins has been studied by Bordwell and Garbisch (335,336) and by Drefahl and coworkers (337,338).

R. C. FAHEY

308

Bordwell and Garbisch (335) find that acetyl nitrate, prepared from nitric acid and excess acetic anhydride, nitrates alkenes to yield a mixture of 8-nitro acetate, 8-nitro nitrate, and nitroalkenes. Qualitative observations indicate that electron-withdrawing substituents retard

OAc

I CH3-C-CHaNOz I

CH3

I

I + CHz=C-CHzNOz + CH34-CHzNOz I

CHs

65%

ON02 CH3

5%

4%

and electron-donating substituents accelerate the reaction; Markownikov addition of acetyl nitrate is found in all cases. Thus, the reaction appears to have electrophilic character. Protonated acetyl nitrate, AcOHNO:, is believed to be the effective nitrating agent, but N2O5 may also be important. The nature of the nitro alkenes formed provides an indication that a carbonium ion intermediate is involved. For the reaction of acetyl nitrate with cyclohexene, Griswald and Startcher (339) were able to demonstrate that 4-nitrocyclohexene was present in the product mixture [eq. (13)];similar results were found with cyclopentene.

The stereochemistry of the 8-nitro acetates has been determined in a number of cases and the results are summarized in Table VIII. Aside from serving as a source of nightmares for those who would attempt to provide a coherent description of these reactions, the results given in Table VIIl emphasize the danger of generalizing about the stereochemistry of a reaction from a limited number of observations. Bordwell et al. (335,336,340) have offered plausible explanations for some of the variations in the stereochemistry of addition. They consider

a

~

_

_

-

1oc 34" 20

-

20" 10"

5b

18b -

20-27" 18-26"

N02-alkene

&NO,-alkene Nitrated in the aryl group. Mixture of conjugated and unconjugated nitroalkenes. cis Isomer gives the same result as the trans isomer.

___

trans cis Ph(CZHs)C=CHCH3, trans cis 1-Phenylcyclohexene 1-Phenylcyclopentene Ph(p-Cl-CeH4)C=CHPhd

Ph(CHS)C=CHCH3

trans

PhCH=CHPh

trans cis

PhCHcCHCH3,

trans cis

CH3CH=CHCH3,

Olefin

Yield,

49 62 65 34 55-75

25 65

70

-

45-50

30-33 30-40

B-N02-OAc

yo

-

50

-

15 75 25

100

-

100

-

-

N

71 69

yo cis

-

100

100

-

50

75 100

85

25

--

-

29 31

yo trans

B-N02-OAc adduct

Addition of Acetyl Nitrate to Olefins

TABLE VIII

340 340 336c 336c 336b

340 340

336a,338

340,337 340

335, 340 335,340

Refs.

8

W

3

>

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

309

310

R. C. FAHEY

that nitration leads initially to a reactive carbonium ion intermediate (227) solvated specifically by the acetic acid molecule released by protonated acetyl nitrate. Collapse of this species before rotation about the C-C bond leads to cis adduct in an eclipsed conformation

I

(227)

cis addition R“= H

(14)

AcOH

AcO trans addition R” = alkyl

[eq. (14), step 11. This is presumed to be the course followed when R” = H and eclipsing of the C-Ph with a C-H bond is involved. If R” = alkyl, the unfavorable eclipsing of the C-Ph and C-R bonds causes collapse via step 1 to be unfavorable and 227 survives long enough to become solvated to 228; this intermediate then collapses preferentially to trans adduct in a staggered conformation (step 2). Loss of a proton from either 227 or 228 can lead to nitroalkene. The more stable cation formed from triarylethylenes is assumed to survive long enough for rotation to occur about the C-C bond so that eclipsing effects lose their importance and nonstereospecific addition results. The less stable cations, derived from the 2-butenes, collapse preferentially cis, even at the expense of eclipsing two C-CH3 bonds as is necessary in the addition to cis-Zbutene. This view of the reaction is necessarily speculative and leaves unexplained the preferential trans addition to 1-phenylcyclohexene and 1-phenylcyclopentene. In any case, it is clear that quite reactive cationic intermediates are formed in the reaction. The fact that aromatic nitration competes with addition shows that a very reactive source of NO,+ is present in the

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

31 1

reaction mixture and it seems probable from the variety of products formed that more than one nitrating agent is involved.

D. Nitrosyl Halides There is an extensive literature on the reaction of nitrosyl chloride with olefins (341,342) [eq. (15)]. The reaction gives 1 :I adducts characterized by their blue color, but in some cases these form colorless dimers or, if the nitroso group has a labile u-hydrogen, isomerize to the oxime. The addition follows the Markownikov rule, nitrosyl chloride being considered to be polarized in the sense NOfC1-.

\

/

C=C

NOCl \ 1 + CCI-CNO \ /

/

+

I' -L

\ I CC1-C=NOH /

(15 )

The reaction has been studied very little from a mechanistic point of view, but Beier, Hauthal, and Pritzkow (343) have examined the kinetics and rates of reaction for a variety of olefins. They find the rate to be first order in both olefin and nitrosyl chloride. The effect of structure on k , is very similar to that found for epoxidation of olefins; relative rates for addition of NOCl to substituted ethylenes in chloroform increase in the order Relative rate =

RCH=CH2 1

RZCH=CHp 20

RCH=CHR 20-30

R2C=CHR > 600

However, trans-stilbene reacts nearly five times as fast as cis-stilbene, whereas for epoxidation the cis isomer reacts faster by a factor of 2. For addition to styrene in chloroform, AH* = 8.1 kcal/mole and AS* = - 43 eu; similar activation parameters were found with cyclohexene. The effect of solvent on the rate of reaction as measured with cyclohexene (343) is illustrated by the relative rates EtzO 0.1

CClr 0.7

n-C,Hls 1

PhCN 7

PhNOz 10

CHCI, 15

The rate tends to increase with the polarity of the solvent but the effect is not as large as for other electrophilic additions and the rate in diethyl ether is unusually low. Surprisingly, aluminum chloride does not accelerate the reaction.

312

R. C. FAHEY

The stereochemistry of NOCl additions has not been widely studied and many of the available results present a confusing picture. Thus, cyclohexene reacts with nitrosyl chloride in liquid sulfur dioxide to give a 60-8070 yield of the trans adduct, but in methylene chloride, chloroform, or trichloroethylene a 10-2470 yield of the cis addition product is obtained (344). In both cases the product was isolated as the dimer. With Ag-octalin (229) nitrosyl chloride forms the trans adduct (230) (345). NO

Cholesteryl acetate (231) forms a nitro chloride (232) with nitrosyl chloride in nonpolar solvents (346), possibly via the NOCl adduct as an intermediate, but it has been noted (346c) that the reaction is slower if

(231)

(232)

the NOCl is purified and that it is accelerated by the presence of NO2. This suggests that a free-radical reaction is involved. The addition of NOCl to tri-~-acetyl-o-glucal (233) (347) and related compounds (347a) in carbon tetrachloride or other nonpolar solvents gives high yields of cis adduct (234). A free-radical mechanism was suggested for these reactions (347a). CH,OAc

$F>NOC?

AcO

CH,OAc

Aco@c,

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

313

Somewhat more is known about the stereochemistry of nitrosyl halide additions to bicyclic systems, mainly from the studies of Meinwald and co-workers (345). They find that nitrosyl chloride and nitrosyl bromide add to norbornene to give 65 and 807,, respectively, of the cis-exo adduct (235) isolated as the dimer. A 55-757, yield of the corresponding adduct (236) was obtained from norbornadiene with NOCl. No rearranged or cyclized products were found, although in small amounts these might have escaped detection. The endo acid 237, which

COOH

(238)

0

o+C-

(239)

reacts with halogens to produce lactones by participation of the carboxyl group, adds NOCl to give 238; less than 10% of 239 could have been formed in the reaction. Zefirov et al. (348) have obtained similar results with 240 which forms 241 with NOCl.

The dominant cis-exo addition in these systems and the minimal importance of cyclization or rearrangement led Meinwald to postulate a molecular addition via a transition state resembling 242 for these

R. C. FAHEY

314

reactions (345). The slower reaction of cis- than of trans-olefins, in both monocyclic (349) and acyclic (343) systems is consistent with a molecular cis addition. While this mechanism accommodates the results for addition to norbornenes, addition by a free-radical mechanism cannot be entirely ruled out. It has already been noted that other NOCl additions appear to involve homolytic mechanisms and it is known that radical additions to norbornene can give substantial amounts of cis-exo adduct (cf. 329b). It is evident that a fully coherent description of the mechanism and stereochemistry of polar NOCl additions to olefins cannot be derived from the data at hand. Acetylenes also react with NOCI, but the reaction appears to be slower than that of olefins and has received very little attention (341,350).

X. MERCURIC SALTS A. Addition to Olefins Mercuric acetate and related mercuric salts readily add to olefins in the Markownikov sense to yield 1:1 adducts (243) which are often isolated as the halomercurial (244). In hydroxylic media, the solvent R H

RCH=CHz

R H

I I + Hg(OAC2) --f ACO-C-C-HgOAC 1 1

NaX

I 1

I 1

+AcO--C--C-HgX

H H (243)

H H (244)

can take part in the reaction [eq. (16)]. The oxymercuration of olefins was discovered by Hofmann and Sand (351) in 1900, and since then an extensive literature has accumulated referring to this reaction. The R H

RCH=CHZ

I 1 + H20 + Hg+’ + HO-C-C-Hg+

I

I

+ H+

(16)

H H

earlier studies have been summarized by Chatt (352), and Zefirov (353) has recently reviewed the stereochemistry of the reaction. The oxymercuration reaction is of considerable synthetic interest because it is rapid and gives high yields of unrearranged adducts which can be converted to other compounds by replacement of the HgX

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

315

group. Thus, Sand and Singer (354) found that the 1 :1 adducts could be demercurated to the alcohol by sodium amalgam. A more convenient reduction is achieved through the use of sodium borohydride (355);

I

-

I

NaBH4

HO-C-C-HgX

I 1

I I

HO-C-C-H

I I

Bordwell and Douglass (356a) have demonstrated the synthetic utility of this reaction in the preparation of alcohols and Brown et al. (356b356d) have extended and refined the oxymercuration-demercuration reaction sequence for alcohol synthesis. The oxymercuration reaction is reversed in the presence of hydrogen halides and the rates and kinetics of both oxymercuration and deoxymercuration have been investigated. The deoxymercuration reaction has been extensively studied by Kreevoy and co-workers (357), who have shown that the rate is first order in both mercurial and acid, and that the slow step involves heterolytic C-0 bond cleavage; the values of log k2 for deoxymercuration of RCH(OCH3)CH2HgI vary linearly with

-

I I I I + slow \ / + H+ XHg-C-C-OR C=C I / I I H / \ u* for R = XCHz and p* = - 2.77 (357d). A related study of the deoxymercuration rates of ArCHOEtCH,HgCl (Ar = substituted phenyl) gave p = -2.93 (358). The effect of alkyl substitution on the rate of deoxymercuration is illustrated by the relative rates of elimination from the olefin adducts (358). XHg-C-C-OR

HgCl

H $H OEt Relative rate = 1

HgCl

H3C#H

HgCl

H3C#H

OEt 14

OEt 1560

HgCl

H3C#cH3 OEt 86

It is of interest to compare these results with those obtained from studies of the oxymercuration reaction. A number of kinetic studies (352,359-361) show that the rate is first order in olefin and first order in mercuric salt. Especially informative is the recent study by Halpern and

R. C. FAHEY

316

Tinker (361) of the oxymercuration of olefins by Hg2+ in water. They find for substituted ethylenes, XCH:=CH2, that log k, correlates with UX and p* = - 3.3. However, I-pentene-5-01 (245) reacted much faster than predicted by the correlation, and the product was the cyclic ether (246), showing that the reaction occurs with neighboring-group

(249

(245)

participation, The relative rates for addition to ethylene vary with methyl substitution in the order

20

1

Relative rate =

>200

0.3

1

Addition of Hg(OAc), to olefins in methanol also follows secondorder kinetics, first order in each reactant, and it has been shown that the reaction is accelerated by strong acids and retarded by sodium acetate (362). These results indicate that an initial equilibrium of the type shown in eq. (17) or (18) is involved. The relative rates for Hg(OAc), Hg(0Ac)Z = ACOHg+

+ AcO-

+ Hg(OAc)z = (olefin-HgOAc)+ + AcO-

olefin

(17) (18)

addition to isomeric hexenes in methanol have been determined by Doring and Hauthal (363) to be n-Bu

Et

L

L

Et 18

Relative rate =

Et

1

142

u

Et

Relative rate =

Et

1.5

6

0.05

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

3 17

and similar patterns are observed with other alkenes (364). These results show that alkyl substitution at the carbon which forms the C-0 bond accelerates the reaction, but that substitution at the carbon which forms the C-Hg bond slows the reaction. It should be emphasized that this variation in reactivity with alkyl substitution is substantially different from that found for any of the other electrophilic additions considered here. The only reactions which show a pattern of reactivity even vaguely similar are acid additions to olefins (Sect. 11-A). Oxymercuration and deoxymercuration in most acyclic and monocyclic olefin systems are stereospecific trans processes. Much of the earlier work, reporting cis stereochemistry for oxymercuration reactions, has been proven incorrect. The review by Zefirov (353) discusses the earlier errors in assignment of configuration, and only the more recent results will be presented here. That cyclohexene undergoes oxymercuration in a stereospecific trans fashion has been demonstrated by X-ray (365), NMR (53,366), and IR (355c) studies of the adduct formed. Consistent with this is the fact that the trans adduct (247) undergoes deoxymercuration 105-107 times as fast as the cis adduct (248) (357b). The hydroxymercurials obtained

OCH, (247)

H

(24)

from cyclobutene, cyclopentene, cycloheptene, and cis-cyclooctene have also been shown by Traylor and Factor (367a) to have the trans configuration. However, the oxymercuration of trans-cyclooctene, where attack at one side of the double bond is severely hindered, occurs by cis addition (367). The configuration of the adducts obtained from acyclic olefins has been assigned on the basis of the stereospecificity of elimination; the adduct from cis alkene regenerates cis alkene upon deoxymercuration. This has been demonstrated for the 2-butenes (357c) and the stilbenes (368). A more direct demonstration of the stereochemistry and a more quantitative estimate of the stereospecificity for addition to acyclic olefins are desirable, but the predominant trans stereospecificity of these reactions is satisfactorily established.

318

R. C. FAHEY

For these systems, the kinetic, rate, and stereochemical results support an AdE3 trans addition mechanism. The transition state for the reaction is represented by 249. Substituents at the C-0 carbon affect the rate of reaction by interacting with the net positive charge at this

H

position. The retarding effect of alkyl substitution at the C-Hg carbon probably results from two factors: ( I ) increased steric crowding at this position, and (2) the decrease in bond energy in going from sp2 to sp3 hybridized carbon being larger for a C-H bond than for a C-C bond (369). Lucas, Hepner, and Winstein (370) proposed in 1939 that oxymercuration proceeds via a mercurinium ion (250) as an intermediate and most subsequent studies have included such a species in the mechanistic formulation of the reaction. There is very little concrete evidence for the existence of such mercurinium ions, although recent NMR studies

(371) have provided preliminary evidence for such species. The mercurinium ion may be assumed to be reversibly formed from the olefin and the mercuric salt, possibly in the equilibrium of eq. (18), but there is at present no evidence which demands that this be so. In any case, the variation of reaction rate with alkyl substitution shows that the transition state for the reaction does not closely resemble 250.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

319

I t is also clear that an open carbonium ion (251) is not involved along the reaction path, since, if such a species were reversibly formed from either the olefin or the I ,2-adduct, the oxymercuration-deoxymercuration process could not occur with complete stereospecificity. The steric direction of attack by the mercuric salts can be influenced by substituents as Henbest et al. (372) have shown. They find that while 252 gives only 253 (372a), the 4-substituted cyclohexenes (254) give 255 (372b). In the latter case, it is presumed (372) that the substituents

A (255) X = OH, OCH,, CH,OH, CN

(254)

can serve as ligands for mercuric ion and thus stabilize the transition state for attack cis to the substituent. The oxymercuration of (-)-I ,3-dimethylallene has been shown by Waters and Caserio (373) to give (-)-256 by trans addition, the absolute configurations being established as shown. The reaction also gives some 257 and the ratio of 256 to 257 is about 4:l (374). The preferential H

4

c=c-c

CH3 ClHg H ‘‘\ C

\

/’

\

CHJ Hg(0Ac)z

MeOH

H ClHg

/CH3 C C

’

‘I OCH,

H ‘

NaCl

>+

+

\

/c=c\

CHj(OCH3)CH

CH3

( - 14256)

/

(257)

H

CH3

R. C. FAHEY

320

formation of 256 can be understood in terms of the steric requirements of the transition state. It is reasonable to expect that the steric interaction of the CH, and the HgOAc groups is relatively less important in the transition state (258) leading to 256 than is the interaction between the CH3 and OCH3 groups in the transition state (259) leading to 257 (374). AcOHg

f3

CH,

AcOHg

‘.,

1

‘,:

%=C #Y /

H----CS +

/

H3c

*’.

;c-C

2

H3C----C S+

H

/

H

OCH,

H

(25s)

**.

/”

\

fH3

0CH3 H

(259)

The oxymercuration of bicyclic olefins often follows a different stereochemical course from that of monocyclic and acyclic olefins. Thus, Traylor and Baker (355c,375) have shown that norbornene oxymercurates entirely cis-ex0 and that no rearrangement accompanies

A

Hg(OAc), cH,oH > NaCl

+

&:zH3

addition. The oxymercuration of bicyclo[2.2.2]octene gives a mixture of the cis (260) and trans adducts (261) when the reaction is carried out

(W @%

HO (261)

w%

in aqueous acetone, but, if the same reaction is repeated in the presence of 0.14M NaOAc, 75y0 of the product is 262, the remainder being 261 (375). I n acetic acid, 262 is the sole product of reaction. As Traylor (376a) has pointed out, the usual trans addition mechanism is disfavored for these bicyclic systems because the required trans coplanar arrangement of atoms can be achieved only at the expense of

*

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

321

OAc

bond angle strain in the ring. This situation is further worsened in the case of norbornene because the endo 4,5-protons hinder endo attack at the double bond. Molecular cis addition, however, is favored in these systems, since a cis coplanar arrangement of atoms is readily achieved. The fact that the cis-acetate (262) and the trans-alcohol (261) are formed from bicyclo[2.2.2]octene in the presence of sodium acetate indicates that the acetate ion completing the addition was bonded to the mercuric ion initiating the attack. Thus, the mechanism leading to cis adduct can be described as a molecular cis addition proceeding via a transition state resembling 263 (376a).

(263)

Consistent with this view is the observation by Bond (376b) that bicyclo[2.1. llhexene, an even more strained ring system than norbornene, undergoes cis addition of mercuric acetate at over 100 times the rate of norbornene. Here steric arguments cannot be invoked to explain cis addition, and the importance of bond ang!e strain is evident. The fact that 1,4,7,7-tetramethylnorbornene(264) oxymercurates cisexo without accompanying rearrangement (377) might be considered as

v

-A 0

t

V

HgOAc Ac

R. C. FAHEY

322

evidence against a molecular cis addition, since the syn-7-methyl group should destabilize the transition state for this process. The argument is not compelling, however, since inspection of models indicates that the six-center cyclic transition state (265) is not obviously more unfavorable than the transition state for endo attack. It is much more difficult to understand why apobornylene (266) undergoes oxymercuration-demercuration to give only the ex0 alcohol (267) (356d). If this

reaction were to occur by a molecular cis addition mechanism, a fourcenter cyclic transition state (268) is required and this would seem to suffer serious steric hindrance from the 7-methyl group. On the other hand, if an AdE3 cis addition mechanism proceeding via a transition

(268)

(269)

state resembling 269 were involved, the effect of the syn-7-methyl group might be less serious. Since the water molecule is not bound to the mercuric ion, both species can assume orientations in the transition state which minimize steric interactions. There appears to be no precedent for a termolecular cis addition of this type, but norbornene derivatives are especially suited for such cis additions and this mechanism, if not common, is at least plausible. It was noted earlier that hydrogen chloride attacks the double bond of apobornylene from the ex0 direction (Sect. II-A4), but that epoxidation occurs mainly endo (Sect. VII). The oxymercuration of other norbornene derivatives follows a similar course. Norbornadiene oxymercurates cis-ex0 without accompanying rearrangement or conjugate addition, although secondary rearrangement of the primary adduct does lead to the 1,5-adduct expected from con-

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

323

jugate addition (378). Both endo- (35%) and exo-dicyclopentadiene (379) add mercuric salts cis-exo at the 5,6-double bond. Other examples are given by Zefirov (353). In each case the stereochemistry is consistent with a molecular cis addition, although an A d ~ cis 3 addition mechanism explains the results equally well when the reaction involves participation by the solvent. However, not all oxymercurations of norbornene derivatives occur by cis-ex0 addition. If a substituent capable of serving as a neighboring group is present in the molecule, trans addition can occur. Thus, the endo acid (270) (372a) and its methyl ester (380) oxymercurate to yield

6

(270)

(271)

4

the lactone (271) and 272 oxymercurates to the ether (273) (372a,380). Bly and Bly (381) have found that 274 gives a cyclic ether upon oxy-

CH,OH

(272)

&a

&OH

HgCl

CH2-0

(273)

(274)

(275)

niercuration and the structure has been assigned as 275 based on NMR studies by Factor and Traylor (380). In each of these examples the neighboring group is properly oriented to serve as the nucleophile for attack on the double bond and the trans addition mechanism discussed for acyclic and monocyclic systems becomes favored. In effect, these additions involve an internal AdE3-typetrans addition mechanism; the addition to 272 can be described as proceeding via a transition state such as 276. The remarkable feature of the oxymercuration of olefins is that the reaction has almost all of the usual features of an electrophilic addition but that structural rearrangement, substitution, and conjugate addition

R. C. FAHEY

324

hHgX x\

X

I

/x

.

He

f

CH,-O\

! s+

(276)

\c:.._..____. ' %, / \&* C / \ / ~

H

y3

+.*' / _._...-. c\ ,**'

(277)

(278)

do not accompany the reaction-the process is strictly a 1,Zaddition. None of the available results require the intermediacy of either a mercury-olefin complex (277) or a mercurinium ion (278) in the oxymercuration of olefins, but if such species are involved then they must be reversibly formed from olefin and mercuric salt and they must be quite stable toward rearrangement.

