Advances in Physical Organic Chemistry, Volume 07

Advances in

Physical Organic Chemistry

This Page Intentionally Left Blank

Advances in

Physical Organic Chemistry Edited by

V. GOLD Department of Chemistry King’s College, University of London

VOLUME 7

1969

Academic Press, London and New York

ACADEMIC PRESS INC. (LONDON) LTD Berkeley Square House Berkeley Square, London, W1X 6BA

U.X. Edition published by ACADEMIC PRESS INC. 11 1 Fifth Avenue, New York, New York 10003

Copyright 0 1969 By Academic Press Inc. (London) Ltd.

All Rights Reserved

No part of this book may be reproduced in any form by photostat, microfilm, or any other means, without written permission from the publishers

Library of Congress Catalog Card Number: 62-22125

PRINTED I N OREAT BRITAIN BY SPOTTISWOODE, BALLANTYNE AND COMPANY LIMITED LONDON AND COLCHESTER

CONTRIBUTORS TO VOLUME 7 M. ANBAR,Exobiology Division, Ames Research Center, N A S A , Moffett Field, California 94035, U.S.A. D. BETHELL, Robert Robinson Laboratories, University of Liverpool, England. M. R. CRAMPTON,Department of Chemistry, The University, Durham, England.

V. GOLD,King’s College, University of London, Strand, London, W.C.2. England. Z. RAPPOPORT, Department of Organic Chemistry, The Hebrew University, Jerusalem, Israel.

V

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CONTENTS CONTRIBUTORS TO VOLUME 7

.

V

Nucleophilic Vinyl ic Substitution ZVI RAPPOPORT I. Scope . 11. Introduction . 111. The Addition-Elimination Route . A. Introduction . B. Element Effects and the Carbanionic Theory . C. The Stereochemistry of the Addition-Elimination Route D. Reactivity in the Addition-Elimination Route. . E. Substitution with Rearrangement (The “Abnormal” . Substitution) F. Summary . IV. The Elimination-Addition Routes . A. The cr,p-Elimination Route . B. The P,p-Elimination-AdditionRoute (The Carbenic Mechanism) . C. The &y-Elimination-Addition Route (The Allenic Mechanism) . V. The S,1 Route. VI. Substitutions Following Primary Rearrangements (The Prototropic Routes) . VII. Substitution via Two SN2Reactions . VIII. Substitution in the Presence of Metal Salts . Acknowledgments . References .

1 2 6 6 10 31 62 73 74 74 76 91 92 98 102 107 107 108 108

The Reactions of Hydrated Electrons with Organic Compounds M. ANBAR I. Reactions of Hydrated Electrons with Different Func117 tional Groups . vii

viii

CONTENTS

A. Saturated Hydrocarbons, Alcohols, Ethers and . Amines B. Alkenes . C. Carbonylic Compounds . D. Haloaliphatic Compounds . E. Other Electrophilic Functional Groups on Aliphatic Compounds . F. Aromatic Compounds . G. Heterocyclic Compounds . H. Organic Free Radicals . I. Concluding Remarks , 11. Radiobiological Implications of the Reactions of . Hydrated Electrons with Organic Compounds . A. Carbohydrates, Fatty Acids and Steroids B. Amino Acids and Peptides . C. Polypeptides and Proteins . D. Purines, Pyrimidines and Nucleic Acids . 111. Mechanism of the Reactions of Hydrated Electrons with Organic Compounds . A. The Energy of Activation of the Reactions of Hydrated Electrons . B. The Primary Products of eTq Reactions . C. The Mechanism of Electron Transfer . IV. Conclusion . References .

117 118 119 124 126 128 131 134 136 136 138 139 139 140 141 142 143 144 148 148

Structure and Mechanism in Carbene Chemistry D. BETHELL

I. Introduction . A. Definitions and Scope . B. Nomenclature and Pormalism . 11. The Structure of Carbenes . A. Theoretical Considerations . B. Direct Observation of Carbenes . 111. Carbenes as Transient Intermediates in Reactions in Solution . A. Criteria . B. The Decomposition of Diazoalkanes and Related Compounds .

153 163 157 157 157 160 169 169 170

ix

CONTENTS

C. Base-Induced a-Elimination D. Organometallic Reagents . IV. Mechanisms of Reaction of Carbenes in Solution A. Excitation, Multiplicity and Reactivity . B. Insertion . C. Addition to Olefins . D. Rearrangement . V. Conclusion . References .

177

.

184 187 187 190 194

200 202 202

Meisenheimer CornpI exes M. R. CRAMPTON

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I. Introduction A. Historical Aspects . B. Survey of the Reactions of Aromatic Nitro-Corn. pounds with Bases 11. Structural Studies of the Adducts . A. Adducts from Picryl Ethers B. Adducts from 1,3,5-Trinitrobenzene . C. Products from Picramides (2,4,6-Trinitroanilines) . D. Adducts from Other Substituted Trinitrobenzenes . E. Adducts from meta-Dinitrobenzenes . F. Adducts with Other Compounds . 111. Equilibrium and Kinetics Studies . A. Variation of Reactivity with Substrate Structure . B. Variation of Reactivity with the Attacking Nucleophile . C. Effects of Solvent on the Stabilities of the Adducts . References .

211 211 212

214 215 219 227

233 234 239 241 242

250 252 254

Protolytic Processes in H20-D20 Mixtures V. GOLD 259 I. Introduction . A. General Background . 269 263 B. List of Important Symbols . 11. “Simple” Equilibrium Theory for Reactions Involving 265 Aqueous Hydrogen Ions .

X

CONTENTS

A. Assumptions . B. Acid Dissociation as a Function of n . C. Extension of Simple Equilibrium Theory to Acid Catalysis . D. Acid Catalysis by Species other than H,O+ . 111. Solvent Isotope Effects in Relation to the Brmsted Catalysis Law . A. Acidity Constants of Hydrogen Ions . B. Application of the Catalysis Law . IV. Critique and Possible Improvements of Simple Theory . A. The Formula of the Hydrogen Ion and the Value of the Fractionation Parameter I . B. The Rule of the Geometric Mean . C. Absence of other Kinds of Solvent Isotope Effect . V. Applications of Theory to Experimental Results for Hydrogen Ions . A. Summary of Available Results for HzO-DzO Mixtures. B. Some Case Studies . VI. Catalysis by Species other than Hydrogen Ions in Aqueous Solution . A. Carboxylic Acids B. Hydroxide Ions . C. “Water-Catalysed” Reactions . VII. Solvents other than Water. A. Water-Dioxan Mixtures . B. Methanol . VIII. Speculative Generalities . References . AUTHOR INDEX. CUMULATIVEINDEX OF AUTEORS CUMULATIVE INDEX OF TITLES

. .

265 268 271 277 277 277 279 281 281 284 287 294 295 297 312 312 316 319 322 322 323 325 32 7 333 347 349

NUCLEOPHILIC VlNY LIC SUBSTITUTION ZVI RAPPOPORT

Department of Organic Chemistry, The Hebrew University, Jerusalem, Israel

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

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I. Scope 11. Introduction 111. The Addition-Elimination Route A. Introduction. B. Element Effects and the Carbanionic Theory C. The Stereochemistry of the Addition-Elimination Route D. Reactivity in the Addition-Elimination Route . E. Substitution with Rearrangement (The “Abnormal” Substitution) F. Summary IV. The Elimination-Addition Routes. A. The a,P-Elimination-AdditionRoute . B. The ,k?,B-Elimination-Addition Route (The Carbenic Mechanism) C. The B,y-Elimination-AdditionRoute (The Allenic Mechanism) V. The S,1 Route VI. Substitutions Following Primary Rearrangements (The Prototropic Routes) VII. Substitution via Two 4 2 ’ Reactions VIII. Substitutions in the Presence of Metal Salts References. .

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I.

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1 2 5 5 10 31 62 73 74 74 75 91 92 98 102 107 107 108

SCOPE

THISreview deals with the replacement of substituents in the vinylic position by anionic or neutral nucleophiles. Its division according to mechanistic routes suffers from the fact that for many systems there is a strong connection and mutual intercalation between several routes, but we will try to show the similarities in the behaviour of different systems and to discussthe various criteria which have been used for differentiation between the mechanistic pathways. Some topics, e.g. the stereochemistry and the element effect, are discussed in greater detail than others, especially when the data could be collected in convenient tables. No attempt has been made to cover all the synthetically used vinylic substitution reactions of which reviews are available, e.g. on /?-chlorovinyl ketones (Kochetkov, 1952, 1961 ;Kochetkov et al., 1961 ;Pohland and Benson, 1966), fluoro-olefins (Chambers and Mobbs, 1965) or tetracyanoethylene (Cairns et al., 1958; Cairns and McKusick, 1961). 1

2

ZVI RAPPOPORT

Nucleophilic vinylic substitution has previously been reviewed by de la Mare (1958), Patai and Rappoport (1964) and Rybinskaya (1967). While allylic SN2'reactions formally include a nucleophilic attack at the vinylic carbon atom, they are not discussed, except in cases when they have direct connection to the replacement of vinylic substituents.

11. INTRODUCTION Nucleophilic vinylic substitutions, owing to the inertness of simple vinyl halides, have the reputation of being difficult to conduct. Actually, a large number of these reactions are rather facile, provided that an activating group is attached at a vinylic position. The relative inertness of the unsubstituted vinyl halides compared to their saturated analogues is ascribed to the operation of the + M effect of the halogens (Hughes, 1938, 1941). The partial double-bond character of the carbon-halogen bond (equation 1) makes the bond cleavage more difficult. The importance of this factor increases with the degree of bond cleavage in the

transition state, i.e., it is large in SN1 reactions, but it is also expected to contribute to the lower reactivity in bimolecular, SN2-likereactions. Moreover, the sterically most natural approach of the electron-rich nucleophile to the carbon atom is the perpendicular direction where the higher concentration of Ir-electrons will decrease the reactivity by electrostatic repulsion (Catchpole et al., 1948). On the other hand, the transmission of electronic effects of electronattracting substituents which are bonded to the second vinylic carbon via the same rr-system, helps the nucleophilic attack. With strong - M substituents, e.g. cyano, a contributing dipolar structure carries the positive charge on the carbon atom to which the leaving group is attached (equation 2). For many common substituents the - M effect is much larger than the +M effect of the halogen, so that the overall reactivity of the vinylic system is frequently higher than that of the saturated analogue. q

I

L

-

7

NzC-CH=CH-CI

..

-9 n

+

N=C=CH-CH-Cl

~

(2)

While bond formation and bond cleavage are simultaneous in S N ~ reactions of saturated compounds, a vinylic carbon atom can become and remain four-covalent, bonded both to the nucleophile and to the leaving group. The initial difficulty in vinylic attack is therefore com-

NUCLEOPHILIC VINYLIC SUBSTITUTION

3

pensated for in two ways. The halogen leaves from a saturated centre and the negative charge on the neighbouring carbon supplies a driving force for the reaction, and the bond-breaking process may occur after the rate-determining step. The difficulty can also be avoided by attacking either a vinylic or an allylic hydrogen, both of which are more acidic than aliphatic ones, rather than the vinylic carbon. I n this case, the expulsion of the leaving group still occurs from the vinylic carbon, but the presence of a neighbouring negative charge helps in the carbon-halogen bond cleavage. Scheme 1, in which X is the leaving group, Y an activating group and Nu- is an anionic nucleophile, summarizes the routes which are discussed in detail in the following sections. I n line with the designations used previously (Patai and Rappoport, 1964)the carbon carrying the activating group is the a-carbon, and that carrying the leaving group is the @-carbonatom. I n the “addition-elimination ’’ routes, either via a carbanionic intermediate (I)or via a neutral adduct (11),the anionic nucleophile Nu- or the neutral nucleophile NuH attacks the @-carbonwith the expulsion of X. I n the a,@-route(IV), the p,p-route (VI) and the @, y“elimination-addition ” routes (VII), H X is eliminated in the initial step, and the nucleophile and hydrogen are then added to the intermediates. Substitution occurs also by heterolytic C-X bond cleavage in an SN1 process (X). Initial prototropy followed by substitution can also give vinylic substitution products (XII, XIV), as well as two consecutive SN2’ reactions (XV) where the leaving group leaves from an allylic position. Variations in the detailed behaviour of several of these routes result in the formation of rearranged products. The nucleophile could be attached to the a-carbon of the product via both the addition-elimination (111)and the elimination-addition (V) routes. Migration of the double bond, placing the nucleophile in the product either at a vinylic position (VIII, XI) or at an allylic one (IX, XIII) is also possible. Replacement of the halogen by a metal atom, and further reaction with an electrophile Ef (Curtin and Harris, 1951a, b; Curtin et al., 1955) also result in a formal vinylic substitution (XVI),but will not be discussed here. Nucleophilic vinylic substitutions are closely related to nucleophilic aromatic substitutions, as in both the leaving group leaves from an unsaturated carbon atom. However, the vinylic substitution routes are much more diverse, and disclose more of the details of the reaction. Stereochemical study of the reaction can give information on the lifetime of the intermediate and about the structure of the transition state

I. RiCX=CYRB

+Nu-

RlCNuX---CYRa

___f

1..

11.

-X-

-

____t

-HX

RICNuX-CHYR2 .txuli

111. RICX=CHY

A

IV. RICX=CHY

___t

-EX

RKXfX-CHNuY

-EX

R1-Y

V. VI. VII.

CHXdYR1

5

R'R*CHCX=CYR3

-EX __t

+NuH

:C=CYRl

--E

R'RZC=C=CYR3

VIII.

IX.

-X-

X. XI.

RlCX=CR2Rs

R'R2CH.CX=CYR3

+ RIC==CR2R3

+

-

+Nu-

_____f

+Nu-

+ R'R2kCX-CHYR3

RWNu=CYRa

Addition- elimination via an c,p-adduct.

RICH4NuY

Addition- elimination wiul rearrangement.

RXCNu=CHY

a,p-Elimination-addition.

R'CH=CNuY

or,p-Elimination-addition with rearrangement.

CHNu=CYR'

p,j3-Elimination-addition.

R'RWHCNu=CYRS

p,y-Elimination-addition.

R'R2CdNu-CHYR3

p,y:Elimination- addition with rearrangement.

RIR~CNU-CH=CYR~' p,y-,Elimination-addition with rearrangement. RlCNu=CRZR3

SNl reaction.

R I R ~ C ~ N U - C H Y R ~Substitution following initial prototropy.

4

--f

XIII. R*CX=CY-CHR2R3

--f

RlCHX-CY=CRZR3

+Nu+ RICHNU-CP=CR~R~

.1

XIV.

XVI.

Addition- elimination via "direct substitution".

R ' R ~ C H C X U ~ Y R ~Prototropy vinylic substitution + prototropy route

XII.

XV.

R'CNu=CYRa

RlCX=CRZRs

+Nu-

-

RlCX=CR2-CR3R4Y

-Y-

+Y-

R ~ C N U X - C R ~ = C R ~ R ~- xRiC=CRZR3

+E+

RlCNu=CY-CHR2R3

Prototropy --f allylic substitution + prototropy route.

RlCNu=CRLCR3R4Y

Substitution via two SN2' rearrangements.

R'OE=CRzR3 P

SCHEME 1

Allylic substitution following initial prototropy.

Gubstitution via vinylic carbanion.

NUCLEOPHILIC VINYLIC SUBSTITUTION

5

which is not available in aromatic systems. Several of the vinylic routes have no counterpart in the aromatic systems, while in the others the aliphatic intermediates, e.g. acetylenes, are much more stable than their aromatic counterparts, e.g. the arynes. The similarity between the two reaction categories is shown by the work of Beltrame et al. (1967b) on the reaction of 1,l-bis(p-nitropheny1)2-haloethylenes with ethoxide ion. The vinylic system is a vinylog of the nitrohalobenzenes which are usually studied in SNAr reactions. The activation parameters and the effect of substituents in the two systems were found to be comparable. 111. THEADDITION-ELIMINATION ROUTE

A. Introduction The addition-elimination route is the most studied one in Scheme 1. Since it involves a reaction of the nucleophile with the vinylic carbon atom, it is also the one which in actual fact is most correctly described as a “nucleophilic vinylic substitution”. We will therefore deal with it in the greatest detail. The direct attack at the vinylic carbon by the electron-rich nucleophile suggests that the reaction will be facilitated by diminishing the electron density at the double bond. This could be done by groups which are capable of spreading the negative charge, either by inductive or by resonance effects, and polarize the double bond in such a way that a partial positive charge is developed at the p-carbon atom. Since the contribution of structure (1) which aids the nucleophilic attack is dependent on such activation, the higher the charge-spreading ability of the group, the more facile will be the substitution via the additionelimination route. R1\ X

/y

,c=c p a‘R2

-

-

R\+ , y c-c

x’p

a\Ra (1)

A nucleophile with high carbon-basicity is necessary in this route, but if it is too basic, competition by elimination-addition routes will take place owing to attack on hydrogen rather than on carbon. Maioli and Modena (1959) had suggested that the attack of the nucleophile could take place by three closelyrelated variants of the same process (Scheme 2). I n the first one (i), the nucleophile Nu- attacks perpendicularly, and bond-breaking and bond-forming take place simultaneously. This was called the “direct substitution route”. I n the second one (ii),

6

Z V I RAPPOPORT

bond-breaking lags behind bond formation and the intermediate is a carbanion, which later eliminates the leaving group. The intermediate in the third route (iii) is the +addition product which forms the substitution product by elimination of the proton and the leaving group.

\ -*-

\

X’

I

‘R2

Nu-c-c X’

-/

‘R2

-A-

R1CNu=CYR2

SCHEME 2

Routes (i)and (ii)differ only in the life-time of the intermediate, although the “intermediate” of route (i) might only be a transition state. We will see that the stereochemistry of the product and the element effect can give information on this question. Most of the evidence points to a short-lived carbanionic intermediate, but in some examples an c@adduct seems essential. Since even the “direct substitution” is in itself an addition-elimination process involving the nucleophile and the leaving group, and since differentiation between the routes of Scheme 2 is not always possible, we will designate all routes of Scheme 2 as “additionelimination ”. The three routes are not always kinetically distinguishable. Silversmith and Smith (1958), for example, mentioned that the second-order with ethoxide kinetics in the reaction of l,l-diphenyl-2-fluoroethylene ion fits a reaction via a carbanionic intermediate, or the formation of a fluoroether, if the latter is either formed rapidly and decomposed slowly ( k , k , / ( k - , + k,)$ k4), or if it formed in a rate-determining step (klk,/(k-1 +k&k,). PhiCLCHF

+ EtO-

ki E-1

Sh&CH(OEt)F

.-

EtOH, En

k-’

PhzC=CHOEt

PhzCH-CH(0Et)F

Jf

+ EtO-

N U C L E O P H I L I C V I N Y L I C SUBSTITUTION

7

The stereochemistry of the substitution depends on the configuration of the substrates and on the specific route involved. A relationship between the configuration of the starting material and the product is expected for (i). The life-time of the carbanion formed in (ii) determines whether the reaction is stereospecific or gives the same cis-trans ratio from both cis and trans isomers by thermodynamic control. If an a,P-adduct is formed from an olefin possessing an a-hydrogen, the product configuration will be determined by the more stable transition state leading to elimination. With no a-hydrogen, both the cis and the trans isomers will give retention of configuration, provided that the two adducts from the two isomers do not interconvert, and that the addition and the elimination occur in the same fashion, e.g. trans. It will be shown that the substrate configuration is retained in the substitution product in most systems, and deviations usually indicate the intervention of other mechanisms. The interaction of strongly activated rr-acidic olefins with a basic nucleophile sometimes leads to the initial formation of charge-transfer complexes. Truce et al. (1965)mentioned that a mechanism involving an initial formation of charge-transfer complexes, such as ArS-(C12CACClJ and ArS-(Cl,C~C(Sh)Cl)-,is possible. Coloured complexes are formed in the reaction of tetracyanoethylene with primary and tertiary aromatic amines leading to N- and p-tricyanovinylation, respectively (McKusick et al., 1958). Tricyanovinyl chloride (Dickinson et al., 1960) and 1,2-dicarbethoxy-1,2-dicyanoethylene(Kudo, 1962) behave similarly. It was suggested that in the tricyanovinylation a a-complex (3)is formed from the .rr-complex of tetracyanoethylene and tricyanovinyl chloride (2) (Rappoport, 1963; Rappoport et al., 1964), and that an adduct (4) is formed from 1,a-dicarbethoxy-1,2-dicyanoethylene. Isotope effects suggested that (3) follows different decomposition routes to the final substitution products, depending on the leaving group (Scheme 3). Even if charge-transfer complexes may not be detected owing to their low equilibrium constants, it is attractive to assume that their formation plays an essential role in many vinylic substitutions. This would place the two reactants in favourable positions, and the complex may be a good precursor for a complete transfer of an electron pair. However, at present, this suggestion is only tentative and requires much more experimental support. Various mechanistic routes, such as addition, cyclization, etc., are available for the carbanions formed in the reactions of nucleophiles with activated o l e h s (Patai and Rappoport, 1962). Their competition with substitution can give information regarding the life-time of the ca,rbanionic intermediate. The retention of configuration of both isomers of

6

ZVI R A P P O P O R T

8

f

C(CN)Y=C(CN)X

(2) n-Complex

6

NRa I

C(CN)X-C(CN)Y

H

CX=C( CN)Y

(3) oLComplex

\.I

k?Y H

( X = Y = C02Et)

C(CN)=C(CN)Y

I

C(CN)X-I~(CN)Y (X = Y= Chi)

SCHEME 3

olefins having an a-hydrogen suggests that the expulsion of the leaving group is faster than the addition of a proton to the carbanion. On the other hand, formation of PhNH. CH=C(CN) .CH=CH. CN from the reaction of /3-chloroacrylonitrile with aniline (Scotti and Frazza, 1964) or of' (5) in the reaction of pyridine with perfluorocyclobutene (Pruett et al., 1952) may indicate the formation of long-lived intermediates.

NUCLEOPHILIC VINYLIC SUBSTITUTION

9

Internal cyclization to the oxirane (7) rather than to the substitution product (8) is found in the alkaline epoxidation of tetracyanoethylene (Linn et al., 1965). This may be due to a longer life-time of the intermediate ( 6 ) with the cyano leaving group, compared to carbanions with halide leaving groups. (NC)zC=C(CN)g

+ OOH-

\

4-

(NC)2C-C(CN)2

(NC)aC(OOH)-%W)a

‘d (7)

(NC)C(OOH)=C(CN)z (6)

(8)

From the many synthetic data (only a small part of which are included in this review) it can be seen that chlorine is displaced by a variety of nucleophiles which are more nucleophilic than the chloride ion, such as fluoride (Law et al., 1967), thiocyanate (Koremura and Tomita, 1962), arsenate (Backer and van Oosten, 1940), selenophenolate (Chierici and Montanari, 1956) or selenocyanide (Perrot and Berger, 1952) ions. Sulphinate anions, which displace the chlorine atom of fi-chlorovinylketones (Kochetkov et al., 1961), are themselves displaced by piperidine from 1,2-di-p-nitrophenylsulphonylethylene(Montanari, 1957). Trifluoromethylthiolate ion is displaced by methoxide ion (Harris, 1967), while the more basic methylthiolate ion is displaced by amines and carbanions (Gompper and Toepfl, 1962). While hydroxide ion and carbanions displace the cyano group (Webster, 1964), this group can be introduced at the vinylic position by displacement of the trialkylammonium group of RCO .CH=CHNR;Cl- (Nesmeyanov and Rybinskaya, 1957 ; Rybinskaya and Nesmeyanov, 1966). Carbanions (Cottis and Tieekelmann, 1961 ;Gelin and Makula, 1965) or amines (Claisen and Hasse, 1897; Kamlet, 1959) were found to displace alkoxide ions from the ethoxymethylene derivatives of active methylene compounds or from dicyanoketene acetals (Middleton and Englehardt, 1958) but the amino group of ( 9 )was displaced by hydroxide ion, probably owing to the special stabilization of the formed cyanomalonaldehyde anion (10) (Trofimenko,

10

Z V I RAPPOPORT

1963). The highly nucleophilic and basic carbanions derived from Grignard reagents (Schroll et al., 1965; Weintraub, 1966) or from active methylene compounds (Severinet al., 1964,1966)displace the substituted amino group of enamines. Somewhat unusual is the displacement of the azido group of ArCO .CH=CHN3 by either piperidine or methoxide ion (Nesmeyanovand Rybinskaya, 1962). The above examples demonstrate that a stronger nucleophile generally displaces a weaker one, although this is not always correct. The operation of the addition-elimination route and its details are inferred from the use of several criteria which will be discussed in the order below : (a) The element effect, i.e. comparison of the substitution rates of compounds which differ only in the leaving group, extended also to study of the competition of two leaving groups attached to the same or to different carbon atoms, of the same molecule. (b) The stereochemistry of the substitution. (c) The reactivity of various systems as a function of the structural parameters. The hydrogen-exchange criterion will be discussed in connection with the elimination-addition route.

B . Element Effects and the Carbanionic Theory 1. The element effect

One of the most powerful tools for finding out whether the leaving group participates in the rate-determining step of the reaction is comparison of rates with compounds differing only in the leaving group. Comparison of predictions regarding the relative reactivity of such compounds with the actual results can show whether the mechanism of substitution remains the same for the compared compounds, and if this is the case, what is the extent of bond-formation and bond-breaking in the rate-determining step. This “element effect ” was used in nucleophilic aromatic substitution (Bunnett et al., 1957 ; Bunnett, 1958) especially for halide ions as the leaving groups. I n the two-step additionelimination route, where a carbanionic intermediate is first formed by bond-making to the nucleophile and the product is then formed by rupture of the bond to the leaving group, the identification of the rate-determining step may be basedon this effect. The fluorine-carbon bond is much stronger than either the chlorine-carbon or the bromine-carbon bond. Hence, a mechanism which requires a considerable degree of halogencarbon bond stretching in the transition state (i.e. when bond-breaking is important) should show a slower reaction for the fluoro-olefin compared to the other halo-olefins. On the other hand, if the addition intermediate is formed in the rate determining step, the more polarized and the less hindered system will be the more reactive. Fluorine is the smallest and

NUCLEOPHILIC VINYLIC SUBSTITUTION

11

also the most electronegative among the halogens, so that both the electronic snd the steric factors would make the fluoro-olefin the most reactive in this route. On comparing bromo- and chloro-olefins it is assumed that the two halogen atoms polarize the double bond similarly, while the C-Br bond is expected to be broken faster than the C-C1 bond. The element effect is usually studied for the easily available chloroand bromo-olefins, but larger differences are expected on comparing them to the fluoro-olefin. Only two systems have been investigated in this respect. In the reaction of piperidine with PhCO.CMe=CHX (X = F, C1) at 30" in ethanol and in dimethylformamide the kF/kclvalues are 204 and 263, respectively (Beltrame et al., 1968). I n the reaction of 1,l-diphenylvinyl halide with ethoxide ion in ethanol, Ph&=CHX+EtO-

-+ PhzC=CHOEt +X-

(X=F, C1, Br)

the fluoride gave kz= 4.6 x M - ~ sec-' at 100" (Silversmith and Smith, 1958), while at 120' k2= 0-846 and 1.2 x M - ~sec-l for the chloride and bromide, respectively (Beltrame and Favini, 1963),giving kB,/kcl = 1.4. The extrapolated kF/kClvalue at 100" is 290, showing that this is a clear-cut case of rate-determining formation of an intermediate. 1,l-Diphenylvinyl ethyl ether was not always the sole product; 100, 91 and 400/, of it are formed when X = F , C1 and Br, respectively. Diphenylacetylene formed in an elimination-rearrangement process (p-RCeH4)2C=CHX+EtO-

4 P-RC~H~EC. CeH4R-P

accounts for the rest of the product. The above substitution rate constants were obtained by the dissection of the overall rate into two competing processes. Since the rearrangement is more pronounced when R is electron-donating, the evaluation of the element effect for the substitution is more difficult, but kBr/kC1 ratios of 2-3 were estimated for R = Me, Me0 (Beltrame and Carr&, 1961; Beltrame and Favini, 1963). When R = N 0 2 the substitution is the sole pathway and the ratios are 1.25-1.35 between 20-50" (Beltrame et al., 1967b). The k,,/k, ratios for the elimination-rearrangement process at 120" are 20,46 and 41 for R = H, Me and MeO, respectively. Bond-breaking is therefore important, and slow elimination of halide ion from vinyl carbanions, which are formed in pre-equilibrium, seems plausible (Jones and Damico, 1963). ,!?-Halopnitrostyrenes show ratios of 1-9-2.6 with PhS- (Marchese et al., 1968) while the ,!?-halocrotononitrilesgive ratios of 5-5-9 with the same nucleophile (Theron, 1967). There is other evidence that the latter reaction is an addition-elimination, and it is possible that bond-breaking plays a role in these substitutions.

12

Z V I RAPPOPORT

Since the bond cleavage is not important in the addition-elimination route, the element effect could be used for differentiation between it and the elimination-addition route, provided that a closely related model to the system studied is available. Such models for calibration of the (11)and the element effect for the u-arylsulphonyl-/3-haloethylenes a-arylsulphonyl-p-halopropenes(12)are the u-methyl analogues (13)for which the u,p-elimination-additionroute is impossible. Table 1 shows that for either cis- or trans-(13),the kB,/kclratiosarenear unity for highly ArSO&H=CHX (11)

ArSOZCH=CMeX

(12)

ArSO&(Me)=CHX

(13)

basic nucleophiles, such as MeO- and amines, and slightly higher with the PhS- ion. With PhS- and N;, which have relatively low hydrogen basicity and high carbon nucleophilicity, the kBr/kC1ratios for the eleven substituted derivatives from the series (11)and (12)are very similar, the values being 2.0-3.0. The higher element effects are shown by the cis isomers but the differences are small. With more basic nucleophiles, the element effects for (11)and (12)depend on substrate, nucleophile and configuration. The trans isomers, for which trans elimination of hydrogen halide is impossible, show kBr/kC1ratios of 0-74-1-13. These ratios are similar to those of (13)with the same nucleophiles, suggesting that the additionelimination route is the main and probably the only one for product formation. The values themselves show that C N u bond formation probably precedes the C-X bond breaking to a considerable extent. The kB,/kcl ratios for the cis isomers are very sensitive to the nature of the nucleophile, being 109-1 85 for MeO-, 18.3-38 for cyclohexylamine and 3.0-4-2 for di-n-butylamine with (ll),while derivatives of (12) show ratios over 200 for both amines. These element effects point to the intervention of an additional route, probably u,p-elimination-addition, which will be discussed in more detail in the following sections. While the p-methyl group seems to modify the kBr/kC1ratios, the effect is not mainly steric in origin, since the ratios are similar for the two amines which have different steric requirements. Caution should be exercised in using the element effect even when both compounds compared react via the same route. The higher reactivity of tricyanovinyl chloride (Dickinson et al., 1960) compared to that of tetracyanoethylene (McKusicket al., 1958) suggests a high element effect kCl/kCN. However, in the multistep reaction leading to the product, the leaving group participated in the rate determining step when X = CN, but not when X=Cl (Scheme 3) (Rappoport, 1963; Rappoport et al., 1964).

NUCLEOPHILIC VINYLIC SUBSTITUTION

13

TABLE1 Element Effect ( kBr/kcl) for the Reaction of cis and trans p-R1C6H&302CR2=CR3Hal Pairs with Various Nucleophiles at 0 ' in MeOH k€Ir/kCl

R1

R2

R3

p-NO2

Me

H

13

p-Me

H

H

11

185

0.84

H

H

H

11

144

0.84

p-NO2

H

Me

12

109

-

H

H

H

11

-

0.74

p-NOa

Me

H

13

1*4"

1.13'

p-NOa

H

H

11

38

1.01

p-Me

H

H

11

18.3

0.98

H

H

H

11

21

0.88

p-NO2

H

Me

12

213

-

p-NO2

Me

H

13

1.4'

0.74'

p-NO2

H

H

11

4.2

0.84

p-Me

H

H

11

3-5

1.08

H

H

H

11

3.0

1-03

p-NOS

H

Me

12

p-NO2

Me

H

13

2.6"

2.3"

p-Me

H

H

11

2.3

2.15

H

H

H

11

2.4

2.2

p-NO2

H

Me

12

2.4

p-NOa

H

H

11

3.0"

2.0"

pMe

H

H

11

2.6"

2-10

H

H

H

11

2-15"

2.0"

Nucleophile MeO-

n-Bu2NH

PhS-

At 25'.

Series

cis

trans

Reference

0.93"

0.85'

Maioli et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Modena et al., 1960 Campagni et aE., 1960 Maioli et al., 1960 Campagni et al., 1960 Campagni et aE., 1960 Campapi et al., 1960 Modens, et al., 1960 Maioli et al., 1960 Campagni et al., 1900 Campagni et al., 1960 Campagni et al., 1960 Modem et al., I960 Maioli et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Modem et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960

233

-

-

14

Z V I RAPPOPORT

2. The “geminate” element effect (both leaving groups on the same carbon atom) The presence of two different leaving groups at the double bond, either on the same carbon or one on each of the two carbon atoms, gives rise to other types of element effects. When the two groups X and Y are attached to the same carbon atom, the two transition states do not lead to the same product, as was the case with the element effect just discussed, but to two different products. The two transition states differ not only in the leaving group but also in the p-group which stabilizes them: Y stabilizes the transition state leading to the expulsion of X, while X stabilizes the transition state leading to the expulsion of Y. h,-xR1R2C=CNuY

+

R~R~C=CXY N ~ -

__+

R~R~C-CN~XY

-€ h,-Y-

R’R2C=CNuX

This element effect will be called the “geminate element effect”k l / k 2 , and it is related to the ratio of the substitution rates of R1R2C=CX2and R1R2C=CY2 by Nu- in the following way:

ki/kz = [(ki/k4)/(k2/k3)1 X kdk3 where k3 and k4 are the rate constants for the processes defined below : R1R2C=CX2+NuR1R2C=CY2+Nu-

-% R1R2C=CNuX -% R1R2C=CNuY

The ratio k l / k 4is therefore the element effect k,/ky of the preceding section for the pair R1R2C=CXY and R1R2C=CY2, and k 2 / k 3 is k y / k x for the pair R1R2C=CXY and R1R2C=CX2. For good carbon nucleophiles, the value in parentheses is expected to be close to unity, as discussed above, i.e. k l / k 2 k4/k3. Owing to lack of experimental data this analysis has not yet been applied. It would be of interest to compare, for example, the substitution rates of R1R2C=CC12and R1R2C=CF2 and to evaluate in what cases chloride would leave preferentially to fluoride from R1R2C=CFC1 systems. From Table 2, which contains the results for several systems for which the geminate element effect is possible, it seems that the competition between two leaving groups results, in most cases, in expulsion of the less basic one. Thus, the highly basic amino or alkylamino groups always remain attached to the double bond while the bonds to the less basic met hylthio , t rifluoromet hylthio , cyano, fluoro, chloro or ethoxy groups are cleaved. However, the amino group is expelled in preference N

TABLE 2

Leaving Groups in Intramolecular Competition System

Nucleophile

Leaving group

Product

Reference Josey, 1964

N&- or NH3

CH(CN)~ MeOzC. C(CN)=C(SMe)NHPh (NC) 2C&( CN)NHBu (NC)zC--C(OR)NHz (NC)zC==C(CN)OEt (NC)zC=C( CN)Cl

m 3

(NC)zC=C(NHZ)Cl CF3COCl=C(NMePh)cl (CFaS)zC=C(SCF3)NEt2 (CF3S)zC=C( SCF3)OMe ROzSC(CN)=C(CN)SOzR (NC)CCI=C(CN)Cl

EtOH PhNHMe FMeORNHz F-

MezNH NHRlRZ CaH5NMez CsH5NMez

NH3 MeSCNROEtOc1-

[CFaC(C(CN)z)zIMeO2C. C(CN)=C(NHz)NHPh (NC)2C==C(NMez)NHBu (NC)zC==C(NH2)NR'R2 p-Me2N. C6H4. C(CN)=C(CNz)a p-MezN .C&C(CN)=C(CN)2

c1-

(NC)zC==C(OEt)NH2 CF3. CO. CCl=C(NMePh)Z (CF3S)zC----C(NEtz)F (CFsS)zC=C(0Me)z (NC)C(NHR)=C(CN)SOzR ( N C ) C C l 4 ( C N ) F+ (NC)CF=C(CN)F (NC)aC=C(CN)z (NC)zC=C(CN)Cl CFs CCl=CF2 CF3. CCl=C(SC4Hg-n)F CF3. CCI==C(SC&b-n)Cl EtOzC. C(CN)=C(NHAr)COzEt EtOzC .C(CN)=C(NHAr)CN CHClF .CO N E t z CHClF.CO.NEtz CFz=CFRe( C0)s CFz=CFFe(CO)z-n-CsH5 PhCF=CPhCl EtOCF=CPhCl

clFPSF3CSRSO, c1-

CN-

c1-

CF3. CCl-CC1F CF3. CCl=CClF

Fn-C4HgS-

c1c1-

EtOzC .C(CN)=C(CN)COzEt

h

CFZ=CFNEtz CCLF=CFNEtz CFZ=CFCl PhCF=CFCl EtOCF=CFCl a

Fm

2

OHOHRe(C0); Fe(CO)z-n-CsH; PhLi PhLi

CNCOzEta F-

Fc1c1F-

F-

Formed via the intermediate (NC)zC=C(CF3)NHNHz.

+

.

+

.

* See text.

Josey, 1964 Gompper and Toepfl, 1962 McKusick et al., 1958 Martin et al., 1966 Dickinson et aZ., 1960 Dickinson et al., 1960; Rappoport et al., 1964 Middleton et aZ., 1958 Scherer et al., 1966 Harris, 1967 Harris, 1967 Martin, 1963 Rohm and Haas, 1962 DuPont, 1961 Miller et al., 1960 Thompson, 1955 Kudo, 1962b Kudo, 1962b Yakubovich et al., 1966 Yakubovich et al., 1966 Jolley and Stone, 1965 Jolley and Stone, 1965 Meier and Bohler, 1957a Meier and Bohler, 1957b

ZVI R A P P O P O R T

16

to the very basic trifluoromethyl group. Chloride and sulphinate ions are found to be better leaving groups than cyanide ion. Deviation from this generalization is found in the reaction of tricyanovinyl ethyl ether with N,N-dimethylaniline, in which the ethoxy rather than the less basic cyano group is substituted. This discrepancy may result from a difference in the details of the substitution mechanism for this ether compared to the other compounds of Table 2. The validity of a scale of leaving aptitude based on the geminate element effect should be tested by comparing closely-related leaving groups, such as the halogens, rather than by comparing widely different groups, e.g. amines with halogens. If basicity is the main factor, chloride ion should always be a better leaving group than fluoride ion. The data of Table 2 do not support this conclusion. With fluoride ion or with the transition metal carbonyl ions, chloride competes favourably with fluoride, while fluoride leaves preferentially on reaction with phenyllithium. Substitution products of both fluoride and chloride are formed with butylthiolate ion. The available data are too limited for generalisation regarding the dependence of the geminate element effect on the nucleophile. It is predicted that in an acidic medium a protonated amino group will leave preferentially to many other groups. While this geminate element effect has not been investigated in such media, it is known that the salts of /?-alkylammoniumvinyl ketones are better ketovinylation reagents than 8-chlorovinyl ketones (Nesmeyanov and Rybinskaya, 1957). Reaction of 1,2-dicarbethoxy-l,2-dicyanoethylene with p-substituted anilines gave the product of substitution of either the cyano (14) or of the carbethoxy group (15). When the olefinlamine ratio was 1:2, (14) predominated, while (15) predominated when the ratio was 2 : 1 (Kudo, 1962b). Tertiary aromatic amines gave (16), where only the cyano group was lost (Kudo, 1962a). Formation of (15) is interesting since carbethoxy is a very unusual leaving group, and the amount of the nucleophile does not usually change the geminate element effect. Formation of &,/?-adduct (17) of t’heamine and the reactive olefin, may explain the C0,Et eliminaNC\

NC,.

COzEt

,c=c’ EtO&

,C02Et

,c=c EtOzC

\

t HCN NHAr

f ArNH2

\CN

NHAr

,c=c \CN

EtOzC (15)

+

HC02Et

NUCLEOPHILIC VINYLIC SUBSTITUTION

17

tion. A similar intermediate (4) was obtained from reaction at the p-position of aromatic amines. p-RzNCsH4C(COzEt)=C(CN)COzEt (16)

ArNHC(CN)(COzEt)-CH(CN)COzEt (17)

I n the presence of amine, (17) may eliminate HCN or HC0,Et. An amine-induced elimination of HCOzEtis depicted in (18) and is possibly favoured by formation of hydrogen bonds of the carbonyl oxygen with the amino hydrogen, and of the amino nitrogen with the a-hydrogen. However, it does not explain the dependence of the (17)/(15)ratio on the amine and, if formation of (18) is quantitative, it even contradicts it. NC,

,NHAr C-

/CN

3. The “vicinal ” element effect (the leaving groups on neighbouring

carbons);Park’s carbanionic theory An additional type of element effect, which will be called the “vicinal element effect’’ is possible when two leaving groups are attached at both ends of the same double bond. Whether X or Y leaves earlier, or which one leaves alone when only monosubstitution occurs, depends on the preferred position of the attack of the nucleophile, and on the reversibility of this step. For irreversible attack, the (19)/(20) ratio would be determined by the relative electrophilicity of the a- and the p-carbon

atoms, which is determined by the activating ability of both a- and 8-substituents. For reversible attack, the ratio would be determined by the relative carbon basicity of the nucleophiles for the two carbon atoms, and by the relative leaving ability of X and Y. The presence of a strong activating u-group always controls the substitution course, e.g. compound (21) loses only the chlorine to the carbonyl group (McBee et al., 1962b)while (22) loses the vinylic chlorine atom rather than fluorine (Scherer et al., 1966).

18

ZVI RAPPOPORT

The vicinal element effect was studied recently in cyclic polyhalogenated Olefin8, especially by Park and coworkers. While for these compounds only addition-elimination operates, the allylic halogens may be the ones replaced in competition with the vinylic ones (see below). Extensive work has been done on the reaction of substituted halocyclobutenes with EtO- ions in ethanol. Conformational complications possible in the alicyclic systems are small, and the effect of a-and P-substituents to the negative charge of the intermediate carbanion could be separated (Park et al., 1965). When X = Y attack at either position would give carbanions which are equally stabilized by the a-group, and the products would be determined by stabilization of the carbanion by groups 8- to the negative charge. When the j3-groups are equal, and X and Y are different, the a-stabilization could be evaluated. The results of Park’s group on the ethoxide ion reactions have been summarized by the following empirical rules (Park et al., 1966) which will be referred to as “Park’s carbanionic theory”. The main assumption is that, even when the double bond is substituted by the mildly electronattracting halogens, the substitution intermediate is a carbanion. The nucleophilic attack is assumed to give always the carbanion best stabilized by substituents in the a-position to the negative charge. In the terminology of this theory “a-” and “j3-stabilization” relate to the negative charge, i.e. in (23)Y is an a-stabilizing group and X, Nu, RS and R4 are /3-stabilizing groups. The NMR evidence shows that the electron-attracting ability of the halogens increases with their size, R ‘ R Z ~ ~ ; ~

+-Nu-

__f

@a

NU

(23)

NUCLEOPHILIC VINYLIC SUBSTITUTION

19

probably since the spreading of the negative charge over a large atomic volume more than compensates for the lower electronegativity of the heavier halogen. Therefore, a larger halogen atom is expected to stabilize the negative charge better than a smaller one, and from studies by Hine et al. on the haloform ions, the expected order of a-stabilization is : I > Br > C1 >F > CF, > EtO. If the attack on the two carbons involved gives two carbanions which are equally stabilized by a-substituents, the one having the better t9stabilizing groups would be formed preferentially or, if steric effects are important, the one with the lower steric interactions. Increase of the a-stabilization would reduce the importance of /3-stabilization. An important assumed property of the intermediate carbanion is that its further reactions are independent of its way of formation, and the leaving group may be the one which was either allylic or vinylic in the original olefin. The less basic 8-leaving group would be eliminated preferentially, probably in the order I- > Br- > C1- > F- RO- > H-. Fluoride ion would not leave from a CF2group when another potential leaving halogen is available. Finally, for two identical potential 8-leaving groups, the one forming the most stable olefin would be eliminated. The formation of both vinylic and allylic products could also be explained in terms of competing vinylic SN2 and SN2' substitutions. Since the carbanionic theory is simpler, and it also accounts for the formation of saturated ethers in weakly basic conditions, it seems preferable to a combination of mechanisms, and the examples below are discussed according to it. Reaction of ethoxide ion with 1,2-dichlorotetrafluorocyclobutene (24) gives both the monoether (26) and the triether (30) (Park et al., 1951).

=-

20

ZVI RAPPOPORT

The initially formed carbanion is (25),from which preferential replacement of chloride over that of fluoride ion gives (26). Further attack could give (27),which is stabilized by a-chlorine, rather than (31),which is stabilized by an a-ethoxy group, and (28)is expected to be formed by the loss of the less basic fluoride. Further attack on (28)would give (29), which is stabilized by a-chlorine, preferentially to (32),which is stabilized by a-fluorine, and the loss of fluoride rather than ethoxide ion will give the triether (30). Since this ether is the final product of the reaction FZ EtO

of (24)with ethoxide ion, and it could also be formed by one vinylic substitution and two SN2 allylic reactions without rearrangement, the formation of the rearranged triether (33)from the reaction of the monoether (26)with methoxide ion (Park et al., 1963a)fit the predictions of the

M:q:Et MeO-

C1-

OEt

OMe

(33)

carbanionic theory. A similar reaction gives analogous results with 1,2-dichlorohexafluorocyclopentene and alkoxide ions (Dreier et al., 1964) where the dimethoxy-ether (34) was also isolated (McBee et al., 1962a). F

The effect of j3-substituents (Park et al., 1965) is demonstrated by the reactions of 1,2,3-trichlorotrifluorocyclobutene (35) with sodium ethoxide. While stabilization by a-chlorineis commonto both carbanions (36and 37)formed by attack at the two vinylic positions, (36)is stabilized by j3-chlorineand ,!?-fluorine,and (37)by two jl-fluorine atoms. Assuming

NUCLEOPHILIC V I N Y L I C SUBSTITUTION

21

that the relative stabilization at the /?-positionis similar to that of the a-position, i.e. is higher with the larger halogen, (36) should be more stable. Indeed, the substitution products (38 and 39) formed from (36) and (37), respectively, are formed in the ratio 61 :39, which is in agreement with this assumption.

(35)

I

I

a-Stabilization of bromine exceeds that of chlorine as judged by the 1:3 ratio of the monoethers (41) and (42) from the reaction of l-bromo-2chlorotetrafluorocyclobutene (40) with EtO- ion.

:I@:

EtO-b

"'uFzF2nFz C1-

OEt

(4)

+

EtO

(411

-Br

(42)

It is expected that by substitution of (43) which has a-groups similar to those of (40), and/?-groupssimilar to those of (35), both the carbanions F z q F C l

OEt

Br-

c1 (43)

+

Fzp;:

EtO Br

(44)

(45)

1

1

22

ZVI RAPPOPORT

(44) and (45) will be formed. While a-stabilization will favour (44) over (45) by a ratio of 3 :1, the /I-stabilization of (45) will exceed that of (44) by a ratio of 61 :39. If the effects of a- and /I-substituents are additive, a 57 :43 ratio of (46) to (47) is expected by combination of the above ratios. The formation of the monoethers in a ratio of 68:42 (and less accurately in other systems) confirms this additivity. The effect of y-groups may sometimes be important, ifthey are able to participate in the spreading of the negative charge. The formation of (51) rather than (48) from the reaction of MeO- ion with (49), probably reflects such stabilization via the intermediate ion (50) (McBee et al. 1962a).

C ! l h C l

c1

\ I OMs (48)

C;l-2l (0Me)z

(OM42 +

MeO-+

(49)

A steric alternative to the carbanionic theory would assume that the less hindered position is always being attacked. The formation of (44) with the higher steric interactions may be an argument for the operation of electronic rather than steric effects. Another example is the exclusive formation of the ether (53) from the reaction of (52) with ethoxide ion (Park et al., 1967a). This is in line with the expected higher stabilization by a /3-CF2group compared to a /3-CH2group but, owing to the small size of the fluorine atom, both (53) and its isomer (54) should be formed if the reaction is governed by steric control. It should be mentioned, however,

that for nearly equal steric effects, the electronic ones are expected to take over. I n the systems described above, only two products were formed owing to the preference of halogen to leave the C(0Et)Hal group rather than

NUCLEOPHILIC VINYLIC SUBSTITUTION

23

the CFHal group. However, in less favourable cases two vinylic and two allylic substitution products may be formed. 3,3-Difluoro-1,2,4,4tetrachlorocyclobutene (55) gives primarily the two vinylic substitution products (58) and (60) and an allylic one (59), via the carbanions (56) and (57) which are formed in a,ratio 89: 11. This high ratio reflects the

higher stabilization of 8-chlorine atoms over 8-fluorine atoms, while the formation of more (59) than (58) shows that the chlorine in the CCI, group is a better leaving group than that in the C(0Et)Cl group. With the already evaluated higher stabilization of u-bromine over a-chlorine ((40)+ (41)+ (42)) and on the assumption of additivity it could be predicted that (61) would give a 57:43 ratio of (62) to (63).

E;p;

F'c]"'

+

Br -C1

q c 1 2 OEt c1

Br (61)

(62)

(63)

/ 7 Fznc12 .

.

Br

-OEt 34%

(59) 4%

2

(65)

TABLE 3

TRT-

Subst,itution in Halocyclobutenes

RIR2

X

+NU-

RZZn R 3 ; '

+Nu-

~

R

l

R

D

C

NU

R : q R Y

RilqR:'

R'R'p;

X

Y

R1,RZ

R3,R4

Nucleophile

c1 C1 Br c1 Cl Cl

c1

H

C1 C1 c1

c1 Br H c1

F,F F,F F,F F,F F,F F,F F,F F,C1 F,C1 F,F

F,F F,F F,F F,F F,F F,F F, Cl F,F F,F C1,Cl

EtOEtOEtOEtOMeOEtOEtOEtOEtOEtO-

C1 C1

EtO

C1,Cl F,F

F,F C1,Cl

EtOEtO-

a

Br

Substitutionproduct

V

v+v v+v v+v

A A

v+v v+v A V+A+V V A

Y

NU

NU

NU

EtO

R k R ' p R 4

X

X

Br I I

"'"' 9

NU

yoI

yo 11

1OOb 25 10 2.5 100

75 90 97.5

100 39 42 100 11 34

61 58 89 66 100

Leaving group from (I) C ( 0 E t )* * .C1 C(OEt).--Br CI.--Br CI..-Cl C F * . .F CF. * .F C ( O E t ) - . -C1 C(OEt)---Br C F . . .C1 C ( 0 E t ) . * *C1 C(OEt)...Br

Leaving group from (11)

CBr---I CCl. * -1 C ( 0 E t ) - . *C1 C ( 0 E t ) . * .C1

Nu

Reference Park et al., 1951 Park et al., 1965 Park et al., 1968 Park et al., 1968 Park et al., 1963a Park et al., 1963b Park et al., 1965 Park et al., 1965 Park et al., 1963b Park et al., 1965

CC1- . .C1+ C ( 0 E t ) . . .C1 C ( O E t ) - . .C1 Park et al., 1965 CCl.. .c1 Park et al., 1965

C1

c1 EtO c1 c1 F

c1 c1

C1 F

H

c1

C1

c1

c1 C1 c1

a

F C1

F, F

EtO-

C1. E t O C1, E t O F. F EtO, E t O MeO, E t O F, F F, F F, F H, E t O

EtOEtOEtOEtOMeOEtOEtOEtOEtO-

I F

A

v+v A V V V V V V V

100 29

71 100

lo@ 47

53 100 100 100

CCI.. .c1 C(OEt)..*CI C(OEt).*-Cl C ( 0 E t ) . * *C1

C(OEt)...CI C(OEt)...Cl C ( 0 E t ) . . *C1 C(OMe).-.F C(0Me). . .F C ( O E t ) - . .C1

C(OEt)..*F

100 100

C(OEt)** * F

100

C(0Me). . .F

BH,

100

CH.. .F

Piperidine

100

C(N<)-..F

Morpholine

100

C(N<). . .F

Park et al., 1966 Park et al., 1965 P a r k et al.,1965 Park et al., 1966 Park et al., 1965 P a r k et nl., 1963a Park et al., 1966 P a r k et al., 1967a Park et al., 1967a Park et al., 1963b

Park and Frank, 1967 Park and Frank, 1967 Park and Frank, 1967 Park and Frank, 1967

2

c:

cz m

FQFz

F,F

H,H

BH,

100

V

Park a n d Frank, 1967

c: W

m

I3 H

H

I3

9

20 V

c1

OMe c1

F,F

F,F

Me3MH (M = Si, Ge)

V

100

100

C(OMe).--F

CMMe3. * Cl

Park a n d Frank, 1967

Cullen and Styan, 1966

2

TABLE 3-continued Substitution" product

%I

Leaving group from (I)

Leaving group from (11)

X

Y

R1,RZ

R3,R4

Nucleophile

Br C1

F EtO

F,F F,F

F,F F,F

EtMgBr EtMgBr

V V+A

100 100

C1 C1

Et MegAs

F,F F,F

F,F F,F

EtMgBr MezAsH

V+A V

25

75 100

C1

H

F,F

F,F

LL4lH.I

V+A

63

37

CF.0.F

CH. * .C1

NaBH4

V+A

16

84

CF-.*F

CH- . .C1

% I1

CEt . . .F C(OEt)*..C1+ CF. * * F CEt**.Cl

Reference Sullivan el al., 1964 Sullivan et al., 1964

CF- . .F Sullivan et al., 1964 C(AsMe2).. .C1 W e n and Dhaliwal, 1967

MeS BUS F

F F MezAs

F,F F,F F,F

F,F F,F F,F

MeSBuSMezAsH

V V V

100 100 100

C(MeS). . *F C(BuS)* * F C(MezAs).. .F

F

PhzP

F,F

F,F

PhzPH

V

100

C(Ph2P). * . F

F

F

F,F

F,F

Nuc

V

100

CN. *F

.

Burton and Johnson, 1966 Burton and Johnson, 1966 Cullen et al., 1967 Pruett el al., 1950 W e n and Dhaliwal, 1967 W e n and Dhaliwal, 1967 c

A=Allylic product; V=Vinylic product. I=II. oNu-=Et2PH(CullenetaZ., 1967);BuS- (Pruett et al., 1950); MeS- (Cullen etal., 1967); PhaPH (Cullen and Dhaliwal, 1967); MezAsH (Cullen andDhaliwal, 1967); Mo(CO),, Re(C0); (Jolley and Stone, 1965); P(0Et)a (Knunyants et al., 1964); MeClzSiH, MesSnH (Cullen and Styan, 1966); MeO- (Parket al., 1949).

NKJCLEOPHILIC V I N Y L I C S U B S T I T U T I O N

27

The actual ratio found is 66: 34, i.e. the stabilization by two 8-chlorine atoms exceeds that calculated from the reaction of (55) (Parket d., 1965). Similar reactions of substituted cyclobutenes are collected in Table 3, which lists the attacked system, the nucleophile and the leaving group, and the ratio of allylic to vinylic products. The following order of leaving ability of 8-substituents is obtained from the Table :

The broken line shows the bond cleaved. Ring size has little effect on the ratio of the two vinylic haloethers formed in the reaction of 1,2-dihaloperfluorocycloalkeneswith ethoxide ion. The ratios of the ether carrying the heavier halogen to the second one are 3, 9 and 39 for the (Cl, Br), (Br, I)and (Cl, I)substituted pairs in 1,2-dihalohexafluorocyclobutenesand 3.3, 8.1 and 32 for the 1,a-dihaloheptafluorocyclopentenes (Park et ul., 1968). This a-stabilization is the same one as found from exchange experiments of the haloforms hydrogen (Hine et ul., 1967; Slaugh and Bergman, 1961). While secondary amines give usually the same type of substitution products as alkoxides, the vinylic substitution product with primary amines is capable of prototropy. Further attack by the amine results in the formation of the iminoamines such as (66) (McBee et al., 1965). does However, 1-chloro-2-dimethylarsino-3,3,4,4-tetrafluorocyclobutene

F u N H M e

not give a trisubstituted product with dimethylarsine, but the divinylic derivative (67) (Cullen and Dhaliwal, 1967) showing that the behaviour of this large nucleophile is inconsistent with either steric or electronic control of the reaction. The carbanionic theory does not fit all types of nucleophiles, as shown by Burton and Johnson's work (1966), on substitutions with complex

28

ZVI RAPPOPORT

metal hydrides. While both LiAlH, and NaBH, replace the vinylic fluorine of (68, n = 2,3), the analogous compounds with vinylic chlorine (70, n = 2,3) give bothvinylic (69) and allylic products (71). The (71)/(69) ratios are 11 and 5 for LiAlH, and NaBH4 for n = 3, and 1.7 and 0-2 respectively for n= 2.

H- - r

L 168)

F

+

MH4-

Hr l € i

Hzr(r:-i (69)

+ MH4-

H

___f

+ (69)

__f

c1 -

The carbanionic theory predicts that (71) should be the main or the exclusive product. This is found with (70, n = 3) as well as in the reaction of LiAlH, with (72) which gives only (73) (Feast et al., 1966). Formation

of (73) requires that the higher stabilization by an a-Cl over that of a-F is more than compensated by the higher stabilization of the P-CF2 and P-ClH compared to P-CH2and P-CFH groups. The results for the four-membered ring are different. The strong dependence of the (71)/(69) ratios on the size of the reacting hydride suggests the operation of steric control for bulky nucleophiles, where the larger nucleophile is more selective, attacking the less hindered position. The results are even more complex with Grignard reagents. Exchange reactions, forming e.g. (74), are sometimes the main ones, but l-bromopentafluorocyclobutene gives (75) with EtMgBr, as expected according to the carbanionic theory. While all the five substitution products of (76) with EtMgBr (Sullivan et al., 1964) could be accounted for by the theory and the reasonable leaving-group order C.HEt > “OEt

c..

‘Et

29

NUCLEOPHILIC VINYLIC SUBSTITUTION

the explanation also demands that a-C1 and two P-Et groups stabilize less than a-Et, P-Et and 13-Cl, contrary to the theory. Moreover, the

F

+

YZI_IFZ

EtMgBr

F

F 2 n b3;

-

Et

MgBr

(75)

(74)

EtO

1%)

dependence on ring size is similar to that found for the metal hydrides. While EtMgBr gave exclusively the disubstituted vinylic products (78) when reacting with perfluorocyclobutenes and pentenes (77, X = F, n = 2,3), the dichloroperfluoro compounds (77, X = C1) gave both (78) and the rearranged (79)with (78)/(79)ratios of 4.6 and 1.5 for n = 2 and n = 3 , respectively (Park et aE., 1967b). Two possible sources for the

n-

r ( C F d n 1 Et

EtMgBr

X

+

r

z

E

h

Et

X

(77)

-

1

F (79)

(78)

difference from alkoxides might be the differences in the solvents used (ethers vs. alcohols) and in the bulkiness of the Grignard reagents. Moreover, reactions with hydrides and Grignard reagents should be subject to kinetic control owing to their irreversibility, and the different course with ethoxide ion might reflect reversibility with the less basic nucleophile. The carbanionic theory is inadequate for systems with vinylic fluorines. Both vinylic fluorines are replaced in polyfluorocyclobutene (Park et al., 1949) (Table 3) while 1,2-dichlorotetrafluorocyclobutene(24) gives the triether (30). The differences were ascribed to higher reactivity of the vinylic fluorine compared to the chlorine, as a result of the steric and the electronic factors already discussed (Stockel et al., 1964, 1965). Both chlorines of (24) are replaced if an activating group is introduced in the first substitution step, as in the formation of (80) (Frank, 1965). (RO)sP

c1n

C

1

-

(RO)z(O)PJ ( C F I I p ( 0 ) ( O H ) . (80)

30

ZVI RAPPOPORT

The degree of preference of elimination of the vinylic fluorine (Park et al., 1968) depends on the ring size. No rearranged product is formed with perfluorocyclobutene,4% allylic product is formed in the methoxide ion-perfluorocyclopentene reaction, and 15-3 1% of the rearranged 3-alkoxynonafluorocyclohexenes (83) are formed in addition to the 1-alkoxy isomers (82) from decafluorocyclohexene (81) with different alkoxides (Clayton et al., 1965). On the other hand, methyllithium and LiA1H4gave 98-100% of the vinylic substitution products (Sayers et al., 1964; Evans et al., 1963). Rearranged and unrearranged products are formed in equal amounts from 1-hydro- and 1-methylnonafluorocyclohexene. These results were again ascribed to the formation of carbanionic intermediate from which elimination is faster than internal rotation. It was also assumed that the addition and the elimination of the nucleophile and the leaving group occur in trans fashion, and therefore the leaving group has to leave from a position cis to the entering nucleophile. Competition between the cis-fluorine of the CF2 group with the trans-, but more easily cleaved, fluorine of the C(0R)F group, gives both (82) and (83). As expected by this reasoning, more (83) is formed with increase in the electron-attracting power of R. The lower stereochemical opposition to cis elimination in the smaller ring systems was thought to contribute to the higher proportion of the vinylic isomers,

B

The data for competition between formation of (19) and (20) in aliphatic systems are more limited, but they are only partly accounted for by the carbanionic theory. Attack on chlorotrifluoroethylene, for example, is nucleophile-dependent : fluorine from the CF2 group is replaced on reaction with PhMgBr (Tarrant and Warner, 1964), PhLi (Dixon, 1966) and LiNBu2 (Yakubovich et al., 1966), while Re(C0);

NUCLEOPHILIC VINYLIC SUBSTITUTION

31

and Fe(C0)2-n-C6H; ions replace the chlorine atom (Jolley and Stone, 1965). CFZ=CFRe(CO)s

Re(CO)a f---

CCIF=CFz

PhLi ___f

PhCF=CClF

The attack at the CF2 group of 1,l-dichloro-2,2-difluoroethylene by EtMgBr (Tarrant and Warner, 1954), the attack at the CF2 group of phenoxytrifluoroethylene by phenoxide ion (England et at., 1960) and the replacement of the 1-fluorine of 1-diethylaminotrifluoroethylene with water (Yakubovich et al., 1966) are in line with predictions based OP the carbanionic theory. On the other hand, the attack of triethyl phosphite at the terminal difluoro group of o-iodoperfluoro1-olefins (Knunyants and Pervova, 1962) could be explained by steric control. A competition between two strongly activating groups of l-butylsulphonyl-I-chloro-2-p-tolylsulphonylethylene results in the replacement of the p-tolylsulphonyl group by piperidine, sodium sulphide or sodium bisulphite (Backer et al., 1953). It is probable that the extra stabilization of u-chlorine coupled with the differences in basicity of the two sulphinate anions controls the direction of the reaction.

C. The Stereochemistry of the Addition-Elimination Route The stereochemical course of substitution by the addition-elimination route is related to the structure of the transition state and to the timing of the bond-forming and bond-breaking processes. The terms “retention”, “inversion” and “racemization ” will be used respectively to denote the processes in which the geometrical arrangement of thegroups in the substitution product remains the same (equation 3), or changes NU

R

(M), cis

(85), cis

(86),trans

@I), trans

(&()+Nu(86) +Nu-

___*.

Either (84) or (86)

+ Nu-

Retention

J

1

(87)+X’

(85)fX4(85) or (86)or ( 8 5 ) (86)

+

(3)

Inversion

(4)

Racemization

(5)

32

Z V I RAPPOPORT

to the isomeric structure (equation a), or processes in which the same mixture of both isomers (or only one of them) is formed from the two isomeric starting materials (equation 5 ) . These terms are not exactly analogous to those used for substitutions at a saturated carbon atom, but they are sometimes used as such in the literature. We will denote the a-substituents as M (medium) and L (large). 1. The one-step substitution Gold (1951) was the first to suggest that the stereochemical consequences of the substitution depend on the mode of nucleophilic attack, i.e. whether the attacked carbon atom of the transition state is planar or tetrahedral. A planar transition state (88) which is analogous to that of a SB2 reaction would be obtained if the nucleophile attacks in the plane of the substituents, being collinear with C j and the leaving group. bonds are sp-hybridized, one of the I n (88), the collinear R-C,-Cfi remaining p-electrons participates in the formation of

(W

(88)

(87)

.rr-bond, while the other one is involved in the weak bonding of Cfi to both the entering and the leaving groups. The stereochemical outcome of the SN2mechanism (equation 6 ) would be inversion of the configuration for both isomers, as the C,-Cj bond retains its double-bond character during the substitution. On the other hand, if a tetrahedral intermediate carbanion is formed by an sp2+ sp3 route, it should give, according to Gold, a mixture of both isomers, bond is not restricted. provided that free rotation around the C,-Cj Stereochemical data for choosing between the alternatives were not available to Gold, but it was shown with molecular models for the reaction of /3-bromostyrenes with iodide ions (Miller and Yonan, 1957) that the reaction site is highly shielded. In (88), the groups N and M (i.e. I and H) and L and X (i.e. p-O2NC6H4and Br) are almost within bonding distances and, since bond formation is impossible, the repulsion energy is high enough to exclude contributions from it. The packed geometry around the double bond results in severe steric repulsion even when smaller groups are involved, since the steric interactions of cis groups which play a role in the ground states of olefins with 120” angles around C, or C,, will be more serious in (88) with the four 90b angles

NUCLEOPRILIC VINYLIC SUBSTITUTION

33

around Cg. Moreover, a-activating groups are usually polyatomic and their bulkiness would increase the shielding of the reaction centre to attack from the plane of the substituents. The operation of the SN2mechanism was actually suggested only for the substitution of the 8-halo-a-pentachlorostyrenes with EtO- ion (Ross et al., 1952). It was shown later (Huett and Miller, 1961) that this reaction belongs to the elimination-addition category. A one-stage displacement giving retention by a front-side attack via (89)is no longer analogous to the SN2reaction, and requires distortion of the two lobes of the p-orbital involved in the substitution to ca. 110" angle. Such a structure for the transition state was dismissed for

nucleophilic aromatic substitution (Bunnett and Zahler, 1961), or for vinylic reactions (Bunnett, 1959). I n addition, an inversion mechanism would then also be required to account for those cases in which a mixture of both isomers was observed, and both (88) and (89) would have to be invoked. 2. Substitution via tetrahedral intermediate The element effects are best explained by assuming a two-step process. Recent discussions on the stereochemistry therefore dismiss the one-step mechanism and explain the stereochemical results with the aid of intermediate carbanions. We will first discuss the theory of the substitution in general form and then evaluate the experimental data according to it. The discussion is partially along the lines of those of Miller and Yonan (1957), Jones e t al. (1960) and Rappoport et al. (1963). a, The general scheme. Scheme 4 gives the various conformers of the intermediate carbanions formed by nucleophilic attack on a pair of cis-trans isomers, and which are important for discussing substitution or isomerization. It also defines,the rate constants for the various processes, where k2 with superscript is the rate constant for elimination of X- or Nu- from the conformer, and where the various rate constants for rotation, kr,t carry superscripts to indicate the angle of rotation required to form them from the conformer given as superscript. The symbols (c) and (t) differentiate between conformers obtained from cis and trans

34

ZVI R A P P O P O R T

Nu-

1

,$93'

___F

M--

NU

R

NUCLEOPHILIC VINYLIC SUBSTITUTION

36

isomers, respectively. Reactions with X- are neglected. The negative charge on the a-carbon is not shown. Scheme 4 is based on three assumptions: (A) The nucleophile attacks perpendicularly to the plane of the molecule, giving a tetrahedral arrangement of the groups around the j?-carbon. (B) The groups on the a-carbon remain planar in the carbanion. (C) Elimination of the leaving group occurs perpendicularly to the plane of the incipient double bond of the product. It should be noted that assumption (B)is not an essential one. Indeed, Miller and Yonan (1957) and Rappoport et al. (1963) discussed the substitution and the isomerization reactions in terms of a pair of rapidly inverting carbanions (94) and (95). If inversion is rapid enough, then the a-carbon atom is, on average, planar. Discussion in terms of (94) and (95) would give similar results but should be slightly modified by including both rotation and inversion rates (see also Miller, 1968). For example, 60" rotation followed by elimination from a planar carbanion, would give the same stereochemicalresults as a fast inversion, 60" rotation and trans elimination of the nucleophile and the electron pair from (94) which is formed by trans addition. I n the absence of exact NU

Nu

knowledge of the structure of the carbanion we prefer discussion in terms of planar structure, avoiding in this way the question of cis or trans elimination of the nucleophile and the electron pair. This assumption seems fair, as the carbanion itself is derived from a planar starting material. b. Retention, inversion and racernization. The primary carbanions, formed from the cis and trans isomers by the nucleophilic attack, are (90) and (93), respectively. Rotations of 0", 60°, 120" and 180" would yield conformers from which either Nu- or X- could be eliminated according to (A) and (C) above. The chemical and stereochemical courses of the reaction are summarized in Table 4. Obviously, a 0" rotation followed by elimination of Nu- re-forms (90) or (93) and is therefore not detectable directly, although some indirect data are obtained from isomerization studies (Rappoport et al., 1963). If the leaving group leaves after 60" rotation only, from con-

36

ZVI RAPPOPORT

formers (91c) and (92t), the overall result is substitution with complete retention of configuration. If it leaves after 120' rotation only, i.e. from conformers (92c)and (91t) ,the result is substitution with complete inversion. A 180" rotation followed by expulsion of Nu- from either (90) or (93) results in isomerization of the starting olefin. Complete retention for both isomers is expected only if the rate constants kJ9lc) and k2(92t),for the elimination of X- from (91c)and (91t) respectively, are much larger than the value of kfzt leading to (92c) and (91t).Retention is therefore kinetically controlled, and would be observed if bond-breaking lags but slightly behind bond formation. The difference from the one-step retention is both in the direction of the nucleophilic attack and in the timing of the bond-making and bond-breaking processes. The eclipsing pairs during the process of formation of (91c) and (92t) are (R,M) and (R,L) for the cis and the trans isomers, respectively. The requirements for inversion are more stringent. Here, bondbreaking lags more behind bond formation, and the intermediates (91c) and (92t) should be by-passed in preference to (92c) and (91t): hence kiz:(90)& kL9lC)and k:393)BkL92t). On the other hand, ki$' should be lower than ki92c)and k:tt(93) smaller than kL91t), i.e. once the conformers (92c) and (91t) are formed, they should not be by-passed by a free rotation. Inversion in preference to retention could be visualized as resulting either from a high-energy barrier to formation of (91c) and (92t) B k::t) and a low population of these conformers, or from comparable population but more difficult elimination (kiz:(90)3 kL9lC)2 k120(93) rot 9 and k:t:(90)-g kz2(c),kif:(93)
TABLE 4 Expected Steric Course in Vinylic Substitution via Intermediate Carbanions Angle of rotation

Steric course'

Chemical course

No change Substitution Substitution Substitution

180"

Retention Retention Inversion Retention + Inversion Inversion

Isomerization

> 360'

Racemization

Substitution

60°+ 120"+ 180"+ >360"

Retention + Inversion + Racemization

Substitution + Isomerization

O0

No change Substitution Substitution Substitution

180"

Retention Retention Inversion Retention + Inversion Inversion

Isomerization

> 360"

Racemization

Substitution

Retention+ Inversion + Racemization

Substitution + Isomerization

Elimination from

O0 60" 120° 60" 120'

+

60' 120° 60"+ 120"

+

+

60" 120" 180°+ >360"

Leaving group

Interacting pairs"

According to the "competition theory" (p. 39) for short-lived carbanions. According to thermodynamic control for longlived carbanions. The interacting pairs are those of the three preceding lines, depending on the degree of rotation involved. (I

w -J

38

ZVI RAPPOPORT

before X-- can be eliminated, i.e. both %:!(") and k&93)should be higher than kL9l') and k&92c). If the formation of (93) from the cis isomer, or of (90) from the trans isomer, is faster than the elimination of either Nu- or X-, then the carbanions lose their identity after 180" rotation. The stereochemistry of the product would accordingly be determined not by the configuration of the starting material, but by thermodynamic control. The same single isomer or mixtures of both isomers would be obtained from both cis and trans starting materials. Substitution would now occur via (91c = 91t) and (92c = 92t), but these are obtained by free rotation. We arbitrarily define them in Table 4 as obtained by >360" rotation, meaning that X- is eliminated when the carbanions derived from the cis and the trans isomers are no longer distinguishable. The thermodynamic controlling factor would be the "cis-effect", according to which the elimination transition states resemble the products in their relative steric interactions (Curtin, 1964; Eliel, 1962). Competition between (R,M) and (Nu,L) interactions in the transition state leading to the cis configuration, and between (R,L) and (Nu,M) interactions in the transition state for the trans product, would determine the product ratio. For example, for the same nucleophile, if R =H, the trans isomer would predominate if the (Nu,L) interactions are larger than the (Nu,M) interactions. Increase in the percentage of cis isomer is expected with increase in the size of R. With a small Nu and a bulky R group, the cis isomer would predominate owing to the larger (R,L) interaction, but for a small and constant R more trans isomer would be formed on increasing the size of Nu. We will refer to carbanions which give elimination faster than rotation, being responsible for the clean retention or inversion for both isomers, as "short-lived carbanions ". They may be short-lived if the C-X bond breaking has very slightly progressed even at (90) and in conformations on the way to (91) concurrently with the bond formation. The simultaneous development of partial double-bond character between C, and Cg creates a barrier for rotation. The conformer which requires the least rotation is formed, and the properly situated X leaves from this conformation. An alternative explanation, based on high population for conformations (91c) and (92t), seems much less likely. If the above analysis is correct, pathway (90)+ (93) is forbidden and concurrent isomerization of the starting material with clean retention in the substitution is impossible. Since retention is sometimes obtained from a combination of the addition-elimination and the eliminationaddition routes, the appearance of concurrent isomerization would point to this route for product formation rather than to addition-elimination

NUCLEOPRILIC YINYLIU SUBSTITUTION

39

alone. Similar arguments predict that isomerization of the starting material is not expected when only inverted product or a mixture of retained and inverted products are formed via short-lived carbanions. Long-lived carbanions are essential .but not always sufficient for the isomerization, as this is dependent on the relative leaving ability of Xand Nu- from the intermediate. Generally, the weaker nucleophile of the two leaves in preference, and isomerization would be observed only if the elimination of Nu- is not much slower than that of X-. c. Formation of cis-trans mixtures. The “competition theory” and the “preferred retention mechanism ”. Formation of different cisftrans product ratios from the reaction of cis and trans olefins could result from four different causes: (a) Mixture of retention and inversion routes via short-lived carbanions. (b)Mixture of retention, inversion and racemization routes via short- and long-lived carbanions. (c) Partial isomerization of the starting material before and during the substitution. (d)Isomerization of the product during and after the reaction by nucleophiles present in the reaction mixture. Since cases (c) and (d) are not directly related to the substitution, they distort the real product distribution and should be evaluated by control experiments. It is recommended that product ratios should be recorded as early as possible and extrapolated to zero reaction time. Case (c) could be recognized either by the appearance of isomerized starting material or by irregularities in the kinetics, if isomerization is faster than substitution and if the cis and trans isomers differ in reactivity. When the cisltrans ratios from both isomers are not very different from each other, racemization probably contributes to the product, although differentiation between (a)and (b) is difficult. The product ratios from the two isomers should be discussed in terms of (a)if they differ strongly. Each isomer is then assumed to be formed by a kinetically controlled process, and. the relative contributions of the retention and inversion mechanisms are given by the ratio of retained to inverted product. Vernon and coworkers (Jones et al., 1960) suggested that this ratio would be determined by competing different steric interactions during the formation of the conformer allowing elimination, rather than by the steric interactions in the transition state of the elimination itself. The cisltrans ratio obtained from the cis isomer would be determined by competition between (R,M) interaction on the one hand and (X,L) or (Nu,M) interactions, whichever the highest, on the other. The relative order of these interactions could be estimated from models and used to predict whether retention or inversion will be dominant. It can be concluded that the ratio of retained to inverted product would be different starting from the cis or the trans isomer. We will call this

40

Z V I RAPPOPORT

the “competition theory”. The predictions according to it and the above discussion are given in Table 4. Alternatively, it is possible that the very short life-time of the carbanion is the product-determining factor. Since less rotation is required for it, retention would always be preferred, and inversion would be observed only if the conformer obtained after 60’ rotation is by-passed either as a result of the stability of the carbanion, or if the rotation and the elimination rates are comparable. We will call this route in which the importance of retention, inversion and isomerization decrease in this order, the “preferred retention mechanism ”. Discrimination between conformers due to steric interactions leading to them does not play a role in determining the product ratio, and the difference in the degree of retention for each member of the pair of isomers cannot be predicted. A “steric element effect” may operate if the cisltrans ratio is determined by the competition theory. The leaving group is not involved in the (R,M) interaction which controls the amount of retention of the cis isomer, but if the (X,L) interaction is larger than the (Nu,M) interaction, it would control the amount of inversion. When compounds with X = C1 and X = Br are compared, the bulkier bromine should cause less inversion. The same arguments show that more retention is expected on increasing the size of the nucleophile. Another prediction is that more inversion would be obtained for both isomers on increasing the size of R. For thermodynamic control more retention is expected for the cis isomer on increasing the size of R, but more inversion for the trans isomer. This difference may be of some value for differentiation between kinetic and thermodynamic control. It should be emphasized that the stereochemistry should be studied for both isomers, since work with one isomer only can result in wrong identification of the substitution mechanism. Table 5 summarizes the stereochemical information available for reactions which are assumed to follow the addition-elimination route. Unfortunately, the reliability of the data is not the same for all the systems. Earlier work, where minor products were neglected and proper control experiments were not performed, is subject to some uncertainties. For example, when 100% of one isomer was reported, this generally means that only one product was isolated. Recent data, obtained with more sensitive and less destructive methods, such as NMR,are much more reliable. The data are arranged by grouping together reactions with the same type of nucleophiles and discussed in the same order. Mechanisms involving retention, mixture of retention and inversion and racemiza-

TABLE5 Steric Course in the Addition-Elimination Route

Substrate" cis-ClCH=CH. CN

Nucleophile p-MeC.&S-

cis-MeCCl=CH. CN tram-MeCCl=CH. CN) cis-MeCCl=CH .CN tram-MeCCl=CH .CN c i s - M e C B d H .CN tmm-MeCBr=CH. CN) cis-MeCBr=CH.CN

PhS-

I

EtSPhSEtS-

&-Arc0.CH=CHCI tram-ArCO. CH=CHCl) (&=C&, p-ClCsH4, p-MeOC&)

1

c ~ s - A ~ CC OH . dHC1 tram-ArCO. C H d H C l C i s - C l C H d H . COzH

PhS-

p-NOzCsH4S-

ArS-

Substitutionb product %trans yocis 95 10 > 97 <2 > 98 1 2 98 3 97 4 100 5

100 0 100

0

Steric course of

reaction

5 90 <3 >98

Retention

Scotti and Frazza, 1964

Retention

Theron, 1967

t2

Retention

Theron, 1967

Retention

Theron, 1967

Retention

Theron, 1967

Retention

Angeletti and Montanari, 1958; Landini and Montanan, 1967

Retention

Angeletti and Montanari, 1958 Montanan, 1956; Angeletti and Montanari, 1958

>98 2 97 3 96

0 95

0 100 0 100

Retention

(Ar= C6H5, p-MeCeH4, p-NOzC&) cis-PhCBr=CH. COzH t r a m - P h C B d H . COzH tram-MezCHCCl=CH. COzEt cis-MeCCI=CH. COzEt t r a m - M e C C l d H . COzEt

I

ArSPhSPhS-

Reference

Isomer mixture Isomer mixture 100 0 95 5 3 97

Racemization? Retention Retention

Angeletti and Montanari, 1958 Pizey and Truce, 1965 Pizey and Truce, 1965

TABLE &-continued

Substrate5

Nuc!eophile

Substitutionb product %cis %trans

Steric course of

reaction

Reference -

cis-MeCCl=CH .COzEt trans-MeCCl=CH.COZELI cis-MeCCl=CH. COzEt trans-MeCCl=CH .COzEt

I

95 0 91 15

5 100 9 85

Retention

Pizey and Truce, 1965

Retention or Retention + Inversion Retention or Retention Inversion Retention or Retention + Inversion Retention

Jones et al., 1960 Theron, 1967

c i s - M e C B d H . COzEt t r a n s - M e C B d H . COzEt

PhS-

94 4

6 96

c i s - M e C B d H .COzEt t r a n s - M e C B d H . COzEt

EtS-

94 6

6 94

100 0 100 0

0 100 0 100

100 0 100 0

0 100 0 100

Retention

100 100

0 0

Retention Retention

Maioli et al., 1960 Maioli et al., 1960

100

0 0 100

Retention Retention

Maioli et al., 1960 Angeletti and Montanari, 1958

ck-p-NOzC6H4.SO. C H d H B r p-NOzCaHrStvans-p-NO&aH~.So.CH=CHBr] cis-ArSO .C H d H C 1 A&trans-ArSO .CH=CHCl) (Ar=C&, p-NOzCaH4, P - C l c d h ) cis-PhSOz. C C l d H C l PhStrans-PhSOz .CCl=CHCl) cis-ArSOz .CH=CHCl PhStvans-ArSOz.CH=CIICI] (Ar=C&. p-ClC,~H4,p-MeCd%, p-NOz. CsH4) cis-ArSOz. CH=CMeBr PhScis-ArSOz. CH=CMeCl PhS(Ar=p-NOz. CaH4, p-MeCeH4) cis-ArSOzCMdHCl PhSc i s - A r C B d H . COzH PhSt r a n s - A r C B d H COzH (h=p-NOz.C6H4, m-NOz. CSH4)

.

100 0

+

Retention

Retention

Theron, 1967 Montanari and Negrini, 1959 Modena, 1958; Montanari and Negrini, 1959 Montanari and Negrini, 1957a Modena, 1958; Modena and Todesco, 1969

C~~-CH(CHO)=CHSCN cis-MeC(N02)=CMeN02 tra~-MeC(N02)=CMeNOz tram-p-MeCa4.SCCl=CHCl cis-Arc0 .C H d H C l tram-ArCO CH=CHCl (AX!= C6H5, p-NOZ.C6H4) trans-PhCO CH=CHNMe:Cl-

. .

Cis-PhSOzCCldHCl trans-PhSOaCCl=CHCl] tram-MeCO.CH=CHCl c~~-P~CC~=CHNOZ trans-PhCCl=CHNOz cis-ClCH=CHCN trans-ClCH-CHCN cis-ClCH4H.COzH trans-ClCH=CH. COzH cis-ArSOzCH4HCl

PhSO;

PhSO, CNSCNSEt2NCSS-

ArSeN,

cis-p-MeCsHg.SOz. CH=CH. SOz. C&Me-p tram-p-MeCsH4.S O z . CH=CH. SOz. CsH4Me-p cis-MeC(NOz)=CMeNOz N, trans-MeC(N02)=CMeNOz

100 0 100 0 100 0 90 0 0 0 0 0 100

0 100 0 100 0 100 10 100 100 100 100 100

100 0

0 100

0

100

Retention?

0 100 100 1ood 1008

Retention

100 0 0 Od Od

1000 OC

100 0 100 0 90 0 100' 0"

-

0

00

l0OC 0 100 0 100 10 100 0 ' 100'

Retention

Marchese et al., 1968

Retention

Marchese et al., 1968

Retention

Beltrame and Beltrame, 1968 Meek and Fowler, 1968

Retention Racemization?

Rasp, 1966

Racemization

Emmons and Freeman, 1957 Truce and Kassinger, 1958a Angeletti and Montanari, 1958

Inversion or Racemization Retention

Retention? Racemization?

Rybinskaya and Nesmayanov, 1966 Montanari and Negrini, 1957a Benson and Pohland, 1964 Iwai et al., 1965

Retentionc

Bikales, 1965

Retention

Chierici and Montanari, 1956 Modena and Todesco, 1959 Meek and Fowler, 1968

Retention Retention Racemization?

2

4

d F M 0

Emmons and Freeman, 1957 IP

W

TABLE&-continued

Substrate'

Nucleophile

cis-ClCH=CHCN tmns-ClCH=CHCN) c ~ s - A ~ S OCZH . 4HC1 tran.s-ArSOz. C H d H C l ) cis-p-MeCaH4. SOz. C H d H . SOz. CeH4Me-p trans-p-MeCsH4. SO2 .CH=CH. SOz. CsH4Me-p cis-CF3. CCl=C(CF3)Cl' trans-CF3. C C l d ( C F & I ' )

95 5 100 0 95

EtOMeO-

] MeO-

cis-CF3.CCl=C(CF3)C1' traw-CF3. CCl=C(CFs)Cl' ciS-CF3. CCI==C(CF.q)Cl' trans-CFs. CCId(CF3)Cl' cis-MeCCl=CH. COzEt t r a n s - M e C C l d H.COzEt cis-p-NOz. Cs&CH=CHBr trans-p-NOz.CsH&H=CHBr) cis-p-MeOCaH4CPh=CHCl'

I

MeO(0°) EtO- ( 2 5 0 ) (50") (25") i-Pro-

ArO-

IC1-

trans-p-MeOCaH4CPhdHCli trans-MeCOCH=CHCl cis-ClCH=CHCN tras-ClCH=CHCN] cis-ArSOzCH=CHCl

I-

Substitution* product yocis %trans

(170') (186') (170") (186') . .

Piperidine Cyclohexylamine

0 93 31 97,2 94.5 94.9 30 96.5 28 100 100 ca. lOOh ca.Oh 60 56 22 28 0 0 0 0 0

5 95 0 100 5 100 7 69 2.8 5.5 5.1 70 3.5 72 0

Steric course of reaction

Reference

Retention

Scotti and Frazza, 1964

Retention

Maioli and Modena, 1959

Retention

Meek and Fowler, 1968

Retention + Inversion Retention + Inversion

Park and Cook, 1965 Park and Cook, 1965

Retention + Inversion Racemizationg

Park and Cook, 1965

0

Jones et al., 1960

Y

N

td k-

ld ld

0

ca. OA ca. lOOA 40 44 78 72 100 100 100 100 100

2

Retention

Miller and Yonan, 1957

Retention + Inversion

Beltrame et al., 1966

Retention? Racemizationj

Benson and Pohland, 1964 Scotti and Frazza, 1964

Racemizationj

Modena et al., 1959

0 'd

td

c ~ s - A ~ S OCZ H . dHCl trans-ArSO~.C H d H C 1 )

BuzNH

c G - A r S O z .C H d H C I trans-ArSOz .CH=CHCl)

MezNH

1

C&'-~-M~C~H~.SOZ. C H d H .SO2 .C6H4Me-p tr~m-p-MeCsH4.802.CH=CH. SO2 .CaH4ME-p c~~-RC(NO~)=C(NOZ)R ~v~~~-RC(NO~)==C(NO~)R (R=Me, Et, Ph) ow-PrC(NOz)=C(NOz)Me tram-PrC(NOz)=C(N02)Me cis-ClCHdHCN trana-ClCHdHCN) c~s-A~SO C ZH. d H C I trans-ArSOz .CH==CHCl]

I

cis-p-MeCgH4.SOz. C H d H . SOz. C,&Me-p truns-p-MeCaHa. S O z . C H = C H . SOz. CsH4Me-p)

Cyclohexylamine

0 0 0 0 0 0

Amines Amines

(MeZN)zC=NH NH

/ \ CHz-CHz NH

/ \

look

Racemizationj

Modena et al., 1959

rno

Racomization j

Ghersetti et al., 1965

100 100 100

Racemization'

Meek and Fowler, 1968

100 100

@ Ok

Racemization j

lOox

Emmons and Freeman, 1957

1od

0 '

Racemization'

1oox 100 0 100 0

0 100 0 100

Retention

Emmons and Freeman, 1957 Fanshawe et al., 1965

Retention

Truce el aZ., 1967

100 0

0 100

Retention

Meek and Fowler, 1968

100

0 100

Retention

Truce et al., 1967

0 5

d

CH-CHz c i s - C I C H d H .COzEt t r a n s - C l C H d H .C02Et) trans-MeCO. C H d H C 1 Ck-PhCCldHNOz tram-PhCCl=CHNOz trans-PhSOz .C H d H B r tra~-(CHB~CH)zSO,' cis-p-MeC&4.S0~.C H d H . SOz. CeHaMe-p tr~ns-p-MeCsH4.S O z . C H d H . SO2 .CaH4Me-p cw-ClCH==CHCl trana-CiCH=CHCI]

I

cis-PhCHdHBr tram-PhCHdHBr

NH

/ \ CHz-CHz NMe3, MezNH Morpholine P(OEt)3

PhZPPhzP-

95

loor look

ox ox

Retention? Racemizationj

Benson and Pohland, 1964 Iwai et al.. 1965

0 0 0 0 100 0 100 0

100 100 100 100 0 100 0 100

Retention? Retention? Racemization

Kataev et aZ., 1965 Kataev et al., 1965 Meek and Fowler. 1968

'

Retention

Aguiar and Daigle, 1964

Retention

Aguiar and Daigle, 1964, 1965

Substrate” ck-PhCH=CHBr trum-PhCHdHBr) trans-PhCHdPhBr trans-MeCO.CH=CHCI ck-MeCCI=CH.COzEt tram-MeCCI=CH.COzEt tram-MeCO.C H d H C I cis-ClCHdH.COzH truns-ClCH=CH.COzH ois-ClCHSH.COzH &um-CICH=CH.COzH cW-CICH=CH.COzMe trans-ClCHdH .COzMe ck-p-MeCeH4.S 0 2 . CH=CH .SOz .C6Hae-p

Nucleophile PhzAsPhzAsCNCH(C0zEt)z CR(C0zEt)z MeMgBr PhMgBr PhMgBr, CuCl PhMgBr

Substitutionb product %cis %trans 100 0 100

0 100 0

0 100 0 0 81 4 99 10 99 9 0

100 0 100 100 19 96 1 90 1 91 100

Steric coupse of

reaction Retention Inversion or Retention?m Retention? Retention Retention? Retention + Inversion?“ Retention + Inversion?n Retention+ Inversion?” Inversion or Racemization?”

Reference Aguiar and Archibald, 1967 Aguiar et al., 1967 Benson and Pohland, 1964 Gidvani et al., 1932 Kochetkov et al., 1961 Gafni, 1965 Klein and Gafni, unpublished Klein and Gafni, unpublished Meek and Fowler, 1968

The t e r n “cis” and “tram” refer to the activating and the leaving groups unless otherwise stated. * Obtained as close as possible to kinetically-controlledconditions. A different product was isolated from each isomer, but the geometricalconfiguration was not determined. Only one product was isolated from both isomers, but its structure was not determined. The product is a substituted furoxan, obtained by elimination of nitrogen and cyclization. ’“ci8’’ and “tram” refer to the chlorine atoms. Probably results from a /3,y-eliminationaddition. A Products were determined indirectly. The kinetic analysis showed that retention is the main pathway at early stages. ‘‘ck” and “tram” refer to the anisyl and the chlorine substituents. j Probably results from a post-isomerization,see text. One product was claimed to be isolated, but its structure was not determined. Owing to the strong hydrogen bonding in the cis configuration we assume this The result is probably for thermodynamic control, since the other isomer to be the product. Only one bromine was substituted. isomerizeseasily to that observed. The primary products reacted further with excess reagent. The values for the percentage of the isomers are probably only approximate. Only small amount of material was isolated by chromatography, in conditionswhich may cause isomerization.

NUCLEOPHILIC VINYLIC SUBSTITUTION

47

tion are apparently needed in order to account for the experimental results. d. Reactions with thio-nucleophiles and with azide ion. Retention is clearly preferred for nucleophiles having high carbon nucleophilicity and relatively low hydrogen basicity, such as the sulphur nucleophiles (thioethoxide, thiophenoxides, sulphinate, dithiocarbamate ions), arylselenide and azide ions. The combination of a highly active nucleophile aad a good a-activating group renders most of these reactions facile enough even at room temperature. Thus, p-halovinyl derivatives activated by arylsulphoxide (Modena, 1958; Montanari and Negrini, 1959), arylsulphonyl (Maioli et al., 1960; Modena, 1958; Modena and Todesco, 1959), carboxyl (Autenrieth, 1887, 1889, 1890, 1896; Montanari, 1956, 1958; Montanari and Negrini, 1957), carbethoxy (Scheibler and Voss, 1920; Jones and Vernon, 1955; Morris et al., 1958; Jones et al., 1960; Pizey and Truce, 1965; Theron, 1967), cyano (Scotti and Frazza, 1964; Theron, 1967), aroyl (Angeletti and Montanari, 1958; Landini and Montanari, 1967) and mono- and di-nitrophenyl groups (Marcheseet al., 1968) gave complete retention of configuration for both isomers. Shortlived carbanions are therefore essential in these systems and no isomerization of the starting material should be observed. Indeed, no evidence of such isomerization, either by change in the rate constants during a run, or by actual isolation was reported. Isomerization of some products was reported, however, e.g. the trans-a-aroyl-/I-arylthioethylenes obtained by substitution of the correspondingchloro-derivatives, isomerized with excess base to the cis isomers (Landini and Montanari, 1967). Earlier work on the substitution of ethyl p-chlorocrotonates by PhSion (Jones et al., 1960) have indicated less retention (85% for the cis and 64% for the trans isomer, where cis and trans refer to the methyl and the carbethoxy groups) than reported in the more recent and accurate investigation of Pizey and Truce (1965) (97% and 95% retention, respectively). No new data are available for the EtS-/p-chlorocrotonate reaction which gave 85% retention for the cis and 91% retention for the trans isomer. The somewhat higher degree of retention (88%) from the cis isomer after shorter reaction times, may point to a kineticallycontrolled higher degree of retention, as found for the PhS- reaction. The values were, however, analyzed by Jones et al. in terms of the competition theory. The models predict that retention with eclipsing (Me,C0,Et) and (Me,H) pairs for the cis and the trans isomers, respectively, would be preferred over inversion with the corresponding (C02Et,Cl), (EtS, H) and (EtS, CO,Et), (Cl, H) eclipsing pairs. While this analysis is in agreement with the experimental results, it is difficult to understand why complete retention would be observed with PhS-

48

ZVI RAPPOPORT

but not with IZtS-. The 94-98% retention for the corresponding bromo esters and the bromo- and chloro-crotononitriles with both thio-nucleophiles (Theron, 1967) suggest that the actual degree of retention is probably higher than reported. The competition theory also predicts more retention with a bulkier nucleophile. Ethyl /?-chlorocrotonate showed more retention with mesitylthiolate ion than with thiophenoxide ion, but it is of little diagnostic value as in both cases the degree of retention was very large. The prediction that increasing size of R would lessen retention was not borne out. Pizey and Truce (1965) found that reaction of (96) with PhS- gave complete retention for R =Me or i-Pr, and Maioli et al. (1960) had shown that retention is the only pathway for the (97)-PhS- reaction with R = H or Me. Retention is therefore preferred even if the (i-Pr, C0,Et) interactions during the 60" rotation are higher than either R,

,COzEt

C1,

,SOzAr

C1

'H

R

'H

,c=c

,c=c

the (PhS, C0,Et) or the (Cl, H) interactions during the 120' rotation. A more rigorous test of the competition theory would be to increase further the size of R in order to find out at what degree of steric interactions retention would cease to be the exclusive pathway. From the above it is clear that groups which are usually known as capable of stabilizing carbanions do not make the life-time of the carbanion long enough for free rotation. The substitution could be visualized as occurring within the carbanion by an internal SN2reaction with the electron pair of the a-carbon attacking with .rr-bond formation, while concurrently the C-X bond is broken. Hence, the greater the ability of the activating group to spread the negative charge, the smaller should be the nucleophilicity of the electron pair and the longer the life time of the carbanion. However, the experimental evidence is that even when the charge-spreading capacity of the a-group is changed by a large factor, e.g. from nitroaryl to aroyl, retention is still exclusive and the carbanions are still short-lived. Nevertheless, continued increase in the activating power of the a-substituent should finally result in racemization. This could be obtained by using an a-nitro group or two a-activating groups. Indeed, in the reaction of cis- and trans-3,4dinitro-3-hexcne with p-toluenethiolate or azide ions, the same product was obtained from both isomers (Emmons and Freeman, 1957). This was ascribed t o the formation of a long-lived intermediate in agreement

NUCLEOPHILIC V I N Y L I C SUBSTITUTION

49

with our prediction, but another explanation is possible : for groups such as nitro or cyan0 which are not usually cleaved when attached to a saturated carbon, the cleavage of the C-X bond is slower than the internal rotation. This is reminiscent of the substitutions of XC(CN)= C(CN)2 with N,N-dimethylaniline. When X = CN, the proton leaves before the cyanide ion, while when X = C1, C-C1 bond-breaking precedes the C-H bond breaking (Scheme 3). I n addition, the possibility that a post-isomerization is fast owing to the powerful activating a-nitro group cannot be dismissed. The formation of only one isomer from the with substitution of cis and trans a-nitro-/3-chloro-/3-phenylethylenes thiocyanate ion (Iwai et al., 1965) which was shown to have the trans configuration (Rappoport and Hoz, 1968)may point to the racemization mechanism, but control experiments were not conducted. This system is now being reinvestigated. The apparent racemization in the formation of only trans-3-p-nitrothiophenoxypropenal from both cis- and trans-thiocyanatopropenal (Raap, 1966) may be due either to the use of the leaving thiocyanato group, which should be a worse leaving group than the halides, or to a post-isomerization reaction ; the necessary control experiments were not carried out. There are no data regarding the stereochemistry for systems with two strong a-activating groups, but even the carbanions formed from such compounds may react further before complete rotation. Sodium hypochlorite oxidation of cis and trans (98) gave epoxides with retained R1R2C=C(CN)C02Et (98)

geometrical arrangement of the substituents (Robert, 1966). Here, the internal attack on the hypochlorite oxygen should be faster than the rotation in the carbanion. There are two systems in which substitution with arylthio anions does with trans not give sole retention. l-p-Tolylthio-l,2-dichloroethylene chlorines gave withp-toluenethiolate ion only the 1,2-bis(p>-toluenethio)chloroethylene with trans arylthio groups (Truce and Kassinger, 1968a). Since the other isomer was not investigated, the reaction may belong to either the inversion or the racemization category. The reaction conditions are much less drastic than those required for eliminationaddition. The competition theory would favour retention with (H, C1) interaction, over inversion with (Cl,SAr)interactions. On the other hand, for thermodynamic control, it is possible that the (SAr, SAr) (H, Cl) interactions are higher than the (SAr, C1) (H, SAr) ones and the reaction is directed towards the trans product. This relatively unstabilized

50

ZVI RAPPOPORT

carbanion seems therefore long-lived enough to give complete racemization. A possible explanation is that the carbanion is so nucleophilic that it is protonated very rapidly to give the a#-adduct. Once this is formed, it rotates faster than it eliminates HCl, therefore giving the more stable product (Truce, 1967). Mixtures of isomers were obtained from the reaction of cis- and transa-bromocinnamic acid with arylthiolate ions (Angeletti and Montanari, 1958). The corresponding m- and p-nitro acids reacted faster but gave complete retention. The slower reaction of the unsubstituted acids was probably followed by isomerization of the product, since /l-thioacrylic acids iaomerize in similar media (Montanari, 1960). Solvent was found to affect the cisltrans ratio of the products. Thus, cis- 1,2-di-p-toluenesulphonylethylene gave 90 and 80% retention with thiophenoxide ion in ether and methanol, respectively, while azide ion gave 90% retention in aqueous acetonitrile and lower degrees of retention in dimethyl sulphoxide and in aqueous methanol (Meek and Fowler, 1968). Since isomerization was found to take place in the last case, the significance of the other results is not clear, although it may be expected that in systems which are prone to racemization, a solvent effect on the cis/trans ratio will be observed. e. Reactions with alkoxide ions. I n substitution with the strongly basic alkoxide ions, the intervention of an elimination-addition for the cis isomer can complicate the stereochemicaloutcome. Retention was found for the reactions of EtO- ion with cis- and trans-/3-chloroacrylonitriles (Scotti and Frazza, 1964) and MeO-, EtO- and PhO- ions with a-arylsulphonyl-/3-chloroethylenes(Maioli and Modena, 1959). The reaction of MeO- and EtO- ions with cis-p-MeC,H,SO,CH=CRCl (R=H, Me) (DiNunno et al., 1966) showed the intervention of eliminationaddition (p. 86) but both routes gave retention of configuration. EtO-, PhO- and p-NO,C,H,O- ions gave in each case the same ether from both ethyl p-chlorocrotonates (Jones et al., 1960). It was shown recently that EtO- ion reacts via the p,y-elimination-addition route (Theron, 1967), which probably also operates for the other alkoxides. Formation of both isomers (100 and 101) from the reaction of alkoxide ions with cis-(99) and truns-2,3-dichlorohexafluoro-2-butene(102) (Park and Cook, 1965) should result from a genuine addition-elimination since elimination-addition is impossible, and there was no isomerization of the starting olefin. MeO-, EtO- and i-Pro- ions gave 95+2% retained cis ether (100) from the cis isomer (99), and 70 f 204 trans ether (101) from trans-(102). The preferred retention points to short-lived carbanions. If CF, interactions are the larger ones, as suggested by the models, the competition theory predicts predominant inversion for (99)

but less so with the bulkier i-Pro- than with MeO-; (102) should give either equal amounts of (100) and (101) or excess retention, which would decrease with the size of the alkoxide ion. None of these predictions is fulfilled. However, if the order of steric interactions is C1> CF3>OR, as suggested by the preference of the trans isomer from the 1,1,2-trichlorotrifluoro-1-propene-alkoxide reaction (Cook, 1967), the competition theory predicts more retention for the cis isomer. These results also fit the “preferred retention mechanism ”, although the different degree of retention for the two isomers is not explained. Formation of both (100) and (101) requires that the carbanions (103) and (104) have longer life-times than those carrying only one cyano or one arylsulphonyl group. Although CF3 is less activating than these OR

I

(103)

OR I

(104)

groups, the additional charge delocalization by the a-chlorine and the P-CF, substituents is apparently enough to increase the life-time of the intermediates. f. Reactions with halide ions. Halide ions (excluding F-) are not expected to have high nucleophilicity towards an sp2-hybridized carbon atom (Johnson, 1967). Substitution by halide ions was investigated only for two systems activated by the a-aryl group. p-Bromo-p-nitrostyrenes in n-butylcellosolve showed preferred retention with iodide ions (Miller and Yonan, 1957),although its exact degree was not determined, and the reaction was analysed in terms of inversion and rotation in tetrahedral intermediates (94) and (95). With the progress of thereaction all the four isomeric bromides and iodides were formed from either isomer. If the substitution occurred with pure retention, neither the excess nucleophile nor the leaving group could cause isomerization. Actually,

ZVI RAPPOPORT

52

isomerization was found, and it may be concluded that the substitution gives both retention and inversion. However, the low reactivity of the series required the use of high temperatures, and isomerization could be obtained by reversible addition of the solvent to the double bond. A combination of retention and inversion is in line with the results for the second system. Beltrame et ul. (1966) followed the chlorine exchange and the concurrent isomerization of the two isomers of l-p-anisyl-lphenyl-2-chloroethylene (105 and 106) with labelled chloride ion (CI-*) in dimethylformamide. The same steric interactions are An

\ /c' /c=c

I'h

\H (105), cia

An\

,c=c

/H

An =p-MeOCsHa

Ph \c1 (106), trans

expected for both elimination transition states (107 and 108) [(H, An), (Ph, Cl) and (H, Ph) and (Cl, An), respectively], assuming that anisyl interactions are nearly equal to phenyl interactions. Thermodynamic control predicts nearly equal amounts of cis and trans substitution products. Since, in the absence of chloride ion, no isomerization took

An--

c1*

H (108)

place, a common intermediate for the substitution and isomerization seems plausible. Such an intermediate, e.g. (109), formed by attack on the cis isomer (105) was assumed to be involved in four routes for elimina(105) +C1-

cia-Cl+c1-* trans-Cl+ c1- *

*

c1*

2

+

cis-c1* Cl-

An--&---

El

c1

H (109) SCHEME 5

trans-C1'

+c1-

53

NUCLEOPHILIC VINYLIC SUBSTITUTION

tion of the chloride ion, as shown in Scheme 5. It was also assumed that there is the same chance of retaining or inverting configuration along path (1) as along path (2) : this is required if (109) has indistinguishable chlorine atoms, i.e. kl= k2. With this assumption, the exchange-rate is half of the rate constant for formation of (109), and constant (kexch) the fraction of inversion for each isomer is ki/2kexch,where ki is the isomerization-rate constant. The results (fifth column of Table 6) show preferred retention for both isomers, which increased with decrease in temperature. The higher retention of (106) was ascribed to a lower stabilization of (108) in which the chlorine atoms flank the anisyl group, compared to (107) in which they flank the phenyl group. Higher electrostatic repulsion between the chlorines and the anisyl ring, results from the + T effect of the methoxy group. TABLE 6 Rate Constants and Stereochemical Course for the Reactions of (105) and (106) with Labelled Chloride Ion

Isomer &-(105)

t,'C

170 t r a ~ ~ - ( 1 0 6 )170 &-(105) 186 t r a ~ - ( 1 0 6 ) 186

yo Retention

yo Retention by

10%e,,,

lo%,

by Scheme 6

kinetic control

3.10 5.36 13.0 20.1

2.47 2.37 11.4 11.2

60 78 66 72

20 64 12 44

Since cis-C1, cis-Cl*, trans-Cl* and trans-C1are formed by 0", 60", 120" and 180" rotations, respectively, if (107) is symmetrical with respect to the chlorine atoms, the carbanion is long-lived and the same cisltrans ratio is expected from both isomers. The explanation of the higher retention for the trans isomer by using (107) and (108) is equivalent to discussion in terms of short-lived carbanions. Retention and isomerization via short-lived carbanions requires that each act of retention or inversion would be accompanied by exchange, and no truns-C1 is expected. Dissection of the exchange rate into retention and inversion contributions by assuming kinetic control (last column of Table 6) shows high inversion for the cis isomer and similar contributions of retention and inversion for the trans isomer. Since both the "preferred-retention mechanism " and the " competition theory " predict more retention for both isomers, this analysis is inconsistent with the results. Unfortunately, difficulties in the separation of the isomers (Beltrame,

64

ZVI R A P P O P O R T

1967) prevented the determination of the amount of exchange in the inverted product alone. Such an approach would be valuable, as the inverted product should contain either half of the labelled chlorine or none, according to whether the carbanion is long- or short-lived. The formation of mixtures from (105) and (106) is interesting in view of the retention observed for more activated systems. The high reaction temperature is probably responsible, since extrapolation of the values of the degree of retention at the two temperatures to room temperature predicts complete retention for both (105) and (106). g. Reactions with amines and related nucleophiles. With amines as nucleophiles, either retention or formation of the more stable trans enamines was observed. The stereochemical course seems to be independent of the activating group, since a-arylsulphonyl-/3-chloroethylenes give both retention (Truce et al., 1967) or only trans-enamines (Modena et al., 1959), and the same is true for reactions with /3-chloroacrylonitrile (Scotti and Frazza, 1964; Fanshawe et al., 1965). It is more dependent on the amine involved, since only trans isomers are formed from cyclohexylamine, dimethylamine, di-n-butylamine or piperidine, whereas ethyleneimine and N,N,N,N’-tetramethylguanidine give enamines with retained configuration. If the trans isomers arise from long-lived carbanions, the (H, CN) and (H, C,H,,NH$) interactions should be lower than the (H, H) and (CN, C6HloNH,+)ones for fi-chloroacrylonitriles, and the (H, R,NH$), (H, ArSOz) interactions should be lower than (H, H) and (Adoz,RzNH$) ones for the a-arylsulphonyl-fichloroethylenes. Whereas it is possible that the (amine,activating group) interactions are the largest ones, this analysis could not be applied to the ethyleneimine and the tetramethylgunanidine reactions which give kinetically controlled products. Owing to the high basicity of amines, it may be argued that the trans isomer gives retention via the addition-elimination route, whilst the cis isomer reacts by a,fi-elimination-addition.Modena and coworkers (Modena et al., 1959; Ghersetti et al., 1965) dismissed the latter route in alcoholic solvents on kinetic and stereochemical grounds, assuming that trans addition of the amine to the intermediate sulphonylacetylene would give the cis product. McMullen and Stirling (1966a, 1966b) and Winterfeldt and Pruess (1966) have recently shown that the stereochemistry of the addition of amines to activated acetylenes is more complicated (Winterfeldt, 1967). Secondary amines usually give the trans-enamines, e.g. the addition product of piperidine and cyanoacetylene is identical with the substitution product of /3-chloroacrylonitriles with piperidine (Scotti and Frazza, 1964). Ethyleneimine is an exception since it gives only cis-enamine by addition t o ethyl propiolate

NTJCLEOPHILIC V I N Y L I C S U B S T I T U T I O N

55

(Dolfini, 1965; Truce and Brady, 1966). Primary amines give mixtures, the cisltrans ratios of which are dependent on the structure of the acetylene, the amine and the solvent. Both McMullen and Stirling (1966a) and Truce and Brady (1966) found that the enamines primarily formed, except those of ethyleneimine, give subsequently the stable trans isomers, and elimination-addition for the cis isomer would therefore give inversion rather than retention. Hence, whatever is the structure of the kinetically controlled product, the rule of trans-addition (resulting in cis isomers)which applies to the reactions of thioanions with acetylenes (Truce, 1961), is not adequate for addition of amines. Eliminationaddition for both isomers is contradictory to the rate criteria (p. 77) since the substitution rate is similar for both isomers of P-chloroacrylonivalues for a-arylsulphonyl-p-chloroethylenesare trile, and the keis/ktrafis similar to those for good carbon nucleophiles (Table 7). Until recently, no satisfactory explanation for the behaviour of amines had been given, although the difference from azide or thioanions was thought to arise from the different charge type of the reactions. Since the ethyleneimine enamines are expected to survive without isomerization, the formation of retained enamines in both ethanol and benzene solution for the reactions of ethyleneimine with cis- and trans-ethyl p-chloroacrylates, a-arylsulphonyl-/?-chloroethylenes(Truce et al., 1967) and 1,2-di-p-toluenesulphonylethylenes (Meek and Fowler, 1 968) argues strongly for a kinetically controlled retention with amines. This is followed by a rapid isomerization to the trans-enamine in the cases of initial formation of cis-enamine. Such isomerization could be described by equation (7) (McMullenand Stirling, 1966a)and it was shown recently by NMR that the enamines (lll),where X,=X,=CO,Me or COMe,

show free rotation around the C,-Cp

bond even at room temperature.

H\ ,C='C Me2N

'x2

(111)

Ethyleneimine enamines do not isomerize owing to the inhibition of formation of (110) as a result of the angle strain involved. A confirmation ofthis hypothesis is that the reaction of N,N,N,N-tetramethylguanidine with /?-chloroacrylonitrilegives the retained enamines (Fanshawe et al., 3

56

ZVI RAPPOPORT

1966) since isomerization again requires the creation of strain at the nitrogen of (110). On the other hand, there should be no such hindrance to the formation of (110) in the other amines studied, and transenamines are formed. According to this hypothesis both neutral and anionic nucleophiles react by the same retention mechanism, and the difference in the structure of some of the products arises from a, post-isomerization step. An alternative explanation is based on the charge type of the reaction. The zwitterions which are initially formed on reaction with amines show two characteristic features: (a) The conformers (112) and (114) with eclipsed nucleophile and electron pair have extra stabilization resulting from the interaction of opposite charges. (b) An ammonium proton is available in the vicinity of the negative charge. +

4.

I

(112)

X(113)

(114)

As a result of (a), an electrostatic barrier restricts the rotation, thus increasing the life-time of the zwitterionic conformer (112), and it was suggested that the rate of elimination of N from (112) is higher than the f12)) et al., 1963). Moreover, rate of internal rotation ( k ~ ~ ~ 1 2 ) > k(Rappoport the nucleophilicity of the electron pair on the a-carbon atom decreases by interaction with the positive charge and, when rotation around the C a 4 p bond takes place, conformer (113) is traversed rapidly and, once (114) is obtained, thermodynamic control takes over. I n addition, as a result of (b), protonation may be faster than the 60" rotation, forming (115) in an almost concerted cis addition. I n (115) the electrostatic barrier to rotation disappears, and rotation could again be faster than the elimination of HX, resulting in thermodynamic control. The zwitterionic hypothesis could be tested by using the anion of the amine as the nucleophile, making the primary intermediate a carbanion

57

NUCLEOPHILIC VINYLIC SUBSTITUTION

rather than zwitterion. The reaction of trans-8-chloroacrylonitrilewith lithium piperidide gave low yield of only the trans-enamine (Scotti and Frazza, 1964), with the main reaction being polymerization. The experiment is inconclusive since trans-enamine would be formed by either thermodynamic or kinetic control. However, the approach is promising in deciding between the two hypotheses, since post-isomerization of retained material would predict formation of trans-enamine from both the amine and its anion. The zwitterionic mechanism can account for the retention in the tetramethylguanidine reaction if the positive charge is carried by the two more basic dimethylamino groups rather than by the nitrogen bound to the 8-carbon of (116).

No such explanation is possible for ethyleneimine, and the experiments with this nucleophile are the best argument for the retention mechanism. On the other hand, some evidence for the longer life-time of the intermediate formed with amines may be inferred from the formation of small amounts of (116a) from piperidine and 8-chloroacrylonitrile, in addition to the main substitution product. (116a) is also the sole substi=Ph, R2=H) but no such products were tution product with aniline (R1 reported for reactions with oxygen or sulphur nucleophiles. For formation of (116a) the initially-formed carbanion should be long-lived enough as to attack another 8-chloroacrylonitrile molecule (Scotti and Frazza, 1964).

.

RIRaN. CHCl CHCN + CICH=CHCN

-

+ R1R2N. CHCl .CH(CN) .CHCl .CHCN + R1RZN. CH=C(CN). CH=CHCN (116a)

An indirect way for estimating the relative life-times of a pair of isomeric zwitterionic intermediates can be obtained from the work of Meek and Fowler (1968). Ethyleneimine and 1,2-di-p-toluenesulphonylethylenes give not only the retained vinylic enamines, but also the addition product (116b). Since (116b) is stable t o elimination in the reaction conditions, substitution and protonation are competing processes.

58

(116b)

The ratio of addition to substitution products was 0.5 and 9 for the cis and the trans isomers respectively, and this was explained in terms of what can be called “intermolecular competition theory ”. The steric interactions on the way to the two transition states for the elimination with retention were suggested to govern the competition between the two processes. On the way to the transition state starting from the zwitterion derived from the cis isomer (116c) there are only (H, H) interactions, compared to (H, ArS02) interactions for the transition state derived from the zwitterion formed from the trans isomer (116d). Moreover, (116c) may also be favoured by electrostatic interaction between the positive nitrogen and the negatively polarized ArSOz group, while in (116d)the two groups are far away. Since the protonation rates are expected to be similar, the lower addition/substitution ratio for the cis isomer reflects a relatively shorter-lived carbanion.

ArOzS - 8 --&--H

ArOig --&--H

H

ArOzS

H

(116c)

SOzAr

(116d)

Substitution with nucleophiles having P or As at the nucleophilic centre should show in principle a similar behaviour as amines. Indeed, only trans-2-p-toluenesulphonylethylenephosphonate (117b) was p-MeCeH4. S 0 2 . CH=CH

.S02.CeH4Me-p + P(0Me)S

+

p-Mec6H.1. SO2 .CH-CH.

S02. CeH4Me-p +

I

+P(0Me)a (117a)

p-MeCeH4SOzCH=CHP(O)(OMe)2 (117b)

obtained from either cis- or trans-1,2-di-p-toluenesulphonylethylene and trimethyl phosphite, even if the reaction was conducted at 30” (Meek and Fowler, 1968). This was explained by suggesting that isomer-

-

NTJCLEOPHILIC VINYLIC SUBSTITUTION

59

ization may occur by reversible addition of methyl phosphite to the intermediate (117a). Triethyl phosphite (Kataev et al., 1965)with transa-arylsulphonyl-/3-bromoethylene or trans-bis(p-bromovinyl) sulphone gives only the trans product, as expected for either mechanism. The cis-olefinswere not investigated. Both cis- and trans- 1,2-dichloroethylenesand cis- and trans-p-bromostyrenes gave complete retention with the anionic Ph2P- nucleophiles (Aguiar and Daigle, 1964, 1965a, 196513). Although the retention with the dichloroethylenes may result from elimination-addition (p. 78) the reaction with /?-bromostyreneshould be of the addition-elimination type. Retention was also observed for the reaction of diphenylarsenide ion Ph2As- with cis- and trans-/?-bromostyrenes (Aguiar and Archibald, 1967). Surprisingly, a-bromo-trans-stilbene gives, with the same nucleophile, the inverted substitution product a-diphenylarsino-cis-stilbene (Aguiar et al., 1967), but since it was established that the u-diphenylarsino-trans-stilbeneis isomerized to the cis isomer by heating in ethanol alone, it was suggested that either the initial reaction course is retention, or that elimination-addition is possible. It is noteworthy that the use of these strong nucleophiles results in the addition-elimination route for the unactivated halo-olefins. No details are available regarding the stereochemistry of the substitution by the neutral Ph,PH or Ph2AsH nucleophiles. Since the substitution products are stable to isomerization (except for the a-diphenylarsino-trans-stilbene),probably owing to the lower basicity of P and As compared to nitrogen, the two mechanistic explanations discussed are acceptable. h. Reaction with carbanions. Carbanions, being good carbon nucleophiles and strong bases, react by a multiplicity of mechanisms. While ,!I-halocrotononitriles react via the elimination-addition route (Boularand and VessiBre, 1967), methyl and phenyl magnesium bromides react with the p-chloroacrylic acids and esters to form mainly (81-99%) retained crotonic and cinnamic acid derivatives (Klein and Gafni, unpublished). The degree of retention is dependent on the solvent (ether or tetrahydrofuran) and on the presence of CuCl, as well as on the Grignard reagent used. The kinetically-controlled &/trans ratios are not always Ph\ C1,

H

,c=c

,COzH

‘X

PhMgBr

/COzH

/c=c H

+

Ph\

,c=c

H

\

H

PhMgBr ___j

/H

‘COzH

60

ZVI RAPPOPORT

known accurately, since addition compounds, e.g. (118),which are sometimes formed by the excess reagent, are probably produced from the primary products with different rates. With the less reactive diethylmalonate anion, Gidvani et al. (1932) found only retained products on reaction with the ethyl /3-chlorocrotonates. Carbanions are thus similar to the other anionic nucleophiles. i. Substitution in s y s t e m with two equal /3-leaving groups. Monosubstitution is possible in substrates with two identical /3-leavinggroups, e.g. for l,l-dimethylthio-2-carbethoxy-2-cyanoethylene (119) with aniline or ammonia (Gompper and Toepfl, 1962)or for j,/l-dichlorovinyl ketones with ethoxide or thiocyanate ions (Nesmeyanov et al., 1961). (MeS)&=C(CN>. COzEt -I-PhNHz (119)

4

PhNH. C(MeS)=C(CN).C0,Et

Truce and Kassinger (1958b) found only one product, which was assumed to be the cis isomer, from the reaction of p-tolylthiotrichloroethylene with p-toluenethiolate ion. It was shown later (Truce et al., 1965)that it is the trans isomer.

Analysis of the analogous reaction of the n-propylthio system (Truce et al., 1965) showed the formation of 94% of the trans isomer together with 6% of the cis isomer.

940,;

6%

I n t'hese systems, the conformer (120) formed by the nucleophilic attack, could give by 60' rotation either (121a) or (121b), both capable of eliminating the chloride ion. The eclipsing pairs on the way to (121a) and (121b) are (Cl, M) and (Cl, L), respectively. For complete retention, the geometry of the product would be determined by competition between these two interactions according to the competition theory, or by the relative cis effects in the conformers (121a)and (121b)themselves. For example, for RSCC1=CCl2 where Nu, L = R S and M=Cl, the interactions on the way to (121a) and (121b) are (Cl, C1) and (Cl, RS) respectively, and the competition theory predicts more cis isomer. On the other hand, if the cis effect determines the products, the two lower

N U O L E O P H I L I C V I N Y L I C SUBSTITUTION

61

(RS, C1) steric interactions compared to (RS, RS) and (Cl, C1)interactions should lead to more trans isomer, assuming that the RS interactions are largest. The preference for the trans isomer is in line with the latter

c’ez

M--

YU +NU __f

C1

M--

(121a)

=v::

c1

c1

(121b)

hypothesis and the excess interactions for the (PrS, PrS), (Cl, C1) pairs over two (PrS, C1) pairs is calculated to be 2 kcal mole-l. Although analysis in terms of short-lived carbanions fits the stereochemistry discussed up to now, the results should not be taken as indicative of short-lived ions. Thermodynamic control via long-lived carbanions will give the same results, as was actually suggested by Truce and coworkers. The proportion of isomers (trans/& dichloro = 73 :27)from thereaction of 1,1,2-trichloro-3,3,3-trifluoropropene with methoxide ion (Cook, 1967) also fits both the competition theory and thermodynamic control if the order of steric interactions is C1> CF, > OMe. CF3.CCl=CC12

+ MeO-

+

CF3\

/

,c=c

c1

C1

\OR

+

CF3,

/c=c

C1

/OR ‘C1

27%

730,h

On the other hand, the reactions of 4,4-dichloro-3-buten-2-one (122) with PhS- and PhO- ions give, respectively, 88% and 100% cis products

,c=c H

‘c1

8876 c1

McCO, (122)

H

/c=c

+

,c=c H 12%

OPh

\c1

\SPh

62

ZVI R A P P O P O R T

(Gudkova, 1962). This is unexpected on the basis of steric interactions and was ascribed to the operation of the elimination-addition route. The effect of size of the a-substituent was investigated by Tarrant et al. (1964) in the reaction of propynyl-lithium with substituted trifluoroethylenes. With X = C1 or Br, the transleis ratio of the product was 4 : 1 and 3 : 1 , while with larger X groups, such as CF, or CH=CH2, only trans isomers were formed. CF2=CFX +MeC=CLi

--f

MeC-C.CF=CFX

j. Retention of conjiguration in a n allylic ion. The short life-time of the intermediate could also be inferred from retention of configuration further away from the reaction site. Reaction of EtMgBr with a 80: 20 mixture of the two isomers of (123) which differed only in the geometry at the exocyclic double bond, gave an 80: 20 ratio of the corresponding substitution products (124). Similarly, a 95 :5 mixture of the corresponding ethers was formed from a 95 :5 mixture of (123) with ethoxide ion. While the configurations were not determined, it is highly probable that the configuration of the allylic double bond was retained in the substitution products (Park and McMurtry, 1967). The expulsion of the

fluoride ion is therefore faster than the isomerization of the intermediate allylic ion. k. Conclusions. The stereochemistry of the addition-elimination route accords in most cases with short-lived carbanionic intermediates in which the elimination of the leaving group is faster than internal rotation. Most of the carbanions are short-lived enough to give complete retention, while a few give also some inversion. I n these cases, the competition theory is not always able to predict the isomer ratio obtained. Where thermodynamically controlled products are suspected to be formed via long-lived carbanions, the possibility of isomerization, as well as the intervention of other mechanistic routes, should not be overlooked.

D. Reactivity in the Addition-Elimination Route Since Fond making is assumed to be the rate-determining step, it is expected that the relative reactivities of different activated olefins will be similar to those found in other nucleophilic reactions (e.g., additions)

NUCLEOPHILIC VINYLIC SUBSTITUTION

63

at carbon-carbon double bonds (Patai and Rappoport, 1964). This is indeed observed, at least qualitatively. The reactions are also, as expected, of the second order, first order in the nucleophile and first order in the olefin. The main factor which determines the reactivities is the ability of the a-substituent to spread the negative charge in the transition state. The large number of qualitative observations notwithstanding, quantitative data are limited. The rate constants, extrapolated to O'C, where necessary, for comparisons, and the corresponding activation parameters are collected in Table 7, on which the discussion below is based . 1. The eflect of the a-activating group

Data are available for a-arylsulphonyl, arylsulphoxide, aroyl, cyano, carbethoxy and nitroaryl activating groups, but in no case was the same nucleophile studied with all compounds. The comparisons are therefore indirect, and short series of reactivity orders are combined, with the assumption that the nucleophilicity order is only slightly substratedependent. The following comparisons are possible : A p-toluenesulphony1 group is 2.2-3.8 times more activating than the cyano group as judged from the reaction of the cis and trans isomers of a-substituted haloethylenes with piperidine. Phenylsulphonyl and benzoyl have similar activating effects on a trans ,&chlorine, but each is 2700 times more activating than two p-nitrophenyl groups in their reaction with ethoxide ion. From the reaction rates of di-n-butylamine and piperidine with a-benzoyl and a-propionyl-a-methyl-p-chloroethylenesand /I-chloro-a-methyl-a-p-toluenesulphonylethylene, and when allowance is made for the rate retarding effect of the p-methyl group in the latter compound, the relative reactivity order of benzoyl, propionyl and phenylsulphonyl is 30 :3 : 1. The cis- and trans-p-chloro-a-phenylsulphonylethylenes are 55 and 28-40 times more reactive than the a-sulphoxide analogues with PhSand MeO- ions, respectively. Although the corresponding arylthio derivatives were not investigated quantitatively, they are much less reactive. Comparison of cyano and carbethoxy groups is possible only for the crotonate system where the ,&methyl group may affect the relative reactivities. Ethylthiolate ion is 7-8 times more reactive with 8-chlorocrotononitriles than with ethyl p-chlorocrotonates, but phenylthiolate ion shows high configuration-dependence. The cis and the trans nitriles react faster than the corresponding esters by factors of 11 and 1-4, respectively. Introduction of an o-nitro group into the mildly reactive cis and transj3-bromo-p-nitrostyenesincreasesthe rate with PhS-ion 3400 and 41,500

T ~ L7 E

Rate Constants and Activation Parameters in the Addition-Elimination Route eis Substrate p-NO..CsH4.CH=CHBr p-NOa.CeH4.CHdHCl pNOa.CeH4.CH==CHBr 2,4-(NOs)aCsHa.CH=CHBr PhaC=CHF PhaWHCl (p-MeCeH4)nWHCl f m-MeOCsH4M===-CHCI (v-NOsC;H4jCPh=CHBr (p-MeOCeH4)cPh=CHcl f v-MeOCaH4EPh=CHCl &NO$. Ce6)d2=CHCl (p-NOa. CeHi)aC=CHBr ClCH4HCN MeCcldHCN MeCBMHCN MeCBdHCN MeCcl==CH.COaEt MeCcldMe. COsEt CHs=CCl .CHa .COsEt C H d B r CHI. COsEt PhCO C H 4 H C I p-MeCsH&O.C H S H C l p-clCeH1C0. C H d H C 1 p-BrCeH&O. C H S H C I PhCO CMe===CHF

. . . .

PhCO CMedHCl

Nucleophile

IPhSPhSMeOPhSMeOEtOpMeCeH4Sp-MeCeH4Sp-MeCsHdp-MeC6HBclBrEtOEtOPiperidine EtSPhSEtSPhSEtSWSEtSEtOPhSPhSEtOEtOEtOEtOPiperidine Piperidine

Ns-

Na-

Solvent Bu(0CHs. CHdrOH &OH MeOH MeOH MeOH MeOH EtOH DMF DMF DMF DMF DMF DMF EtOH EtOH MeOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH DMF 98% EtOH 98% DMF

tram

104kEa at00

AH*

AS*,,

1.9 x lo-^^ 013' 0345

23.9 17.2 18.3

-24 -17.8 -11.6

1150

13.2

-14.3

16.2 18.9 21.1

-240 -196 -170

0.46b 0037" 00025' 0~00012'

171,000' 4 6 x 10-l3' 17 x 10-6. 015' 01150 200 203 66.3' 1340 331f 24.3 055 0.142' 0.093' 17.7f 375f

35.3 18.5 18.6

13.5 147 16.1 19.9

104ka at 0" 5.3 X 10-'Oo 0.68" 1.26" 3.1 x lo-" 52,300 389

239,0OOc -456 5.4 x lo-"= 25.4 x 10-O' -12.5 -12.9 267 416 387' 13,700' 348f -20.5 56 -235 2.23 -21.5 -8.3 407O 97a 510" 167O 22.300" 47,100" 1.544 24.6"

AH+

AS+w

27.9 17.0 17.6 24.4 11.8 183

-16 -15.2 -1l.6 -2.8 -11.8 -7.1

326

13.9 15.4

101 98 102 10.1 12.3 16.2

Reference

Miller and Yonan, 1957 Marchese et al., 1968 Marchew et al., 1968 Marchew et d.,1968 Marchew et al., 1968 Blarchese et al., 1968 Silversmith and Smith, 1958 Beltrame et al.. 1967c Beltrame et d.,1967c Beltrame et al., 1 9 6 7 ~ Beltrame and Beltrame, 1968 Beltrame et d.,1966 -10d Beltrame et al., 1966 Beltrame et al., 1967b Beltrame et al., 1967b Scotti and Frazza, 1964 "heron, 1967 Theron, 1967 Theron, 1967 Theron, 1967 -16.5 Jones et al., 1960 Jones d al., 1960 -17.5 Jones et d.,1960 Jones et d., 1960 Theron, 1967 Theron, 1967 Kudryavtseva et al., 1963 -9.5 Kudryavbeva et al., 1963 -13.5 Kudryavtseva et al., 1963 -8.5 - 1 0 5 KudryavtSeva d al., 1963 Beltrame et al., 1968 Beltrame et al., 1968 -306 Beltrame d al., 1968 -11.1 Beltrame et al., 1968

.

PhCO CMe=CHCl

.

Piperidhe Piperidine n-ButNH

Ns-

MeO-

MeOH

PhCO C P h S H C l

N3-

EtCO .CMe===CHCl

NaPiperidine Piperidine Piperidme

yl:p"

Na-

NtPiperidine Piperidine PhCO.CH=CH.NOn' MeOH ~NO~.C~HI.SO.CH----CHCI PhSMeOPhSOa. C C I 4 H C I PhSMeOPhSOs.CH4HCI PhS-

.

PhSOr CH==CHCI

EtOH

0.0880

0.46' 360 40 2800 230

870 100 42,000 690 2000 20'

10.1 8.8

168 18.4 12.6 11.0 12.2 12.9 162 11.2 102 16.4

690

45.5'

180

105

6.3 42

3.4 52.5

PhS-

4820 43'

MiO-

ea. 26,000 ea. 500,000

1540 51' 88 303 3.0 54 400 670 4250

Cyclohexylamine MeOH MeOH n-BunNH PhSOr.CH4HBr

15.4' 32.50 7.34' 0.0170 0.67O 1.26' 6.7" 1.44' 03' 1.1' 016'

DMF

MeOH 98% EtOlf 98% D m EtOH DMF EtOH 94% EtOH-4y: DMF 98% DMF 96%EtOH-4%DMF DMJ? MeOH' MeOH MeOH MeOH XeOH MeOH MeOH

MeOH MeOH MeOH EtOH EtOCyclohexylamine MeOH MeOH n-BuaNH MeOH PhsMeOH p-MeCsH& EtOH p-MeCsH4SMeOH PhCHsSMeOH NsMeOH MeO-

133 125 1090 2000 9.0' 45

16.4

-1

14.5' 64

163

EtOH

3100

21.6

+19

248

15.2

N.-

EtO-9

12.5 12.0

-16.5 -17.5

14.1 141

ca. 10,000

Beltrame et al., 1968 Beltrame et d.,1968 Beltrame ~t al., 1968 Beltrame el al., 1968 -23 Beltrame el al., 1968 -10 -30 Baltrame et al., 1968 Beltrame et al., 1968 -32.7 Beltrame et al., 1968 -31.2 Beltrame el al., 1968 -33.1 Beltrame el al., 1968 -17.1 -39.5 Beltrame et al., 1968 Beltrame et al., 1968 -44.4 Nesmeyanov el at., 1966 Modem. 1958 Modena, 1958 Modena, 1958 Modena, 1958 Modena and Todesco, 1959 Modena and Todesco, 1959; Campagni et d.,1960 Maioli and Modena, 1959; Campagni el al., 1960 Campagni el al., 1960 Modena el al., 1959; Campagni et d.,1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960 -13 Modem and Todesco, 1959 -12 Modena and Todesco, 1959 Modena and Todesco, 1958 Modem and Todesco, 1959 Modem and Todesco, 1959 -8.5 DiNunno et al.. 1966; Maioli and Modena, 1959 -9.5 Maioli and Modena, 1959 -342 -376

TABLE7 (continued) cia 104kz atO" Substrate p-MeCsHa. SOa .C H 4 H C 1

Nucleophile

MeOH MeOH MeOH MeOH p-MeCsH4. S O a . C H 4 H B r MeOH N3MeOH MeOCsclohex slamine MeOH MeOH nIBuzNH MeOH pClCsH4.SOa.CHdHCl PhSMeOH N3MeOMeOH Cvclohexvlamine MeOH MeOH nIBulNH MeOH m-ClCaH4.SOa.CH==CHCl PhSMeOH N3MeOH .MeOCyclohexylamine MeOH MeOH n-BuzNH MeOH 9-NOz.CsHa.SOz.CH==CHCl PhSMeOH N3MeOH MeOCyelohexylamine MeOH n-BuzNH MeOH MeOH p-NOz.CeHa.SOz.CH.=CHBr N3Cyclohexylamine MeOH MeOH n-BusNH MeOH pMeCsH4. SOZ C M d H C I PhSMeOMeOH MeOH n-BuzNH p N O a . C s H 4 . S O a . C M d H C I PhSMeOH MeOMeOH Cyclohexylamine MeOH MeOH n-BuzNH MeOH p-NOa.CsH4. S O n . C M e d H B r PhSMeOH MeO-

.

Piperidine Cyclohexylamine n-BuzNH PhS-

AE*

trans &*as

104ka at^"

AH*

AS*z5

Reference

Solvent 760 465 23.8 2480 23.1' 17,800 84.1 84.3 6960 5.4 430 17.3 92.4

48,000 53.4 2800 87.8 648 1550' 3360 710 1.73" 0155' 00155' 178a 2.7" 0.13" 0.460 4123.2'

129 11.6

-26.0 -27.5

142 194 12.0 11.1

-21.5 +6.5 -26.5 -26.5

13.8

-17.5

10.9

-27.5

15.9 17.5 14.5 14.1 18% 14.7 132 152 17.3

-17

-16

-31.5 -13 -6 -26.5 -29.5 - 8.5 -11

600 2.30 28.5 864 30.0' 53.5 2.2 30.6 2430 7.0 253 7.3 112 3700 145' 405 93%' 190 23,000 71.0 1680 386 658 1560' 38.8 553 0.66" 0.25' 0.0116" 533= 4.6' 0.049" 0.266° 130" 3.0'

12.6 12.1

-28.5 -25.5

15.1 154 12.2 11.3

-18 -8.0 -27.5 -25.5

14s

-13.5

11.3

-27.5

16.8 14.7 14.6 15.3 16.2 15.5 14.3 14.9 17.9

-15.5 -25.5 -31.5 -12.5 -14 -25.5 -24.5 -12 -8.5

Modeua et al., 1959 Modena et al., 1959 Modena et al., 1959 Campagni e l al., 1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Campagni et al., 1960 Modena and Todesco, 1959 Modena and Todesco, 1959 Maioli and Modena, 1959 Modena et al., 1959 Modena et at., 1959 Modena and Todesco, 1959 Modena and Todesco, 1959 Maioli and Modena, 1959 Modena et al., 1959 Modeua et al., 1959 Modena and Todesco, 1959 Modena and Todesco, 1959 Modena, 1958 Modena et al., 1959 Modena et al., 1959 Campagni et al., 1960 Campagni e l al., 1960 Campagni et al., 1960 Modena et al., 1960 Modena et al., 1960 Modena et al., 1960 Modena et al., 1960 Modena et al., 1960 Modena et al., 1960 Modena et al., 1960 Modena et at., 1960 Modena et al., 1960

MeOH MeOH MeOH EtOH MeOH p-MeC6Hr. SOa C H 4 M e B r MeOH MeOH MeOH MeOH p-NO2 ,CeH4. SOa .CH=CMeCl PhSMeONeOH Cyclohexylamine MeOH n-BuaNH MeOH p-NOa.CaH4. SOa.CH=CMeBr PhSMeOH MeOMeOH Cyclohexylamine MeOH u-BuzNH MeOH p-MeCaHa.SOa.CH=CMeCl

.

a

Cvclohexvlamine UIBU~NH MeOEtOPhsMeOCvclohexvlamine nIBuaNH

Extrapolated value.

* A t 100".