B. Addition to Acetylenes It is well known that mercuric salts catalyze the addition of water, alcohols, and carboxylic acids to acetylenes. In 1936, Hennion, Vogt, and Nieuwland (382) proposed that these reactions proceed via intermediate mercury adducts. The intermediate can be isolated under RCrCR

+ R'OH

H6Aa

__f

HA

+HA

RC(OR')=C(HgA)R

RC(OR')=CHR

(R'-H)

RCOCHaR

appropriate conditions. Nesmeyanov (383) has found that a quantitative yield of the trans adduct (279) can be obtained when acetylene is allowed to react with HgClz in aqueous hydrogen chloride. Thus acetylenes will add mercuric chloride, whereas olefins will not. The HCECH

+ HgCla

ClHg HCI

---f

Hao

H

\ c=c/ /

H

(279)

chemistry of vinyl mercurials has been extensively investigated by Nesmeyanov and his co-workers and many of their papers have been collected in a single volume, available in English translation (384). The kinetics and rates of acetylene oxymercuration have not been studied in detail and any discussion of the mechanism of reaction is, therefore, necessarily speculative. Lemaire and Lucas (385) have studied

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

325

the reaction of 3-hexyne with H ~ ( O A Cin ) ~acetic acid containing perchloric acid. Upon mixing the reagents they noted a sharp drop in acidity while the unsaturation, measured by bromine titration, decreased at a slower rate. They proposed that the reaction involved rapid reversible complex formation, followed by a slow conversion to product. It was RCrCR

+ H + + Hg(0Ac)z (RC-CR

(RC-CR

*

HgOAc)+

+ HOAC

slow

HgOAc)+ + product

suggested that the complex has the mercurinium ion structure (280).

,

Ia

,’

,

,.HgOAc

...* +._--.

.

cL.--*

/

-C

(280)

Evidence for an analogous intermediate in the mercuric ion catalyzed hydration of acetylene has been reported by Tempkin, Flid, and Malakhov (386). Budde and Dessey (387) have examined the mercuric ion catalyzed reaction of acetylenes in aqueous dioxane-perchloric acid solutions. Based on product yield and spectral observations, they postulate a 2 :1 acetylene-mercuric ion intermediate in the reaction, but the structure of this species is uncertain. The stereochemistry of mercuric salt additions to acetylenes has not been thoroughly studied. The trans addition of HgC12to acetylene has already been mentioned. It has been shown that 2-butyne adds Hg(OAc)2 in acetic acid at room temperature to give the trans adduct (281) in 70y0 yield, but at higher temperatures 282, 2.83, and 284 are also formed

(388). The addition of Hg(OAc), to tolane in acetic acid gives the cis adduct (389). Some acetylenic alcohols form cyclic ethers with mercuric PhC-CPh

Hg(0Ac)a

NaCl

Ph

+

\ c=c /Ph

/

ClHg

\

OAc

R. C. FAHEY

326

salts by a process which involves trans addition. Thus, 285 gives 286 by an addition-elimination sequence (390).

P"

CH3-C -C =C-Ph

I

CH3- ?-OH

HgCI; EtOH'

Me

From these limited observations it appears probable that mercuric salts add to acetylenes by mechanisms analogous to those described for olefins, but further kinetic and stereochemical results are necessary before a detailed description can be given.

XI. SOME COMMENTS AND CONCLUSIONS

In the preceding sections, the stereochemistry and mechanism of the more important electrophilic addition reactions have been discussed. The coverage, in most cases, has been illustrative rather than comprehensive. While numerous questions about the stereochemistry of addition or the mechanism of reaction involved with specific electrophiles or substrates are as yet unanswered, some general trends emerge from the available results and are worth noting here. Of the possible limiting mechanisms for electrophilic addition outlined in Section I, the AdE2 mechanism has been the one most often encountered. Depending upon the electrophile and the substrate structure, the intermediate cation can have either an open or a bridged ion structure. In the absence of special effects, stereospecific trans addition implies a bridged structure for the intermediate, whereas nonstereospecific addition or preferential cis addition indicates that an open cation is involved. On this basis the nature of the intermediate cation involved in various electrophilic additions can be assigned as in Table IX. With the exception of addition of acids, for which only results on additions to cyclohexenes are available, and fluorination, for which the data are incomplete, a bridged ion is the intermediate in addition to nonconjugated olefins. Addition to arenes, however, involves open ions unless the electrophile involves an especially effective neighboring-group atom. The balance between open and bridged ions appears to be about even for bromine addition to arenes.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

TABLEIX

327

Nature of the Intermediate in AdE2 Additions" Olefin type X+

Arenes

Nonconjugated alkenes

H+ F+ c1+

0 0 0 0,€3 B

0, B(?)

Br + RS I+

+

?

B B B B

B

* 0, open cation; B, bridged cation.

As has been noted before (235,355c), a similar trend can be seen in the products of addition to norbornene. From the results summarized in Table X, we see that the amount of 1,2-trans adduct formed in the reaction increases with increasing capacity of the electrophile to serve as a neighboring group. Throughout this review the ratio of rearranged product to 1,Ztrans adduct has been discussed in terms of a competition between the onium ion (287) and a nonclassical norbornyl cation (288), but the rearranged products might also be rationalized in terms of classical TABLEX

Products of Addition to Norbornene X

XY DCI Clz

Y

Refs.

69 136 Brz 234 ArSCl 316-318

6 16

287

60 3.5 -

-

34 25.5

65

-

< 13

57

27

6 -

-

328

R. C. FAHEY

norbornyl cations. The focal point for discussion of this point has most recently been the addition of acids to norbornenes (Sect. 11-A-4). While acetylenes and olefins add acids by an A d ~ 2mechanism at comparable rates, it has been noted that halogen and sulfenyl halide additions to acetylenes are slower than to the corresponding olefins. This has been attributed to the fact that acetyleneshave higher ionization potentials than olefins (113a) and to ring strain in the cyclic cation (289) (391). Another factor which may be important was called to the

author’s attention by Professor C.L. Perrin; namely, for those reagents which react more slowly with acetylenes than with olefins, the T system in 289 has the unfavorable four-election configuration analogous to that in the cyclopropenyl anion. To the extent that this destabilizes 289, addition to acetylenes via an AdE2 bridged-ion mechanism will be less favorable than addition to olefins by the same mechanism. However, the m system in the open cation (290) has the more favorable configuration analogous to that of the ally1 anion, so that, if the melectron configuration is the deciding factor, addition via an open cation should not be less favorable for acetylenes than for olefins. A comparison of rate data for the nonstereospecific addition of halogen to arenes and the corresponding arynes would allow a test of this prediction, but appropriate data are not yet available. A number of examples of additions proceeding via an A d ~ 3fruns addition mechanism have been noted. The oxymercuration of acyclic and monocyclic olefins appears to occur exclusively by this type of mechanism, while A d ~ 3trans addition of hydrogen halides to cyclohexene and acetylenes can compete with addition via the AdE2 mechanism. In these examples, rapid reversible formation of a mercurinium or protonium ion may precede formation of the transition state, but

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

329

this is still open to question. Tentative evidence for an AdE3 mechanism has been obtained for bromine addition to unreactive olefins and iodine addition to acetylene. Addition by an Ad,3 mechanism can only be clearly demonstrated through a combination of rate and product studies, and since there have been only limited attempts to find or demonstrate this type of mechanism, it is not entirely surprising that so few examples are known. The Ad,3 cis addition mechanism is likely to be quite rare, although its possible intervention in the oxymercuration of norbornenes has been noted (Sect. V-A). Examples of reactions involving molecular cis addition of electrophilic reagents are also rather rare. Epoxidation of olefins involves this type of mechanism but represents a rather special case. Molecular cis addition should be most favored for additions to strained bicyclic systems and the results for addition of acids and nitrosyl chloride to such systems have been interpreted in terms of such a mechanism. The best example of a molecular cis addition mechanism involving an electrophilic reagent is probably the clean cis-exo addition of mercuric acetate to norbornene where a six-center cyclic transition state is involved. In order to define clearly the mechanism of a given electrophilic addition, it is necessary to know the kinetics, the rates, and the stereochemistry of addition to a variety of olefins under a given set of reaction conditions. For many of the electrophilic additions discussed here, and especially for those involving additions to acetylenes, there exist substantial gaps or deficiencies in the available experimental results. To the extent that this is so, our mechanistic view of the reaction has been necessarily incomplete or speculative, and further studies are needed to complete our understanding of the reaction. It is hoped that this review has served not only to summarize what is known about the stereochemistry and mechanism of electrophilic additions, but also to help point out those areas where further investigation would be most useful.

Acknowledgments 1 wish to express my gratitude to all of the authors who provided manuscripts prior to publication, and to thank Professors F. G. Bordwell, S. J. Cristol, E. L. Eliel, C. L. Perrin, P. E. Peterson, T. G . Traylor, W. R. Vaughan, W. L. Waters, and Dr. M. L. Poutsrna for valuable discussions and suggestions. I am also indebted to the Alfred P. SIoan Foundation, whose support aided the preparation of this review, and to Mrs. Dorothy Prior for her patience and care in preparing the manuscript.

330

R. C. FAHEY

References 1. P. F. Frankland, J. Chem. SOC.,101, 654 (1912). 2. S. W. Benson and A. N. Bose, J . Chem. Phys., 39,3463 (1963); S . W. Benson and G. R. Haugen, J. Am. Chem. SOC.,87,4036 (1965). 3. A. W. Francis, J. Am. Chem. SOC.,47, 2340 (1925). 4. R. Robinson, Outline of an Electronic Theory of the Course of Organic Reactions, Institute of Chemistry of Great Britain and Ireland, London, 1932. 5 . C. K. Ingold, Chem. Reo., 15, 225 (1934). 6. F. C. Whitmore and F. Johnston,J. Am. Chem. SOC.,55, 5020 (1933). 7. P. D. Bartlett and D. S. Tarbell, J. Am. Chem. SOC.,58,466 (1936). 8. C. K. Ingold, Structure and Mechanism in Organic Chemistry, Cornell University Press, ithaca, New York, 1953. 9. R. A. Ogg, Jr., J. Am. Chem. SOC.,57, 2727 (1935). 10. M. J. S. Dewar and R. C. Fahey, J. Am. Chem. SOC.,85,2248 (1963). 11. I. Roberts and G. E. Kimball, J. Am. Chem. SOC.,59, 947 (1937). 12. (a) M. J. S. Dewar, J. Chem. SOC.,1946,406; (b) M. J. S. Dewar and A. P. Marchand, Ann. Reu. Phys. Chern., 16, 321 (1965). 13. L. J. Andrews and R. M. Keefer, Molecular Complexes in Organic Chemistry, Holden-Day, San Francisco, 1964. 14. P. B. D. de la Mare and R. Bolton, Electrophilic Atfditions to Unsaturated Systems, Elsevier, New York, 1966. 15. 0. Maass and C. H. Wright, J. Am. Chem. SOC.,46,2664 (1924). 16. D. Cook, Y. Lupien and W. G . Schneider, Can. J. Chern., 34,957 (1956). 17. H. C. Brown and J. D. Brady, J. Am. Chem. SOC.,74,3570 (1952). 18. A. J. Streitwieser, Jr., in Progress in Physical Organic Chemistry, Vol. I , S. J. Cohen, A. Streitwieser, Jr., and R. W. Taft, Eds., Interscience, New York, 1963, p. 1. 19. J. B. Conn, G. R. Kistiakowsky, and E. A. Smith, J. Am. Chern. SOC.,60, 2764 (1938). 20. D. V. Banthorpe, Elimination Reactions, Elsevier, New York, 1963. 21. F. R. Mayo and C. Walling, Chem. Reo., 27, 351 (1940). 22. C. Walling, Free Radicals in Solution, Wiley, New York, 1957, Chap. 7. 23. W. A. Pryor, Free Radicals, McGraw-Hill, New York, 1966, p. 206 ff. 24. Ref. 14, Chap. 3. 25. R. H. Boyd, R. W. Taft, Jr., A. P. Wolf, and D. R. Christman, J. Am. Chem. SOC.,82,4729 (1960). 26. J. Manassen and F. S. Klein, J. Chem. SOC.,1960,4203. 27. B. T. Baliga and E. Whalley, Can. J. Chem., 42, 1019 (1964). 28. V. Gold and M. A. Kessick, J. Chem. SOC.,1965, 6718. 29. J. P. Durand, M. Davidson, M. Hellin, and F. Coussemant, Bull. Soc. Chim. France, 1966, 43, 52. 30. F. G. Ciapetta and M. Kilpatrick, J. Am. Chem. SOC.,70,639 (1948). 31. W. M. Schubert, B. Lamm, and J. R. Keeffe, J. Am. Chem. SOC.,86, 4727 (1964). 32. A. G. Evans and J. Halpern, Trans. Faraday SOC.,48, 1034 (1952). 33. Ref. 14, Chap. 4.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

331

34. M. Mollard, B. Torck, M. Hellin, and F. Coussemant, Bull. SOC.Chim. France, 1966, 83, 1186. 35. F. R. Mayo and J. J. Katz, J. Am. Chem. SOC., 69, 1339 (1947). 36. F. R. Mayo and M. G. Savoy, J. A m . Chem. SOC.,69,1348 (1947). 37. Y. Pocker, J. Chem. Soc., 1960, 1292. 38. Y. Pocker, Abstracts, 148th National Meeting, American Chemical Society, Chicago, September, 1964, p. 235. 39. I. V. Smirnov-Zamkov and G. A. Piskovitina, Ukr. Khim. Zh., 28,531 (1962). 40. W. C. Deno, F. A. Kish, and H. J. Peterson, J. Am. Chem. SOC.,87, 2157 (1965). 41. P. E. Peterson and G. Allen,J. Am. Chem. Soc., 85,3608 (1963). 42. P. E. Peterson, C. Casey, E. V. P. Tao, A. Agtarap, and G. Thompson, J . Am. Chem. Soc., 87, 5163 (1965). 43. Ref. 14, Chap. 5. 44. J. A. Berson, "Carbonium Ion Rearrangements in Bridged Bicyclic Systems," in Molecular Rearrungement.7, Vol. 1, Part 2, P. de Mayo, Ed., Interscience, New York, 1963, p. I 1 1. 45. E. L. Purlee and R. W. Taft, Jr., J. Am. Chem. SOC., 78, 5807 (1956). 46. W. M. Schubert and B. Lamm, J . Am. Chem. SOC.,88, 120 (1966). 85,2245 (1963). 47. M. J. S. Dewar and R. C. Fahey, J. Am. Chem. SOC., 48. M. J. S. Dewar and R. C. Fahey,J. Am. Chem. Soc., 85,3645 (1963). 49. M. J. S. Dewar and R. C. Fahey, Angew. Chem., 76,321 (1964); Angew Chem. Intern. Ed. (Etigl.), 3,245 (1964). SO. G. S. Hamniond and J. Warkentin,J. Am. Chem. SOC., 83,2554 (1961). 5 1. K. Fukui, Tetrahedron Letters, 1965, 2427. 52. C. H. Collins and G. S. Hammond, J. Org. Chem., 25,911 (1960). 53. S. Wolfe and P. G. C. Campbell, Can. J . Chem., 43, 1184 (1965). 54. G. S. Hammond and T. D. Nevitt,J. Am. Chem. SOC.,76,4121 (1954). 82,4323 (1960). 55. G . S. Hammond and C. H. Collins, J. Am. Chem. SOC., 56. R. C. Fahey and R. A. Smith, J. Am. Chern. Soc., 86, 5035 (1964). 57. S. Wolfe and P. G. C. Campbell, private communication. 58. R. C. Fahey and M. Monahan, Chem. Commun., 1967,936. 59. R. C. Fahey and M. Monahan, unpublished results. 60. S. Winstein and D. S. Trifan, J. Am. Chenz. Soc., 71,2953 (1949). 61. P. D. Bartlett, Non-Classical lons, Benjamin, New York, 1965. 62. S. J. Cristol, W. K. Seifert, D. W. Johnson, and J. B. Jurale, J. Am. Chem. Soc., 84, 3918 (1962). 63. S. J . Cristol and E. F. Hoegger, J. Am. Cheni. Soc., 79,3438 (1957). 64. N. A. LeBel, P. D. Beirne, E. R. Karger, J. C. Powers, and P. M. Subramanian, J. Am. Chem. SOC., 85, 3199 (1963). 65. J. K. Stille, F. M. Sonnenberg, and T. H. Kinstle, J. Am. Chem. SOC., 88, 4922 ( I 966). 66. S. J. Cristol, L. K. Gaston, and D. W. Johnson, Tetrahedron Letters, 1963, 185. 67. S. J. Cristol and G. C. Fusco, J . Org. Chem., 32, 106 (1968). 86, 2601 (1964). 68. H. Kwart and J. L. Nyce, J. A m . Chem. SOC., 69. H. C. Brown and K.-T. Liu, J. Am. Chern. SOC., 89, 3900 (1967).

332 70. 71. 72. 73.

R. C. FAHEY H. C. Brown and K.-T. Liu, J. Am. Chem. Soc., 89, 3898 (1967). H. C. Brown and K.-T. Liu, J. Am. Chem. Soc., 89, 466 (1967). S. J. Cristol and R. Caple, J. Org. Chem., 31, 2741 (1966). S. J. Cristol, T. C. Morrill, and R. A. Sanchez, J. Org. Chem., 31, 2719

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107. G. L. Hekkert and W. Drenth, Rec. Trav. Chim., 82,405 (1963). 108. H. G. Richey and J. M. Richey, in Carbonium Ions, Vol. 2, G. A. Olah, and

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ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

337

246. E. A. Shilov and I. V. Smirnov-Zamkov, Izu. Akad. Nauk SSSR, Otdel. Khinz. Nauk, 1951, 32. 247. R. J. Cvetanovic, F. J. Duncan, W. E. Falconer, and W. A. Sunder, J. Am. Chern. Soc., 88, 1602 (1966). 248. J. G . Traynham and J. R. Olechowski, J. Am. Chem. Soc., 81, 571 (1959). 249. S. Freed and K. M. Sancier, J. Am. Chern. Soc., 74, 1273 (1952). 250. G. S. Forbes and A. F. Nelson, J . Am. Chem. SOC.,59, 693 (1937). 251. J. C. Ghosh and S. K. Bhattacharyya, Sci. Cirlt. (Cdcrctta), 3, 120 (1937). 252. D. S. Trifan and P. D. Bartlett, J. Am. Chem. SOC.,81, 5573 (1959). 253. G. Fraenkel and P. D. Bart1ett.J. Anz. Chern. Soc., 81, 5582 (1959). 254. P. S. Skell and R. R. Pavlis, J. Am. Chern. Soc., 86, 2956 (1964). 255. M. K. Eberhardt, Te/rahet/ron, 21, 1383, 1391 (1965). 256. S. W. Benson and A. Arnano. J. Chenz. Phys., 36, 3464 (1962). 257. S. I. Miller and R. M. Noyes,J. Am. Chem. Soc., 74,3403 (1952). 258. P. W. Robertson, J. B. Butchers, R. A. Durham, W. B. Healey, J. K. Heyes, J. K. Johannesson, and D. A. Tait, J. Chenz. SOC.,1950, 2191. 259. Ref. 14, p. 128. 260. D. L. H. Williams, Tetrahetlrori Lerters, 1967, 2001. 261. E. W. Rengevich, V. I. Staninets, and E. A. Shilov, Dokl. Akad. Nurrk SSSR, 146, I I 1 (1962). 262. M. de Moura Canipos and L. do Amaral, Arch. Pharin., 298,92 (1965). 263. D. D. Tanner and B. G. Brownlee, J. Am. Clienz. Soc., 88, 771 (1966). 264. G. Heublein, Z. Chern., 6, 186 (1966). 265. A. Bowers, L. C. Ibaiiez, E. Denot, and R. Becerra, J. Anz. Chenz. Soc., 82, 4001 (1960); A. Bowers, E. Denot, and R. Becerra, J. Am. Chern. SOC.,82, 4007 (1960). 266. (a) A. Hassner and C. Heathcock, J. Org. Chern., 30, 1748 (1965); (b) A, Hassner and C. Heathcock, Tetruhetlron Letters, 1964, 1502; (c) A. Hassner. M. E. Lorber, and C. Heathcock, J. Org. Chern., 32, 540 (1967). 267. (a) G. Drefahl and K. Ponsold, Chem. Ber., 93, 519 (1960); (b) G . Drefahl, K. Ponsold, and G. Kollner, J. Prakt. Chern., 23, 136 (1964). 268. C. G. Gebelein and D. Swern, Clzerrz. h i / . (Lorrtlorr), 1965, 1462. 269. F. W. Fowler, A. Hassner, and L. A. Levy, J. Am. Chern. Soc., 89, 2077 (1967). 270. S. Winstein, E. Grunwald, R. E. Buckles, and C. Hanson, J. Am. Cheirz. Soc., 70, 816 (1948); S. Winstein and E. Grunwald, &it/., 68, 536 (1946); S. Winstein, E. Grunwald, and C. Hanson, ibid., 70, 812 (1948); H. J. Lucas and H. K. Garner, ibid., 72, 2145 (1950). 271. A. C. Pappas, Actu Chent. Scant/., 2 , 292 (1948). 272. D. Swern, Orpniic Reactiorrs, Wiley, New York, Vol. 7, 1953, p. 378. 273. Ref. 14, Chap. 8. 274. N. W. Schwnrtz and J. H. Blunibergs, J. Org. Cliein., 29, 1976 (1964); P. Renolen and J. Ugelstad, J. Chirn. Phys., 57, 634 (1960). 275. D. Swern, J . Am. Cherrz. Soc., 69, 1692 (1947). 276. Y. lshii and Y. Inanioto, Kogyo Kaguzr~Zusslii,63, 765 (1960); Clioiz. Ab.\/r., 58,4393b (1963).

338

R. C. FAHEY

277. B. M. Lynch and K. H. Pausacker, J. Chern. SOC.,1955,1525; Y. Ogata and I. Tabushi, J . Am. Chern. SOC.,83, 3440 (1961). 278, P. D. Bartlett, Record Chem. Progr. (Kresgl-Hooker Sci. Lib.), 11, 51 (1 950). 279. W. H. T. Davison, J. Chem. SOC.,1951,2456; P. A. GiguBre and A. Weingartshofer Olmos, Can.J. Cheni., 30,821 (1952); D. Swern, L. P. Witnauer, C. R. Eddy, and W. E. Parker, J . Am. Chern. Soc., 77, 5537 (1955). 280. (a) H. Kwart and D. M. Hofmann,J. Org. Chern., 31,419 (1966); (b) K. D. Bingham, G. D. Meakins, and G. H. Whitham, Chem. Commun., 1966,445; (c) H. Kwart, P. S. Starcher, and S. W. Tinsley, Chem. Commun., 1967, 335. 281. (a) H. B. Henbest, B. Nicholls, W. R. Jackson, R. A. L. Wilson, N. S. Crossley, M. B. Meyers, and R. S. McElhinney, Bull. SOC.Chim. France, 1960, 1365; (b) H. B. Henbest, Spec. Publ. Chem. SOC.,London, 19, 83 (1965); and references cited in these papers. 282. L. Goodman, S. Winstein, and R. Boschan, J. Am. Chem. Soc., 80, 4312 (1958). 283. H. B. Henbest and J. J. McCullough, Proc. Chem. SOC.,1962,74. 284. B. Rickborn and S. Y. Lwo, J. Org. Cherrz., 30, 2212 (1965). 285. H. M. Walborsky and D. F. Loncrini, J. Am. Chem. SOC.,76,5396 (1954). 286. H. Kwart and T. Takeshita, J. Org. Chem., 28, 670 (1963). 287. P. G. Gassman and F. G. Pape, J. Org. Chem., 29, 160 (1964). 288. H. B. Henbest and B. Nicholls, J. Chem. SOC.,1959, 221. 289. See footnote 15 of ref. 69. 290. (a) S. Winstein and R. B. Henderson, in Heterocyclic Compounds, Vol. I, R. C. Elderfield, Ed., Wiley, New York, 1950, p. 22; (b) E. Eliel, in Sferic Ejects in Organic Chemistry, M. S . Newman, Ed., Wiley, New York, 1956, p. 106; (c) R. E. Parker and W. S. Isaacs, Chern. Reo., 59,757 (1959). 291. G. Berti and F. Bottari,J. Org. Chem., 25, 1286 (1960). 292. (a) J. G. Traynham and W. C. Baird, Jr., J. Org. Chern., 27, 3189 (1962); (b) A. Endo, M. Saito, Y. Wada, and Y . Fushizaki, Nippon Kagaku Zasshi, 85, 797 (1964); Chem. Abstr., 63,4555b (1965). 293. J. Meinwald, S. S. Labana, and M. S. Chadha, J. Am. Chem. SOC.,85, 582 (1963); J. T. Lumb and G. H. Whitham, J. Chem. SOC.,1964, 1189. 294. H. H. Schlybach and V. Franzen, Ann. Chem., 577, 60 (1952). 295. V. Franzen, Cheni. Ber., 87, 1219, 1478 (1954). 296. J. K. Stille and D. D. Whitehurst, J. Am. Chem. SOC.,86, 4871 (1964). 297. N. Kharasch, in Organic Sirlfrtr Compounds, N. Kharasch, Ed., Pergamon, New York, 1961, Chap. 32. 298. F. A. Drahowzal, in Organic Siilfiir Compounds, N. Kharasch, Ed., Pergamon, New York, 1961, Chap. 31. 299. N. Kharasch and C. M. Buess, J. Am. Chern. SOC.,71, 2724 (1949). 300. (a) W. H. Mueller and P. E. Butler, J. Am. Chem. SOC.,88, 2866 (1966); (b) W. H. Mueller and P. E. Butler, J. Org. Chem., 32, 2925 (1967); (c) W. A. Thaler, W. H. Mueller, and P. E. Butler, J . h i . C/tetn. Soc., 90, 2069 (1968); (d) W. H. Muellcr and P. E. Butler, J. Am. Cliem. Soc., 90, 2075 (1968). 301. (a) W. L. Orr and N. Kharasch,J. Am. Chenz. SOC.,78, 1201 (1956); (b) A. J. Havlik and N. Kharasch, ibid., 78, 1207 (1956).

ELECTROPHILIC ADDITIONS TO OLEFINS A N D ACETYLENES

339

302. A. V. Kalabina, E. F. Kolmakova, T. I. Bychkova, Y. K. Maksyutin, E. A. Denisevich, and G. I. Smolina, Zh. Obsheh. Khim., 35, 979 (1965). 303. N. R. Slobodkin and N. Kharasch, J. Org. Chem., 25, 866 (1960). 304. G. M. Beverley and D. R. Hogg, Chem. Commun., 1966, 138. 305. M. de Moura Campos, J. A m . Chem. SOC., 76,4480 (1954). 306. (a) W. L. Orr and N. Kharasch,J. Am. Chem. SOC., 75,6030 (1953); (b) D. R. Hogg and N. Kharasch, J. Am. Chem. SOC.,78, 2728 (1956). 307. D. S. Campbell and D. R. Hogg, J. Chem. SOC.,1965, 5887; J. Chem. SOC. ( B ) , 1966, 109, 294. 308. H. Kwart and L. J. Miller, J. Am. Chem. SOC., 83, 4552 (1961). 309. C. Brown and D. R. Hogg, Chem. Commun., 1965, 357. 310. D. J. Pettitt and G. H. Helmkamp, J. Org. Chem., 29, 2702 (1964). 311. D. J. Cram, J . Am. Chem. SOC.,71, 3883 (1949). 312. N. R. Slobodkin and N. Kharasch, J. Am. Chem. Soc., 82, 5837 (1960). 313. A. J. Havlik and N. Kharasch, J. Am. Chem. SOC., 77, 1150 (1955); 78, 1207 (1956). 314. G . H. Schmid and V. M. Csizmadia, Can.J. Chem., 44,1338 (1966). 31 5 . G. D. Brindell and S. J. Cristol, in Organic Surfur Compounds, N. Kharasch, Ed., Pergamon, New York, 1961, p. 129. 316. S. J. Cristol, R. P. Arganbright, G. D. Brindell, and R. M. Heitz, J. Am. Chem. Soc., 79, 6035 (1957). 317. H. Kwart and R. K. Miller, J . Am. Chem. Soc., 78, 5678 (1956). 318. H. Kwart, R. K. Miller, and J. L. Nyce, J. Am. Chem. Soc., 80, 887 (1958). 319. S. J. Cristol, R. Caple, R. M. Sequeira, and L. 0. Smith, Jr., J. Am. Chem. SOC., 87, 5679 (1965). 320. N. Kharasch and C. N. Yiannios, J. Org. Chem., 29, 1190 (1964). 321. W. E. Truce, H. E. Hill, and M. M. Boudakian,J. Am. Chem. Soc., 78,2760 (1956). 322. V. Calo, G. Melloni, G. Modena, and G. Scorrano, Tetrahedron Letters, 1965, 4399. 323. A. Dondoni, G. Modena, and G. Scorrano, Bull. Sci. Fac. Chim. Ind. Bologna, 22, 26 (1964); through Chem. Abstr., 61, 10613 (1964). 324, L. T. Zakharkin, Izu. Akad. Nauk SSSR, Otdel, Khim. Nauk., 1959, 437; Chem. Abstr., 53, 21617 (1959). 325. L. DiNunno, G. Melloni, G. Modena, and G. Scorrano, Tetrahedron Letters, 1965, 4405. 326. N. Kharasch and S. J. Assong, J. Am. Chem. Soc., 75, 1081 (1953). 321. W. E. Truce and M. M. Boudakian, J. Am. Chem. Soc., 78,2748 (1956). 328. (a) F. Montanari and A. Negrini, Gazz. Chim. Ital., 87,1061 (1957); (b)G. H. Schmid and M. Heinola, J. Am. Chem. Soc., 90, 3466 (1968). 329. (a) H. Shechter, Record Chem. Progr., 25, 55 (1964); (b) H. Shechter, J. J. Gardikes, T. S. Cantrell, and G. V. D. Tiers, J. Am. Chem. SOC., 89, 3005 (1967). 75,3275 (1953); S. Bresadola, 330. C. C. Price and C. A. Sears,J. Am. Chem. SOC., P. Canal, A. Wenz, and E. Gallinella, Chim. Ind. (Milan),45,937 (1963). 33 1. H. Shechter, F. Conrad, A. L. Daulton, and R. B. Kaplan,J. A m . Chem. SOC., 74, 3052 (1952).

340 332. 333. 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344. 345. 346.

347. 348. 349. 350. 351. 352. 353. 354. 355.

356.

357.

R. C. FAHEY J. C. D. Brand and I. D. R. Stevens, J. Chem. Soc., 1958, 629. T. E. Stevens and W. D. Emmons, J. Am. Chem. Soc., 79,6008 (1957). T. E. Stevens, J. Org. Chem., 24, 1136 (1959). F. G. Bordwell and E. W. Garbisch, Jr., J. Am. Chem. Soc., 82,3588 (1960). (a) F. G. Bordwell and E. W. Garbisch, Jr., J. Org. Chem., 27, 2322 (1962); (b) 27, 3049 (1962); (c) 28, 1765 (1963). G. Drefahl, H. Crahmer, and W. Thomas, Chem. Ber., 91,282 (1958). G. Drefahl and H. Crahmer, Chem. Ber., 91, 745, 750 (1958). A. A. Griswald and P. S. Startcher, J. Org. Chem., 31,357 (1966). F. G. Bordwell and J. B. Biranowski, J. Org. Chem., 32,629 (1967). L. J. Beckham, W.A. Fessler, and M. A. Kise, Chem. Rev., 48,319 (1951). K. A. Oglobin and D. M. Kunovskaya,Zh. Org. Khim., 1,1713 (1965); K. A. Oglobin and V. P. Semenov, Zh. Org. Khim., 1, 1356, 1361 (1965) and early papers in this series. T. Beier, H. G. Hauthal, and W. Pritzkow, J. Prakt. Chem., 26,304 (1964). M. Ohno, M. Okamoto, and K. Nukada, Tetrahedron Letters, 1965,4047. J. Meinwald, Y.C. Meinwald, and T. N. Baker, 111, J. Am. Chem. Soc., 85, 2513 (1963); 86, 4074 (1964). (a) K. Tanabe and R.Hayashi, Chem. Pharm. Bull. (Tokyo), 10,1177 (1962); (b) A. Hassner and C. Heathcock, J. Org. Chem., 29, 1350 (1964); (c) W. A. Harrison, E. R. H. Jones, G. D. Meakins, and P. A. Wilkinson,J. Chem. Soc., 1964, 3210. (a) W. J. Setontein, J. H. Jordaan, and J. White, Tetrahedron Letters, 1964, 1069; (b) R. U. Lemieux, T. L. Nagabhushan, and I. K. O’Neil, Tetrahedron Letters, 1964, 1909. N. S. Zefirov, P. Kadziauskas, V. N. Bazanova, and Y. K. Yur’ev, Zh. Obshch. Khim., 35, 752 (1965); Chem. Abstr., 63, 4233 (1965). G. Wilke, Angew. Chem., 75, 10 (1963); M. Ohno, M. Okamoto, and N. Narase, Tetrahedron Letters, 1965, 1971; M. Genas, P. Assoudre, C. Bernier, C. Poulain, and T. Rull, Bull. Soc. Chim. France, 1965, 2833. I. Owai, K. Tomita, and J. Ide, Chem. Pharm. Bull., 13, 118 (1965); Chem. Absrr., 62, 14541 (1965). K. A. Hofmann and J. Sand, Chem. Ber., 33, 1340, 1353,2692 (1900). J. Chatt, Chem. Rev., 48, 7 (1951). N. S . Zefirov, Russ. Chem. Rev., 34, 527 (1965). J. Sand and F. Singer, Chem. Ber., 35, 3170 (1902). (a) H. B. Henbest and B. Nicholls,J. Chem. Soc., 1959,227; (b) J. H. Robson and G. F. Wright, Can. J. Chem., 38, 21 (1960); (c) T. G. Traylor and A. W. Baker, J. Am. Chem. Soc., 85, 2746 (1963). (a) F. G. Bordwell and M. L. Douglass, J. Am. Chem. Soc., 88, 993 (1966); (b) H. C. Brown and P. Geoghegan, Jr., J. Am. Chem. Soc., 89, 1522 (1967); (c) H. C. Brown and W. J. Hammar, J. Am. Chem. Soc., 89, 1524 (1967); (d) H. C. Brown, J. H. Kawakami, and S. Ikegami, J . Am. Chem. Soc., 89, 1525 (1967). (a) M. M. Kreevoy, J. Am. Chem. Soc., 81, 1099 (1959); (b) M. M. Kreevoy F. R. Kowitt, J. Am. Chem. Soc., 82, 739 (1960); (c) M. M. Kreevoy and L. T. Ditsch, J. Am. Chem. Soc., 82,6127 (1960); (d) L. L. Schaleger, M. A.

ELECTROPHILIC ADDITIONS TO OLEFINS AND ACETYLENES

341

Turner, T. C. Chamberlin, and M. M. Kreevoy, J. Org. Chem., 27, 3421 (1962);(e) M. M. Kreevoy, L. L. Schaleger, and J. C. Ware, Trans. Faraday Soc., 58,2433 (1962); (f) M. M. Kreevoy and B. M. Eisen, J . Org. Chem., 28, 2104 (1963); (9) M. M. Kreevoy and M. A. Turner, J. Org. Chem., 29, 1639 (1964); (h) 30,373 (1965). 358. K. Ichikawa, K. Nishimura and S . Takayama, J. Org. Chem.,30,1593(1965). 359. E. R. Allen, J. Cartledge, M. M. Taylor, and J. F. Tipper, J. Phys. Chem., 63, 1437, 1442 (1959). 360. J.-C. Strini and J. Metzger, Bull. SOC.Chim. France, 1966,3145,3150 (1966). 89,6427 (1967). 361. J. Halpern and H. B. Tinker, J. Am. Chem. SOC., 362. K. L. Mallik and M. N. Das, J. Am. Chern. Soc., 82, 4269 (1960); A. K. Chandhuri, K. L. Mallik, and M. N. Das, Tetrahedron, 19,1981 (1963). 363. C.-E. Doring and H. G. Hauthal, J. Prakt. Chem., 22, 59 (1963). 364. F.Asinger, B. Fell, G. Steffan, and G. Hadik, Chem. Ber., 97,1568 (1964). 365. A. Brook and G. Wright, Acta Cryst., 4,50 (1951). 366. M. Anderson and P. Henry, Chem. Ind. (London), 1961,2053. 367. (a) T. G.Traylor and A. Factor, private communication; (b) W. L. Waters, private communication. 368. A. Rodgman, D.A. Shearer, and G. F. Wright, Can. J. Chem., 35, 1377 (1957). 369. M. J. S. Dewar and H. N. Schmeising, Tetrahedron, 11, 96 (1960); D.S. Noyce and M. D. Schiavelli, J. Org. Chem., 33, 845 (1968). 370. H. Lucas, F. Hepner, and S. Winstein, J. Am. Chem. SOC.,61,3012 (1939). 371. V. I. Sokolov, Yu.A. Ustynyuk, and 0. A. Reutov, Dokl. Akad. Nauk SSSR, 173,1103 (1967);Y. Saito and M. Matsuo, Chem. Commun., 1967,961. 372. (a) H. B. Henbest and B. Nicholls, J. Chem. SOC.,1959, 227; (b) H. B. Henbest and R. S. McElhinney, J. Chem. Soc., 1959, 1834. 373. W. L. Waters and M. C. Caserio, Abstracts, 154th National Meeting, American Chemical Society, Chicago, Illinois, 1967. 374. W. L. Waters and E. F. Kiefer, J. Am. Chem. SOC.,89, 6261 (1967). 375. T. G.Traylor and A. W. Baker, Tetrahedron Letters, 1959, 14. 376. (a) T.G.Traylor, J . Am. Chem. SOC.,86, 244 (1964); (b) F. T.Bond, private communication. 377. T. T. Tidwell and T. G. Traylor, J. Org. Chem., 33,in press (1968)and private communication. 378. S. Winstein and M. Shatavsky, Chem. Ind. (London), 1956, 56; K. C.Pande and S. Winstein, Tetrahedron Letters, 1964,3393. 379. J. K. Stille and S. C. Stinson, Tetrahedron, 20, 1387 (1964). 380. A. Factor and T. G. Traylor, J. Org. Chem., 33,in press (1968). 381. R. K. Bly and R. S. Bly, J. Org. Chem., 28, 3165 (1963). 382. G. F. Hennion, R. R. Vogt, and J. A. Nieuwland, J. Org. Chem., 1, 159 (1936). 383. A. N. Nesmeyanov and A. E. Borisov, Izv. Akad. Nauk SSSR, Org. Khim. Naitk, 1945, 146 (Ref. 384,p. 281); 384. A. N. Nesmeyanov, Selected Works in Organic Chemistry, Engl. transl. by A. Birron and Z. S. Cole, Macmillan, New York, 1963. 385. H. Lemaire and H. J. Lucas, J. Am. Chem. SOC.,77,939 (1955).

342

R. C. FAHEY

386. 0. N. Tempkin, R. M. Flid, and A. 1. Malakhov, Kinetics Catalysis (USSR) Engl. Transl., 4, 233 (1963). 387. W. L. Budde and R. E. Dessey, J. A m Chem. SOC.,85,3964 (1963). 388. A. E. Borison, V. D. Vil'chevskaya, and A. N. Nesmeyanov, Dokl. Akad. Nauk SSSR,90, 383 (1953); Ref. 384, p. 388. 389. G . Drefahl, G. Heublein, and A. Wintzer, Angew. Chem., 70, 166 (1958). 390. A. Fabrycy and J. Kubala, Zh. Obshch. Khim., 31, 476 (1961); through Chem. Abstr., 55, 22276 (1961). 391. Ref. 14, p. 216.

Author Index Numbers in parentheses are reference numbers and show that an author’s work is referred to although his name is not mentioned in the text. Numbers in italics indicate the pages on which the full references appear. A

Aaron, H. s., 27(129)7 28(129), 29(144, 145), 38(144,145), 90 Abel, E. W., 151, 187 Abraham, R. J., 54(233), 93, 157(227), 162(227), 188 Abrahamson, K . H.. 115(78), 133(78), 138(78), 184 Abramson, W. E., 205(44), 233 Adams, D. G., 152(203), 187 Adin, N. G . , 13(61), 14(61), 88 Agtarap, A,, 244(42), 331 Aguiar, A. M., 6(19-24), 7(19), 17, 18 (20-23), 48(22), 50(19), 73(293,294), 87, 95 Aguiar, H., 73(293,294), 95 Ahmad, M., 115(61). 1% 158(61), 183, 186 Ahrland, S., 16(82), 88 Akabori, S., 172(297), 190 Aksnes, D., 17(90), 89 Aksnes, G., 17(90), 38(160), 69(280), 74, 86(296,343), 89, 91, 95, 96 Al-Azrak, A., 230(122), 235 Alberty, R. A.. 256(83), 332 Alcais, P., 281(196), 335 Alexander, S., 1 1 I , 112(41), 113, 122, 183 Allan, E. A., 157(234), 188 Allen, E. R., 315(359), 341 Allen, G., 244(41), 331 Allen, L. C., 194-196(9), 232 Allen, R . G., 258(97), 332 Allerhand, A., 107(25), 113(57), 115(68-71,73,77), 121, 125, 126(70), 133-135(68), 157(70), 158(57,70,71), 159, 175(73), 182-184, 188

Allinger, N. L., 156(213), 188 Allmann, R., 7(30), 87 Allred, E. L., 137(138), 150(138), 185 Alt, G. H., 274(166), 286(221), 334,336 Altman, J., 174(310), 191 Altschuler, L., 285(21 I), 336 Alver, E., 85(342), 96 Amano, A., 292(256), 337 Amaral, L. do, 292(262), 337 Anbar, M.,107(18), 182 Anderson, C. L., 137( 138), 150(138), 185 Anderson, D. F., 157(228), 188 Anderson, E. W., 107(22), 109, 121(22), 154, 157, 158(220,221), 182, 188 Anderson, J. E., 100(7), 137(137,139), 150(137,139), 162(137), 163(253), 164 (137), 170(282b), 182,185, 189, 190 Anderson, J. K., 11 3(56), 183 Anderson, M., 317(366), 341 Anderson, W. A., 5(15), 47(197), 49 (197), 86, 92, 107(19), 115(19), 139 (1 9), 182 Andreades, S., 138(150), 151(150), 186 Andrews, E. B., 198(20), 232 Andrews, L. J., 241(13), 330 Androes, G . , 162(248,249), 189 Anet, F. A. L., 115(61), 119(83), 121 (83), 140, 148(182,183), 157, 158(61, 83), 160, 167, 168(277-279). 170, 176 (328,330-332), 183, 184, 186, 187, 189-191, 213(62), 233 Archibald, T., 6(20,23), 18(20,23), 87 Arens, J. F., 16(74), 88 Arganbright, R. P., 266(142), 302(316), 303(316), 334,339 Armstrong, R., 288(233), 336 343

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

344

AUTHOR INDEX

Aroney, M. J., 53(214,215), 93 Asinger, F., 317(364), 341 Assong, S.J., 304, 339 Assoudre, P., 314(349), 340 Atkinson, J. R., 281(194), 282(194), 286 (194). 288(194), 335 Avarbock, H. S.,256(82), 332 Avram, M., 276(174), 334 Axelrad, G., 29(148), 69(278), 90, 95

B Bachman, G. L., 221(95), 234 Bader, J. M., 283(203), 335 Bader, R. F.. 213(62), 214(64), 233 Bailey, W. J., 9(41), 87 Baird, W. C., Jr., 298(292), 299, 338 Baker, A. W., 315(355), 317(355c), 320, 323(355c), 327(355c), 340 Baker, T.N., 111, 312-314 (349, 340 Baldeschwieler, J. D., 119(84,85), 184 Baliga, B. T., 243(27), 330 Balzer, W. D., 9(44), 13(58), 87, 88 Banholzer, K., 131(104), 184 Banks, R. E., 148(173), 186 Banthorpe, D. V., 243(20), 330 Barash, L., 200(37,38), 223(98), 233, 234 Barbier, G., 281(196), 335 Bardos, T. J., 148(184), 187 Barfield, M., 119(85), 184 Barlow, M. G., 148(173), 186 Barrow, R. F., 198(20), 232 Barsukov, L. I., 41(178), 43(186), 84 (333), 91, 92, 96 Bartell, L. S.,3(9), 72(9), 86 Bartle, K. D., 79(316), 84, 96 Bartlett, P. D., 240. 250(61), 273(164), 275(168), 276, 282(7), 292(252,253), 295,330,331,334,335,337,338 Barton, D. H. R.,274(166), 286,334, 336 Bates, R. B., 143(158), 186 Baudler, M., 15(67,71), 88 Bazanova, V. N., 313(348), 340 Beauchamp, J. L., 113(54), 183 Becerra, R.,293(265), 294(265), 337