At 24O At 180'. A t 186'. f A t 25". Reacts probably via elimination-addition. h A t 30° Nitro is the leaving group. 9 Contains 0.0024 P acetate buffer. C

d

'

0.23" 057" 21 698 7.7 7420 58 30 141 719 7.7 4.5 342 78,500 2100 1050

14.1 146 19.4 184

-28.5 -24.5 -1 +8

0.076' 0.20'

14.1 14.7

-34.5 -25.5

Modena et al., 1960 Modena et al., 1960 DiNunno et al., 1966 DiNunno el al., 1966 Maioli et al., 1960 Maioli et al., 1960 Maioli el al., 1960 Maioli et al., 1960 Maioli et al., 1960 Maioli et al., 1960 Maioli et al., 1960 Maioli et al., 1960 Maioli et al., 1960 Maioli el al., 1960 Maioli et al., 1960 Maioli el al., 1960

68

Z V I RAPPOPORT

times, respectively and 12,500 times for the reaction of the trans isomer with MeO-. Judging by this rate increase, the 2,4-dinitrophenyl group is even more activating than p-nitrophenylsulphonyl. It is the strongest activating group known for which there are stereochemical data for the addition-elimination route. The combined order of activating ability of or-substituents is : 2,4-(NOz)CaHs > PhCO > EtCO > PhSOz > CN > COzEt > PhSO > p-NOzCaHc > PhS

> C1

where the PhSO and the CO,Et groups may exchange places. The introduction of an a-chlorine as a second activating group into /3-chloro-rr-phenylsulphonylethylenehas only small effect on the reactivity. With MeO- ion the rate increases 2.3- to 3.8-fold, and with PhS- ion 4-to 21-fold. The relative activating ability of the halogens was discussed in Section (IIIB,3). The requirement for a positive ,&carbon is also reflected in Table 8, which summarizes the known Hammett p values. All these are positive, with the least reactive system showing the highest response to substituent change. The p value for the diarylhaloethylene-ethoxideion reaction is the highest, followed by that for the reaction with the more reactive p-toluenethiolate ion. I n the a-arylsulphonyl-B-chloroethylene series, the highest values are again for the slow azide reaction, but TABLE8 Hammett's p values for Nucleophilic Vinylic Substitutions P

System ArzC=CHCl

Nucleophile EtO-

Solvent, t"C

trans

cis

EtOH, 120

3.38

EtOH, 50

4.17

3.4

hzC=CHCl

p-MeCaH&3-

DMF, 50

ArSOz. CH=CHCl

n-BuzNH

MeOH, 0

1.50

1.48

h S O z . CH=CHCl

Cyclohexylamine

MeOH, 0

1.22

1-21

ArSOz .CH=CHCI

NI

MeOH. 25

1.84

1.85

ArSOa .CH=CHCl

PhS-

MeOH, 0

1.60

1.84

ArSOz .CH=CHCI

MeO-

MeOH, 0

1.56

1.60

Reference Beltrame et al., 1967b Beltrame et al., 1967b Beltrame et al., 1967c Modena et al., 1959 Modena et al., 1959 Modena and Todesco, 1959 Modena and Todesco, 1969 Maioli and Modena, 1959

NUCLEOPHILIC VINYLIC SUBSTITUTION

69

values with other nucleophiles are not much different. The similarity of the p values for cis-trans series is noteworthy. The reactivity order of the a-aroyl-8-chloroethylene-ethoxideion reaction does not follow the Hammett equation (Kudryavtseva et al., 1963),since the activating order of p-substituents is p-C1> H >p-Br > p-Me. The anomalous position of the p-Br derivative, which should be more reactive than the unsubstituted one, was ascribed to the operation of the + M effect of the bromine atom, which is stronger than its usual --I effect. Only small differences are found between pairs of cis-tram isomers reacting via the addition-elimination route (Table 7) while high differences are usually associated with the elimination-addition routes. The ktfane/keis ratio of ca. 50 at 0" for the 8-brorno-2,4-dinitrostyrene-PhSreaction is unusually high compared to the normal ratios (0.3-4)with this nucleophile. Decreased reactivity of the cis isomer, resulting from steric interactions between the nitro group and the bromine, which force the activating aryl group out of the plane of the double bond, may be responsible. The PhSO,C(Cl) =CHCl-PhS- reaction also shows a large kd8/ktr,,,, value of 15, but the value is only 3 for the smaller MeO- ion. 2. The effectof the @-activatinggroup The effect of the 8-activating group was discussed in relation to the element effects. It was shown recently (Theron, 1967)that in its reaction with PhS' ion the chlorovinylacetic ester (125) is three-times more reactive, and 1.4 times less reactive than the cis- and trans-ethyl 8-chlorocrotonates,respectively. This is remarkable, since the activating

CHz=CCl-CHZCO,Et (125) group is attached to the 8-position, and separated &om the reaction site by one methylene group. 3. The effect of a- and 8-methyl groups A methyl group attached to the double bond should decrease the rate of the nucleophilic attack by increasing the electron density and the steric interactions at the double bond. I n addition, an a-methyl group should decrease the overall rate even for highly basic nucleophiles, by blocking the elimination-addition route. Substituent effects in a-aqlsulphonyl-8-haloethylenesbear out this prediction. The rate retardation by an a-methyl group, kH/kMeis more pronounced for the less reactive p-methyl derivative than for the p-nitro derivative. For several nucleophiles, kH/kMe values for the former derivative are higher by one order of

70

Z V I RAPPOPORT

magnitude. Anionic nucleophiles (MeO- and PhS-) show lower retardation (kH/kMeare 27-52 for the p-nitro derivatives and 255-630 for the p-methyl derivatives) than di-n-butylamine (where the corresponding values are 166-240 and 1530-2460). The higher values for thep-methyl derivative are in line with the higher response to accelerating effects for the less reactive systems. a-Methylation of ethyl /?-chlorocrotonatealso causes a 170-foldrate decrease with EtS- ion. The effect of /?-methyl groups was investigated only for the &-aarylsulphonyl-/3-bromo-or /?-chloro-ethylenes. The 2.4- to 3-9-foldrate decrease with MeO- ion, as well as the 1.3- to 3.2-fold decrease for /?bromo-a-~-nitrobenzenesulphonylethylene-di-n-butylamineand cyclohexylamine reactions, may point to a contribution of the eliminationaddition route with these nucleophiles. When the elimination becomes more difficult, either for thep-methyl derivative or with a chlorine leaving group, a /?-methylgroup decreases the substitution rate 20- to 84-fold with the same amines. With PhS- ion, for which other substitution routes are less probable, the rate retardation is higher (322- to 3100fold). An a-phenyl group is expected to increase the rate owing to its chargespreading ability. However, introduction of a-phenyl into the a-benzoyl/!-chloroethylene system deactivates more than an cr-methyl group, the effect being higher for reaction with azide ion (kMe/kPh= 37-90) than for piperidine (kMe/kPh= 5-12). This is probably due to a reduced planarity of the benzoyl group with the double bond as a result of the steric effect of the phenyl group. 4. The relative reactivities of the nucleophiles Of the many nucleophiles which have been used in vinylic substitutions, the relative reactivities of only a few are known. A nucleophilicity is given in Table 9. order towards /?-chloro-a-p-toluenesulphonylethylene From Table 7 it could be inferred that the same order although with somewhat different relative reactivities exists for systems in which bromine is the leaving group, or which have a- or /!-methyl substituents, or different p-substituents. The relative reactivities of cyclohexylamine and azide ions are sometimes reversed for other systems. Since approximately half of the nucleophiles are basic enough to follow the eliminationaddition route when possible, comparisons should always be made for reactions with activated olefins with cis relationship of the leaving group and the a-hydrogen. As seen from Table 9, thio nucleophiles are the best ones, their reactivity being increased by electron-donating substituents. The less basic cyclohexylamine is also the least reactive of the amines. The relative reactivities of di-n-butylamine and piperidine are the

NUCLEOPHILIC VINYLIC SUBSTITUTION

71

reverse of their basicities. This may result from a lower steric interaction in the transition state of the substitution by the cyclic amine. The reactivity of the halide ions could not be evaluated directly since they have not been studied with the same substrate. However,p-toluenethiolate ion is nine orders of magnitude more reactive than chloride ion towards 2-chloro-1,l-diarylethylenes in dimethylformamide. Although comparison may not be justified (see below), a similar reactivity ratio exists for the reactions of /3-bromo-p-nitrostyrene with iodide ion in butyl cellosolve and thiophenoxide ion in methanol. Bromide ion is 0.6 times as reactive as chloride ion towards l-anisyl-l-phenyl-2chloroethylene. These relative reactivities of the halide ions should be regarded only as rough estimates. Their very low reactivity is also shown by the chloride exchange in ethyl /3-chlorocrotonate, which is at least los times slower than the substitution by thioethoxide ion (Jones et al., 1960) while trichloroethylene does not exchange at all even at 245" (Bantysh et al., 1962). TABLE9 Relat'iveNucleophilicities Towards trans-p-MeC~H4SO2CH=CHCl in MeOH at 0'

Nucleophile

Relative nucleophilicity

C1-, Br-, I-

ca. 10-7"

N,

0-63b 1.0 12.4 28 174 260 290 4530

Cyclohexylamine n-BuzNH MeOPhSPiperidine p-MeCsH4SPhCHzS-

Reference Miller and Yonan, 1957; Beltrame et al., 1966, 1967c Modena and Todesco, 1959 Modena et al., 1959 Modena et al., 1959 DiNunno et al., 1966 Modena and Todesco, 1959 Modena el al., 1959 Modena and Todesco, 1959 Modena and Todesco, 1959

a Based on relative reactivities towards diarylchloroethylenes and 8-bromo-p-nitrostyrenes. Calculated by taking E,= 15 kcal mole-'.

It is noteworthy that the PhS-/MeO-rate ratios are not much different for the unreactive /?-bromo-p-nitrostyrene and its very reactive 2,4dinitro analogue, being 4000 and 13,000, respectively. The relative reactivities of Table 9 differ from those towards saturated carbon atom, as measured by the n-values of the Swain-Scott equation,

Z V I RAPPOPORT

72

but the order is similar to that found for nucleophilic aromatic substitution reactions (Bunnett, 1963). That a relative nucleophilicity scale based on one solvent and one substrate may not be applicable for different conditions and systems is clearly demonstrated by the work of Beltrame et al. (1968). While the lcpiperidine/kN;ratio towards the substrate of Table 9 is approximately 410 at 0" in methanol, the ratios for ethanol kpiperidine(EtOH)/ kN$8% are 74, 10 and 0.55 towards a-benzoyl-/3-chlorostyrene (125a), 1-chloro-2-benzoylpropene(125b) and 1-acetyl-2-chlorocyclopentene (125c),respectively. Since the change from ethanol to 98% aqueous ethanol will only slightly change the polarity of the solvent, this amounts to areversal of reactivity of the two nucleophiles, and to a change of three orders of magnitude in the relative reactivity. PhC==CHCl

MeC=CHCl

I

I

COPh

COPh

(125a)

(125b)

(,l25c)

The ICpiperidine(DMF)lkN~~8% DMF) ratios for (125a),(125b)and (125c) at 0' are 10,1.3 and 0.08, respectively, i.e. decrease in the same order and to about the same degree as the ratios in ethanol. While the change in the ratio in dimethylformamide may be accounted for by the enhancement of reactivity in the (slightly aqueous) dipolar aprotic solvent (Parker, 1965),the occurrence of the same trend in ethanol, and especially the dependence on the structure of the attacked substrate, points to the need for caution in the construction of nucleophilicity scales. .

A

5 . Activation, parameters

The activation energies for the a-arylsulphonyl and a-aroyl or a-acyl8-haloethylenes are in the 10-18 kcal mole-I region. The differences between cis and trans isomers are usually small (1-2 kcal mole-I). Higher differences (up t o 4 kcal mole-l) were observed for the very unreactive systems of haloarylethylenes, which also showed the higher activation energies. The differences between cis and traw isomers with alkoxide ions, as well as the relatively high value for ethyl /3-chloro-amethylcrotonate probably indicate the intervention of a$- and p,yelimination-addition routes. Solvent effects on the activation energies are observed in the reactions of carbonyl-activated haloethylenes. The values for the reaction with piperidine are smaller (by ca. 1 kcal mole-l) in dimethylformamide

WUCLEOPHILIC VINYLIC SUBSTITUTION

73

compared to ethanol, while those for the azide ion reactions are higher (by 2-4 kcal mole-l). The activation entropies are mostly negative, as expected for reactions in which one species is formed from two. The differences between the values for the isomers are generally low. The most interesting feature of these values is the large increase in the activation entropy when the azide ion reaction is conducted in dimethylformamide instead of in ethanol.

E. Substitution with Rearrangement (The “Abnormal” Substitution) When the leaving and the activating groups are attached to the same carbon atom, the activation of the a-carbon is usually too low to enable substitution .via addition-elimination. Nucleophilic addition of the nucleophile and a proton is however possible, the nucleophile being attached to the /3-carbon. A hydrogen atom bonded to this carbon may then be eliminated with the a-leaving group, forming a rearranged product in which the nucleophile is attached to the /3- rather than to the a-carbon atom (equation 8). Other reaction courses, e.g. cyclizations, RCH=CXY+NuH + RCHNU-CHXY

- HX + RCNUECHY

(8)

followed the a,/3-adduct formation from active methylene compounds (Sopova et al., 1963, 1964). and 1-bromo-1-nitro-1-olefins The intermediate adduct is generally stable enough so that spontaneous dehydrohalogenation does not take place. For example, the 3-(arylthio)-2-halonitriles which are obtained from thiols and a-chloroacrylonitrile, form rearranged products only in the presence of dehydrohalogenating base (Birum and Heininger, 1957; Heininger and Birum, 1965). CHz=C(CX)Cl+ArSH

base +ArSCH2.CH(CN)Cl d ArSCH=CHCN

An interesting system is that where the activating group itself is capable of leaving as a carbanionic entity. Rybinskaya et al. (1963) found that both “normal substitution product ”, 1-benzoyl-2-methoxyethylene (126) and the “abnormal product ”, l-benzoyl-l-methoxyethylene (127) are formed from the reaction of 1-benzoyl-2-nitroethylene with methanolic methoxide ion. The relative electrophilicities of the carbon carrying the nitro group and that carrying the benzoyl group are obtained by measuring the rates of formation of (126) and (127). I n acetate buffers, 30% of the attack is u to the nitro group, and 70% a to the benzoyl group. An a,p-adduct is formed in the latter case, decomposing subsequently to (127). While one of the product-forming steps leading to (127) is slow, its amount is nevertheless determined in the

74

ZVI RAPPOPORT

primary addition step which is thought to be irreversible. The slow step is the ionization of the proton a to the benzoyl group, and it is followed by rapid loss of NO, (Scheme6). At 25", 106kvaluesare kl= 605, k2 = 275 and k3= 5-4 (Nesmeyanov et aZ., 1966). The similar activation energies associated with kl and k, suggest that bond formation to the nucleophile is the rate-determining step for both. PhCO .CH=CHNO2 -tMeO-/MeOH

PhCO . C(OMe)-CH2N02

PhCO . CH=CHOMe (126)

1

- NOa-

.

PhCO C(OMe)=CHZ (127)

SCHEME 6

F. Summary Owing to the emphasis in our treatment on criteria rather than on individual reactions, the various arguments that a specific reaction series followed the addition-elimination route were spread among the different sections. It is worthwhile to summarize that the use of stereochemical, isotope exchange, kinetics and element effects show that the a-arylsulphonyl-/3-haloethylenes(Modena et aZ.), the /I-halo-a-nitrostyrenes (Modena et aZ.,) the a-aroyl-P-haloethylenes (Montanari et d.) and the /3-halocrotonic esters and nitriles (Theron, 1967) systems react with thioanions via this route. Use of some of these criteria together show its operation for other reaction systems.

IV. THEELIMINATION-ADDITION ROUTES When a proton is available for expulsion in the vicinity of the leaving group, both may be eliminated. Consecutive addition of the nucleophile Nu and hydrogen to the elimination product finally yields a vinylic substitution product. These " elimination-addition " routes are the

N U C L E O P H I L I C V I N Y L I C SUBSTITUTION

75

a,/?-elimination-addition, forming an intermediate acetylene (equation 9), the /?,/?-elimination-addition forming an intermediate carbene (equation 10) and the /?,y-elimination-addition forming an intermediate allene (equation 11). - HX +NuH + RC=CY +RCNu=CHY

RCX=CHY

-

- HX

HCX===CHY 4 :C=CHY R'R2CH-CX=-CHY

- HX

RlRW=C=CHY

+ NuH HCNu=CHY + + NuH RlRZCH-CNu=CHY +

(9) (10) (11)

A. The a,/?-Elimination-Addition Route This is the most common of the elimination-addition processes. When the a-carbon carries both the activating group and an hydrogen, the acidity of the latter increases and when the nucleophile is basic enough and the leaving group is in a favourable geometry for elimination, HX is eliminated, forming the acetylene (128). Addition of the base B used in the elimination, or another nucleophile Nu-and a proton gives the substitution products (129) and (130).

Various criteria have been used to deduce the operation of this mechanism. Since some of them are dependent on comparison with the addition-elimination route, the competition between these two routes will be also discussed. (1) The nature of the attacked system. Unactivated systems, such as those having only the leaving group as a vinylic substituent, usually react via the elimination-addition route. With the increase in the activation, competition with other routes may become important. (2) The nature of the nucleophile. The elimination-addition route requires a strong base which is capable of abstracting the proton. Competition between attack at carbon and at hydrogen will occur if hydrogen and carbon basicities of the nucleophile are both high. The base and the nucleophile are not necessarily the same. A strong base present in the reaction mixture, e.g. RO-, may be responsible for the elimination, while a weaker one, which is a better nucleophile, e.g. RS-, may add preferentially to the acetylene. The elimination-addition route

76

Z V I RAPPOPORT

should be always considered for alkoxide ions and amines, but it may also operate for some of the more basic thioanions. (3) The product conjguration. No stereochemical relationship between the configuration of the starting olefin and that of the substitution product is expected if both isomers react by elimination-addition. The same acetylene is formed from both isomers, and the same product or mixture will be formed since the stereochemistry of the product is determined in the addition step. The stereochemistry of nucleophilic addition to acetylenes has recently been reviewed (Winterfeldt, 1967). Thioanions were found to give trans-addition, i.e. the nucleophile and the activating group are in cis positions in the product. The configuration of a cis starting material would therefore be retained in the substitution product (Truce, 1961; Stirling, 1964a). Alkoxide ions add in a transfashion to most systems (Miller, 1966; Winterfeldt, 1966; Eaton and

'*\ /c=c /y H

H '

base __j

HCzCY

RSH

RS\

/c=c

___f

H

/p

'H

Stubbs, 1967) but not always so (Winterfeldt et al., 1966; Harris, 1967; Theron, 1967). The addition of amines, which is dependent on the nature of the amine involved (e.g. Huisgen et al., 1967) was discussed in more detail on pp. 54-58. Sometimes the cis isomer reacts via elimination-addition (see (5) below) while the trans isomer reacts via addition-elimination. Since the configuration is retained in the latter route, either addition-elimination for both isomers, or elimination-addition for the cis and additionelimination for the trans isomer would show overall retention of configuration. (4) Isolation and study of the behaviour of the intermediate. Although a substituted acetylene is the intermediate in the elimination-addition route, its isolation is dependent on the relative rates of its formation and destruction by the nucleophilic addition. Acetylenes can sometimes be isolated as the main reaction products, but in other cases, they have only been detected spectroscopically, or they may be trapped if they are very reactive. Detection of acetylene does not always prove that it is a reaction intermediate. Since generalization regarding the stereochemistry of the nucleophilic addition to acetylenes may be misleading, the independent behaviour (stereochemistry of addition, rate of disappearance) of the alleged intermediate acetylene should be studied. I n favourable cases, these data enable quantitative dissection of the substitution process into its addition-elimination and elimination-addition components.

NUCLEOPHILIC VINYLIC SUBSTITUTION

77

(5) The con$guration of the starting olejn. The proton and the leaving group must be in trans positions for elimination. This is possible for the cis isomer (having cis leaving and activating groups) but not for the trans isomer. The cis isomer thus prefers the elimination-addition route, while the trans isomer mostly reacts via addition-elimination, even if the other conditions favour the elimination-addition. If both isomers react by the latter route, the easier trans elimination would predict high keis/kt,,, values. If they follow different routes, their relative reactivities are also expected to be different, and the cis isomer is usually the more reactive one. The difference will also be reflected in the activation parameters. In most cases the activation energy is higher for the elimination-addition route, but examples are known where the differences are small. (6) Element effects. The importance of bond-breaking in either ElcB or E2 processes, which are the ones expected to operate in the formation ratios for the elimination-addition, of acetylenes, predicts high kBr/kC1 (7) Isotope exchange and isotope effects. The vinylic hydrogen is lost and reintroduced from the solvent during the elimination-addition process. Incorporation of deuterium from deuteriated solvents is therefore expected. Depending on the elimination mechanism, hydrogen isotope effects would be also sometimes observed when RCX=CDY is compared with RCX=CHY. Several of the above criteria are usually used together in order to ascertain the reaction mechanism. The examples below will demonstrate their use, as well as the close relationship between the eliminationaddition and the addition-elimination routes. 1. Reactions of polyhabethylenes

The rule of trans addition of thio nucleophiles to acetylenes (Truce and Simms, 1956; Truce et al., 1960, 1961; Truce, 1961) and other criteria had been used by Truce and coworkers in their systematic study of the substitution routes of the chloroethylenes with p-toluenethiolate ion. The monosubstitution of vinyl bromide (Truce et nl., 195613)probably occurs via elimination-addition owing to the low reactivity of the halo-oleh. Acetylene is the only product formed with alkoxide ions or aniline. cis-Dichloroethylene (131), with a favourable geometry for trans elimination, gave cis-1,2-di-p-tolylthioethylene (135) in basic solution (Truce et ab., 1956a) while the trans isomer was unreactive in the same conditions. This difference, combined with the independence of the reaction rate of the thiolate concentration, suggested a slow primary

ZVI R A P P O P O R T

78

dehydrohalogenation. The high activation energy, 34 kcal mole-1 was indeed close to that of elimination by MeO- in methanol (Miller and Noyes, 1952). A fast trans-addition to the chloroacetylene (132) formed, (133). Indeed, independently should give cis-1-arylthio-2-chloroethylene prepared (132) gives (133) and (135) on reaction with arylthiolate ions in basic solution. It was also shown that (139), the trans isomer of (133), C’,

H

,c=c

,C’

Et0__f

ArS\

ArS-

HCsCCI

\H

__j

H

,c=c

ArSC-CH

HC1

__j

\H

+

(134)

ArS\ ,SAr ,C=C H H ‘ (135)

is not an intermediate, since it yields only 10% of (135) in conditions where (131) gives (135) quantitatively. The configuration of (135) and the necessity for a strong base during its formation from (133) indicate a second elimination-addition step via (134). Although 1,1-dichloroethylene (136) can undergo trans-elimination, its hydrogens are less acidic than those of the 1,2-isomer,which e.g., is able to form a mercury derivative of (132) with K2Hg14while (136) cannot. On the other hand, the electrophilicity of the p-carbon is increased by the combined effect of the two a-chlorines, and with p-toluenethiol both the addition product (137), and the “abnormal substitution product ” (139) are formed (Truce and Boudakian, 1956a). Formation of (139), rather than of its isomer (133), was ascribed to the tendency to decrease the steric interactions between large groups in the transition state for SAr

EtO-

ArS

H’

‘c=c

/

‘C1

H

NUCLEOPHILIC VINYLIC SUBSTITUTION

79

elimination (the “cis effect ”) (Curtin, 1954; Eliel, 1962). Since (139) has lower steric interactions than (133), the conformation for the elimination is probably (138). The requirement of a strong base for the further reaction of (139) and the formation of the cis-l,2-di-p-tolylthioethylene(135) indicate elimination-addition via (140), since the trans isomer should be formed (139) + ArSC=CH

--f

(135)

(140)

either from the c+adduct or from a short-lived carbanion. The (139) --f (140) reaction should be sluggish since it is a cis elimination, and the yields of (135) are correspondingly low in the usual conditions. Trichloroethylene (141), which combines the structural features of gives the trisubstituted product both 1,l- and cis-1,2-dichloroethylene, (145) by a multi-step reaction (Truce and Kassinger, 1958a). Since the formation of the monosubstitution product (143) requires the presence of base, and since the substitution product is a sterically hindered one, this stage is probably an elimination-addition. Additional evidence is the preparation of (143) from independently prepared (142), and the deuteriation of (141) in the presence of Ca(OD), (Leitch and Bernstein, 1950). The formation of the trisubstituted product (144) which was ascribed to an addition-elimination owing to the difficulty of dehydrobromination, and the trans configuration of (144), have already been discussed. The formation of (145) again requires strong base, and is again an elimination-addition.

ArSCHCl-CHClSAr

ArS\ __f

,c=c

.c1

/H

EtO__t

\SAr (144)

t-Butylthiolate ion gives parallel results to those with p-toluenethiolate ion, but the reaction with cis-1,2-dichloroethylene does not require an additional base, since the nucleophile is basic enough to effect dehydrohalogenation (Flynn et al., 1963). At high temperatures

80

ZVI RAPPOPORT

it is even sufficiently basic to cause cis-dehydrohalogenation of trans1,2-dichloroethylene,which is followed by the formation of cis-l,2-di-tbutylthioethylene. The reaction with sulphite ion follows, at least initially, a, similar course (Truce and Boudakian, 1956b), and other thiols react similarly (Parham and Heberling, 1955). Obviously, tetrachloroethylene (146) which is sufficiently active owing to the four chlorine atoms, could react only via the additionelimination route, and the trans-disubstituted product (149) is formed by two such consecutive steps (Truce and Kassinger, 1958b; Truce et al., 1965). It is interesting that the monothioaryl derivative (147) reacts only in the presence of base. Since elimination-addition is impossible, this was taken as indication that the base is required for the formation of the carbanion (148) which should be the reaction intermediate in this case. The tetrasubstituted product is obtained under drastic conditions only. c12c=cc12

AIS-

%

,c=c c1

(146)

4

ArSCCl-CC12SAr

‘c1

-

(147)

ArS ,c1 \c=c \SAr cl/

ArS-

sealed tube

(ArS)2C=C(SAr)2

That the substitution mechanism depends on the nature of the nucleophile is shown by the formation of the ketene acetals (151) from the reaction of vinylidene chloride with alkoxide ions. It was suggested that two consecutive eliminations-additions take place, and that in both cases the alkoxide attacks the acetylene at the substituted carbon (Kuryla and Leis, 1964). Since chloroacetylene (132) is also an interHzC=CC12 (136)

RO-

ROH

RO---+

H W C l M H2C=C(OR)CI (132)

(150)

HC=COR

ROH __f

H&=C(OR)z (151)

mediate in the substitution of cis-l,2-dichloroethylene, it is expected to give the same substitution product. Indeed, reaction of /3-methoxygave the ethoxide ion with 1,l-, cis-l,2- and trans-l,2-dichloroethylenes same /3-alkoxyethyl acetal (152) (KuryIa, 1965). Since l-bromo-2H2C=CC12 or cis- and trans-ClCH=CHCl

.

MeOCHa CHZO-

HeC=C(OCHz. CH20Mo)z (152)

NUCLEOPHILIC VINYLIC SUBSTITUTION

81

ethoxyethylene (153, X = Br) gives the mixed acetal(l54) with the same nucleophile, the intermediate in the alkoxide reaction is probably (153, X = C1) rather than (150), and the (136) -+ (151) reaction involves both routes (IV) and (V) of Scheme 1. XCH-CHOEt X=Br

+MeOCHz. CH20- + CHZ=C(OEt)OCHz. CHaOMe

(154)

(153)

2. Reactions of cyclic halo-oleJins The formation of a symmetrical acetylenic intermediate which is too reactive to be isolated has been investigated by studying the scrambling of the two carbon atoms in the substitution products. The l-halocycloalkenes would form the highly strained and reactive cycloalkynes by elimination. 1-Phenylcyclohexene is formed from 1-chlorocyclohexene and phenyllithium (Wittig and Harborth, 1944) and the corresponding labelled compound was therefore investigated (Scardiglia and Roberts, 1957; Montgomery et al., 1965). (155a) Reaction of equimolar mixture of l-chlorocyclohexene-6-C14 and l-chlorocyclohexene-2-C14(155b) with phenyllithium in ether at 150" gave 1-phenylcyclohexenewhich retained 23% of the radioactivity in l-phenylcyclohexene-1-C14 (157d). Since, in the absence of isotope effects, the symmetrical intermediate cyclohexynes (156a) and (156b) have equal probability to react at either carbon, each of the four substituted cyclohexenes (157a-157d) should contain one-quarter of the activity.

*)(

C1

(155a)

$. - [0' o'] C1

+

PhLi

(155b)

PhLi

__f

+

(156a)

yJ*

Ph

(157a)

(156b) Ph

+

()*+ (157b)

6*+ (jp* Ph

(157c)

(157d)

A similar investigation of l-chlorocyclopentene-1-C14 (158) (Scardiglia and Roberts, 1957; Montgomery et al., 1965)gave at the same conditions 1-phenylcyclopentenewith 48-9%, 36.2% and 14.9% of the label at the 1,2, and the 5 positions, respectively. This distribution fits a symmetrical

82

ZVI RAPPOPORT

cyclopentyne intermediate (159) since it was assumed that (160c) is formed by phenyllithium-promoted rearrangement of its initiallyformed allylic isomer (160b). Ph

Ph

Ph

(16Oa)

(160b)

(160c)

Only (157b), ( 1 5 7 ~ )and (160a) could be formed via an exclusive addition-elimination route, and this route, followed by rearrangement, should be less favourable than the or#-elimination-addition route which quantitatively explains the product ratios. The alternative /3,y-elimination-additionroute, forming the cycloallenic intermediate (161, n = 2 , 3) could not be dismissed, since the equilibrium between a cycloallene and the corresponding cycloalkyne

favours the former for (161, n=6-9) (Moore and Ward, 1963). The products from 1-chlorocyclopentene could be equally accounted for if attack on (161) at the central carbon gave half of the product, the other half being formed by reaction at the terminal positions followed by allylic rearrangement. Roberts and coworkers argued against such an intermediate by citing the selectivity of arynes to nucleophiles,assuming that cycloallenes too would show selectivity. The similar ratios of products formed by attack at the central to the terminal positions of the alleged cycloallenic intermediates for both the chlorocyclopentene and cyclohexene series are in contrast to this expected selectivity. That 1,2-cyclohexadiene (161, n = 3) is formed in a related system, from the reaction of 1-bromocyclohexene with potassium t-butoxide in dimethyl sulphoxide, is shown by trapping it by the highly reactive 1,3-diphenylisobenzofuran(162). The Diels-Alder adduct (163), differs from that, of cyclohexyne (164) which was obtained from 1,2-dibromocyclohexene and Mg in the presence of (162). The product (164) did not isomerize to (163) (Wittig and Fritze, 1966). Similarly, internal substitution in 2-halo-3-(2-hydroxyethoxy)-cyclohexene (165), catalysed by t-BuO- ion (Bottini and Schear, 1965) pro-

83

NUCLEOPHILIC VINYLIC SUBSTITUTION

do

(161, n=3)

Ph (163)

ceeds via the substituted cyclohexadiene (166). It is noteworthy that the product (167) is an “abnormal substitution product ”, formed by route (IX) of Scheme 1.

Additional evidence for the chloroacetylenic intermediate in the phenyllithium reaction is therefore necessary. Montgomery and Applegate (1967) have found that 1-chloro-2-methylcyclopenteneand 1-chloro-2-methylcyclohexene(168, n = 2, 3), which are incapable of forming cycloacetylenes,gave no substitution product, although formation of a cycloallenic intermediate was not prohibited. The isomeric 2-chloro-3-methylcycloalkenes (169, n = 2, 3) which can form a cycloacetylenic intermediate, gave about equal amounts of the two substitu(CH2)n-CHz

I

MeC=CCl

1

(168)

(CHz)n-CHMe

I HC-CCl

(169)

I

PhLi

- I

(CH2)n-CHMe

I

C

C(170)

(CH&-CHMe

- I

HC= (171)

(CHz),,-CHMe

I + PhC= I CPh

(172)

I

CH

84

ZVI RAPPOPORT

bion products, (171) and (172), corresponding to the addition of phenyllithium to either acetylenic carbon of (170). Moreover, when the three abstractable protons of l-chlorocycloalkenes are replaced by deuterons (173, n = 2, 3,4) the coupling product contains 1-84and 0-14,1.93and 0.82 and 1-96and 0.17 allylic and vinylic cleuterons for n = 2, n = 3 and n = 4, respectively. The corresponding isotope effects are 3.6, 5.3 and 7.2. Whereas the isotope effects are

(rT2 Y

DC= a

CCI B

(173)

consistent with elimination with a considerable C-H bond cleavage, the nearly complete retention of allylic deuterons excludes a /l,y elimination. However, formation of (170) would require the complete loss of the vinylic deuteron, which is not the case. The small amount of deuterium for n = 2 and n = 4 was ascribed to allylic isomerization products of the initially formed y,y-dideuteriated products, while the higher amount for n = 3 was ascribed to the protonation of the organolithium intermediate by another (173) molecule. The symmetrical nature of the intermediate is evidenced from the deuteron magnetic resonance spectra of the products (Montgomeryet al., 1967). The spectrum of that derived from the reaction of (173, n = 4) showed two types of saturated deuterons of equal intensity, fitting equal amounts of (175) and (176), and making the route (173) + (174) + (175) + (176) very likely.

The products from the lithium piperidide-catalysed substitution of (173, n = 3) by phenyllithium are also compatible with the above picture. Routes (IV) and (V) of Scheme 1 therefore operate together for the cyclic halo-olefins. An unsymmetrical acetylenic intermediate is formed from 3-bromo-2cyclooctenone (177) which gave on reaction with base in methanol-d a substituted methoxyether (179) with over 90% vinylic deuterium (Eaton and Stubbs, 1967). The intermediate was shown to be 2-cyclo-

NUCLEOPHILIC VINYLIC SUBSTITUTION

86

octynone (178) rather than 2,3-~yclooctadienone,by trapping it with (162).

In conclusion, the differences in the nature of the cyclic intermediates seems to be dependent on the base system, the leaving group, the relative reactivity and the rate of interconversion of the cycloallenic and cycloacetylenic intermediates. 3. Reactions of activated systems The elimination-addition routes can be traced by exchange of a labelled vinylic hydrogen in the elimination step, or by incorporation of deuterium from the solvent in the addition step. Whereas the absence of exchange argues generally against the operation of these routes, its occurrence is not unequivocal proof for them. Both cis and trans a-deuteriated #3-halo-cc-p-toluenesulphonylethylenes( 11-a-D) gave deuteriated phenyl thioethers with PhS- ion, whilst the ethers from the reaction with MeO- ion contained no deuterium (equation 12). I n MeOD, the ,%methyl derivatives (12) gave undeuteriated product with PhS- ion, and deuteriated ether with MeO- ion (equation 13), while the a-methyl derivative (13)gave no incorporation from the solvent (equation 14). The results fit an addition-elimination mechanism for the PhSion, and an elimination-addition route for reaction of the MeO- ion. However, deuterium exchange is not sufficient indication for the latter route, since (11) exchanges its hydrogen faster that it can undergo the vinylic substitution by MeO- ion (Ghersetti et al., 1961). Values of ArSOz. CD=CH. SPh

PhS-/MeOH

ArSOz. CD=CHCl

MeO-/MeOH

ArSOz. CH=CHOMe (11-a-D)

ArSOz. C H = C M e . SPh

ArSO2. CM-CH.

SPh

PhS-/MeOD

t -ArSOz

PhS-/MeOD

.CH=CMeCl

MeO-/MeOD

ArSOz. CD=CMeOMe (12) MeO-/MeOD

ArSOz. C M e C H C 1 t ArSOz CMe==CHOMe (13)

.

86

ZVI RAPPOPORT

kexch/k8ubs are 50, 75 and 120 for cis- and trans-chloro-(11), and for trans-bromo-(1l),respectively. Moreover, no deuterium isotope effect was observed for the reaction of PhS- and MeO- with (11-a-D). The results are consistent with a preliminary base-catalysed fast reversible equilibration of the a-hydrogen leading to exchange. Concurrent attack of the base at the /3-carbon competes with trans elimination to acetylene, and exchange could be observed for either mechanism, or even in the absence of substitution (Scheme 7). With a weaker base, e.g. PhS-, the exchange is slower than substitution. The trans isomer favours addition-elimination, while the cis isomer reacts, at least partially, via the acetylenic intermediate, showing an element effect. The absence of an isotope effect suggests an ElcB mechanism. ArSOz .i%I-CH(OR)Hal

(2). kr t- ArSOz. CH=CHHel+

RO-

.-

(I),

ki

(-1).

-

ArSO2 .C=CHHd k-1

ArSOz . C=CH

ArSOZCH=CHOR

1

(5).

+ROH

ArSO2. CH=CHOR SCHEME 7

Addition-elimination follow the ( - 1) e (1) + (2) -+ (3) route, with exchange when k l , k-l $ k2, and without exchange when k 24k l , while elimination-addition follow the ( - 1) GZ (1) + (4) 3 ( 5 )route. Since both the stereochemical results and the exchange experiments are inconclusiveregarding competition of the two reaction routes for the cis isomer, the dissection of the reaction into the contributions of the two routes requires the isolation or the estimation of the intermediate. Under suitable conditions, p-toluenesulphonylacetyleneis the main product from bromo-(ll), while it is only detected by infrared spectroscopy during the reaction of chloro-(11). Dissection of the overall substitution rate constant (k,) into contributions from elimination-addition (keum) and addition-elimination (kBUb)is possible when the rate of the alkoxidecatalysed addition of alcohol to the intermediate acetylene (kadd) and the concentrations of the latter during the reaction are known. Such analysis for cis-(11)and (12) (Table 10) shows that at 0" the contributions of the two processes to the overall rate are nearly equal, but the importance of the elimination-addition route increases with the temperature, kexm/ksub= 3.0 and 1.4 for (11)and (12)respectively at 25" (DiNunno

TABLE10 Rate Constants and Activation Parameters for the Various Processes in the Reaction of cis-ArSOzCH=CRCl with MeO- in Methanol at 0 ' "

H Me

a

0.96 0-38

4.40 1.28

21.2 22.2

+8 +10

0.51 0.17

24 24

+26*5 +13

0.45 0.21

17 20

-1 -1

1.1 0.8

The Erst fourvaluesareobserved,theothersarecalcdated. (kinM-lSe~-~, E,in kcalmole-1, AS* ine.u.) Apparent values for the overall process.

88

ZVI RAPPOPORT

et al., 1966). Dissection of the activation parameters shows that the high overall activation energy for (11)is composed of the activation energy of the addition-elimination route, which is identical with that of the trans isomer (reacting via this route alone), and a higher value as expected for the elimination-addition route. The similarity in rates for the two processes results from activation entropy compensation. The high element effects for the reactions of amines with (11)and (12) suggest multiplicity of mechanistic routes. The second-order kinetics and the very slow exchange of cis-bromo-(11-a-D) in isopropanol fit addition-elimination (Ghersetti et al., 1965). I n methanol, kexoh/kBUb values for reaction of cyclohexylamine with cis and trans-chloro-(11) and cis- and trans-bromo-(11) are 13, 11, 20 and 23, respectively, and 0.9, 0.6, 1.4 and 0.8 for the corresponding reactions of di-n-butylamine. While trans-bromo-(11) and cis-chloro-(11) showed normal kinetics in methanol and in ethanol, the rate constants with cis-bromo-(11)and (12) decreased with time, but steady second-order behaviour could be achieved by addition of the perchlorate of the amine used. While this fits an amine-promoted elimination-addition, where the ammonium salt formed shifts the equilibrium to the left (equation 15), the slow -

ArSOzCH=CHHal+ RNHz

+ ArSOzC=CHHal+

RNHj

(15)

exchange in the less acidic isopropanol suggests that the amines themselves react via addition-elimination, while the more basic alkoxides, formed according to equation (16) are responsible for the eliminationaddition route. RNHz + R’OH

+ R’O-+ RNH:

(16)

The values of k,/k, (1.6-2.2) and of k,,/kcl (108) for the cis-p-halo-pnitrostyrenes-Me0- reaction (Marchese et al., 1966, 1968) point to an elimination-addition, while the trans isomers show negligible hydrogen exchange and react by a route analogous to (1) + (2) --f (3) of Scheme 7. Both the kci8/kt,,,, ratios and the activation energies may be misleading, as is clear from Table 11. The Table summarizes the various kinetic parameters for several pairs of cis-trans isomers which are assumed to react via the elimination-addition and the addition-elimination routes, respectively. The k~,/kt,,, ratio is over 400 for the bromo compound, but only 3.3 for the chloro compound. On the other hand, the activation energies for both bromo compounds are similar, while that for the cischloro isomer is 5 kcal molev1 higher than that for the trans isomer. Positive activation entropies seems to be associated with the elimination processes, and negative ones with those which are assumed to be addition-eliminations. The cis-chloro compound gives only 10%

TABLE11 Kinetic Parameters for Comparison of the Elimination-Addition and the Addition-Elimination Routes with MeO- ion in Methanol cis isomer

Substrate

E.

AS'

2,4-(NO&C&. CH=CHBr 4-NOzC6H4.CH=CHCl 4-NOzCsHd.C H d H B r p-MeCeH4SOzCH4HCI p-MeCeHdSOzCH=CHBr pMeCsH4SOzCH==CMeCl MeCCl=CH .CNb M e C B d H .CNb

20 29 25 24"

+6 +12 +9 +26"

24" 22 18

+13' +12 -1

kBr kc,

108 185 352 6.5

tram isomer

5 k,

Em

AS'

1.6 2.2

19 24 25 17

-7 -7 -3 -8

1-08 1.36

24 20

+22 +15

k,,

k,,

0.88 0.84 257

kl3

k,

0.99

1.03 1.06

kd, ktranr

149 3.3 444 0.7 332 0-47 0.012

Reference

Marchese et al., 196th Marchese et al., 196813 Marchese et al.,1968a D~NUMO et al., 1966 Maioli et al., 1960 DiNunno et al., 1966 Theron, 1967 Theron, 1967

H

I4

9

Data for the elimination-addition process. Reaction with EtO- ion; cis and tmm refer to relationship between the Me and the CN groups.

?I

0

2

90

Z V I RAPPOPORT

substitution via addition-elimination. Contrary to the behaviour of other systems (Miller and Lee, 1959)the absence of hydrogen exchange with the solvent and the low isotope effect points to a concerted elimination with high carbanionic character at C,. Isolation of acetylene from cis-/3-chIoro-cc-p-methoxybenzoylethylene, and the activation energies of 19.1 and 13.6 kcal mole-1 for the cis and the trans isomer, respectively, indicates the operation of eliminationaddition (Montanari, 1967). 2-Butynonitrile is the main product from excess /3-halocrotononitriles with EtO- and PhO- ions. Excess nucleophile adds to the acetylene forming initially trans (methyl and cyano groups) nitriles, which subsequently isomerize to the cis isomers. The kB,/kclratios of 6.5 and 257 for MeCX=CH

- HX .C N +RO- + MeC=C.

CN

+ROH

.

MeC(OR)=CH CN

the cis and the trans series, respectively, the values of kci8/ktTans (0.47 and 0.012 for the chloro and the bromo series) and the small element effect with EtO- ion (except for the bromo compound) fit an ElcB mechanism. The addition of a /3-methyl group to ,!?-chloroacrylonitrile, which reacts via addition-elimination, is therefore sufficient to change the reaction course, probably by decreasing the electrophilicity of the /3-carbon. Whereas the stereochemistry and the ktrans/kcisvalues for most thio nucleophiles reactions point to addition-elimination, the ratios kt,,/kcia = 10-2, and kBr/kC1= 33, the deuterium exchange and the isolation of intermediate acetylene in the 8-bromocrotononitrile-EtSreaction suggest that this is a rare case of an elimination-addition with a thioanion (Theron, 1967). 2-Butynonitrile (180) and mixtures of both substitution isomers are formed in the reaction of Grignard reagents with /3-halocrotononitriles (Boularand and Vessibre, 1967). Under similar conditions, the isomer ratios are identical starting either from the cis or the trans substrate. Moreover, tram-p-bromocrotononitrile gave 1 :1 and 1: 1.8 cisltrans ratios of MeCR=CH. CN for R =Et and Ph, respectively, exactly the same ratios as are found for the reactions of (180) with EtMgBr and PhMgBr.

, + Me,/c=c /CN

Me Br

‘CN

Et

CN

Et

‘H

EtMgBr

MeC=C.CN

The corresponding halocrotonate esters react with EtO- mostly via the P,y-elimination-additionroute. However, the isolation of a 2-butyne

91

NUCLEOPHILIC VINYLIC SUBSTITUTION

ester rather than a 2,3-butadiene ester from ethyl trans-j3-bromocrotonate at low base/substrate ratio indicates a,/?-elimination. The ratios kH/kD= 1.8 and kBr/kCl= 17, as well as the incorporation of deuterium from the solvent, confirm this interpretation. Reisolated starting material shows no such incorporation, which suggests that the step analogous to (2)of Scheme 7 is much faster than step (1) (Theron, 1967).

B. The /?,/?-Elimination-AdditionRoute (The Carbenic Mechanism) This is a relatively rare route in which both elements of HX are eliminated from the /?-carbon, leaving a carbene (181)(equation 17). Among other reactions, the carbene may also capture the nucleophile, giving a /?-substitutionproduct. CHX=CHY

+ baee, -HX

:C=CHY

+NuH

___j

CHNu=CHY

(17)

(181)

Both l-bromo-3-methyl-1,2-butadiene (182)and 3-bromo-3-methyl-lbutyne (183)give in aqueous ethanol the same product mixture, containing mainly propargyl alcohol and ether, but no allenic derivative (Shiner and Humphrey, 1967). I n the presence of both PhS- and OHions, an identical product mixture (32% allenic and 52% propargylic thioether) is again formed from both isomers. This and the rate acceleration by base were ascribed to the formation of a common allene-carbene intermediate which was written as (184at)184b)(Scheme 8). Since the exchange rate of the terminal allenic hydrogen is 10-20 times faster than the rate of formation of other products from (183),the proton is MezC=C=CHBr

Me2CBr-CdH

92

ZVI RAPPOPORT

probably lost in a pre-equilibrium rather than in a concerted /3,/3elimination. The rate depression by KBr points to a loss of bromide ion in the rate-determining step. Either EtO- or PhS- ion could be captured by the carbene. Without base, PhS- ion gave different product distributions from the two isomers, e.g. a 55 :45 ratio of (185) to (186) from (183), with no hydrogen exchange. This was explained by nearly equal contributions of SN2and SN2' mechanisms. The formation of t-butoxyvinyl ether (188) from bromomethylenecycloheptene (187) and t-BuO- proceeds via intermediate alkylidenecarbene (Erickson and Wolinsky, 19.65).

C . The /3,y-Elimination-Addition Route (The Allenic Mechanism)

A proton on a y-carbon may be eliminated in competition with a proton on the a-carbon, and subsequent addition of the nucleophileto the central carbon atom of the intermediate substituted allene (189) would result in an overall substitution (equation 18). In this p,y-eliminationR'RZCH-CX=CR3R4

+B

-HX- R1R2C=C=CR3R"

+ NuH ---+ R ~ R ~ C H - C N U = C R ~ R ~ (1 8)

addition route, a strongly basic nucleophile and an activated y-hydrogen are required, an element effect and deuterium incorporation would be observed, and isolation and independent study of the intermediate are desirable. Stereochemicallimitations are small, since the trans configuration of the y-hydrogen and the /3-leavinggroup is achieved for either the cis or the trans starting material, which differ only in the configuration at the a-carbon. Beltrame et al. (1964) suggested this route for the reaction of 1,l-diphenyl-2-halopropene (190) with EtO- ion which gives the substitution product (191) and a cyclobutane (192) which is a dimer of the alleged intermediate allene (193). The reaction is characterized by an element effect (kB,/ko= 2a-2.79 at 80-126"), and by rate coefficients which are

NUCLEOPHILIC VINYLIC SUBSTITUTION

93

200-fold higher than those of the l,l-diphenyl-2-haloethyleneswhich react by addition-elimination. The vinylic ether (191) is the main product although more (192) is formed when X = Br than when X = C1. The ratio (191)/(192) is dependent on the ratio (Et0-)/(190), being e.g. 3.6 and 10 for ratios of 2.5 and 10 of EtO- to (190, X=C1) at 125-130'. The most probable route to (192) is by dimerization of (193), but (191) could be independently formed in an addition-elimination. This is excluded, since in this case a rate determining base-promoted dehydrohalogenation for formation of (193) requires the ratio (191)/(192) to be independent of the (Et0-)/(190) ratio, and (190) would also be expected to be less reactive than Ph,C=CHX, contrary to what is found. Alternatively, if both (191) and (192) are formed from (193), their ratio should depend on the base concentration if the rate constants for eliminaand nucleophilic addition (kadd) are of comparable magnitude. tion (Slim) It was found (Beltrame et aE., 1967a) that indeed only (191) and (192) are formed from the independent reaction of (193) with EtO-, and that the above rate constants and that for the dimerization (,%dim)were similar in magnitude. At 125O, kelim(C1) = 3-2x kelim(Br) = 5-7 x kadd = 3.2 x M - ~sec-l. The good agreement of the and kdim= 7.5 x calculated (191)/(192) ratios based on these values with the observed ones argues in favour of (193) as an essential substitution intermediate which does not accumulate owing to its rapid transformation to (191) and (192). The low element effect fits an E2 mechanism tending towards ElcB elimination. I n principle, the nucleophile can attack the allene at two different positions, but the products show exclusive attack at the central carbon atom, similarly to other nucleophilic additions to allenes (Eglinton et al., 1954; Stirling, 1964b; Taylor, 1967). This may result from the stabilization of the carbanion (194), formed by attack at this position, by the two phenyl groups. The ion (194) may be protonated at either one of the terminal positions of the allenic system, and low amounts of

(195) may be formed in addition to (191) in the reaction of (190) with ethoxide ion. It was assumed that the prototropic rearrangement (195) -+ (191) would, however, be fast, since in the similar addition of methanol to phenylsulphonylallene (196) (Stirling, 1964b)the kineticallycontrolled product (197) isomerizes to its conjugate isomer (198). The

94

ZVI RAPPOPORT

compound (196) is itself formed from 2-chloro-3-phenylsulphonylpropene, and formation of (197) is again due to the &y-eliminationaddition route (Stirling, 1964~). Ph&H-CH(OEt)=CHz (195)

PhSOZCH==C=CHz +MeOH + PhSO&H-C(OMe)=CHz (196)

+ PhSO&=C(OMe)Me

(197)

(198)

Formation of (195) is another type of “substitution with rearrangement ” reaction (route VIII of Scheme l), in which migration of the double bond takes place. Competition between the p,y- and the a$-elimination-addition modes is possible in the systems studied by Bottini and coworkers. N-(2Bromoally1)alkylamine (199) with NaNHz in liquid NH:, gives mainly 1-alkyl-2-methyleneaziridine(200) together with a lower amount of N-alkylpropargylamine (201) (Pollard and Parcell, 1951; Bottini and Roberts, 1957). The driving force for this intramolecular substitution of the unactivated vinyl bromide (199) is probably the presence of the CH2=CBr-CHzNHR

NaNHs

CH2=C-CH2

\N/

+

HC=CCH2NHR

I

R (199)

(200)

(201)

very strong nucleophilic amide ion in the vicinity of the reaction site. The four different routes which were considered a priori (Bottini and Roberts, 1957) were : (1) Direct intramolecular substitution (equation 19). (2) An addition-elimination sequence via (203) (equation 20). (3) A P,y-elimination-addition via the aminoallene (204) and the carbanion (205) (equation 2 l ) , and (4) the a$-elimination-addition via (201) (equation 22), (Scheme 9). Isolation of high yields of (201) from the analogous reaction of N(2-chloroallyl)alkylamineargues against its involvement as a substitution intermediate. The sensitivity of the acetylene to nucleophilic addition rather than its mere isolation should be considered as part of the evidence concerning its role as an essential intermediate. Since neither (199) nor (200) exchange their CH2-hydrogens with the solvent, the isolation of labelled (200) from the reaction in tritiated liquid ammonia excluded (1) as the main substitution, while (2) and (4) are excluded since the exocyclic methylene was not labelled. The incorporation of tritium at

I/‘B-FG

t t

NUCLEOPRILIC VINYLIC SUBSTITUTION

6-y

95

96

Z V I RAPPOPORT

the methylene ring protons of (200) could be accounted only by the allenic mechanism (3), via (204) + (205) (Bottini and Olsen, 1962). It was suggested that in the transition state for the formation of (205), i.e. in (206), the electron pair of the nitrogen attacks the nearest p-orbital whose axis lies in the plane defined by the three allene carbon atoms and the nitrogen, pushing back the incipient exocyclic carbon atom from the line of the other two carbons.

Hence, in the competition between @3- and p,y-eliminations,the latter is preferred. The (200)/(201)ratio is only slightly sensitive to the nitrogen substituent R. For several, not too large R groups, the ratio is 3-4: 1 (Bottini and Dev, 1962; Bottini et al., 1963). The importance of steric effects is shown by the low (32:68) ratio for R=t-Bu. When 6 , ~ elimination is not possible, q3-elimination takes place in preference to direct substitution. The acetylene (208) and not the azetine (209) is formed from (207) (Bottini et al., 1962).

Nucleophilic attack at the terminal atom of an allenic system can give another type of rearranged substitution product, where the nucleophile is attached to the allylic position (equation 23) (route I X of Scheme RlR*CH--CX=CR3R"

+ Nu-

+ R'RZC=C=CR3R" - HX

+Nu-

+ +H+ R1R2CNu-CH=CR3R4

(23)

1). Intramolecular substitution by the alkoxide of N-n-butyl-N-

(2-haloallyl)ethanolamine (210) gives exclusively 3-t-butyl-2-vinyloxazolidine (211) and no substituted morpholine (212) (Bottini et al., 1964),possibly owing to the higher stability of the five-membered ring. The reaction between ethyl p-chlorocrotonates and EtO- was reported to give only one ethoxy ester (Jones et al., 1960). Reinvestigation has

-

NUCLEOPHILIC VINYLIC SUBSTITUTION

HzC=CCl-CHz-N(t-Bu)-CH2.

97

NHa-

CHzOH

shown that, all four cis and trans chloro and bromo esters (213) formed also ethyl 2,3-butadienoate (Theron, 1967). trans-(213) also gave the acetylene (216), and the substitution product was shown to be cis (methyl and carbethoxy) (218). The kBr/kC1ratios of 1.45 and 17 for cis- and trans-(213), the keis/ktrans values of 0.21 and 2.5 for X=C1 and X = B r , respectively, and the ICH/kDvalues of 1.0 and 1.8 for cis- and trans-(213) fit B,y-elimination-addition. Deuterium from the solvent was incorporated at both the methyl and the vinyl positions of (218), but not in recovered (213). Of the three routes for formation of (218) from (215) (Scheme lo), (215) --f (218) is excluded, since vinylic deuterium was not incorporated. Both the (215) --f (217) --f (218) and the (215) -+ (216) + (218) routes account for the isotope exchange. The independent addition of ethanol to (215) gave both (218) and an isomer, which was assumed to be (217) formed by kinetic control. The most probable substitution course is therefore (213) + (214) --f (215) --f (217) --f (218). C H I . CX=CHCOaEt (213)

EtO-

-

CHz .CX=CHCOzEt (214)

CHZ=C=CHCOzEt

EtOH

I

CHs.C(OEt)=CH.COzEt

/

(218)

SCHEME 10

Competition with cr,,!l-eliminationwould be less important if a strong The

- M substituent is attached to the y-, rather than t o the a-carbon.

Z V I RAPPOPORT

98

bromophosphonate (219) gives the substituted enamine (222, X = NMe,) by direct addition to the intermediate allene phosphonate (220), where the formation of the rearranged product is governed by the conjugation achieved in the product. A variant of this route with EtO- ion is the allene (220) -+ acetylene (221) rearrangement which is followed by addition to give again (222, X = OEt) (Sturtz, 1967).

II

0 (219)

V. THES,1 ROUTE Formation of vinylic carbonium ions by various routes has been suggested in recent years by several workers. Addition of electrophiles, mostly protons, to various acetylenes is the most investigated pathway (Whitlock and Sandvick, 1966; Richey and Buckley, 1964; Noyce et al., 1965; Letsinger et al., 1965; Bott et al., 1964, 1965; Peterson and Duddey, 1966; Peterson and Kamat, 1966; Fahey and Lee, 1966), but their formation was also suggested in the reaction of vinyltriazenes in acidic solution (Jones and MilIer, 1966) or in the deamination of vinylamines (Curtin et al., 1965). However, solvolytic formation of vinyl cations has been investigated in very few cases. p-Amino, p-acetamido- and p-methoxy-a-bromostyrenes (219) give, in 80% aqueous ethanol, only the corresponding acetophenones. aBromostyrene forms mainly acetophenone and some phenylacetylene, and the p-nitro derivative gives only p-nitrophenylacetylene (Grob and Cseh, 1964). There are several arguments favouring the suggested SN1 route for all the compounds excluding thellast one. The reactions are f i s t order during a run in the presence of triethylamine, and independent of its concentration, whereas elimination-addition and additionelimination are dependent on the base concentration. a-Bromostyrene solvolyses 10 times faster in 50% ethanol than in 80% ethanol, as expected for a reaction with a highly polar transition state. Finally, the substituent effect is very large: the solvolysis rate changes by nine

99

NUCLEOPHILIC VINYLIC SUBSTITUTION

orders of magnitude between the p-amino and the unsubstituted compounds (Table 12). Although Hammett's p+ was not calculated, its value should be negative and high, contrary to those of the additionelimination route (Table 8). The reactivity differences are mainly due to activation energy changes. TABLE12 Rate Constants for the Solvolysis of a-Bromostyrenes"

R in p-RCeHr. CBr=CHz

Me0 NHCOMe H

104icl at 100'

E,, kcal mole-'

AS;,,, e.u.

2.3b 3.6 x 10-5 9.3 x 10-6' 4.2 x 10-gb

20.6 27.8 28.7 34.1

- 4.3 - 6.7 - 12.3 - 7.8

In 80% ethanol in the presence of Et3N. Extrapolated value.

Both the ketone (226) and the acetylene (227) could be visualized as arising from a rate-determining formation of the carbonium ion (224) followed either by elimination of a proton, or by addition of water molecule and ketonization of the formed enol (225). Since the bond

cleavage is rate-determining, electron-donating substituents will stabilize the carbonium ion by contributions of structures such as (228). Since this requires coplanarity of the double bond and the benzene ring, (224) has a linear allenic geometry at C,.

Solvolysis of trianisylvinyl bromide (229, X-Br) is only 1.7 times faster than that of a-bromo-p-methoxystyrene (Rappoport and Gal, 1968). The participation of the neighbouring /3-anisyl groups in the solvolysis, if any, is small, probably because the groups are held too far

100

ZVI R A P P O P O R T

by the rigid geometry of the double bond. The element effect for (229), (kB,/kcl= 58 at 120') points to considerable bond cleavage in the rate( p-MeOCeH4)zC=C(CeH40Me-p)Hal

(229)

determining step. The m values of the Grunwald-Winstein equation, as calculated from the rates at two different aqueous alcohol compositions, are 0.63 for (223,Ar=Ph) at 170" and 0.53 for (229,Hal=Cl) a t 120'. These are somewhat lower than those for S,1 reactions in saturated systems (Winstein et al., 1957), probably owing to the higher reaction temperatures. I n the solvolytic decarboxylation of potassium trans p-halocinnamates (230)and acrylates in aqueous ethanol, both the ketones (226) and the acetylenes (227)(e.g. 12% acetophenone from (230,Ar=Ph) were found. The cis isomers (231)gave only acetylenes by an assumed concerted fragmentation (Grob, et al., 1964). The intermediate formation Ar

\ ,c=c

/H

-COa, -Br-

ArCOCHs -k ArCECH

_____f

Br

Ar\ Br'

,coz-

,c=c ,

'H

-Cot, -Br-

ArCZCH

of vinylic carbonium ion was suggested by the strong effect of electrondonating substituents. The 400-fold rate increase of 13-bromocinnamate solvolysis over that of u-bromostyrene, which forms the same final product, was ascribed to the stabilization of the intermediate by an internal solvation of the opposite charges as in (232). Capture of (232) by the solvent, ketonization and decarboxylation of the /I-ketoacid formed gives (226).

o=c /? ;\

;

H-C=C-R

Jacobs and Fenton (1965) suggested that the allenic carbonium ion

(234a)is an intermediate in the formation of the propargyl alcohol (235)

N U C L E 0 P H I L I C V I N Y L I C 9 U B S T I T U T I 0N

101

by the hydrolysis of the haloallene (233).The alcohol (235)is formed by an easier nucleophilic attack on the positive carbon of (234b)rather than PhzC=C=CPhX (233)

- X__f

+

PhzC=C=CPh (234a)

t--)

+

Ha0

PhZC-CGCPh

+PhzC(OH)-CGCPh

(234b)

(235)

X = C l , Br

on that of (234a).However, the allenic ether (237)was obtained from the bromide (236)with MeO- ion. The preferential attack at the allenic Me&. CPh=C=CBrPh

MeO-/MeOH ____f

Me&. CPh=C=C(OMe)Ph

(236)

(237)

position of the carbonium ion reflects steric hindrance by the bulky t-butyl group to attack at the propargylic position. While the structural similarity of (236)and a-bromostyrene may indicate a similar mechanism, the suggested S,1 route is still tentative. Zugravescu et al. (1958) considered the reaction of /3-aroyl-j3bromoacrylic acid salts (238)with base to be an S,1 process via (239)on p-RC&.

CO .CBr=CH. COT+ NaOH

.

+

p-RCaH4. CO C=CH. CO;

(238)

4

products

(239)

the evidence of first-order kinetics at 65' for R =Me, Me0 and H. However, the reaction order is between one and two for R = Me0 and Me at 55", and for R = H at 45", and electron-donating substituents decrease the rates relative to R = H, p being 0-81. The intermediate order was ascribed to an S,2 contribution and the substituent effect was explained as follows : For R = H, the conjugation of the .Ir-electrons of the double bond with those of the carbonyl group decreases their conjugation with the p-electrons of the halogen, thereby increasing its mobility. With the electron-richer phenyl residue, conjugation with the ring increases at the expense of conjugation with the carbonyl group, and the p - 7 ~conjugation increases, resulting in decreasing halogen mobility. However, the substituent effect is opposite to that for the SN1 route as discussed above, but fits an addition-elimination path. The kinetics at 65" may be explained by a fast base-catalysed addition forming the a,P-adduct (240),followed by its rate-determining solvolysis. Decreasing the temperature or substitution by electron-donating substituents p-RC&.

CO .C(0Me)Br-CHz

(240)

.CO;

102

ZVI R A P P O P O R T

decrease the rate of formation of (240), so that competition between the two steps becomes important, and an intermediate reaction order is obtained .

VI. SUBSTITUTIONS FOLLOWING PRIMARY REARRANGEMENTS (THEPROTOTROPIC ROUTES) I n systems such as (241) which are capable of prototropic change, basic nucleophiles could cause preliminary rearrangement to (242). The migration of the double bond places the leaving group in the reactive allylic position, and its replacement becomes very facile. The primary substitution product (243) is the allylic one, but further prototropy could form the vinylic substitution product (244) formally derived directly from (241) (equation 24). This route, which requires highly R'CHzCH==CR2X (241)

RO-

R'CH=CH

RO.CHRZX +

(242)

RlCH=CH. CHR20R (243)

RO-

RlCHz. CH=CRZOR

(24)

(24)

basic nucleophiles for the two prototropic rearrangements, would give the same substitution product starting from either one of the two geometric isomers, owing to the formation of the common product (243). A priori both (243) and (244) could be observed (routes XI11 and XIV of Scheme 1). cr-Bromocrotonic acid (245) (Owen, 1945) and a-bromoisocrotonic acid (246) (Owen, 1945; Pfister et al., 1945) were found to give the same a-methoxycrotonic acid (249) with methanolic hydroxide ion. Some u,p-dimethoxybutyric acid (250) and p-methoxycrotonic acid (252) were also formed (Scheme 11). Other alkoxides react similarly but the amount of the normal substitution product decreases at the expense of the p-alkoxycrotonic acid with increasing bulk of the alkoxide, in the order MeO- > EtO- > i-Pro- > t-BuO-, and with t-BuO- only the latter product was formed. While (250) and (252) probably arise from (249) and (251), (249) itself could be formed either via abnormal addition to the elimination product tetrolic acid (253), via the rearrangementsubstitution pathway (247) + (248), or via direct substitution through a long-lived carbanion. A differentiation between those routes has not been made for a-bromocrotonic acid. However, a-bromoacrylic acid, which is incapable of a prototropic change but should be more reactive in direct substitution,

103

NUCLEOPHILIC VINYLIC SUBSTITUTION

MeCH(OMe).CH(OMe).COzH

MeCH==C(OMe). c O 2 H MeCEC. COzH (253)

H

Me H

t

(249’

CHz=CH.CHBr .C02H \

/

,C=c

\

COzH

__t

(247)

Br

MeCH(OMe)CHBr.COzH

(2461

CHz=CH .CH(OMe).COaH (248)

+MeC(OMe)=CH.

(2511

COaH

(252)

SCHEME 11

gives no normal substitution product (256). Only the methanol addition product (254) and the abnormal substitution product (255) are formed (Owen and Somade, 1947). H&=CBr.COzH

RO__f

CH2(0R).CHBr.COzH (254)

RO-

CH(OR)=CH.COaH (255)

The structurally related a-bromocinnamic acid (257) gave only dehydrobromination with alkali (Owen and Sultanbawa, 1949a). PhCH=CBr .COzH (257)

Direct evidence for the prototropic route in a substituted crotonic acid was obtained from reactions of p,p-dimethylacrylic acid (258) (Owen and Sultanbawa, 1949a). With alkoxides, both unsaturated alkoxy acids (259) and (260) were isolated, and differentiation between the substitution-rearrangement route (258) + (259) + (260) and the rearrangement + substitution + rearrangement route (258) + (261) + (260) + (259) could be made. According to the former, the amount of (260) should increase at the expense of (259) with the progress of the reaction, while according to the latter the opposite is expected. It was found that (260) decreased, while (259) increased, during the reaction, and this evidence in favour of the prototropic rearrangement, coupled with the inertness of bromoacrylic acid, suggests that the same mechanism operates also for a-bromocrotonic acid. The absence of (248)

104

ZVI RAPPOPORT

in the latter reaction was ascribed to a faster and more complete (248) + (249) rearrangement, At equilibrium there is 90% of the u,p-compared

RO-

MezC=CBr. COzH (258)

CHZ=CMe.CHBr.COzH

RO__f

MezC=C(OR) .COzH (259)

CHz=CMe. CH(OR).COzH

(261)

(260)

to 10% of the p,y-unsaturated u-methoxy acid. For the methoxycrotonic acids, the u,p-isomeris practically the only one in the equilibrium mixture. Mixtures of u-methoxy-u,P- and &y-unsaturated acids have been obtained from other reactions, such as that of 2-bromo-2-pentenoicacid with sodium methoxide (Alles and Sultanbawa, 1956), and the relative amounts of the two acids depend on the position of the prototropic equilibria in the systems. Both isomers were obtained from u-bromocyclohexylideneacetic acid (262) by alkoxide substitution, but the

.

CBr COzH (262)

u,P-derivative was only 5% of the substitution product (Newman and Owen, 1952). I n the same conditions, both the “abnormal substitution product ” (264) and y,y-dimethoxycrotonic acid (265) are formed from

.

.

MeOCHz CH=C(Br) COzH + (263)

.

.

MeOCHz CH(OMe)=CH COzH + (Me0)zCH. CH=CH (264)

.COzH

(265)

a-bromo-y-methoxycrotonic acid (Owen and Sultanbawa, 1949b). The product (261) is formed by another variant of the route, as the initial prototropy is probably followed by substitution with allylic rearrangement. The effect of the y-methoxy group on the reactivity of the allylic halogen may be sufficient to bring about SN1solvolysis, in which MeOion is captured at the positive end of the allylic system. When the leaving group is attached to the central carbon atom of a prototropic system, it remains vinylic after the prototropic change. Whereas the substitution in the rearranged compound is not necessarily easier, the product structure may be determined by this rearrangement.