Beck, B. H., 159(224), 174(224), 176 (336), 188, 192 Beck, P., 8(34,35), 9(40), 10(40,47), 29 (35). 81(47), 87 Beckett, C. W., 155(212), 288 Beckham, L. J., 311(341), 314(341), 340 Bedford, G. R.,133(121), 185 Beier, T., 311, 314(343), 340 Beineke, T. A., 71(287), 84(287), 95 Beirne, P. D., 250(64), 331 Bell, R. P., 281, 282, 286, 288(194,195) 335 Bene, G. L., 47(200), 92 Benezra, C., 46(194), 48(194), 50, 53 (220), 79(194), 84, 85(336), 92, 93,96 Bennett, W., 288(233), 336 Benson, S. W., 193(5), 194(5), 209(52), 210(54), 216(52), 232,233, 239,242 (2), 258, 292(256), 330,332,337 Bercz, C. V., 10(48), 87 Bercz, J. P., 10(48), 87 Berg, G. R. van der, 29(143), 34(143), 90 Bergel'son, L. D., 38(161,164), 41(161, 164,177,778), 42(161,164), 43(164, 186), 84(333), 92, 96, 258(96), 291, 332,336 Berger, A., 109(35), 133(35), 183 Berger, J. G., 218(75), 234 Berger, S. B., 109(33), 182 Bergesen, K., 74, 85(339), 86(296), 95, 96 Berlin, A. J., 158(214,216), 159(216), 188

Berlin, K. D., 17(86), 57(245), 88, 94 Berliner, E.,285(21l), 333 Bernheim, R. A., 200(39), 233 Bernier, C., 314(349), 340 Bernstein, H. J., 53(217), 93, 100(1), 182 Berry, R. S.,64, 94 Berson, J. A., 244(44), 250(44), 331 Berti, G., 288, 298(291), 336, 338 Bertrand, J. A., 52(211), 84(211), 92 Bestmann, H. J., 41(175), 91 Beveridge, A. D., 14(62), 88 Beverley, G. M., 300(304), 339 Bezugliji, V. D., 84(334), 96

AUTHOR INDEX

Bhattacharyya, S. K.. 292(251), 337 Bienvenue-Goetz, E., 281(196), 335 Bieron, J. F., 168(271.273,274), 189,190 Bingham, K. D., 295(280b), 338 Binsch, G., 97, 111(51), 122(92), 131 (92), 155(209), 1701291), 183, 184, 188, 190 Biranowski, J. B., 308(340), 309(340), 340 Bissell, E. R., 263(126), 333 Bissing, D. E., 42(183), 92 Bither, T. A., 77(302), 95 Blackburn, G. M., 52(209), 92 Blade-Font, A., 8(36), 29(148), 39(166, 167), 69(36), 87, 90, 91 Bladon, P., 76, 95 Blakeley, R., 56(241), 57(241), 93 Blanchard, E. P., 218(71,72), 234 Blasse, G., 54(230), 93 Blears, D. J., 133(112), 134(112), 138 (147), 185, 186 Bloch, F., 102, 103, 11 I , 182, 183 Bloembergen, N., 110(38), 115(38), 183 Blomstrom, D. C., 218(69), 234 Bloom, M., 115(75), 184 Blum, A., 125(94), 133(94), 134, 184 Blumbergs, J. H., 295(274), 337 Bly, R. K., 323, 341 Bly, R. S., 268, 323,334,341 Boche, G., 170(283), 190, 272(160), 286, 334,336 Boll, W. A., 175(318), 191 Bohlmann, F., 259(113), 333 Bollinger, J. M., 265(131), 276, 282, 294 (1311, 333 Bolton, R., 242, 243(24,33), 244(24,33, 43), 256(81), 265, 267(151), 276(173), 277(137), 281, 292(259), 295(273), 328 (391), 330-335, 337, 342 Bond, F. T., 321, 341 Bopp, R. J., 259,333 Borden, M. R . , 263(127), 333 Bordwell, F. G., 307, 308, 309(335, 336a-c,340), 315, 340 Borecka, B., 81(324), 96 Borisov, A. E., 324(383), 325(388), 341, 342

345

Borkovec, A. B., 53(220), 93 Bornstein, J., 263(127), 333 Boschan, R., 296,338 Bose, A. N., 239(2), 242(2), 258(2), 330 Boter, H. L., 29(143), 34(143), 83(330), 90, 96 Bott, R . W., 258(109), 333 Bottari, F., 298(291), 338 Bottini, A. T., 148, 186, 187 Boudakian, M. M., 304, 305(321), 339 Bourn, A. J. R., 119(83), 121(83), 157, 158(83), 170, 184, 188, 190 Bovey, F. A., 107(22), 121(22), 154, 157, 158(220,221), 182, 188 Bowers, A., 293, 294(265), 337 Boyd, D. R., 57(246), 94 Boyd, R . H., 243(25), 330 Boys, S . F., 196(10), 232 Brady, J. D., 242,330 Brand, J. C. D., 139(151), 163(253), 186, 189, 306(332), 340 Brandon, R. W., 199(28,29),200(28,29), 221(28), 232 Braun, H., 81(321), 96 Braun, J., 27(129), 28(129), 90 Breliere, J. C., 137(141), 186 Bresadola, S., 306(330), 339 Brindell, G.D., 302, 303(316), 339 Brook, A., 317(365), 341 Brophy, J. J., 10(46), 18(46), 742951, 87,95 Brown, C., 300,339 Brown, C. J., 172(296), 190 Brown, D. H., 65(270), 72(270), 94 Brown, D. M., 60(255), 94 Brown, H. C., 16(81), 88, 242, 252, 298 (289), 303, 31 5 , 322(356d),330-332, 338,340 Brown, H. W., 138(149), 139, 186 Brown, M. A., 170(284), 190 Brown, N. M. D., 76, 95 Brownlee, B. G., 292, 337 Brownstein, S., 157(235,240), 188 Bruce, M. I., 176(329), 191 Brudvik, L. J., 86(343), 96 Buckler, S. A., 9(41), 24(115,116). 87. 89

AUTHOR INDEX

346

Buckles, R. E., 268, 280(187,188,) 283 287(204), 293(270), 334, 335, 337 Budde, W. L., 325, 342 Buenker, R. J., 194-196(9), 232 Buess, C. M., 299, 300(299), 338 Burham, R. L., 283(202), 335 Burlitch, J. M., 221(89,90), 234 Bush, J. B., 148(180), 187 Bush, R. P., 151, 187 Bushweller, C. H., 137(145), 160, 164 (145), 186, 188, 189 Butchers, J . B., 292(258), 337 Butler, P. E., 277(177), 299, 302(300d), 300(300d), 335, 338 Bychkova, T. I., 299(302), 339 Bystrov, V. F., 148(181), 187 C

Cabaleiro, M. C., 272, 334 Cadiot, P., 81(324), 96 Calder, I. C., 173(304-306), 191 Calo, V., 305(322), 339 Calvin, M., 162(248,249), 189 Cammarata, A., 2(6), 86 Campbell, D. S., 300, 339 Campbell, I. G . M., 8, 28(33), 87 Campbell, P. G . C., 247, 248, 317(53), 331 Canal, P., 306(330), 339 Cantrell, T . S., 306(329), 314(329b), 339 Caple, R., 252, 253, 254(76), 256(90, 91), 257(90-92), 303(319), 332, 333, 339 Carhart, R. E., 162(246), 189 Carlson, C. G.,160(244), 189 Carr, H. Y., 115, 183 Carroll, R. L., 15(68), 88 Carter, R. P., 72(292), 95 Cartledge, J., 315(359), 341 Caserio, M. C., 288, 292(228a), 319, 336, 341 Casey, C., 244(42), 331 Casper, J., 28(131), 90 Casteignau, G., 25(119), 89 Caughlan, C. N., 52(212), 92 Cervinka, O., 6(28), 13(28), 26(28), 87

Chadha, M. S., 298(293), 338 Chamberlin, T . C., 315(357), 341 Chandhuri, A. K., 316(362), 341 Chang, W.-H., 24(114), 89 Charrier, C., 81(324), 96 Chatt, J., 16(82), 88, 314, 315(352), 340 Chen, F., 115(70,72), 126(70), 157(70), 72), 159, 183, 188 Cheer, C. J., 266(146), 334 Chia, L. H . L., 53(215), 93 Chignell ,G., 57(246), 94 Chodkiewicz, W., 81(324,325), 96 Chopard, P. A., 40(171), 41(171), 91 Christ, H. A., 175(322), 191 Christman, D. R., 243(25), 330 Christmann, K. F.. 42(180,181), 91 Ciapetta, F. G., 243(30), 330 Ciganek, E., 175(317), 191, 223(99), 234 Claeson, G., 162(248,249), 189 Closs, G. L., 193, 198(25), 199(28,29), 200(28,29), 203(25), 204(42), 207(42), 221(28,42,81-84, 94), 224(103), 227 (42,81,83,84,110), 228(42), 229(42,113, I14), 230(42,119,117,127), 232-235 Closs, L. E., 221(81,94), 224(103), 227 (81), 234, 235 Clutter, R . J., 47(195), 92 Coburn, R . A., 172(299), 190 Coe, D. G., 17(85), 88 Coffey, R. S., 221(95), 234 CoRman, D. D., 77(302), 95 Cohen, J. S., 52(209), 92 Cohen, S. T., 15(66), 88 Colburn, C. B., 143(157), 186 Collin, R. L., 51(205), 52(205), 92 Collins, C. H . , 246(52,55), 247, 331 Collis, M. J., 274(167), 334 Colter, A. K., 131(105,106), 184, 185 Conn, J . B., 242(19), 265(19), 280(19), 330 Conner, S. H., 76(298), 95 Connor, T. M., 100, 101, 182 Conrad, F., 306(331), 339 Conrow, K., 167, 189 Conti, F., 132(113), 133(113,115), 185 Cook, A. G., 16(76), 59(76), 88 Cook, D., 242(16), 258(16), 330

AUTHOR INDEX Cooke, M., 176(329), 191 Cooper, M. A., 54(233), 93 Cope, A. C., 131, 184 Copeland, R. F., 76(298), 95 Corbridge, D. E . C., 2(7), 4, 5(7), 25(7), 86 Corey, E. J., 44, 92 Cotton, F. A., 72(290). 95, 176(325,326), 191 Coussernant, F., 243(29,34). 244(29,34), 330, 334 Covitz, F., 71(285), 95 Cowley, A. H., 15(66,68,73), 88 Cox, J. R., Jr., 52(211), 70(282), 84 (211), 92, 95 Coyle, J . J., 221(83,84), 227(83,84,110), 230(110,117), 234, 235 Coyne, D. M., 28(133), 90 Crahrner, H., 307(337,338), 309(337, 338), 340 Cram, D J , 13, 24( 109), 88, 89, 148 (183), 187, 301, 339 Craven, R. L., 256(89). 257(89), 332 Crawford, R . J., 210(55), 233 Cristeau, H. J . , 81(321). 96 Cristol, S. J., 250, 252, 253, 266(142, 143), 268, 277, 278( 143), 284( 152), 289, 302, 303, 331, 332, 334, 336,339 Crofts, P. C., 57(249), 58(249), 94 Crossley. N. S., 296(281), 297(281), 338 Crurnbliss, A. C., 221(88), 234 Crunden, E. W., 57(243), 93 Csapilla, J., 256(91), 257(91), 332 Csizrnadia, V. M . , 302, 339 Curtin, D. Y . , 151, 160, 187, 189 Cvetanovic, R. J., 21 5(65), 233, 292 (247), 337 D Dahlqvist. K. I., 110. 140-142, 183, 186 Daigle, D., 6(19,21.22), 7(19), 17(19), 18 (21,22), 48(22), 50(19), 73(293), 87, 95 Dailey, B. P.,157(233), 188 Dale, J., 127(96), 184 Dalton, D. R., 285(210), 336 Daly, J. J., 3(8), 23(100,101,103), 53 (216), 86, 89, 93

347

Daniels, R., 137(142,143), 164(142,143), 186 Daniewski, W. M., 4(13), 48(13), 50 (203), 86, 92 Danyluk, S. S., 133(112), 134(112), 185 Das, M. N., 316(362), 341 Dasent, W. E., 259(113), 291(113a), 328 ( I 13a), 333 Daulton, A . L., 306(331), 339 David, J. G., 54(223), 93 Davidson, A. J., 148(179), 187 Davidson, G., 16(77), 88 Davidson, M., 243(29), 244(29), 330 Davidson, N., 155(208), 188 Davidson, R. S., 7(32), 87 Davies, N. R., 16(82), 88 Davies, W . C., 28(138), 90 Davis, D., 167(266), 189 Davis, M., 6(24), 20, 21, 87, 89 Davison, A., 176(325), 191 Davison, W. H . T., 295(279), 338 Davoust, C. E., 199(29), 200(29), 232 DeBoer, T. J., 121(89), 139(89), 184 Delpuech, J. J., 100(4), 182 DeMore, W. B., 193(5), 194(5), 232 Denisevich, E. A., 299(302), 339 Denney, D. B., 13(60,61), 14(60,61), 17 (89), 22, 27(140), 45, 74, 88-90, 95 Denney, D. Z., 22,45,89 Dennis, E. A., 52(213), 71, 72, 92, 95 Deno, W. C., 244(40), 331 Denot, E., 293(265), 294(265), 337 Desai, N. B., 45(192,193), 78(304), 92, 95 DeSornbre, E. R., 17(84), 88 Dessey, R. E., 325, 342 Dewar, M. J. S.,240, 244(47,48), 245 (10,47-49), 318(369), 330, 331, 341 Diehl, P., 175(322), 191 Diehr, H. J., 18(91), 89 Dijk, C. van, 29(143), 34(143), 90 Dilaris, I., 27(130), 90 Di Leone, R. R., 17(89), 89 Dillon, R. T., 256(85), 286, 332, 336 Dirnitrieva, V . N., 84(334), 96 Dirnroth, K., 7(29), 87 Dinulescu, I. G.,276(174), 334

348

AUTHOR INDEX

DiNunno. L., 304(325), 305(325), 339 Ditsch, L. T..315(357), 317(357c), 340 Dix, D. T., 130(102), 152(203,204), 184 187 Dixon. J. A., 158(215), 173(215), 188 Dixon. R. N., 196(14), 232 Doring, C.-E.. 316,341 Doering, W. v. E., 175, 191, 203, 207 (47), 217(67), 218(77), 233, 234 Dombrovskii, A. V . , 79(310), 95 Dombrovskii, V. A., 79(310), 95 Dondoni, A., 305(323,) 339 Donohue, J., 23(104,105), 89 Dort, H. M., van, 157(238), 188 Douglass, M . L., 31 5, 340 Downing, A. P., 144(162), 186 Drago, R. S., 52(208), 72(291), 92, 95 Drahowzal, F . A., 299(298), 338 Drefahl, G., 262, 293, 307, 309(337, 338). 325(389), 333, 337, 340,342 Drenth. W.. 258(100,103-107), 259 ( I 05), 332, 333 Drozd, G . I., 65(267), 94 Druck, S.J.. 137(140), 186 Dubois, J. E., 265(133). 280(189), 281, 333. 335 Duddey, J. E., 2S9, 333 Dudek, G. O., 56(242), 57(244), 93,94 Duncan, F. J., 215(65), 233, 292(247), 33 7 Durand, J. P., 243(29), 244(29), 330 Durham, R. A., 292(258), 337 Duval, E., 47(200), 92 Dvorko, G. F., 262.333 E

Eaborn, C., 258(109), 333 Eberhard, A,. 71(286), 95 Eberhardt. M. K.,292(255), 337 Ebsworth, E. A. V., 16(77), 88 Eddy, C. R.,295(279), 338 Edmundson, E. S., 17(87), 56(236), 79 (316), 84, 88, 93, 96 Eichelberger, L., 288(232), 336 Eichler, S.,42(185), 92 Eisen. 6. M., 315(357). 341

Elhafez, F. A. A., 13(56), 88 Eliel, E. L., 153(206), 155(210), 187, 188, 286, 298(290), 336, 338 Eliopoulos, G., 27( 130), 90 Elleman, D. D., 5(17), 47(17), 52(17), 87 Emmons, W. D., 17(88), 46(88), 88, 149 (186), 187, 306, 307, 340 Emsley, J . W., 5(16), 87, 100(2), 182 Endo, A., 298(292), 338 Engberts, J. B. F. N., 121, 137(90), 184 Engel, G., 175(315), 191 Englert, G., 175(323), 191 Epstein, M., 24(116), 89 Etten, R. L. van, 148(179), 187 Etter, R. M., 221(93), 230(126), 234, 235 Evans, A. G., 243(32), 330 Eyles, C. T., 31(151), 65(15l), 70(151), 90 Eyring, H., 122, 134(128), 184, 185

F Fabrycy, A., 326(390), 342 Factor, A., 317, 323, 341 Fahey, R. C., 237, 240(10), 244(47,48), 245( 10,47-49), 246(56), 248(56,58,59), 258(101), 260(101,114,119, 261(114116),266(141),268(156),273(141,156),

274(141,156), 276(156), 279(182), 283 (206), 330-335 Fahr, E., 149(187), 187 Faisst, W., 157(226), 188 Falconer, W. E., 292(247), 337 Faller, J. W., 176(325,326), 191 Faltus, H., 54(229), 93 Fano, U., 1 1 1(47), 112(47), 183 Farah. B., 228(11 I), 235 Farcasiu, M., 276(174), 334 Farlow, M. W., 77(302), 95 Farmer, R. F., 163(25Sa), 189 Farnum, D. G., 291, 336 Feeney, J., 5(16), 87, 100(2), 182 Fell, B., 317(364), 341 Fenton, G. W., 68(276), 69(276), 95 Fessler, W. A., 311(341), 314(341), 340

AUTHOR INDEX Fields, D. B., 263(126), 333 Finegold, H., 53(219), 93 Fischer, R. H., 221(87), 234 Fischer, W., 149(187), 187 Fittig, R., 256(86), 332 Flid, R. M., 325, 342 Fliszar, S., 42(184), 92 Flory, K., 221(87), 234 Flowers, M. C., 212(58,59), 233 Fluck, E., 11, 88 Fogel, J., 48(196), 92 Fontal, B., 22(97), 89 Forbes, G. S., 292(250), 337 Ford, J. A., Jr., 43(187), 92 Forrester, 1. L., 283(202), 335 Forsen, S., 110, 118, 119, 140-142, 183, 184, 186 Forst, D., 65(266), 94 Foster, J. M., 196(10), 232 Fowler, F. W., 293, 337 Frack, H. F., 27(129), 28(129), 29(144), 38(144), 90 Fraenkel, G., 130(102), 133(109), 152 (203,204), 184, 185, 187, 292(253), 337 Francis, A. W., 240, 330 Franconi, C., 132(113), 133(109,113, 122, 123), 185 Frank, A. W., 59(254), 94 Frank, G. A., 41(179), 42(179), 91 Frankiss, S.G., 15, 88 Frankland, P. F., 238(1), 330 Franzen, V., 298(294,295), 338 Fraser, G. W., 65(270), 72(270), 94 Fraser-Reid, B., 285(209), 335 Freed, S., 292(249), 337 Freeman, J. P., 44(191), 92 Freeman, K. L., 57(248), 94 Freeman, P. K., 255, 332 Freeman, R., 5(15), 47(197), 49(197), 86, 92 Freiberg, L. A., 156(213), 188 Frey, H. M., 193(3), 210, 212(58-61), 213(63), 231, 233 Fricke, G., 15(67), 88 Friebolin, H., 107(24), 157(226,236), 162(24,236,247,250), 163(24,236), 165 (259), 166(24,259-261), 182, 188, 189

349

Friedman, L., 218(75), 234 Fryer, C. W., 132(113), 133(113), 185 Fuchs, H.,12(53), 13(53), 88 Fukui, K., 246, 331 Fulmor, W., 145(169), 186 Fusco, G. C., 250(67), 331 Fushizaki, Y.,298(292), 338 G

Gagnaire, D., 79(314), 80, 96 Gallagher, M. J., 1, 10(46), 18(46), 57 (248), 59(253), 74(295), 87,94,95 Gallinella, E., 306(330), 339 Ganter, C., 165(258), 170(285), 190 Garbisch, E. W., Jr., 307, 308, 309(335, 336a-c), 340 Gardikes, J. J . . 306(329), 314(329b), 339 Gardner, P. D., 286,336 Garner, A. Y.,207(48), 233 Garner, R. H., 144(165,167), 145(165), I86 Gamier, F., 265(133), 280(189), 333, 335 Garrat, P. J., 173(304,305), 191 Gassman, P. G., 297(287), 338 Gaston, L. K., 250(66), 331 Gaudy, E. T., 17(86), 88 Gault, I., 172(298), 190 Gault, R., 287, 336 Gebelein, C. G.,293, 294(268), 337 Gehring, D. G., 133(114), 185 Geise. H.J., 84(332), 96 Genas, M., 314(349), 340 Generosa, J. I., 214(64), 233 Geoghegan, P., Jr., 35(356b), 340 Gerig, J. T., 173, 174, 191 Gerrard, A. F., 23(108), 89 Gershman, N. E., 74(297), 95 Gerstl, R., 228(112), 230(118,) 235 Ghosh, J. C., 292(251), 337 Gibbons, W. A., 198(24,27), 232 Gibson, C. S., 81, 96 Gidley, G. C., 265, 278, 334 Gigukre, P. A., 295(279), 338 Gilbert, R. E., 286, 336 Gilboa, H., 174310). 191

350

AUTHOR INDEX

Gill, D., 109(34), 183 Gillespie, R.J., 64,76,94 Ginsburg, D., 174(310), 191 Glasstone, S . , 122(93), 184 Glazer, E. S . , 157(223), 158(223), 170, 188, 190 Gloyna, D., 18(92), 89 Goh, S . H., 229(114), 235 Gold, V.,243(28), 244(28), 330 Goldsmith, D. J., 266(146), 334 Goldwhite, H.,22,89 Gompper, R.,13qI32), 185 Goodman, L.,280(191), 296,335, 338 Gordon, M . , 4(13), 47(198), 48(13), 49 (198),86, 92 Gore, E. S . , 133(112), 134(112), 185 Gorestein, D. G., 85(340), 96 Gosselink, D.W . , 143(158), I86 Gould, C. W., Jr., 273,274(162), 334 Gramas, J . V., 200(39),225(108), 233, 235 Grant, D. M., 134(128), 185 Gratz, J . P.. 22(99), 89 Gray, P.,139( I54a). 186 Grayson, M . , 9,70(281),87,95 Greatbanks, D., 133(121), I85 Greco, C . V., 78(304), 95 Green, M.,2(3), 28(135,136),32(153), 35,75(3), 86, 90, 176(329). 191 Griesbaum, K.. 277(177), 335 Griffin, C . E., 4,44(190), 47(198), 48 ( I3,14),49(l4,198),50( 14,203).SS(25l) 86, 92. 94 Griffin, R.W., 172(299). I90 Griffith, D. L., 147,157(223),158(223), 186, 188 Griffiths, J. E., 72(292),95 Griswald, A. A,, 308,340 Grosse, D., 144(160), I86 Grostic, M.F.. 255,332 Grubbs, E. J., 151, I87 Grundemann, E., 149,187 Grunwald, E., 107(16), 109(16), 159, 166(262). 182. 189, 293(270), 337 Giinthard, H., 261,333 Gunther, H., 175(318-321), 191 Gugler, B.A., 133(119), 185

Gutman, G., 289(238), 336 Gutowsky, H. S . , 105, 106,107(11-13,

25), 109(11), 113(57), 115, 121, 125, 126(70), 132(13), 133(13,68), 134(68), 135(68), 148( 176), 157(70), 158(57,7& 72), 159.175(73), 182-184, 186, I88 Gutsche, C. D., 221(95), 234 Gwynn, D. E., 170(287), 190 H

Haak, P. J. van der, 121(89), 139(89), 149(190), 184, 187 Haake, P., 26(121), 71, 89 Haake, P. C., 70(284), 71,72(284), 95 Haber, R.G., 286,336 Hadik, G., 317(364), 34I Hagernan, H. J., 286,336 Hahn, E. L., 105, 109,115(14), 182 Hall, H. K . , Jr., 284(208), 335 Hall, L.D., 79(315), 96, 115(61), 158 (61), I83 Hallam, H. E., 54(223), 93 Halmann, M.,57(247), 94 Halpern, A., 32(154), 90 Halpern, J., 243(32), 315,330, 34I Hamer, J., 163(255a), I89 Hamer, N.K., 6(27), 23(107,108),28 (27),34(27,107), 60,75,87, 89, 94 Hamilton, W .C., 66(272), 71,94 Hamrnaker, A. G.. 133(119), 185 Hammar, W . J., 315(356c), 340 Hammond, G.S., 136(134), 185, 217 (68),224(68), 234, 245,246(52,54,55), 247,331 Haney, C., 143(157), 186 Hanifin, J . W., Jr., 13(60), 14(60), 88 Hanna, J . G., 287(223), 336 Hansen, K . W., 3(9), 72(9), 86 Hanson, C., 293(270), 337 Haq, M.Z., 160,189 Harris, G. S., 14(62), 88 Harris, P.L., 258(95), 332 Harris, R. K . , 115(60),138(148), 157

(239),158(60,217), 159(60,217),162 (251), 173(60), 183, 186, 188, 189 Harrison, W. A., 312(346), 340

AUTHOR INDEX Hart, F. A., 26(125). 89 Hartman, J. S., 168(277), 190 Hartz, H. D., 230(123), 235 Hartzler, H. D., 207(49), 233 Harvey, M. C., 276(175), 335 Harvey, R. G., 17(84), 88 Hassner, A., 287, 293, 312(346), 336, 337,340 Haszeldine, R . N., 148(173), 186 Hata, K., 172(297), 190 Hatch, L. F., 286, 336 Haugen, G. R., 239(2), 242(2), 258, 330, 332 Hauthal, H. G., 311, 314(343), 316, 340, 34 I Havinga, E., 285, 286, 336 Havlik, A. J., 299(301b), 300(301b), 302, 338,339 Hayakawa, N., 167(263,264), 189 Hayashi. R., 312(346), 340 Hays, H. R.. 57(245). 94 Healey, W. B., 292(258), 337 Heathcock, C., 293(266), 312(346), 337, 340 Heaton, L., 265(138), 280,333 Hechtl, W., 272(160), 334 Heidberg, J., 113(56), 183 Heilbronner, E., 170(291), 190 Heine, H. W., 148(180), 187 Heinola, G. H., 306, 339 Heiss, A. H., 125(94), 133(94), 134, 184 Heitz, R. M., 302(316), 303(316), 339 Hekkert, G. L., 258(107), 333 Heller, S. R., 45(193), 78(304), 92, 95 Hellin, M., 243(29,34), 244(29,34), 330, 33 I Hellman, H. M., 272, 334 Hellwege, D. M., 17(86), 88 Hellwinkel, D., 30(150), 67, 74(150), 76, 77(274d), 90, 94, 95 Helmkamp, G. H., 300, 339 Henbest, H. B., 295, 297(281,283,288), 315(355), 319,323(372a), 338,340,341 Henderson, R. B., 298(290), 338 Henderson, W. A., Jr., 207(47), 233 Hendrickson, J. B., 153, 164, 168, 188190, 285(210), 336

351

Henniger, G., 24(112), 89 Henning, H. G., 18(92), 89 Hennion, G. F., 279, 324, 335, 341 Henry, P., 317(366), 341 Hepner, F., 318, 341 Herail, F., 54(225,226), 93 Herbig, K., 218(69), 234 Herzberg, G., 194(8), 195(8), 197, 198 ( I 7,18), 232 Hess, H., 65(266), 94 Hester, R. E., 16(78), 88 Heublein, G., 283, 284(205), 293, 325 (389), 335, 337, 342 Hey, L., 68(277), 95 Heyes, J. K., 292(258), 337 Higuchi, J., 199(32), 232 Hilgetag, G., 28(132), 90 Hill, H. E., 303321). 339 Hindersinn, R. R., 57(245), 94 Hine, J., 193(3), 231 Hinton, R. C., 24(1 lo), 89 Hirsch, J. A., 153, 187 Hirst, R. C., 134(128), 185 Hoard, L. G., 65(266), 94 Hoberg, H., 218(76), 234 Hocking, M. B., 41(172), 42(172), 91 Hoeg, D. F., 221(88), 234 Hoegger, E. F., 250(63), 331 Hofer, W., 10(45), 29(142), 87, 90 Hoffman, R. A., 115(79), 118, 119, 184 Hoffman, A. K., 203,233 Hoffman, H., 8(34,35), 9(40), 10(40), 16 (80), 18(91), 23(106), 29(35), 69(279), 80, 87-89, 95, 96 Hoffmann, P., 7(29), 87 Hoffmann, R., 196(15), 205(43,45,46), 209(53), 232, 233 Hofmann, D. M., 295(280a), 338 Hofmann, K. A., 314, 339 Hogeveen, H., 258(103,104), 332 Hogg, D. R., 300,339 Holliman, F. G., 26(124), 28(124), 89 Hollis, D. P., 138(149), 139, 186 Holm, C. H., 105, 106, 107(13), 132(13), 133(13), 182 Holrnes, R. R., 24(11 I), 65(306), 72 (292), 89, 95

352

AUTHOR INDEX

Holst, J. P. C., 5(18), 87 Hood, F. P., 107(22), 121(22), 154, 157, l58(220,221), 182, 188 Hopperdietzel, S., 291(244), 336 Hopton, F. J., 151, 187 Horensky, S., 228( I 1 I), 235 Horing, M., 28(131), 90 Horner, L.,2(5), 5(18), 6(26), 8, 9(39, 40,44), 10(5,40,45,47,48), 11(49), 12, 13, 14(57), 26, 27(26,139), 28(123), 29(35,141,142), 31(152), 38, 43, 74 (141), 79(310), 81(47), 8 6 9 0 , 95 HottedahI, B. H., 85(342), 96 House. H. O . , 41(179), 42(179), 91 Howatson, J., 62(260), 94 Howden, M. E. H., 167(266), 189 Howell, R. G., 276(175), 335 Huber, H., 272(160), 334 Hudson, R. F., 2(3), 28(135,136), 32 (153), 35, 38(120), 40(171), 41(171), 42(120,184), 56(120,237), 57(243), 62, 75(3), 86, 89-93 Huisgen, R., 170(283), 190, 272, 286, 334, 336 Huisman, H. O., 149(189,190), 187 Hummel, K. F., 223(100), 234 Hunziker, H., 261,333 Hutchinson, C. A., Jr., 198(25), 199(28, 29,35,36), 200(28,29,35), 201(36), 202 (35,36), 203(25), 221(28). 232, 233 I IbBiiez, L. C., 293(265), 294(265), 337 Ichikawa, K., 315(358), 341 Ide, J., 314(350), 340 Ikegami, S., 315(356d), 322(356d), 340 Inamoto, Y ., 295(276), 337 Inglefield, P T., 1 15(78), 133(78), I38 (78). 184 Inglis, F., 14(62), 88 Ingold, C. K., 68, 69(276), 95, 240, 330 Inhoffen, E., 259(113), 333 lonin, B. I., 49(202), 92 Irving, J., 148(180), 187 Isaacs, W. S., 298(290), 338 Jsbell, A. F., 58(250), 94

Ishii, Y . , 295(276), 337 Issleib, K., 11, 14(62), 23(106), 88, 89 Jtoh, K., 225(105), 235 Iuzhakova, 0 . A., 148(181), 187 Ivanova, Zh. M., 65(267), 94 Ivin, S. Z., 65(267), 94 Iwamura, H., 167(263,264), 189 Izzo, P. T., 145(169), 186 J

Jackson, W. R., 296(281), 297(281), 338 Jacobs, T.L., 258(102), 332 Jacobson, R. A., 65(266), 94 Jacques, M. S., 168(278,279), 170(284), 190 Jaffe, H. H., 52, 92 Jambotkar, D., 40(170), 91 Janusonis, G. A., 113(56), 183 Jarvis, B. B., 289, 303, 336 Jeffery, E. A,, 258(99), 332 Jenkins, C. R., 151, 187 Jenkins, 1. D., I , 59(253), 94 Jensen, F. R., 158(214,216), 159(216, 224), 160, 167, 174(224), 176(336), 188, 189, 192 Jensen, K. A., 14(63), 88 Jijovici, C. T., 276(174), 334 Joachim, G., 41(175), 91 Johannesson, J. K., 292(258), 337 Johns, J. W. C., 197(18), 198(18), 232 Johnson, A. L., 137(138), 150(138), 185 Johnson, A. W., 39(168), 40(168), 91 Johnson, C. R., 266(146), 334 Johnson, C. S., 100(8), 101, 111, 115 (76), 117(76), 182-184 Johnson, D. W., 250 (62,66), 331 Johnson, E. A., 266(148), 334 Johnson, F. A., 143(157), 186, 263(128), 264(128), 333 Johnson, G. A., 9(43), 87 Johnson, J. W., 9(42), 10(42), 13(42), 31 (421, 87 Johnson, M. D., 272,334 Johnston, F., 240(6), 330 Jon& J., 107(25), 113(57), 121, 125, 158(57), 182, 183

AUTHOR INDEX Jonas, V., 133(125), 134, 135(125), 185 Jones, D., 285(210), 336 Jones, D. W . ,79(316), 84, 96 Jones, E. R. H., 312(346), 340 Jones, K., 16(78), 88 Jones, M., Jr., 222(96,97), 223(100), 234 Jones, M. E., 39(169), 91 Jones, V. K., 41(179), 42(179), 91 Jordaan, J. H., 312(347), 340 Jordan, P. C. H., 196(12), 232 Jovanovich, A. P., 163(246), 189 Jovtscheff, A., 287, 336 Jung, A., 149(187), 187 Junge, B., 164256), 174(256), 189 Jungermann, E., 47(195), 92 Jurale, J. B., 250(62), 331 Jusk, M. E., 198(21), 232 Jutz, C., 144(160), 186 Juvinall, G. L., 5(17), 47(17), 52(17), 87 K

Kabachnik, M. I., 54(227), 93 Kabuss, S . , 107(24), 157(226,236), 162 (24,236,250), 163(24,236), 165(259), 166(24,259-261), 182, 188, 189 Kaczynski, J. A., 143(158), 186 Kadibelban, T., 78(305), 95 Kadziauskas, P., 313(348), 340 Kaesz, H. D., 176(328,330), 191 Kainosho, M., 172(297), 190 Kalabina, A. V . ,299(302), 339 Kamai, G., 2(6), 86 Kaneko, H., 43(188), 92 Kanyaev, N. P., 282, 288(200), 335 Kaplan, F., 107(23), 121(23), 143, 152 (1991, 182, 186, 187 Kaplan, J. I., 110(39), 111, 183 Kaplan, L., 288, 289(235,236a,236b), 327(235), 336 Kaplan, M. L., 157(229), 163(255), 188, 189 Kaplan, R. B., 306(331), 339 Karger, E. R., 250(64), 331 Karkower, E., 115(78), 133(78), 138 (78), 184 Kames, H. A,, 130(102), 184

353

Karpenko, T. F., 262(123), 333 Kartch, J. L., 273(165), 274(165), 276 ( I 65), 279( 180), 334, 335 Kasiwagi, H., 262, 333 Katz, J. J., 243(35), 331 Katz, T. J., 4, 6(25), 21, 87 Kawakami, J. H., 315(356d), 322(356d), 340 Kay, J. C., 52(208), 92 Keay, L., 56(237), 93 Keefer, R. M., 241(13), 330 Keeffe, J. R., 243(31), 244(31), 330 Keldsen, G., 29(148), 90 Keller, C. E., 176(327), 191 Keller, H., 131(104), 184 Kempf, R . J., 200(39), 233 Kende, A. S., 145(169), I86 Kenyon, G. L., 4(12), 48(12), 49(12), 54, 86, 93 Keough, P. T., 9(43), 70(281), 87, 95 Kerillova, K. M., 85(338), 96 Kerst, F., 56(241), 57(241), 85(341), 93, 96 Keske, R. G., 162(245,246), 163(255b), 189 Kessick, M. A., 243(28), 244(28), 330 Kessler, H., 145(170), 186 Ketcham, R., 40(170), 91 Khaikin, L. S., 3(10), 86 Khairullin, V. K., 57(245), 94 Kharasch, M. S., 258(94), 332 Kharasch, N., 299, 300(299,301b,306), 302, 304, 305(320), 338, 339 Khorana, H. G., 70, 95 Kiefer, E. F., 319(374), 320(374), 341 Killheffer, J. V., 47(195), 92 Kilpatrick. M., 243(30), 330 Kimball, G. E., 240, 282, 288(11), 330 King, G. W., 196(13), 232 Kinnaird, J. K., 125(94), 133(94), 134, 184 Kinstle, T. H., 250(65), 251, 331 Kintzinger, J. P., 150(192), 174(192), 187 Kirmse, W., 193(2,4), 194(4), 219(78), 23 I , 232, 234 Kirsanov, A. V., 65(267), 94

354

AUTHOR INDEX

Kise, M. A., 311(341), 314(341), 340 Kish, F . A., 244(40), 331 Kistiakowsky, G. R., 242(19), 265(19), 280( 19), 330 Klebe, J., 225(106,107), 235 Klein, F. S., 243(26), 330 Klein, M., 168(273), 190 Klinck, R. E., 140(155), 186 Klink, W., 27(139), 43(139), 90 Kluger, R., 85(341), 96 Knaack, D. F., 268, 334 Knorr, R., 165(258), 189 Knunyants, I . L., 56(238-240), 93 Kodolov, V. I . , 57(245), 94 Kobrich, G., 193(6), 221(85,87), 232, 234 Koelle, U., 144(161), 186 Koenigsberger, R., 266(149,150), 267 (149,150), 268(150) 334 Koeppl, G. W., 148(185), 187 Kohler, B., 198(25), 199(29,36), 200 (29), 201(36), 202(36), 203(25), 232, 233 Kollner, G., 293(267), 337 Kolmakova, E. F., 299(302), 339 Kopecky, K. R., 217(68), 224(68), 234 Koptyug, V. A., 176(337), 192 Kornegay, R. L., 107(22), 121(22), 154, 157, 158(220,221), 182, 188 Korpiun, O., 82, 83(327), 96 Korsch, B. H., 137(144), 164(144), 186 Korver, P. K., 121(89), 139(89), 149 (1901, 184, 187 Kosolapoff, G. M., 57(245,249), 58 (249), 94 Kostyanovskii, R. G., 148(181), 187 Kovtun, V. Yu, 41(178), 91 Kowitt, F. R., 315(357), 317(357b), 340 Kramer, H.E. A., 136(131,132), 185 Krauss, M., 196(11), 232 Krawiecki, C., 28(137), 90 Kreevoy, M. M., 315, 317(357b,357c), 340,341 Kreiter, C. G., 176(328), 191 Krespan, C. G., 24(113), 89 Krishnamurthy, G. S., 148(185), 187

Kriz, O., 6(28), 13(28), 26(28), 87 Kubala, I., 326(390), 342 Kubo, R., 109, 182 Kugel, L., 57(247), 94 Kukhtin, V. A., 85(338), 96 Kulczycki, A., Jr., 223(100), 234 Kumli, K. F., 8(36,38), 28(38), 29(148), 69(36), 87, 90 Kumura, K., 198(26), 232 Kunovskaya, D. M., 311(342), 340 Kuppers, H., 230(125), 235 Kurland, R. J., 113(55), 131(105,106), 167. 171(292,295), 183-185,190 Kuryleva, M. A., 57(245), 94 Kwart, H., 251, 288, 289(235,236a, 236b), 295(280a,280c), 297(286), 300, 302(317,318), 327(235), 331, 336,

338,339 Kwiatkowski, G. T., 44, 92 Kyllingstad, V. L., 39(168), 40(168), 91 Kyogoku, Y.,54(231), 93

L

Labana, S. S.,298(293), 338 Lacher, A. J., 168(274), 190 LaFlamme, P., 217(67), 233 Laidler, K. J., 122(93), 155(211), 184, 188, 208(51), 233 Laird, R. K., 198(20), 232 Lambert, J. B., 11(51), 88, 151, 152, 162(245,246). 163(255b), 175(316),

187, 189, 191 Lambie, A. J., 56(236), 93 Lamm, B., 243(31), 244(31,46), 330,331 Landauer, S. R., 17(85), 88 Lane, C. A., 256(82), 332 Lansbury, P. T., 168(271-274), 189, 190 LaPlaca, S. J., 66(272), 71, 94 LaPlanche, L. A., 132(107), 185 Larsson, L., 60(256), 94 Lauer, D., 54(222), 93, 135, 185 Lauter, W., 28(131), 90 LeBel, N . A., 250(64), 331 Lee, D. G., 85(341), 96 Lee, D.-J., 258(101), 260(114,115), 261 (1 14-1 16), 332,333

AUTHOR INDEX Lee, J., 149(188), 187 Leermakers, P. A., 217(68), 224(68), 234 Le Fkvre, R. J. W., 53(214,215), 93 Leffler, J. E., 159 Lehmann, G., 28(132), 90 Lehmann, G. J., 230(123,124), 235 Lehn, J. M., 113(58), 137(137,139,141), I50(137,139,192), 162(137), 163(58, 254), 164(137), 170(281), 174(192), 183, 185-187, 189, 190 Leitch, L. C., 279, 335 Lernaire, H., 324, 341 Lemieux, R. U., 285(209), 312(347), 335,340 Lengyel, I., 41(175), 91 LCpingle, M., 261(117), 333 Lerch, A., 230(119), 235 Letsinger, R. L., 42(182), 91 Leung, Y . C., 15(64), 88 Levy, L. A., 287, 293,336,337 Lewis, R. A., 83(327), 96 Lichtenstadt, L., 2(1), 28(1,131), 86, 90 Lieske, C. N., 60(257), 94 Lin, C. C., 54(232), 93 Lin, C. H., 230(127), 235 Lin, Y. S., 170, 190 Linde, J. van der, 285, 336 Lipscomb, W. N., 23(105), 52(210), 71, 84(210), 89, 92 Lishnevskii, V. A., 265(132), 280(190), 333,335 Little, R . Q., 256(89), 257(89), 332 Liu, K.-T., 252, 298(289), 303(289), 331, 332,338 Loewenstein, A., 100, 101, 107(1618), 109(16,17,35), 133(35,126), 135(126), 148(177), 174(310), 182, 183, 185, 187, 191 Logothetis, A. L., 148(178), 187 Lomas, J. S., 266( I48,149), 267( 149), 334 Loncrini, D. F., 297(285), 338 Long, J. W., 283(201), 335 Longuet-Higgins, H. C., 173(305), 191, 196(I2), 205(44), 232, 233 Looney, C. E., 138, 139(153), 186

355

Lorber, M. E., 293(266), 337 Loshadkin, N. A., 56(239,240), 93 Lucas, H. J., 256(85), 273, 274(162), 286, 287, 293(270), 318, 324, 332, 334, 336, 337,341 Ludington, R. S., 57(245), 94 Liittringhaus, A., 157(236), 162(236, 250), 163(236), 165(259), 166(259, 261), 188, 189 Lumb, J. T., 298(293), 338 Lunk, H. E., 272,334 Lupien, Y., 242(16), 258(16), 330 Lusk, D. I . , 221(88), 234 Lutz, R. E., 256, 332 Luz, Z., 109(34), 115(67), 183 Lwo, S. Y.,297, 338 Lydy, D. L., 52(208), 92 Lynch, B. M., 295(277), 338 Lynden-Bell, R. M., 15(72), 88

M Maasbol, A., 176(328,330), 191 Maass, O., 242( 15), 258(93), 330, 332 McBride, J . J., Jr., 47(195), 92 McCall, D. W., 105, 107(11), 109(11), 182 McCarty, C. G., 151, 160(244), 187, 189 McConnell, H. M., 105, 109, 115(62, 631, 182, 183 McCreath, M. K., 148(173), 186 McCullough, J. J., 297(283), 338 MacDonald, D. B., 157(227), 162(227), 188 McElhinney, R. S., 296(281), 297(281), 319(372), 338, 341 McElvain, S. M., 229(115), 235 McEwen, W. E., 2(4), 8, 9, 10(42), 13 (42), 28(38,133,134), 29(148), 30, 31 (42,149), 38(4), 39, 69, 77(303), 86, 87, 90, 95 McGee, T. W., 283(202), 335 McKenzie, A., 288(229), 336 Mackor, E. L., 176(333,334), 191, 192 MacLean, C., 176(333,334), 191, 192 McNab, J. G., 258(94), 332 McNab, M. C., 258(94), 332