105

NUCLEOPHILIC VINYLIC SUBSTITUTION

Reactions of /?-halovinylaceticacid derivatives (266)with nucleophiles give crotonic acid derivatives (274) (VessiBre, 1949; Theron, 1967) by prototropy either preceding the substitution step, or following it. For example, /I-halovinylacetonitriles (X= CN) gave only /?- substituted cis-crotononitriles with excess EtO- or PhO- ions. Allenic and acetylenic nitriles were isolated in the reaction course. The occurrence of primary rearrangement when Hal=Cl was evident by the isolation of /?-chlorocrotononitriles from the reaction of (266, X = CN, Hal = C1) with these anions, while the bromo-compound did not give any rearrangement. With thio nucleophiles, the main products were the unrearranged derivatives, formed by addition-elimination process. The corresponding esters (X = C0,Et) gave only rearranged substitution derivatives with oxyanions, and mostly unrearranged ethyl 2-phenylthio-3-butenoate (269) with PhS- ion. The cis crotonic esters formed were probably derived from a post-isomerization reaction. These results, coupled with the study of exchange (e.g. the substitution

r

CHZ=C(Hal)CHzX

-41

CHZ=C(Hal)-CHX (267) --Hal-

+ Nu-

CH2 .C(Hal)=CHX (270)

+H+

I CH3 .C(Hal)=CHX

(271)

l

1

SCHEME 12

TABLE13 Substitution Routes for CHz=C(Hal).CHzX by Various Nucleophdes

X

Hal

Nucleophile

Substitution product

Substitutionroute N

C1, Br C1, Br Br C1, Br Br

c1

PhSEtSEtOEtOEtS-, PhSEtO-

CN

c1

PhO-

CN

Br

PhO-

CN

c1

EtS-, PhS-

COzEt COzEt COzEt

CN

CN COzEt

(266) -+ (269) --f (274) (266) -+ (267) 3 (268) --f (269) 3 (274) (266) -+ (267) -+ (268) -+ (269) -+ (274) (266) -+ (267) 3 (268) -+ (269) + (274) (266) -+ (267) -+ (268) -+ (269) -+ (274) (266) + (267) 4 (270) -+ (271) 3 (272) -+ (273) -+ (274)+ (266) -+ (267) + (268) 3 (273) -+ (274) (266) -+ (267) --f (270) + (271) + (272) -+ (273) -+ (274)+ (266) -+ (267) -+ (268) -+ (273) -+ (274) (266) -+ (267) 3 (268) -+ (269) -+ (274)+ (266) 4 (267) -+ (268) -+ (273) --f (274) (266) + (267) --f (268) 3 (269) --3. (274)+ (266) -+ (267) + (270) 3 (271) -+ (274)

2 w

P id id

*

+d 0

w

H

NUCLEOPHILIC VINYLIC SUBSTITUTION

107

of the esters by EtS- ion was accompanied by an a-hydrogen exchange with the solvent), has shown the existence of many variants of the rearrangement-substitution routes, depending on the substrate and on the nucleophile. These are summarized in Scheme 12 and in Table 13 (Theron, 1967). VII. SUBSTITUTION VIA Two SN2‘ REACTIONS When halogen atoms are attached to a vinylic carbon and also to one allylic to it, an SN2’ process converts the vinylic halogen into an allylic one, while the formerly allylic one is replaced, and a new olefin is formed. Another SN2‘ attack at the new terminal vinylic carbon would result in the replacement of the original vinylic halogen. The vinylic halide can thus be exchanged in two consecutive SN2’ reactions. This mechanism was suggested for the reaction of 1,3-dichlorotetrafluoropropene with F- which gives 1,1,1,2,3,3,3-heptafluoropropane, by nucleophilic addition of F- to the substitution product (equations 26-27) (Miller et al., 1960). SN2’ .CClFz +F- * CClFz .CF=CF2 + C18N2’ CClFa .CF=CFz +F- +CFz=CF. CF3 + C1H+ C F z S F . CF3 + F- +CF3. EF .CF3 * CF3. C H F .CF3

CClF=CF

(26) (26) (27)

The reversible fluoride ion-catalysed rearrangements of perfluoroolefins (Miller et al., 1960) may also cause vinylic fluorine-fluorine exchange by a similar mechanism.

VIII. SUBSTITUTION IN THE PRESENCE OF METALSALTS Vinylic substitutions in otherwise unreactive systems can take place easily in the presence of metal salts. The chlorine atom of vinyl chloride is replaced by acetic acid, isopropyl alcohol and n-butylamine in the presence of catalytic amounts of PdC1, in iso-octane (Stern et al., 1966). CHz=CHOAc CHZ=CHCl

CHz=CHOCHMe2 CHz=CHNHBu

The mechanism was not specified but it was suggested that the reaction involved formation of a vinyl chloride-PdC12 complex, which is followed

108

ZVI RAPPOPORT

by displacement of chlorine by the nucleophile from the solution or by exchange with a nucleophilic ligand. If the complex is structurally similar to the ethylene-PdCl, complex, back donation of electrons from the metal to the double bond would.increase the electron density at the substituted carbon and facilitate the carbon-halogen bond cleavage. The exchange of the acetate groups of vinyl acetate with those of CD,. C02H, which is catalysed by mercuric acetate, was claimed to involve direct displacement of the vinylic acetate (Samchenko and Rekasheva, 1965), although an electrophilic addition-elimination seems more plausible.

ACKNOWLEDGMENTS The author is indebted to Drs. P. Beltrame, E. W. Cook, J. Klein, S. I. Miller, G. Modena, F. Montanari, J. D. Park, F. Theron, W. E. Truce and R. Vessibre for kindly making available unpublished data and for commenting on specific points. Thanks are especially due to Professor S. Patai who critically read the whole review, suggested the terms geminate” and “vicinal” for the element effects, and made many valuable suggestions. 66

REFERENCES Aguiar, A. M., and Archibald, T. G. (1967). J . Org. Chem. 32,2627. Aguiar, A. M., and Daigle, D. (1964). J . Am. Chem.SOC. 86, 2299. Aguim, A. M., andDaigle, D. (1965a). J. Org. Chem. 30,2826. Aguiar, A. M., and Daigle, D. (1965b). J. Org. Chem. 30, 3527. Aguiar, A. M., Archibald, T. G., and Kapicak, L. A. (1967). Tetrahedron Letters 45, 4447. Alles, B. J. P., and Sultanbawa, M. U. S. (1956). J . Chem. SOC.3472. Angeletti, E., and Montanari, F. (1958). Boll. 8ci.fac. chim. ind. Bologna 16, 140. Autenrieth, W. (1887). Ber. 20, 1531. Autenrieth, W. (1889). Ann. 254, 222, 246. Autenrieth, W. (1890). Ann. 259, 332. Autenrieth, W.(1896). Ber. 29, 1639. Backer, H.J., and van Oosten, R. P. (1940). Rec. Trav. Chim. 59, 41. Backer, H. .J., Strating, J., and Hazenberg; J. F. A. (1953). Rec. Trav. Chim. 72, 813. Bantysh, A. N., Zel’venskii, Y. D., and Shalygin, V. A. (1962). Zhur. Fiz. Khim. 36, 57. Beltrame, P. (1967). Personal communication. Beltrame, P., and Beltrame, P. L. (1968). cfazz. chim. ital. 98,in press. Beltrame, P., and CarrQ, S. (1961). Guzz. chim. ital. 91,889. Beltrame, P., and Favini, G. (1963). cfazz. chim. ital. 93,757. Beltrame, P.,C a d , S., Macchi, P., and Simonetta, M. (1964). J. C k m . SOC.4386. Beltrame, P., Bellobono, I. R., and FBre, A. (1966). J. Chem. SOC.( B )1165.

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Sopova, A. S., Perekalin, V. V., and Ledednova, V. M. (1963). Zh. Obshchei Khim. 33, 2143. Sopova, A. S., Perekalin, V. V., and Yurchenko, 0. I. (1964). Izv. Akad. Nauk SSSR, Otd. Khim. Nauk, 34, 1188. Stern, E. W., Spector, M. L., and Leftin, H. P. (1966). J. Catalysis 6, 152. Stirling, C. J. M. (19648). J. Chm. SOC.5856. Stirling, C. J. M. (196413). J. Chem. SOC.5863. Stirling, C. J. M. (19640). J. Chem.SOC.5875. Stockel, R. F., Beachem, M. T., andMegson, F. H. (1964). Can.J. Chem. 42,2880. Stockel, R. F., Beachem, M. T., and Megson, F. H. (1965). J. Org. Chem. 30,1629. Chim. France 1345. Sturtz, G., (1967). Bull. SOC. Sullivan, R., Lacher, J. R., and Park, J. D. (1964). J. Org. Chem. 29, 3664. Tarrant, P., and Warner, D. A. (1954). J. Am. Chem. SOC.76, 1624. Tarrant, P., Savory, J., and Iglehart, E. S. (1964). J. Org. Chem. 29, 2009. Taylor, D. R. (1967). Chem. Rev. 67, 317. Theron, F. (1967). Ph.D. Thesis, University of Clermont-Ferrand. Thompson, W. L. (1955). Ph.D. Thesis, Cornell University. Trofimenko, S. (1963).J. Org. Chem. 28, 3243. Truce, W. E. (1961). I n “Organic Sulphur Compounds”, Vol. 1 (N. Kharash, ed.), p. 112. Pergamon, London. Truce, W. E. (1967). Personal communication. Truce, W. E., and Boudakian, M. M. (1956a). J. Am. Chem.Soe. 78,2748. 78,2752. Truce, W. E., and Boudakian, M. M. (1956b). J. Am. Chem. SOC. Truce, W. E., and Brady, D. G. (1966). J. Org. Chem. 31, 3543. Truce, W. E., andKassinger, R. (1958a). J. Am. Chem.Soc. 80, 1916. 80, 6450. Truce, W. E., and Kassinger, R. (1958b). J. Am. Chem. SOC. Truce, W. E., and Simms, J. A. (1965). J. Am. Chem.SOC. 78,2756. Truce, W. E., Boudakian, M. M., Heine, R. F., and McManimie, R. J. (1956a). J . Am. Chem.SOC. 78, 2743. Truce, W. E., Hill,H.E., andBoudakian,M. M. (195610).J.Am. ChemSoc. 78,2760. Truce, W. E., Bannister, W., Groten, B., Klein, H., Kruse, R., Levy, A., and Roberts, E. (1960). J. Am. Chem.SOC. 82, 3799. 83, 4636. Truce, W. E., Klein, H. G., andKruse, R. B. (1961). J. Am. Chem. SOO. Truce, W. E., Rossmann, M. G., Perry, F. M., Burnett, R. M., and Abraham, D. J. (1965). Tetrahedron 21,2899. Truce, W. E., Pam, J. E., andGorbarty, M. L. (1967). Chem. & Ind. (London),660. Vessibre, R. (1959). Bull. SOC.Chim. France 1645. Webster, 0 .W. (1964). J. Am. Chem.SOC.86, 2898. Weintraub, P. M. (1966). Chem. & I d . (London) 1497. Whitlock, H. W., Jr., and Sandvick, P. E. (1966). J. Am. Chem.SOC. 88, 4525. Winstein, S., Fainberg, A. H., andGrunwald, E. (1957). J.Am. Chem.Soc.79,4146. Winterfeldt, E. (1966). Ber. 99, 450. Winterfeldt, E. (1967). Angew. Chem. (I&. Ed. Engl.) 6,423. Winterfeldt, E., and Pruess, H. (1966). Ber. 99, 450. Winterfeldt, E., Krohn, W., and Pruess, H. (1966). Ber. 99, 2752. Wittig, G. and Fritze, P. (1966). Angew. Ghem. (I&. Ed. Engl.) 5 , 846. Wittig, G., and Harborth, G. (1944). Ber. 77, 306. Yakubovich, A. Y., Sergeev, A. P., and Fogelzang, E. N. (1966). Zh. Obshchei. Khim. 36, 1317. Zugravescu, I., Ralea, R., and Petroveanu, M. (1958). Analele Stiint. Univ. A.I. Cuaa, IaaiSect. 1 4 , 181 (Chem.Abs. 1969,53, 19965).

THE REACTIONS OF HYDRATED ELECTRONS WITH ORGANIC COMPOUNDS M. ANBARl Exobiology Division, Ames Research Center, N A S A , Moffett Field, California 94035, U.S.A. I. Reactions of Hydrated Electrons with Different Functional Groups . . A. Saturated Hydrocarbons, Alcohols, Ethers and Amines . B. Alkenes C. Carbonylic Compounds . D. Haloaliphatic Compounds E. Other Electrophilic Functional Groups on Aliphatic Compounds . F. Aromatic Compounds G. Heterocyclic Compounds . H. Organic Free Radicals . I. ConcludingRemarks 11. Radiobiological Implications of the Reactions of Hydrnted Electrons with Organic Compounds A. Carbohydrates, Fatty Acids and Steroids . B. Amino Acids and Peptides C. Polypeptides and Proteins D. Purines, Pyrimidines and Nucleic Acids . . 111. Mechanism of the Reactions of Hydrated Electrons with Organic Compounds A. The Energy of Activation of the Reactions of Hydrated Electrons B. The Primary Products of eTq Reactions . C. The Merhnnism of Electron Transfer . IV. Conclusion . References .

.

. .

.

.

.

.

. .

.

.

. .

117 117 118 119 124 126 128 131 134 135 136 138 139 139 140 141 142 143 144 148 148

THE discovery of hydrated electrons in the radiolysis of water is undoubtedly one of the outstanding events in chemistry in this decade. Hydrated electrons have been found to react with many organic compounds in aqueous solution, and the kinetics of the reactions have been measured. From these kinetic studies, as well as from the detection of intermediates and the identification of final products, sufficient information has accumulated to allow a comprehensivediscussion of the mechanisms of these reactions. Hydrated-electron reactions are, by definition, electron-transfer processes, which are not very common in classical organic chemistry. The kinetic studies have shown, however, that the electron behaves analogously to a classical nucleophilic reagent and, although this analogy On leave from The Weizmann Institute of Science, Rehovoth, Israel. Present address: Stanford Research Institute, Menlo Park,California 94026. This work has been carried out at the NASA Ames Research Center, Moffett Field, California, where the author, on leave from the Weizmann Institute of Science, was a senior research associate of the National Research Council, the National Academy of Sciences, Washington, D.C. 115

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M . ANBAR

does not imply an analogous transition state, it has most interesting bearings on the electronic structure of organic compounds and their electron affinities. The understanding of the reactivity of hydrated electrons toward organic compounds in aqueous solutions is important in the interpretation of the radiolytic and photolytic behaviour of aqueous systems containing organic solutes, including living systems. This reason alone makes it worthwhile to study the reactions of hydrated electrons, but my feeling is that these reactions are more important because they may contribute to the understanding of the reactivity and electronic structure of organic compounds in general. The chemistry of organic compounds is far more methodical than inorganic chemistry. The physicochemical properties of organic compounds in homologous series change more or less systematically. It is therefore possible to predict the chemical behaviour of a given organic compound by analogy and extrapolation from the known properties of other compounds. The studies of reactions of hydrated electrons with organic compounds have been, therefore, studies of homologous series. The reactions of hydrated electrons with organic compounds appear to be mediated by specific functional groups, and it is the reactivity of these groups that determines the rate of the eCq reactions. This approach produced some quantitative correlations between the reactivity and the electron density in the reactive functional groups. This interpretation is, however, an oversimplification, and it seems more reasonable to assume that the reactivity of a given molecule is a function of its overall electron affinity. Although at first approximation the electron seems to become incorporated at a certain site on the acceptor molecule, the electronic and vibrational configurations of the primary product evidently readjust within < sec to a non-excited rearranged molecule that has accommodated the additional electron. Since all the reactions studied are exoergic, this rearrangement is accompanied by release of energy, most probably of a radiationless type, and it results in the formation of the so-called ‘ primary ” product. With very few exceptions, organic compounds do not form stable products following single-electron transfer reactions ; thus, as a rule, the “primary” products are unstable organic radical anions or radicals. The final products of the eLq reaction8 will therefore be the result of subsequent reactions of these “primary ” products. The experimental methods used in the investigation of the hydrated electron include competition kinetics and product analysis, as well as pulse-radiolysis and flash-photolysistechniques. All these methods have

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been described comprehensively in recent reviews (Dorfmann and Matheson, 1965; Hart, 1966; Walker, 1967); they will not be discussed here. The reactions of organic compounds have also been discussed in the same reviews as well as in an earlier review by the author (Anbar, 1965),but the large amount of new information that has accumulated in recent years gives us a much better insight into these reactions and their mechanisms, and requires a revision of some of the earlier theories. The reactions of hydrated electrons with the different types of organic compounds will be discussed from the standpoints of chemical reactivity and the identity of the primary products, following the classical pattern of functional groups. From this information we shall try to derive the most plausible mechanisms of these reactions.

I. REACTIONS OF HYDRATED ELECTRONS WITH DIFFERENT FUNCTIONAL GROUPS A. Saturated Hydrocarbons, Alcohols, Ethers and Amines Saturated hydrocarbons are non-reactive toward eCq (Hart et al., 1964b), as are also their hydroxy and amino derivatives. We define a compound as “non-reactive” if its rate of reaction with eap is comparable with or less than that of the (eZq+H2O) reaction. The rate of “slow” reactions (proceeding with apparent specific rates of the order of lo6 M - ~ sec-l or less) may easily be overestimated because of the presence of reactive trace impurities. Methanol and ethanol are non-reactive, and the estimated upper ~ respectively (Anbar limits of their specific rates are lo3 and 20 M - sec-l, and Hart, 1964a; Feldmann et at., 1965). Ethers are also probably nonreactive toward eCq, as may be inferred from the measured low reactivities of diethyl ether (Hart et al., 196413) and furan (Szutka et al., 1965). The reactivity of polyhydroxy alcohols toward eLq has not been investigated to date, but from the measured reactivity of sugars it may be inferred that they are non-reactive. The (low)reactivity of sugars may be attributed solely to their carbonylic functional group ; glucose, ribose and arabinose were found to react with eZq at rates lower than lo6 M - ~sec-l (Davis et al., 196513; Phillips et al., 1966). The non-reactivity of amines may be deduced from the behaviour of the potassium-ethylenediaminewater system (Dewald et al., 1963), in which the hydrated electrons formed have been shown to disappear at a rate comparable with that of the (egq+ H,O) reaction in pure water. It may be concluded that organic compounds composed only of H, C, 0, and N atoms, and containing no wbonds, are non-reactive toward e&

118

M. A N B A R

B. Alkenes The reactivity of a C=C double bond is rather low, as can be seen from the rate of reaction of ethylene (k< 2.5 l o 6 M - - ~sec-l) (Cullis et al., 1965). Electron-donating groups, such as OH, make the ethylenic bond even less vulnerable for electron acceptance, as can be concluded from the non-reactivity of vinyl alcohol and pyrrole (Szutka et al., 1965; Scholes and Simic, 1964). Electron-withdrawing groups enhance the reactivity of ethylene derivatives; thus methacrylate, fumarate and maleate ions are found to react at a rate close to the diffusion-controlledlimit (Hart et al., 1964b). Maleate monoanions as well as tetracyanoethylene react at diffusioncontrolled rates (k> 10’O M-’ sec-l) (Hart et al., 1964b). The conclusion that the ethylene bond acts as the main electrophilic centre in the latter cases is based on the fact that acetate ions are non-reactive, and nitriles react at rates more than two orders of magnitude lower than the diffusioncontrolled limit (Anbar and Neta, 1967a). Replacing R in RCH=CH2 by an ester, amide or olehic group (R = CO .OR; CO .NH2, CH = CH2) enhances the reactivity of the ethylene functional group up to the diffusion-controlled limit, as can be seen from the reactivities of ethyl fumarate, acrylamide and butadiene (Hart et al., 1964b). A comparison of these compounds with ethyl acetate and acetamide, which are only moderately reactive (Anbar and Neta, 1967a), corroborates the assignment of the ethylenic function group as the main electrophilic centre. The high reactivity of cinnamate ions and of styrene, both of which react at diffusion-controlledrates (Hart et al., 1964b; Szutka et al., 1965), is due to the effect of the phenyl group on the C=C functional group, since both toluene and phenylacetate ions react a thousand times slower (Anbar and Hart, 196413). Most of these “activated” ethylene compounds react at diffusioncontrolled rates. It is therefore impossible to derive any quantitative correlation between the electron-donating capacity of the adjacent groups and reactivity. The products of the (e,+RCH=CH,) reaction are RCH-CH; carbanions. Some of these have been identified by their chemical reactivity. Others have been observed through their absorption spectra by means of pulse-radiolysis techniques. The carbanion of acrylamide, for instance, has been shown to dimerize, to react with other free radicals, inducing anionic polymerization, and to react with oxygen, Ag’ and Fe(CN)g- ions, presumably by electron-transfer reactions (Chambers et al., 1967). The absorption spectrum of the product of the (dimethyl fumarate + e&) reaction has been observed in alkaline solution. The rate

T H E REACTIONS O F HYDRATED ELECTRONS

119

of reaction of this species with oxygen has been measured and found to be almost diffusion controlled (Adams et al., 1967b).

C. Carbonylic Compounds The carbonyl group is highly reactive toward eTq, but its reactivity is strongly influencedby adjoining groups. For example, the rate constants decrease by four orders of magnitude when the methyl groups of acetone are replaced by amino groups. The effect of the substituents R and R’ on the reactivity of R . CO .R‘ has been correlated with their Taft u* values (Hart et al., 1967). This correlation included aldehydes (R=H), ketones (R=CH3), carboxylic acids (R=OH), amides (R=NH2) and esters (R=OR). Since the values for R and R’ are additive, the rates of reaction have been correlated wih (ug+ &.). For aldehydes, ketones and carboxylic acids, the reactivity of the compound was found to decrease with the electron-withdrawing capacity of R and R’, and a linear correlation was found between logk and (ud + ud,)with a negative slope of 0.74 for a range of rates over two orders of magnitude from cyclohexanone to pyruvonitrile. The effect of R and R’ on the rates is directly correlated with their effect on the C=O bond length, as manifested by the change in u(C=O) stretching frequency. As the C=O bond is shortened, the electron density in the r-orbital increases, resulting in a decreased tendency to accommodate an additional electron. Amides and esters exhibit a different dependence of their rates on the electron-donating capacity of the adjacent groups. In this case electronwithdrawing groups enhance the rate of reaction. A linear correlation between logk and (u*+ cr*) is observed, with a positive slope of 1.2. This behaviour has been attributed to the mesomeric effect of these substituents, which can also be inferred from their effect on u(C=O). The mesomeric forms R

\c-os-

H2N8+/

and R \C-O8-

ROsf’

depress the double-bond character of the C=O group. This makes the carbonyl bond non-reactive towards eLg, and creates a new electrophilic centre of somewhat lower reactivity. The mesomeric form of esters R’

‘c-o-

R20+/

120

M. ANBAR

although non-reactive at the carbonyl bond, has a finite electron affinity at the alkoxy oxygen. This electron affinity will increase with the electron-withdrawing capability of R1. The reactivity of RlCO .OR2 esters toward eTq correlates with an increase in u* of R1; there is a hundredfold increase in reactivity from (CH,),C. CO. OCH, (u*= 1.15) to CF,.CO.OCH, (u*=3.03). The reactivities of formamide and acetamide seem to be due to the R

\COa-

HzW+/

mesomeric form, and they fit satisfactorily on the same (logk - u*)curve as the esters (Hart et al., 1967). The reactivity of the carboxylic acids HCO.OH, CH,.CO.OH, O-OC(CH2)2.C0.0H and (CH,),C.CO.OH seems to depend both on the inductive and mesomeric effects (Hart et al., 1967). The reactivity of eyq with carboxylic acids has also been interpreted in terms of a Brlansted relationship (i.e., taking the hydroxylic hydrogen as the reactive centre) with reasonable success (Rabani, 1965). Following this correlation one would, however, predict succinic acid (pK,=5.6) to be considerably less reactive than acetic acid ( p K a= 4.75) and the latter less reactive than formic acid ( p K a= 3-75), contrary to the experimental findings. It may be concluded, therefore, that the proton-donor capacity of carboxylic acids is not a primary factor in their reactivity towards cap. The substitution of an a-hydrogen on a carboxylic acid by an aminogroup decreases the reactivity. The rate constants of glycine and alanine are 8 x 10"and 6 x 10"M - ~sec-l, respectively (Davis et al., 1965a). This low reactivity of amino acids is expected because they are predominantly in the form of a zwitterion. Other amino acids exhibit higher reactivity, owing to other reactive functional groups (Braams, 1965, 1966). Peptides show a significantly higher reactivity than amino acids (Davis et al., 1965a; Braams, 1967). This reactivity was suggested to be due primarily to the ammonium functional group and not to the carbonyl group of the peptide. This conclusion was inferred from the comparison between the reactivities of acetyl-glycine and glycyl-glycine, which differ by an order of magnitude, as well as from the pH dependence of the reactivity of the latter compound. Further, a linear correlation between the logarithms of the dissociation constants of the ammonium groups of amino acids and dipeptides and the logarithms of the specific rate constants has been demonstrated (Braams, 1967). This correlation, ranging over four orders of magnitude in rate, has a slope of 0.8. It should be noted, however, that the product of reaction of eyq with the

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acid forms of amino acids is ammonia (Garrison, 1964; Adams and Michael, 1967) and not hydrogen atom as might have been expected according to Rabani from his Brcansted relationship (Rabani, 1965). It may be suggested that the reactive centre of amino acids and peptides is the carbonylic group, which is activated toward a nucleophilic attack by the adjacent ammonium group. The higher the pK value of this group, the smaller is its inductive effect on the carbonylic functional group. This puts the reactivities of amino acids and peptides in line with the behaviour of esters and amides, as expected from the general behaviour of carbonylic compounds. The a*-correlation for carbonylic compounds suggested by Hart et al. (1967) can be applied to additional compounds ; thus, 2-ppolidone (k= 1.3 x lo7 M-' sec-l) (Szutka et al., 1965), asparagine in alkaline solution (k= 2.4 x lo'), acetylglycine and acetyl-alanine at pH = 9 (k lo7M - ~sec-l) (Braams, 1966) react at a rate practically equal to that of acetamide (k= 1.7 x lo7M - ~sec-l) (Hart et al., 1967). The ring closure seems to have little effect on the reactivity of the carbonylic group. Urea (k< 3 x lo6 M - ~sec-l) (Hart et al., 1967) is less reactive than expected according to log k - u* correlation. This has been explained by the fact that urea may be represented by the electronic structure N

which lacks any well-defined electrophilic centre. Consequently, a very low reactivity is expected. On the other hand, oxamate ions react significantly faster than expected (Hart et al., 1967). The stabilization of the mesomeric form of the oxamate ion by hydrogen bonding may probably account for the high reactivity of this compound. The oxamate ion may exist in the forms :

Hydrogen bonding stabilizes the carbonyl group on the carboxylate ion, thereby providing the oxamate ion with two highly reactive electro-

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M. ANBAR

philic centres. This assumption may explain the high rate constant (4 x l o 9 M - ~sec-l) for this compound. It is interesting that p-benzoquinone,

reacts at a lower rate than acetone (k= 1.4 x lo9 M - ~sec-l) (Hart et al., 1964a) despite the conjugation of the system and its relatively high oxidation potential. A possible explanation may be the strong inductive effect of the C=C bonds, which shortens the C=O bond and simultaneously increases the electron densities in the C=C and C=O double bonds. This is one of the few cases in organic chemistry when a statement may be made about a correlation between redox potentials and eCq reaction rates, and it seems that, as in inorganic chemistry (Anbar, 1968b), these two parameters are not always directly correlated. Although they are not carbonylic compounds, carboxylate ions should be discussed here in conjunction with the carboxylic acids. Owing to its resonance stabilization, the -COT group has no low-lying vacant orbital or any positive electron affinity; thus it is non-reactive toward eLq. Carboxylate ions with aliphatic chains, which may also carry OH or NH2 groups, are evidently non-reactive. This has been shown in the cases of formate, acetate, citrate, lactate, oxalate, glycinate and ethylenediaminetetra-acetate ions, all of which react with eLq at rates lower than l o 6 M - ~sec-l (Anbar and Neta, 1967a). Oximes behave analogously to carbonyls in their reactions with eLq, and their log k versus u* plot has a comparable p value. Their reactivity is somewhat lower than that of ketones ; for example, acetoxime reacts at a rate of 3.0 x los M - ~sec-l, compared with 6 x l o B M - ~sec-l for acetone, and acetaldoxime (k= 7.2 x l o 7 M - ~sec-l) is less reactive than acetaldehyde (k= 3.5 x lo9 M - ~sec-l) (Hart et al., 1964a, 1967). The lower reactivity of the oximes may be partially due to the inductive effect of the OH group on the nitrogen atom. This effect lowers the dipole moment from 1.3 Debye units (D) for propylamine to 0.9 for acetoxime. By contrast, the dipole moments increase from 1.6 D for propan-2-01 to 2.9 for acetone. The primary product of the reaction eLq+ R1.CO .R2is (R'. CO. R2)-. This is a strong base and will react with water to give a R'R260H

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123

radical (Gordonetal., 1964;Kevanetal., 1964; Adams et al., 1964, 1967a). These species have been demonstrated by flash radiolysis or electron spin resonance (E.S.R.) for several carbonyl compounds. The equilibrium constant for the reaction (CH,. CO .CH3)- + HzO -+ CH, .&OH.CH, -t OH- has been determined (pK= 12.2) (Asmus et al., 1966b). The value is consistent with previous findings that the transient in alkaline solution is identical with the primary product formed from isopropanol by hydrogen abstraction. The predominance of CH,. CO .CH, in alkaline solution may also be deduced from its reactivity in this medium (Adams et al., 1967a). The analogous transients of acetophenone and fluorenone have been observed (Adams et al., 1964,1967b) as well as that formed from thiobarbituric acid (Gordon, 1964). The negative-ion derivatives of acrylamide, methacrylamide and acrylonitrile may be considered as further CO. R2)- (Dainton, 1967). The electron transfer from examples of (RI. (CH, .CO .CH,)--to acetophenone has been found to proceed at a rate of 8 x lo8 ~ - s e c - l(Adams et al., 1967a). Thesamespecieshasbeenfoundto react efficiently with bromoacetate and bromopropionate ions, and this reaction, which is probably an electron-transfer process, results in a quantitative debromination of the bromaliphatic compounds (Anbar and Neta, 1967~).The electron adduct of benzoquinone was found to react very rapidly with water to form the semiquinone (Adams and Michael, 1967). The primary products of the reactions with ketones probably undergo disproportionation to give the parent compound and the corresponding secondary alcohol. 2(R1.C0.R2)- -+ R1.C0.R2+R1.6HOH.R2+20H-

The primary products of carboxylic acids decompose in two parallel first-order processes (Thomas, 1964; Hart, 1964; Anbar, 1965). (RCO.OH)- ----+ RCO.0- + H

There is little information on the chemical fate of the intermediates formed from esters and amides in the reactions with eLq. It is suggested that they decompose to give acyl radicals : (R1.CO.OR)- -+ R1.CO+R20R1. CO .NH2 R1.CO +R'.CO +HzO

-+ R1.CO + NH, --f

R2.CO .OH+RIC€IO

124

M. ANBAR

The acid forms of amino-acids have been shown (Garrison, 1964; Willix and Garrison, 1967; Ayscough et al., 1967) to decompose according to RCH(NHs+).COz-+ e- -+ RCH(NH3).COZ- -+ R C H . COz-

+ NH3

Peptides were also suggested to undergo deamination following the incorporation of an electron (Willix and Garrison, 1967). I n summary, carbonylic compounds are electrophilic reagents and practically all such compounds investigated exhibit a measurable reactivity toward eTq. The reactivities of these compounds strongly depend on the inductive and mesomeric effects of the adjacent groups. The inductive and mesomeric effects on certain reactive centres may also be considered as effects on the overall electron affinity of the molecules, which is a function of the energy level of the lowest vacant orbital. The ultimate fate of the substrate after having accommodated an additional electron depends on its chemistry and, in particular, on the dissociation energy of the RCO-X bond, which determines whether (RC0X)- will undergo dissociation or electron transfer.

D. Haloaliphtic Compounds Fluoroaliphatic compounds have been found to be non-reactive towards eZq, as can be seen from the behaviour of fluoro- and trifluoroacetate ions (Anbar and Hart, 1965a). The same conclusion may be inferred from the behaviour of trifluoroacetone and methyl trifluoroacetate (Hart et al., 1967),the reactivity of which has been shown to be fully accounted for by that of the carbonylic functional group. An organically bound fluorine atom does not act as an electrophilic centre, in accord with the high electronegativity of fluorine, resulting in entirely occupied low-lyingorbitals on the fluorine atom. Organicallybound fluorine resembles, therefore, the hydroxylic oxygen, the amino nitrogen and the saturated carbon atoms, all of which have their lowlying orbitals completely filled. Chloro-, bromo- and iodo-aliphatic compounds have been investigated for their reactivity towards eZq(Szutka et al., 1965) and the results have been interpreted by assuming that the halogen atom is the reactive electrophilic centre (Anbar and Hart, 1965a). I n all homologous halocompounds the order of reactivity is F 4C1< Br < I. The relative reactivities of the four monohalo acetates are 2 x 1:5 : 10. The reactivity of a given halogen atom was found to be increased by the inductive effect of adjacent electron-withdrawing groups and to decrease by adjacent electron-donating groups. A quantitative examination of the

THE REACTIONS O F HYDRATED ELECTRONS

125

kinetic data has shown that the inductive effect of the adjacent group on the reactivity of a given halogen atom is satisfactorily represented by Taft’s o* function. The specific rates of chloro-aliphatic derivatives range from 4 x lo8 M - ~ sec-l for compounds carrying a deactivated chlorine atom, e.g. chloroethanol, to the diffusion-controlledCF,Cl, an activated chloroderivative (Anbar and Neta, 1967a). Polychloro-derivatives, e.g. CHCl, or CCl,, react at diffusion-controlled rates (k= 3 x 1O1O M - ~sec-’) (Hart et al., 1964a). This is expected in view of the inductive effect of adjacent chlorine atoms in addition to the statistical factor in polychloroderivatives. It has been pointed out that the reaction cross-sections of CC14 and CHCl, are significantly larger than the “geometrical ” dimensions of these molecules, a result that strongly suggests electron tunnelling (Anbar and Hart, 1968). Bromo-aliphatic compounds behave similarly to their chloroanalogues, and their specific rates range from 1.6 x l o QM-’ 8ec-l for deactivated bromoethanol to diffusion-controlledrates. Iodo-derivatives react with eLq at diffusion-controlled rates (Anbar and Neta, 1967a). Chloroaliphatic compounds have been shown to undergo quantitative dechlorination on reaction with e , (Hayon and Allen, 1961; Stockdale and Sangster, 1966). Bromo- and iodo-derivatives follow a similar pattern (Anbar, 1965; Anbar and Neta, 1967c). This dehalogenation is not a result of a dissociative electron capture RX+e- --+ R + X -

which generally is an endothermic process (Anbar, 1965), but is due to the decomposition of an intermediate : RX+e,

--+ RX- + R + X -

Evidence that the cleavage of the R X bond does not take place in the rate-determiningstep could be derived from the absence of a solvent effect on the rate of eTq+ RX reactions (Anbar and Hart, 1965a) and from the fact that the activation energy of the (eLq+ RX) reaction is the same for compounds with quite different R-C1 bond strengths (Anbar and Hart, 1967). The decomposition of RX-, which is probably a very fast reaction, is induced by the solvation of X- and may be regarded as a typical SN1process. The existence of RX-, which is an analogue of X: (Anbar and Thomas, 1964),has been inferred from the kinetic behaviour or radiolysed chloroaliphatic compounds (Logan and Wilmot, 1966). Convincing evidence

126

M. ANBAR

for the formation of CH,Br- in the gas phase has been advanced (Johnson and Simic, 1967),and the formation of CH,I- as intermediate could help to explain the behaviour of other systems. The formation of CClT in the gas phase was also postulated (Reed, 1962). Although the lifetime of CH,I in aqueous solution has been shown to be shorter than lo7 sec, this does not exclude its existence as a short-lived intermediate (Thomas, 1967). No direct observation of RX- by pulse-radiolysis or flash-photolysis techniques has been achieved to date. RX- and especially RCI- are expected to be demonstrable by nanosecond pulse techniques. Unlike IT or CI,, the dissociation of RX- will be irreversible, since the organic free radical formed on dissociation will rearrange within < sec to a configuration that will not interact with X-. The only organically bound, pseudohalogenic group that has been studied to date is the cyano-group. It seems to have some electrophilic reactivity, as can be seen from the reactivities of cyanoacetate (k= 4 x lo7 M - ~sec-l), acetonitrile (k= 3.0 x l o 7 M - ~sec-l) and propionitrile (k= 1.5 x lo8 M - ~sec-l) (Anbar and Neta, 1967a). The reactivity of CN as an electron-accepting group may be placed somewhere between fluorine and chlorine, which is in accord with its inductive effect, manifested in the pK values of the corresponding monosubstituted acetic acids. There is no information on the primary or secondary products of these reactions. I n view of the C-C bond strength and the relatively low solvation energy of cyanide ions, it seems reasonable to assume that H RCN radicals will be formed as secondary products. RCN-+HzO

--i’

H RCN+OH-

These will then disproportionate to give RCH=NH, which in turn will hydrolyse to give aldehydes. The reduction of nitriles to aldehydes by eZq awaits experimental verification.

E. Other Electrophilic Functional Groups on Aliphatic Compounds No systematic study has been made to date on electrophilic functional groups of aliphatic compounds other than the carbonylic group and the halogens. The kinetic behaviour of sulphur-containing compounds is too inconsistent to allow far-reaching generalizations. It seems that RSH compounds are highly reactive in neutral solutions (pH = 6-7) and approach the diffusion-controlledlimit. This is true of cysteine, penicil-

THE REACTIONS O F HYDRATED ELECTRONS

127

lamine, cysteamine (Braams, 1966),and methyl mercaptan (Armstrong and Wilkins, 1964). RS- in alkaline solution (pH > pK) is significantly less reactive. Cysteine, HS. CH2.CH(NH,) .COO, (k= 7.5 x lo7 M - ~ sec-l), thioglycollate ions (k= 8-2 x l o 7M - ~sec-l), glutathione (k= 3.2 x 10” M - ~sec-l at pH = 6.4) and thiophenolate ions at pH = 11 (k= 4.7 x lo7) are representative examples (Anbar and Neta, 1967a). Thioethers R1SR2 show a reactivity comparable with that of RS-. Methionine, CH,S .CH, .CH2.CH(NH,). CO .OH, reacts at a rate of 3.5 x lo7 M - ~ sec-l and djenkolate ions (3,3’-methylenedithio-bis-2-aminopr~pionate) react at a comparable rate (Braams, 1966). Disulphides RSSR are highly reactive, the rates of most of them, like cystine, homocystine, oxidized glutathione and cystamine, approach the diffusion-controlled limit (Braams, 1966). Thiocarbonyls are highly reactive, as can be seen from the reactivity of thiourea (k= 3 x loQ)(Charlesby et aZ., 1965). It may be stated that, generally, the sulphur compounds are far more reactive than their oxygen homologues. Transient products of sulphur-containing compmnds have been observed in the cases of cystine (Adams et aZ., 1967a) and thiourea (Charlesby et al., 1965). It has been shown that RSSR- undergoes a reversible dissociation RSSR-

+ RS+RS-

( k = 1.2 x 104 M-1

sec-1)

followed by RSSRS -+ RSSR

whereas in acid solution RSSR-+H+

+ RSSRH

+ RS+RSH

I n the case of thiourea it was suggested that the free radical formed by a reaction with water, (NH,),CS- -+ (NH,),CSH + OH-, acts as a hydrogenating agent toward polyethylene oxide (Charlesby et al., 1965); however, an electron-transfer mechanism from (NH2),CS- cannot be excluded. Another highly reactive functional group is the nitro-group. All RNOz compounds examined approach the diffusion-controlled rate limit (Anbar and Neta, 1967a). A closer examination shows that the reaction cross-sections of trinitromethane and trinitromethyl ions are higher than the “geometrical ” dimensions of these molecules, implying electron tunnelling (Anbar and Hart, 1968). Nitromethane and its anion CH2N0, react with eTq at diffusion-controlled rates (k= 2.1 and 0.66 x 10” M - ~sec-I, respectively) to give CH,NO,, which has been observed

128

M. ANBAR

by pulse radiolysis. This species is a weak acid (pK= 4.4) capable of electron transfer to tetranitromethane at a very fast rate (fc = 1.2 x l o 9 M - ~sec-l) (Asmus et al., 1966a). It might be of interest to investigate the reactivity of additional functional groups by examining organic cyanates, thiocyanates , selenides, tellurides, phosphines, arsenides and others. All these compounds, which are expected to be reactive towards eTq, await investigation that may help to evaluate their electron affinities.

F. Aromatic Compounds The study of the reactivity of e , towards an extensive series of monosubstituted benzene derivatives CeH6X revealed the first linear freeenergy relation for reactions of hydrated electrons (Anbar and Hart, 1964b). The specific rates of these reactions ranges over four orders of magnitude from 4 x lo6 M - ~see-l for phenol to 3 x 1O1O M - ~sec-l for nitrobenzene. The specific reaction rates of substituted benzenes with eLqhave been related to that of benzene and expressed in terms of r ) values, where r ) =log ( k C s H s X / k C s H s H ) . Comparable values of r) are obtained for monosubstituted toluenes and phenols. The r ) values, indicating the relative reactivity of an aromatic system carrying a given substituent, have been correlated with the effect of the same substituent on the reactivity of these systems towards nucleophilic or electrophilic reagents. A quantitative evaluation of these effects has been achieved by the use of Hammett’s pu equation, log (kCeHsX/ kCeH,)=po. When the r ) values were plotted against the u values compiled by Van Bekkum et al. (1959),a satisfactory correlation was obtained for all substituents studied ( p = 4.8), with the exception of bromine and iodine. Both bromo- and iodo-benzene derivatives show a higher reactivity than expected from the effect of these substituents on the electron density in the ring. This specific effect is probably due t o the additional electrophilicity of the carbon-bound halogen atoms that has been manifested in the haloaliphatic compounds. It seems that the electron-donating capacity of the nucleus of chlorobenzene or chlorobenzoate ions practically eliminates the electrophilicity of the bound chlorine. A series of para-derivatives of benzoic acid was examined for their rates of reaction with eLq, and their q values, relative to benzoic acid, were calculated. These r ) values are proportional to the u values of the monosubstituted benzene series, and p = 0.74 was found for the benzoate series. The behaviour of the benzoic acid series shows that in contrast to

THE REACTIONS O F HYDRATED ELECTRONS

129

aromatic substitution reactions, u values of different substituents are not additive; however, a constant p is obtained for a homologous disubstituted series in which one substituent is kept constant and the other is being changed. The higher the rate constant of the monosubstituted parent compound, the lower will be the p values of the series. A molecule, CBHBX, that has a high probability of accepting an electron, will be affected to a lesser extent by an additional substituent. The smaller p values observed in the more reactive series may also be anticipated in view of the fact that the rate of these reactions approaches the diffusion-controlled limit, 1O1O M - ~sec-l, where a further increase in rate is impossible. Surprisingly similar results are obtained when monosubstituted benzenes react with solvated electrons in methanol ( p = 4.7) (Sherman, 1966). This result, which is in accord with other cases examined both in H20 and MeOH (Anbar and Hart, 1964b), suggests that the rates of e;; reactions are independent, at first approximation, of the dielectric constant of the solvating medium and of its viscosity. The implication of this finding will be discussed in Section 111. The erqrate constants correlate better with “normal ” u values derived from electrophilic substitution than with cr “para” values obtained from data of nucleophdic reactions. This is not surprising in view of the fact that the eLq reactions constitute an interaction of an electron with the .rr-orbitalsof the ring, as in electrophilic substitution, rather than with effects on electron distribution and polarizability of a certain substituent. It should be remembered, however, that the “classical” treatment, which tries to describe the behaviour of a molecule by the combined action of a number of parameters, is just an oversimplification. It is plausible that the u function is correlated with the gain in free energy on addition of an electron to a given aromatic compoundin aqueous solution, which is, in turn, a major factor in eCq reactions. Reliable information on the electron affinitiesof these compounds in the gas phase would be helpful. It should be mentioned here that a semiquantitative agreement is observed between the reactivities of aromatic compounds with eLq and rough values of their electron affinities in the gas phase (Lovelock, 1961). The primary product of the reaction PhR + eTq is the PhR- anion. This species may undergo one of three reactions : N

P h X - --• Ph+X-

PhX-

Ha0 --+

PhXH+OH-

P h X - + Y --+ PhX+Y-

(Anbar et at., 1967) (Sangster, 1966)

(Adams et nl., 1967b, Arai et aZ., 1967)

130

M. ANBAR

-

These may be followed by PhXH

Ph+XH

Ph+Ph + (Ph)z PhSH +PhSH

__f

\

PhSHz + PhX (PhSH)s

(Land and Ehort, 1967)

Transient PhX-or PhXH has been observed by pulse radiolysis in the cases of benzene (Guarino and Hamill, 1964), benzaldehyde (Chutny, 1967), benzoic acid (Sangster, 1966), trimesic acid (Gordon, 1964), phthalic acids (Gordon et al., 1964), p-naphthol (Gordon, 1964), nitrobenzene and benzonitrile (Chutny, 1967),phenol (Land and Ebert, 1967), trinitrophenol (Gordon, 1964),and acetophenone and fluorenone (Adams et al., 1967b). There is not sufficient quantitative information on the rates of the secondary dissociation and protonation reactions. The rate of PhR- + H,O+is probably diffusion-controlled,as may be inferred from the analogous reaction in alcohols (Arai and Dorfmann, 1965). The reaction PhR- + H20 + PhRH + OH- is much slower and, by analogy to the reaction of alcohols, the first-order rate constant may be estimated to be about lo7sec-l. This is still too fast for observation by microsecond techniques (Sangster, 1966). It may be of interest to investigate these reactions by nanosecond techniques, especially when it is possible to distinguish between ortho-, meta- and para-derivatives of the cyclohexadienyl radicals produced. This may add information on the electron distribution within the carbanionic aromatic molecules. The lifetimes of some of these carbanions may be limited by their dissociation to a phenyl radical and a stable anion. This pattern of reaction has been demonstrated in the eTQ-inducedquantitative deiodination of the iodobenzoic acids, as well as in the debromination ofp-bromophenol (Anbar et al., 1967). One of the few cases that has been thoroughly investigated by pulse radiolysis is the chemistry of C6H5NO;, which, unfortunately, is not a typical aromatic carbanion. This ion radical has the electron attached t o the nitro-group, and on protonation C6H6NO2His produced. This species is different from the adduct formed by the reaction C6H5NO2+ H --f CBH6NOz(Asmus et al., 1966~).C6H5N02Hwas found to be a relatively weak acid (pK = 3.2) that undergoes disproportionation to give nitrobenzene and C6H5N(OH)2. The latter species undergoes dehydration to give nitrosobenzene. On the other hand, C6H5N0, is relatively stable and transfers its excess electron to C6H5N0 at an appreciably fast rate (k=4.1 x 10' sec-I). An analogous

THE REACTIONS O F HYDRATED ELECTRONS

131

system studied is the reaction C6H6N0+ eLq --f C6H6NO- followed by C6H5NO- H+ + C6H5NOH(Asmus et al., 1966a). Several reactions of aromatic compounds have been investigated for their energies of activation. These include p-bromophenol, phthalate, benzoate, benzensulphonate ions, benzyl alcohol, phenylalanine and phenyl acetate, the specific rates of which range from 3-7 x 10' to 1.2 x 1O1O M - ~sec-l. The energies of activation of all these reactions were found to be the same, namely, 3-5 & 0.5 kcal mole-l (Anbar et al., 1967). This corroborates the conclusion that the rate-determining step in eTqreactions with aromatic compounds involves one and the same process, namely, the accommodation of an electron into the aromatic substrate. The subsequent reactions discussed above may be fast or slow but are not involved in the rate-determining step of the reaction of the hydrated electron.

+

G. Heterocyclic Compounds The reactivity of heterocyclic compounds towards eLq can generally be deduced from the chemical behaviour of the aliphatic and aromatic systems discussed in the previous Sections. Thus one finds, for instance, that pyrrolidine (1) (tetraethyleneimine) (Szutka et al., 1965)and proline

(2) in alkaline solution (Braams, 1966) are non-reactive, like any other

amine. The slight reactivity reported for hydroxyproline (3) in alkaline solution (k= 1.1x l o 7 M - ~sec-l) (Braams, 1966) must be due to trace impurities, as it is hard to understand a difference in rate of one order of HOCH-CH2

I

I

CH2 C H . C O 2 \ /

NH

(3)

132

M. ANBAR

magnitude between proline and hydroxyproline. Interestingly enough, pyrrole (4) is also non-reactive (k= 6 x lo6 M-’ sec-l) (Szutka et al., 1965) despite the conjugated carbon skeleton. It has been suggested that the CH-CH

II

II

CH CH \ / NH

imine group donates electrons to the terminal points of the butadiene structure, thus eliminating their electrophilicity (Anbar, 1965). I n view of the behaviour of pyrrole, it is suggested that the measured rate of pyrrolidine (k=4.2 x loe M - ~sec-l) is much higher than expected and may be due to trace impurities. Analogous behaviour is observed in the case of furan (5) (k= 3 x lo6 M - ~sec-’) (Hart et al., 1964a). The latter rate constant may be considered an upper limit. Thiophene ( 6 ) is CH-CH

II

II

CH CH ‘ 0 ’

CH-CH

It

CH S ‘’

/I

CH

somewhat more reactive as expected for a thioether ; however, its reactivity (k= 6.5 x lo7 M-I sec-l) (Szutka et al., 1965)is not appreciably higher than that of methionine (k= 3.5 x l o 7 M - ~sec-’) (Braams, 1966), implying that the butadiene conjugation effect is suppressed also in this case. The effect of the NH electron-donating group in a heterocyclic system on an electrophilic centre is demonstrated again in the case of indole (7), which is significantly less reactive than styrene (k= 7-8 x l o 8 and 1-1x 1O1O M - ~sec-l, respectively) (Hart et al., 1964b). Here the

THE REACTIONS O F HYDRATED ELECTRONS

133

NH group deactivates both the ethylenic bond and the aromatic nucleus. As the reactivity of tryptophane (8) in alkaline solution (k= 1-8 x lo8 M - ~sec-l)

(Braams, 1966) is significantly lower than that reported for

indole, the measured rate of the litter may be partly due to trace impurities ;the deactivating action of the heterocyclic NH is thus even more pronounced. Imidazole ( 9 ) seems to be more reactive than pyrrole, its carbon HC-N

It

HC,

II

.,CH NH

analogue (k= 2.2 x lo7 M-* sec-l) (Braams, 1966). This is to be expected from the polarization of the C=N bond, which makes the carbon an electrophilic centre. It should be remembered, however, as has been shown in Section IC, that the C=N bond is less reactive than the C = O bond. The imidazolium ion is much more reactive (k= 4 x l o 9 M - ~sec-') (Braams, 1966) than the base. This may be explained by the strong inductive effect of the ammonium group on the >C=N- reactive centre. Histidine shows good agreement with the behaviour of imidazole; k = 3.9 x log i c l sec-l for the acid form and 1.2 x lo7 M-I sec-l for the basic form (Braams, 1966). The pK, value of imidazole (6.9) is comparable with that of HzPOr (pK=7.2), but its reactivity is over two orders of magnitude higher. This demonstrates again a protonic acid that does not fit into Rabani's Brarnsted relation (Rabani, 1965). It should be remembered that the reactivities of formic and acetic acids included in Rabani's treatment have been shown to be accounted for by their carbonylic groups. Thus the suggested Brprnsted relation may be adequate for certain inorganio protonic acids only. The higher polarity of the C=N bond and the resonance effect are probably the reason for the higher reactivity of pyridine (k= 1.0 x lo9

134

M. ANBAR

M - ~sec-') (Hart et al., 1964a). It has been pointed out that the replacement of a carbon atom of a double bond by a tertiary nitrogen atom increases the reactivity of the compound by two orders of magnitude (Anbar, 1965). This is true in the cases of pyrrole and imidazole, benzene and pyridine, as well as in the cases of thioazole and thiophene ( E = 2.5 x loo and 6-5x lo', respectively) (Anbar andNeta, 1967a). I n the case of the purines and pyrimidines, the electrophilicity of the \ ,C=Nand C=O group generally outweighs the deactivating action

of the OH and NHz groups; thus all these compounds approach the diffusion-controlled limit. Some differences in rate, like that between adenosine and adenosine-5-phosphate (3.1 x 1O1O and 3-8x l o 9 M - ~sec-l, respectively) (Scholes et al., 1965), may be accounted for by the double negative charge of the latter species. Transient products of the reactions of heterocyclic compounds with eLq have been observed for adenine, purine, cytosine, methylcytosine and thiobarbituric acid (Gordon, 1964) as well as for pyridine (Cercek and Ebert, 1967). A systematic study of the chemical behaviour of these transients is desired, as some of them may be intermediates of biochemical and radiobiological importance. H. Organic Free Radicals

It has been generally accepted that paramagnetic species react with hydrated electrons at diffusion-controlledrates (Anbar, 1965). Aliphatic radicals of the type R1R2R36(where R = H or alkyl groups) seem to be an exception to this rule. It has been shown in pulse-radiolysis studies that the product of the reaction CHBOH+ OH, namely, 6HzOH, reacts with eLq at a rate at least one order of magnitude less than that of the reaction eLq + OH. Methanol is therefore routinely added to pulseradiolysis matrix solutions to convert the reactive OH radicals to relatively inert CH20Hradicals. I n high-intensity radiolysis and photolysis experiments, methanol has been shown to remove OH radicals quantitatively without affecting the concentration of the electrons, which were subsequently converted quantitatively to hydrogen molecules by the reaction eLq + eyq (Anbar and Meyerstein, 1966a, b). The latter results indicate that the rate constant of the reaction CHzOH+ eTq is less than l o 8 M - ~sec-l. The relative reluctance of CH20H to accept an electron and form CHzOH- + CH30H is probably due to the stabilization of CHzOH in a planar form, which tends to shed an additional electron and form a carbonium, CHzOH+. The latter species converts to fomrtldebyde following a proton transfer to the solvent.

THE REACTIONS O F HYDRATED ELECTRONS

135

The tendency of 6H20Hto act as electron donor has been demonstrated in the gas phase (Baxendale and Gilbert, 1965)

+

+ +

N ~ O CH~OH --+ C H ~ O N~ OH

as well as in aqueous solution (Asmus et ab., 1966c)

The latter reaction has been studied for a number of a-alcohol radicals and its rate was found to correlate with Taft’s a* values for the corresponding alkyl residues. It has been further shown that the a-alcohol radicals undergo acid-base dissociation at pH < 13, yielding highly reactive reducing agents RHCO- ; the latter species transfer an electron to nitrobenzene at a diffusion-controlledrate (Asmus et al., 19660). Several alkyl radicals, including (CH3).$0H, CH,. bHOH, 6H20H, CH, .6H .CO .OH and 6Hz.CO .OH, were found to transfer an electron to haloaliphatic compounds (Anbar and Neta, 1967b). RHCOH + R’X --+ RHCO +H++RX-

It is reasonable to conclude that radicals with a strong tendency to lose an electron will have a rather low electron affinity and, consequently, a relatively low reactivity towards eYq. I. Concluding Remarks The reactions of hydrated electrons with organic compounds are an example of the applicability of the elementary principles of “classical ” physical organic chemistry to a family of non-conventional reactions in organic chemistry, namely, single-electron-transferreactions. The intramolecular electron distribution as perturbed by inductive and resonance effects is the essence of physical organic reactivity. The excellent correlation between the reactivity of organic compounds towards hydrated electrons and their intramolecular electron distribution, as derived from kinetic and structural data, corroborates the adequacy of the somewhat naive theories of physical organic chemistry. It may be stated here that the hydrated electron interacts with organic systems just as expected from a hydrated electron. This statement may sound trivial, but it is not difficult to imagine the disturbing notion that would have resulted if these reactions had behaved in discord with the accepted theories. The mechanisms of these reactions will be discussed in Section IIJ.

136

M. ANBAR

11. RADIOBIOLOGICAL IMPLICATIONS OF THE REACTIONS OF HYDRATED ELECTRONS WITH ORGANICCOMPOUNDS The great effort invested in the investigation of theradiolytic behaviour of organic compounds in aqueous solutions has been justified by the assumption that the major part of the radiobiological damage to the living cell at the molecular level may be described by the radiolytic behaviour of organic solutes in aqueous solution. Ultimately, this effort led to the discovery of the hydrated electron and its reactions. There has been a tendency among radiation chemists to use the information on the kinetic and stoicheiometric behaviour of dilute aqueous solutions containing biochemical solutes for interpreting mechanisms of molecular radiobiology. Such a comparison may possibly be justified for the reactions of OH radicals and H atoms. The analogous treatment of hydrated-electron reactions seems, however, to be a gross oversimplification that might easily result in erroneous conclusions. Although water constitutes over 50% of living matter, the latter cannot be regarded under any circumstances as a dilute solution. I n fact, most of the intracellular water is bound as water of hydration to the different constituents of the cell, and it is rather difficult to envisage “free ” water aggregates, consisting of hundreds of water molecules, within the living cell. Such aggregates are required, however, for the formation of the “primary” products of radiolysis according t o the “diffusion” theory (Kupperman, 1967). Even if one modifies the diffusion theory to suggest that a major fraction of the primary radicals is not formed in “spurs” (Anbar, 1968a), substantial amounts of water are still required to enable the hydration of electrons ejected from their sites of ionization. It may be estimated that at least 10 free water molecules are required for the formation of a hydrated electron, including its outer sphere of hydration. If the electron ejected will be thermalized in a region that is not constituted solely of water molecules but contains a high percentage of other molecules, there is a very small probability for the formation of a hydrated electron. The electron in this case may be incorporated in one of the other constituents of the complex biological system, or it may be solvated by a complex matrix that does not consist of water molecules only. It has been shown that electrons may be solvated in highly concentrated electrolyte solutions ( 10 M), provided they are non-reactive (Anbar and Hart, 1965~). The physicochemical and chemical properties of these solvated electrons do not differ strongly from those of eTQ. Alternatively, the thermalized electron may be transferred through one of the biopolymer molecules, even before undergoing solvation, until it is trapped in a potential “trap,” at an appreciable

=-

THE REACTIONS O F HYDRATED ELECTRONS

137

distance from the site of its thermalization. Further, it is plausible that complete thermalization is not a prerequisite for the incorporation of an electron into a molecule, as it is for its solvation. As the cross-sections for the trapping of epithermal (sub-excitation) electrons by molecules with a positive electron affinity are appreciable, the role of solvated electrons in molecular radiobiology may be of secondary importance. It is suggested, therefore, that hydrated electrons are not likely to be formed in the intracellular fluid and that the formation of solvated electrons is also of low probability in the presence of solutes that are capable of accommodating electrons. On the other hand, it should be remembered that electrons are being formed in radiolysed living systems and are finally incorporated in certain functional groups of the molecules involved. A qualitative, and perhaps a semiquantitative, correspondence is expected between the tendency of the constituents of the living cell to incorporate an electron and their reactivity towards hydrated electrons in dilute solutions. From this standpoint only, it may be beneficial to acquire qualitative as well as quantitative information on the reactions of biopolymers and their functional groups with hydrated electrons. The information actually required by molecular radiobiology is the identity of the functional group that undergoes a non-reversible change following the incorporation of an electron. I n other words, molecular radiobiology needs information on the chemical fate of the system during the to sec after the incorporation of the electron. Within this time the electron might have migrated over relatively long distances within a given biopolymer and perhaps might have left it altogether to become incorporated irreversibly in an adjacent molecule. Two parameters determine the fate of the electron within a polymeric system. One is the relative affinity of the different functional groups that act as potential traps for the electron. The other is the rate of an irreversible chemical change-the cleavage of a bond forming an anion and a free radical or the accommodation of an H+ ion to form a free radical-that might take place in one of the functional groups following the incorporation of an additional electron. The probability of occurrence of a chemical change in a certain functional group is a combined function of its electron affinity and the rate ( R )of the irreversible reaction. The electron affinity of this group relative to that of all other groups in the system determines the time fraction ( r )of residence of the electron in it. The probability of a chemical change occurring in a particular group ( p ) is, therefore 131 =

R1rJZR.i7.i

138

M. ANBAR

The kinetic studies on eLq outlined in Sections I and I1 provide an estimate for the relative electron affinities of different functional groups. The rates of proton transfer or bond-cleavage reactions of different functional groups may become available in the not too distant future by direct measurements in dilute solutions using nanosecond techniques. This kinetic information may, however, have a rather limited value for molecular radiobiology, because the rates of the irreversibIe changes (Ri) strongly depend on the close environment of the particular functional group. Thus a proton donor is required for the proton-transfer reaction, or the presence of an adjacent general acid may facilitate the cleavage of an anionic species. These effects of local environment, which are so important in protein chemistry, may play a crucial role in molecular radiobiology and may thus limit the applicability of extrapolation from the behaviour of monomeric solutes. I n the following paragraphs, we shall describe the known information on the reactivity of different constituents of the living cell with hydrated electrons, bearing in mind that the information described does not represent part of the mechanism of radiobiological damage. Hydratedelectron reactions may, therefore, be used in molecular radiobiology, with appropriate caution, merely as model processes for electron-transfer reactions which undoubtedly take place in the radiolysed cell.

A. Carbohydrates, Fatty Acids and Steroids Carbohydrates are practically non-reactive towards hydrated electrons, and upper limits of specific rates of the order of l o 6 M - ~sec-l have been reported (Davis et al., 1965b). The result is consistent with the non-reactivity of alcohols and ethers. Higher saturated fatty acids are insoluble in water even in their anionic forms. From the non-reactivity of acetate and propionate ions, as well as that of saturated hydrocarbons, one may infer that carboxylate ions of higher fatty acids will also be non-reactive towards eTq. From the low reactivity of ethylene, it may be inferred that the naturally occurring unsaturated fatty acids will also exhibit a very low reactivity. Fats-the esters of higher fatty acids-are expected to show a slightly higher reactivity (of the order of lo' M-I sec-l). Steroids have not been investigated to date for their reactivity because of their low solubility in water. From their composition and structure it may be predicted that only the ketosteroids will show an appreciable reactivity towards eLq. I n short, carbohydrates, fatty acids and their common derivatives are not expected to act as electron traps in the living cell where sufficiently high concentrations of far more reactive substrates are present.

THE REACTIONS O F HYDRATED ELECTRONS

139

B. Amino Acids and Peptides Amino acids exhibit a low reactivity towards eTq unless they carry a reactive functional group (Braams, 1965, 1966; Davis et al., 1965a). Compounds of the type RCH(NH,) .CO (where R = alkyl, H) have an extremely low reactivity (k< lo6 M-I sec-I). The more reactive amino acids include tyrosine, phenylalanine, tryptophane, arginine (1-5 x l o s M - ~sec-l) and, last but not least, histidine, cysteine and cystine (k > 5 x loQ M-I sec-l). The reactivities of the former four amino acids can be accounted for by their aromatic or guanidinium functional groups. The latter three acids show a strong pH effect on their reactivity. Histidine in its acid form is about two orders of magnitude more reactive than the zwitterion, which, in turn, is about six times more reactive than the anionic form (Braams, 1966). The former change in reactivity is due to the difference in reactivities of the imidazolium ion and imidazole. Cysteine shows a similar change in reactivity between the RSH and RSforms. Cystine reacts at a diffusion-controlled rate (k= 1-3x 1O1O M-I sec-l at pH=6-1). The decrease in rate of the latter amino acid at alkaline pH (k= 2-5x loQ M - ~sec-I at pH = 10.7) (Braams, 1966)may be attributed primarily to the negative charge of the acid. Oligopeptides are more reactive than the u-amino acids, which do not carry any additional electrophilic factional groups, It has been pointed out in Section I that the enhanced reactivity of oligopeptides may be attributed to the activation of the carbonylic group, which is even further enhanced when the amino-group is protonated.

,

C. Polypeptides and Proteins The rates of reaction of polylysine (mol. wt.=44,000) and polyglutamic acid (mol. wt. = 13,000)with eyq have been measured by pulse radiolysis in the pH range 6-12 and in the presence of an inert electrolyte up to 0.5 M NaCl (Anbar and Meyerstein, 1967). The reaction rate of polylysine decreases with pH (k= 1 5 ~ 0 , 8 ~ 0 , 1 ~ 2 , 0 ~ 1x, 010l1 ~ 0M 3 - ~sec-' at pH = 6, 7.5, 9, 10.5, and 11.9, respectively). I n the neutral pH range, 7 < pH < 8, the addition of NaCl decreased the reactivity (k= 10.0, 0.9, 0-15, 0.07 x 10l1 M - ~sec-l in the presence of nil, 0.01, 0-05, and 0 . 5 ~ NaCl, respectively). Polyglutamic acid, on the other hand, showed a constant reactivity (k= 8 x los M-I seep1) in the pH range 6-12; the addition of 0 . 5 NaCl ~ increased this rate to 3 x lo9 M-I sec-l. Polylysine in neutral solution is evidently much more reactive than lysine (k= 2 x lo7 at p H = 7.8) or lysyl-lysine (k< 5 x 10' M - ~sec-' a t pH = 8). This enhancement in reactivity is probably related to the multi-

140

M. ANBAR

positive charge of this polyelectrolyte, as the neutralized molecule is less reactive by over three orders of magnitude. The charge has two effects : first, it increases the dimensions of the molecule forming a long helix compared with the coiled neutral polymer; second, it creates a potential field that attracts the negatively charged eYq. The charge may be masked by gegenions, resulting in an effect similar to neutralization. A quantitative evaluation of the specific rates of polylysine reveals that both the positively charged polyelectrolyte and the coiled neutral polypeptide react with eLq at diffusion-controlled rates. The rate of the polyglutamate + erq reaction also seems to approach the diffusion-controlledlimit. It should be remembered that throughout the experimental pH range, the polyacid is in a negatively charged partially coiled form. It may be concluded, therefore, that an electron that encounters a polyelectrolyte molecule is removed from solution by an irreversible process and, although it may not be incorporated into any particular sec), it has little chance orbital for a considerable length of time ( > to escape the high concentration of trapping sites provided by the polyelectrolyte. Another explanation would be that the polyelectrolyte has a kind of conductivity band. I n the latter case, it is expected that the reactivity of the polymer should be the sum of the reactivities of the individual trapping sites. The latter theory of intramolecular electron transfer in nonconjugated polyelectrolytes, which may find support in the behaviour of the ribonucleasecopper(n) system (Levitzky and Anbar, 1967), is in accord with the observed agreement between the specific rates of gelatine, lysozyme and ribonuclease and the sum of specific rates of the constituent amino-acid residues (Braams, 1965, 1967). The latter agreement may, however, be fortuitous, and these proteins, which react at rates approaching the diffusion-controlled limit, may act as overall electron traps according to the first mechanism. I n any case, it is evident that the behaviour of polymeric molecules differs qualitatively &om that of low-molecular-weight substrates. This conclusion puts serious doubts on any direct extrapolation of the behaviour of monomeric constituents of living matter to that of biopolymers. Moreover, it should be remembered that the latter conclusion has been drawn from the behaviour of biopolymers in dilute solution in contrast to the even more complex situation inside a living cell.

D. Purines, Pyrimidines and Nucleic Acids Purines and pyrimidines are highly reactive towards hydrated electrons, as has been described in Section I, and most of them react at

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diffusion-controlledrates. It is expected that any molecule of biological activity containing a purine or pyrimidine group will be equally highly reactive. As expected, DNA reacts with eTqat a diffusion-controlledrate ( k > 10l2 M - ~ sec-l) (Scholes et al., 1965). I n view of the very high electron affinities of all the nitrogen bases in DNA and owing to the ease of electron migration through the rr-bond-complexed purines and pyrimidines, it is impossible to predict at present which of the four reactive constituents of DNA will be the final acceptor of the added electron. Moreover, in the living cell it is possible that the electron originally accepted by the DNA will ultimately reduce one of the functional groups on the protein envelope of the nucleic acid. Alternatively, an electron accepted by that protein may induce the ultimate chemical change in the nucleic acid. It may be stated, in conclusion, that any aggregate of biopolymers in a living cell will incorporate an electron on encounter; thus little radiobiologicalinformation is to be gained from kinetic studies on these systems in dilute solutions. Consequently, any attempt to evaluate radiobiological protective agents using the reasoning of competition kinetics in dilute solutions is meaningless.

111. M E C ~ N I S OF M THE REACTIONS OF HYDRATED ELECTRONS WITH ORGANICCOMPOUNDS Electron-transfer processes have become more important in organic chemistry in recent years because of developments in organic electrochemistry, photochemistry, radiation chemistry and biochemistry. The reactions of hydrated electrons are electron-transfer processes by definition and, since they involve the same electron donor, they provide invaluable information on the nature and behaviour of the organic electron acceptor. Although many of the electron-transfer processes in organic chemistry may be more complicated than the hydrated-electron reactions, the latter may give an insight into the fundamentals of electron transfer involving organic molecules. There are two major sources of information on the mechanism of a reaction-its rate and the identity of its products. I n Section I we presented the available information on the reactivity of different organic compounds and the identity of the “final ” products of these reactions. Before considering the mechanisms of eTq reactions, we must examine the effect of temperature on the rate of these reactions and discuss the nature of the precursors of the “primary” products. The experimental findings on the activation energies of these reactions provide important clues to the understanding of their mechanism.

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A. The Energy of Activation of the Reactions of Hydrated Electrons The energy of activation of many eCq reactions with organic compounds has been measured both by competition kinetics (Anbar and Neta, 1965, Anbar et al., 1967) and by pulse radiolysis (Anbar and Hart, 1967). The great majority of reactions investigated, with about 25 different compounds, were found to have an activation energy ( A E )of 3-5 0.5 kcal mole-'. Only phenylacetate was found to have an apparently lower AE (Anbar and Neta, 1965); this is probably the result of a secondary reaction with the electron adduct of trichloroacetate, the competing compound (Logan and Wilmot, 1966). The eLq reactions that have been shown to have such a uniform energy of activation range in their reaction rates from the diffusion-controlled limit down to lo5 M - ~sec-l. If one considers inorganic compounds as well, one finds that AE for the eCq+H,O reaction, which proceeds at a rate lo4 times slower than the slowest rate cited above, is also equal to the others within the experimental error (Anbar, 1968b). It has been pointed out (Anbar and Hart, 1967; Logan, 1967) that reactions near the diffusion-controlled limit are expected to have a constant apparent activation energy of 3-4 kcal mole-l, which is equal irresto the activation energy of diffusion of solutes in water (AEdiff), pective of their actual energy of activation (AEact). For reactions proceeding at rates slower than lo 8 M - ~sec-l, the measured activation energy represents the actual enthalpy barrier of the reaction. There are two possibilities regarding the actual activation energies of eyq reactions. One is that the fast reactions proceed with AE,,, = 0, like many ion-radical reactions; thus the observed AE is due only to AEdiff. The slower reactions, on the other hand, have an activation energy of 3-4 kcal mole-l, which is coincidentally equal to AEdiff.The invariance of the apparent activation energy over the whole range of reactivities would thus be fortuitous. The other possibiliky is that most es;, reactions, fast and slow, have a constant AE,,, of about 3-5 kcal mole-l. The value of LIEdiffof eTq in water is expected to be considerably lower f conventional solutes in water, as no cavity has to be formed than d E d i fof in the former process. I n most eFq reactions, the diffusion coefficient of eLq contributes over 80% to the sum of the diffusion coefficient. Thus, it is likely that the measured AE of the diffusion-controlled eCq reactions is actually a measure of AE,,,. This conclusion may find support in the fact that the reaction H30++ HzO --+ HzO+ H30f, which determines the rate of diffusion of H+ in water, has an activation energy of only 2 4 kcal mole-' (Luz and Meiboom, 1965). As the diffusion of H,O+ is the predominant factor in

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the diffusion of the reactants in the reaction H3Of+erq, the observed value of AE = 3-2 kcal mole-1 for the latter reaction (Thomas et al., 1964 cannot be due to the diffusion-controlledrate; it suggests the contribution of an intrinsic activation energy dependent on the hydrated electron. It has been found that the relative reaction rates of electrons in ice with different solutes at 77" K are identical, within the experimental error, with the relative reaction rates of the same solutes with eTq in water at 300" K (Kevan, 1967). Half of the compounds examined in ice react in H20at diffusion-controlledrates, whereas the others react more slowly. It may be suggested, in view of these results, that all e& reactions in ice, dow and fast, have the same AE,,,; this may or may not be equal to AE,,, in liquid water. It is unlikely that such an invariant energy of activation results from the energy requirements of a transition state involving different substrates of different chemical nature. One may therefore attribute the observed invariant activation energy to an energy requirement of the hydrated electron. If eyq required a minimum amount of enthalpy before it could be transferred into a substrate molecule, one could explain the experimental findings. Once this minimum energy requirement was met the electron would be transferred into the various organic substrates without any additional enthalpy of activation. Another possible interpretation of the very small variance in AE will be discussed below (Section IIIC).

B. The Primary Products of eTq Reactions

It has been demonstrated that hydrated-electron reactions invariably proceed by the transfer of an electron from its site in the solvent into a vacancy in the acceptor molecule, irrespective of the charge of the latter e~~++n+

--f

A("-l)f

(where n is a positive or negative integer or zero). The electron-transfer process must take place without violating the Franck-Condon restriction, namely, that none of the atoms involved sec) of the actual electron change position during the instant ( < transfer. As it is rather unlikely that the acceptor molecule should have an electron vacancy at its vibrational and electronic ground state, most e; reactions must result in the formation of excited molecules as their primary products. It is probable that after accommodating an additional electron the interatomic bond distances, and in many cases the whole

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atomic configuration of the product molecule will differ from those of the acceptor molecule. Thus, at the very first instant following electron transfer, avibrationally and occasionallyan electronicallyexcited product may be formed. The de-excitation of the vibrationally excited state may take place sec). It should be remembered within the time of a few vibrations ( < that on the conventional “chemical ” time scale one seldom considers intermediates with lifetimes sec; thus most of these excited primary products may be overlooked from the chemical standpoint. One cannot, however, neglect these excited products when considering the detailed mechanism of the electron transfer. The de-excitation of the excited primary products may produce secondary excited products. The latter, in turn, may undergo deexcitation or dissociation within < sec. The species that survive this time interval may still be highly reactive intermediates that react with each other, with the solvent or with other solutes. These intermediates seldom survive longer than milliseconds; thereafter they form the secondary or tertiary more stable products. I n cases of diffusion-controlledreactions the primary product must be produced in an excited state at the instant of the electron transfer. For the slower reaction, one could envisage two pathways to the formation of the excited product, the f i s t being identical t o that suggested for the diffusion-controlled reactions, namely, the formation of an excited product from a substrate at its ground state. The second involves an excited acceptor molecule formed in a pre-equilibrium. Although one cannot exclude this second possibility altogether, it is not very plausible because there are very few multiatomic molecules with a vibrationally excited state, which is fully appropriate for the accommodation of an additional electron and which involves an excitation energy of only 3-5 kcal mole-I. As such vibrationally excited states are rather shortsec), their rate of production must be unreasonably high lived ( to allow their interaction with eYq. Low-lying electronically excited states ( E .c 0.2 V), which may persist for lO-’O sec or more, are very uncommon and could not account for most of the SIOWeFq reactions.

C . The Mechanism of Electron Transfer There are two ways of describing the transfer of an electron from its site in the solvent into the orbitals of a substrate. One is the classical^' mechanism, which involves an overlap of the orbitals of the substrate and those of eFq, and the formation of a transition state followed by a rapid electron transfer. The other is a non-classical electron tunnelling

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through a potential barrier separating the hydrated state of the electron and that of an electron incorporated in the acceptor molecules. The transition-state mechanism is expected to depend strongly on the availability of an orbital on the substrate molecule that can overlap the orbital of e,g (Anbar and Hart, 1965b). The availability of such an orbital may be correlated with the electron affinity of the substrate. Reactions followingthis mechanism will tend to exhibit a highly localized electrophilic centre. The approach of the electron acceptor to the transition state is expected to require a certain rearrangement of bond lengths and configuration to facilitate electron transfer without violation of the Franck-Condon restriction. We shall see from the following discussion that such a mechanism is not highly plausible. A conventional transition state involves the existence of a species with a higher free energy than both reactants and products, which has a lifetime of the order of a single vibration sec. The transition state of an eap reaction, if it existed, is expected to have a lifetime of the order of an electronic transition, namely, sec ; therefore, the equilibrium between it and the reactants might involve the electronic states only, because the atoms do not move during the transition. As the suggested transition state resembles both reactants and product, we cannot envisage the electron in an excited state within the very low activation energy found for so many eTq reactions. From the standpoint of the potential-energy profile of the system, it seems that there is little effect of the potential-energy barrier between the reactants and products on the rate of electron transfer. The hydrated electron is held in the solvent by an energy of hydration of about 40 kcal mole-I (Baxendale, 1964; Jortner and Noyes, 1966). I n addition, there is a potential barrier due to the electrostatic repulsive force of the native electrons of the acceptor molecule. The outer sphere of solvent molecules and gegenions is also expected to contribute to the potential barrier. All these should result in an overall potential-energy barrier much higher than the invariant 3.5 kcal mole-I observed, even after accounting for the gain in free energy following the electron transfer into its initial state in the excited primary product. It may be concluded, therefore, that the electron manages to tunnel through this energy barrier without forming a transition state. I n fact, it would be surprising if tunnelling would not take place in view of the very small mass of the electron. The tunnelling process evidently may have a transmission coefficient smaller than unity, especially when there is insufficient orbital overlap between eFqand the acceptor orbital (geometricalhindrance or thickness of barrier). I n such cases, the transmission coefficient depends strongly on the gain in free energy on electron transfer ( A G ) . When there is a

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M . ANBAR

substantial gain in dG,the electron is expected to tunnel, with a transmission coefficient of unity, over distances even longer than those required for orbital overlap. The tunnelling mechanism is characterized by a linear free-energy dependence between the free-energy change, AG, and the reaction rate. The larger the value of AG, the faster is the rate. For a certain AG, the reaction rate should depend on the distance of closest approach of the reactants which, in turn, is a function of electron-orbital overlap. It should be noted that AG cited above is the change in free energy on accommodation of an electron in the excited product and not the change in free energy attaining the ground state. As we shall see below, there are times when the overall free energy change down to the product at its final ground state might affect the rate of eTq reactions. The tunnelling mechanism has been strongly indicated when many diffusion-controlled reactions have been examined quantitatively (Anbar and Hart, 1968). Of a large number of diffusion-controlled reactions examined, over 80% exhibited a rate in excellent agreement with that predicted by the Smoluchovsky-Debyeformula (Debye, 1942)

where E

N

= macroscopic dielectric constant of water = 78.6 at 25°C;

molecules mole-I; k = Boltzmann’s constant = 1.38 x 10-la erg deg-l. = Avogadro’s number = 6.025 x

The diffusion coefficient of the hydrated electron De,,-= 4.7 cm2 sec-l was determined from its ionic mobility (Schmidt and Buck, 1966). The = 2.5 A was assumed on the basis of theoretical predicradius of eyq,reaQtions. D, and r, are the diffusion coefficient and the van der Waals radius of the substrate molecule. However, several electron acceptors exhibit a significantly higher reactivity than predicted by the cited formula. These compounds include inorganic and organic compounds, all of which are excellent oxidizing agents. The organic compounds include carbon tetrachloride, chloroform, carbon disulphide and tetranitromethane, as well as nitrophenolate, trinitrophenolate and trinitromethyl ions. All these reagents are expected to have outstandingly high electron affinities. One way to interpret the results is to assume that these compounds have a significantly larger reaction cross-section than their crystalline or

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van der Waals radii. The latter assumption is in accord with the electrontunnelling mechanism, which allows, for reactions with a very large gain in free energy (dG > 100 kcal mole-I), electron transfer over larger distances than determined by the electron orbital overlap at their ground states. An additional argument in favour of electron tunnelling as opposed t o the transition-state mechanism may be derived from the fact that each of the free-energy correlations demonstrated for protonic acids (Rabani, 1965), amino acids and peptides (Braams, 1966), aromatic compounds (Anbar and Hart, 1964b), haloaliphatic (Anbar and Hart, 1965a) and carbonylic compounds (Hart et al., 1967) include positively charged, neutral, and negatively charged substrates. If a conventional transition state were involved, it might be expected that the solvation energy of this transitition state, which is different in each case, would affect the free energy of activation. The lack of such an effect strongly suggests an electron transfer before a rearrangement of the solvation shell around the product, a process that is expected to be an integral part of the formation of a transition state. The surprisingly comparable rates of reaction of aromatic compounds in water and methanol (Anbar and Hart, 1964b; Sherman, 1966) and of other compounds in water and ice (Kevan, 1967)may be used as supporting evidence for the prevalence of the electron-tunnelling mechanism. The formation of a transition state must have resulted in a different potential barrier and different energetics of the transition states because of the differences in solvation of the reactants and products. Although it is still too early to make final generalizations on the mechanisms of eTq reactions, it seems that the tunnelling mechanism is the only one consistent with the experimental data available at present. I n molecules with high electron affinity there is little doubt that an electron vacancy is available at a potential-energy level lower than that of the hydrated electron. This facilitates tunnelling with a high probability. Other cases may be envisaged, however, where the level of the vacancy in the substrate molecule is higher than that in erq. If such a molecule encounters eTq, there is only a low probability of the electron being able to reside in the substrate. If the electron-containing substrate molecule rearranges to a configuration that accommodates the electron at an appreciably lower level, there is a substantial increase in the probability of the reaction being completed. The overall probability of the reaction producing the final product depends on the electron affinity of the substrate before any atomic rearrangements take place and on the ease of subsequent rearrangement. The latter process, whose rate is a function of the energy difference between the initial and final states of

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the product molecule, may be a single or multistage process. Each state may involve a certain activation energy of the order of 3-4 kcal molep1. Vertical electronic transitions may also become part of the degrading processes. The probability of an efficient overall electron transfer will be, in this case, a function of AGO, the free-energy change involved in the formation of the final non-excited product. The first stage of this mechanism involves electron tunnelling, whereas the subsequent steps, one of which may become rate determining, may proceed via consecutive transition states. Some of these subsequent consecutive steps may also involve rearrangements of the solvation shell, whereas others may result in an irreversible bond cleavage. From electron-affinity studies in the gas phase, it may be concluded that certain organic molecules, such as benzene, may be incapable of irreversible electron capture unless the product becomes stabilized by solvation. The dependence of the reactivity on AGO, which is expected from both mechanisms, may help to understand the good correlation with Hammett and Taft’s u functions. These may be, therefore, regarded as a measure of the effect of different substituents on the overall electron affinities of organic molecules in aqueous solution. The latter conclusion, if accepted and verified, may be regarded as a major contribution of eLqreactions to physical organic chemistry. IV. CONCLUSION Over 350 different organic compounds have been investigated to date for their reactivity with hydrated electrons (Anbar and Neta, 1967a). This is probably the most extensively studied single reaction in physical organic chemistry. This effort has not been invain, since it led to a better understanding of one of the most fundamental processes in chemistryit demonstrated electron tunnelling in organic chemistry and resulted in the discoveiy of many novel organic intermediates. The investigation of the chemical behaviour of the latter, which is presently in its very early stages, may become one of the important fields of research in physical organic chemistry in years to come. REFERENCES Adams, G . E., andMichael,B. D. (1967). Truns.FurudaySoc.63,1171. Adams, G. E., Baxendrtle, J. H., and Boag, J. W. (1964). Proc. Roy. SOC.(London) Ser. A . 277, 549. Adams, G. E., McNaughton, G . S., andMichael,B. D. (1967a). I n “The Chemistry of Ionization and Excitation” ( G . R. A. Johnson and G. Scholes, eds.), Taylor and Francis, London, p.281.

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Adams, G. E., Michael, B. D., and Richard, J. T. (1967b). Nature 215,1248. Anbar,M. (1965). I n “Solvated Electrons”, Am. Chem. SOC.Adw. Chem. Ser. 50, 55. Anbar, M. (1968a). I n “ Fundamental Processes in Radiation Chemistry ” (P. Ausloos, ed.). John Wiley and Sons, New York. Anbar, M. (1968b). Quart. Rev. (London)22, in press. Anbar, M., and Hart, E. J. (1964a). Unpublished results. 86,5633. Anbar, M., and Hart, E. J. (1964b). J. Am. Chem. SOC. Anbar, M., and Hart, E. J. (1965~).J. Phys. Chem. 69, 271. Anbar, M., and Hart, E. J. (1965b). J. Phys. Chem. 69,973. Anbar, M. and Hart, E. J. (1965~).J. Phys. Chem. 69, 1244. Anbar, M., and Hart, E. J. (1967). J. Phys. Chem. 71,3700. Anbar, M., and Hart, E. J. (1968). I n “Radiation Chemistry” Am. Chem. Soc. Adw. Chem.Ser., 81, 79. Anbar, M., and Meyerstein, D. (1966a). Chem. Commun. 57. Anbar, M., and Meyerstein, D. (1966b). Trans. Paraday SOC.62, 2121. Anbar, M., and Meyerstein, D. (1967). Unpublished results. Anbar, M., and Neta, P. (1965). Chem. Commun. 365. Anbar, M., and Neta, P. (1967a). Intern. J. Appl. Rad. Isotopes 18,493. Anbar, M., and Neta, P. (1967b). J. Chem. Soc. ( A ) ,837. ( A ) ,841. Anbar, M., and Neta, P. (1967~).J. Chem. SOC. Anbar, M. and Thomas, J. K. (1964). J. Phys. Chem. 68,3829. Anbar, M., Alfassi, Z. B., and Bregman-Reisler, H. (1967), J. Am. C h m . SOC. 89, 1263. Arai, S., and Dorfmann, L. M. (1965). J. Chem. Phys. 41, 2190. Arai, S., Grev, D. A., and Dorfman, C. R. (1967). J. Chem.Phys. 46, 2572. Armstrong, D. A., and Wilkins, V. G. (1964). Can. J. Chem. 42,2631. Asmus, K. D., Beck, G., Henglein, A., and Wigger, A. (1966a). Ber. Bunsengea. 70, 869. Asmus, K. D., Henglein, A., Wigger, A., and Beck, 0. (1966b). Ber. Bunsenges. 70, 756. Asmus, K. D., Wigger, A., and Henglein, A. (1966~).Ber. Bunsenges. 70,862. Ayscough, P. B., Mach, K., Oversby, J. P., and Roy, A. K. (1967). Chem. Commun. 1084. Baxendale, J. H. (1964). Radiation Res. Suppl. 4, 139. Baxendale, J. H., and Gilbert, G. P. (1965). Science 147, 1571. Breams, R. (1965). I n “Pulse Radiolysis” (M. Ebert, J. P. Keene, A. J. Swallow and J. H. Baxendale, eds.), p. 171. Academic Press, New York. Breams, R. (1966). Radiation Res. 27, 319. Braams, R. (1967). Radiation Res. 31, 8. Cercek, B., and Ebert, M. (1967). Trans. Faraday SOC. 63, 1687. Chambers, K. W., Collinson, E., Dainton, F. S., Seddon, W. A., and Wilkinson, F. (1967). Trans.ParadaySoc. 63,1699. Charlesby, A., Fydelor, P. J.,Kopp, P. M., Keene, J. P., and Swallow, A. J. (1965). I n “Pulse Radiolysis” (M. Ebert, J. P. Keene, A. J. Swallow and J. H. Baxendale, eds.),p. 193. Academic Press, New York. Chutny, B. (1967). Nature 213, 593. Cullis, C. F., Francis, J. M., and Swallow, A. J. (1965). Proc. Roy. SOC.(London) Ser. A 287, 15. Dainton, F. S . (1967). I n “The Chemistry of Ionization and Excitation” (G. R. A. Johnson and G. Scholes, eds.), p. 3. Taylor and Francis, London.

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Davis, J. V., Ebert, M., and Swallow, A. J. (1965a). I n “Pulse Radiolysis” (M. Ebert, J. P. Keene, A. J. Swallow and J. H. Baxendale, eds.), p. 165. Academic Press, New York. Davis, J. V., Griffiths, W., and Phillips, G. 0. (1965b). In “Pulse Radiolysis” ( M . Ebert, J. P. Keene, A. J. Swallow and J. H. Baxendale, eds.), p. 181. Academic Press, New York. Debye, P. (1942). J . Electrochem. SOC.82, 265. Dewald, R. R., Dye, J. L., Eigen, M., and de Maeyer, L. (1963). J . Chem. Phys. 39, 2388. Dorfmann, L. M. and Matheson, M. S. (1965). In “Progress in Reaction Kinetics” (G. Porter, ed.), Vol. 3, p. 237. Pergamon Press, Oxford. Feldmann, C. H., Dewald, R. R., and Dye, J. L. (1965). I n “Solvated Electron”, Am. Chem.SOC. Adv. Chem.Ser. 50,163. Garrison, W. M. (1964). Radiation Res.Suppl. 4, 158. Gordon, S. (1964). Radiation Res. Suppl. 4 , 2 1 . Gordon, S., Hart, E. J., and Thomas, J. K. (1964). J . Phys. Chem., 68 1262. Guarino, J. P., and Hamill, W. H. (1964). J . Am. Chem.SOC.86, 777. Hart, E. J. (1964). Radiation Res. Suppl. 4, 87. Hart, E. J. (1966). I n “The Chemical and Biological Action of Radiation” (M. Haissinsky, ed.), Vol. 10, p. 2. Masson et Cie, Paris. Hart, E. J., Gordon, S., and Thomas, J. K. (1964a). J . Phys. Chem. 68,1271. Hart, E. J., Thomas, J. K., and Gordon, S. (196413). Radiation Res. Suppl. 4,74. Hart, E. J., Fielden, E. M., and Anbar, M. (1967). J . Phys. Chem. 71,3993. Hayon, E . , and Allen, A. 0. (1961). J.Phys. Chem.65,2181. Johnson, G. R . A., and Simic, M. (1967). J . Phys. Chem.71,2775. Jortner, J., and Noyes, R. M. (1966). J . Phys. Chem. 70, 770. Kevan, L. (1967). J . Am. Chem. SOC. 89,4238. Kevan, L., Moorthy, P. N., and Weiss, J. J. (1964). J . Am. Chem.Soc. 86,771. Kuppennan, A. (1967). I n “Radiation Research” (G. Silini, ed.), p. 212. NorthHolland Publishing Co., Amsterdam. Land, E. J.,and Ebert, M. (1967). Trans. B’awday Soc. 63, 1181. Levitzki, A., and Anbar, M. (1967). J . Am. Chem.Soc. 89, 4185. Logan, S. R. (1967). Traw. Faraday Soc. 63, 1712. Logan, S. R., and Wilmot, P. B. (1966). Chem. Commun. 558. Lovelock, J. E. (1961). Natwre 189, 729. Luz, Z., andMeiboom, S. (1964). J . Am. Chem. SOC.86,4768. Phillips, G. O., GrifEths, W., and Davis, J. V. (1966). J . Chem.SOC. ( B ) ,194. Rabani, J. (1965). I n “Solvated Electron”, Am. Chem. SOC.Adv. Chem. Ser. 50, 242. Reed, R. I. (1962). “Ion Production by Electron Impact”. Academic Press, London. Sangster, D. F. (1966). J.Phys. Chem. 70, 1712. Schmidt, K., and Buck, W. (1966). Science 151, 70. Scholes, G., and Simic, M. (1964). J . Phys. Chem. 68, 1731. Scholes, G., Shaw, P., Wilson, R. C., and Ebert, M. (1965). I n “Pulse Radiolysis” (M. Ebert, J. P. Keen, A. J. Swallow, and J. H. Baxendale, eds.), p. 151. Academic Press, New York. 88, 1567. Sherman, W. V. (1966). J . Am. Chem.SOC. Stockdale, J. A., and Sangster, D. F. (1966). J . Am. Chem. SOC.88, 2907. Szutka, A., Thomas, J. K., Gordon, S., and Hart, E. J. (1965). J . Phys. Chem. 69, 289.

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Thomas, J. K. (1964). Radiation Res. Suppl. 4, 87. Thomas, J. K. (1967). J.Phys. Chem. 71, 1919. Thomas, J. K., Gordon, S., and Hart, E. J. (1964). J . Phys. C h m . 68, 1524. Van Bekkum, H., Verkade, P. E., and Wepster, B. M. (1959). Rec. Trav. Chim. 78, 815. Walker, D. C. (1967). Quart. Rev. (London)21, 79. Willix, R. L. S., and Garrison, W. M. (1967). Radiation Res. 32, 452.

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STRUCTURE AND MECHANISM IN CARBENE CHE MlSTRY D. BETHELL Robert Robinson Laboratories, University of Liverpool, England I. Introduction

.

.

A. Definitions and Scope B. Nomenclature and Formalism . 11. The Structure of Carbenes . A. Theoretical Considerations . B. Direct Observation of Carbenes . 111. Carbenes as Transient Intermediates in Reactions in Solution . A. Criteria . B. The Decomposition of Diazoalkanes and Related Compounds C. Base-induced or-Elimination . D. Organometallic Reagents . IV. Mechanisms of Reaction of Carbenes in Solution . A. Excitation, Multiplicity and Reactivity . B. Insertion . C. Addition to O l e h s . D. Rearrangement . V. Conclusion . References . .

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

. .

153 153 157 157 157 160 169 169 170 177 184 187 187 190 194 200 202 202

I. INTRODUCTION A. Definitions and Scope FORmany years, a group of organic reactions has been recognized in which the products can be represented formally as arising from a reactive intermediate containing one divalent carbon atom which has only six valence electrons. Such an intermediate is generally referred to as a carbene. However, more recently, evidence has accumulated which suggests that in some of these reactions carbenes are not in fact produced: in some cases the observations point to the involvement of carbanions, carbonium ions or covalent organometallic intermediates, while in other cases the precise const,itution of the reactive species has not been delineated. Accordingly, these reactions which show the qualitative features of carbene reactions are now referred to by the more non-committal epithet “carbenoid” (Friedman and Shechter, 1959). The noun carbenoid 153

154

D . BETHELL

has also been suggested for those intermediates which, while not free carbenes, give rise to products expected in reactions of carbenes (Closs and Moss, 1964; for a critique of this terminology, see Goldstein and Dolbier, 1965). Features which are commonly taken to characterize carbenoid reactions are : (i) the formation of cyclopropanes from olefins; (ii) the insertion of a group CRR‘ into a single bond (in intramolecular reactions, this often leads to the formation of cyclopropanes); (iii) the formation of dimeric olefins from CRR’-groups. These processes are formulated as reactions of the carbene RR’C: in equations ( 1 ) to (3). All need not occur simultaneously for a reaction to

\

-C-X /

+ :CRR’

+

\

-C-CRR’X /

(2)

[X= H, CR”3, halogen, etc.]

be classified as carbenoid. I n the addition of carbenes to olefins, four products are possible in principle (I to 4). Of these, 1 and 2 have the same relative arrangement of the groups a, b, c and d as the parent olefin and are products of cis-addition to the double bond. Products 3 and 4 are the result of trans-addition of the carbene. A selection of the sources of carbenoids with an indication of the probable nature of the intermediates and leading references, is given in Table 1. More detail on the most important reactions will be given in later sections. The literature of carbene chemistry has been extensively reviewed up to 1964 (Miginiac, 1962; Chinoporos, 1963; Hine, 1964; Kirmse, 1964; Ledwith, 1964; Bell, 1964; Frey, 1964; DeMore and Benson, 1964; Cadogan and Perkins, 1964; Rees and Smithen, 1964; Rozantsev et al.,

TABLE1 Sources of Carbenoids

Reactant

Diazoalkctne,G RR’CNNl Diazirine,b RR‘CNa j Ketene, RR‘C=C==O Alkyl halide, RR’CHX [X =halogen] gem-Dihdides, RR’CXz gem-Diazides, RR’C(N3)z Ketals, RR’C(0R)z

mi&, RR’C- .~

R Z [e.g. ZR:= SMez]

Epoxides,

n /-\

Olehs, R R G = C < Trihalomethylmetal compounds, RmM.CX3[e.g.M=Hg,Sn]

b

JPhotolysis(1, g) (Thermolysis(1, g) Photolysis (1, g) Lithium alkyl(1) Other bases (1) Lithium alkyl(1) CrSO4 (1) Zn/Cu [X=I] (1) Photolysis (8) Thermolysis (1) Thermolysis (1) Photolysis (1)

Probable intermediate

RR’C: RR‘C : RR‘C : RR’CLiX or RR‘C : RR’XC- or RR’C : RR’CLiX or RR’C : RR’G-Crz+ RR’XC .ZnX RR‘C: RR‘C : RR’C : RR‘C :

Reference Huisgen, 1955; Zollimger, 1961 Schmitz, 1967 Ho and Noyes. 1967 Kobrich, 1967 Bethel1 et al., 1967; Hanna et al., 1961 Kobrich, 1967 CastroandKray, 1966 Simmons et al., 1964 Barash et al., 1967 Lemalet al., 1966; Nairetal., 1968 Hruby and Johnson, 1962; Rothberg and Thornton, 1964 Trost, 1966

Photolysis (1)

R‘RC:+ >C=O

Kristinsson and G r f i , 1965,1966; Trozzolo et al., 1967

Photolysis (1)

xzc:

Richardson et al., 1965; Jones et al., 1966

RR’C : F2C :

Franzen and Joschek, 1960 Heicklen et al., 1965; Saunders and Heicklen, 1965 Seyferth et al., 1965a, b, 1967; Clark and Willis, 1960

RR’C-C(

CXZ Cyclopropanes, \” / ,C-C, [X=H, Cl]

a

Conditions (phase)

Thermolysis (1) Photolysis [R, R’=F] (g) Thermolysis (1)

General formula intended t o indicate linear arrangement of CNN. General formula intended t o indicate cyclic arrangement of CNN.

x2c:

156

D . BETHELL

1965; Herold and Gaspar, 1965). More recently particular aspects have been covered (Birmse, 1965; Kobrich, 1967; Bethel1 and Gold, 1967; Wagner and Hammond, 1968) and annual reviews of progress in the field published (Capon et al., 1966, 1967, 1968). The aim of the present article is to review critically some of the recent work on carbenes and carbenoid reactions in solution. The coverage of the increasingly voluminous literature will not be comprehensive: the selection of material has been made according to personal interest and assessment of the value of the work. The discussion is organized in the following sections :

(i) the direct study of carbenes and the structural information obtained therefrom ; (ii) the structure of reactive intermediates in carbenoid reactions in solution ; (iii) the reactions of carbenes, with particular reference to the relationship between the multiplicity of carbenes and the pattern of their reactivity. Carbenoid reactions are, of course, of considerable synthetic utility in organic chemistry, but consideration of this aspect is beyond the scope of the present work. While reactions in solution will be the major preoccupation, evidence from investigations of carbenes in the gas phase and in the solid state will also be included, although due caution must be exercised in translating conclusions from one phase to another. Further restrictions to the scope of the present article concern certain moleculeswhich can in one or more of their canonicalforms be represented as carbenes, e.g. carbon monoxide : such stable molecules, which do not normally show carbenoid reactivity, will not be considered. Nor will there be any discussion of so-calledtransition metal-carbene complexes (see, for example, Fischer and Maasbol, 1964; Mills and Redhouse, 1968; Fischer and Riedel, 1968). Carbenes in these complexes appear to be analogous to carbon monoxide in transition-metal carbonyls. Carbenoid reactivity has been observed only in the case of certain iridium (Mango and Dvoretzky, 1966) and iron complexes (Jolly and Pettit, 1966), but detailed examination of the nature of the actual reactive intermediate, that is to say, whether the complexes react as such or first decompose to give free carbenes, has not yet been reported. A chromium-carbene complex has been suggested as a transient intermediate in the reduction of gem-dihalides by chromium(I1) sulphate because of structural effects on the reaction rate and because of the structure of the reaction products, particularly in the presence of unsaturated compounds (Castro and Kray, 1966) The subject of carbene-metal complexesreappears in Section IIIB. I

CARBENE CHEMISTRY

157

B. Nomenclature and Formalism The term carbene will be used as the generic term. Particular structures will be designated using the system of nomenclature in which carbenes are treated as derivatives of the parent speciesmethylene ( CH2:). Thus, for example, 5 will be referred to as dimethylmethylene rather than dimethylcarbene (which derives from the now obsolescent carbinol convention) or isopropylidene (which might lead to confusion with stable molecules in more complex organic structures). The system is clumsy and obscure, however, in handling compounds in which the divalent carbon is located in a ring. Kirmse's suggestion of using the prefix " carbena-" in a fashion similar to the use of aza-, oxa-, etc. in organic heterocyclic nomenclature has much to recommend it and will be used where necessary in the subsequent discussion. On this basis, 6, for example, would be named 1-carbena-2-methylcyclopentane.

The divalent carbon atom in carbenes is associated with two nonbonded electrons for which it has available two orbitals. Consequently, carbenes should be capable of existing in states of differing multiplicity according as the total spin quantum number of the electrons is zero (singlet state, all electrons paired) or unity (triplet state, two unpaired electrons). Herein lies much of the current interest in carbenes. I n what follows, the symbol >C: will signify a carbene of unspecified multiplicity, >CtJ. will indicate a singlet carbene and >Cft a carbene in a triplet state. Skell's suggestion (Etter et al., 1959) that the term methylene be reserved for triplets and carbene for singlets does not appear to have been widely adopted by workers in the field and will not be used here.

11. THESTRUCTURE OF CARBENES

A. Theoretical Considerations Simple considerations of the electronic structure of carbenes indicate that, of the six valence electrons associated with the divalent carbon, four are taken up by the two covalent bonds and two are non-bonding. The divalent carbon atom has two orbitals available to accommodate

158

D . BETHELL

the non-bonding electrons which, if the orbitals are degenerate, should be assigned one to each and with parallel spins, in accordance with Hund's rule. The resultant species would have total spin S= 1 and thus be a triplet. If, on the other hand, the available orbitals are non-degenerate, then the non-bonding electrons could be assigned with paired spins to the orbital of lower energy. With such an electronic configuration, X = 0 and the species would be a singlet. However, if the energies of the orbitals are relatively close, a tripIet state could well be of lower energy because of the reduced electrostatic interaction of electrons in different orbitals. Much of the interest in carbenes has centred on the existence of these low-lying states of different multiplicity. A great deal of effort has been devoted to attempts to deduce the populated states of carbenes of various compositions,their energies and associated molecular dimensions. Considering the simplest carbene, methylene, it is clear that it could have a linear structure (Dma-symmetry)or be bent (C,,-symmetry). I n the former case, using the Is-orbitals of hydrogen and the 2s- and 2p-orbitals of carbon, two (T molecular orbitals can be constructed and these can clearly accommodate the C-H bond electrons. A degenerate pair of orbitals, similar to carbon atomic p-orbitals, are the ones of nextlowest energy. The linear structure of methylene would thus correspond to a triplet state. Bending the linear CH, molecule should have little effect on the p-type orbital perpendicular to the plane of bending, which now becomes bl in the C',,-group. The in-planep-type orbital, however, would acquire s-character by mixing with the carbon 2s atomic orbital, becoming a1 in the C,,-group (Walsh, 1953). The different character of thetwoorbitals can be stressed by denoting the in-plane orbital by (T and the out-of-plane orbital b y p (Hoffmann et al., 1968). I n the bent configuration the carbene could be in either a singlet state (the lowest being designated ' A or a triplet state (lowest, 3B,)as indicated above. On this basis a substantial number of not wholly conclusive attempts have been made to treat methylene theoretically. Both VB and MO approximations have been used, but, in particular, there has been no consensus of theoretical opinion as to whether the ground state of methylene is a singlet or a triplet. The literature up to 1964 has been critically reviewed by Gaspar and Hammond (1964). Until recently, little theoretical attention has been directed towards substituted methylenes. However, general chemical experience and results of spectroscopic investigations suggests that electrons in the (Tand p-orbitals are, in appropriate cases, delocalized further. Recently, extended Hiickel theory has been applied to a wide variety

159

CARBENE CHEMISTRY

of carbenes in an attempt to establish their preferred conformations (Hoffmann et al., 1968). Using fixed values for the lengths of the bonds involved,l the total binding energy of the carbene in the 2, up and p 2 states was calculated using bond angles and angles of rotation as variable parameters. A selection of results is presented in Table 2. Since the TABLE2 Structural Parameters and Multiplicities of Lowest Singlet ( ~ 2 and ) Triplet (up)States of Carbenes RR’C : Predicted by Extended Huckel Theory5

Assumed bond lengths (A)

R H F c1 Br

H H H H CHI H C&5

H H H ck=N H CF3

R‘ H F c1 Br F c1

Br CH3b CH3” C6H5 c6H5 CH=CH2 CkCH

c=-N C=N CF3 CF3

rC-R

A

RCR‘(’)

rC-W

1.10 1.33 1.72 1.89 1.10 1.10 1.10 1.10 1.54 1.10 1.54 1.07 1.10 1.10 1.54 1.10 1.54

1.10 1.33 1.72 1.89 1.33 1-72 1.89 1.54 1.54 1.54 1-54 1.54 1.46 1.54 1.54 1.54 1.54 ~

02

115 98 112 114 103 110 111 116 120 N 122 134 118* N 127 127 127 118 122

N

N

up

155 108 124 126 116 129 131 146.5 143 143c 165d 140f 180 180 180 N 155 165

Ground-state multiplicity T S S T

s

T T T T T T T T T T T T

__-

Taken from Hoffmann et al., 1968. Staggered conformation. c Bending in the plane of the phenyl ring. Phenyl rings rotated 45’ about C&-C: bond. C :G-H bent out of the plane of the three carbon atoms. f :C-H bent in the plane of the three carbon atoms and towards the double bond (‘I cis”-conformation). a

b

calculations do not include electron interaction, they do not permit purely theoretical predictions to be made about the ground states of the molecules. However, from comparison of the results of the calculations 1 Some of the choices of bond lengths seem surprising, e.g. 1.54 Afor Ph-CH,particularly because, in one case at least, the predicted molecular conformation is a sensitive function of the lengths of the bonds to the divalent carbon atom.

160

D. BETRELL

with the multiplicities of the ground states of certain carbenes, known from spectroscopic studies, a “rule of thumb’’ has been arrived at for the prediction of ground-state multiplicity. Although some controversy surrounds the extended Hiickel treatment, the results will probably form the starting point of many future experimental studies.

B. Direct Observation of Carbenes The understanding of reactions involving transient formation of carbonium ions and carbanions has been greatly assisted by studies on related species which, under suitable conditions, could be obtained in stable form. While attempts have been made to obtain carbenes in pure stable form, for example, by rapid condensation of gaseous pyrolysates known by mass spectrometry to contain carbenes (for a recent example, see Martin and McGhee, 1968),these have not so far proved very fruitful. Accordingly, direct studies of carbenes have been made by: (i) observation of transient carbenes, e.g. by flash photolysis; (ii) “matrix isolation”, i.e. the generation of carbenes in dilute solution in rigid matrices (crystals or glasses) at low temperatures, conditions under which the carbenes are quite stable. The observational techniques used are spectroscopic in all cases. Electronic and vibration-rotation spectroscopy have been used for the simplest structures such as methylene and the halomethylenes : the phase in which the carbene is examined does not seem to have much influence on the observed spectra (Bass and Mann, 1962). For more complicated carbenes, structural information has been largely gleaned from EPR, spectroscopy using the matrix isolation technique, and this of necessity restricts studies to triplet states. 1. Electronic and vibration-rotation spectroscopy. Methylene

After a prolonged search, the electronic spectrum of methylene generated in the gas-phase by flash photolysis of diazomethane was recorded by Herzberg and Shoosmith (1959). Absorption at 1415 A was favoured at high pressures of nitrogen and was attributed to a linear triplet species (Herzberg, 1961a). A band at 5500-9500 showing rotational fine structure was more prominent at high ratios of diazomethane to nitrogen and associated with the IAl + IB, transition of the singlet. Complete analysis of the spectra indicated the molecular dimensions (Herzberg, 1961a; Herzberg and Johns, 1966).

C A 8B E N E C H E MIST R Y

161

Dijwromethylene The emission spectrum of an excited state of difluoromethylene, obtained by discharge through CF,, was the first authenticated spectroscopic examination of a carbene (Venkateswarlu, 1950; E. B. Andrews and Barrow, 1950; see also Marsigny et al., 1968). Absorption by the ground state was reported later (Laird et al., 1950) and the spectral information analysed (Duchesne and Burnelle, 1951, 1953): a singlet A

ground state with FCF 110-120" was indicated. More recent studies (Mann and Thrush, 1960; Thrush and Zwolenik, 1963; Mathews, 1966; F. X. Powell and Lide, 1966) using flash photolysis and discharge techniques have led to revised molecular dimensions: TC-F, 1-30 A; A

FCF, 104.9'. Isolation of difluoromethylene in an argon matrix has enabled examination of the ultraviolet (Bass and Mann, 1962)and infrared spectra (Milligan et al., 1964),and the results are in good agreement with those from the gas phase: ultraviolet absorption, 2300-2670 A; infrared fundamentals at 668, 1102 and 1222 cm-l. Simple MO calculations have assisted assignment of the ultraviolet absorption and suggest that there is a substantial winteraction between fluorine and the vacant orbital on carbon (Simons, 1965).

Dichloromethylene Matrix isolation has so far been the favoured technique. Generation of dichloromethylene by pyrolysis of carbon tetrachloride, for example (Steudel, 1967),also produces trichloromethyl radicals, and this appears to complicate the assignment of the infrared spectrum (L. Andrews, 1968a). However, using dichloromethylene produced either from carbon tetrachloride and lithium atoms (L. Andrews, 1968a, b) or from carbon atoms and chlorine (Milligan and Jacox, 1967) and held in an argon matrix, symmetric (vl) and asymmetric (v3) C-C1 stretching frequencies have been assigned (719.5 and 745.7 cm-l respectively). The assignment is supported by a normal co-ordinate analysis, and, since the C-Cl frequencies are very similar to those in dichloromethane, it has been suggested (L. Andrews, 1968b)that there is little .rr-interactionbetween the chlorine atoms and the divalent carbon. Chloro- and Fluoromethylene Absorption spectra of these carbenes in the region 4000-9000 have been obtained by flash photolysis of the corresponding dibromohalomethane (Merer and Travis, 1966). Analysis of the spectra leads to the conclusion that the lower state in the observed transitions is a singlet. Table 3 summarizes values of bond lengths and angles which have been

162

D . BETHELL

obtained by analysis of the electronic and vibration-rotation spectra of carbenes. I n addition, electronic spectra of triplet diphenylmethylene and some substituted analogues, 9-carbenafluorene (7) and the related diarylmethylene 8 in solid solutions have been reported, but little structural information has been derived (Gibbons and Trozzolo, 1966; Moritani et al., 1966, 1968; Closs et al., 1966a; Trozzolo and Gibbons, 1967). Polarized optical absorption studies have been carried out on diphenylmethylene (Closs et al., 1966a; Hutchison, 1967).

2. EPR Spectroscopy

Carbenes, obtained in stable form usually by photolysis of the corresponding diazoalkane in a solid matrix at low temperature, can be observed by EPR spectroscopy when they are either aligned in a crystal (Brandon et al., 1962) or randomly oriented in a glass (Murray et al., 1962). Because of the low temperature at which the observations are made-77°K is typical-the carbene is usually taken to be in its ground state. For an organic molecule possessing two interacting unpaired spins, the spectrum is described using the spin Hamiltonian

2 = @HS + DSZ,+E(S:-Si) where S( = 1) is the spin operator and S,, 8, and S , its components along the molecular axes as shown in 9, H is the magnetic field, the Bohr magneton and g the Land6 splitting factor. The symbols D and E represent the zero-field splitting parameters which characterize the splitting of the molecular energy levels due to the interaction of the unpaired electrons in the absence of a magnetic field. The EPR spectra of dicarbenes can be treated in an analogous fashion (Trozzolo et d., 1963; Wasserman et al., 1967). Values of D and E obtained from EPR spectra of carbenes are collected in Table 4. Attempts have been made to obtain values theoretically using the MO method (Higuchi, 1963a, b ; Wasserman, 1965). The magnitudes of the zero-fieldsplitting parameters have been used to

TABLE3 Structural Parameters for Electronic States of Carbenes from Electronic and Vibration-Rotation Spectra

Carbene, RCR' R R'

H

H

Source

CHzNNIhv

Phase

Gas

State

'A1 3&

'B1

H

F

CHFBrzlhv

Gas

H

Cl

CHCLBrzlhv

GaS

'A1

F

F

Ar matrix

1A1

C1

Gas Armatrix

1Al

c1

CFzNzlhu CzF&l/discharge Li+CCll

l A1

1A"

1A"

1A1

zc-B

1.11 1.03 1.05 1.12 1.12 1.12

r-g

1.11 1.03 1.05 1.31 1.30 1.69

-

-

1.32 1.30

1.32 1.30

-

-

R~R!

102.4' 180" 140" 102' 127" 103' 134 5' 100-8" 104.9' 100f 9"

Reference

Herzberg, 1961a; Herzberg and Johns, 1966 Herzberg, 1961a; Herzberg and Johns, 1966 Henberg, 1 9 6 1 ; Herzberg and Johns, 1966 Merer and Travis, 1966b Merer and Travis, 1966b Merer and Travis, 1966a Merer and Travis, 1966a Milligan et al., 1964 Mathews, 1966;F. X. Powell and Lide, 1966 L. Andrews, 1968b

TABLE4 Zero-field Splitting Parameters and Derived Bond Angles for Carbenes

Carbene

Matrix

PCTFE PCTFE PCTFE PCTFE PCTFE PCTFE PCTFE "Fluorolube (CsFs -

"

D(cm-1)

E(cm-1)

Angle

0.628 0.626 0.541 0.609 0.606 0.553 0.863 1.002 1.002 0.712 0.723 0.72 0.744 0.518 0.515 0.496 0.405 0.456 0.435 0.47 1 0.493

0.000 0.000 0.0035 0.000

180" 1SO"

-

0.000

0.000 0.000 <:0.002

0.0033 0.021 0.027 0.024 0.0437 0.0313 0.0251 0.0265 0.0194 0.0202 0.0208 0.0243 0.0209

-N

-

180" 180" 180" 180" 180° 165-70" 160" 160" 160" 140'

-

155'

-

150'

-

Reference

Bernheim et al., 1965 Bernheim et al., 1965 Bernheim et al., 1965 Bernheim et al., 1965 Bernheim et al., 1965 Bernheim et al., 1965 Bernheim et al., 1965 Wasserman et al., 1965a Wasserman et al., 1965a Wasserman et al., 1965b Wasserman et al., 1965b Wasserman et al., 1965b Wasserman et al., 1965b Wasserman et al., 196513 Higuchi 1963b; Trozzolo etal., 1962 Wasserman et al., 1965b Trozzolo et al., 1964 Trozzolo et al., 1965 Trozzolo et al., 1965 Trozzolo et al., 1965 Trozzolo et al., 1965

0

m

m

Y

N

3

W t-

CARBENE CHEMISTRY

i u

h

tW

2 u

i

U

.B .4

B I

u)

2

8

0

q

165

166

D . BETHELL A

deduce structural information, particularly concerning RCR’ (Higuchi, 1963b) and the distribution of the unpaired electrons over the nuclear framework (Moritani et al., 1967). The parameter D measures the magnetic dipole interaction along the z-axis and is roughly proportional to Rd3, where R is the average separation of the unpaired spins. I n conjugated carbenes, small values of D imply substantial delocalization of the electron in thep-type orbital. The other parameter, E, is a measure of the difference between similar magnetic dipole interactions along the 2- and y-axes. For a given bond angle at the divalent carbon, D and E turn out to be approximately proportional to the spin densities in the non-bonding carbon orbitals. As indicated in Section IIA, for a linear carbene the non-bonding orbitals are degenerate p-type and, accordingly, E = 0. With increased bending of the carbene, the s-character of the orbital increases and so too does E . Indeed, it has become in-plane (q) customary roughly to equate the ratio EID with the fractional s-character in this, the u orbital (Higuchi, 1963b; Wasserman et al., 1964a, b). Thus, EID = 0 indicates linearity at the divalent carbon; E/D = 1/3 indicates an angle of 120°, i.e. sp2 hybridization of the divalent carbon. Doubt about some of the underlying assumptions has been expressed, however (Hoffmann et at., 1968). Another uncertainty about the validity of structural deductions from values of D and E exists. It is observed that for diphenylmethylene the magnitudes of D and E show a small dependence upon the nature of the host matrix (Trozzolo et at., 1964; Wasserman et ab., 1965a; Hutchison, 1967; Wasserman and Yager, 1967). This is illustrated in Table 5, in which the spectral line widths are also indicated. The smallest values of D and the narrowest lines are observed using diphenyl ether, benzophenone or diphenyldiazomethane as the matrix, compounds which probably have geometries somewhat similar to bent diphenylmethylene. It may be, therefore, that for these compounds the matrix sites into which diphenylmethylene fits are uniform and accommodate the carbenes with the minimum perturbation of the spin-spin interaction and molecular geometry. The broader lines in the other matrices may indicate nonuniformity in the available sites, so that the observed D-value represents some sort of average and the uncertainty in E may be relatively large. Values of D and E ought therefore to be reported with the matrix specified (cf. Table 4), a practice not universally adopted by workers in the field. While structural deductions from zero-field splitting parameters should be regarded with caution, some reassurance that the influence of the host may not be overwhelming comes from the following observations : sources of diphenylmethylene of quite different spatial requirements lead t o identical EPR spectra (Wasserman and Yager, 1967),and

167

CARBENE CHEMISTRY

the use of diphenylacetylene, which is linear, as the matrix does not lead to the formation of linear diphenylmethylene (Table 5 ) . TABLE 5 The Influence of the Host Matrix on EPR Line Widths and Zero-field Splitting Parameters for DiphenylmethyleneQ

Line width Matrix “Fluorolube ” n-Hexane,C6H14 Diphenyl ether, (CaH5)zO Benzophenone, (c8Hs)zCO Diphenyldiazomethane, (C,&)zC” Diphenylmethane, (CaH5)zCHz Fluorene, ClsHlo Diphenylacetylene,c&. CGC. CsH5

a

D(cm-1)

E(cm-1)

(gauss)

0.415 0.408 0.402

0.0197 0.0188 0.0182 0.0194 0.0188 0.0187 0.0187 0-0189

93 88 18 19 17

0-405

0.405 0.407 0.409 0.409

67

95 89

Trozzolo el al., 1964.

From the results in Table 4, it can be seen that, while a number of triplet carbenes appear to be linear, the arylmethylenes in particular would seem to be bent. Estimates of the bond angle at the divalent carbon atom, where these have been made from the EPR results, are included in the Table. The agreement with the angles predicted for the up electronic configuration by extended Huckel theory (Table 2) is remarkably good. However, the large angle ( > 135”)suggested by the EPR results for 9-carbenafluorene (7) (and certain other cyclic carbenes) is much too large to be accommodated in an undistorted fluorene carbon skeleton. This has led to the suggestion that the bonds to the divalent carbon atom are bent (Wasserman et al., 1964a, b ; see Moritani et al., 1967 for a similar conclusion for a seven-ring carbene, 8), but further investigation seems desirable to ascertain whether this is well-founded. The carbenes obtained by photolysis of a- and p-naphthyldiazomethanes each show two triplet signals in their EPR spectra (Trozzolo et al., 1965). The observed spectra are independent of the matrix used, and have therefore been assigned to geometric isomers of the carbenes (10 a, b ; 11 a, b). Arylmethylenes are expected to show such behaviour provided that the lifetime of the individual isomeric forms is long on the EPR time-scale and provided that the spin densities on nearby atoms in the rr-system, particularly the carbon atoms ortho to the divalent centre, are different. This leads to different interactions between the

168

D . BETHELL

unpaired electron in the .rr-system and that in the in-plane orbital in the two geometric isomers. Quantum-mechanical calculations of spin densities then enables the two sets of D-and E-values to be assigned to syn- or anti-isomers.

(b)anti

(a) SY’O

(b) anti

(a) sY,r

(10)

(11)

I n the form in which it has so far been applied to the study of carbenes, EPR spectroscopy is unable to investigate the hyperfine interactions of the unpaired spins with the constituent atomic nuclei because of the broad lines which are observed. However, the technique of electron nuclear double resonance (“endor”) promises to permit such investigations to be made, so providing even more detailed information about the electronic structure of carbenes (Hutchison, 1967). 3. Mass spectrometry A limited amount of work has been carried out on the mass spectrometric investigation of carbenes generated pyrolytically, for example by the reaction CC1,. SiC1, + CI,C: + SiCI4. The ionization potentials so obtained combined with the heats of formation of the precursors yield values of the heats of formation of the carbenes. Results so far reported are restricted to a small number of simple structures : these are listed in Table 6. The exothermic nature of difluoromethylene is particularly noteworthy. TABLE6 Ionization Pot,entials and Heats of Formation (25”)of Carbenes in the Gas Phase

Carbene I.P. (eV)

Reference

CHz CFz

10.4 11.7

Herzberg, 1966b Fisheretnl., 1965; Pottie, 1965

CClZ

9.8

J. S. Shapiro and Lossing, 1968

AHf (kcal .mole-1) 86 - 39 57

Reference

Kerr, 1966 Fisher et al., 1966; Pottie, 1965; Margrave, 1968 J. S. Shapiro and Lossing, 1968

CARBENE CHEMISTRY

169

111. CARBENESAS TRANSIENT INTERMEDIATES IN REACTIONS IN SOLUTION A. Criteria Section I1 provides ample evidence that carbenes are formed and can be directly observed both in the gas phase and in solid solutionsunder appropriate circumstances. Moreover, carbenes so formed do show the chemical reactions which typify carbenoid behaviour, for example, when a matrix containing carbenes at low temperature is allowed to warm up. In the liquid phase, carbenes have been detected by direct (flash photolytic) observation only recently (Moritani et aE., 1968) in consequence of their reactivity when allowed freely and frequently to collide with other molecules. Indirect methods of detection are therefore usually necessary. The definitions adopted for the terms carbene and carbenoid permit ready categorization of reactions as carbenoid by simple investigation of the structures of the products. However, such a procedure will not by itself enable a more detailed characterization of the reactive intermediate to be made. A widely-used method of investigation, which represents the next stage in sophistication, is to examine the partitioning of the intermediate between competing reaction paths leading to the different products. Early investigations (Doering et at., 1956) of the reaction of methylene with alkanes in the liquid phase showed that the carbene was inserted into primary, secondary and tertiary carbonhydrogen bonds with almost equal ease. The conclusion to be drawn from this observation is that methylene is highly energetic and reacts virtually at every collision. This represents a limiting pattern of behaviour, and it might be argued that any departure from it indicates that the intermediate involved is not really a carbene and should therefore be classified as carbenoid. Such an approach to the characterization of reactive intermediates in solution does not bear close examination. While all carbenes would, because of their electronic structure, be expected to be highly reactive, the pattern of reactivity to be anticipated of a free carbene having a particular structure cannot be predicted a priori. The situation is complicated further by the possibility of involvement of carbenes in different electronic states (seeSection IV) and by the influence of the solvent (G. A. Russell and Hendry, 1963). For example, 12 represents a singlet carbene solvated by a hydroxylic solvent, while 13 shows the same carbene solvated through its vacant orbital by an ether: the carbene in the former case has features in common with a carbonium ion-pair, but in the ethereal solvent i t might acquire the characteristics of an ylid. I n the triplet state, the same carbene might show radical-like behaviour.

170

D . BETHELL

R,8+ 8Ct&**.H-OR

R”

A more logical approach is to attempt to demonstrate at what stage in the overall reaction of a carbenoid source, RR‘CAB, to give products, RRCYZ, the groups A and B are detached and the groups Y and Z annexed. The problem resembles that of distinguishing between unimolecular and bimolecular mechanisms of substitution at a saturated carbon atom, and the general procedures employed are indeed quite similar. Thus, for example, one criterion for reaction by way of the carbene RR’C: might be that, for a series of reagents RR’CAB, the pattern of reactivity should be independent of the nature of the groups A and B. Another operational criterion, based upon the premise that carbenes are highly energetic and therefore formed in very endothermic processes, might be that the rate of disappearance of the reagent RR’CAB should be independent of the concentration of the Y- and Z-containing reagent : carbenoid species are anticipated to be less reactive than the carbene itself and so might give rise to an overall second-order kinetic law. Examples of the application of procedures such as these will be found in the following pages. I n general, carbenoid reactions in which an organic molecule decomposes thermally or photochemically without the use of metal salts or organometallic reagents are thought to involve “free ” carbenes : baseinduced reactions more often involve carbenoids. However, both halves of this generalization have their exceptions.

B. The Decomposition of Diaxoalkanes and Related Compounds 1. Diazoalkanes

The photolysis of diazoalkanes both in the gas phase and in solution is a carbenoid reaction. Moreover, the results of EPR-spectroscopic investigations (Section IIB) demonstrate that triplet carbenes can be generated by irradiation of diazoalkanes. That the reactive intermediates in carbenoid reactions are free carbenes is usually taken as self-evident. While such an assumption is probably wholly justified in most cases, it is worth remembering that both in the gas phase and in solvents such as n-hexane, the electronic absorption spectra of simple diazoalkanes show definite fine structure (Bradley etal., 1964a). This implies that the photoexcited state is bonding (Hoffmann, 1966)and consequently may have a life-time long enough to enable it to react directly with another molecule

171

CARBENE CHEMISTRY

rather than decompose unimolecularly to give a carbene. Evidence in favour of this view has been reported for the reaction of diazomethane with acetone in the presence of alcohols (Bradley et al., 1964a), and further support comes from observations that diazomethane can act as a photosensitizer (Prinzbach and Hartenstein, 1962, 1963; Bradley and Ledwith, 1967). The thermal decomposition of diazoalkanes is also a reaction in which the involvement of carbenes is often assumed. I n both photolytic and thermal decompositions in aprotic solvents, insertion products are accompanied by dimeric azines and olefinw (equation 4). Their formation

\

,C:NN \

---+ >C:

,C:"

)C=N--N=C

< + >c=c<

+

insertion products

(4)

is readily rationalized as resulting from attack by the carbene at the terminal nitrogen atom and central carbon atom of the diazoalkane respectively (see, for example, Bethell et aE., 1965; Reimlinger, 1962, 1964), even when the diazo-grouping is severely sterically hindered (Zimmerman and Paskovich, 1964). However, it is now evident that in some thermal decompositions,two molecules of diazoalkane can yield the symmetrical azine directly without the intervention of the carbene (Overberger and Anselme, 1964; Bethell and Whittaker, 1966; see also Yates et al., 1962). I n interpreting any reaction of a diazoalkane, care has to be taken that products have not arisen by acid catalysis (for a review, see More O'Ferrall, 1967)or from decomposition of the diazoalkane on the surface of the reaction vessel (Bethell et al., 1965). The distinction between carbenoid and carbonium ion mechanisms is not always straightforward. Thus, treatment of phenyldiazomethane with trifluoracetic acid in an olefinic solvent produces substantial (50-60%) yields of phenylcyclopropanes, typical carbenoid products, together with other substances most readily rationalized aa arising from intermediate carbonium ions (Closs et al., 196613). The formation of the cyclopropane occurs only in the presence of the acid, yet deuterium-labelling studies suggest that the cyclic compound is not formed by reaction of discrete benzyl cations with the olefin. A tentative interpretation of these observations has been given in which the diazoalkane, hydrogen-bonded to the acid, is thought to react with the olefin by way of a transition state formulated as 14. Hydrogen-bonded complexes of diazoalkanes with hydroxylic compounds may also be responsible for the absence of a significant kinetic hydrogen-isotope effect in the thermal reaction between certain diazocompounds and water (Bethell and Whittaker, 1966; Engberts et al.,

172

D. BETHELL

1966; More O'Ferrall, 1967). Usually, however, the reaction of diazoalkanes and alcohols is formulated in terms of complete proton transfer

to give the related carbonium ion (see, for example, Kirmse and Horn, 1967). Such a mechanism seems unlikely for the alcohol-promoted non-photolytic reaction between diazomethane and acetone giving apparently carbenoid products of addition and insertion (equation 5) (Bradley et al., 1964b). I n all these reactions, more detailed kinetic investigations are clearly desirable. CHzNN + (CH3)zCO

ROH

lo\

+ (CH3)zC-CHz

+ CHs.CHz.COCH3

(5)

2. Toluene-p-sulphonylhydraxones(Tosylhydrazones)

The problem of distinguishing between carbenoid and carbonium ion mechanisms of decomposition of diazoalkanes in protic media arises also in interpreting the base-induced decomposition of tosylhydrazones. I n the original procedure for this widely-used reaction (W. R. Bamford and Stevens, 1952), the tosylhydrazone of a carbonyl compound is treated with the sodium salt of ethylene glycol in refluxing glycol. A mixture of olefins and alkoxyethanol is produced (equation 6). Many RR'C = N .NHSOz. C7H7

R"0-

R OH

RR'C = N . NSOz. C7H7

__f

C7H7SOi + RR'CNN --+ Products

(6)

other solvents have been successfully used : of particular relevance in the present context is the use of high-boiling aprotic solvents such as diglyme. The decomposition of tosylhydrazones can also be induced photochemically (Dauben and Willey, 1962 ;Nozaki et al., 1964). Under some conditions, the intermediate diazoalkane can be isolated (W. R. Bamford and Stevens, 1952; Closs et al., 1963; Kaufman et al., 1965) and kinetic studies have confirmed that the cleavage of the anion of the tosylhydrazone to give the diazoalkane and toluene-p-sulphinate ion is rate-determining (J. W. Powell and Whiting, 1959). However, under typical reaction conditions the diazoalkane decomposes thermally aa it is formed.

CARBENE CHEMISTRY

173

Since kinetic studies of the decomposition of the tosylhydrazone throw light only on the formation of the diazoalkane, the subsequent decomposition has usually been studied by examination of the proportions of the various reaction products, supplemented by isotopic labelling experiments. A favoured system for study is camphor tosylhydrazone (65) which gives mixtures of camphene (16) and tricyclene (17) in proportions dependent upon the “protonating ability” of the solvent (Powell and Whiting, 1959; Clarke et al., 1962; for similar interpretations for other tosylhydrazones, see Bayless et al., 1968). Thus, tricyclene, which could be regarded as an intramolecular insertion product of the carbene derived from diazocamphane, is favoured in solvents of low protonating ability, while the rearranged olefin, camphene, which can be rationalized as a carbonium-ion product, is favoured in the more acidic alcohols like ethylene glycol. It has therefore become customary to regard the proportions of tricyclene and camphene as measures of the relative amounts of decomposition by the carbene and carbonium ion routes. However, the observations (R. H. Shapiro et aE., 1967)that the ratio of camphene to tricyclene in the sodium methoxideinduced reaction in solvent diglyme decreases on increasing the base

?;

.NHTs

1151

concentration (cf. Smith et al., 1965) and that, in a solvent containing deuterons (as DzO), the tricyclene contains deuterium in an amount which also decreases with increasing base concentration, suggest a more complex reaction scheme. This is shown in Fig. 1,and its most important feature is that the tricyclene is regarded as coming from both carbene and carbonium ion precursors. The intermediate bicyclo[2,2,l]heptyl cation has been written in Fig. 1 in its unbridged form by analogy with conclusions reached from studies of the Bamford-Stevens reaction of 18 stereospecifically deuteriated in either the 6-exo-or 6-endopositions (Nickon and Werstiuk, 1966). Under aprotic conditions (diglyme/sodium methoxide), the product is entirely norticyclene (19), formed without loss of deuterium in keeping with carbene formation followed by intramolecular insertion. Under standard protic conditions, 19 still constitutes more than 90% of the reaction product, but 19% of the label is lost from exo-deuteriated starting material and 52% from the endo-deuteriated compound,

174

D . BETHELL

suggesting the incursion of the carbonium-ion route. In the symmetrical bridged carbonium ion 20, (or a rapidly-equilibrating pair of unbridged ions) the 6-exo- and 6-endo-hydrogens would be equivalent : a cationic intermediate of lower symmetry would therefore seem to be involved.

1 1 D FIQ. 1. Thermal decomposition of diazocamphane in a deuteriated solvent (R. H. Shapiro el al., 1967).

That carbenoid insertion products can be formed from cationic precursors is underlined by investigations of the base-induced decomposition of 21. Bicyclobutane (22), which could be rationalized as a product of intramolecular carbene insertion (Frey and Stevens, 1964),

H

D-

.

CH=N NHTs

A

CARBENE CHEMISTRY

175

is formed preferentially when the base concentration is low and the solvent one of high proton availability (Smith et al., 1965; Bayless et al., 1965). Some inconsistencies exist in the published reports of the incorporation of deuterium in bicyclobutane formed from 21 in deuteriated ethylene glycol (Wiberg and Lavanish, 1966; Cook et al., 1966), but these could have arisen through the use of different bases at different concentrations relative to the tosylhydrazone. However, the formation of butadiene and cyclobutene not containing deuterium suggests that these rearranged olefins are products of the carbene route (Smith et al., 1965). Analogous conclusions have been reached from studies of the products of decomposition of tosylhydrazones of the type RCH=NNHTS, where R is i-propyl or t-butyl (Bayless et al., 1968). I n summary then, there appears to be a duality of mechanism in the base-induced decomposition of tosylhydrazones, products arising from both carbenes and carbonium ions. The structures of the products are an unreliable guide to their precursors, and the use of deuteriated tosylhydrazones or solvents is preferable for this purpose. Even then ambiguities remain, for hydrogen isotope exchange with a deuteriated solvent is conceivable at the diazoalkane stage (Bayless et al., 1968; Wiberg and Lavanish, 1966; see also Bayless and Friedman, 1967), and this could be related to the influence exerted in some cases on the reaction products by changes in the base concentration (Smith et al., 1965; Wiberg and Lavanish, 1966; Babad et al., 1967) and in the cation associated with the base (R. H. Shapiro, 1966). The mode of formation of the proposed carbonium-ion intermediates is not, of course, revealed by mere observation of the incorporation of deuterium from the solvent into the reaction products. This could occur by proton transfer from the solvent to the diazoalkane, as shown, for example, in Fig. 1, but might conceivably take place by proton transfer to an intermediate carbene (Kirmse, 1963; see Section IVB). Examination of the effect of changing from a protio- to a deuterio-solvent on the partitioning of a tosylhydrazone between products from carbene and carbonium-ion intermediates could throw further light on this subject. 3 . Decomposition of diaxoalkanes catalysed by metals and metallic

derivatives Diazoalkanes decompose under the influence of metal halides and other Lewis acids, e.g., ZnCl,, HgCl,, BF3 to produce, among other things, a-haloalkyl derivatives of the metal (see,for example, Wittig and Schwarzenbach 1969, 1961; Bethel1 and Brown 1967; Ledwith and Phillips

176

D . BETHELL

1962,1965). I n some cases these organometallic products show carbenoid reactivity as discussed in Section IIID. Metallic copper and copper salts and complexes, e.g. copper(1) and copper(I1) chlorides, copper(I1) sulphate and acetylacetonate, also promote the decomposition of diazoalkanes in carbenoid reaction (for a review, see Muller et al., 1966). The formation of organometallic intermediates has not so far been observed directly, but indirect evidence suggests that the reactive species is electrophilic and probably incorporates the metal. Por example, the reactive intermediate from CuS04catalysed decomposition of ethyldiazoacetate converts olefins to cyclopropanes, showing little selectivity between double bonds in different environments (Etter and Skell, 1958). However, its stereoselectivity in this type of reaction is quite different from that of the intermediate (carbene) obtained by photolysis of the same diazoalkane precursor (Skell and Etter, 1961 ;see also Cowan et al., 1964). Moreover, unlike the photochemically generated carbene, the intermediate from the catalytic decomposition does not appear to undergo insertion into carbon-hydrogen bonds. Again, a-diazoketones (RCO .CRNN), which on thermal or photochemical decomposition are thought to give first an a-ketomethylene, RCO .CR', which then rearranges to the corresponding ketene RR'C=C=O, react in the presence of copper or its salts with little rearrangement : substantial yields of products of intermolecular carbenoid reactions are formed instead (see, for example, Huisgen et al., 1964; Yates and Crawford, 1966). The differences between coppercatalysed and photochemical decompositions of diazoalkanes has been demonstrated with other reagents (Kirmse and Kappa, 1965; Kirmse and Dietrich, 1965; Kirmse and Grassmann, 1966). Indirect evidence such as this does no more than indicate that the intermediate formed in copper-induced reactions is different from the carbenes thought to be produced in thermal and photochemical decompositions of diazoalkanes. However, the long-held view (Yates, 1952) that a carbenecopper complex is the reactive intermediate in these catalysed reactions gains strong support from a recent observation that the decomposition of ethyl diazoacetate induced by the chiral complex 23 in the presence of styrene gives a mixture of the cyclopropanes 24 and 25 which is optically active (Nozaki et al., 1968). This strongly suggests a direct interaction of the carbenoid centre with the copper complex in the product-determining stage of the reaction, although a diazoalkane-copper complex is not completely ruled out as the reactive entity. If a carbene-copper complex is the important intermediate in all these reactions, the nature of the bonding becomes of interest. At various times structures 26 (Skell and Etter, 1961), 27 (Cowan et al.,

CARBENE CHEMISTRY

177

1964) and 28 (Kirmse and Horn, 1967) have been written. Considerations similar to those which apply to copper probably are applicable in

CsH5.bH .CH3

(23)

cu /O\C/OEt I

y: CH (26)

(25)

(24)

ELI+:;<

(27)

&,:A< (28)

the silver ion-induced decomposition of diazoalkanes (Kirmse and Horn, 1967). 4. Diazirines

The cyclic isomers of diazoalkanes, diazirines also decompose under the influence of heat and light to give carbenes (Schmitz, 1967; Milligan et al., 1964; Mitsch, 1965; Moss, 1967). They are, however, much less sensitive to acid-catalysed decomposition than their open-chain counterparts. They should therefore represent a useful source of carbenes, since the interpretation of the results of experiments would not be complicated by the necessity of considering the involvement of carbonium ions. I n some cases, however, there is evidence that thermal and photochemical transformation of diazirines into the isomeric diazoalkane takes place (Overberger and Anselme, 1963 ; Amrich and Bell, 1964; see also Hoffmann, 1966), though this has not been confirmed elsewhere (Moore and Pimentel, 1964; Frey and Stevens, 1965).