356

AUTHOR INDEX

MacNicol, D. D., 139(151), 186 Maercker, A,, 38(162), 91 Maerten, G., 135, 185 Mahler, W., 64(265), 65(269), 73(269), 94 Maier, L., 11, 29(147), 87, 90 Maier, W., 157(236), 162(236,247,250), 163(236), 188, 189 Maklyaev, F. L., 56(239), 93 Maksyutin, Y.K., 299(302), 339 Malakhov, A. I., 325, 342 Malcolm, R. B., 79(315), 96 Malkes, L. Y.,84(334), 96 Malli, G. L., 196(13), 232 Mallik, K. L., 316(362), 341 Mallory, F. B., 175(322,324), 191 Manassen, J., 243(26), 330 Manatt, S. L., 5(17). 47(17), 52(17), 87, 175(324), 191 Mann, D. E., 198(21), 232 Mann, F. G., 2(2), 6(24), 8, 20, 21. 23, 24(110), 26(124,125), 28(124,138), 86, 87, 89, 90 Mannschreck, A., 133(120,124), 144 (161), 149, 151(195), 168(269,270), 185-187, 189 Marchand, A. P., 240(12), 330 Mare, P. B. D. de la, 241, 243(24,33), 244(24,33,43), 256(81), 265, 266, 267 (149-151), 268, 275, 276(173), 277, 281, 292(259), 295(273), 328(391), 330-335,337, 342 Mark, V., 16, 81,88,96 Markl, G., 7(31), 24(117,118), 47(117, 118), 87,89 Markov, S. M., 56(239,240), 93 Marktscheffel, F., 9(41), 87 Marolewski, T., 227(109), 235 Marr, D. H., 140(155), 186 Marsi, K. L., 28(134), 90 Marsili, A., 288, 336 Martin, D. J ,47(198), 49(198), 58(251), 92, 94 Martin, G , 136(133), 185 Martin, M., 136(133), 185 Martinelli, L., 40(170). 91 Martini, T., 170(288), 190

Marullo, N. P., 151(194), 187 Mataga, N., 225(105), 235 Matesich, M. A., 258(110), 259(110), 333 Matsuo, M., 318(371), 341 Maxwell, D. E., 105, 109, 115(14), 182 May, L., 137(140), 186 Mayants, L. S., 54(227), 93 Mayo, F. R., 243(21,35,36), 330, 331 Meakins, G. D., 295(280b), 312(346), 338,340 Mecke, R., 107(24), 162(24), 163(24), 165(259), 166(24,259,261), 182, 189 Meiboom, S., 107(16-18), 109(16,17, 34,35), 115(67), 133(35), 158(218). 182, 183, 188 Meinhardt, N. A., 280(187), 335 Meinwald, J., 289(240), 298(293), 312 (343, 313, 314(345), 336, 338,340 Meinwald, Y.C., 312(345), 313, 314 (349,340 Meinzer, R. A., 107(25), 125, 182 Meisenheimer, J., 2, 28(1,131), 86, 90 Melera, A., 133(126), 135(126), 173 (302), 185, 190 Melillo, J. T., 21(94), 89 Melloni, G., 304(325), 305(322,325), 339 Meloy, G. K.,107(23), 121(23), 143, 182, 186 Mentrup, A., 8(39), 9(39,40), 10(40), 87 Merenyi, R., 41(175), 91, 170(288), 175 (312,314,315), 190, 191 Merer, A. J., 198(22,23), 221(22), 232 Merkle, H . R., 221(85), 234 Merrall, G. T., 274(167), 334 Merritt, R. F., 263, 264(128,129a,129b), 333 Metzger, J., 315(360), 341 Metzger, S H . , 58(250), 94 Meyer, E., 26(123), 28(123), 89 Meyex, R., 261,333 Meyer, R. B., 130(100), 184 Meyer, W. L., 130(100), 184 Meyers, E. A., 76(298), 95 Meyers, M. B., 296(281), 297(281), 338 Michael, A., 262, 333

AUTHOR INDEX

Michalski, J., 27(126-128), 28(137), 29 ( I 2 6 1 28,146), 32( 126,128,154), 33 (127,146,155), 34(146,156), 35, 79, 89-91,95 Mikolajczyk, M., 27(126-128), 29(126128), 32(126,128,154), 33(127,155), 34(156), 35(158), 36(159), 79(312, 313), 83(329), 89-91, 96 Milburn, R. M., 259(113), 291(113a), 328( 1 13a), 333 Miller, E., 286(219), 336 'Miller, E. G . , Jr., 60(257), 94 Miller, F. A., 15(65,69). 88 Miller, J. I., 27(129), 28(129), 29(144, 145), 38(144,145), 90 Miller, J. L., 283(204), 287(204), 300, 335, 339 Miller, R. K., 302(317,318), 339 Miller, R . L., 137(138), 150(138), 185 Miller, S. I., 148(185), 187, 292(257), 294, 337 Miller, W. B., 26(121), 89 Miller, W. T., Jr., 221(86), 234 Milligan, D. E., 198(21), 232 Milton, K. M., 256(88), 257(88), 332 Mironova, D. F., 262(122), 333 Mishra, A,, 210(55), 233 Mislow, K., 21, 27(140), 74(140), 82, 83(327), 89, 91, 96, 130(101), 147 (101), 184, 272, 334 Mitchell, E. W., 17(87), 88 Mitsch, R. A,, 198(21), 221(92), 232, 234 Mode, V. A., 52(208), 92 Modena, G., 304(325), 305(322,323, 325), 339 Moen, R. V., 53(220), 93 Moffatt, J. G., 70(283), 95 Mokuolu, J. A. A., 3(1 I), 86 Mollard, M., 243(34), 244(34), 331 Monahan, M., 248(58,59), 331 Moniz, W. B., 158(215), 173(215), 188 Montanari, F., 304, 339 Montgomery, R. E., 22(99), 89 Moore, D. W., 133(117), 185 More, W. B., 210(54), 233 Moriarty, R. M., 137(140), 186

357

Moritani, I., 198(26), 225(104,105), 232, 235 Morrill, T. C., 253, 254(76), 332 Morse, A. T., 279(179), 335 Mortimer, F. S., 54(224), 93 Mosher, W. A., 133(114), 185 Moss, R. A., 204(42), 207(42), 221(42), 223(101,102), 227(42,1 lo), 228(42, 112), 229(42,116), 230(42,110,118), 233-235 Moura Campos, M. de, 292(262), 300 (305), 337,339 Muelder, W. W., 54(228), 93 Mueller, D. C., 11(51), 88, 151, 152, 187 Mueller, W. H., 53(220), 93, 277(177), 299, 302(300d), 303(300d), 335, 338 Muetterties, E. L., 62, 64(265), 65(269), 68, 73(269), 77(302), 79, 94-96 Mui, J. Y.-P., 221(90), 234 Muller, G., 42(180), 91 Muller, N., 157(232), 173(232), 188 Murahashi, S. I., 198(26), 225(104,105), 232, 235 Murphy, M. R., 137(140), 186 Murray, R. W., 157(229), 163(255), 188, 189, 199(30,33,34), 200(30,33,34,37), 202(34), 221(30,33,34), 232, 233 Murrell, J. N., 170(291), 190 Musco, A., 176(326), 191

N Nachtigall, G. W., 266(143), 277, 278 (143), 289(239), 334, 336 Nagabhushan, T. L., 312(347), 340 Nagabhushanarn, M., 17(86), 88 Nagarajan, K., 157(223), 158(223), 188 Nair, P. M., 127(97), 184 Narase, N., 314(349), 340 Navada, C. K., 148(184), 187 Naylor, P. G., 266(145), 334 Negrini, A., 304, 339 Neikarn, W. C., 157(233), 188 Neirnysheva, A. A., 56(238-240), 93 Nelson, A. F., 292(250), 337 Nenitzescu, C. P., 276(174), 334

AUTHOR INDEX

358

Nesmeyanov, A. N., 324, 325(388), 341, 342 Neuman, R . C., 133( I 1 I ,I 2 9 , 134, 135(111,125), 136(134), 185 Neumer, J. F., 148(177), 187 Nevitt, T. D., 246(54), 247, 331 Newman, M. S., 130(102), 184, 281, 335 Newmark, R. A., 111, 113, 124, 127 (46,98,99), 183, 184 Newton, M. G., 52(21 I), 84(21I ) , 92 Nicholls, B., 296(281), 297(281,288), 315(355), 319(372), 323(372a), 338, 340, 341 Nicholls, D., 21(95), 89 Nicholson, C. R., 6(25), 21(25), 87 Nieuwland, J. A., 324, 341 Nishimura, K., 315(358), 341 Nishino, M., 198(26), 225(104,105), 232, 235 Nixon, E. R., 15(70), 88 Nordlander, J. F., 176(339), 192 Norman, R. 0. C., 284, 287(207), 335 Norris, R. O., 279(184,185), 335 Noth, H., 24(112), 89 Noyce, D. S., 158(214,216), 159(216), 188, 256, 258(110), 259(110), 318 (369), 332, 333, 341 Noyes, R. M., 292(257), 294, 337 Nozaki, K., 288(230,231), 336 Nseic, S., 85(336), 96 Nukada, K., 312(344), 340 Nunes, F., 263( I27), 333 Nyce, J. L., 251, 302(318), 331, 339 Nyquist, R. A.. 54(228). 93 0

Ogden, P. H.. 151(196), 187 Ogg, R. A., 139(152), 186, 240(9), 288 (230,231), 330, 336 Oglobin, K. A., 311(342), 340 Ohme, R., 149, 187 Ohno, M., 312(344), 314(349), 340 Okamoto, M., 312(344), 314(349), 340 Okazaki, M., 43(188). 92 Oki, M., 167(263.264), 189

Olah, G. A., 176(335), 192, 265(131), 276, 282, 294(131), 333 Olechowski, J. R., 292(248), 337 Olijnsma, T., 121, 137(90), 184 Oliver, W. H., 259(113), 291(113a), 328 (1 13a), 333 Ollis, W. D., 144(162), 172(300), 186, I90 Omelanczuk, J., 27( 127), 29( 127), 33 (127), 89 O'Neil, 1. K., 312(347), 340 Ooms, A. J., 29(143), 34(143), 90 Orr, W. L., 299(301a), 300(306), 338, 339 Orrell, K. G., 149(188), 187 Osyany, J. M., 148(182), 187 Oth, J. F . M., 41(175), 91, 170(288),173 (303), 175(312-315), 190, 191 Ourisson, G., 46(194), 48(194), 50, 53 (220), 79(194), 84, 85(336), 92, 93, 96 Owai, I., 314(350), 340

P Paddock, N. L., 5 2 , 9 2 Padgett, A., 196(1I ) , 232 Pagilagan, R . U., 57(245), 77(303), 94, 95 Palenik, G. J., 23(104), 89 Pande, K. C., 323(378), 341 Pandit, U. K., 149(189,190), 187 Panse, P., 42(185), 92 Panshin, 0. A , , 148(181), 187 Pape, P. G., 297(287), 338 Pappas, A. C., 294(271), 337 Parisek, C. B., 29(148), 30(149), 31 (149). 90 Parker, R. E., 298(290), 338 Parker, W. E., 295(279), 338 Pausacker, K. H., 295(277), 338 Paust, J., 2391 19,121-123), 235 Patwardhan, A. V . , 45(193), 78(304), 92, 95 Pavlis, R . R., 292(254), 337 Pawson, B. A., 131(103,104), 184 Paxton, H . J., 6(307), 95 Payne, D. S., 3(11), 24112), 86,89

AUTHOR INDEX Payne, M., 260(115), 261(115), 333 Peake, A., 168(280), 190 Pearson, G. A., 199(35), 200(35), 202 (35), 233 Peer, H. G., 277(177), 335 Peerdeman, A. F., 5(18), 87 Perrin, C . L., 328 Peterson, D. J., 13(58), 88 Peterson, H. J., 244(40), 331 Peterson, P. E., 244(41,42), 258(1 lo), 259, 331, 333 Petro, V. P.. 62(260), 94 Petrov, A. A., 49(202), 92 Pettit, R.,176(327), 191 Pettitt, D. J . , 300, 339 Peyerimhoff, S. D., 194-196(9), 232 Philipsborn, W. v., 133(115), 185 Phillips, D. D., 49(199), 92 Phillips, W. D., 100(6), 127, 132, 138, 139(153), 182, 185, 186 Piette, L. H . , 107(19), 115(19), 133 (116a), 139(19,152), 182, 185, 186 Pinchas, S., 57(247), 94 Piskovitina, G. A,, 243(39), 246(39), 247, 331 Pitteroff, W., 230( 120), 235 Pitzer, K. S., 155(212), I88 Plapinger, R. E., 61(259), 94 Platenburg, D. H. J. M., 83(330), 96 Pliszka-Krawiecka, B., 33(155), 90 Pocker, Y., 243(37,38), 244(38), 245 (38), 331 Pokras, S. M., 170(285), 190 Polanyi, J. C., 155(211), 188 Polekhin, A. M . , 56(239,240), 93 Politt, J., 259(113), 333 Pollard, G. R., 49(199), 92 Ponsold, K., 293(267), 337 Pope, W. J . , 81, 96 Pople, J . A,, 53(217), 93, 100(1), 182 Popov, E. M . , 54(227), 93 Poulain, C., 314(349), 340 Poutsma, M. L., 265, 266(136,14O), 272, 273, 274(134,135,165), 275(136), 276(165), 277, 279, 333-33.5 Powers, J. C., 250(64), 331 Powles, J. G., 109, 115(32), 182

359

Pragnell, M. J., 23, 89 Prelog, V., 13, 88 Premuzic, E., 157(234,237), 188 Price, B. J., 113(58), 136(135,136), 137 (135,136), 162(136), 163(58), 164 (135,136), 172(298), 183, 185, 190 Price, C. C., 285(21 I), 306(330), 336, 339 Price, E., 166(262), 189 Pring, M., 281(195), 282(195), 286(195), 288( 199, 335 Pritchard, J. G., 266(144), 334 Pritzkow, W., 311, 314(343), 340 Prohaska, C . A., 53(218,220), 93, 144 (163,166), 145(166), 186 Proszynska, K., 32(154), 90 Pryor, W. A., 243(23), 330 Pugenstrecker, A., 256(86), 332 Purcell, E. M., 115, 183 Purlee, E. L., 244(45), 249(45), 331 Puterbaugh, W. H., 281, 335

Q Quin, L. D., 22, 81, 89, 96

R Raban, M., 130(101), 147(101), 184 Radeglia, R., 149, 187 Radlick, P., 171(293), 190 Ramanathan, N., 45(192), 78(304), 92, 95 Ramey, P. S., 268(152), 284(152), 334 Ramirez, F., 45, 66, 71, 77, 78(304), 92, 94, 95 Ramsay, M. V. J., 167(265), 189 Ranft, J., 47(200), 92 Ranus, W. J., 289(238), 336 Rao, B. D. N., 119(86), 184 Rapp, A., 9(40), 10(40), 12(53), 13(53), 87,88 Ratajczak, A., 29(146), 33(146), 34 (146), 35(158), 90, 91 Ratts, K . W., 41(173), 91 Rave, T. W . ,57(245), 94 Ray, J. D., 139(152), 186

360

AUTHOR INDEX

Raymond, F. A., 255, 332 Reddy, G. S., 54(221), 93, 133(114), 185 Redfield, A. G., 1 I1(50), 183 Ree, T., 134(128), 185 Reeves, L. W., lW5), 115(66,75,78), I33(78), 138(78), I39(66,154a), 157 (230,231,234,237), 162(66,252), 182184, 186, 188, 189 Rehak, J., 54(229), 93 Reilly, C. A., 5(15), 6(25), 21(25), 47 (197), 49(197,199), 86, 87, 92 Reilly, E. L., 138, 186 Rengevich, E. W., 292(261), 337 Renolen, P., 295(274), 337 Rettig, K. R., 222(96,97), 235 Reusch, W., 157(228). 188 Reutov, 0. A., 318(371), 341 Rezvukhin, A. I., 176(337), 192 Richey, H. G., 258, 333 Richey, J. M., 258,333 Rickborn, B., 297, 338 Ridd, J. H., 266(147), 334 Riddell, F. G., 113(58), 163(58,254), 170(281), 174(309), 183, 189-191 Rieker, A., 145(170). 186 Riggs, N. V., 137(144), 164(144), 186 Rigny, P., 133(126), 135(126), 185 Rissrnann, G . , 168(270), 189 Roark, D. N., 133(125), 134, 135(125), 185 Robert, J. B., 79(314), 80(317,318), 96 Roberts, I., 240,282, 288(1 I), 330 Roberts, J . D., 121, 122(92), 127, 131 (92), 147, 148, 152(199-202), 157 (223), 158(88,222,223), 165, 170, 173, 174, 176(329), 184, 186-191, 288, 336 Robertson, P. W., 259(113), 281(198), 291, 292(258). 328( 11 3a), 333,335, 33 7 Robinson, M. J. T., 174(309), 191 Robinson. R., 240,330 Robison. G. L., 279(182), 335 Robson, J. H., 315(355), 340 Rodgman, A., 317(368), 341 Rogers, D. B., 133(121), 185 Rogers, M. T., 107(21), 121(21), 132 (107), 133(21.116b), 134(21), 182, 185

Rondestvedt, C. S., Jr., 289(237), 336 Rose, H., 135, 185 Roseman, K. A., 137(142,143), 164 (142,143), 186 Rosenfelder, W. J., 286(220), 336 Roth, W., 218(77), 234 Roth, W. R., 171(294), 175, 190, 191 Rothbaum, H . P., 281(198), 335 Rowland, F. S., 219(79,80), 227(80), 234 Rubin, M. B., 113(55), 167, 183 Ruchardt, C., 42(185), 92 Rull, T., 314(349), 340 Russell, J., 258(93). 332 Rydon, H. N., 17(85), 88 S Sack, R. A., 109, 182 Saeva, F., 168(272), 190 Sagatys, D. S., 148(185), 187 Saika, A., 105, 107(12), 182 St. Janiak, P., 24(109), 89 Saito, M., 298(292), 338 Saito, Y., 318(371), 341 Salama, A., 275, 334 Salem, L., 170(290), 190 Salvadori, G., 42(184), 92 Sarnitov, Y.Y . ,85(338), 96 Samuel, W., 28(131), 90 Sanchez, R. A., 253, 254(76), 332 Sanchez del Olmo, V., 266(149), 267 (149), 334 Sancier, K. M., 292(249), 337 Sand, J., 314, 315, 340 Sandstrom, J., 133(127), 1 3 3127), 137 (127), 185 Sans, T. T.,15(65), 88 Sargeant, G. D., 273(164), 334 Satchell, D. P. N., 258(99), 332 Sato, T.,172(297), 190 Sauer, L., 149(187), 187 Sauermann, P., 291(244), 336 Saunders, M., 109(26), 113(53), 115(76), 117(76), 121(91), 147, 175, 176(335, 338), 182-184, 192 Savoy, M. G., 243(36), 331

AUTHOR INDEX Saxby, J. D., 53(214,215). 93 Schaleger. L. L., 315(357), 340, 341 Schawlow, A. L., 146(171), 186 Schedlbauer, F., 10(47), 81(47), 87 Scheibe, G., 144(160), 186 Scheiner, P., 256(91), 257(91), 332 Schellenbeck, P., 16(80), 80, 88, 96 Schiavelli, M . D., 258(1lo), 259(110), 318(369), 333, 341 Schleyer, P. v. R., 176(335), 192, 254, 289(235), 327(235), 332, 336 Schlosser, M . , 42(180,181), 78(305), 91, 95 Schlybach, H. H., 298(294), 338 Schmeising, H. N., 318(369), 341 Schmid, G. H., 302, 306,339 Schmid, H. G., 107(24), 157(226), 162 (24), 163(24), 166(24,260,261),182, 188, 189 Schmidt, L., 15(71), 88 Schmutzler, R., 54(221), 64(265), 65, 76 (300). 93-95 Schneider, H.-J., 283(206), 335 Schneider, W. G., 53(217), 93, 100(1), I33( 116a), 182, 185, 242( l6), 258 (1 61, 330 Schober, D., 229(113), 235 Schollkopf. U., 230(119-125), 235 Schoenthaler, A. C., 256(89), 257(89), 332 Schroder, G., 170(288), 173(303), 175 (312-315), 190. 191 Schubart, R., 175(320), 191 Schubert, C., 268( 1 56), 273(156), 276 ( 156), 334 Schubert, W. M., 243(31), 244(31,46), 330,331 Schumacher, H., 230(122), 235 Schunn, R. A., 62, 94 Schupp, 0. E., Ill, 43(187), 92 Schuster, 1. I., 131(105,106), 184, 185 Schwartz, G. M., 221(82), 234 Schwartz, N. W., 295(274), 337 Schwarzenbach, K., 218(73), 234 Scorrano, G., 304(325), 305(322,323, 325), 339 Searle, R. J. G., 40(171), 41(171), 91

361

Searles, S., Jr., 258(102), 332 Sears, C. A., 306(330), 339 Sederholm, C. H., 11I , 113(46), 124, 127, 158(214,216), 159(216), 183, 184, 188 Seiber, J. N., 83(328), 96 Seidel, W., 14(62), 88 Seifert, W. K., 250(62), 331 Seiffert, W., 144(160), 186 Sekuur, T. J., 157(238), 188 Semenov, V. P., 311(342), 340 Senyavina, L. B., 41(178), 91 Sequeira, R. M., 303(319), 339 Sergeev, G. B., 280(190), 335 Serguchev, Y. A., 279(181), 335 Setontein, W. J., 312(347), 340 Seus, E. J., 43(187), 92 Seven, A., 81(325), 96 Sexton, A., 266(149), 267(149), 334 Seyferth, D., 48(196), 58(252), 92, 94, 221(89,90), 234 Shadinger, G. H., 262, 333 Sharp, D. W . A., 65(270), 72(270), 94 Shatavsky, M., 323(378), 341 Shearer, D. A., 317(366), 341 Shechter, H., 306, 314(329b), 339 Sheldon, R. A., 7(32), 87 Sheldrich, G. M . , 16(77), 88 Shemyakin, M. M . , 38(161,164), 41 (1 61,164,176-1 78), 42(161,164,176), 43(164,186), 84(333), 91, 92, 96 Sheppard, N., 115(60), 157(239), 158 (60,217), 159(60,217),173(60), 183,188 Shilov, E. A., 262(124), 279(181), 291 (246), 292(261), 333, 335, 337 Shimanouchi, T., 54(231), 93 Shook, H. E., Jr., 22(98), 81, 89, 96 Shoosmith, J., 197(16), 232 Shore, S. G., 62(260), 94 Shoulders, B., 176(327), 191 Shryne, T. M., 27(129), 28(129), 29 (145), 38(145), 90 Shubin, V. G., 176(337), 192 Shubina, L. V . , 84(334), 96 Shuler, W. E., 53(220), 93 Siddall, T. H., 111, 53(218,220), 93, 144, l45( 165,166,168), 186

362

AUTHOR INDEX

Siegel, S., 133(110,117,118), 134110, 118), 185 Siggia, S., 287(223), 336 Silky, R., 199(29), 200(29), 232 Simmons, H. E., 218, 234 Simonnin, M. P., 51(204), 81(324), 92, 96 Singer, F., 315, 340 Singh, G., 58(252), 94 Sinn, H., 259(113), 291(244), 333, 336 Skell, P. S., 200(39), 207, 217(66), 221 (91,93), 225( 106,107), 230(126), 233235, 258(97), 292(254), 332, 337 Skovronek, H. S., 21 1(93), 234 Slichter, C. P., 102(9), 105, 107(11), 109 ( I I ) , 112(52), 182, 183 Slobodkin, N. R., 299(303), 302(312), 339 Smallman, R. V., 136(135), 137(135), 164(135), 185 Smirnov-Zamkov, 1. V., 243(39), 246 (39), 247, 291(246), 331,337 Smith, C. P., 78(304), 95 Smith, E. A., 242(19), 265(19), 280(19), 330 Smith, G. E., 27(129), 28(129), 90 Smith, J. C., 258(95), 332 Smith, L. A., 167, 189 Smith, L. O., Jr., 303(319), 339 Smith, R. A., 246(56), 248(56), 331 Smith, R. D., 218, 234 Smolina, G. I., 299(302), 339 Snyder, E. I., 53(220), 93 Snyder, J. P., 291, 336 Snyder, L. C., 199(31), 200(31), 232 Sokolov, V. I., 318(371), 341 Solodovnik, V. D., 41(178), 91 Solomon, I., 110(38), 115(38), 183 Soloway, S. B., 49(199), 92 Sondheimer, F., 173(301,302,304-306), 190, 191 Songstad, J., 69(280), 95 Sonnenberg, F. M., 250(65), 251,331 Sonnet, P. E., 53(220), 93 Spaeth, C. P., 139(153), 186 Spasskii, S. S., 57(245), 94 Spassov, S. L., 157(223), 158(223), 188

Speakman, J. C., 3(1 I), 86 Speckamp, W.N., 149(189,190), 187 Spencer, C. J., 23(105), 89 Speziale, A. J., 41(173). 91 Spitzer, R., 155(212), 188 Spragg, R. A., 138(148), 162(251), 186, 189 Staab, H . A., 54(222), 93, 133(124), 135, 151(195), 164(256), 174(256), 185, 187, 189 Stach, L. T., 268(153), 274(153), 334 Stamhuis, E. J., 258( l05,l06), 259(105), 332 Stammreich, H., 15(65), 88 Staninets, V. I., 292(261), 337 Startcher, P. S., 295(28Oc), 308, 338, 340 Steffan, G., 317(364), 341 Steger, E., 54(229), 93 Steinberg, G. M., 60(257), 94 Steinhoff, G., 76(305), 95 Steitz, T. A., 52(210), 71, 84(210), 92 Stejskal, E. O., 107(20), 109(20), 182 Stepanyants, A. U., 148(181), 187 Stephens, F. S., 41(174), 91 Stermitz, F. R., 268(152), 284(152), 334 Sternhell, S., 47(201), 92 Stevens, C. L., 286, 337 Stevens, I. D. R., 212(61), 233, 306 (332), 340 Stevens, T. E., 263( 130), 306, 307, 333, 340 Stewart, W.E., 145(168), 186 Stiles, A. R., 49(199), 92 Stille, J. K., 250(65), 251, 298(296), 323(379), 331,338,341 Stinson, S. C., 323(379) 341 Stone, F. G. A., 16(83), 88, 176(329), 191 Storey, R. N., 65(306), 95 Story, P. R., 163(255), 189 Stothers, J. B., 140(155), 186 Strange, J. H., 109, 115(32), 182 Streitwieser, A. J., Jr., 242(18), 330 Strini, J.-C., 315(360), 341 Strgmme, K. O., 157(230,231), 162(252), 188, 189

AUTHOR INDEX Subramanian, P. M., 250(64), 331 Summerbell, R. K., 272, 334 Sumrell, G., 276(175), 335 Sunder, W. A., 292(247), 337 Sunners, B., 133(116a), 185 Sutcliffe, L. H . , 5(16), 87, 100(2), 182 Sutherland, I. O., 113(58), 136(135,136), 137(135,136). l44( 162), 162(136), 163 (58), 164(135,136), 167(265), 172(298, 300), 183, 185, 186. 189, 190 Svetich, G. W., 52(212), 92 Swalen, J. D., 54(232), 93 Swan, J. M . , 5 5 , 93 Swern, D., 275(169), 293, 294(268), 295 (272,275,279), 334, 337, 338 Szantay, C., 148(184), 187 Szwarc, M., 21(95), 89 T Tabushi, I., 295(277), 338 Taft, R. W . , Jr., 243(25), 244(45), 249, 275, 330, 331, 334 Tait, D. A., 292(258), 337 Takayama, S., 315(358), 341 Takeda, M., 107(20), 109(20), 182 Takeshita, T., 297(286), 338 Talbot, H. P., 256(84), 332 Tanabe, K., 312(346), 340 Tang, Y. N., 219(79,80), 227(80), 234 Tanner, D. D., 265, 266(142), 277, 280, 292, 333,334, 337 Tao, E. V. P., 244(42), 331 Tarbell, D. S., 240(7), 276, 282(7), 330, 335 Tarlin, H. I., 263(127), 333 Tavs, P., 85(337), 96 Taylor, M. M., 315(359), 341 Tedder, J. M . , 263(125), 333 Tempkin, 0. N., 325, 342 Tener, G. M., 70(283), 95 Terry, E. M., 288(232), 336 Thaler, W. A., 299, 338 Thiele, E., 115(77), 184 Thomas, C. B., 284, 287(207), 335 Thomas, L. F., 168(280), 190

363

Thomas, W., 307(337), 309(337), 340 Thompson, D. D., 115(62,63), 183 Thompson, D. S., 127(98), 184 Thompson, G., 244(42), 331 Thurmaier, R. J., 283(203,240), 287 (204), 335 Tidwell, T. T., 321(377), 341 Tieman, C. H., 49(199), 92 Tiers, G. V . D.. 151(196), 158(219), 187, 188, 306(329), 314(329b), 339 Ting, I., 281(198), 335 Tinker, H. B., 315(361), 316, 341 Tinsley, S. W., 295(28Oc), 338 Tipper, J. F., 315(359), 341 Tochtermann, W., 168(269), 189 Todd, Lord, 52(209), 92 Tolkmith, H., 83(328), 96 Tomita, K., 109, 182, 314(350), 340 Torck, B., 243(34), 244(34), 331 Toromanoff, E., 287(226), 336 Tosch, W. C., 157(232), 173(232), 188 Townes, C. H., 146(171), 186 Travis, D. N., 198(22,23), 221(22), 232 Traylor, T. G., 315(355), 317, 320, 321 (376a,377), 323, 327(355c), 340, 341 Traynham, J . G., 292(248), 298(292), 299,337,338 Trepka, R. D., 24(109), 89, 148(183), 187 Trifan, D. S.,250(60), 292(252), 331, 337 Trippett, S.,7(32), 31(151), 38(163, 165), 39(169), 42(163), 65(151), 70 (151), 87, 90, 91 Trozzolo, A. M., 198(24,27), 199(30,33, 34), 200(30,33,34,37), 201(40), 202 (34), 221(30,33,34), 232, 233 Truce, W.E., 304, 305(321), 339 Trumbull, E. R., Jr., 288(233), 336 Tsolis, A. K., 27(140), 74(140), 90 Tsubimora, H., 198(26), 232 Tsuboi, M., 54(231), 93 Tulimowski, Z., 28(137), 90 Turner, A. B., 148(180), 187 Turner, M. A., 315(357), 341 Tyssee, D. A., 26(121), 89

AUTHOR INDEX

364

U Ugelstad, J., 295(274). 337 Untch, K . G . . 171(292,295), 190 Usacheva, G. M., 2(6), 86 Usher, D. A., 52(213), 60(255), 71, 92, 94

Ustynyuk, Yu. A., 318(371), 341 Uyeda, R. T., 27( 129). 28( 129), 29( 149, 38(145), 90 V Valicenti, J. A., 286, 336 Valls, J., 287(226), 336 Vander Auwers, A. M., 21 3(62), 233 Van Der Voorn, P. C., 72(291), 95 Vander Werf, C . A., 8(36,38). 9(42), 10 (42). 13(42), 28(38,133,134), 29(148), 30(149), 31(42,149), 39(166,167), 69 (36,378), 87, 90, 91, 95 Van Dine, G. W., 196(15), 232 Van Wazer, J. R., 16, 81, 88, 96 Varian Associates, 120, 184 Vaughan, W. R., 256, 257, 332 Vaver, V. A., 41(1 78). 43( 186), 91, 92 Velez, D. C., 9(42), 10(42), 13(42), 29 (148), 31(42), 87, 90 Venkateswarlu, P., 198(19), 232 Verbanc, J. J., 279(183), 335 Ver Nooy, C . D., 289(237), 336 Verrier, J., 80(317,318). 96 Vil'chevskaya, V. D., 325(388), 342 Vilkov, L. V., 3( 10). 86 Viossat, V., 54(225), 93 Vogtle, F., 151(195), 168(270), 187, 189 Vogel, E., 175(318,320,321),191 Vogt, R. R., 279(184), 324, 335, 341 Vold, R. L., 11 5(74), 184 Voskuil, W., 16(74), 88 W

Wada, Y ., 298(292), 338 Wadsworth, D. H.,43(187), 92 Wadsworth, W. S., Jr., 17(88), 46(88), 83, 88, 96 Wagener, E. H., 151(194), 187 Wagner, E. L., 26(122), 89

Wagner, J., 150(192), 174(192), 187 Wagner, R. I., 5(17), 47(17), 52(17), 87 Wagner-Jauregg, T., 61(259), 94 Walborsky, H.M., 297(285), 338 Wall, R. E., 70(282), 95 Wallace, R., 139(151), 186 Wallerberg, G., 60(256), 94 Walling, C., 243(21,22), 265(138), 280, 330,333, 335 Walsh, A. D., 194(7), 195, 232 Walter, U.,168(269), 189 Walter, W., 133(126), 185 Walton, D. R. M., 258(109), 333 Wangsness, R. K., 11 1(48), 183 Ward, L. F., Jr., 49(199), 92 Ware, J. C., 315(357), 341 Warkentin, J., 245, 331 Waser, J., 15(64), 88 Wasserman, E., 199(30,31,33,34), 200 (30,31,33,34,37,38),201(40) 202(34), 221(30,33,34), 223(98), 232-234 Waters, W. L., 288, 292(228a), 317 (367), 319, 320(374), 336,341 Way, J. K., 8, 28(33), 87 Wedel, B. v., 219(78), 234 Weil, J. A., 113(56), 125(94), 133(94), 134, 183, 184 Weingartshofer Olmos, A., 295(279), 338 Weitkamp, H., 41(175), 91 Welch, F. J., 6(307), 95 Wells, E. J., 115(66,74,75), 139(66), 162 (66), 183, 184 Welsh, C. E., 279(186), 335 Wenz, A., 306(330), 339 Werf, S . van der, 121, 137(90), 184 Wescott, L. D., 221(91), 234 Westheimer, F. H., 4, 48(12), 49(12), 52 (213), 54, 56, 57(241,244), 70-72, 85, 86, 92-96 Weyna, P. L., 229(115), 235 Whalen, D. M., 221(86), 234 Whalley, E., 243(27), 330 Whang, J. J., 131(104), 184 Wheatley, P. J., 3(8), 41(174), 86, 91 Whetstone, R. R., 49(199), 92 White, J., 312(347), 340 Whitehurst, D. D., 298(296), 338

AUTHOR INDEX

Whitesides, G. M.. 152(199-201), 170 (287), 176(339), 187, 190, 192 Whitham, G. H., 295(280b), 298(293), 338

Whitmore, F. C., 240, 330 Whittaker, A. G., 133(110,l17,ll8), 134(110,118), 185 Wiberg, K . B., 168, 190 Wild, D., 168(270), 189 Wilder, F. N., 256, 332 Wiley, G. A,, 289(240), 336 Wilicenus, J., 256(84), 332 Wilke, G., 314(349), 340 Wilkinson, P. A., 312(346), 340 Williams, D. L. H . , 266(145), 292(260), 334,337

Williams, G., 276, 334 Williamson, F. G., 136(136), 137(136), 162(136), 164(1 36), 185 Wilson, E. B., 127(95), 184 Wilson, R. A. L., 296(821), 297(281), 338

Wilt, J. W., 289(238), 336 Wingler, F., 218(74), 234 Winkler, H., 5(18), 6(26), 9(40), 10(40), I1(49), 12, 13, 14(57), 26(54), 27(26), 28(123), 29(141), 31(152), 38(26), 74 (141), 87-90 Winkler, H. J. S.. 131(104), 184 Winstein, S., 171(293), 176(328,330), 190, 191. 250(60), 273, 280(191), 284 (208), 286, 287, 290, 291(242), 293 (270), 296, 298(290), 318, 323(378), 331, 334-338, 341 Wintzer, A,, 325(389), 342

Wise, W. B., I13(55), 167, 183 Witanowski, M., 152(200,202), 187 Witnauer, L. P., 295(279), 338 Witschard, G., 44(190), 92 Wittig, G., 63, 69, 81, 94, 96, 218(73, 74), 234 Woessner, D. E., I15(65), 183 Wolf, A. P., 243(25), 330 Wolf, R., 80(317), Y6 Wolfe, S., 247, 248, 317(53), 331 Wolowsky, R., 173(302,305), 190, 191 Womer, W. D., 280(188), 335 Wood, C. S., 175(324), 191

365

Woodbrey, J. C., 107(21), 121(21), 133 (21,116b), 134(21), 182, 185 Woodward, L. A., 16(77), 88 Woodward, R. B., 205(43,45,46), 233 Woodworth, R . C., 207, 217(66), 233 Wright, C . H., 242(15), 330 Wright, G., 317(365), 341 Wright, G. F., 315(355), 371(368), 340, 34 I Wright, R, S., 70(283), 95 Wright, W. V., 281(197), 335 Wurmb-Gerlich, D., 133( 124), 185 Wyer, J. A., 168(280), 190 Wyman, B. M., 276(175), 335 Wysocki, D. C., 4(14), 48-50(14), 86

Y Yager, W. A., 199(30,31,34), 200(30,31, 34,37,38), 201(40), 202(34), 221(30, 34), 223(98), 232-234 Yamada, F., 113(53), 147, 183 Yamaguchi, I., 157(240), 188 Yamamoto, Y., 225(105), 235 Yang, N. C., 227(109), 235 Yates, K., 281(197), 335 Yiannios, C. N., 304, 305(320), 339 Young, D . P., 9(42), 10(42), 13(42), 29(148), 31(42), 87, 90 Young, L. B., 133(111), 135(111), 185 Young, W. G., 256(85), 284(208), 286, 332, 335, 336

Yur'ev, Y. K., 313(348), 340 Yvernault, T., 25(119), 89

Z Zakharkin, L. T., 305(324), 339 Zanger, M., 69(278), 95 Zefirov, N. S.,313, 314, 317, 323,340 Zeger, J. J., 60(257), 94 Zeiss, G. D., 196(15), 232 Zigman, A. R., 289(238), 336 Zimmer, C., 262,333 Zimmerman, A., 21(94), 89 Zwaneburg, B., 258( IOO), 332

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

Subject Index Alcohols, exchange in (NMR), 109 Aldehydes, rotational barriers in, 139 Alkenyl phosphorus compounds, 47 Alkoxycarbenes, 230 Alkyl diethylphosphinates, 60 Alkyl nitrites, rotational barriers in, 139 Alkylphosphonothioic acids, optically active, 27 Allylic halides, addition of hypochlorous acid to, 266 Amides, rotational barriers in, 100, 132 stable conformers of, 136 vinylogous, rotational barriers in, 136 Amines, intermolecular exchange in (NMR), 109 p-Aminonitrosobenzenes, rotational barriers in, 139 Ammonia, inversion barrier in, 146 Angelic acid, 256 Annulenes, inversion barriers in, 173 Apobornylene, 252, 297, 322 Arenes, addition to, of acids, 244ff of bromine, 283ff of chlorine, 266ff Arsine oxides, racemization of, 29 Arylcarbenes, 228 Arylmethylenes, 198ff, 221 Asymmetric induction, 13 Asymmetric synthesis, 26 Aziridines, inversion barriers in, 148

A

AB exchange (NMR), 113, 121 Absolute configuration, by the quasiracemate method, 26 Absorption mode (NMR), 104, 106 AB spin system, intramolecular exchange of, 113, 121 Acenaphthene, 245, 264, 268,284, 302 Acenaphthylene, see Acenapthene Acetamidinium chloride, rotational barrier in, 136 Acetylenes, addition to, of acids, 258ff of bromine, 291 of chlorine, 279 of iodine, 292ff of mercuric salts, 324ff reaction with peracids, 298 Acetyl nitrate, 307ff Acids, addition of, t o acetylenes, 258ff to arenes and dienes, 244ff t o bicyclic olefins, 25Off to nonconjugated olefins, 246ff to olefins, 242ff to cr,@-unsaturatedcarbonyl compounds, 256ff hard and soft, 38 Activation energy, determination of, by microwave spectroscopy, 99 by NMR, 123ff by rotational spectra, 99 Activation parameters, calculation of from NMR data, 122ff Acyclic P(III) compounds, conformational analysis of, I5 Acyclic phosphorus compounds, chiral, 8 Acyl ylids, 40 A d ~ additions, 2 mechanism, 240ff, 281ff, 326ff A d ~ additions, 3 mechanism, 240ff, 248, 261ff, 281ff, 294, 318, 322ff, 328ff

B Barriers, see Inversion barriers, Rotational barriers Bases, hard and soft, 38 Benzal bromide, 221 Benzamides, rotational barriers in, 144ff 3-Benzamidocyclohexene, 296 Benzocycloheptenes, inversion barriers in, 166 367

368

SUBJECT INDEX

Benzonorbornadiene, 252, 266, 277ff, 289 Benzylbutylmethylphosphine,9 N-BenzyI-0,N-dimethylhydroxylamine, inversion barriers in, 147 Benzylmethylphenylpropylphosphonium bromide, 26 Benzylphosphonium salts, chiral, reaction with alkoxide, 31 Bicyclic olefins, addition of acids to, 2508 addition of bromine to, 288ff addition of chlorine to, 2778 Bicyclo[3.1.0]hexene-2, 255 Bicyclo[4.2.l]nonatriene, 21 Bicyclo[2.2.2]octene, 320 Biphenyl derivatives, rotational barriers in, 130 Biphenyls, bridged, inversion barriers in, 167 Bis-(diphenylphosphine)ethenes, 17 Bisphosphonium salts, cyclic, 73 Bis-trifluoromethylmethylene, 200 Bis-Wittig reagent, 84 Bloch equations, 102. 104, 111, I18 Bond angles, in phosphorus compounds, 3 Bond lengths, in phosphorus compounds, 3, 52 Bridged carbonium ion, see Carbonium ion, bridged Bromine, addition of, to acetylenes, 291 to arenes and polyenes, 283 to olefins, 280ff kinetic forms of, 281 mechanism of, 281 Wagner-Meerwein rearrangement during, 281 Bromine chloride. 283 Bromocarbene, 221, 227 1-Bromocyclohexene, 286 Bromonium ion, 282ff 3-Bromonortricyclene, 288 B-strain, in phosphorus compounds, 16 Bulvalene, 99 108, 109, 175 I ,3-Butadiene, 272, 286

2-Butene, electrophilic additions, 274, 286, 302, 307, 309, 317 reactions with carbenes, 213ff, 222ff 4-terf-Butylcyclohexene, 286, 291 fert- Butylethylene, 266, 281, 300 1-Butyne, 279 2-Butyne, 279, 325 C

Carbamates, inversion barriers in, 137 rotational barriers in, I36 Carbene additions, stereochemistry of, 219 stereospecificity of, 203 Carbenes, absorption spectra of, 198 bent bonds in, 200 electron configurations of, 194 electron nuclear double resonance (ENDOR) of, 199 electron spin resonance of, 198 matrix isolation technique for, 198 structures of, 194 triplet state spin Hamiltonian for, 199 zero-field splitting parameters of, 199 Carbenoids, 194, 203, 220 Carboethoxycarbene, 230 Carbonium ion, bridged versus open, 326 Carbonium ions, hydride shifts in, 176 Carr-Purcell spin-echo, 11 5 Chlorine, addition of, to acetylenes, 279ff to arenes and polyenes, 266ff to olefins, 265, 273ff Chloroacetylene, 304 Chlorocarbene, 198, 221, 227 Chlorocyclohexane, equatorial isomer, 160 Chlorocyclopropane, 221 Chlorodiazomethane, photolysis of, 221 Chloromethylene, 227 Chloronium ion, 273ff 2-Chloro-1-phenylpropene, 268 Cholest-2-ene, 274 Cholesteryl acetate, 3 I2

SUBJECT INDEX Coalescence temperature (NMR), 108, 113, 122ff r-Complex, 240 Complex magnetization, 104 Conformational analysis, by NMR, 99 Convolution integral technique, 121 Cope rearrangements, degenerate, 175 Cyanine dyes, rotational barriers in, 144 2-Cyanoethylphosphonium salts, 10 Cyclobutene, 317 [runs-Cyclodecene, rotational barrier in, 131 1,3-Cycloheptadienes, inversion barriers in, 167 Cycloheptane, inversion barrier in, 164 Cycloheptatriene, 7-cyano-7-trifluoromethyl-, 175 inversion barrier in, 167 Cycloheptene, 317 hetero analogs of, inversion barriers in, 165 1,3-Cyclohexadiene, 245 1,4-Cyclohexadiene, 274 Cyclohexane, ring inversion in, 100 undecadeutero, inversion barrier in, 157 Cyclohexanes, I ,I-disubstituted, inversion entropies for, 156 inversion barriers in, 153, 158, 160 monosu bsti t uted, inversion entropies for, 156 polysubstituted, inversion barriers in, 157 Cyclohexene, electrophilic additions to, 246, 274. 286, 293, 300ff inversion barrier in, 160 Cyclohexenes, 4-substituted, 319 Cyclohex-2-enol, 296 cis,cis,cis-1,4,7-Cyclononatriene, inversion barrier in, 171 Cyclooctane, conformations of, 168 pentadecadeutero, 168 Cyclooctanes, substituted inversion barriers of, 168 Cyclooctatetraene, bond-shift in, 170 electrophilic additions to, 272, 286

369

inversion barrier in, 170 metal carbonyl complexes, NMR of, 176

Cyclooctatetraenyldimethylcarbinol,

inversion barrier in, 170 Cyclooctatrienone, inversion barrier in, 169 Cyclooctene, 300, 317 Cyclopentadiene, 284 Cyclopentadienylidene, 200, 223 Cyclopentene, 308, 317 Cyclopropane, 214, 224