C. Base-Induced a-Elimination This type of reaction, in which two groups attached to the same carbon atom are lost synchronously or successively under the influence of a base, is one of the most widely investigated in carbene chemistry. The hydrolysis of chloroform was probably the first reaction in which intermediate carbene formation was suggested (Geuther, 1862), and its reinvestigation by Hine in the early 1950’s placed carbene chemistry in solution on a firm footing (Hine, 1964). The kinetic considerations of Hine were supplemented by experiments in which the intermediate

D. B E T H E L L

178

dihalomethylenes were trapped by thiophenoxide and halide ions. Trapping with olefins to form cyclopropanes in 1954 (Doering and Hoffmann, 1954)was the first of countless applications of this reaction. While there can be no doubt that dihalomethylenes are readily formed by the action of bases on haloforms such as bromodichloromethane (equation 7), relatively minor structural changes can make carbene formation unfavourable relative to other modes of decomposition, even though the reaction products are those typical of carbenoid reactions. CHClzBr+B-

fast-

BH tCC12BrBr-

-=

+ :CClz

--+ fa8t

Products (7)

A simple example of the hazards involved in even short extrapolations is provided by studies of the reaction of bases with bromomalononitrile (29) in the presence of tetramethylethylene. The product (equation 8) is the corresponding 1,l-dicyanocyclopropane, analogous to the dihalocyclopropanes formed from haloforms and olefins. Bromomalononitrile is isoelectronic with bromodichloromethane, and the CH3 CH3 CHBr(CN)z+ (CH&C:C(CHs)z (29)

NEts

H h B r -

+H3CkCH3

(8)’

CN

suggestion (Swenson and Renaud, 1965)that dicyanomethylene, formed by a-elimination of HBr under the influence of triethylamine, adds to the olefinic double bond is not unreasonable. However, 29 adds to olefins to give an intermediate bromodinitrile (Boldt and Schulz, 1966) in a photocatalysed and therefore probably radical reaction (Boldt et al., 1967). On treatment of this intermediate with base, 1,3-elimination of HBr occurs giving the cyclopropane (equation 9). Dicyanomethylene has been prepared from the corresponding diazoalkane (Ciganek, 1965, 1966; Wasserman et al., 1965a).

179

C A R B E N E CHEMISTRY

More usually in base-induced a-elimination, carbanions or their organometallic equivalents have proved to be a complicating factor, since in some cases they can show carbenoid reactivity. Their interrelation with carbenes is shown in Fig. 2, and it can be seen that criteria other than the nature of the reaction products are necessary in order to prove that carbenes are involved in a particular case. A simple kinetic criterion is applicable in those a-eliminations which lead to the formation of dimeric olefins (see Fig. 2). I n basic media, a number of organic halides and 'onium salts, characterized by the absence of a 8-hydrogen, undergo this reaction. It can be formulated as

'-.:.:/k;.: -M+Y-

+ M+B-

">C<"

R'

Y

-BX

+---

__f

R R/C-YM+ \-

-4

R,C: R"

+M+Y-

FIG.2. Carbenoid reactions in base-induced or-eliminations.

a carbene reaction (equation 10 b, c) or as successively a bimolecular displacement of halide ion by an a-halocarbanion and a 8-elimination (equation 10 d, e). On the assumption that carbenes are highly energetic

180

D . BETHELL

species, step 10(b) should be rate-limiting for a carbene mechanism, and the rate of reaction should show a first-order dependence on the concentration of the starting material. I n the bimolecular displacement/ /3-elimination sequence, step 10(d) is expected to be rate-determining, and this should lead to a second-order dependence of the rate on the concentration of the starting material. The second-order rate law has been observed in dimerizing or-eliminations of 9-bromofluorene (30;R = H ) in t-butyl alcohol (Bethell, 1963) and diphenylmethyl chloride (31) in dimethyl sulphoxide (Hanna and Wideman, 1968; cf. Ledwith and Shih-Lin, 1964) and, indeed, the intermediate “dimeric halide” can be isolated in some circumstances. (Hauser et al., 1956; Bethell and Cockerill. 1966). The bimolecular displacement mechanism is thus clearly established. However, the observation of a first-order dependence on the rate of elimination on the concentration of certain 9-halofluorenes carrying electron-withdrawing substituents (30;R=2-C1, 2-Br, 2-CN, 4-CN, 2-N02, 4-NO,) when the reaction is induced by alkali-metal t-butoxides in t-butyl alcohol is suggestive of a change in the mechanism (Bethell and Cockerill, 1964). Since exchange of the a-proton with the solvent is much more rapid than elimination, the formation of the a-halocarbanion cannot be ratedetermining. Detailed consideration of substituent effects, particularly the insensitivity of the rate of elimination to changing the %halogen, enabled the carbene mechanism to be excluded also (Bethell et al., 1967). The first-order kinetic law in this case at least appears to arise from aratelimiting dissociation of an or-halocarbanion/alkali metal ion pair to give the free carbanion, both species being capable of displacing halide ion from the reactant.

The only other published application of this kinetic criterion is to

+

or-eliminations from 4-nitrobenzyl derivatives (32; X = C1, SMe,) in aqueous organic solvents containing hydroxide ion (Hanna et al., 1961; Swain and Thornton, 1961; Rothberg and Thornton, 1964; Doleib and Iskander, 1967a). Exchange of the or-hydrogen is again rapid compared with the elimination, and the intermediate carbanion can be readily trapped using carbonyl compounds (Doleib and Iskander, 1967b; Yoshimine and Hatch, 1967). The disappearance of 32 follows a first-

CARBENE CHEMISTRY

181

order kinetic law, and this has been interpreted as indicating rate-limiting formation of 4-nitrophenylmethylene. However, radical anions are readily formed from nitrobenzyl compounds under basic conditions (Kerber et al., 1964; G . A. Russell and Danen, 1968 and references therein) : that formed by electron transfer to, say, 4-nitrobenzyl chloride could lose chloride ion giving the 4-nitrobenzyl radical which, by rapid dimerization and dehydrogenation, could be transformed to the dimeric olefin. There is no EPR-spectroscopic evidence for the formation of the

+

radical ion from 32, (X=SMe2) in the presence of hydroxide ion, but the elimination is accelerated by light and shows some initial inhibition when hexaphenylethane is added. Sulphonium ylids on irradiation are known to be converted to dimeric olefins, and to convert olefins to cyclopropanes (Trost, 1966): the carbene mechanism cannot therefore be ruled out definitely (G. A. Russell and Danen, 1968). The absence so far of unequivocal proof of carbene formation by a-elimination of hydrogen halide from organic halides and related reactions using hydroxide and alkoxide ions or weaker bases suggests that more detailed investigations of some reported carbenoid reactions may be justified. Thus carbenoid behaviour in the reaction between benzal chloride and potassium t-butoxide in the presence of olefins seems to be critically dependent upon the nature of the solvent (McElvain and Weyna, 1959; Cawley and Westheimer, 1960) and the reaction temperature (Hodgkins et al., 1964). A widely exploited procedure for bringing about carbenoid reactions of organic mono- and gem-dihalidesis by use of lithium alkyls. Examples are given in equations (11) and (12). Dimeric olefin formation, stereospecific cyclopropane formation from olefins, and insertion into carbonhydrogen bonds have all been observed in suitable cases, together with further reactions of these products with excess of the lithium alkyl.

(CH3)3C.CHI2 f CH3Li

---+

(ICirInse and Wedel, 1963; Goldstein and Dolbier, 1965)

182

D . BETHELL

By treating halides with lithium alkyls at low temperatures (<- 100') in ethereal solvents, especially tetrahydrofuran, followed by protolysis or carbonation, it is possible to show that an a-haloalkyl lithium is formed as the first intermediate in these reactions (Kobrich and Trapp, 1963; Kobrich et al., 1964; Miller and Whalen, 1964; Hoeg et al., 1965). The a-haloalkyl lithium derivatives are quite stable at these very low temperatures in the presence of tetrahydrofuran, in which they seem to be insoluble. However, they are capable of acting as nucleophiles and displace halide ions from reactive alkyl halides such as methyl iodide and benzyl chloride. On raising the temperature to about -65", an irreversible exothermic decomposition occurs. Olefins do not apparently cause decomposition of a-haloalkyl lithium reagents at - loo", but at higher temperatures they are converted to the corresponding cyclopropane at rates which seem to be in the order of nucleophilic activity of the olejin. I n this reaction, then, the reactive intermediate behaves as an electrophile, as predicted for the carbene (see Section IVA). The problem remains of whether the reagent which actually attacks the olefin is the alkyl lithium itself or the carbene derived from it. Both possibilities are shown in Fig. 2. However, since the nature of the olefin appears to affect the rate of decomposition of a given cr-haloalkyl lithium, it would seem that the active species is not the free carbene. Further evidence supporting the view that a-haloalkyl lithium reagents can themselves show carbenoid reactivity comes from the different patterns of reactivity and stereoselectivity shown by intermediates generated by alkyl lithium/organic halide combinations compared with those from, for example, photolysis of the corresponding diazoalkane (Closs and Coyle, 1962, 1965). Thus, the cyclopropane formed according to equation (11) shows complete retention of the cis-arrangement of the methyl groups of the reactant olefin, whereas photolysis of diphenyldiazomethane gives a mixture of the cis- and transdimethylcyclopropanes (Etter et al., 1959). A comparison of the relative reactivities of a series of olefins towards benzal bromide/methyl lithium and photolysed phenyldiazomethane is given in Table 7 (see also Tables 8 and 9). I n appropriate cases, the values have been divided into contributions leading to syn- and anti-isomeric phenylcyclopropanes (33). The results suggest that intermediates of different selectivity and steric requirements are involved in the two reactions, the intermediate from phenyldiazomethane being less selective and therefore presumably less stable (Clossand Moss, 1964). The explanation would not seem to be quite as simple as this: the greater selectivity of the intermediate generated by methyl lithium stems in most cases from a readier production of the thermodynamically less stable syn-product in which the phenyl

183

C A R B I N E CHEMISTRY

group is on the same side of the plane of the three-membered ring as the greater number of alkyl substituents. R

+

R

R

H

Ph (anti)

(@Yn)

(33) TABLE7 Relative Reactivities of Olefins towards Carbenoids Generated in Different Ways@ Relative reactivity ( - 10') Olefin

CeH5.CHBrz jCH3Li

C6H5. CHNN/hu

1.1

0.51 0.51

0.53 2'2

\=,

@

0.91

0.96 0.88

(1.00)

(1.00)

1.7

0.91

2.0 1.4

1.7 1.6

Closs and Moss, 1964.

A general representation of the transition state for cyclopropane formation from an a-haloalkyl lithium and an olefin is shown in 34 (Closs and Moss, 1964; Hoeg et al., 1965). The similarity with 14 is noteworthy. I n 34 the or-halogen is shown as being displaced as a halide ion by the nucleophilic o l e h , with some electrophilic assistance from lithium. Different degrees of bond formation and cleavage can be envisaged a t the transition state, reaction of the free carbene and olefin being one limiting situation. The analogy with unimolecular and bimolecular nucleophilic substitution at aliphatic carbon is obvious. The participation of carbenes in the insertion reaction at - 90" shown 7

184

D. BETHELL

(34)

in equation (12) has been excluded by an ingenious method using compounds 35 and 36 (Goldstein and Dolbier, 1965). From a comparison

of the intermolecular isotope effect on the rates of reaction of 35 and 36 (determined by the energy of the transition state of the overall reaction) and the intramolecular isotope effect on the reaction product from 36 (controlled by the energy of the transition state in the productdetermining step), it could be deduced that the transition states are in fact the same. This is consistent with either a one-step mechanism without intermediate carbene formation or with the scheme shown in equation (131, provided that k b e L , . However, since the magnitude of the intramolecular isotope effect shows a marked dependence on the nature of the u-halogen, the intermediate, if it is formed, cannot be a free carbene. (CH&C.CHILi

k.

k-.

intermediate

kb __f

(13)

D. Organometallic Reagents Carbenoid reactions of certain organometallic compounds may be classed as a-eliminations. The problems encountered in deducing the reaction mechanism are largely similar to those met with in interpreting the base-induced u-eliminations discussed in the previous section. Reactions which fall in this category are those of the u-haloalkyl derivatives of a number of metals and these can be readily prepared, often by treatment of a diazoalkane with a metal halide (for a review, see Seyferth, 1955). Such derivatives have been reported for mercury (Seyferth and Burlitch, 1964; Seyferth, et al., 1965a, b; Ledwith and Phillips 1962, 1965),magnesium (Wittig and Wingler, 1964a),zinc (Simmonsand Smith

CARBENE CHEMISTRY

185

1959; Blanchard and Simmons 1964; Simmons et al., 1964; Wittig and Schwarzenbach, 1959, 1961 ; Wittig and Wingler, 1962, 1964b; Bethel1 and Brown, 1967), indium, cadmium (Wittig and Schwarzenbach, 1961), aluminium (Hoberg, 1962), tin (Clark and Willis, 1960; Seyferth et aZ., 1966) and lead (van der Kerk, 1966). These compounds are much less reactive than the related alkali-metal derivatives mentioned in Section IIIC: stable solutions can be obtained at about room temperature usually, but on heating in the presence of a suitable reaction partner, such as an olefin, they undergo carbenoid reactions. Relatively few detailed mechanistic studies have been described, but the available evidence points to a fairly complex pattern of behaviour. I n certain cases it has been shown that the rate of reaction of the a-haloalkyl derivative with a second reagent, such as an olefin or diazoalkane, is dependent upon the concentrations of both reactants (Blanchard and Simmons, 1964; Bethel1and Brown, 1967). Such observations are consistent either with a one-step bimolecular reaction of the organometallic compound as such and the other reagent or with a rapid preequilibrium forming an intermediate, followed by a slow reaction of this intermediate with the second reactant. The latter alternative is represented in equation (14), in which kb[olefin]
with an olefin is usually discounted, and the one-step mechanism preferred. Such a mechanism has been proposed for the reaction of a-halomethyl zinc derivatives with olefins (Simmons-Smith reaction) and the transition state formulated as 37 (cf. 34 and 14) (S'immons I-+..*$

........ ...CHz ....

'h,,*:

**-

(C-c

,,\\\'

\

(37)

et al., 1964). This representation accords with the invariable observation of stereospecific &-addition to the double bond of olefins in this reaction. The thermal decomposition of phenyl(trihalomethy1)-mercury compounds, CBH5.Hg.CX,, in the presence of olefins yields the dihalocyclopropane virtually quantitatively. A typical example is expressed in equation (15). The initial rate of disappearance of the organometallic

186

D. BETHELL

compound in this case is independent of the concentration of olefin present, but in the later stages of the reaction the rate shows a small CsHs.Hg.CClzBr

+

h’ ------+

benzene, 80’

C&..HgBr

f

C1

dependence on the structure of the olefin, decreasing for olefins with the highest reactivity towards known sources of dichloromethylene (Seyferth et al., 1967). Moreover, added phenylmercuric bromide, one of the products, retards the reaction. These observations are consistent with the scheme shown in equation (14)with kb[olefin] somewhat less than k-$&H6. HgBr] and :Ccl, as the reactive intermediate ; the reaction velocity is then given by equation (16). There is independent evidence

for the insertion of dichloromethylene into mercury-halogen bonds as required for step ( -a) in equation (14) (Gordon et al., 1966). Alternative formulations of the decomposition of C6H6.Hg .CC1,Br are possible but these can probably be ruled out : in particular, BrC1,C- does not appear to be formed, since reagents which are known t o trap the carbanion are ineffective in the reaction (Seyferth et al., 1965b). The direct formation of dichloromethylene in this reaction parallels that of difluoromethylene from bromodifluoromethane and alkali (Hine and Langford, 1957). It is not yet clear, however, whether carbene formation is restricted to the trihalomethyl derivatives of mercury. For example, the isomer distribution in chloro-olefins obtained by thermolysis of a,a-dihaloalkyl mercury compounds such as 38 (equation 17) is similar to the almost thermodynamic distribution found in the carbenoid reaction of the related gem-dichloride with methyl lithium. A concerted decomposition and rearrangement, by-passing the carbene, has been suggested,however (Landgrebe and Mathis, 1966b). RR’CH .CClz. Hg .CHRR’

(38)

90” + RR’C-CHCI,

ctc.

+ RR’CH .HgCl (17)

Another general type of mechanism has been proposed for the reaction of a-haloalkyl aluminium compounds with olefins (Hoberg, 1962). This involves initial addition of the organometallic compound across the double bond followed by a y-elimination (equation 18). The evidence

187

C A R B E N E CHEMISTRY

supporting this mechanism, which bears a formal resemblance to that in equation (9), is the isolation of 39 by hydrolysis of reaction mixtures.

(39)

The observation of stereospecific cyclopropane formation requires not only that both reaction steps be stereospecific but also that there be no conformational equilibration in the intermediate adduct. Further, more subtle tests of equation (1 8) need to be devised. IV. MECEANISMSOF REACTION OF CARBENES IN SOLUTION A. Excitation, Multiplicity and Reactivity A prerequisite of any meaningful discussion of the reactivity of a transient intermediate is a knowledge of its constitution. I n carbene chemistry ideas on reactivity and constitution have grown side by side and this sometimes leads to such absurdities as discussions of the multiplicity of carbenes in reactions for which there is no proper evidence to indicate whether a carbene rather than, say, an orgrtnometallic compound is involved. Even when firm evidence for carbene involvement is available, a discussion of reactivity poses certain problems. Figure 3 outlines the modes of decomposition of diazoalkanes, indicating some of the intermediates which could be formed and which might give rise to products. Both thermal and photochemical reactions are shown, including photolysis sensitized by compounds, such as benzophenone, which readily undergo intersystem crossing from an excited singlet to an excited triplet state followed by triplet energy transfer to the diazoalkane. While all these potential intermediates must be considered, not all of them need be involved in product formation in a particular reaction. For example, in the thermal decomposition of a diazoalkane for which the related carbene is known to be a ground-state triplet, the first-formed singlet carbene might be consumed to form stable products much more rapidly than it underwent spin inversion to the triplet state. The time-scale of events is indicated by a recent estimate of 1 psec for the lifetime of 8 in the singlet state in solution at room temperature (Moritani et al., 1968). I n studies of carbene reactions in the gas phase, the selectivity of the

188

D . BETRELL

reactive intermediates between, say, primary, secondary and tertiary carbon-hydrogen bonds in insertion reactions generally increases, and the stereospecificity of cyclopropane formation from olefins decreases with increasing total pressure, including that of chemically inert gases, in the system. However, at pressures greater than atmospheric the trend is reversed (Rabinovitch et al., 1965), and this accords with the low selectivity and high stereospecificity often observed in solution. A dependence of reactivity and stereospecificityon the wavelength of the radiation used in photochemical experiments has also been reported (see, for example, Ho et al., 1965; Ha and Noyes, 1967; Kibby and Kistiakowsky, 1966). It must be stressed that caution has to be observed in

Products Products Products Products FIG.3. Intermediatesin the thermal and photochemical decompositionof diazoalkanes. Asterisks indicate excited species; s = singlet, t =triplet.

interpreting such experimental results in gas-phase reactions because of the possibility of further reaction of excited primary products before collisional deactivation (Ring and Rabinovitch, 1968 ; for general discussions, see Frey, 1964; Gaspar and Hammond, 1964). It has been argued (DeMore and Benson, 1964) that these observations are explicable in terms of carbenes having different degrees of excitation and without explicit consideration of states of different multiplicity. On this view, carbenes formed at low pressures react in highly excited states before they can undergo deactivation by collision, and their selectivity is therefore low. With increasing pressure in the system, deactivation is more likely before a collision leading to chemical reaction; the lower excitation of the carbene is then reflected in its lower reactivity and greater selectivity. Evidence to the contrary has been reported, however (Herzog and Carr, 1967).

CARBENE CHEMISTRY

189

A more widely held view, argued persuasively by Gaspar and Hammond (1964),is that carbenes of different multiplicity react in ways which are quantitatively, and in some cases qualitatively, different, and that the spin state of the carbene must be taken into account in any discussion of reactivity. Since, for many carbenes, spectroscopic evidence (Section IIB) indicates that the ground state is a triplet, low reactivity and high selectivity is often regarded as being associated with this spin state. Further, the triplet state is associated with non-stereospecific addition to olefins, whereas stereospecific addition is usually taken to indicate reaction by way of the singlet state. The view that electronic states of different multiplicity need not be considered cannot easily be ruled out, since both deactivation of vibrationally excited carbenes and intersystem crossing between singlet and triplet states are brought about by collision with other molecules. The difficulty is not restricted to reactions in the gas phase : in solution, collisional deactivation and collision-induced intersystem crossing can still be expected to compete with collisions leading to chemical reaction. However, the parallelism between the variation in stereospecificity in the gas-phase addition of methylene to the 2-butenes with the pressure of inert gas (Prey, 1959, 1960; Anet et al., 1960; Bader and Generosa, 1965) and the spectroscopic observation of singlet and triplet methylenes by Herzberg (Section IIB) provides strong support for the alternative view. An analogous parallelism has been recognized for methylene insertion (Richardson et al., 1960, 1961). Further evidence that singlet and triplet carbenes react in experimentally distinguishable ways is provided by the reduction in the stereospecificity of addition of photolytically produced rnethylene to olefins when carbene formation is photosensitized either in the gas phase, by mercury (Duncan and CvetanoviE, 1962), or in solution by benzophenone (Kopecky et al., 1962; Jones et at., 1967a, b). Paramagnetic species, such as transition-metal ions and oxygen, and heavy atoms should also promote spin relaxation of carbenes to their triplet states with a resultant reduction in stereospecificity and increase in selectivity. However, their use for this purpose2 does not seem to have been exploited systematically so far (Kopecky et al., 1962; Wescott and Skell, 1965). A “heavy” atom effect has been reported in the closely related field of nitrene chemistry (Anastassiou, 1966, 1967). On a simple view of the reactivity of carbenes, and accepting the argument that singlet and triplet states show different chemical Oxygen has frequently been added to reactionmixtures as a trap for radicals (Hamilton and Giacin, 1966) and triplet carbenes (see, for example, Tang and Rowland, 1966, McKnight et al., 1967; R. L. Russell and Rowland, 1968). Nitric oxide has also been used in this way (Halberstadt and McNesby, 1967).

190

D . BETHELL

behaviour, it might reasonably be expected that a singlet carbene would behave rather in the manner of other reactive carbon species having an even number of electrons, that is to say, like carbonium ions and carbanions though without the effects associated with the electrical charge. Indeed, 40 has been suggested as a suitable formalism for carbenes so as to lay emphasis on this dual analogy (Jennen, 1966). While substituents might be expected to enhance the carbonium-ion or carbanion-character, the electrophilic nature of carbenes is usually regarded as dominant, since the divalent carbon is associated with only six electrons as is a carbonium centre. However, the presence of a non-bonded pair of electrons at the electrophilic centre should lead to a quite different pattern of reactivity for the carbene compared with a carbonium ion. I n the language of Pearson, carbenes should be much softer electrophiles than carbonium ions and react more readily with soft, polarizable nucleophiles (Pearson and Songstad, 1967). Explicit tests of this prediction have not yet been reported, although carbene centres do seem to favour reaction with polarizable groupings (see, for example, Robson and Shechter, 1967). By contrast, carbenes in triplet states should, on this simple view, show reactions similar to those of

(40)

odd-electron molecules, although the coupling of spins evident from the EPR results makes the analogy imperfect. The extent to which the predictions from these simple considerations are borne out will become evident in the following account of recent work on main types of carbene reactions.

B . Insertion Consideration of the rule of spin conservation leads to the formulation of the insertion of a singlet carbene into, say, a carbon-hydrogen bond as a one-step process involving a three-centre, cyclic transition state (equation 19). For the same reason, insertion of a triplet carbene is expected to be a multi-step reaction in which free radicals are formed as discrete intermediates (equation 20). Arguments have, however, been advanced for a mechanism similar to that of equation (20) for insertion by singlet methylene, the intermediate radical pair being held together and undergoing efficient recombination because of contributions from ionic states (DeMore and Benson, 1964). On the other hand, un.expectedly high yields of insertion products from gas-phase photolyses

CARBENE CHEMISTRY

191

of diazomethane in the presence of propane and the butanes have led to the suggestion that triplet methylene may be able to insert directly into carbon-hydrogen bonds (Ring and Rabinovitch, 1966).

RR‘C f f+ H - C I

\

--+

Products which can be ascribed to the intermediate formation of radicals have long been observed in carbene reactions. I n the gas phase these products could arise by homolytic decomposition of excited primary products before collisional deactivation rather than from radicals generated in the course of insertion. This is not so in solution. It is found that, in the thermal decomposition of diphenyldiazomethane (Bethel1et al., 1965)or photolysis of diphenylketene (Nozaki et al., 1966) in toluene solution, the product of insertion of diphenylmethylene into the benzylic carbon-hydrogen bonds, 1,1,2-triphenyIethane, is accompanied by substantial amounts of 1,1,2,2-tetraphenylethane and bibenzyl. This is a strong indication that discrete diphenylmethyl and benzyl radicals are formed, and, taken in conjunction with EPR (Section IIB) and other evidence (Etter et al., 1969) that diphenylmethylene is a ground-state triplet, would support the view that equation (20) is an adequate representation of triplet insertion. The search for evidence to support the direct mechanism of insertion of singlet carbenes into carbon-hydrogen bonds has produced puzzling, and in some cases apparently contradictory results. For example, methylene is reported to react with the bridgehead C-H bond of bicyclo[2,2,2]octane at a normal rate and, of necessity, with retention of configuration (Doering, 1964a), consistent with the formulation in equation (19). On the other hand, the bridgehead C-H bonds in nortricyclene (19) have been found to be unusually unreactive compared with other C-H bonds towards ethoxycarbonylmethylene (Sauers and Kiesel, 1967), and this has been taken to indicate substantial charge separation in the transition state (cf. Doering and Knox, 1961). It is by no means clear how much of the difference between these two, at present, qualitative observations is to be ascribed to the different structures of the carbenes involved. Equation (19) requires that insertion

192

D . BETHELL

occur in all cases with retention of configuration. Greater than 95% retention has been reported for insertion of methylene into the a-carbonhydrogen bonds of the 1,2-diacetoxycyclopentanesunder conditions where the singlet species is probably involved (Franzen, 1962). Complete retention is also found in the insertion of dichloromethylene, thought to be a ground-state singlet (Section 11; Wescott and Skell, 1965; see also Engelsma, 1965), into the carbon-mercury bond of di-2-butylmercury (Landgrebe and Mathis, 1966a). Furthermore, dichloromethylene apparently inserts into the C(2)-H bond of di(2-methylbuty1)mercury with unexpected ease (Seyferth and Washburne, 1966; Landgrebe and Mathis, 1966a) and with some 20% net retention of configuration (Landgrebe and Thurman, 1967, 1968). No explanation has yet been advanced, however, for the reported insertion of dichloromethylene into the benzylic C-H bond of 2-butylbenzene with complete racemization (Franzen, 1964). The results of these investigations cannot be regarded as conclusive as far as the mechanism of insertion is concerned until a more systematic study of the stereochemical course of the reaction for a range of structures has been carried out. Taken at face value, the presently available results indicate a complex pattern of behaviour. Polar influences have been examined in the insertion of dichloromethylene, generated from phenyl(bromodichloromethyl)mercury, into the silicon-hydrogen bond of a series of substituted dimethylphenylsilanes (Seyferth et al., 1968). Fitting the observed relative rate constants to the Hammett, equation gives a p-value of - 0.632, indicating electrophilic attack by the carbene but relatively little charge separation in the transition state. The preferred formulation of the transition state is 41, which accords with the observation of insertion with retention of configuration (Sommer et al., 1968). While the cyclic, three-centre arrangement in 41 seems plausible as a representation of singlet insertion in many cases and is consistent with the low hydrogen-isotope effects observed in insertions into C-H bonds (Simon and Rabinovitch, 1963; Chesick and Wilcott, 1963;see also Goldstein and Baum, 1963; Goldstein and Dolbier, 1965), extension of this approach to other carbenes is desirable.

CH3

Singlet insertion by way of a three-centre cyclic transition state may not, in any case, be an invariable rule. The insertion of methylene into carbon-chlorine bonds (Franzen, 1959 ;Bradley and Ledwith, 1961)may

193

C A R B E N E CHEMISTRY

involve chlorine atom abstraction and radical recombination as observed in gas-phase reactions (Setser et al., 1965; C. H. Bamford et at., 1965). This could be consistent with the 90% racemization reported in the insertion of methylene into the C-C1 bond of optically active 2-butyl chloride (Doering, 1964b). Stepwise, but heterolytic, mechanisms have been suggested in the insertion of carbenes into oxygen-hydrogen bonds. The reactivity of water and halide ions towards dihalomethylenes parallels their reactivity in SN2 displacements (Hine and Dowell, 1954), suggesting that an electrophilic carbene attacks water initially by way of the non-bonded electron pair on oxygen giving an ylid (equation 21). An analogous mechanism could be followed in the insertion of carbenes into the + XzC:+HzO

Xz6-0Hz

--f

Products

(21)

0-H bond of alcohols if proton transfer from oxygen to the adjacent carbon atom occurred in the ylid. Evidence both for and against the involvement of ylids in the reactions of methylene with ethers has been reported (Franzen and Fikentscher, 1958; Jones et at., 1967a, b ; Prey and Voisey, 1968). A quite different heterolytic mechanism has been put forward for the reaction of diphenylmethylene with alcohols to form diphenylmethyl alkyl ethers (Kirmse, 1963). The ability of alcohols to suppress the reaction of the photolytically generated carbene with oxygen increased with increasing acidity of the alcohol. When sodium azide was present, the ylids of diphenylmethyl azide and alkyl ether were close to those obtained by solvolysis of diphenylmethyl chloride under the same conditions. Equation (22) is a plausible formulation of the reaction. PhzCHN3 hv

PhzCNN + Na+PhzC:

Rohi RO- + PhZCH+

(22)

+

PhzCHOR

However, under somewhat different conditions (aqueous acetonitrile at 8 5 O ) , no evidence for the free carbonium ion could be found (Bethel1et al., 1965). Moreover, the invariance of the product proportions when water is replaced by deuterium oxide, coupled with the observation of a large tritium isotope effect on the formation of diphenylmethanol, is consistent only with the ylid mechanism (equation 21) (Bethel1 et al., 1969). For reaction of diarylmethylenes with alcohols, substantial hydrogen-isotope effects are observed, consistent with both equations 21 and 22.

194

D . BETHELL

The pattern of substituent effects on the magnitude of the isotope effects suggests a wide variation in transition state structure with changing structure of both the carbene and alcohol (Bethell, Howard and Newall, unpublished). At its limits, the range of structures could embrace both ylid and proton-transfer mechanisms.

C. Addition to Olefins Despite closely reasoned counter-arguments (DeMore and Benson, 1964), the commonly held view, due to Skell, is that singlet carbenes add to olefins in a stereospecific cis-manner, whereas attack by triplet carbenes leads to non-stereospecificaddition (Skell and Woodworth, 1956). The rationale of this view is that a singlet carbene should react with the olefin to form a cyclopropane in a one-step, concerted process because in this way it could occur with conservation of spin (equation 23): the addition would thus be stereospecifically cis. On the other hand, a concerted addition of a triplet carbene would violate the rule of spin conservation : in consequence, a multistep reaction, in which spin inversion of an intermediate 1,3-diradicttlconstitutes a discrete process

c

R&!?

+ “>C=C” 6

ta\

\d

I t

+ b,C-T-CRz

b C

b,t I 1 ,C-C-CRz

a

I

d

__f

a

R

prior to cyclization, is preferred (equation 24). Rotation about the carbon-carbon single bonds of the intermediate diradical could occur

CARBENE CHEMISTRY

195

at a rate comparable to that of spin inversion, as indicated in equation (24), and this could therefore lead to non-stereospecificaddition. As pointed out by Gaspar and Hammond (1964), the logic of this widely-held and much applied interpretation, despite its plausibility, does not bear close scrutiny. Thus, singlet addition does not have to be concerted merely because it could be without breaking the spin conservation rule. Moreover, there is little independent evidence concerning the relative rates of spin inversion and rotation about single bonds in diradicals. A recent theoretical examination of the question raises doubt about the symmetry of the transition state for addition of singlet carbenes to olefins (equation 23). Synchronous addition of bent singlet methylene (electronic configuration cr2 in Hoffmann’s treatment) to both ends of the double bond using the filled o-orbital is disallowed by the considerations of orbital symmetry which have proved so successful in dealing with other cycloadditions (Hoffmann, 1968 ; Hoffmann and Woodward, 1965). On the other hand, the symmetry-allowed synchronous interaction of the vacant p-orbital on the divalent carbon atom and the r-orbital of the olefin seems unlikely since it would not lead smoothly to the cyclopropane geometry. One possible interpretation, which would bring Skell’s hypothesis into line with orbital-symmetry considerations, is that synchronous addition involves an excited linear singlet methylene (Anastassiou, 1968). Such a process is allowed if the vacant p-type orbital of the carbene interacts with the olefinic rr-orbital. Reaction by way of excited carbenes is quite conceivable, at least under some conditions, and the gain in energy from simultaneous formation of two carbon-carbon bonds could favour such a mechanism over stepwise a1ternatives. Scheiner’s observations (1964) on spin inversion and bond rotation in nitrogen-containing diradicals lends support to Skell’s view. Direct photolysis of the triazolines 42 and 43 gives the related aziridines, 44 and 45 with predominant retention of the geometric arrangement of the methyl and adjacent phenyl substituents. Photolysis in the presence of a triplet sensitizer, benzophenone, results in a product distribution showing much lower stereoselectivity. The inference is that

196

D . BETRELL

direct photolysis of the triazolines results in loss of nitrogen and formation of a singlet diradical in which ring closure is faster than bond rotation. The triplet diradical, formed in the sensitized decomposition, must undergo spin inversion and ring closure at a rate somewhat less than that of conformational equilibration. Though strictly relevant only to the addition of nitrenes to carbon-carbon double bonds, there is no reason to suppose that the conclusions cannot be extended to carbene addition. Thus, while non-stereospecificsinglet addition and stereospecific triplet addition need not be impossible, the consensus of opinionseems to be that Skell’s original hypothesis is substantially correct. The addition of halomethylenes to olefins appears to fit the predictions of the theory. Thus, dichloromethylene, which is thought to be agroundstate singlet, adds stereospecifically cis under a variety of conditions (Wescott and Skell, 1965). Chloro- and bromomethylene also show stereospecific addition when generated thermally or photochemically from the related diazo-compound (Closs and Coyle, 1965; see Section IIB). Diphenylmethylene, which is thought to be a ground-state triplet, adds non-st(ereospecifica1lyto olefins when generated by photolysis of diphenyldiazomethane, in accordance with expectation (Etter et al., 1959). The stereospecific formation of 1,l-diphenylcyclopropanesfrom olefins and dibromodiphenylmethane when treated with methyl lithium (Closs and Closs, 1962) probably signifies reaction by way of an organolithium reagent rather than a carbene (see Section IIIC). Addition of 9-carbenafluorene (7) generated photolytically appears to be nonstereospecific, as expected in view of EPR evidence that it is a groundstate triplet (Doering and Jones, 1963; Funakubo et al., 1963).3 On the other ha&, the carbenes 46 and 47 which are also groundstate triplets, add stereospecifically to cis- and tram-2-butenes

(Murahashi et al., 1967) and phenylmethylene shows only a small tendency to give products of trans-addition to double bonds (Gutsche et al., 1962; Closs and Moss, 1964). Methylene, too, invariably adds 3 A similar conclusion based on experiments in which 9-diazofluorene was decomposed thermally in the presence of maleic and fumaric esters is unreliable, since these olefins could react directly with the diazoalkane giving the observed CyClOprOpaneS by way of intermediate pyrazolines, and the appropriate kinetic check was not carried out.

197

CARBENE CHEMISTRY

stereospecifically to olefins in the liquid phase (Skell and Woodworth, 1956, 1959; Doering and La Flamme, 1956),suggesting that the reaction takes place through the singlet state even though this is not the ground state. The remarkable sensitivity of the stereochemical course of addition to the constitution of the carbene within closely related groups of structures deserves detailed investigation. One approach, which has proved revealing in the case of 9-carbenafluorene and which may be generally applicable, is to examine the influence of additives which can deactivate electronically excited carbenes without undergoing reaction themselves (e.g. hexafluorobenzene) or which react preferentially with carbenes of a particular spin state (e.g. oxygen and butadiene, which are both thought to react preferentially with triplet carbenes). The technique is analogous to well-

FI:NN

hv

I

Flfl

-t? F1

F1 = the 9-fluorenylidenemoiety. FIG.4. A mechanistic scheme for the photolysis of 9-diazofluorene in the presence of cis-2-butene.

established procedures for the study of gas-phase reactions. In the photolysis of 9-diazofluorene in the presence of cis-2-butene, the &-addition product is formed in twice the yield of the trans-product. The ratio is progressively reduced, however, as hexafluorobenzene is added to the olefin solvent, and increased in the presence of oxygen or butadiene (Jones and Rettig, 1965; for an analogous observation in the photolysis of (MeO.CO),CNN, see Jones et al., 1967a). These observations can be interpreted according to the scheme shown in Fig. 4. On this scheme, it is evident that if spin inversion is irreversible, the ratio of cis- to transaddition should be a function of the concentration of the olefin, since the fist-formed singlet carbene is partitioned between cis-addition to the double bond and spin inversion which is probably not dependent upon the olefin concentration. The exploitation of this situation in carbene chemistry in solution does not appear to have been reported. It has, however, been used in studies of the multiplicity of nitrenes (McConaghy and Lwowski, 1967). Somewhat similar techniques have been employed

198

D . BETHELL

in studying the reactions of carbon atoms in triplet (T) and metastable singlet (lDand 3s') states when condensed with olefins on to cold surfaces (Skell and Engel, 1965a, b, 1966a, 1967; for other examples of carbenoid behaviour by constituents of carbon vspour, see Skell and Wescott, 1963; Sprung et al., 1965; Skell et al., 1965; Skell and Engel, 1966b; Skell and Harris, 1966). A further stereochemical complication arises in those cases where a carbene having two different groups attached to the divalent carbon atom (e.g. PhCH:) adds in a stereospecifically cis-manner to olefins, such as cis-2-butene, to give two epimeric (syn- and anti-) products (cf. equation 1). Ratios of yields of syn- and anti-products formed in a variety of carbenoid reactions are listed in Table 8. I n general, the ratios TABLE 8 Syn/anti Product Ratiosa in Cyclopropanes Obtained by the Addition of Carbenes and Carbenoids to Olefins

Carbenoid PhCH: ClCPh BrCPh Cl%F ClCH : BSH:

Source

P h C H " / h v (- 10') PhCHBrz/CHaLi( - 10') PhCHClz/KOBut(60-75") PhCHBrz/K0B~t(25~) PhCBrNa/hv(25") (CClaF)zCO/KOBut(- 12') CICHNN( - 30") CHzC12/C4HsLi(- 35") BrCHNX( -30")

h u 1-1 1.3 1.5 1.28 1.31 2.35 1.0 1.6 1.0

1.1 2.4 3.0 1.35 1-55 3.08 1.0 5.5 1.0

Reference

1.0 2.1 1.7 -

CIoss and Moss, 1964 Closs and Moss, 1964 ClossandCoyle, 1966 Moss and Gerstl, 1966 Moss, 1967 - Moss and Gerstl, 1966 1.0 Closs andCoyle, 1965 3.4 Clossand Schwartz, 1960 1.0 ClossandCoyle. 1965

T h e syn-isomer istaken t o be that inwhich thesubstituent written first in thestructure listed under " Carbenoid" lies on the same side of the plane of the cyclopropane ring as the larger number of alkyl substituents. @

indicate a preference for the formation of the more sterically hindered, and therefore less stable, product, in which the bulkier carbenoid substituent lies on the same side of the plane of the cyclopropane ring as the larger number of olefinic substituents. Carbenes generated from diazoalkanes lead to synlanti ratios close to unity, though lower values have been reported in one instance (Skell and Etter, 1961). With one exception, values of the ratio which are larger than unity are observed in base-induced a-eliminations, where the evidence for the involvement of free carbenes is least reliable. Interpretations of synlanti ratios in terms of a balance of steric repulsion and electrostatic attraction between

TABLE9 Relative Reactivities of Some O l e b s towards Addition of Carbenes and Carbenoids in Solution

Source

Carbenoid

)==-(>1)

- v \ " "

BrZC: c12c:

CHBr3/KOBut( - 20 to 0") C H C ~ ~ / K O B-U20 ~ (t o 0')

3.5 6.6

3.2 2.9

(1.0) (1-0)

0.23

FzC: ClFC : BrCH : ClCH :

CFzNzlhv ( 25') (CClzF)zCO/KOBut( - 12") B r C H " ( - 30') C l C H " ( 30") CHzClz/CgHgLi( - 35') T */CHzFz (gas phase) EtO .CO .C H " / h v PhBrCNzlhv (25') PhCHBrz/KOBu*(25') PhCHNNlhv ( - 10") PhCHBrz/CHsLi ( - 10') ArCHNNlhv ( - 10') ArCHBrz/CHsLi ( - 10") ArCHNN/hv ( - 10") ArCHBrz/CHaLi ( - 10') A r C H N N p v ( - 100) ArCHBrzlCHsLi ( - 10')

31.0 1.18 1.20 2.81 2.10 1.8 4.4 1.6 -

6.5 1.18 1.78 1.48 1.8 2-5 1.3 3.6 2.0 2.9 2-1

(1.0) (1-0) (1.0) (1.0) (1.0) (1.0)

0.078 0.14 1.02 0.99 0.91 1.08

(1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0)

0.53 0.29 2.0 1.8 2.1 1.35 2.1 1.8 1.7 1.9

FCT: EtO.CO.CH: PhBrC:

N

-

-

-

-

-

-

Reference

- Skell and Garner, 1956 0.011 DoeringandHenderson, 1958; Moss and Gerstl, 1967a,b - Mitsch, 1965 0.097 0.0087Moss and Gerstl, 1967a, b 1.10 0.75 Closs and Coyle, 1965 1.09 0.74 Closs and Coyle, 1965 0.45 0.23 Closs and Coyle, 1965 1.40 0.73 Tang and Rowland, 1967 - (1.0) Skell and Etter, 1958 - Moss, 1967 0.26 - Moss, 1967; Moss and Gerstl, 1966 0.15 1.1 Closs and MOSS, 1964 1.1 0.59 0.96 Closs and Moss, 1964 0.88 Closs and Moss, 1964 1.3 0.63 Gloss and MOW, 1964 0.50 0.93 Closs and Moss, 1964 1.2 1.0 Closs and Moss, 1964 0.56 1.0 Gloss and MOSS, 1964 0.91 0.56 0.90 Clam and MOSS,1964 0.15

-

200

D . BETHELL

the olefinic and carbene substituent groups have been given. However, these seem ill-conceived without detailed consideration of the constitution of the attacking species, especially since in some cases the ratio is solvent-dependent (Closs and Moss,.1964). The relative reactivities of a series of olefins in addition reactions with a given carbene might be expected to throw light on the nature of the carbene and, in particular, on its electronic state (Skell and Woodworth, 1959). Table 9 contains such values, obtained in competition experiments, for a series of carbenes and carbenoids. I n all cases, the most highly alkylateh double bonds are the most reactive, and this is generally taken to indicate that the attacking species is an electrophile. I n many instances, the range of relative reactivities is quite small, suggesting a rather unselective attacking species. However, no clearly defined pattern of effects of substituents in the carbene emerges from the relative reactivities, even within the closely related group ofp-substituted phenylmethylenes. Steric effects of alkyl substituents attached to the double bonds are clearly evident from the sharp fall in reactivity towards dichloromethylene of terminal olefins, R .CH: CH2, in the sequence R =ethyl > i-propyl > t-butyl (Moss and Mamantov, 1968 ; see also BBzaguet and Bertrand, 1966; Nefedov et al., 1962). Methyl groups attached /3 to the double bond have a much smaller effect. Application of the Hammett pa equation to the related reaction of ethoxycarbonylmethylene with substituted benzenes indicates that here too the carbene behaves as an electrophile of low selectivity (Baldwin and Smith, 1967).

D. Rearrangement The reaction most commonly formulated as involving the rearrangement of a carbene is the Wolff rearrangement of diazoketones to give nitrogen and a ketene as shown in equation (25). The reaction can be R . CO .C(N2)R’ + Nz + R .CO .C. R’ + O=C=CRR’ (25) brought about by photolysis or thermal decomposition of the diazoketone, or by treatment with “ catalysts ” such as silver oxide or benzoate. The analogy between the (singlet) carbene rearrangement and carbonium-ion rearrangements has long been stressed. However, the available evidence for the involvement of carbenes is by no means convincing. The mechanism outlined in equation (25) seems plausible enough in the photolytic and thermal reactions (Franzen, 1957), but the mechanism of the “catalysed’’ rearrangement has yet to be studied in detail. Arguments have been advanced that group migration is syn-

CARBENE CHEMISTRY

201

chronous with loss of nitrogen from the diazoketone (Kaplan and Meloy, 1966). A rearrangement, analogous to that of acylmethylenes proposed in the Wolff reaction, has recently been suggested to account for the production of alkyl aryloxy- or alkyloxyacetates when phenyl or ethyl diazoacetate is photolysed in alcoholic solution (equation 26) (Shafer N2. C H . CO .O R

-

:C H . CO .O R dROCH=C=O

ROE

+ROCHzCO .OR’

(26)

et al., 1966; Chaimovich et al., 1968; Strausz et al., 1968). The presence of a carbonyl substituent on the divalent carbon atom is not essential, however, and, significantly, thioether groups migrate more readily than alkoxy-groups (Robson and Shechter, 1967). a-Sulphonylmethylenes, RSO,CR’, do not appear to undergo rearrangement to sulphenes RR’C=SOZ (van Leusen et al., 1964). to diarylacetylenes The transformation of l,l-diaryl-2-halo-ethylenes on treatment with alkyl lithium or other strongly basic reagents (FritschButtenberg-Wiechell rearrangement) (equation 27) can be formulated as a carbene rearrangement. However, the observation that the arylgroup trans to the vinylic halogen is the one which migrates suggests that the l,s-shift and loss of halogen from the intermediate carbanion are synchronous (for a review, see Kobrich, 1967). Olefins can be con-

verted to alkylidene cyclopropanes under the reaction conditions, as exemplified in equation (28) (Hartzler, 1964; Erickson and Wolinsky, 1965) and carbenes are still sometimes suggested as reaction intermediates. Electron-releasing substituents in the aryl group facilitate rearrangement, but this would be expected whether the 1,2-shiftoccurred at the alkenyl lithium or carbene stage.

Thermal rearrangement of diazoalkanes seems a more reliable source of carbenes, though even here stereospecificityin migration is sometimes observed and routes not involving carbenes may need to be considered (5.W. Powell and Whiting, 1961). Relative migratory aptitudes of aryl groups to adjacent carbene centres have been reported in two structural situations but the results are rather similar. The pattern of migratory

202

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aptitudes accords with the view that carbene rearrangements are similar to some carbonium ion rearrangements. Comparative data are shown in Table 10. The large migratory aptitude of the o-tolyl group seems to suggest that steric strain at the migration origin may be an important contributing factor in the rearrangement of such carbenes. TABLE 10 Relative Migratory Aptitudes of Substituted Phenyl Groups (Ar) in Rearrangements of Carbenes and Carbonium Ions

Intermediate Source

Substituent p-OMe p-Me 0-Me H p-c1 p-NO2

ArCPhz .CH: ArCMez .CPh ArCPhz .CHNN ArCMez .CPh=NNTs (go0) (160")

hCHPh. CHz+ ArCHPh. CHzNHz/HNOa (70-80")

-

1.9a, 1.670 1.36b 4.00'' (1.00)b 1.15b 0.60b

1.9OC (1.00)C 0.67C -

1.446 0.896

Zimmerman and Munch, 1968. Sargeant and Shechter, 1964. C Landgrebe and Kirk, 1967. 6 Ciereszko and Burr, 1952. b

V. CONCLUSION

It should be evident that the study of carbenes is a lively and fertile area of chemical experimentation and speculation. However, even now the body of accepted experimental data is fairly small and fragmentary, and the scope for further investigation vast. I n particular, relatively little seems to be understood about the interaction of the divalent carbon atom with the substituents attached to it and the effect of this interaction on reactivity. REFERENCES Amrich, M. J., and Bell, J. A. (1964). J . Am. Chem.SOC. 86, 292 Anastassiou, A. G. (1966). J . Am. Chem. SOC.88, 2322. Anastassiou, A. G. (1967). J . Am. Chem. SOC.89, 3184. Anastassiou, A. G. (1968). Chem. Comm. 991. Andrews, E. B., and Barrow, R . F. (1960). Nature 165, 890. Andrews, L. (196th). Tetrahedron Letters 1423.

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Milligan, D. E., Mann, D. E., Jacox, M. E., and Mitsch, R. A. (1964). J . Chem. Phya. 41, 1199. Mills, 0. S., and Redhouse, A. (1968). J . Chem. SOC.( A )642. Mitsch, R. A. (1965). J . Am. Chem. Roc. 87, 758. Moore, C. B., and Pimentel, G. C. (1964). J . Chem.Phys. 41,3504. More O’Ferrall, R. A. (1967). Adw. Phys. Org. Chem. 5 , 331. Moritani, I., Mumhashi, S.-I., Nishino, M., Kimura, K., and Tsubomura, H. (1966). Tetrahedron Letters 373. Moritani, I.,Murahashi, S.-I.,Nishino,M.,Yamamoto,Y., Itoh, K., andMatega, N. 89,1259. (1967). J . Am. Chem.SOC. Moritani, I., Murahashi, S.-I., Ashitaka, H., Kimura, K., and Tsubomura, H. (1968). J . Am. Chem.SOC.90, 5918. Moss, R. A. (1967). Tetrahedron Letters 4905. Moss, R. A., and Gerstl, R. (1966). Tetrahedron 22, 2637. Moss, R. A,, and Gerstl, R. (1967a). J . Org. Chem. 32,2268. Moss, R. A., and Qerstl, R. (1967b). Tetrahedron 23, 2549. Moss, R. A., and Mamantov, A. (1968). Tetrahedron Letters 3425. Muller, E., Kessler, H., and Zech, B. (1966). Portschr. C h m . POrsCh. 7, 128. Murahashi, S.-I., Moritani, I.,and Nishino, M. (1967). J . Am. Chem.SOC.89, 1257. Murray, R. W., Trozzolo, A. M., Wasserman, E., and Yager, W. A. (1962). J . Am. Chem.SOC. 84,3213. Nair, R. M. G., Meyer, E., and Griffin, G. W. (1968). Angew. Chem. 80, 442 (Int. Ed. 7, 462). Nefedov, 0. M., Manakov, M. N., and Ivaschenko, A. A. (1962). Izw. Akad. Nauk. S.S.S.R. Otd. Khim. Nauk. 1242. Nickon, A., and Werstiuk, N. H. (1966). J . Am. Chem.SOC.88,4543. Nozaki, H., Noyori, R., and Sisido, K. (1964). Tetrahedron 20, 1125. Nozaki, H., Naksno, M., and Kondo, K. (1966). Tetrahedron 22,477. Nozaki, H., Takaya, H., Moriuti, S., and Noyori, R. (1968). Tetrahedron 24,3655. Overberger, C . G., and Anselme, J.-P. (1963). Tetrahedron Letter8 1405. Overberger, C . G., and Anselme, J.-P. (1964). J . Org. Chem. 29, 1188. Pearson, R. G., and Songstad, J. (1967). J . Am. Chem. SOC.89, 1827. Pottie, R. F. (1965). J . Chem.Phys. 42, 2607. Powell, F. X., and Lide, D. R. (1966). J . Chem. Phys. 45, 1067. Powell, J. W., and Whiting, M. C. (1959). Tetrahedron 7, 305. Powell, J. W., and Whiting, M. C. (1961). Tetrahedron 12, 168. Prinzbach, H., andHartenstein, J.H. (1962). Angew. Chem.74,651 (Int.Ed. 1,507). Prinzbach, H., andHartenstein, J. H. (1963). Angew. Chem.75,639 (Int.Ed. 2,477). Rabinovitch, B. S., Watkins, K. W., and Ring, D. F. (1965). J . Am. Chern. SOC. 87, 4960.

Rees, C. W., and Smithen, C. E. (1964). Adw. Heterocyclic Chem. 3,57. Reimlinger,H. (1962). Angew. Chem.74,153. Reimlinger, H. (1964). Ber. 97,339, 3503. Richardson, D. B., Simmons, M. C., and Dvoretzky, I. (1960). J . Am. Chem. SOC.82, 5001. Richardson, D. B., Simmons, M. C., and Dvoretzky, I. (1961). J . Am. Chem. SOC. 83, 1934.

Richardson, D. B., Durett, L. R., Martin, J. M., Putnam, W. E., Slaymaker, S. C., and Dvoretzky, I. (1965). J . Am. Chem.SOC.87, 2763. Ring, D. F., and Rabinovitch, B. S. (1966). J . Am. Chem. SOC.88, 4285. Ring, D. F., and Rabinovitch, B. S. (1968). J . Phys. Chem. 72, 191. Robaon, J. H., and Shechter, H. (1967). J . Am. Chem. SOC.89, 7112.

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MEISENHEIMER COMPLEXES M. R. CRAMPTON

Department of Chemistry, The University, Durham, England

.

I. Introduction A. Historical Aspects . B. Survey of the Reactions of Aromatic Nitro-Compounds with Bases 11. Structural Studies of the Adducts . A. Adducts from Picryl Ethers . B. Adducts from 1,3,5-Trinitrobenzene. . C. Products from Picramides (2,4,6-Trinitroanilines) . D. Adducts from Other Substituted Trinitrobenzenes . E. Adducts from meta-Dinitrobenzenes. . F. Adducts with Other Compounds 111. Equilibrium and Kinetic Studies . . A. Variation of Reactivity with Substrate Structure B. Variation of Reactivity with the Attacking Nucleophile . C. Effects of Solvent on the Stabilities of the Adducts . References .

.

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

. .

211 211 212 214 215 219 221 233 234 239 241 242 250 252 254

I. INTRODUCTION A. Historical Aspects THE intense colours produced by the addition of bases to solutions of aromatic trinitro-compounds have interested chemists for more than eighty years (Hepp, 1882; Lobry de Bruyn, 1890). These initial colourforming interactions which are reversed by acid are generally followed by slower irreversible nucleophilic substitution reactions. However, early workers found that in favourable cases highly coloured solids could be isolated. Thus Lobry de Bruyn and van Leent (1895)succeeded in separating red crystals with a green lustre by the addition of aqueous base to a solution of 1,3,5trinitrobenzene in methanol, while other crystalline solids were reported from the reactions of alkyl picrates and alkoxides (Jackson and Boos, 1898), 2,4,6-trinitrotoluene and alkoxide (Hantzsch and Kissel, 1899) and 2,4,6-trinitrobenzoic acid and alkoxide (van Leent, 1896). Formulations of the coloured species popular around 1900 include that of Meyer (1894, 1896) as an ion produced by removal of one of the potentially acidic ring-hydrogens and that of Hantzsch and Kissel as addition of base at a nitro-group. However, Jackson and 211

212

M. R . C R A M P T O N

Gazzolo (1900) thought that the intense colours produced from alkyl picrates and alkoxides could be best described by the quinonoid structure 1 (R=R’=alkyl). The first strong chemical evidence that this was indeed the case was provided by Meisenheimer (1902). He obtained identical compounds by the addition of potassium methoxide to 2,4,6trinitrophenetole and potassium ethoxide to 2,4,6-trinitroanisole. Acidification produced in each case a mixture of methyl and ethyl picrates. This led Meisenheimer to the conclusion that these compounds ChN@XOz

H

H NOz.-K+ (1)

+K-02Ny$rz ozN OR

‘

NO2

(2)

OR’

RO

OR’

H

%,/

H

$02

(3)

were formed by the covalent addition of base at C1 to give 1 (R=Me, R’ = Et) ; and he was able to discard the alternative possibilities of base addition at a nitro-group, or at C3 to give the adduct 2 (R = R’ = alkyl). Similar confirmatory measurements were reported by Jackson and Earle (1903) who prepared 1 (R=ethyl, R’=isoamyl) from the two parent ethers. More recently, spectroscopic and crystallographic methods have largely confirmed Meisenheimer’s formula for the stable adducts from alkyl picrates and alkoxides. However the present-day representation would be 3, where the negative charge, which Meisenheimer associated with the para-nitro group, is delocalized about the ring and in the nitrogroups. The alkoxy groups at the sp3-hybridized C1 will lie in a plane perpendicular to the ring. Salts containing cyclohexadienate ions of this and similar types have come t o be known as “Meisenheimer Complexes ”.

B. Survey of the Reactions of Aromatic Nitro-Compounds with Bases Covalently-bound addition complexes have been shown to result from the reactions of a wide variety of aromatic compounds, activated by one or more nitro-groups, with bases or other nucleophilic species. In some cases di-adducts or tri-adducts are also formed by the addition of more than one molecule of base. There is considerable current interest in these adducts and this article will be concerned with their structures and stoichiometries and with the factors governing their stabilities. The second section deals with the spectroscopic and chemical studies which have been used in structural elucidations. Some general principles

MEISENHEIMER COMPLEXES

213

will become apparent in this section, notably that an alkoxy-group in the benzene ring often encourages addition at its position of attachment and that, in the dinitrobenzene series, addition usually occurs para to a nitro group. However, in fact, quite large changes can be brought about not only in reactivity but also in the basic mode of interaction on changing the attacking nucleophile. Similarly, the solvent can have a profound effect and markedly alter the relative stabilities of 1: 1 and 1:2 adducts, the latter being favoured in water relative to other solvents. These effects will be considered in more detail in the third section. . However, owing to the intrinsically high reactivity of aromatic nitrocompounds, a variety of other interactions not involving base addition are also possible. These more general interactions have been reviewed recently (Buncel et al., 1968a): so here it is in place merely to summarize the more important of them. 1. Proton abstraction

Since Meyer’s original suggestion there has been some controversy as to whether the ring-protons of aromatic nitro compounds will ionise in basic media. It has, however, been shown recently that in basic solutions compounds such as 1,3,5-trinitrobenzene and 1,3-dinitrobenzene will exchange ring hydrogens for deuterium or tritium in the solvent (Pollitt and Saunders, 1962; Buncel and Symons, 1966; Crampton and Gold, 1966a). A plausible path for this exchange would be via carbanions such as 4, which would be formed from 1,3,-dinitrobenzene. However, Crampton and Gold have shown that these carbanions, if formed, are

(4)

(5)

present in only small concentration and are not responsible for the colour of these solutions. I n fact, other pathways for exchange may be possible. The possibility of proton loss from a side-chain in compounds such as 2,4,6-trinitroaniline or 2,4,6-trinitrotoluene is discussed later. 2. Electron transfer Another mode of interaction arises from the high electron affinity of aromatic nitro-compounds. This may lead to partial (5) or complete

214

M. R . CRAMPTON

( 6 ) electron transfer from a donor. I n the case of complete electron transfer, radical anions are produced which can be recognized by their electron spin resonance spectra. Such anions have been detected in basic solutions of nitrotoluenes and 1,3-dinitrobenzene (Russell et al., 1962, 1964, 1967). However trinitro-substituted benzenes give small or zero concentrations of radical anions with base owing to the greater stability of the Meisenheimer adducts. Servis (1967) has pointed out that this change in behaviour is consistent with the molecular orbital description of these molecules. Because of the symmetry of the antibonding molecular orbitals, the third nitro-group will greatly increase the stability of the cyclohexadienate-type anion but will not greatly increase the stability of the radical anion. A much weaker chargetransfer interaction (Mulliken, 1952)is thought to be responsible for the colours formed from aromatic nitro-compounds and hydrocarbons or aromatic amines (Weiss, 1942; Briegleb, 1961). 3. Nucleophilic substitution reactions The presence of nitro-groups activates the aromatic ring to nucleophilic substitution and good leaving groups, such as the halogens, are readily replaced. Many studies of these reactions have been made and several reviews written (Bunnett and Zahler, 1951; Bunnett, 1958; Sauer and Huisgen, 1960; Ross, 1963). Strong evidence has been produced that many of these reactions proceed through cyclohexadienate ions of finite stability, such as 7, and in fact the Meisenheimer complexes which are the subject of this review may be particularly stable examples of this general type.

11. STRUCTURAL STUDIESOF

THE

ADDUCTS

Early investigations were based largely on the ability to separate solid. adducts whose composition was determined by analysis. More recently spectroscopic techniques have been used and naturally, in view of the strong colours often produced, visible spectroscopy has proved popular. However this does not in general provide conclusive evidence of the species present. A big impetus to the study of these interactions

MEISINHEIMER COMPLEXES

215

has been given by the application of nuclear magnetic resonance spectroscopy, first described by Crampton and Gold (1964a, b). This technique frequently gives unequivocal evidence of the structures of the species formed and has subsequently been used in many investigations. Some of the structural aspects were previously reviewed by Foster and Fyfe in 1966. A. Adducts from Picryt Ethers 1, With alkoxides Since Meisenheimer’s classical work several different spectroscopic and chemical techniques have been used to confirm his basic formulation of the interaction. The infra-red spectra of the solid salts (Foster and Hammick, 1954; Dyall, 1960) contain the bands typical of ketals expected for structure 3 and are consistent with an increase of negative charge on the nitro-groups relative to the parent ethers. The identity of the visible spectra produced by the addition of methoxide ions to 2,4,6-trinitrophenetole and ethmide ions to 2,4,6-trinitroanisole has been used as evidence that these contain the same complex (3, R =Me, R ‘ = E t ) (Foster, 1955; Gitis and Glaz, 1957). However in view of the fact that the spectra of the systems PicOEt and OEt- in ethanol and PicOMe and OMe- in methanol, which cannot contain the same complex, are indistinguishable (Gold and Rochester, 1964a), this is inconclusive. I n fact, the visible spectra of a variety of complexes symmetrically (R = R’) or unsymmetrically (R # R‘) substituted are all very similar (Foster and Mackie, 1963) with two maxima at c. 4150 A ( E = 28,000 mole-l 1. cm-l) and c. 5000 (E = 19,000 mole-l 1. cm-l). One of the more convincing demonstrations that the structure of the adducts is indeed 3 has come from IH NMR spectroscopy (Crampton and Gold, 1964a). The spectrum of a solution in dimethyl aulphoxide of the solid adduct formed from potassium methoxide and 2,4,6-trinitroanisole shows two bands with intensities representing two and six protons attributed respectively to the ring and methoxyl protons. The resonance due to ring protons at - 8.65 p.p.m. is shifted upfield from the position in the parent anisole ( - 9-07 p.p.m.) while that due to methoxyl protons shows a larger upfield shift from -4.07 to -3.03 p.p.m. (All chemical shifts are quoted relative to internal tetramethylsilane.) The fact that a single band is observed for the six methoxyl protons indicates the equivalence of the methoxyl groups and rules out structures such as 2 (R = R’ =Me). The upfield shift is compatible with the change in hybridization from sp2to sp3 at C1. .Similar spectra have since been obtained for a series of adducts containing various alkoxy groups (Foster et al., 1965; Foster and Fyfe, 1965). A spiro complex derived from glycol, 2,4,6-trinitrophenyl ether has also been reported 8

216

M. R . CRAMPTON

(Murto, 1965). The structure has been confirmed as 8 by the NMR spectrum (Foster et al., 1965) which shows the equivalence of the methylene groups in the complex.

(8 )

(9)

(10)

Zollinger et al. (1967) have made simple Hiickel MO calculations for 2,4,6-trinitroanisole and its methoxide adduct. They find that although the negative charge in the nitro groups increases on complex formation, as expected, the electron density in the ring actually decreases in the negatively charged adduct. The increased screening of the ring protons on complex formation is ascribed to a reduction in the ring current which normally in benzene derivatives causes a shift to low field. Recently crystal structure determinations of the complexes derived from 2,4,6-trinitroanisole and methoxide (Ueda et al., 1967) and 2,4,6trinitrophenetole and ethoxide (Destro et al., 1967)have shown that the two alkoxy groups are indeed identical in the complex and that the plane defined by their oxygen atoms and C1 is orthogonal to the ring. The C6-Cl-C2 bond angle is log", very close to the tetrahedral angle required for an sp3-hybridized carbon. There is then no doubt that the crystalline solids result from addition of alkoxide at C1, and the NMR spectra indicate that no change in structure occurs on solution. However, Servis (1965)made the important observation that, if concentrated sodium methoxide solution was added to a solution of 2,4,6-trinitroanisole in dimethyl sulphoxide, the NMR spectrum initially produced was that of the adduct 9. The spectrum showed two pairs of doublets ( J = 1-2 Hz) due to the spin coupled ring protons with shifts of - 6.17 and - 8-42p.p.m. With time the spectrum gradually changed to that of the thermodynamically more stable C1 adduct (3, R =R'=Me) (see Fig. 1). The conversion of the C3 adduct to the C1 adduct was found to be catalysed by methanol. These conclusions have been confirmed by Crampton and Gold (1966b), who found that the conversion is also catalysed by methoxide ions, suggesting an inter- rather than intramolecular process. I n solutions rich in methanol the rate of conversion is fast so that the NMR spectra obtained initially give no evidence of the C3 adduct. Similar spectra observed by Foster and Fyfe (1965)

217

MEISENHEIMER COMPLEXES

were originally attributed to a di-adduct, 10; however, more recent measurements by the same authors (1966b) have confirmed Servis’s conclusions. These results throw light on the experiments of Ainscough and Caldin (1956), who determined the rates at low temperatures of two reactions

a

b

I

-9.0

I

-8.0

I -7.0

I -6.0

b(p.p.m.1 FIG. 1. NMR spectra (60 MHz), showing ring-proton resonances, of 2,4,6-trinitroanisole plus 0.6 equivalents of sodium methoxide in dimethyl sulphoxide, (a) soon after mixing, (b)after 20 min.

218

M . R. CRAMPTON

between 2,4,6-trinitroanisole and sodium ethoxide using a stopped-flow technique. The slower of the two reactions was thought to give the adduct 3 (R =Me, R' = Et) whereas the fast reaction was attributed to charge transfer. It now seems more likely that the fast reaction studied was the addition of ethoxide ion at C3. Visible spectra of 2,4,6-trinitroanisole in methanol indicate (Gold and Rochester, 1964a; Foster and Mackie, 1963)that at high base concentrations a higher complex is formed. The absorption of the 1:1 adduct 3 (R = R' =Me), with maxima at 4100 and 4900 d is replaced by a single visible band with maximum at 4800 d, attributed to a di-adduct. The probability of this assignment is increased by the observation (Servis, 1967) of two NMR bands with shifts of -6.13 and -8.80 p.p.m., attributed to the ring protons of 10, in solutions of trinitroanisole in dimethyl sulphoxide containing excess sodium methoxide. It is perhaps of interest that, in 1903, Jackson and Earle reported the preparation of a di-adduct from the reaction of trinitroanisole with sodium methoxide in benzene. At very high base concentrations Rochester (1965) and Abe (1966)report that 2,4,6-trinitroanisole is converted into a colourless species, probably the tri-adduct. Calculations (Abe, 1966)indicate that, as is found, the 1: 1 adduct, 3, should have two absorption maxima in the visible regibn, the 1:2 adduct a single visible absorption while the 1:3 adduct should be colourless. 2. With other nucleophiles Azide ions react with 2,4,6-trinitroanisole at temperatures below -10' in aprotic solvents to give an addition complex (Caveng and Zollinger, 1967). The NMR spectrum indicates addition at C1. Similarly it has been found from NMR evidence (Servis, 1967) that diethylamine and triethylamine give adducts at C1 with 2,4,6-trinitroanisole in dimethyl sulphoxide. The latter adduct is unusual in that it is apparently the zwitterion 11. However, addition of triethylamine to Me0

NEts OZN*.

oy$oz H *' .*

.J

H

.................NOZ H sos-

-03s

PjOZ

NOz-

(11)

(12)

the anisole in acetone is reported to result in addition of the acetonate ion (-CH,.CO.CH,) at C3 (Foster et al., 1967). Visible and NMR spectra (Crampton, 1967)indicate that, in aqueous dimethyl sulphoxide, the sulphite ion adds to the 3-position of 2,4,6-

MEISENHEIMER COMPLEXES

219

trinitroanisole, while in water a di-adduct is also formed. The NMR spectrum of the latter shows a single band at - 6.02 p.p.m. for the two ring protons, indicating the structure 12. NMR spectroscopy does then distinguish successfully between the possibilities of base addition at C1 or C3 of 2,4,6-trinitroalkyl ethers. It seems unlikely that a similar distinction can be drawn from the visible spect,ra. Thus the visible spectrum of the methoxide adduct at C3, though not yet published, is said to resemble that of the C1 adduct (Foster and Fyfe, 1966a). Again the visible spectrum of the 1 :1 sulphite adduct, where addition occurs at C3, is somewhat similar to that of a

Wavelength

(8)

FIG.2. Visible spectra in dimethyl sulphoxide of the 1 : 1 adducts of 2,4,6-trinitroanisole formed (a) by addition of methoxide at C1, (b) by addition of sulphite at C3.

typical C1 adduct, though a shift to longer wavelength occurs and the higher wavelength band is less distinct (see Fig. 2). However similar changes are apparent in the spectra of the adducts from 1,3,5-trinitrobenzene with sulphite and methoxide where no diversity of attack is possible. It seems probable that these spectral changes are a function of the attacking nucleophile rather than the position of attack.

B. Adducts from 1,3,5-Trinitrobenzene 1. With alkoxides and hydroxide

Solutions of 1,3,5-trinitrobenzene in methanol containing sodium methoxide are orange-coloured. The visible spectrum with maxima at

220

M. R . C R A M P T O N

TABLE1 Spectroscopic Date for 1:1 Adducts from Alkyl Picrates

Ri

Visible specom Rz

OMe OMe OMe OMe OMe OMe OEt OEt OEt OEt OMe OEt OCH2.CHzO OMe N3 OMe NEtz OMe +NEt3 OMe H

R3

H H H H H H H H H H OMe OMe

Solvent Methanol DMSO Acetonitrile Ethanol DMSO Acetonitrile Acetone Acetonitrile DMSO DMSO DMSO DMSO/Water

Amax(A)

NMR spectrum Chemical shifts (p.p.m.f'

RI

4100, 4860'*0 3.15 4200, 4900d 3.05 4210, 4940' 3.07 4120,4930' -

-

4230, 4960' 4140, 4900 4190,5060

-

_

4.3 3.05 3.08 2.97 3.20

H

Ra

R3

3.15 3.05 3.07

8.85 8.65 8.78

8.85d 8*65'*' 8.7Sd

8.71 8.80 8.70 8.59 8.65

8.71' 8.W 8-70' 8-59' 8.65' 8.64' 8.42' 8*35k

_ -

4.3 -

-

6.17 6.05

-

8.64

-

3.45 4600, 5100 3.85 (ah) - - 4450,6300' CHz.CO.CH3 H OMe Acetone Acetone - 5.32 - 8.35"' CHz.CO.CH3 H OEt a Downfield from tetramethylsilane; * Gold and Rochester (1964a); ' Abe (1966); Crampton and Gold (1964a); ' Servis (1967); f Foster and Mackie (1963); Foster and Fyfe (1965); *Foster et al. (1965); *Zollinger et al. (1967); kcrampton (1967), Crampton (1965); Foster et al. (1967).

sea-

H

4250 and 4950 b is very similar to that of the adducts of picryl ethers with alkoxide and this has suggested an analogous mode of interaction (Foster, 1959) with the formation of the adduct 13. This formula is supported by NMR measurements (Crampton and Gold, 1964a). I n the

parent the three ring hydrogens are equivalent and give only a single resonance (- 9.20 p.p.m.). However, the spectrum of the adduct,

MEISENREIMER COMPLEXES

221

prepared by the method of Lobry de Bruyn and van Leent (1895), in dimethyl sulphoxide solution shows two spin-coupled bands (J = 1.5 Hz)

Wavelength

(1,

FIU.3 (a)

Wovelength

(ti)

FIG.3 (b) FIG.3. Visible spectra of 1,3,6-trinitrobenzene (4 x 10-SM) in methanol containing the followingmolarities of sodium thioethoxide: (a) 1 , 2 4 x 10-4; 2,5 x 10-4; 3 , 2 4 x 10-3; (b) 4, 0.01; 6, 0.036; 6, 0.1; 7, 0.6. These spectra show the conversion of trinitrobenzene to E 1 :1 adduct at low base concentration and 1 :2 adduct at higher base concentrations.

attributed to ring protons. The resonance of the hydrogen at C2 is shifted considerably to high-field (- 6.14 p.p.m.), consistent with the covalency change a t this ring position, while the equivalent hydrogens at C4 and C0 show a smaller high-field shift (to - 8.42 p.p.m.). A band

222

M . R . CRAMPTON

with intensity representing three protons a t - 3-10 p.p.m. is attributed to the methoxyl protons in the adduct. Similar measurements have been described for this and for the ethoxide adduct (Foster and Fyfe, 1965). I n fact, solutions of 1,3,5-trinitrobenzene in methanolic sodium methoxide are unstable and eventually produce 3,5-dinitroanisole (Gold and Rochester, 1964~).This substitution is likely to proceed via structure 14, although this may well represent a transition state rather than a stable adduct. Addition of methanolic sodium methoxide to trinitrobenzene in dimethyl sulphoxide causes a decrease in intensity of the original NMR resonance while new bands due to the adduct are observed. This indicates that exchange of methoxide groups between trinitrobenzene molecules is, on the NMR time-scale, not a rapid process. At high methoxide concentration, bands at - 8.6 p.p.m. (relative intensity 1) and - 6-2 p.p.m. (relative intensity 2) are attributed to the ring protons of the di-adduct 15 (Foster and Fyfe, 1965). A comparative NMR study with thioethoxide and thiophenoxide ions (Crampton, 1968a) indicates the formation of adducts analogous to 13, though the rate of interconversion of complex and unchanged trinitrobenzene is faster than with methoxide. I n methanol solutions thioethoxide ions give 1: 1 and 1: 2 adducts whose visible spectra are shown in Fig. 3. It is of interest that, as with the di-adduct of 2,4,6-trinitroanisole, the 1:2 adduct gives a single absorption in the visible region. Gold and Rochester’s (1964b)study of the interaction with hydroxide ions in water using visible spectroscopy indicated the presence of at least two reversible equilibria. The first, involving 1: 1 interaction, was thought to give the hydroxide adduct, analogous to 13. Addition of aqueous sodium hydroxide to trinitrobenzene in dimethyl sulphoxide (DMSO) gives NMR bands characteristic of a 1: 1 adduct confirming the nature of the interaction (Crampton, 1965). The second interaction in water is likely to produce a di-adduct. 2 . With aliphatic amines The interaction of 1,3,5-trinitrobenzene with aliphatic amines has been studied in a variety of solvents and often gives highly coloured solutions. Arguments have been cited by various groups of workers in favour of interactions involving 1,2,3 and even four amine molecules per molecule of nitro-compound. Lewis and Seaborg (1940) postulated the formation of a zwitterion 16, and the more intense colour formed with ammonia and primary amines than with secondary or tertiary amines was accounted for by increased hydrogen-bond stabilization, as in 17.

02No

223

M E I S E N H E I M E R COMPLEXES

.......*.

..---

0 2

H\+,H.* 0 0,4 N yRN . q NH\ o - lo

-

*-''...~'"H NO%

(16)

H

' H

NO2 (17)

o z yH+

NR2 oz,+HaR2

*-.* i

H

NO2

(18)

Interactions similar to 16 have been invoked to account for the colour formation in dioxane (Foster et al., 1953; Labes and Ross, 1956), chloroform (Foster, 1959b) and ethanol (Foster and Mackie, 1961). Miller and Wynne-Jones (1959) distinguished between the rather weak charge-transfer interaction thought to result from reaction with aromatic amines, and the stronger interaction with aliphatic amines which was considered to give complete electron transfer. Although weak electron spin resonance signals have been observed in some solutions (Miller and Wynne-Jones, 1960), these probably result from side reactions. Briegleb et al., (1960) interpreted the reaction between piperidine and trinitrobenzene as forming a weak charge-transfer complex and also a pair of ions, 18, the cyclohexadienate adduct being responsible for the visible absorption. Similarly the interaction in liquid ammonia has been considered to produce ionic species (Farr et al., 1949; Foster and Mackie, 1962a). I n fact the particular interaction occurring probably depends on the solvent used. Thus Crampton and Gold (196513, 1967) showed that, in the ionizing solvent DMSO, negatively charged adducts, 18, were produced from primary and secondary amines and ammonia. In agreement with this formulation the stoichiometry of the interaction was found to be 2 amine :1trinitrobenzene and the solutions were electrically conducting. The NMR spectra, with bands at - 8.50 and - 5.60 p.p.m., relative intensities 2 to 1, and visible spectra, with maxima at 4500 and 5300 A, were similar to those of the methoxide adduct of trinitrobenzene. However, tertiary amines did not affect the NMR spectrum of trinitrobenzene or give conducting solutions, and the small amount of visible absorption was attributed to primary or secondary amine impurities. Similarly NMR spectra indicate that the adduct 18 ( R = E t ) is initially formed when diethylamine is added to trinitrobenzene in acetone (Foster and Fyfe, 196613). A kinetic study, again using diethylamine, in acetone-ether (Allen et al., 1961) indicated that the reaction was second order in amine; again evidence for 18. The formation of this type of adduct probably involves two steps, an initial loose attachment of an amine molecule to give a species such as

224

M. R . URAMPTON

16, followed by proton abstraction from the added amine by a second amine molecule (Crampton and Gold, 1967). This scheme would appear to be preferable to direct attack of an atnide ion, formed by autoprotolysis, on trinitrobenzene. Thus in ionizing solvents covalent adducts are formed, and the visible spectrum showing two absorption maxima is probably characteristic of this type of interaction. The interaction in chloroform (Foster and Mackie, 1961) where similar spectra were observed and also in dioxane is probably of the same type. However ion-pairing and further ionic association will be more important in these solvents and stoichiometries of 1 trinitrobenzene :3 amine which have been observed may be explicable in terms of ion solvation by the extra amine molecule. I n protic solvents the interaction is complicated by the possibility of the production of anions from the solvent (NR, + ROH + NHR8++ OR-) which may themselves complex with trinitrobenzene. The interaction in inert solvents such as cyclohexane (Liptay and Tamberg, 1962; Foster and Mackie, 1962b) appears to give only rather weak chargetransfer complexes. These give rise to absorption in the ultra-violet rather than the visible region of the spectrum. 3. With other nucleophiles Hepp (1882) and Hantzsch and Kissel (1899) reported the isolation of violet crystals from solutions of 1,3,5-trinitrobenzene containing potassium cyanide. Meisenheimer (1902) interpreted these results as addition of a cyanide ion to give an adduct which can be represented by 19. More recently spectroscopic studies in a variety of solvents have similarly been interpreted as indicating the formation of a covalentlyH

zo$ f ,N~O

H

CN

:.........-. H iOZ (19)

o z NH g NCHzCOR o z H

s''......*''d 5

H

CHzCOR o z N O N O 2

H

' H

NOz

NO2

(20)

(21)

bound adduct (Foster, 1955; &ta and Beranek, 1958; Norris, 1967b; Buncel et al., 19680). The visible spectrum shows two absorption maxima and is similar to that of the adducts with alkoxides. Trinitrobenzene will also form adducts with carbanions generated from ketones. Thus Kimura (1953)reported that reaction with acetone or acetophenone in the presence of alkali gave dark crystalline needles and suggested structure 20. Evidence for this structure was provided

MEISENHEIMER COMPLEXES

225

by the observation that oxidation using hydrogen peroxide under acid conditions gave the corresponding picryl ketones, 21 (R = Me, Ph). Further chemical evidence for 20 has come from hydrogenation studies by Severin and Schmitz (1963). I n addition the NMR spectrum of the potassium methoxide adduct of trinitrobenzene dissolved in acetone gradually changes with time indicating acetonolysis to 20 (Foster and Fyfe, 1965). The resonance of the proton at C2 is at - 5-20 p.p.m. and is split into a triplet ( J = 9 Hz) through coupling with the adjacent methylene protons. Similar products can be obtained by the addition of tertiary amines to solutions of trinitrobenzene in a variety of ketones (NR, + CHRCOR’ + -CRCOR’ +NHR,+) (Foster and Fyfe, 1966c; see also Foster et aE., 1968; Fyfe, 1968b). The reaction with aqueous sodium sulphite is unusual in that the dark red crystals which separate have a stoichiometry of 1 trinitrobenzene: 2 sodium sulphite (Henry, 1962). I n fact in aqueous solutions both 1:1and 1:2 complexes are formed depending on the concentration of sulphite. At low concentration the visible spectrum is reminiscent of other 1:1 adducts (Cfita and Beranek, 1958; Norris, 1967a) while at higher sulphite concentrations the spectrum shows a single broad absorption with maximum at 4900 A (Crampton, 1967) attributed to the 1:2 complex. These spectra are similar to those found using SEtas the reactive anion. The NMR spectra of the adducts with sulphite confirm that these result from the covalent addition of sulphite at one or two ring carbon atoms carrying hydrogen. The colours produced in solutions of iodide or bromide ions (Briegleb et al., 1962) or thiocyanate ions (Crampton, 1968b) almost certainly result from a rather weak charge-transfer interaction rather than covalent-bond formation. The spectral data for a variety of 1: 1 and 1:2 adducts are collected in Table 2. As with the adducts from picryl ethers the visible spectra of 1:1 adducts from trinitrobenzene show two visible maxima whereas the 1:2 adducts have a single rather broad visible absorption. The NMR spectra of the 1:l adducts show, typically, two bands due to ring protons, often exhibiting spin-spin coupling, at c. -8.4 (relative intensity 2) and - 6.0 p.p.m. (relative intensity 1). The position of the low-field band shows little dependence on the nature of the added group,

226

M. R . C R A M P T O N

TABLE2 Spectral Data for Adducts from 1,3,5-Trinitrobenzene H

It

NMR spectrum" spectrum

R

Solvent

hmsx(A)

OMe

Methanol

4250,4950

OMe

DMSO

4300,5100

OEt OEt OH

Ethanol DMSO Water

4240,4970 4450,4850

OH SEt

Water-DMSO Dimethylformamide

4650,5700

SEt SEt SPh SPh NHz

Methanol Methanol-DMSO Methanol DMSO Ammonia

4600,5500 4640,5600 4700,5800 4600,5230

NHz

DMSO

4540,5420

NHMe

DMSO

4520,5380

NMEz

DMSO

4500,5280

NEt2

DMSO

4480,5260

NCSHIO

DMSO

4480,5250

NC5HlO NHMe

Acetonitrile Chloroform

4440,5210 4500,5450

CH2. CO .CH3 CH2 .CO .R CH2 .CO . R CHMe CO R CN

Acetone Methanol DMSO DMSO Chloroform Water Water-DMSO

4640,5720 4650,5520

. .

803-

sos-

4370,6550 4620,5300 4740,5500

C4,&

C2

-

Reference

Gold and Rochester (19640) 8.42 6.14 Crampton and Gold (1964a) Buncel et al. (1968a) 8.41 6.26 Foster and Fyfe (1965) Cdta and Piseckjr (1957) 8.20 6.00 Crampton (1965) Poliitt and Saunders (1965) Crampton (196th) 8.32 5.75 Crampton (196th) Crampton(l968a) 7.45* Crampton (196th) Foster and Maokie (1962a) 8.32 5.52 Crampton and Gold (1967) 8.46 5.68 Crampton and Gold (1967) 8.50 6.60 Crampton and Gold (1967) 8.47 5.68 Crampton and Gold (1967) 8.46 5.55 Crampton and Gold (1967) . Briegleb et al. (1960) Foster and Mackie (1961) 8.45 5.18 Foster and Fyfe (1965) Foster and Fyfe (1966~) 8.35 5.05 Foster and Fyfe (1966~) 8.45 5.30 FosterandFyfe (1966c) Norris (1967b) Crampton (1967) 8.30 6.00 Crampton (1967)

227

MEISENHEIMER COMPLEXES

TABLE&continued H

R

NMR spectrums spectrum R OMe SEt

so3-

Solvent

Anmx(A)

CZ,c4

Methanol-DMSO Methanol Water

-

6.15

5100 4900

CS

Reference

8.60 Foster and Fyfe (1966) Crampton (1968a) 8.60 Crampton (1967)

6.05

0

Chemical Shifts, dowdeld from tetramethylsilane.

b

Single band due to rapid exchange of SPh- between trinitrobenzene molecules.

R. However there is some correlation of the position of the high-field resonance with the electronegativity of the added group. The spectra of the 1 :2 adducts are similar to those of the 1 :1 adducts though, of course, the relative intensities of the high-field and low-field bands are reversed. Although cis-trans isomerism of the type shown in structure 22 is, in principle, possible no evidence for this has yet been obtained.

C. Products from Picramides (2,4,6-Trinitroanilines) 1. With alkoxides and hydroxide Picramide and its N-substituted derivatives introduce the added complication that proton loss may occur from the amino-group to give the Bronsted bases 23 ( R = H , alkyl, phenyl). Green and Rowe (1913) found support for this formula from the alkali metal analyses of the solids formed from many polynitroanilines with bases. I n fact picramide itself has been frequently used as an indicator for establishing H-acidity scales in basic media on the assumption that its indicator behaviour is due t o proton loss (Schaal, 1955;Stewart and O'Donnell, 1962;Stewart et al., 1962). The most likely other alternatives for the products of 1 : 1 interaction of picramides with bases are 24 and 25 (R = H, alkyl, phenyl ; R' =R" = H, alkyl). Formula 24, the analogue of Meisenheimer's formula for the adducts of picryl ethers, was suggested by Busch and

228

M . R. C R A M P T O N

Kogel (1910) for the solids prepared by the action of alcoholic alkali on secondary amines and by Farmer (1959) for the potassium methoxide adduct of picramide. However Gold and Rochester (1964d),who made

a careful equilibrium and kinetic study using visible spectroscopy, suggested formula 25. They found evidence for the production of both ions 25 (R =R" = H, R' =Me) and 23 (R = H) from picramide in methanolic sodium methoxide, whereas 25 (R = R' = R" =Me) was formed from N,N-dimethylpicramide. The visible spectra of the latter compound also indicated the formation of a higher, probably 1 :2, adduct. Similar measurements with sodium hydroxide in water (Gold and Rochester, 1964e) indicated that N,N-dimethylpicramide was unusual in that only a 1:2 complex was formed. Demonstrations of the correctness of these latter formulations have come from NMR measurements. The addition of methanolic sodium methoxide to N,N-dimethylpicramide in dimethyl sulphoxide causes the replacement of the initial resonance due to ring protons in the parent at -8.84 p.p.m. by two bands at -8-46 and -6-17 p.p.m. each representing one proton and showing spin-spin coupling (J=1.5 Hz) (Crampton and Gold, 1964b). This clearly indicates the addition of base at C3 to give 25 (R = R' = R" =Me). I n solutions containing excess methoxide a single band representing two ring-protons at - 6.05 p.p.m. is attributed to the di-adduct 26 ( R = R ' = R " =Me). Similar changes accompany the addition of hydroxide in aqueous dimethyl sulphoxide indicating the formation of 1:1 and 1:2 adducts. The NMR spectra of picramide itself indicate two modes of ionization ; the formation of an adduct at C3 to give 25 ( R = R " = H , R'=Me) is shown by two doublets at -6.14 and -8.61 p.p.m., while proton loss t o give 23 ( R = H ) is shown by a shift to high field of the original band due to ring protons (Crampton and Gold, 1964b, 1966b; Servis, 1965, 1967). Picramide and its Bronsted base are rapidly interconverted by a proton transfer so that in solution containing both species a combined resonance is obtained due to time averaging of the two types of ring protons. The proportion of proton loss occurring depends to some extent on the solvent, though in an equimolar mixture of methanol and

229

MEISENHEIMER COMPLEXES

dimethyl sulphoxide the figure is 20% and this decreases as the amount of methanol in the solvent increases. I n the analogous system with ethoxide ion slightly more proton loss occurs while with the bulkier t-butoxide ion, proton loss is dominant. Farmer (1959) argued in favour of 24 since he obtained the same product from the reaction of picramide with potassium methoxide or 2,4,6-trinitroanisole with ammonia. However, in fact, the anisole is quickly converted into picramide by ammonia (Crampton, 1965) so that both products will result from addition of methoxide to picramide to give 25 (R= R"= H, R' =Me). *

$qH ozN@/o' NRR"

............NO2

OZN.

R'O

OR' NO2(26)

N/Me

-NR

H

OR'

"'*

ozNQ

_. ...........

GO2

NOz

(27)

(28)

02

H

The proportion of conjugate base, 23, to adduct, 25, increases in the series picramide, N-methylpicramide, N-phenylpicramide (Crampton and Gold, 1965a, 1966b; Servis, 1965, 1967). The phenyl group has the expected acid-strengthening effect on the adjacent amino proton and the ion 23 (R =Ph) results exclusively from 1:1 interaction. I n the presence of excess methoxide in dimethyl sulphoxide the dianion 27 (R= Ph, R'=Me) is formed. With N-methylpicramide base addition and proton loss occur though the latter is favoured. Servis has shown that in the anion 28 rotation about the nitrogen-ring carbon bond is restricted so that distinct NMR signals are observed for the nonequivalent ring-protons. At higher methoxide concentration 27 (R =R'=Me) is formed. 2. With other nucleophiles A recent study (Crampton, 1968a) of the reactions of picramides with sodium thioethoxide and thiophenoxide indicates that the sulphur bases have a greater tendency to form adducts analogous to 25 than to abstract an amino proton. Thus picramide with sodium thioethoxide in methanol-dimethyl sulphoxide gives the adduct 29 and there is no detectable proton loss to give the conjugate base. The NMR spectrum shows in addition to the two bands due to ring protons, two bands due to the non-equivalent amino protons (see Fig. 4). These are shifted downfield from the position in picramide consistent with the strengthened hydrogen-bonding of the amino-protons with the ortho-nitro

a

h3

w

0

I b

I

-10

I

-9

1

-0

I

-7

I

-6

I

p.p.m.

FIG.4. NMR spectra (60 M E k ) of picramide in methanol-dimethyl sulphoxide containing sodium thioethoxide. Ratio [EtS-]/[Picramidel is (a) 0.75, (b) 1.0. The ring and amino-protonsof the parent absorb at -9.07 p.p.m. and -9.0 p.p.m. respectively, the other bands are due to the adduct, 29. (Crampton, 1908a.)

231

MEISENHEIMER COMPLEXES

groups expected in the negatively charged adduct. Similarly 1 :1 and 1 :2 adducts are formed from N-methylpicramide by addition at one or two ring-carbons carrying hydrogen. The visible spectra of aqueous solutions of various picramides containing sodium sulphite indicate the presence of two reversible equilibria, (Crampton, 1967). The NMR spectra show that these result from addition of sulphite at one or two ring carbons carrying hydrogen. As with the thioethoxide adducts, distinct resonances are observed for the amino protons in t,he 1 : 1 adducts. The complexes derivedfrom N-methyl and N-phenylpicramides show only a single amino-proton resonance (at - 10.90 and .- 12.25 p.p.m. respectively) suggesting that only one of the possible isomers, 30 or 31, is present in appreciable concentration. TABLE 3 NMR Data for Adducts from Picramides

H

.......-........NO2

....*.......*...-NO?

@:,

0zN.v

OzN H+ ,;

R'

NOz-

NO2 Chemical shifts of ring protonsarb

R

R"

R'

1: 1 adduct

1:2 adduct

6.05

Me

Me

OMe

6.17, 8.46

Me

Me Me

Et Me H H H H H H H H H H H H H

Et Me

OMe OH OMe

sea-

6.18, 8.49 6.1, 8.4 6.28, 8.50 6.15, 8.35 6.14, 8.61 6.09, 8.48 6.08, 8.40 5.73, 8-47 7.10d 6.10, 8.38 6.19, 8.61 6.16, 8.48 6.18, 8-50 6-16, 8.48 6.00, 8.40 6.15, 8.30 6.17, 8.38

CH2.CO.Me

5.35,8.37

Me

Me Me

H H H H H H H Me Me Me Me Me Ph Ph

Me

SO3-

OMe OMe OH SEt SPh

sosOEt OMe OMe

OH SEt

SOBSOa-

-

Reference

Crampton and Gold (1964b, 1966b) 6.04 Servis (1967) 6.0 Crampton and Gold (1966b) Servis (1967) 6.26c Crampton (1967) Crampton and Gold (1966b) Servis (1967) Crampton and Gold (1966b) Crampton (1968a) Crampton (1968a) 6.17c Crampton (1967) Crampton (1965) Crampton and Gold (1966b) Servis (1967) Crampton and Gold (1966b) 6.00 Crampton ( 1 9 6 8 ~ ) 6.07, 6.20C Crampton (1967) 6.26c Crampton (1967) 6.20, 6.28c Crampton (1967) Foster et al. (1967)

232

M. R . CRAMPTON

TABLE 3-continued -NR

R

R'

H Me Me Ph Ph Me H

-

a

OMe OH OMe OMe OMe OMe

NR

Chemical shifts of ring protonsavb 8.46 8.43 8.55, 8.25 8.36 8.37 8.54, 8-20 8.37

6.10, 8.64 6.2, 8.6 6.18, 8.68 6.17, 8.71 6-16, 8.70 6-06, 8.67

Reference Crampton and Gold (1966b) Crampton and Gold (1966b) Crampton and Gold (1966b) Crampton and Gold (196613) Servis (1967) Servis (1967) Servis (1967)

Downfield from internal tetramethylsilane. The solvent consists of dimethyl sulphoxide containing a little alcohol or water. Solvent is water. Fast exchange of thiophenoxide ions between adducts.

The di-adducts show a band or bands at ca. - 6-20p.p.m. with intensity representing two protons. I n the absence of an unsymmetrical substituent at C1 this resonance is a single peak. Thus, as with the di-

233

MEISENREIMER COMPLEXES

adducts from 1,3,5-trinitrobenzene, there is no evidence of formation of cis-trans isomers. NMR spectral data for the ring-protons of various adducts are collected in Table 3.

D. Adducts from Other Xubstituted Trinitrobenxenes 1. Picric acid Because of its high acidity picric acid exists in dilute sodium hydroxide 3600 A). As the concentration of solution as the picrate ion (A,,,, sodium hydroxide is increased, this absorption is gradually replaced by a more intense band (A,,,, 3900 A) which has been attributed by Abe (1960) to 33. Gold and Rochester (1964f) found that the extent of conversion of the picrate ion to complex depends on a high power of base concentration, suggesting that the interaction probably involves more than one hydroxide ion. Evidence that this is the case and that the structure of the complex is in fact 34 has recently been obtained from -0 OH O 2 N q N o 2 H

'%.

:

PjOZ

(33)

H

'..'**..........-NOz

OzN H@H

2 ;@: 0

HO

OH

so3-

-03s

NO2-

NOz-

(34)

(35)

NMR measurements (Crampton and Ghariani, 1968). The resonance due to ring protons which occurs at - 8.8 p.p.m. in the picrate ion is shifted strongly upfield to - 6.1 p.p.m. in concentrated sodium hydroxide solution, indicating a covalency change at both C3 and C5. I n aqueous sodium sulphite solutions the visible spectra indicate the presence of two species in addition to the picrate ion (Crampton and ) visible Ghariani, 1968). At high sulphite concentrations ( > 0 . 5 ~ the spectrum is similar to that in sodium hydroxide solutions (A,,,, 3900 A) and the NMR spectrum shows a band at - 6.17 p.p.m. which is tentatively attributed to the ring protons of structure 35. This anion would be unusual in that it would carry five negative charges. I n solutions containing less sulphite an adduct thought to be formed by addition at C3 is also present. Changes in visible spectra similar to those observed in the presence of aqueous sodium sulphite are observed in solutions containing sodium methoxide in methanol (Rochester, 1965) probably indicating addition of one and two methoxide ions at ring carbons carrying hydrogen.

234

M. R. CRAMPTON

2. 2,4,6-Trinitrotoluene Hantzsch and Kissel (1899) reported the preparation of a violet solid, from the reaction of potassium methoxide with 2,4,6-trinitrotoluene, whose analysis correspond to a monohydrated addition complex. A recent attempt to repeat this preparation was unsuccessful (Crampton, 1965). In fact the violet colour produced in alkaline alcoholic solutions has frequently been attributed to the 2,4,6-trinitrobenzyl anion (Caldin and Long, 1955; Blake et al. 1966). The visible spectrum shows maxima at 3700 and 5100 d and does not closely resemble that of the adducts from 1,3,5-trinitrobenzene. If the anion formed does in fact result from proton loss from the methyl group then hydrogen exchange of these protons with the solvent in basic media should be detectable. There are conflicting reports of the efficiency of such exchange. Miller and WynneJones (1959) and Buncel et al. (1968b) found that exchange occurs fairly rapidly, though Bowden and Stewart (1965) could detect no exchange in alkaline aqueous dimethyl sulphoxide. NMR measurements in methanolic dimethyl sulphoxide are inconclusive (Crampton, 1965; Servis, 1967),probably owing to the production of small concentrations ofradical anions (Russell and Janzen, 1962)which wipe out the spectrum. Present evidence suggests, on balance, that the violet colour produced in alcoholic media is due to the 2,4,6-trinitrobenzyl anion, though adducts formed by the addition of alkoxide, or the 2,4,6-trinitrobenzyl anion itself, to 2,4,6-trinitrotoluene may be produced in some circumstances. Colours have also been noted from the reaction of 2,4,6-trinitrotoluene with sodium sulphite in water (Muraour, 1924; Norris, 1967a) and these almost certainly result from sulphite addition at one or more ring carbon atoms carrying hydrogen (see Crampton, 1967). Similarly the visible spectrum of trinitrotoluene in alkaline acetone (Gitis et al., 1959) showing maxima at 4620 and 5320 A probably indicates addition of the acetonate ion at a ring carbon carrying hydrogen. Recent NMR results (Buncel et at., 19680)show that cyanide ion adds at the 3-position.

E. Adducts from meta-Dinitrobenzenes 1. With alkoxides

I n agreement with expectation and as predicted theoretically (Abe, 1964) a reduction in the number of nitro-groups activating the benzene ring causes a decrease in the tendency to form covalent adducts. However solids may sometimes be isolated, notably from dinitroanisoles. There seems to be general agreement that these result from addition of base at the ring carbon carrying the methoxyl group to give species analogous to Meisenheimer’s adducts from picryl ethers. Thus Gitis

235

MEISENHEIMER COMPLEXES

et al. (1958, 1959) found that the addition of alkoxides to 2,4-dinitrophenyl ethers in benzene produced strongly coloured solutions which on addition of water gave a mixture of ethers, and postulated the formation of the adducts 36 (R=R’=alkyl, X=H). They were able (1963) to separate red solids from the addition of various alkoxides to 2,kdinitroanisole. Similarly 2,6-dinitroanisole gave red crystals with potassium methoxide in benzene which were thought to have structure 37 (R=R’=Me, X = H ) . Pollitt and Saunders (1964) examined the HzC-CH2 RO

OR’

RO

(36)

0

1

0

H

H No2

I

OR’

x (37)

No2

(38)

visible spectra of a variety of 2,4-dinitro-6-X-anisoles and 2,6-dinitro4-X-anisoles (X=OMe, H, C1, COz-, CONH,, CO,Me, CN) in the presence of sodium methoxide. In general two bands are present. The band at shorter wavelength occurs in the region 3500 to 4000 ,.& for both types of compound. However the longer-wavelength band occurs in the range 4800 to 6300 A for the adducts from the 2,4-dinitroanisole and in the range 5350 to 6120 ,.&forthose from the 2,6-dinitroanisole. A general feature is the shift of this latter band to lower wavelength as the electronegativity of the substituent, X, increases. The two series converge in 2,4,6-trinitroanisole (X = NO2) and the spectral similarities to the Meisenheimer adduct of this compound led Pollitt and Saunders to favour the analogous structures 36 and 37 for the dinitro compounds. I n addition they interpreted the observation (Gitis and Kaminskii, 1960) that glycol-2,4-dinitrophenylether has an absorption at 4930 A in basic solution as formation of the spiro complex 38. Confirmation that addition occurs at C1 in 2,4-dinitroanisole has come from NMR spectroscopy (Crampton and Gold, 1965a, 196613; Foster and Fyfe, 1965). Thus on the addition of methanolic sodium methoxide to solutions of the anisole in dimethyl sulphoxide, the band due to methoxyl protons in the parent (at -4.10 p.p.m.) doubles in intensity and shifts to high field (to -2.94 p.p.m.). This confirms the identity of the methoxyl groups in the complex. The bands due to ringprotons show only small shifts to high field and the spin-spin coupling constants are not affected, indicating that no covalency change occurs at a ring carbon carrying hydrogen. Similar spectra have been observed from the solid salts dissolved in dimethyl sulphoxide (Byrne et al., 1967).

236

M. R . CRAMPTON

The changes in NMR spectrum with time in solutions containing excess sodium methoxide which were attributed to the formation of a di-adduct (Foster and Fyfe, 1965) have since been shown to be due to the production of the 2,4-dinitrophenolate ion (Crampton and Gold, 1966b; Foster et al., 1967). This is probably formed by the attack of hydroxide ion produced from traces of water in the solvent. The NMR spectrum of the adduct from glycol-2,4-dinitrophenylether and base has been carefully analysed (Griffin et al., 1967). The four methylene protons give an A2B2pattern consistent with the spiro structure 38. Similarly, confirmation that addition to 2,6-dinitroanisole occurs at C1 has come from NMR spectroscopy. I n the spectrum of the adduct the AX2 pattern of the ring protons, which is present in the parent, is preserved, indicating structure 37 (R = R' =Me, X = H). Again NMR measurements have confirmed that addition occurs at C1 in the methoxide adducts of 2,4-dinitro-6-cyanoanisole(Zollinger et al., 1967) and 2,6dinitro-4-cyanoanisole (Dickeson et al., 1968). The visible spectra of several dinitroanisoles in methanol containing high concentrations of methoxide ions have been interpreted as showing the formation of diadducts (Rochester, 1965; Terrier et al., 1965). 1,3-Dinitrobenzene itself gives a red solution in methanolic sodium methoxide (Crampton and Gold, 1966a) with absorption maximum at 5160 8. Although hydrogen exchange is known to occur at the 2position and free radicals have been reported in similar media (Russell et al., 1964), these are probably side reactions and the colour almost certainly results from a covalently-bound adduct. NMR measurements are inconclusive probably because of the presence of small concentrations of species containing unpaired electrons. However, comparison of the position of the absorption maximum with Pollitt and Saunders's results argues in favour of the adduct of C4, 39, rather than the C2 adduct. Similarly Pollitt and Saunders (1965) found that the positions of the visible absorption maxima of a variety of 5-substituted 1,3Hy$H

OMP O2

HfJo2

COzMr

_. H

e"'.

''"2 1;

ri0, (39)

H

MeOzC

\ NO2 (40)

H

H@/
H

OR

"'%

ioz (41)

dinitrobenzenes indicated addition at C4. It is interesting that they (40) gives report that 1,3-dinitro-4,-6-di(methoxycarbonyl)-benzene with sodium methoxide in dimethylformamide an absorption at 6200 A,

237

MEISENHEIMER COMPLEXES

TABLE 4 Spectral Data for Adducts from Dinitroanisole6 RO

R

X

R'

spectrum hmax(A)

OR'

NMR spectrum"

Ha

H5

He

-

Me

Me

H

5030

Me Me

Me Me

H H

5060

-

8.68 8.65

7.26 7.25

5.09 5.18

Et Et OCHz CHzO

H H

-

8.68

-

7.21

5-10

4930

OCHz .CHzO Me Me

H CN

-

8.55

4780

Me Me

Me Me

CN OMe

4690 5300

Me

Me

Me

5180

-

Me

Me

coz-

5050

-

R

R'

x

.

~

Me Me Me Me OCHBCHZO Me Me Me Me Me Me Me Me

spectrum

-

8.74

-

-

-

6.83

-

5.30

-

8.29

_

-

Pollitt and Saunders (1964) Foster et al. (1967) Crampton and Gold (1966b) Byrne et al. (1967) Gitis and Kaminskii (1960) Griffin et al. (1967) Pollitt and Saunders (1964) Zollinger et al. (1967) Pollitt and Saunders (1964) Pollitt and Saunders (1964) Pollitt and Saunders (1964)

NMR spectrum"

__

Reference ~

H H H CN Me COZCN

Reference

~

5680

-

5312 6260 5880 5350

-

-

7.93 7.67 8.03

5.02 5.09

-

-

-

Pollitt and Saunders (1964) Foster et al. (1967) Foster et al. (1967) Dickeson et al. (1968) Pollitt end Saunders (1964) Pollitt and Saunders (1964) Pollitt and Saunders (1964)

Chemical shifts measured downfield from tetramethylsilane.

238

M. R . CRAMPTON

attributed to the adduct at C2. However the spectrum quickly changes to give a maximum at 5050 8, attributed to the methoxide adduct at C4. Acidification gave the starting material. This appears to be one of the few examples of methoxide addition between the nitro-groups in 1,3-dinitrobenzene and even here it does not result in a thermodynamically stable product. 2,4-Dinitroaniline and 2,4-dinitrodiphenylamine ionize in methanolic dimethyl sulphoxide by proton loss from the amino group (Crampton and Gold, 1964b, 196613). The bands due to ring protons in the NMR spectrum move to high field without change in pattern in the presence of base, consistent with fast exchange between the parent and Bronsted base. Similar spectra are produced on the addition of one equivalent of base to 2,4-dinitroaniline in liquid ammonia (Birchall and Jolly, 1967). However, interestingly, the dianion, 41, is formed in the presence of excess base. The resonance of the proton at C3 shows a large upfield shift from - 8.83 to - 5-24 p.p.m., while a band is observed at - 11.25 p.p.m. due to the amino-proton resonance. Changes in visible spectra in methanol containing high concentrations of sodium methoxide may also indicate the presence of this adduct (Rochester, 1965). 2. With carbanions The reaction of 1,3-dinitrobenzene with alkaline acetone to give a purple-coloured solution was noted as early as 1886 by Janovsky and Erb and is now known as the “Janovsky reaction”. Since then strong colours have been observed from a variety of active methylene compounds and the reaction is used as a test for them. Much of the literature has been summarized by Canback (1949a, 1949b), who suggested the structure 42, and more recently by Pollitt and Saunders (1965). Chemical and spectroscopic evidence is in support of formula 42 and dark purple crystals have been prepared (Gitis and Kaminskii, 1963, 1964; Kimura et al., 1965). Oxidation with hydrogen peroxide in acidic

H a COR

I

“@No2

H

CHzCOCH3

.....-...-.. Go2 (42)

H

....,..-.i

o2

x

5\

3

NOz

H

(43)

(44)

NO2

solutions gives 2,4-&nitrobenzyl methyl ketone. Similarly the NMR spectrum produced by the addition of base to dinitrobenzene in acetone-

239

MEISENREIMER COMPLEXES

dimethyl sulphoxide indicates the presence of 42 with no indication of the formation of the isomer produced by addition at C2 (Foster and Fyfe, 1967). An apparently similar reaction has been described by Zimmerman (1935, 1936). However, here the dinitrobenzene is used in excess and the solvent is ethanol. It has been shown that the colour in these solutions results from anions such as 43 (Neunhoeffer et al., 1961; King and Newall, 1962)which are derived from the initially formed Janovsky adduct by oxidation with the excess nitro-compound. As would be expected, electron-withdrawing substituents at the 5-position in 1,3-dinitrobenzenes increase the tendency to give coloured solutions in the Janovsky reaction. Thus Akatsuka (1960) was able to isolate purple crystals from the reaction of 44 (X = SOs-, C02-) with acetophenone or acetone in the presence of base. Chemical evidence showed that these resulted from addition at C4. Pollitt and Saunders (1965) found that, in general, the visible spectra of these solutions showed two maxima. They attributed the band at shorter wavelength to the C4 adduct and that at higher wavelength t o the C2 adduct. The former usually predominates. However the presence of substituents at either C2 or C4 and C6 appears to inhibit addition at these positions so that the visible spectrum shows only a single maximum (Gitis et al., 1959; Pollitt and Saunders, 1965).

F. Adducts with Other Compounds

It is interesting that in his original report (1902) Meisenheimer described the preparation from 9-nitroanthracene and methoxide of an adduct which he formulated as 45. Confirmation of this structure has come from NMR measurements which show that the resonance of the proton at C10 shifts from - 8-93to - 4-93p.p.m. on complex formation consistent with a covalency change at this ring position (Foster et al., 1967). Again the NMR spectra (Foster et al., 1967; Fendler et al., 1968) Me0

OMe

H NO2-

(45)

indicate that alkoxide addition occurs at C1 in 2,4-dinitro-1-methoxynaphthalene to give 46. The potassium salt has been obtained in

240

M. R . CRAMPTON

crystalline form. Zollinger et al. (1967) calculated that, on complex formation in polycyclic compounds such as this, the electron density will increase in the nitro-groups and also in the adjacent ring but will decrease in the substituted ring. In qualitative agreement with this it is found that the proton at C3 is deshielded on complex formation, the resonance shifting from - 8.66 to - 9.33 p.p.m. The general field of heterocyclic nucleophilic substitution and the role of addition complexes as intermediates has been reviewed by Illuminati (1964). Apparently the effectiveness of the aza group, -N=, in activating an aromatic ring to nucleophilic substitution is similar to that of the nitro-group. I n fact the ability of pyridines, particularly those with electron-withdrawing groups in the 3- and 5-positions, to give strong colours with bases has been known for some time (Mariella et al., 1955), and very recently NMR evidence for the formation of adducts similar to those formed from trinitrobenzene derivatives has come independently from three laboratories. Thus Fyfe (1968s) found that the spectrum of 3,5-dinitropyridine dissolved in dimethyl sulphoxide changed radically on the addition of sodium methoxide. The resonance of the hydrogen at C2 showed a strong shift to high field, indicating the formation of 47. There was no evidence for the formation of the alternative C4 adduct with methoxide, though the acetonate ion was found to attack this position preferentially. Species 48, the analogue in the pyridine series of Meisenheimer's adducts from 2,4,6-trinitro-

c

OMe

anisole, has been obtained in crystalline form by the reaction of 4-chIoro-3,5-dinitropyridine with excess potassium methoxide (Dickeson with methoxide ion et al., 1968) or 4-methoxy-3,5-dinitropyridine (Illuminati and Stegel, 1968). The NMR spectrum in dimethyl sulphoxide shows two bands at -8.78 and -2.92 p.p.m. with relative intensities 1 : 3. The latter authors have also obtained NMR evidence for methoxide addition at an unsubstituted position in two isomeric methoxy-nitropyrimidines. I n addition there is evidence (Abramovitch and Poulton, 1967) that pyridines, when treated with alkyl-lithium, form complexes by addition of an alkyl group at a ring position. Perhaps the most reactive substrate studied so far is 4,g-dinitrobenzofuroxan. Drost, in 1899, found that aqueous solutions of this

MEISENHEIMER COMPLEXES

241

compound were acidic and he was able to separate salts on the addition of base. He suggested that these resulted from replacement of a ringproton by a metal ion, an explanation which has frequently been accepted. However, as early as 1903 Jackson and Earle suggested that these salts might result from addition of hydroxide ion to give 49 or 50. Recent evidence has substantiated their formulation (Brown and

(50)

(49)

Keyes, 1965; Norris and Osmundsen, 1965; Boulton and Clifford, 1965). The NMR spectrum of the potassium salt in dimethyl sulphoxide shows bands at -8.93 and -6.20 p.p.m. due to ring protons and an absorption at -6.55 p.p.m. (which disappears in the salt formed in DzO)attributed to the added hydroxyl group. The latter two resonances are spin-spin coupled (J = 7 Hz). This spectrum does not by itself distinguish 49 from 50. However, Brown and Keyes' experiments with the 5-deuterio compound have established that the addition occurs at C3, to give 49. The high reactivity of 4,6-dinitrobenzofuroxan is shown by the observation that the adduct is almost quantitatively formed in water without added hydroxide ions. On the other hand, benzenes containing a single nitro-group do not readily form adducts. However, Kimura and Thoma (1958) have observed that, under Janovsky conditions, 3,5-disubstituted nitrobenzenes give strong colours,presumably due to the addition of acetonate ion. 4-Nitroaniline ionizes by proton-loss in basic media. However, changes in visible (Rochester, 1965) and NMR spectra (Birchall and Jolly, 1966) in highly alkaline media may indicate addition to the conjugate base. Similarly, Dolman and Stewart (1967) have observed changes in the visible spectra of 3-nitroaniline and nitrobenzene which may possibly indicate base addition.

111. EQUILIBRIUM AND

KENETIC

STUDIES

The studies, mainly spectroscopic in nature, outlined in the last section indicate how the structures of the adducts formed from various classes of nitro-compounds with bases have been determined. This section is concerned with the determination and rationalization of the

242

M. R . CRAMPTON

relative stabilities of these adducts. I n view of the strong colours often produced the most popular technique for the determination of equilibrium consta8ntshas been visible spectroscopy. Thus the measurement of optical densities at an appropriate wavelength frequently provides a means of determining the extent of formation of a coloured species from colourless components. Where the extinction coefficient of the coloured species is known, these measurements lead directly to values of the equilibrium constant for its formation. When the extinction coefficient is not known, licear plots (Benesi and Hildebrand, 1949)can be used to determine the equilibrium constant. However, care must be taken when using such plots, since their linearity does not necessarily imply that only a single coloured species is formed (Johnson and Bowen, 1965) and more than one coloured species may in fact be present. There are three main variables in these equilibrium studies: (i) the nature of the reacting substrate, (ii) the attacking nucleophile, and (iii) the solvent, and these will be considered in turn. A. Variation of Reactivity with Substrate Structure We shall first consider the effects of varying the structure of the substrate on the stabilities of adducts formed with a given nucleophile. The largest body of data in fact relates to reaction with sodium methoxide in methanol though data for some other nucleophiles is available. In general the successive equilibria of a parent compound, P , with a nucleophile, Nu, to form adducts A, B and C can be written: kl

P+Nu

+ + +

A

K1

B C

K, K,

k-1

A+Nu B+Nu

where the negative charges of the various species are neglected. 1. Addition of methoxide ion in methanol

For reactive substrates, such as 1,3,5-trinitrobenzene, which are converted into complex in dilute solutions of sodium methoxide, the equilibrium constant, K,, is adequately expressed in terms of concentrations as [A]/[P][OMe-1. However, for less reactive substrates, such as dinitrobenzenes, significant conversion to complex only occurs at fairly high concentrations of sodium methoxide ; similarly for the higher equilibria of trinitro-substituted benzenes. In these solutions the basicity of the medium cannot be adequately described by the con-

MEISENHEIMER COMPLEXES

243

centration of methoxide ions. For example, Gold and Rochester (1964a) found that the conversion of the first complex of 2,4,6-trinitroanisole to a higher complex depended, apparently, on a high power of the methoxide concentration. They suggested a dependence on the Hacidity scaIe which has been defined in methanolic sodium methoxide (More O’Ferrall and Ridd, 1963). Similarly Terrier et al. (1965) correlated the complex formation of dinitroanisoles with an H- acidity function. In fact the H- acidity scale which defines the ability of the medium to remove a proton from a neutral indicator molecule would appear to be less appropriate than the J- acidity function (Gold and Hawes, 1951; Rochester, 1966) which measures the ability of the medium to add base to a neutral molecule. In methanol this acidity function is defined by :

where K1 is the thermodynamic equilibrium constant for formation of the adduct A with methoxide and KMeOH is the autoprotolysis constant of methanol Rochester (1965) has defined a J-(M) scale using the successive equilibria of 2,4-dinitroanisole (two ionizations), 2,4,6trinitroanisole (two ionizations), the picrate ion (two ionizations) and the 2,4-dinitroaniline anion. This scale which ranges from J--(M) = 18 to 23 allows the determination of the equilibrium constants for formation of the adducts. These will necessarily be less accurate than those determined directIy in dilute solutions of base. In fact Rochester found that the highest equilibria of the picrate ion and 2,4,6-trinitroanisole followed the H - rather than J- acidity scale. However it is unlikely that these molecules can lose a proton in basic media so that the values given in Table 5 assume base addition. The data collected in Table 5 show several interesting features. One of the most notable of these is that for similarly activated substrates the adducts formed by addition at a ring carbon carrying a methoxyl group have considerably greater stability than those formed by addition at a ring carbon carrying hydrogen. Thus the equilibrium constant for addition at the C1 position of 2,4,6-trinitroanisole is about 500 times greater than that for addition to 1,3$-trinitrobenzene. Gold and Rochester (1964~) interpreted this result in terms of inductive and steric effects. The inductive effect of the methoxyl group at C1 will reinforce electron withdrawal from this ring position and thereby promote attachment of base. Also complex formation in the anisole was considered to reduce steric strain between the methoxyl group and flanking nitro-groups by allowing the methoxyl group to bend from the plane

TABLE5 Equilibrium Constants for Complex Formation with Sodium Methoxide in Methanol at 25OC K1 (1. mole-1) Addition at ring carbon carrying

H

Parent lt3,5-Trinitrobenzene 2,4,6-Trinitrodsole 2,4,6-Trinitroanisolea 4-Methoxy-3,5-dinitropyriche N,N-Dimethylpicramide Picramide 2,4-Dinitro-6-cyanodsole 2,6-Dinitro-4-cyanoa~olec Picrate iona 2,4-Dinitroanisolea.d 2,4-Dinitroanisoleb 2,6-Dinitroanisoleb 1,3-Dinitrobenzenea 2,4-Dinitro-l-methoxynaphthalene

OMe

Kz (1. mole-1)

K3

(1. mole-1)

1.54 x 101 7.7 x 103 1.3 x 10-4

4.7 x 103 7

c. 1

3.5 x 10' 1.14 x 103 2,5 3 x 10-4 3 x 10-4 10-3 5 x 10-3 5 x 10-7

2-3 x lo2

1.6 x 10-2 10-5 3 x 10-5 10-4

10-5

Reference Gold and Rochester (1964~) Gold and Rochester (1964a) Rochester (1965) Dickeson et al. (1.968) Gold and Rochester (1964d) Gold and Roohester (1964d) Zollinger et al. (1967) Dickeson et aZ. (1968) Rochester (1965) Rochester (1965) Terrier et al. (1965) Terrier et aE. (1965) Crampton and Gold (1966a) Fendler et al. (1968)

Determined via J--(y)acidity function. Detczmined via H-(P) acidity function using potassium methoxide. c With lithium methoxide. * Bsrnasconi (1968)has recently found a value of 6 x 10-5 1. mole-' for Ki. a b

M E I S E N H E I M E R COMPLEXES

245

of the aromatic ring. No such relief would operate in the case of trinitrobenzene. Recent crystallographic studies (Destro et al., 1967 ; Ueda et aZ., 1967) have confirmed the importance of steric effects. Thus in 2,4,6-trinitrophenetole the nitro-groups at the 2 and 4 positions are twisted by 36" and 61' respectively from the plane of the ring, while in the adducts with base much smaller rotations are found. The value of 7 1. mole-l (Goldand Rochester, 1964d)for N,N-dimethyl2,4,6-trinitroaniline, where addition unexpectedly occurs at C3, is close to two-thirds of the value for 1,3,5-trinitrobenzene, indicating that the electronic effect of the dimethylamino group is small at the 3-position. The factor of two-thirds is a statistical correction for the number of available ring positions. A similar argument would indicate that the C3 adduct of 2,4,6-trinitroanisole should have an equilibrium constant of formation of c. 10 1. molep1. The value for 2,4,6-trinitroanilhe is greater than for its N-dimethyl derivative, which led Gold and Rochester to postulate that the major reaction was probably proton loss from the amino-group. I n fact in methanol base addition is favoured and the larger value may be accountable in terms of stabilization of the adduct by hydrogen bonding between the amino protons and ortho-nitro groups. Replacement of the 6-nitro group in 2,4,6-trinitroanisole by the less electronegative cyano-group has the expected effect of decreasing the equilibrium constant for base addition at C1 (Zollinger et aZ., 1967). However, a much larger decrease is brought about by a similar substitution at the 4-position (Dickeson et al., 1968). This perhaps indicates the importance of a nitro-group para to the position of addition. It is a general feature, apparent from the structural studies, that in compounds containing two nitro-groups in meta-positions addition will occur preferentially at a position para to a nitro-group. Examples of this occur in the adducts of 1,3-dinitrobenzenes, 4,6-dinitrobenzofuroxan and 3,5-dinitropyridine. It follows that, perhaps, Meisenheimer's formula, 1, showing the negative charge associated with the para nitrogroup is not so far removed from the truth. However, the criterion of base addition para to a nitro-group is subordinate to that of preferential addition at B ring carbon carrying a methoxyl group, as seen from the adducts of 2,6-dinitroanisole and 4-methoxy-3,5-dinitropyridine. The values of the equilibrium constants (K,) for complex formation from 2,4.-dinitroanisole and 2,6-dinitroanisole are much smaller than that from 2,4,6-trinitroanisole, as expected. However, the values for the dinitroanisoles are much greater than for 1,3-dinitrobenzene itself, presumably because of similar steric and electronic factors to those which enhance the complex formation of 2,4,6-trinitroanisole relative

246

M. R . C R A M P T O N

to 1,3,5-trinitrobenzene. The adduct from 2,4-dinitro-1-methoxynaphthalene is much more stable than the similar adduct formed from 2,4-dinitroanisole. However, Dewar (1949) has calculated that the formation of a cyclohexadienyl intermediate from a benzene derivative requires a 10 kcal loss in resonance energy while the figure for a naphthalene derivative is only 2 kcal. Thus the more extensive complex formation of the naphthalene derivative is not unexpected. The values of K 2in Table 5 indicate that higher complexes are formed readily from the 1 :1adducts only in the cases of N,N-dimethylpicramide and the picrate ion. The di-adducts from both these compounds will be formed by addition at two ring-carbon atoms carrying hydrogen to give respectively 26 (R = R’ = R”=Me) and the methoxide adduct analogous to structure 34. The special stability of these structures may result from the fact that in the di-adducts the aromaticity of the ring is broken so that some steric strain present in the parents or 1: 1 adducts may be relieved. Where addition occurs initially at C1 as in 2,4,6trinitroanisole the steric strain at C1 is effectively relieved in the 1 : 1 adducts so that there is less tendency to form the higher adducts. 2. Kinetics of methoxide additions I n general it has been found that the formation of adducts by addition of base at a ring-carbon carrying hydrogen is a much faster process than addition at a ring-carbon carrying a methoxyl group. I n the latter case the rate of methoxide addition is sometimes slow enough to be measured by conventional techniques at room temperature. Thus the rates of formation of adducts from 2,4,6-trinitroanisole and methoxide (Gold and Rochester, 1964a) and 2,4-dinitro-l-methoxynaphthalene and methoxide (Fendler et ul., 1968) have been measured by observing the build-up of colour with time. The rate constant, kl, for formation of the trinitroanisole complex has the value 4 1. mole-1 sec-l at 25’ =5 x which, in conjunction with the equilibrium constant, gives kl sec-l. It should perhaps be noted that owing to the much smaller equilibrium constant expected for formation of the C3 adduct than of the C1 adduct, there will be very little of the former adduct present in methanol containing small concentrations of methoxide. Thus the kinetics of formation of the C1 adduct from 2,4,6-trinitroanisole and base will not be affected. An identical value for kLl was determined by Fendler (1966) who measured the rate of loss of 14C label from the methoxyl group of 2,4,6-trinitroanisole in methanolic sodium methoxide. The rate determining step in this process will be the decomposition of the Meisenheimer adduct formed. From the temperature dependence of the rate constant the activation energy for the decom-

M E I S E N H E I M E R COMPLEXES

247

position of the adduct was found to be 19.4 kcal mole-I. Similarly Murto and Vainionpaa (1966) have determined the activation energies for decomposition of several Meisenheimer adducts in water to be 17-19 kcal molep1, while Murto and Kohvakka (1966) found the activation energy for formation of complex in aqueous methanol to be 13 kcal mole-l. This value is close to that of 13.1kcal mole-I found by Ainscough and Caldin (1956) for the formation of an adduct at C1 from 2,4,6trinitroanisole and ethoxide ion in ethanol at low temperatures. In fact the “fast reaction” studied by these workers, which they formulated

??

I I 12-13 kc31

I

A 10-11 kcal

OMe

FIG.5. Potential energy diagram for reaction of 2,4,6-trinitroaniaolewith methoxide in methanol.

as a charge transfer interaction, almost certainly corresponds to the formation of the C3 adduct. The activation energies determined in this latter case were 10-4kcal mole-l for the formation and 13-7kcal mole-l for the decomposition of the complex. It is probably reasonable to assume that somewhat similar values will apply to the complex formed by addition of methoxide to the 3-position of 2,4,6-trinitroanisole in methanol. On this assumption the potential energy diagram shown in figure 5 may be drawn for the formation of adducts from 2,4,6-trinitroanisole and methoxide. The C3 adduct is the kinetically controlled product, though the C1 adduct is thermodynamically more stable. The higher activation energy for addition of base at the ring-carbon carrying 9

248

M. R . CRAMPTON

the methoxyl group has been attributed (Gold and Rochester, 1964; Crampton and Gold, 1966b) to steric strain in the transition state for formation of the adduct. It is reasonable that steric effects will be comparatively unimportant for addition of base at a ring-carbon carrying hydrogen, as in the addition at the 3-position of 2,4,6-trinitroanisole or in trinitrobenzene. Servis (1967) has used Miller’s method of calculation (Miller, 1963),which has often proved successful in predicting the reactivities of systems in nucleophilic aromatic substitution reactions (Hill et al., 1966) to the 2,4,6-trinitroanisole-methoxidesystem. These calculations indicate that, contrary to observation, addition at the

n NMe, I Pic OMe +NMe;?

Me0 NMe2

O

2 H

N

.’.

V OMe

. . NO2

FIG. 6. Suggested schematic potential energy profile for reaction between N,Nclimethylpicrarnide and methoxide in methanol. (Crampton and Gold, 1966b.)

1 position should lead to the kinetically controlled product but that the 3-adduct should be thermodynamically more stable. Activation energies have also been measured for the formation of adducts from 2,kdinitroanisole and methoxide, 16.8 kcal mole-’ and methoxide, (Fendler, 1966), and 2,kdinitro-1-methoxynaphthalene 13.8 kcal mole-1 (Fendler et al., 1968). For the latter compound the activation energy for reversal to reactants was 16.5 kcal mole-l, while the entropies of activation for the forward and reverse reactions were - 17 and - 18 e.u. respectively. Fendler has also calculated that the corresponding entropies of activation for the 2,4,6-trinitroanisole complex are - 14 and - 11 e.u., and as a result has suggested that the

MEISENHEIMER COMPLEXES

249

stabilities of Meisenheimer adducts are dominated by enthalpy effects. This is supported by Miller’s calculations. NMR observations of the spectra of 2,4-dinitroanisole and 2,4dinitro-1-methoxynaphthaleneindicate that in dimethyl sulphoxide the adducts first formed result from addition of methoxide at C1. However, the difference between these compounds and 2,4,6-trinitroanisole may not be profound and here too addition at C3, the ring position carrying hydrogen, would almost certainly be faster than at C1. However, for these compounds the equilibrium constants for formation of the C3 adducts are probably too small to allow their observation even in media containing dimethyl sulphoxide. The same considerations which apply to the formation of complexes from 2,4,6trinitroanisole and methoxide may also apply to N,N-dialkylpicramides (Crampton and Gold, 1966b; Servis, 1967). Thus it seems likely that the observed adduct formed by addition at C3, is less thermodynamically stable than the adduct at C1, the carbon carrying the dimethylamino group, but is formed more rapidly owing to severe steric hindrance in the transition state for formation of the latter adduct. I n fact the potentially more stable adduct is not observed in methanol as it readily loses the dimethylamino group to give 2,4,6-trinitroanisole (Gold and Rochester, 1964d). The potential-energy diagram representing this proposed scheme is drawn schematically in Fig. 6. The potential-energy diagram for N,N-diethylpicramide is likely to be similar, though Servis’s (1967) observation that addition of excess diethylamine to 2,4,6trinitroanisole in dimethyl sulphoxide results in addition of NEtz- at C1 indicates that the energy levels of this adduct and PicOMe +NEt2must be close. 3. Equilibrium studies with sodium sulphite in water The equilibrium constants for the formation in water of the sulphite adducts of a number of nitro-compounds are given in Table 6. Where NMR studies have been carried out these indicate the formation of 1:1 and 1 :2 adducts, addition occurring in each case at an unsubstituted ring position. The formation of the higher complexes is subject to a large salt effect and the values given for K z are those extrapolated to zero ionic strength. It is of interest that the equilibrium constant for sulphite addition to 2,4,6-trinitroanisole is similar in this case to the value for 1,3,5trinitrobenzene, addition occurring in each case at a ring carbon carrying hydrogen. This indicates that the electronic effects of the substituents at C1 do not appear to affect the stabilities of the adducts greatly. The increased stability of the picramide complex may result from some

250

M. R . CRAMPTON

TABLE6 Equilibrium Constants for Formation of Adducts with Sodium Sulphite in Water Substrate

K 1 (1. mole-1)

2,4,6-Trinitrobenzenea 2,4,6-Trinitroanisolea 2,4,6-Trinitroanilinea N-Methyl-2,4,6-trinitroanilinea N,N-Dimethyl-2,4,6-trinitroanilinea 2,4,6-Trinitrobenzaldehydeb 2,4,6-Trinitrotolueneb a b

2.5 x 102 2.1 x 102 1.0 x 104 5.4 x 104 5.4 x 104 2.15 x 103 5.6

Kz (1. mole-1)

Reference

5 x 10-1 5.8 x 101 1.05 1.1 x lo2 2.3 x 103

Crampton (1967) Crampton (1967) Crampton (1967) Crampton (1967) Crampton (1967) Norris (1967a) Norris (19678)

Addition of sulphite occurs at an unsubstituted ring position. Position of addition not determined.

stabilization through strengthening of the hydrogen-bonds between the amino-proton and the ortho-nitro groups in the negatively charged adduct. A similar factor cannot, of course, apply t o N,N-dimethylpicramide though here the bulky substituent at C1 will tend to twist the nitro-groups from the plane of the ring and this may facilitate sterically the addition of sulphite. It is perhaps surprising that a similar effect is not observed with the methoxide adduct of N,Ndimethylpicramide where the stability is similar to that of the methoxide adduct of trinitrobenzene. This may perhaps indicate the greater steric requirements of the sulphite ion over the methoxide ion. The results show that there is some correlation of the values of K 2 for formation of the di-adducts with the size of the substituent at C1. I n these di-adducts the conjugation of the ring is broken so that the steric strain at C1 may be reduced relative to the parent molecules or 1 : 1 adducts. This steric relief would be expected to increase with the size of the substituent at the 1-position.

B. Variation of Reactivity with the Attacking Nucleophile The second variable is the nature of the attacking nucleophile and we shall consider first the reactivities of a series of nucleophiles towards a single substrate. Perhaps the most studied compound is 1,3,5-trinitrobenzene and the equilibrium constants for formation of 1 :1 adducts with a variety of nucleophiles are given in Table 7. However the stability of a given adduct will vary considerably with change of solvent so that values obtained in different solvents are not comparable. I n fact these equilibrium constants give a measure of the thermo-

251

MEISENHEIMER COMPLEXES TABLE7 Equilibrium Constants for Formation of Adducts from 1,3,5-Tri~itrobenzene with Various Nucleophiles ~

Nucleophile OMeSEtSPhOPh-

OHOEtSO3' CNCNOMeSPhNHMe-4 NEtz-" NCsHio-4 4

Solvent

K1 (1. mole-1)

Reference

Methanol Methanol Methanol Methanol Water Ethanol Water Acetone Chloroform DMSO DMSO DMSO DMSO Acetonitrile

1.54 x 10' 3.5 x 103 1.95 c 2 x 10-3 2.7 1.8 x 103 2.5 x 102 1.4 x 105 3.5 x 105

Gold and Rochester (1964~) Crampton (1968a) Crampton (1968s) Crampton (1968a) Gold and Rochester (1964b) Crampton and Ghariani (1968) Crampton (1967) Norris (196713) Norris (1967b) Crampton (1968a) Crampton (1968a) Crampton and Gold (1967) Crampton and Gold (1967) Briegleb et al. (1960)

c. 1 0 9

sx

104

zx

103

1.3 x 10' 6 x 10-2

These values refer to the equilibrium: TNB + 2RR'NH

+

+

(TNB .NRR')- t N H z R R

dynamic affinity of the nucleophiles for an aromatic carbon atom. This quantity which has been termed the "carbon basicity" of the nucleophile (Parker, 1961; Bunnett, 1963) will be expected to differ considerably from the Bronsted basicity, thermodynamic affinity for hydrogen, of the nucleophiles. Measurements made recently in methanol indicate that the order of carbon basicity is EtS- > OMe- > PhS- > PhO- while the order of Bronsted basicity is OMe- > EtS- > PhO- > PhS-, although these orders will vary with change of solvent. Similarly, measurements in water suggest that the sulphite ion has a considerably higher carbon basicity than the hydroxide ion. Comparable values for the carbon basicities of other nucleophiles in protic solvents are not yet available, though the stabilities of these Meisenheimer-type adducts would seem to provide a method for their determination. Carbanions derived from species such as acetone would be expected to have a considerable affinity for trinitrobenzene. In agreement with this expectation it is found that the thermodynamically stable adducts produced by the addition of methoxide ions or diethylamine to trinitrobenzene in acetone result from addition of the acetonate ion. This is reinforced by the ready reaction of acetonate ions with less reactive substrates such as 1,3-dinitrobenxene.

252

M. R. CRAMPTON

With 1,3,5-trinitrobenzene no diversity of attack is possible, though for substituted derivatives such as 2,4,6-trinitroanisole or 2,4,6-trinitroaniline the mode of interaction may vary on changing the nucleophile. Thus structural measurements show that the thermodynamically stable adducts of 2,4,6-trinitroanisole with OMe-, NS- or NEt2- result from addition a t Cl while the apparently stable adducts with SOs- or CH,.CO.CH,- are formed at C3. The failure to detect addition of these latter nucleophiles at C1 may be ascribed to steric strain. This may occur either in the C1 adducts themselves, so that they are no longer thermodynamically preferred to the C3 adducts, or alternatively in the transition states for their formation, so that their formation is very slow. Again the mode of ionization of 2,4,6-trinitroaniline and its N-substituted derivatives depends on the relative affinities for carbon or hydrogen of the particular nucleophile used. Thus sulphur bases such as SEt- and SPh- will preferentially add at the 3-position, while with oxygen bases abstraction of an amino proton also occurs.

C:. Eflects of Solvent on the Stabilities of the Adducts Although the formation of adducts has been reported in a variety of solvents it is probably true to say that the most widely used have been methanol, water and dimethyl sulphoxide, and virtually all the equilibrium constants so far determined relate to these solvents. Generally it has been found that the production of 1: 1 adducts is enhanced in the dipolar aprotic solvents such as dimethyl sulphoxide relative to protic solvents such as methanol. Thus 1,3-dinitrobenzenes give little colour with methoxide ions in methanol though in dimethyl sulphoxide or dimethylformamide strong colours are produced (Pollitt and Saunders, 1964; Crampton and Gold, 1966a). This enhanced reactivity has been put to good effect in structural studies. Thus, most NMR measurements have been made in dimethyl sulphoxide where many nitro-compounds are converted stoichiometrically into 1:1 adducts in the presence of one equivalent of base. There is strong evidence from visible and NMR spectroscopy (Crampton and Gold, 1964a) that dimethyl sulphoxide does not generally affect the basic mode of interaction of the nitrocompound and base but increases the efficiency of the interaction. However, there is some evidence (Foster and Fyfe, 196613) that carbanions formed from dimethyl sulphoxide may sometimes produce adducts. This specific interaction with the solvent is more pronounced in acetone where the acetonate ion is readily produced. Few quantitative data are available for the variation of equilibrium constant for a particular interaction with the solvent. However recently

MEISENHEIMER COMPLEXES

253

the equilibrium constants for formation of the 1:1 adducts from1,3,5trinitrobenzcne and methoxide or thiophenoxide ions have been measured in methanol-dimethyl sulphoxide mixtures (Crampton, 1968a). Using Parker's (1967) nomenclature the equilibrium constants in methanol and dimethyl sulphoxide are related via the solvent activity coefficients, MeoHypMSo, for transfer of the species involved. Thus for the reaction of trinitrobenzene (TNB) with methoxide ions to give the covalent adduct (TNB 0Me)- :

-

The solvent activity coefficientsfor all three species will be expected to have non-unit values. However it might be argued that the values for trinitrobenzene and its adduct will be similar since both are large polarizable species which will be better solvated by the aprotic solvent than the protic one (Parker, 1962). It seems likely then that the major factor in the observed increase in adduct stability by a factor of lo8 results from the increased activity of the methoxide ion in the aprotic solvents. A similar argument would indicate that the increased stability of the thiophenoxide adduct, by a factor of 4 x lo4, results largely from an increase in activity of the thiophenoxide ion in the aprotic solvent. The larger increase in the former case is in agreement with the qualitative prediction that the small methoxide ion which is capable of forming strong hydrogen bonds will be more activated on transfer from methanol to dimethyl sulphoxide than the more polarizable thiophenoxide ion. I n a similar way qualitative measurements indicate that 1: 1 adducts from a variety of nitro-compounds and sodium sulphite are produced more readily in dimethyl sulphoxide than in water. The greater stability of the 1:1 adducts in aprotic solvents is, then, attributed mainly to the enhanced reactivity of the attacking nucleophiles in these solvents. This factor should also favour the production of di-adducts in aprotic solvents and NMR measurements do indicate that these are formed from trinitro-substituted compounds and methoxide ions in media rich in dimethyl sulphoxide. However, there is some evidence that the di-adducts are not particularly well solvated by dimethyl sulphoxide and are in fact better solvated by water. Thus it has been found that 1:2 adducts are very readily formed in water. For example 1,3,5-trinitrobenzene gives both 1:1 and 1 :2 adducts in fairly dilute solutions of hydroxide ions in water, while dimethylpicramide and the picrate ion give evidence only for the production of 1 :2 adducts. Similarly a variety of trinitro-compounds are readily converted into di-adducts in aqueous sodium sulphite solution, although

254

M. R . CRAMPTON

these higher adducts are not formed in media rich in dimethyl sulphoxide. It can be argued that the di-adducts, particularly those formed by sulphite addition, begin to resemble inorganic salts and will be well solvated by water but less well solvated by dipolar aprotic solvents. Thus the di-adduct from trinitrobenzene and sodium sulphite is virtually insoluble in dimethyl sulphoxide but dissolves readily in water. It seems likely that the order of decreasing solvation in dimethyl sulphoxide will be (TNB.OR)-w TNB > TNB-SOs’ > TNB(OR)z=> TNB(S03)a4-,

where R = H, alkyl, while in water this order will be reversed. Solvation by methanol will presumably be somewhere between water and dimethyl sulphoxide. Further evidence for the special stability of 1:2 adducts in water comes from recent measurements of the equilibrium constants for formation of 1:1 and 1:2 adducts from 1,3,5-trinitrobenzene and sodium thioethoxide (Crampton, 1968b). On changing the solvent from methanol to water the value of K1 decreases from 3.6 x los to 2.6 x 10’ 1. mole-l while the value of K z increases from 10 to 1.4 x l o 4 1. mole-’.