D Decalin, inversion barrier in, 173ff Density matrix, Illff, 117ff Deoxymercuration, 315 N,N-Dialkylamides, rotational barriers in, 133 Dialkylphosphinic chlorides, 54 Diaryldiazomethanes, photolysis of, 224 Diastereotopic nuclei, 130 Diaziridines, inversion barriers in, 149 Diazirine, photolysis of, 212 Diazoketones, rotational barriers in,143 Diazomethane, photolysis of, 210ff, 224 triplet state of, 217 Dibenzobicyclo[2.2.2]octadiene, 266 Dibenzobicyclo[2.2.2]octatriene, 293, 303 Dibenzo[u,&ycloheptenylidene, 225 Dibenzylmethylamine, inversion barrier in, 147 1,2-Dibromo-2-phenylethylphosphonic acid, 55 I ,2-Dibromo-l -phenylpropylphosphonic acids, 55 rruns-l,3-Di-f-butylcyclohexane, 156 Di-f-butylethylene, 274 Di-r-butylphenylphosphine,16 Dicarbomethoxymethylene, 223 3,4-Dichloro-l-butene, 272 t runs- 1,4-DichIoro-2-butene, 272 Dichloromethyllithium, 221, 227 Dicyanocarbene, 223

370

SUBJECT INDEX

Dicyanodiazomethane, 223 Dimethylformamide, rotational barrier Dicyclopentadiene, 323 in, 132, 133 Dienes, additions of acids to, 244ff Dimethylmaleic acid, 276 1 ,I -(Diethylamino)phenyIphosphonoDimethylnitrosamine, rotational barrier thioyl-2,3-dimethylimidazolium in, 138 iodide, 83 Dimethyl phosphite, reaction with Diethyl p-carbethoxyethylphosphonate, ketones, 84 47 Dinitrogen pentoxide, addition to ole5,1O-Diethyl-5,1O-dihydrophosphanfins, 306 thren, 20 Dinitrogen tetroxide, 306 Diethyl fumarate, 282 Dioxane, inversion barrier in, 161 Diethyl 2~methylcyclohexylphos1,3,2-Dioxaphospholans, monophonates, 50 substituted, 80 Diethyl 3-methylcyclohexylphos1,2,2-Dioxaphosphorinans,85 phonates, 50 1,3,2-Dioxaphosphorinans,NMR of, 84 0,O;Dieth ylmethylphosphonothioate, p-Dioxene, 272 NMR of, 53 Diphenylbenzylphosphine oxide, 43 Diethylphosphonochloridate,57 Diphenyldiazomethane, photolysis of, Diethyl trans-p-styrylphosphonate,50 22 1 Difluorocarbene, 198 Diphenyldibromomethane, 221 5,5- Difluororcycloheptene, inversion 1,l-Diphenylethylene, 201, 263, 299 barrier in, 165 Diphenylmethylene, 200ff, 221ff 1 ,I -Difluorocyclohexane, inversion Diphenylphosphine, 18 barrier in, 158 Diphosphines, inversion barriers in, 151 Dihalocarbenes, 198, 203, 221, 228 isomeric, 20 Dihalomethylenes, see Dihalocarbenes optically active, 10 5,lO-Dihydrophosphanthrenesystems, Dipotassium cyclooctatetraenide, 21 stereochemistry of, 21 Dispersion mode (NMR), 104 7,12-Dihydropleiadenes,inversion barriers in, 168 E 1,2-Diiodoethylene, 294 Diisopropylphosphinyl chloride, 56 Echo envelope (NMR), 116 Dimethylacetamide, rotational barrier Electron nuclear double resonance in, 132 (ENDOR), 199ff 1,3-DimethylaIlene, 319 Electron pairs, see Inversion barriers, Dimethylaminofulvenes,rotational and under specific compound barriers in, 144 Electrophilic nitrogen reagents, 306ff N,N-Dimethyl-t-butyl phosphonamide Enamines, rotational barriers in, 144 fluoridate, NMR, 54 ENDOR, 199ff N,N-Dimethylcarbamoyl chloride, Enthalpy of activation, by NMR, 1238 rotational barrier in, 134 Entropy of activation, by NMR, 123ff I ,2-Dimethylcyclohexene, 246, 247 1,2-Dimethylcyclopentene,246 Episulfonium ion, 300 Esters, rotational barriers in, 137 Dimethylcyclopropane, 214, 21 5 1 ,2-Dimethyl-3,3-dicyanocyclopropane, Ethane, rotational barrier in, 124 Ethene-l,2-bisdiphenylphosphine,6 223 I ,2-Dimethyl-3,3-diphenylcyclopropane, rrans-Ethene-1,2-diphosphonic acid, 85 5-Ethyl-5,lO dihydroanthracene, 21 224

SUBJECT INDEX Ethylene hydrogen phosphate, 70 Ethylene phosphate, hydrolysis of, 70 (0-Ethy1)ethylphosphonobromidothioate, 32 Ethyl ethylphosphonothiochloridate,83 Ethyl p-nitrophenyl methylphosphonate, 60 (0-Ethy1)phosphonothioic acid, 35 Exchange involving first-order NMR coupling, 109 Eyring equation, 122 F

F-strain, in phosphorus compounds, 4 Flash-photolysis spectroscopy, 197 Fluorenylidene, l98ff, 225 electronic structure of, 202 stereochemistry of, 222 Fluorine, addition to olefins, 263ff Fluorine labeling technique, 121 Fluorocarbene, 198, 227 Fluorochlorocarbene, 227 Fluorocyclohexane, inversion barrier in, 157 Fluoronium ion, 265 Formamide, rotational barrier in, 133 Free energy of activation (by NMR), 122 Free energies of activation, of substituted ethanes, 129 Free energies of substituted ethanes, 129 Frequency factor, 123 Fumaric acid, 288 2-Furaldehyde, rotational barrier in, 140, 142

G Grignard reagents, allylic, 176 inversion barriers in, 152 Gutowsky, McCall, Slichter Theory, 105, 106 Gyromagnetic ratio, 102 H

Hahn, Maxwell, McConnel Theory, 105 Halocarbenes. 198

371

Hard acids and bases, 38 Heptamethylbenzenonium ion, 176 Heterocycles, six-membered, inversion barriers of, 160 Hexamethylbenzene, 176 1-Hexyne, 279, 304 3-Hexyne, 259, 261,294, 304 Hindered rotation, about single bonds, 127 3,4-Homotropilidene, 175 Hund’s rule, 196 Hydrazones, rotational barriers in, 144 Hydride shifts, 176 Hydrophosphorane, 29 2-Hydroxy-1,I-dimethylethyl cyclohexyl phosphate, 60 2-Hydroxy-2,2-dimethylethylcyclohexyl phosphate, 60 8-Hydroxyphosphondiamidates, 44 I Imines, inversion barriers in, 150 Iminocarbonates, inversion barriers in, 151 Indene, 245, 264, 268, 285 Indenylidene, 200 Insertion of methylene, 214 Intramolecular rearrangements, 175 Inversion barriers, in ammonia, 146 in annulenes, 173 in aziridines, 148 in benzocycloheptenes, 166 in N-benzyl-O,-N-dimethylhydroxylamine, 147 in biphenyis, bridged, 167 in carbamates, 137 in 1,3-~yclopheptadiene,167 in cycloheptane, 164 in cycloheptatriene, 167 in cyclohexane, 153ff in cyclohexanes, substituted, 153ff in cyclohexene, 160 in cis,cis,cis-l,4,7-cyclononatriene, 171 in cyclooctane, 168ff in cyclooctanes, substituted, 168ff

SUBJECT INDEX

372

in cyclooctatetraene, 170 in cyclooctatetraenyldimethylcarbinol, 170 in cyclooctatrienone, 169 in decalin, 173 in decalins, substituted, 174 in diaziridines, 149 in dibenzylmethylamine, 147 in 5,5-difluorocycloheptene,165 in 7,12-dihydropleiadenes, 168 in dioxanes, 161 in diphosphines, 151 in fluorocyclohexane, 157 in Grignard reagents, 152 in heteroanalogs of cycloheptene, 165 in heterocycles, six-membered, 160 in imines, 150 in iminocarbonates, 151 in [2.2]metacyclophanes, 172 in oxaziridines, 149 in pentadecadeuterocyclooctane,168 in perfluorocyclooctane, 168 in phosphorus compounds, trivalent, 151 in piperidine, 161 in 2,2,3,3-tetramethylaziridine,148 in triarylimines, 151 in tri-o-thymodide, 172 in tris-(perfluoropropy1)-hydroxylamine, 148 Inversion of lone electron pairs, 146 Iodine, addition to olefins and acetylenes, 292 Iodine azide, 293 Iodine chloride, 293 Iodine fluoride, 293 Iodine isocyanate, 293 lodobenzene dichloride, 265, 278 Iodocarbene, 227 Iodonium ion, 293 Isobutylene, 275 Isopropyl isopropylphosphonochloridate, 56

K

Ketene, 215 Ketones, rotational barriers in, 139

L Larmor frequency, 102 Ligand reorganization, vii see also Pseudorotation in trigonal bipyramids Line shape, 101 computer programs for, 177 dependence on field homogeneity, 120 theory of, 110 Line width (NMR), 122 a-Lithio phosphonic acid bisamides, 44 Lithium diphenylphosphide, 17ff Lone electron pairs, see Inversion barriers, and under specific compound Longitudinal relaxation time (NMR), 104

Lorentzian line shape, 12Off

M Maleic acid, 288 Markov process, 109 Menthyl phosphinates, 82 ORD of, 83 proton NMR spectra of, 83 Mercuric salts, addition to olefins, 314ff Mercurinium ion, 318, 324 [2.2]Metacyclophanes, inversion barriers in, 172 Methyl acrylate, 306 Methyl rrans-cinnamate, 272 CMethylcyclohexene, 297 4Methylcyclopentene, 297 Methylene, 194, 21OtT absorption spectrum of, 197 heat of formation of, 210 spin multiplicity of, 203ff stereoselectivity of, 204 Methylene addition to olefins, stereochemistry of, 210, 216 Methylene derivatives, 203, 219 Methylene iodide, photolysis of, 218 Methylene triplet, 21 2ff Methyl ethylene phosphate, 70 structure of, 52, 71

373

SUBJECT lNDEX (+)-Methylethylphenylphosphine oxide, configuration, 26 1 -Methyl-I -phenylphospholanium iodide, 85 Methylphenylpropylphosphine, absolute configuration of, 13 oxidation of, 14 Methylphosphine carbanion, 13 Methyl pinacol phosphate, structure of,

52

Michaelis-Arbuzov reaction, mechanism of, 17 Molecular addition, 239,251,255,307,

313,321,329

Molecular complexes, 241ff see also *-Complex Monochlorocarbene, 219 Monofluorocarbene, 219 M onohalocarbenes, 221 Monophosphonium salts, cyclic, 74 Multiple-resonance technique, 118,126 N Napthalene, 266 Naphthylmethylenes, 201 Nitrilium ion, 287 Nitrites, rotational barriers in, 138 4-Nitrocyclohexane, 308 p-Nitrophenyl phenacyl methylphosphonate, 60 Nitrosamines, rotational barriers in, 138 Nitrosyl halides, addition to olefins of, 31 Iff Nitryl chloride, 306 NMR, see Nuclear magnetic resonance Nonconjugated olefins, addition to, of bromine, 286 of chlorine, 273ff Norbornadiene, 253,290,298,313 Norborene, 251,266,277,288,297,

302,313, 320,327

Norbornyl bromide, 288 Norbornyl cation, 176,252,327 Nuclear magnetic resonance, coupling constants, unsaturated Pcompounds, 48

phosphorus-hydrogen, 50 time scale, 99 see also under specific compound Nuclear Zeeman energy, 104 Nucleophilic displacement at unsaturated carbon, 7 0

Ag-Octalin, 312 Olefins, addition to, of acids, 242,246ff of bromine, 280ff of chlorine, 265,277ff of fluorine, 2638 of iodine, 292 oxymercuration of, 314ff reaction with peracids of, 294 Optically active phosphines, reaction with halogens, 14 Optical rotatory dispersion, of phosphorus compounds, 6 Oxaziridines, inversion barriers in, 149 1-0xo-1 -phenoxy-l,3,2-dioxaphosphorinan, 84 Oxymercuration, of olefins, 314ff

P 31P chemical shift, steric effect on, 81 P-compounds, cis-trans N M R coupling constants in unsaturated, 48 P(lI) compounds, 7 P(III) compounds, 8,23,80 cyclic, 19 inversion barriers in, 151 optically active, 13 structures of, 8 synthesis and stereochemistry, 17 P(1V) compounds, 25,82 absolute configuration of, 5 , 26 acyclic, 47 conformational and rotational isomerism, 51 cyclic, 44 neighboring group participation in,

59

374

SUBJECT INDEX

optically active, 26, 28, 79 reduction with lithium aluminum hydride, 74 reduction with trichlorosilane, 9 stereochemistry of, 25 displacement reactions at, 34 steric effects in, 56, 57 P(V) compounds, 77, 85 autoisomerization of, 75 bonding, 62 intramolecular racemization, 64 NMR of, 65, 73 nucleophilic ligand exchange, 78 as reaction intermediates, 22, 27, 68 stereochemistry of, 63 PWI) compounds, 76 stereochemistry of, 76 Pentaarylphosphorane, optically active, 67 Pentadecadeuterocyclooctane,inversion barrier in, 168 Pentadienyllithiums, rotational barriers in, 143 Pentaoxyphosphoranes, 66, 71, 77 Penta-p-tolyphosphorane, 66 2-Pentene, 274 I-Pentyne, 279 Peracids, reaction with olefins and acetylenes, 294 Perfluoroalkylmethylenes, 200 Perfluorocyclohexane, inversion barrier in, 158 Perfluorocyclooctane, inversion barrier in, 168 SIP-H coupling constants, angular dependencies of, 79 Phenanthrene, 267, 285 Phenonium ion, 284 Phenoxycarbene, 230 Phenylacetylene, 279, 304 Phenylbromocarbene, 230 2-Phenyl-2-butene, 301 Phenylchlorocarbene, 230 1-Phenylcyclohexene, 309 I-Phenylcyclopentene, 309 Phenylhalocarbenes, 229 Phenylmethylene, 200,201, 221, 229

I-Phenylpropene, 245. 264, 268ff, 283, 309 Phenylpropiolic acid, 262 1-Phenylpropyne, 260 Phenylselenocarbenes, 230 Phenylthiocarbenes, 230 Phosphacyanines, 7 Phosphacyclobutane, 46 Phosphate esters, bonding in, 52 chiral, 27 conformations of, 53 cyclic, 52, 83 hydrolysis rates of, 53 molecular orbital calculations on, 51 strain energy of, 52 Phosphine oxides, 70 allenic, 81 conformations of, 53 melting points of, 6 optically active, 2, 8, 82 oxidation of, 59 racemization of, 27, 29, 74 resolution of, 26 Phosphines, chiral, synthesis of, 10 conformations of, 53 cyclic, 22 optically active, 8ff polycylic, 24 quaternization of, 12 reactions of optically active, 11 thermal racemization of, 11 Phosphine sulfides, resolution of, 26 Phosphinic acids, cyclic, 72 5-membered cyclic, 85 Phosphites, conformations of, 53 five-membered cyclic, 22 Phosphonate esters, cyclic, 71 NMR, 52 p,r-unsaturated, 47 Phosphoiiium alkoxides, decomposition of, 30 Phosphonium hydroxides, decomposition of, 30 Phosphonium salts, 70 conversion to ylids, 27 2-cyanoethyl, stereospecific decomposition of, 31

SUBJECT INDEX optically active, 2, 8, 26 resolution of, 26 saponification of, 20, 69 Phosphonothioic acids, resolution of, 83 Phosphoramidates, 60 alkaline hydrolysis, 23 amine exchange in, 75 Phosphoranes, cyclic, 67 NMR spectra of, 85 4-Phosphorinanols, 1,4-disubstituted, 81 Phosphorus, 31PNMR, 4 Phosphorus compounds, geometrical isomerism in, 44 octahedral, 76 sterically hindered, 57 trivalent, inversion barriers in, 151 Phosphorus ylids, hindered rotation in, 41 stable, 41 Phosphorylation, 35 Phosphoryl compounds, stereochemistry of, reaction of, 31ff Phosphoryl group, equatorial orientation of, 84 Phosphoryl halides, optically active, 29 Phosphoryl migration, 61 Piperidine, inversion barrier in, 161 Polyenes, addition to, of bromine, 283 of chlorine, 266ff Polyhalomethanes, 221 Polyphosphines, cyclic, 23 Propargylene, 200, 225 Propylene, 307 Propyl propylphosphonochloridate,56 Propyne, 279 Protonium ion, 249 Pseudorotation, in cyclohexanes, 153 in trigonal bipyramids, 64 Pulse repetition rate (NMR), 116 Pyrophosphates, 36

Q Quasi-racemate method, 26

375 R

Rapid passage technique (NMR), 115 Rate constants, determination of, by NMR, 121 Reactive phosphorus intermediates, 7 Relaxation (NMR), 104 Resonance condition (NMR), 102 Rotational barriers, in acetamidinium chloride, 136 in aldehydes and ketones, 139 in alkyl nitrites, 139 in amides, 100, 132 vinylogous, 136 in p-aminonitrobenzenes, 139 in benzamides, 145 orrlio-disubstituted, 144 in carbamates, 136 in cyanine dyes, 144 in N,N-dialkylamides, 133 in diazoketones, 143 in dimethylacetamide, 132 in dimethylaminofulvenes, 144 in NJ”dimethylcarbamoy1 chloride, 134 in dimethylformamide, 132, 133 in dimethylnitrosamine, 138 in enamines, 144 in esters, 137 in ethane 124 in ethanes, substituted, 129 in formamide, 133 in 2-furaldehyde, 14Off in hydrazones, 144 in nitrites, 138 in nitrosamines, 138 in pentadienyllithiums, 143 in tetrafluorohydrazine, 143 in thioamides, 133ff in thiocarbamates, 137 in triphenylmethylcarboniumions, 131 S

Sarin, preparation of optically active, 35 Simmons-Smith reaction, 218

376

SUBJECT INDEX

Slow passage technique (NMR), 105, 1I9

Sodium diphenylphosphide, 18 Soft acids and bases, 38 Spin echo, 115, 126 Spin multiplicities, of a variety of methylenes, 203 Spin-spin coupling, 109ff Stereochemistry, see under reaction type or compound Stereomutation at phosphorus, 45 Stereoselectivity,of carbenoid reactions,

226

Stilbene, 264,268,282ff,301ff,317 Stochastic theory, 109 Styrene, 299,31 1 Sulfenyl halides, addition of, to acetylenes, 304ff to olefins, 299 Sulfoxides, racemization of, 29

T Tetrabenzyl pyrophosphate, 56 Tetrafluorohydrazine, rotational barrier in, 143 Tetraiododiphosphine, 15 2,2,3,3-Tetramethylaziridine, inversion barrier in, 148 Tetramethylethylene, 275

1,4,7,7-TetramethyInorbornene, 321

Tetrolic acid, 262 Thioamides, hindered rotation in, 133 Thiocarbamates, rotational barriers in, 135,137 Thiophosphoryl compounds, stereochemistry of reactions of, 31 Thiophosphoryl halides, 29,32 Tiglic acid, 256 Tolane, 262,279,291,304,325 Transient techniques (NMR), 114 Transmission coefficient, 124 Transverse magnetization (NMR), 106,

Triarylimines, inversion barriers in, 151 Triarylphosphines, resolution of, 81 Tribenzo[a,c,e]cycloheptenylidene, 225 2,4,6-Tri-r-butylphenylphosphinic chloride, 16 Tri-1-butylphosphine, 80 Tri-r-butyl phosphite, 16 Trifluoromethylmethylene, 200 Triisopropyl phosphite, 17 Trimethylene diradical, 204,207ff

Trirnethylene-2-norbornene,250,289 Trimethylethylene, 275

Triphenylcarbonium ions, rotational barriers in, 131 Tri-o-thymodides, inversion barriers in,

172

Triphenylmethylphosphonic acid, 57 2,4,6-Triphenyl-1-phosphabenzene, 7 Triphenylphosphine oxide, conformation of, 53 Triphenylphosphine sulfide, conformation of, 53 Triphenylphosphorusethoxycarbonylmethineylid, 41 Triplet multiplicity of carbenes, 196 Trisilyphosphine, 16 Tris-(perfluoropropy1)-hydroxylamine, inversion barrier in, 148 Trivinylphosphine, 5

U Undecadeuterocyclohexane, inversion barrier in, 157 a#-Unsaturated acids, 286 a,p-Unsaturated carbonyl compounds, 256f

V

Valence isomerizations, 175 Vinylphosphines, 18 NMR spectra of, 4 Vinyl phosphonates, 49 111 photoisomerization of, 50 Transverse relaxation time (NMR), 104, Vinyl phosphorus compounds, iso117,121 merization of, 50

SUBJECT lNDEX W

Wittig reaction, 18, 27, 38, 41, 70 phosphonate modification of, 43 phosphorus stereochemistry in, 38 stereochemistry of, 39, 84 steric effects in, 44

377

Y

Y lids, optically active, 13 Z

Zeeman energy, 104

Topics in Stereochemisty, Volume3 Edited by Norman L. Allinger, Ernest L. Eliel Copyright © 1968 by John Wiley & Sons, Inc.

Cumulative Index, Volumes 1-3 VOL.

Acetylenes, Stereochemistry of Electrophilic Additions. . . . . . . . . . . . .. . Carbenes, Structure of ........................... .. .. Carbene Additions to Olefins, Stereochemi .. Conformational Energies, Table of (Hirsch Conjugated Cyclohexenones, Kinetic 1,2 A Steric Course of (Toromanof). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Helix Models, of Optical Activity (Erewster), . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Rate Processes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kinetic 1,2 Addition, of Anions to Conjugated Cyclohexenones, Steric Course of (Toromanof). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Metallocenes, Stereochemistry of (Schliigl). . . . . . . . . . . . . Nuclear Magnetic Resonance, for Study of lntramolecul .. Processes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Olefins, Stereochemistry of Carbene Additions to Olefins, Stereochemistry of Electrophilic Additions to. . . . . . . . . . . . . .. . .. Optical Activity, Helix Models of (Erewsrer). . . . . . . Optical Circular Dichroism, Recent Applications istry (Crabbh). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optical Purity, Modern Methods for the Determination of (Raban and Mislow). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optical Rotatory Dispersion, Recent Applications in Organic Chemistry (CrabhP) ............................... .. .. Phosphorus Chemistry, Stereochemical Aspects of. . . . . . . . . . . . Polymer Stereochemistry, Concepts of (Goodman). . . . . . . . . . . . . . . . . . . Stereoisomeric Relationships, of Groups in Molecules (Mislow and Rabat?). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

379

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PAGE

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237 193 193 199

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157

2 I

157 39

3 3 3 2

97 193 237 1

I

93

2

199

1 3 2

93 1 13

1

I

1

91