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Meisenheimer, J. (1902). Ann. 323, 205. Meyer, V. (1894). Ber. 27, 3153. Meyer, V. (1896). Ber. 29, 848. Miller, J. (1963). J. Am. Chem. SOC.85, 1628. Miller, R., and Wynne-Jones, W. F. K. (1959). J. Chem.SOC.2375. Miller, R., and Wynne-Jones, W. F. K. (1960). Nature 186, 149. More O’Ferrall, R. A., and Ridd, J. H. (1963). J. Chem. SOC.5030. Mulliken, R. S. (1952). J. Am. Chem.SOC.74, 811. Muraour, H. (1924). Bull. soc. chim. France 35, 367. Murto, J. (1965). Suomen Kemistilehti B 38, 255. Murto, J., and Kohvakka, E. (1966). Suomen Kemistilehti B 39, 128. Murto, J., and Vainionpaa, J. (1966). Suomen Kemistilehti B 39, 133. Neunhoeffer, O., Thewalt, K., and Zimmerman, W. (1961). 2. Physiol. Chem. (Hoppe-Seyler’a)323, 116. Norris, A. R. (1967a). Can. J. Chem. 45, 175. Norris, A. R. (196713). Can. J. Chem. 45,2703. Norris, N. P., and Osmundsen, J. (1965). J. Org. Chem. 30,2407. Parker, A. J. (1961). Proc. ChemSoc. 371. Parker, A. J. (1962). Quart. Rev. (London)16, 163. Parker, A. J. (1967). Adu. Phya. Org. Chem. 5, 173. Pollitt, R. J., and Saunders, B. C. (1962). Proc. Chem. SOC.176. Pollitt, R. J., and Saunders, B. C. (1964). J. Chem.SOC.1132. Pollitt, R. J., and Saunders, B. C . (1965). J. Chem. SOC.4615. Rochester, C . H. (1963). Trans. Farad. SOC.59,2820. Rochester, C. H. (1965). J. C h m . SOC.2404. Rochester, C. H. (1966). Quart. Rev. (London)20, 511. Ross, S. D. (1963). Progreas Phys. Org. Chem. 1, 31. Russell, G. A., and Janzen, E. G. (1962). J. Am. Chem. SOC. 84, 4153. Russell, G. A., and Janzen, E. G. (1967). J. Am. Chem. SOC.89, 300. Russell, G. A., Janzen, E. G., and Strom, E. T. (1964). J. Am. Chem.SOC. 86,1807. Sauer, J., and Huisgen, R. (1960). Angew. Chem. 72, 294. Schaal, R. (1955). J. Chim. Phys. 52,784. Servis, K. L. (1965). J. Am. Chem.SOC.87, 5495. Servis, K. L. (1967). J. Am. Chem. SOC.89, 1508. Severin, T., and Schmitz, R. (1963). Angew. Chem. 75, 420. Stewart, R., and O’Donnell, J. P. (1962). J . Am. Chem.SOC.84,494. Stewart, R., O’Donnell, J. P., Cram, D. J., and Rickborn, B. (1962). Tetrahedron 18, 917. Terrier, F., Pastour, P., and Schaal, R. (1965). Compt. rend. 260, 5783. Ueda, H., Sakabe, N., Janaka, J., and Farusaki, A. (1967). Nature 215, 956. Van Leent, F. H. (1896). Rec. Trav. Chim. 15, 89. Weiss, J. (1942). J . Chem. SOC.245. Zimmerman, W. (1935). 2. Physiol. Chem. 233, 257. Zimmennan, W. (1936). 2. Physiol. Chem. 245, 47. Zollinger, H., Caveng, P., Fischer, P. B., Heilbronner, E., and Miller, A. L. (1967). Helv. Chim. Acta 50, 848.

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PROTOLYTIC PROCESSES IN HZO-D20 MIXTURES V . GOLD King’s College, University of London, Strand, London W.C.2, England

. . . .

I. Introduction . A. GeneralBackground B. List of Important Symbols 11. “Simple” Equilibrium Theory A. Assumptions . B. Acid Dissociation Constant as a Function of n C. Extension of Simple Equilibrium Theory to Acid Catalysis . D. Acid Catalysis by Species other than HsOf . 111. Solvent Isotope Effects in Relation to the Brcansted Catalysis Law . A. Acidity Constants of Hydrogen Ions B. Application of the Catalysis Law . IV. Critique and Possible Improvements of Simple Theory A. The Formula of the Hydrogen Ion and the Value of the Fractionation Parameter !I . . B. The Rule of the Geometric Mean . C. Absence of other Kinds of Solvent Isotope Effect , V. Applications of Theory to Experimental Results for Hydrogen Ions A. Summary of Available Results for H20-D20 Mixtures . B. Some Case Studies . VI. Catalysis by Species other than Hydrogen Ions in Aqueous Solution . A. Carboxylic Acids . B. HydroxideIons . . C. “Water-oatalysed” Reactions VII. Solvents other than Water . A. Water-Dioxan Mixtures . B. Methanol . VIII. Speculative Generalities . References .

.

.

. .

.

. .

.

.

.

.

.

. .

.

. .

.

.

.

. .

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. . . . .

.

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259 259 263 265 265 268 271 277 217 277 279 281 281 284 287 294 295 297 312 312 316 319 322 322 323 325 327

I. INTRODUCTION

A. General Background THEstudy of acid-base reactions and equilibria in mixtures of light and heavy water excited a good deal of interest in the decade following the discovery of the hydrogen isotope deuterium (1933-1942). During the ensuing fifteen years the subject was largely neglected but in the last few years there has been renewed activity both on experimental and theoretical aspects. A problem of immediate concern to physical 269

260

V. GOLD

organic chemists is the question whether kinetic studies in isotopically mixed solvents can provide information about reaction mechanisms additional to what can be learnt from a comparison of reaction velocities in ordinary water and deuterium oxide as solvents. A related question is whether measurements in H20-D20 mixtures can be used to predict results for pure D20 as a solvent. Perhaps this is a less important problem now that deuterium oxide is freely available and relatively inexpensive than it was some years ago. Nevertheless, there are still situations where such extrapolations cannot easily be avoided. The present chapter is devoted exclusively to an analysis of the problems of isotopically mixed solvents. It will not concern itself, except in passing, with the measurement and interpretation of solvent effects on equilibrium and rate constants due to the isotopic change from pure H 2 0to pure D20. The aim is to show to what extent measurements of this type are of practical utility, especially as a tool in the investigation of reaction mechanisms. For this reason, the development, of theory is mainly directed towards compromise solutions of a complex problem, i.e. solutions which enable the theory to be tested and applied but lay no claim to being theoretically unassailable. The guiding principle has been to cast the formulation in terms of parameters or types of measurement which are either known or at least known to be feasible. The isotopically pure solvents H20 and D 2 0 have very similar physical properties. The chief differences occur in those properties which are most sensitively dependent on small changes of liquid structure, for example the temperature of maximum density (which increases from 3-98 to lle2"C on going from HzO t o D20) or the melting point (which is 3~8°Cfor D20)(Kirshenbaum, 1951). The solubility differences of various sparingly soluble substances in H20 and D20, which commonly go up to as much as 20% for both electrolyte and non-electrolyte solutes (see,e.g., ShearmanandMenzies, 1937 ;ChangandChu 1939;Eddy and Menzies, 1940; Ben-Naim, 1965; Krescheck et al. 1965, Broadbank et al., 1968), have similarly been discussed in terms of structural changes (e.g. Swain and Bader, 1960; NBmethy and Scheraga, 1962). No doubt structural differences are also responsible for the 0.36% increase in molecular volume of liquid water on going from H20to D20. The molecular volumes of mixtures obey an ideal mixture law very closely (Kirshenbaum, 1951). However, in the main, the density difference between H 2 0 and its mixtures with D 2 0 is due to the change in average molecular weight. Because of this density difference, the quantitative results for thermodynamic measurements on solutions in H20-D20 mixtures are different according to the concentration scale adopted. For. dilute solutions in ordinary water the difference between

P R O T O L Y T I C P R O C E S S E S IN H Z O - D ~ O M I X T U R E S

261

the molar concentration of a solute (moles per litre of solution) and its molal concentration (moles per kilogram of solvent) is very small, since the densities of dilute solutions in H20 are close to unity. For dilute solutions in DzO, the two concentration scales differ by ca. 11%, corresponding to the density difference between H20 and D20. This is quite an elementary point which has nevertheless occasioned some confusion in the past and to which attention must be paid when results from different groups of workers are being compared. I n particular, solution kineticists almost invariably employ the molarity scale, whereas the results of potentiometric measurements are conventionally expressed in terms of molal concentrations. The so-called aquamolality scale, in which concentrations are expressed as moles per 55.51 moles of solvent (sum of light and heavy water), is identical with molality in H20, and differs only very slightly from molarity over the entire isotopic composition range for low concentrations of solute. It was used as long ago as 1935 by Abel et al. (1935) and quite recently, has been given its distinctive name (for the origin of this name, see Greyson, 1967). The dielectric constant of D20 (77-937 at 25°C) is only approximately 0.3 to 0.4 unit less than that of H20 (Malmberg, 1958; Vidulich et al., 1967), corresponding to the increase in molar volume and hence reduction in the number of molecules per unit volume. Consequently, the A factor in the Debye-Huckel limiting law for interionic activity coefficients is nearly the same in the two solvents (Gary et al., 1964; Noonan and La Mer, 1939). There appear to be no dielectric constant memurements of comparable reliability for H20-D20 mixtures and there is possibly some danger in using a linear interpolation between HzO and DzO because of the formation of the unsymmetrical species HOD (Noonan and La Mer, 1939). Nevertheless it is usually considered permissible to neglect interionic activity Coefficients in comparisons of equilibrium or rate constants in different HzO-D20 mixtures, provided the concentration of ionic solutes is low and equal in the different media. At very low ionic strengths this is certainly justified. It follows from these similarities in solvent properties that equilibrium or rate constants of reactions in which the solvent molecules do not directly participate generally show comparatively small changes when the deuterium content of the medium is altered. This is true even for rates of proton transfer between neutral substrates and acetate ions, which as a rule are reduced by 20-40% on going from H20 to D20 (Bell, 1965). Because of the anionic nature of one of the reactants and of the transition state these reactions are of a type in which solventsolute interactions through hydrogen bonds are probably particularly large, and yet the solvent isotope effect is fairly small. Reactions in

262

V. G O L D

which water molecules are directly involved but in which they take part in a nucleophilic role by attacking through the oxygen atom likewise show comparatively small solvent isotope effects. Solvolyses of alkyl halides, for example, usually suffer a ca. 25% reduction in rate on being transferred from H20to DzO (see, e.g., Laughton and Robertson, 1959). Presumably because these overall effects are so small, such reactions have generally not been investigated in HzO-DzO mixtures. The situation is quite different for the equilibrium or rate constants of reactions associated with the transfer of a proton which, when the solvent is changed to D20,becomes the tramfer of a deuteron. Reactions of this type are those where the acid species from which the transfer takes place is in isotopic exchange equilibrium with the solvent. The common cases in this category are proton transfers from the solvated hydrogen ion, carboxylic acids, ammonium ions, or the water molecule itself. For simplicity, we refer to such reactions as protolytic processes, even though it is understood that both proton and deuteron transfers are to be included under this heading. [The term “hydrion” has been proposed (Ingold et al., 1936) for the positively charged hydrogen nucleus (H+or Df, generally designated L+) but, presumably because of the possibility of confusion with solvated hydrogen ions, the name has not gained acceptance.] Equilibrium and rate constants for such processes generally change by a factor which may be as large as six or seven, and is commonly around three, as one goes from H 2 0 to D20 or vice versa. For instance, the ionic product (or equilibrium constant for autoprotolysis) of D20 is 7.3 to 7.4 times smaller than that of H 2 0 at 25” (Gold and Lowe, 1963, 1967; Covington et al., 1966; Pentz and Thornton, 1967) and the bromination of acetone, catalysed by hydrogen ion, is doubled in rate when HzO is replaced by D20 as solvent (Reitz, 1936). Rate and equilibrium constants of this type in mixtures of HzO and D20 were first studied by La Mer, Gross and Butler and their collaborators. They found that equilibrium and rate constants did not vary linearly with the atom fraction (n)of deuterium in the solvent and Gross (Gross and Wischin, 1936; Gross et al., 193613) offered a theoretical explanation which, in all essentials, corresponds to the “simple theory” set out in Section 11. This theory was greatly clarified by Schwarzenbach (1938) and Gross (1938). These larger differences between results for H 2 0 and D20 and the very definite non-linearity excited a good deal more interest than the small effects noted above. Such easily observed phenomena promised to become a useful source of chemical information, particularly in relation to reaction mechanisms. Further early developments of theory were contributed by Butler and his students (Hornel and Butler, 1936; Orr and Butler, 1937;

P R O T O L Y T I C P R O C E S S E S I N HzO-D 2 0 MIXTURES

263

Nelson and Butler, 1938) and by La Mer’s group (Rule and La Mer, 1938; Kingerley and La Mer, 1941). The kinetic studies up to that time deal with examples in which a pre-equilibrium between the reacting substrate S and the catalysing hydrogen ion preceded the rate-limiting step of the reaction (equation 1)

+

-

S H30+ SH+

$

rate-

limthg

SH++HzO products

It was generally believed that the characteristic non-linear dependence of the rate constant on n was associated with the existence of the preequilibrium (Bell, 1941). For the mutarotation of glucose a linear variation of rate constant with n had been reported (Hamill and La Mer, 1936c) and cited as an example of a mechanism of acid catalysis without pre-equilibrium. Current interest in the subject was revived by a careful review by Purlee (1959), and in 1960 the first theoretical treatment of the rates of rate-limiting proton transfer processes in H20-D20 mixtures was given (Gold, 1960). These two papers were followed by a large number of contributions, especially by the groups of Swain, Long, Kresge, Kreevoy and Gold, which built up the scene surveyed in the following pages. We shall first summarize the simple theory of protolytic equilibria and its extensions to rate constants before considering the modifications and elaborations that have been introduced. The simple equilibrium theory is essentially due to Gross, though we shall cast it in the form and symbolism adopted in recent work. The symbols are summarized in the following sub-section. Only a very small amount of work has been concerned with proton transfer processes not involving the aqueous hydrogen ion. Because they are less import,ant, the discussion of these cases will be deferred till a later section, even though they are in some ways theoretically less complicated.

B. List of Important Symbols Symbol ,4 A-1, A-2, A-SE2

C

Meaning

Page on which defined or Jirst used

parameter of Debye-Huckel theory symbolic designations of reaction mechanisms concentration

268 271,272 287

264

K

KHA(KDA) K” ( K D ) Kw K’ K” K

1

L m

n

P

V. GOLD

Page o n which deJined or Meaning Jirst used fractional abundance of deuterium 266 in species LX fractional abundance of species 2 67 XDH in XL2 parameter of catalysis law ; 279 287 Gibbs free energy 271 rate constant rate constant in H 2 0 (in D20, in 27 1 solvent characterized by n ) rate constant for proton (deuteron) 280 transfer equilibrium constant for HOD 266 formation 268 equilibrium constant in H 2 0 (in D20,in solvent characterized by n) 267 dissociation constant of acid HA in H20 (DA in D20) 278 acidity constant for proton (deuteron) transfer 270 ionic product of water 267 equilibrium constant for H,DO+ formation 267 equilibrium constant for HD20f formation 286 approximation to equilibrium constant for H2DO+and HD,O+ formation 27 1 equilibrium constant for formation of transition state (in H20,D20, solvent characterized by n) 266 fractionation parameter of hydrogen ion 262 general hydrogen nucleus 292 deuterium abundance in product C-L grouping 262 atom fraction of deuterium in solvent 279 statistical factor in catalysis law

PROTOLYTIC PROCESSES I N H20-D20

MIXTURES

265

Page on which defined or jirst used

Meaning product isotope effect 274 reaction rate due to proton 280 (deuteron) transfer X mole fraction 266 transfer activity coefficient 287 Y quotients of transfer activity 288 y , y*, yW coefficients parameter of A-SE2theory 274 279,320 exponent of catalysis law for acid (base) catalysis exponent of catalysis law for 281 carboxylic acids activity coefficient (mean activity 268 coefficient stoichiometric parameter 293 fractionation factor 266 fractionation factor for n 3 0 314 40 ratio 4/d0 314 4rel U symmetry number 266 Note: Solid bars over symbols refer to solutions in D20,broken bars to solutions in H20-D20 mixtures.

ii

I. “SIMPLE” EQUILIBRIUM THEORYFOR REACTIONS INVOLVING AQUEOUS HYDROGEN IONS A. Assumptions An algebraically very simple theory can be developed from a set of five assumptions. As will be shown, its predictions are reasonably borne out by a fair body of data. It is now generally accepted as a suitable basis for discussing simple cases. It can be adapted to meet special circumstances and extended to overcome some of the weaknesses of the assumptions. Indeed, exception can be taken (and has been taken) to nearly every one of these assumptions, and the extent of their validity and the need for modification of the theory are further discussed in Section IV. The assumptions are : (1) The hydrogen ion in H 2 0 solutions contains three protons which are distinguishable from the protons of the water molecule. More simply, we could s&ythat the hydrogen ion has the formula H,O+ and, for con-

266

V. G O L D

venience, we shall refer to the aqueous hydrogen ion by that formula (or L,O+ for the general case).l Nevertheless, it is not denied that the H,O+ ion is further hydrated in aqueous solution. The assumption here is simply that such further hydration does not introduce additional protons, which are capable of being differentiated from those of water, into the hydrogen ion. (2) The isotopic abundance of deuterium in the three hydrogen atoms of the hydrogen ion differs from that in the water. The fractionation parameter involved is designated by the symbol 1, i.e.

The best available direct experimental measurements favour a value of 0.69 & 0.01 or 0.02 for 1 (Gold, 1963; Kresge and Allred, 1963; Heinzinger and Weston, 1964a). Fractionation factors for hydrogen-containing solutes other than the hydrogen ion are represented by the symbol q5, the formal definition being

The symbol FXL, is the fractional abundance of deuterium in the solute XL, and n that in water. (3) The “rule of the geometric mean” (Bigeleisen, 1955)governs isotopic mixing equilibria, such as (4). HzO+DzO

+ 2HOD

(4)

Accordingly, the equilibrium constant of reaction (4) is given by a quotient of symmetry numbers (u).

K =

xiOD

-

uH~O‘DnO

X H l O XDnO

-

&OD

--

1

(where x denotes mole fraction). Similarly, for the formation of isotopically mixed hydrogen ions #H30++@SO+

)H3O++ QD3Of

+ H2DO+ + HDzO+

(6) (7)

1 The charge designation will be omitted when this or any other formula appears as a superscript or subscript.

PROTOLYTIC P R OC E S S ES I N H2O-D 2 0 MIXTURES

267

we have

Kt =

xHIDO 4

- ~2$b~k% = 3

3 x1/3 SO DsO

(8)

%sDO

and

KIt

=

xHD~O

-

x 2 0 x”d0

u1$:0u3a30 =

3

(9)

UHD~O

Since we are dealing in all these equations with dimensionless ratios of mole fractions, we may replace mole fractions by molarities (designated by square brackets) or, indeed, any convenient molecular concentration units. The distribution of H and D among isotopically mixed species is then generally given by a Poisson distribution, i.e. we have for the fractional abundance F of a species XD,H,-, (Cadogan et al., 1955; Kresge, 1964) :

P-0

The quotient of factorials in equation (10) is also equal to the ratio of symmetry numbers of XD,H, and XL,. A physical implication of this assumption is that the occurrence of isotopic substitution in one of the positions of XL, has no effect on the exchange equilibrium of any of the other positions, i.e. the exchange behaviour of the molecule XL, is equivalent to m molecules of a hypothetical solute X‘L containing one hydrogen nucleus per molecule (Block and Gold, 1959). I n other words, thermodynamic secondary hydrogen isotope effects are assumed to be absent. (4) The concentrations of solute species are negligible compared with that of the solvent. This assumption allows us to equate the isotopic abundance in the solvent with that in the medium as a whole and to neglect the dilution of deuterium caused by the addition of an initially light substrate. ( 5 ) There are no other kinds of solvent isotope eSfect. This sweeping assumption embraces all effects not specified before. I n particular, it includes the hypothesis that so-called “transfer ” effects are negligible, implying, for example, that the equilibrium constant for the process

-,

HA+H20

+ HsO++A-

(11)

(involving protium species only) is the same irrespective of the isotopic composition of the medium. I n conventional terms, the equilibrium constant of (11) is also the acid dissociation constant in H20.

V. G O L D

268

B. Acid Dissociation Constant as a Function of n The conventional acid dissociation constant in light water ( K H A ) is to be compared with the measured dissociation constant in H20-D20 of atom fraction n (K,), which corresponds to isotopically composite processes, so that

where [L30+] represents the sum of concentrations of all isotopic hydrogen ions, etc. Equations (12) and (13) have been written with omission of activity coefficients y for the various species (activity coefficients which take the limiting value of unity for the inhitely dilute solution in a particular solvent mixture). According to assumption ( 5 ) ,the constant K,A of equation (12) will apply both to the dissociation of HA in H 2 0 and to the quotient of the concentrations of various fully light species in the isotopically mixed solvent. We can therefore write

The neglect of activity coefficients y in equations (12) and (13)-which meant that they were strictly valid only in the limit of infinitely dilute solutions-is less serious in equation (14).The interionic mean activity coefficient y* for the hydrogen ion and the anion will, at low ionic strengths, be a function of the nature of the solvent only to the extent that the coefficient A in the Debye-Huckel limiting law for activity coefficients depends on the dielectric constant of the solvent. I n view of the similar values of the dielectric constants of H,O and D 2 0 (see p. 261), the resultant difference between activity coefficients in H,O and D 2 0 solutions of the same low ionic strength should be small. (If both K H A and K , are results extrapolated to zero ionic strength, the problem disappears in its entirety.) (See also Section IVC.) The three factors of equation (14)can be expressed in terms of fractionation factors and n on the basis of the assumptions stated. It follows from equation ( 5 ) , (8),(9) or (10) that [HOD] = 2[H20]112[D20]1’2 [H,DO+]

=

3[H30+]2’3[D30+]1/3

[HD,O+]

= 3[H30f]1/3[D30+]2’3

115)

(16)

(17) Applying equation (10) to the water species (for which F =n)we obtain

[HZO] = (1-n),

(18)

PROTOLYTIC P R O C E S S E S I N H 2 O - D 2 0

MIXTURES

[HOD] = 2n(l -n) [D20] =

269 (19) (20)

n2

Similarly we get for the hydrogen ions :

The definition of the fractionation factor (equation 3) can be simplified for the case of a solute containing a single hydrogen nucleus only, so that Equation (‘25)can be rearranged and, by setting [LA] = ([HA] + [DA]), we obtain 1 -n n h A -[LA] = [HA1 l-n

+

Equation (2) leads to an analogous expression involving the fractionation factor 1 for the hydrogen ion. Rearrangement of (2) gives

l-F

=

l-n l-n + n l

and, on substitution of this result in equation ( 2 l ) , we get 1-n

The three factors of equation (14) can therefore be replaced by substitution from equation (18) (remembering that [L20]= 1 for a dilute solution), (26) and (28), to give

KHA- 1 - n + LA K, (l-n+~d)~ Equation (29), derived in this form by Kresge (1964) and by Long’s group (Salomaa et al., 1964a, b ; Schaleger et al., 1966) has not been widely applied since the direct measurement of &,A in aqueous solution is not usually attempted. The use of an experimental value of for acetic acid together with precise measurements of KHA/K, in equation (29) is fairly-though not perfectly-satisfactory (Gold and Lowe, 1968) (see Section IVB 1).

270

V. G O L D

More usually, &A is eliminated from equation (29) by using the experimental value of the dissociation constant in DzO (KDA). As n+l, KB+KDAand equation (29) leads to '$LA

=

13KHA/KDA

(30)

Substitution of this result in equation (29) yields the older and more familiar form of this equation: KHA - 1-n+n13K,,/KDA K, (1-n+nl)3

~

Comparing the form of equation (29) with the chemical equilibrium (11) to which it refers, we see that it is a product of factors of the form (1- n n+),raised to ~1power corresponding to the number of equivalent

+

hydrogen atoms in each set of equivalent hydrogen atoms in the species concerned. The exponent is positive for reactant species ( p )and negative ( r ) for the products of reaction, i.e. for any equilibrium

This conclusion has especially been considered in the context of ionization of polybasic acids (Salomaa et al., 1964a, b ; Schaleger et al., 1966) and of the possibility of formulations of the hydrogen ion in other ways than as H,O+ (Kresge, 1964). A more formal derivation of the equation (32) for the general case follows the same lines as the derivation of equation (29) (Salomaa et al., 196413; Kresge, 1964), the key step being the assumption that the rule of the geometric mean applies to every molecular species containing a set of equivalent exchangeable hydrogen atoms. Equation (32) can be applied to the autoprotolysis of water 2Hz0

+ H3Ot+OH-

(33)

to give, for the ratio of the ionic products

where c $ is~ the ~ fractionation factor for the hydroxide ion. Again, this factor can be replaced by the ratio for the isotopically pure solvents, since, for n = 1,

PROTOLYTIC PROCESSES IN H ~ O - D ~ M OIXTURES

271

so that

The autoprotolysis of water in H20-D,0 mixtures is one of the most thoroughly studied protolytic processes in this context (Gold and Lowe, 1963,1967; Salomaa et al., 1964b; PentzandThornton, 1967)(SeeVB3.).

C. Extension of Simple Equilibrium Theory to Acid Catalysis According to transition-state theory it is possible to consider reaction velocities in terms of a hypothetical equilibrium between reactants and transition state. It follows that the influence of the isotopic composition of the medium on reaction velocity can be considered to be the same as its influence on the concentration of transition states. The kinetic formulation of the problem can thus be replaced by one couched in equilibrium terms, and the equilibrium theory of the preceding section can be applied with a minimum of modification (Kresge, 1964). The rate constant, or catalytic coefficient, (k)for a catalysed reaction can be written as the product of three factors, viz. the equilibrium constant ( K * ) for the process forming the transition state from the reactants, the transmission coefficient, and the specific rate of transition state decomposition ( k T / h ) .We recognize that the third factor is independent of the isotopic nature of the reaction and assume that there is no isotope effect on the transmission coefficient. It follows that

The variation of the ratio K,f/K&with deuterium content of the medium will depend on the hydrogen stoichiometry of the transition-state formation, i.e. on the mechanism of catalysis. Equations (38) to (40) represent the formation of the transition state for the three most commonly considered mechanisms of acid catalysis for hydrogen ions in aqueous solution. They are designated A-1, A-2 and A-SB2 mechanisms, and the appropriate equilibrium constants for the formation of the respective transition states are expressed by equations (41) to (43). Equations for other mechanisms-the existence of which we certainly do not wish to exclude by implication-can be developed in a n analogous fashion. A-1:

S+LSO+

?=

SL++LZO

A-2 :

S+LsO+

+ SL++LzO

+ (sL+)*+Lzo + (LtO---sL+)*

(38)

(39)

272 A-SE2:

A-1 : A-2 :

The general equation (32) can be applied to obtain from equations (41) t o (43) expressions for the ratio K&/KZ as a function of n. There are two types of proton (deuteron) in the transition states found in (39) and (40). To distinguish these, the subscript 1 will be used t o designate the unique proton for all three cases and 2 for the remaining pair of equivalent protons in equations (42) and (43). With this not&fop, we can write :

A- I

(44)

A-2

The ratios K , / K D corresponding to these three equations follow by setting n = 1, so that A-1 :

A-2 :

It is the general shortcoming of pseudo-thermodynamic equations derived from transition-state theory that thermodynamic quantities relating to the transition state cannot be measured independently of the kinetic phenomena. The further development of equations (44) to (46) follows different lines.

PROTOLYTIC PROCESSES IN H ~ O - D ~ M O IXTURES

273

1. The A-1 case This mechanism presents the closest analogy to protolytic equilibrium. Combination of equations (37) and (44) yields

k, l-n+n+, -kH_ - (1-n+nZ)3 which should be compared with equation (29). However, whereas in equation (29) it is-at least in principle-always possible to treat the fractionation factor +LA as a directly measurable quantity, this is not so for in equation (48). It follows from equation (46)that dl =Z3kD/k, and hence equation (48) can be written as

k, _ -- 1 - n + nZ3kD/k, kE (1-n+nZ)3

(49)

which corresponds to equation (31). (The inverted form of the quotients of constants arises from the fact that the H30+species is treated in one case as a product and in the other as a reagent of the underlying equilibrium.) I n its present form equation (49) is fairly new (Gold, 1960)but is essentially a tidied-up version of earlier ideas (Gross et al., 1936b; Purlee, 1959). Its derivation by way of fractionation factors was first published by Kresge (1964). The connection between this case and acid dissociation and the similarity of the resulting dependence of the phenomena on n was recognized by Gross (Gross et al., 193613). 2. The A-2 case The solvent isotope equation on the rate constant follows from equations (37) and (45a):

& - (1--n+n+,)(l -n+n+z)2 (1 - n + nZ)3 kH

(50)

It contains two unknown fractionation factors and only the product

t $ 1 ~ 2 2can be deduced from the rate ratio k H / k D for the isotopically pure solvents, as shown by equation (47a). Accordingly, it is difficult to predict the course of the ratio k,lkH as a function of n. In principle, it should be possible to derive both 4, and t$z from the experimental data, provided these are of sufficient precision. Possible limiting situations for the transition state in this mechanism were discussed by Swain and Thornton (1961a). One of these cases, where the pair of protons resembles the pair of protons in the water molecule, implies the assumption that ~ $ ~ = so 1 , that equation (50) goes over into equation (48). For this situation the predictions for the A-2 reaction are identical with

274

V. G O L D

those for the A-1 case. Even without this exact cancellation an experimental distinction between equations (48) and (50) may be difficult since the value of d2is probably not far removed from unity. I n support of this supposition one can again refer to the extensive set of measured solvent isotope effects on uncatalysed bimolecular solvolyses in which the water molecule similarly acts as a nucleophile; these isotope effects are generally small (Laughton and Robertson, 1959). 3. The A-hYE2 case Since equations (45a) and (45b) are mathematically identical, it follows that the solvent isotope-effect equation (50) applies to this case too. The implications of equation (50) are, however, different for the two mechanisms. The parameter dl in equation (50) for the A-SE2case can be obtained by an independent measurement. It corresponds to the fractionation factor of the proton (in the transition state) which becomes incorporated in the product. Provided that this hydrogen nucleus does not undergo ready isotope exchange after formation of the product, dl can therefore be measured. It follows that the ratio of rates in H,O and D20 can be used to evaluate $2 since, according to equation (47b),

The inverse of d1 has also been called the “product isotope effect” and designated by the symbol r (Gold and Kessick, 1964b, 1965a, b). Using equation (51) and the symbol r in place of drl, equation (50) now takes the form _ k, -- (1-n+n/r)[l -n+n(j3rk,/kH)112]2 (52) k, (l-n+nl)S The difference between product isotope effects ( r ) and rate isotope effects (kH/kD)was independently recognized by Kreevoy and Kretchmer (1964) and by Gold and Kessick (1964). Equation (52) has been used for predicting the dependence of k, on n for the hydration of isobutene (Gold and Kessick, 1965a, b). During the transformation of reactants to product according to the A-SE2 mechanism a pair of protons, originally part of the solvated hydrogen ion, become part of a water molecule. At the transition state these protons may be thought to be intermediate in nature between protons of water and protons of the hydrogen ion. Kresge (1964) has therefore suggested that their fractionation d2 may be expressed in terms of a parameter cc which measures the degree of conversion of

PROTOLYTIC P R O C E S S E S I N H 2 O - D 2 0 M I X T U R E S

275

reactants to products at the transition state. According to this suggestion, 42 -- p a (53) For a transition state which resembles the reactants so that the hydrogen ion is essentially intact, 42approaches I in value. For a transition state in which the proton-in-transit has been entirely transferred to the substrate S, so that the other protons have attained a water-like state, 42=1. On substitution of equation (53)in (51), one obtains and equation (50)becomes

Equation (55)was originally obtained by a slightly different line of reasoning (Gold, 1960). This earlier approach suggests the possibility of a more quantitative interpretation of the parameter a and gives added insight into the implications of equation (54). This treatment will be considered in Section 111. It should be noted that, for the limiting case when a = 1, the degree of proton transfer in the transition state is complete and equation (55) reduces to the form of equation (as),i.e. the A-1 mechanism is seen to be a limiting case of the A-SE2 mechanism. Experimental evidence for equation (55)was first reported by Kresge (1964) for proton (deuteron) addition to 1,3,5-trimethoxybenzene in H20-D20 ;the rate constants are obtainable from an analysis of kinetic measurements of hydrogen isotope exchange reactions. This model of a proton transfer from the hydrogen ion suggests that the character of the non-transferred protons changes monotonically on going from H30+ to the transition state. The fractionation factor 42= POLis intermediate between fractionation factors for H30+ (4 = I ) and water (4 = 1). The transferred proton does not change its character in this manner. Its fractionation factor, given by equation (56), has always been found to be much lower than that for the initial or final state of the proton in its transit from H30+to SH+. Figure 1 is intended to illustrate the general shape of the functions described by equations (31) or (49) (to which the other mechanisms for H30+also approximate). Throughout the foregoing derivations it has been emphasized that the behaviour of rate coefficients is-on the assumption of transitionstate theory-directly parallel to the behaviour of the equilibrium

276

V . GOLD

constants for the formation of transition states (see equation (37)). The manner in which these equilibrium constants depend on the deuterium content of the solvent follows from the general equation (32). It is 3

3. G

2

2

2.0 I Y \

r

Y

I

1-0

I

0

I

0

06

I

0.8

\ 3-2 1.

n

FIG.1. Graphs to illustrate equations (31) and (49).

obvious, therefore, that equations (32) and (37) can be telescoped, to give a general expression for the variation of any rate constant with n, viz.

The two products are taken over the sets of equivalent hydrogen atoms in transition state and reactants, respectively, and t and r represent the numbers of equivalent hydrogen atoms in each set.

PROTOLYTIC PROCESSES I N H ~ O - D ~ M OIXTURES

277

D. Acid Catalysis by Species other than H,OS The A-SE2 mechanism implies a rate-limiting proton transfer from the aqueous hydrogen ion to the reagent substrate. I n suitable systems this mechanism can be tested by the observation of general acid catalysis, e.g. in acetic acid-acetate buffers the reaction velocity contains distinct contributions due to catalysis by hydrogen ion and undissociated acetic acid. Since acetic acid contains a single acidic hydrogen atom, as opposed to three for the aqueous hydrogen ion, the variation of its catalytic coefficient with deuterium content of the medium is predicted to show entirely different behaviour (Gold, 1960). For the rate-limiting proton transfer from a monobasic acid HA to a substrate S, S+HA -+ SH++A-

the transition state S---H---A contains a single proton and equation (56) therefore takes the form

k,

1-n+n$*

& -- l-n+n$LA It is an empirical fact that the fractionation factor $LA for acetic acid has a value close to unity (Gold and Lowe, 1968), whence it follows that kn should be a linear function of n, as has been observed (Gold and Waterman, 1968a, b). The profoundly contrasting behaviour of the catalytic coefficients for the hydrogen ion and for a monobasic acid, in the predicted manner, powerfully supports the analysis in terms of exchange effects as against an interpretation in terms of transfer effects (see IVCI). Again it is possible to replace the fractionation parameter for the transition state by the rate coefficient ratio in isotopically pure solvents, so that (Gold, 1960)

-kn_ - l - n + n $ L A k D / k H

(57)

l-n+n$,, This example is further discussed in Section VIA. kH

111. SOLVENT ISOTOPE EFFECTS I N RELATION TO CATALYSISLAW

THE BR0NSTED

A. Acidity Constants of Hydrogen Ions Early workers in the field of H20-D20 systems recognized that it was possible to define different acidity constants for the isotopic hydrogen ions, that for an isotopically mixed ion it was necessary to distinguish between proton acidity and deuteron acidity and that it

V. GOLD

278

was advisable to separate differences in acidity due to intrinsic effects from statistical effects arising from different numbers of protons or deuterons in the various species (Gross et aZ., 193613; Orr and Butler, 1937; Nelson and Butler, 1938). If the rule of the geometric mean (and the other three assumptions stated in Section IIA) are again assumed to apply to the isotopic distribution among the L30+ species and likewise to the LzO species, there are some simple relationships between various acidity constants. These follow directly from equations (18) to (24) and (27). We can define six acidity constants and, as shown in equations (58) to (63), substitute in the defining equations for the concentrations of water and hydrogen ion isotopes [see equations (18) to (24) and (27)]. The superscript and subscript respectively denote the hydrogen isotope to which the particular acidity constant refers and the isotopic hydrogen

G , D O

=

[HzO][D+] - (1- n + nZ)3 [D+] IHzDO+I 3nz [L30+]

The important outcome of these substitutions are the relations between proton acidity constants, (64) and (65), and the corresponding relations between deuteron acidity constants, (66) and (67). "Ez,o

2

=

3 K&

(64)

P R O T O L Y T I C P R O C E S S E S I N H ~ O - D Z OM I X T U R E S

279

The numerical factors in these equations are statistical; they correspond to differences in the number of the relevant hydrogen nuclei. The factor consisting of a power of 1 represents a thermodynamic secondary isotope effect.

To proceed further it is necessary to make some assumption concerning the connection between acidity constant and rate constant of proton (deuteron) transfer (kgLaOor kgLpO).A connection is suggested by the Brmsted catalysis law (Bramsted and Pedersen, 1924; Brransted, 1928) : k g L ~ O = P HL a o uH(K#L~O/?-)HL~O)a kgLaO

= PDLaO aD(KgLiO/r)DL~O)a

(68) (69)

The symbols have their usual significance except for the explicit designations of the isotopes concerned. The statistical factor pHLnO denotes the number of protium atoms in HL20+ (the general symbol for hydrogen ions containing one or more protium nuclei); the corresponding significance attaches to pDLaO. Applying equation (68) to equations (64) and (65) (Gold, 1960), we obtain @%DO = W aG o (70) @DaO

=

i1-2cL kg80

(71)

and similarly from equations (69), (66) and (67)

The numerical factors in equations (70) to (73) are again statistical. The factors involving 1 raised t o a power imply kinetic secondary isotope effects. The replacement of one protium atom by one deuterium atom increases the rate constant by F. This “inverse” isotope effect is qualitatively intelligible since the non-transferred nuclei are more tightly bound in the transition state than they were in the reactants. The existence of the secondary isotope effect also means that the ratio of rate constants in H20 and D20 (kH/kD)is not a measure of the primary isotope effect, whereas kZao/3k&,o is. To obtain the primary isotope effect it is necessary to divide kH/kDby 12u. (For experimental evaluations of primary and secondary isotope effects see Kreevoy et al., 1964; 10

280

V. GOLD

Kresge and Onwood, 1964; Gold and Kessick, 1965b. These and more recent determinations have been reviewed by Williams and Kreevoy, 1968.)

For a reacttion in H20-D20 mixture the rate of the part of the reaction initiated by (or due to) proton transfer to the substrate (vH) will be given by the sum of the three products of rate constant and concentration corresponding to hydrogen ions HL20+ vH =

k&o[H3O+] + ~

+

~ Z D O [ ~ Z ~ O ~ &+ J] Z O [ ~ ~ Z O + ~

(74)

These quantities can be expressed in terms of equations (21) to (23), (27), (70) and (71) so that

Correspondingly, according to equations (22) to (24), (27), (72) and (73) the total rate of deuteron transfers is

The second-order rate constant for the total reaction in H20-D20 mixture, defined as

k,

+

= @V,)/[SI[L30+1 €I

(77)

is accordingly given by

Recognizing that the contribution from H30+is the only one operative in H 2 0 (and that from D30+ in D20), we can replace the symbols kg30 and kg30 by the rate coefficients k, and kD, respectively, which are the measured second-order rate constants of the reactions in the isotopically pure media. (This step again implies the assumption that general medium isotope effects can be neglected.) With this substitution and on dividing through by k, we obtain equation (57), derived in Section IICl on a different basis. The parameter u was introduced in different ways in the two derivations. I n Kresge's derivation (1964) a is a measure of the degree to which the two non-transferred hydrogen nuclei have changed from being hydrogen ion-like to being water-like when the transition state is reached. Gold's derivation (1960) introduces CI as the exponent of the Brransted catalysis law for the hydrogen ions as general acids. This exponent is also thought to correlate with the degree of proton transfer

PROTOLYTIC PROCESSES I N H ~ O - D Z OM I X T U R E S

281

of the proton in transit for the transition state. In both versions, therefore, u appears as some kind of index of the extent to which the transition state is product-like relative to being reactant-like. The interpretation of u as a Brransted exponent suggests an independent approach to its evaluation from the study of general acid catalysis with other catalysing acids. There is no a priori reason why the a of the Brmsted catalysis law (relating, most usually, to a comparison of the catalytic reactivity of a series of carboxylic acids) should also apply to the catalytic effects of the hydrogen ions H30+,H2DO+and HD20+as proton acids. Williams and Kreevoy (1968) have reviewed this problem and concluded that values of u deduced from experiments with weak acids do not appear to differ significantly from values of CL deduced from studies of hydrogen ion catalysis in H20-Dz0 systems. However, it is not possible to give a definitive answer to this question. Where we wish to draw attention to this distinction the symbol will be used for values of the Brransted exponent for carboxylic acids, and u will be taken to relate to the isotopic hydrogen ions. I n any case, the analysis given suggests that the value of u deduced from HzO-D20 experiments is as useful an index of transition-state structure for the hydrogen ion-catalysed reaction as the value of uA is for the transition state in catalysis by weak acids. It should be noted that it is, of course, not permissible to use the Brransted catalysis law to relate rates of proton transfers to rates of deuteron transfers. No such suggestion is implied by the application of equations (68) and (69). IV. CRITIQUEAND POSSIBLE IMPROVEMENTS OF SIMPLETHEORY The development of the theory outlined in Sections I1 and I11 was based on a set of assumptions, stated somewhat axiomatically in IIA. We now examine the validity of these premises and ask what modifications of the simple theory are justified in the light of this examination. A. The Formula of the Hydrogen Ion and the Value of the Fractionation Parameter 1 The idea that the hydrogen ion can best be represented by the formula H,O+ is widely accepted, and the characteristic form of the equations for acid-base equilibria in HzO-DzO mixtures is a direct consequence of this assumption (Gold, 1960). In spite of the success of the simple theory in thus accounting for experimental results (see Section V) the assumption of the formula H30+was fairly recently called in question

282

V. G O L D

by Long and his collaborators (Halevi et ul., 1961). They proposed a “non-specifically solvated proton” (in practice, a model containing a single fractionating hydrogen nucleus) as an alternative for the hydrogen ion in solution, and argued in favour of the possibility of its correctness on the basis of somewhat limited data. However, the autoprotolysis of water provides a system for which the theory is more sensitive to the precise proton stoichiometry, and one which thus lends itself to a more diagnostic test of this hypothesis. On the basis of new experimental measurements on this equilibrium, Gold and Lowe (1963, 1967) ruled out the model of the non-specifically solvated proton. These measurements and conclusions were also confirmed by Long’s group (Salomaa et al., 1964a). Additional evidence in favour of the formula H,O+ comes from the combination of different methods of measurement of the fractionation parameter 1. It has been shown that the results are mutually consistent only if there are three fractionating hydrogen nuclei per hydrogen ion (Gold, 1963; Kresge and Allred, 1963; Heinzinger and Weston, 1964; Gold and Kessick, 1966a). As a result, the theory of the non-specifically solvated proton has generally been rejected (see, however, Halevi, 1964) and it seems superfluous to argue the point in detail now. On the other hand, does the formula H,O+ give sufficient expression to the extent of solvation of the aqueous hydrogen ion? There is persuasive evidence that the formula H,04+ (l),with three further molecules of water of solvation, is a better representation of the hydrogen ion in solution than H,O+ (Eigen, 1963). Such a formula would imply H

H

I

I

.O-H

H-0..

‘H

\ /

H”

0

I

-r;I H’

i,

‘H

(1)

that there are two types of hydrogen nuclei in the hydrogen ion. The only question relevant to the present issue is whether the six hydrogen nuclei of the three “outer” water molecules are in any way distinguishable from the protons of water molecules not adjacent to hydrogen ions. Measurements of I at different values of n point to the presence of three nuclei per hydrogen ion, as has just been mentioned. More exactly, these measurements indicate that there are three hydrogen

P R O T O L Y T I C P R O C E S S E S IN R z O - D ~ O MIXTURES

283

nuclei whose fractionation factor q3 differs markedly from unity. The evidence does not rule out the presence of additional hydrogen nuclei, so long as their fractionation factors are close to unity. Of course, as far as the phenomena now under discussion are concerned, a statement that the fractionation factor of certain water molecules is unity is tantamount to saying that they are indistinguishable from bulk water. I n other words, there is no point in complicating equations or formulae by considering them separately. Our experimental evidence is not definite enough to state that there is no isotope fractionation at all beyond the H30 group, but it seems too insignificant to require the specific inclusion of additional water molecules in the formula of the hydrogen ion at the present stage of development of theory. The small effect from the further solvation of the H30f ion may alternatively be described as a “medium effect” (see also Section IVC4). The calculation of the value of 1 from NMR measurements (Gold, 1963; Kresge and Allred, 1963) does not require knowledge of the number of equivalent hydrogen nuclei in the hydrogen ion. However, it does depend to a minor extent on the influence of the anion of the mineral acid used on the position of the proton resonance of the aqueous solution. The determinations of 1 cited above do, in fact, assume that neglect of this effect introduces no serious error, and the agreement between values of 1 derived for hydrochloric acid and for perchloric acid (Gold, 1963; Gold and Kessick, 1965a) adds some support to this assumption. However, the experimental error of the method and the assumption about the anion effect detract from the certainty with which the value of 1 is known. Similar uncertainties attach to the determination of 1 from the isotopic composition of the water vapour over solutions of perchloric acid in H20-D20 mixtures (Heinzinger and Weston, 1964; Heinzinger, 1965). Accordingly, the best value of 1 may possibly have error limits of the order of f 0.02. By general agreement, the value 0.69 at 25” is the currently accepted one for I , and has been adopted in the most recent work from several laboratories. Practically all existing experimental work on equilibria and reaction velocities in HzO-DzO mixtures relates to a temperature of 25’ but it may be noted that Heinzinger and Weston (1964) have also considered the temperature-dependence of 1. Their conclusions provide the basis for dealing with results at different temperatures. The nature of the problem of the anion effect in the determination of 1 by NMR measurements is further discussed for the solvent system CH30H-CH30D (Section VIIB) for which the discussion can be taken a little further than for H20-D20. Earlier evaluations of 1 (0.635, Nelson and Butler, 1938; 0.67, Purlee,

284

V. G O L D

1959) were based on EMF comparisons of cells containing HzO and DzO as solvent (Abel et al., 1935; Noonan and La Mer, 1939). The assumptions involved in these calculations can be criticized. A reconsideration of the problem (Salomaa and Aalto, 1966) in the light of additional EMF measurements has led to a result (0.693 at 25") in agreement with the generally adopted value. Clearly, the uncertainty in the precise value of I is reflected in a corresponding uncertainty in values of K , or Ic, calculated from equations such as (31) or (51). To put the matter in perspective, we tabulate below (Table 1) the percentage changes in k,/k, for n = 0 6 brought about by a change of +0-01 in the value of 1, on the basis of equation (51). The implications of the figures for the quantitative interpretation of k, - n curves are obvious. TABLE1 Percentage change in X-, (calculatedfrom equation 51) resulting from change of value of I from 0.69 to 0.70

Value of k D / k E 4 3 2 1 0.75 0.50 0.25

Percentage change in k , at n= 0.5

+ 0.7 + 0.4

- 0.04 - 0.7 - 0.9 - 1.1

- 1.4

B. The Rule of the Geometric Mean The assumption of this theorem enters into the theory in connection with the relative abundance of HzO, HOD and D20 and that of H,O+, H,DO+, HDzO+and D,O+ (equations (5), (8) and (9)). The equilibrium constant K for the isotope mixing of water (equation (4))is a determinable quantity. Its value, in the gas phase, can be found by statistical mechanics based on analysis of the vibration-rotation spectra of water. The most recent value obtained by this method, using the best available spectroscopic data and correcting a theoretical error present in some of the earlier calculations, is 3.85 at 25" (Wolfsberg, 1969). Direct massspectroscopic studies of the gas-phase equilibrium have yielded results in reasonable agreement with these calculations. Friedman and Shiner (1966), whose brief summary of their findings includes the statement

PROTOLYTIC PROCESSES I N H2O-D2O

MIXTURES

285

that their value also applies to equilibrium in the liquid phase, found K = 3-76 ? 0.02, a result essentially confirmed by another group (3.74 + 0.07; Pyper et al., 1967). Earlier values for K range from 3.27 to 3.97; these determinations were critically reviewed by Weston (1965). Whilst the value 3.96 (Urey, 1947) is sufficiently close to 4 to justify the use of the rule of the geometric mean, and forms the basis of Purlee’s (1959) revision of the theory, the same cannot be said of some of the lower values. (Gross’s use of K = 4 was largely intuitive.) On the basis of Topley and Eyring’s (1934) calculations, Orr and Butler (1937) were led to adopt K = 3.27 and to modify the theory by introducing a function which corrects for this departure from the rule of the geometric mean. Their treatment unfortunately robs the theory of much of its transparent simplicity, and one may surmise that this accounts for the comparative lack of interest in H20-D20 systems between 1939 and Purlee’s review twenty years later. Nevertheless, since the elegance of a theory must not take precedence over its validity, we now have to enquire what modifications of our treatment are dictated by the new values of K . With use of computers, it is easy to utilize the theory for any appropriate value of K . One may replace the expressions (18) to (20) for the relative concentrations of H 2 0 ,HOD and D 2 0 by the three simultaneous equations (79) to (81), and use the computed values of the concentrations (Pentz and Thornton, 1967 ; Gold, 1968b). [HODI2 = [H,OI[D2OI

[H20] = 1 - n - [HOD]/2

(79)

(80)

The resulting change in values of k%(or K,) calculated for a given ratio kD/kE(or KDA/KHA)from the values calculated by use of equations (51) or (31) is small but definite, if the value of K is taken as 3.76. The effect appears more prominently for large values of k D / k , (or K,A/KDA). Whilst these deviations from the simpler theory are not large, it may altogether be doubted that the manner of their calculation is soundly based (Gold, 1968b). As was said a few lines above, the validity of the rule of the geometric mean also affects the calculation of the relative amounts of H,O+, H,DO+, HD,Of and D,O+, and it is not entirely logical to neglect this aspect. It has been shown, with the aid of numerical calculations, that the assumption of a corresponding

V. G O L D

286

departure from the rule of the geometric mean for the three reactions (82) to (84) (i.e. taking K ’ = K ” = K’’’=$K1’2)leads to far-reaching compensation, and the calculated values usually differ much less from the predictions of equation (31) (Gold, 1968b). At present we have no independent data on which to base better estimations of the equilibrium constants of reactions (83) and (84), and the particular

E-O/H+ H ‘

H-0’

D ‘D

K‘,

2 H-0

/H \D

choice of K” suggested above is open to debate. The only conclusions we venture to draw at this stage are that the use of K = 3 4 for water and neglect of the possible inadequacy of the rule of the geometric mean for the hydrogen ion is probably a less satisfactory procedure than the adoption of the rule of the geometric mean for both species and, secondly, that methods of analysis of data for reactions involving the hydrogen ion as a reactant or product which attach significance to differences of less than 1% in k, or K , are at present unjustified (irrespective of the precision of the experimental results used). The breakdown of the rule of the geometric mean for HOD also has more straightforward consequences for isotope fractionation equilibria. If K # 4 , fractionation factors $ of substances in isotope exchange equilibrium with H20-D20 solvents are predicted to depend on the atom fraction n of deuterium in the system. For example, if K = 3 . 8 , $ should decrease by 5% on going from very low to very high values of n (Gold, 1968b). Experimental tests of this effect have shown the existence of such a trend in fractionation factors (Gold, 1968b; Kresge and Chiang, 1968). Despite the fact that this variation in $-values is comparatively large, the effect evidently cancels to a certain extent in the more complicated equations for the solvent isotope effect on equilibrium and rate constants, and the cancellation is almost complete when suitable equilibrium constants for the disproportionation of H,DO+ and HD20+ are taken.

PROTOLYTIC PROCESSES IN H,O-D,O

MIXTURES

287

C . Absence of other Kinds of Solvent Isotope E#ect It was recognized by La Mer and Noonan (1939; Noonan and La Mer, 1939) that the comparison of chemical processes in isotopically different solvents involves a general “medium ” or “transfer” effect, in addition to any effect due to the occurrence of exchange equilibria. The point was further developed by Kingerley and La Mer (1941) in relation to acid-base equilibria, but these authors also showed that in many cases the transfer contribution is of minor importance. Because of the relative size of the two contributions, most workers have paid little or no attention to the transfer contribution. Precisely the opposite view, namely that the entire or, at least, a large part of the solvent isotope effect on proton transfer processes was due to the transfer effect, was propounded by Long and his group (Halevi et d.,1961) but has been abandoned in their more recent work. Nevertheless, the size of the transfer contribution ought to be considered when an exact analysis of experimental data is attempted. The problem can be formally expressed by the introduction of a transfer activity coefficient which is in the following designated by the symbol y. The inclusion of activity coefficients into the “simple” equations was briefly considered by Purlee (1959) but his discussion fails to draw attention to the distinction between the transfer effect and the activity coefficient (y) which expresses the non-ideal concentration-dependence of the activity of solute species (defined relative to a standard state having the properties of the infinitely dilute solution in a given solvent). This solvent isotope effect on activity coefficients y is a much less important problem than the transfer effect, at least for fairly dilute solutions. For example, we have already mentioned (Section IA) that the nearequality of the dielectric constants of H20 and D 2 0 ensures that mean activity coefficients yi of electrolytes are almost the same in the two solvents over the concentration range in which the Debye-Huckel limiting law applies. For 0-05 M solutions of HC1 the difference is within 0.1% and thus entirely negligible in the present context. Of course, more sizeable differences appear if concentrations are based on the molality scale (Gary et al., 1964a) (see Section IA). 1. Transfer activity coeflicients

The transfer activity coefficient y for a solute S in H,O-D,O mixture for the process is defined in terms of the Gibbs free energy (dGLtrsnsfer) sc+o + L

o

(85)

288

V. G O L D

where the symbol S denotes a solute in H 2 0 (the standard state) and $ the same solute in H$3=D20. (The symbol will be used to designate this solute in D2 0 solution.) The subscripts in equation (85) are a reminder that we consider the transfer of S from one infinitely dilute solution to another infinitely dilute solution, i.e. that any effects due to differences in y have already been eliminated. We write AGtransfer =

RT 1nYs

(88)

(the broken bar again being applied to indicate the mixed solvent). It follows that, for infinitely dilute solutions, an equilibrium constant, say that of reaction (87), S + Q

in H,0-D20 mixture , in H 2 0 ( K a 7 )as

(87)

(ga7) can be related to that of the same reaction

2, Transfer activity coeficients and acid dissociation

Applying this reasoning t o equation ( 1 1 ) , we draw a distinction between the dissociation constant of the proton acid HA (i.e. the equilibrium constant of (11))in light water and the same equilibrium constant in H20-D20 mixture. By analogy with equation (88) the solvent dependence of the equilibrium constant HA is expressed as

Equation (as),modified similarly to recognize the solvent-dependence of the dissociation constant KHA, then becomes (91)

or (92)

As n -+ 1 , Ki, -+KDA,so that the expression corresponding to (30) takes the form $LA = l3 F I I A K H A / E D A (93)

PROTOLYTIC PROCESSES IN H 2 O - D z O

MIXTURES

289

and, on substitution of this expression for $LA in equation (92), equation (94) is obtained: K EA - 1 - n ?d3F H A K H A l i f D A (94) (1 - n + n1)3F H A Km

+

This modification of equation (31) is still based on the rule of the geometric mean, the use of which was in part justified in Section IVB. To some extent the arguments presented there concerning the cancellation of certain effects explain why it has been assumed in the derivation of (94) that fractionation factors, $ and I , are independent of the isotopic composition of the solvent. However, we should note that, apart from the imperfections of the rule of the geometric mean, effects due to the existence of a free energy of transfer can in principle make fractionation factors vary with n, though in practice the effect is expected to be small, To elucidate this point most simply let us refer to equation (25) and either assume that the rule of the geometric mean holds or, so as to show that this argument is entirely independent of the rule of the geometric mean, assume that the fractionation of LA is referred to a monohydric solvent LS. In the latter case $LA becomes equal to the equilibrium constant K g gfor the exchange reaction HA+DS

z +

DA+HS

(96)

and, adopting the formalism used in equation (88),

Equation (96) now expresses the medium-dependence of the fractionation factor (or KQ5).However, we note that the quotient of activity coefficients contains ratios of the form y H A / y D A which really represent isotope effects on transfer activity coefficients. For this reason, the activity coefficient quotient in equation (96) is expected to vary less rapidly with the isotopic composition of the solvent than the factor Y . Furthermore as a practical step, the inclusion of the variation of fractionation factors due to the transfer effect is an unrealistic refinement at the present time. The factor F H A in equation (94) can be replaced by TEA if it is permissible to assume that Gibbs free energies of transfer are linear functions of n. With this simplification the consequences of the transfer effect are reduced to the inclusion of a single parameter in the expression for the solvent isotope effect. However, we must ask ourselves whether equation (94) and its simplified form are improvements in the sense of having greater predictive value t,han the unmodified equation (29). The answer to this

290

V . GOLD

question depends on whether the parameter FHAcan be obtained from some other measurement or a priori calculation. The discussions of this and related topics (Goodall and Long, 1968; Arnett and McKelvey, 1969) suggest that this problem is unlikely to be solved in the immediate future. To that extent, equation (94) represents no more than an anticipatory advance in formulation. On the other hand, it is true that precise measurements of K , for monobasic acids as a function of n indicate that equation (29) is imperfect and that the assumption of a value of FHAdiffering slightly from unity allows the data to be more satisfactorily fitted to equation (94) (Gold and Lowe, 1968). However, the correction required is small. It is therefore far from certain that it can unambiguously be identified with the transfer correction (see Section V). 3. Transfer activity coeflcients and acid cataZysis

A corresponding modification of equation (44) allows the expression for k,/kH of A-1 reactions to include a correction for the transfer effect. Recalling the definition of K* in equation (41) and noting that its reciprocal bears a formal resemblance to the definition of an acid dissociation constant (equation (12)), we may proceed from equation (44) by steps similar to those which led from equation (29) to (94), viz. :

where

Equations (97) and (98) are the counterparts of (91) and (92). According to equation (37),we may now write

_ E, -- ( l - n + n + l ) Y & kH (l-n+~z,E)~ and the fractionation factor (bl can be expressed in terms of the rate ratio for the isotopically pure solvents (cf. equations (51) and (93))

PROTOLYTIC P R O C E S S E S I N R z O - D ~ O M I X T U R E S

291

Equations (94) and (102) can be obtained by an alternative procedure. Starting from equation (31) and noting that it should apply only t o the case where the constants K,, K H A and K D A relate to the same medium, i.e.

Substituting equations (89) and (90) in (103), we now obtain

If isotope effects on transfer activity coefficients are negligible (cf. the paragraph following equation (96)), the ratio F H A / Y D A can be set equal to unity, and equation (104) reduces to (94). The derivation of (102) in this way is analogous. We can treat the case of A-SE2 reactions most simply on the basis of these considerations by starting from equation (78) and again noting that the “constants”4n this case the rate coefficients kgto and k&,must be taken to refer t o the same medium as ka, the measured catalytic coefficient in the mixed solvent. Hence

We recall that it has been assumed that an isotope effect ratio of rate coefficients is the same as a ratio of equilibrium constants for the formation of the respective transition states (see equation (37)). In the present instance these equilibria are (cf. equation (40)) S+HsO+

+ (S---H---OHi)*K$

S +DsO+

+ (S-- -D-- -OD:)*

and

K$

and, by analogy with equations (87) and (go),

Accordingly, the catalytic coefficientsof hydrogen ion in the isotopically pure media (kH and ED) are related to the coefficients of H,O+ and D30+in isotopically mixed media by the equations zf,o = k H F & &g,O

=

&DY$/Fg

(110) (111)

292

V. GOLD

so that equation (105) becomes

With the previously discussed assumption about isotope effects on transfer activity coefficients (p. 291) we obtain

-

k,

=

[(I -n)kHY* +nP+2uiEDH*/P*](1 -n+nZl--~ ) (1 -n+nz)3

(113)

and note that this expression satisfies the requirement to go over into (102) for the case o( = 1 (i.e. the limiting case when the A-SE2 mechanism becomes indistinguishable from the A- 1 mechanism). Equation (1 13) allows us to arrive at an estimate of the importance of transfer effects for A-SEZ reactions in which the transferred hydrogen acquired by the product does not readily undergo isotopic exchange out of the product. Under such conditions the ratio of the first two terms in the first factor of equation (113) measures the ratio of protium to deuterium in the product, i.e. ~

l--m - (l-n)kHH* m ,11+2"ED

where m is the fraction of D-compound in the product. It follows that a determination of this product ratio, when combined with values of 1, kHIED,and CL, leads to avalue of H*,provided that all other assumptions of the theory may be taken to be valid. The problem is further discussed with reference to actual examples in Section VB4. 4. The connection between transfer and exchange evffects

The existence of transfer effects implies a change in solvent-solute interactions as the nature of the solvent is altered. I n general it is not get possible to express such effects in terms of specific molecular interactions. However, for the slight change corresponding to the replacement of H20 by D 2 0 an approach to this problem can be indicated (Gold, 1968a). Liquid water is considered to be a mixture of several of mole fraction xi,each having a different discriminawater species (Wi) tion with respect to hydrogen isotopes. The mean value of the respective i

fractionation factors is by definition equal to unity, i.e.

1. i=l

The dissolution of a solute P is considered to perturb the proportions

PROTOLYTIC PROCESSES IN H ~ O - D ~ M OIXTURES

293

of the water species and possibly create new types, and can therefore be written as a chemical reaction

where ( 4 2 ) is the (algebraic) increase in the number of Wi molecules as a result of dissolving one molecule of P. The isotope effect on this equilibrium corresponds to the exchange equilibria

Pap+ i(di/2)Wi 2-1

+ Piq + i ( 4 2 ) W i i=l

At equilibrium the ratio of concentrations of P in a mixed solvent and in water will be equal to the inverse of the transfer activity coefficient, --

y =

[PI [PI

~

fi [Wi]*C‘Z fi

= %=l

~Wi]dt/2

(117)

a=1

Remembering that a concentration quotient of this form can be expressed in terms of fractionation factors and n (cf. equation (32)) and assuming that the total number of water molecules per unit volume does not change (as is very nearly true), we can write

The transfer effect has therefore formally been represented as a fractionation factor. This development is of no immediate assistance to us in a practical sense, since the required information about values of di and +iis not yet available. These considerations illustrate why it is easy to mistake lack of agreement between calculated and experimental values of k,, due to the assumption of an incorrect reaction mechanism, for a medium effect. If the model of a reaction to which the simple equilibrium theory is applied is in error, the solvent isotope effect expression (56) will contain some incorrect factors of the form (1 - n + n+). Suppose, for example, that the expression (48) or (49)-applicable to a reaction of A-1 mechanism-is used in conjunction with experimental data for an A-2 mechanism. Analysis of the results should lead to the conclusion that a factor of the form (l-n+n+)2 (cf. equation (50)) has been omitted from the required theoretical equation. However, alternatively the conclusion might be drawn that equation (100) ought to have been used in place of (48),and the lack of agreement would then be ascribed to the presence of the factor Y&. But Y & is itself a quotient of transfer

294

V. GOLD

activity coefficients (equation (99)), and since each of these corresponds to a product of factors (1- n + n + ) (equation (118)), it may be possible formally to reproduce equation (60) by a combination of equations (100) and (118). If-as is frequently likely to be the case-r& in equation (50) differs much less from unity than does the elucidation of the exact position may be very hard. Of course, it can also be argued that ifa “transfer effect ” is expressible by including in the relevant equation factors of the form of equation (118), then such a chemically definite model of the “transfer” effect amounts to a more complete statement of the reaction mechanism. To that extent, therefore, the border line between exchange and transfer effects in mechanistic solvent isotope effect studies becomes shrouded in semantics. A particular case in point is that of the aqueous hydrogen ion itself. We have assumed that its fractionation behaviour is adequately described by a single parameter 1 characterizing the exchange of three equivalent hydrogen nuclei (see Section IVA). However, if we chose to include, in our formula of the hydrogen ion, water molecules in the vicinity of the HsO unit, as in formula, 1, for example, then additional factors (1-n+n+) would appear in our various expressions. Formula 1 would give rise to a total of nine factors (instead of three for H,O), i.e. (1 -1~ n+iinner)3 (1 - n n+outer)6. Again it becomes a matter of taste whether such a formulation is identified with a chemically definite structure 1, or as a “transfer” effect. I n the light of the preceding discussion one would have to say that the.“transfer” effect arises from the creation of six new sites as a result of dissolving H,O+ in water.

+

+

V. APPLICATIONS OF THEORY TO EXPERIMENTAL RESULTS The presentation of the subject matter so far has been cast in a somewhat deductive form, starting from a small number of axioms and exploring the mathematical consequences flowing therefrom or from individual minor modifications of the basic assumptions. The approach has been followed to establish the connection between very simple postulates and mathematically cumbersome-looking expressions for medium isotope effects. The procedure seems justified since it appears to us that the simple postulates are not seriously in error and will be substantially retained in any more complete theory. Possible improvements have been discussed in a mathematical vein, rather than by appealing to experimental data to point out where the basic theory is in need of modification. We hope that the reasons for this procedure have not entirely been lost in the algebra. Basically, the simple theory is fairly satisfactory. Its shortcomings are discernible only by precise

PROTOLYTIC PROCESSES I N H z O - D z O

MIXTURES

295

quantitative studies and it has generally been found impossible to associate them definitely with any particular objectionable feature of the assumptions. We now turn to a consideration of the experimental evidence, to examine the adequacy of the theory and the predictive value of rate measurements in isotopically mixed water as a tool in the study of reaction mechanisms. A general summary of known investigations is given in Table 2. This is followed by a somewhat detailed discussion of a small number of selected cases. Some of these (and some other) examples have been treated in depth in earlier reviews (Purlee, 1959; Salomaa et al., 1964a; Albery, 1967; Williams and Kreevoy, 1968). We shall not go over the same ground again where the present point of view does not materially affect the conclusions reached in these earlier discussions. Very early reviews by Wynne-Jones (1935) and La Mer (1936) are mainly of historical interest. Studies of the discharge of hydrogen at metal surfaces present additional problems and have not been included (see, e.g., Johnston andDavis, 1942; SalomonandConway, 1965; Bockris et al., 1965).

A. Summary of Available Results for H20-D20 Mixtures TABLE2 General Survey of Investigated Systems 1. Ionization constants

Acid

Reference

Date

Remarks

Acetic acid

a-d

1936-1940 1936 1938 1964, 1968

Conductance Quinhydrone electrode Specific catalysis Glsas electrode (see also Section VB1) Example of polyprotic acid Example of polyprotic acid (see also Section VB2)

e

f

BI

h

Ammonium ion Arsenic acid

i h

1964 1964

Benzoic acid 2,4-Dinitrophenol Formic acid Hydroquinone Imidazolium ion 2-Naphthol

2.

1938 1967 1937 1938 1967 1966

k 1

j

k cz

k

2-Nitrophenol Periodic acid

In

Phosphoric acid, K1

n, g j

Picric acid Water

P, 9, ,%.

Kz

0

n, xx, YY

1967 1966 1936,1964 1938 1936 1963-1967 1936-1936

Spectrophotometry Glaas electrode Ground state and fist excited singlet state Spectrophotometry Glass electrode, polybasic acid (see also Section VB2) Distribution measurements Glass electrode

296

V. GOLD

TABLE2-continued 2. Reaction velocitiea Substrate

Reaction

Acetal Acetic anhydride

Acid hydrolysis Spontaneous hydrolysis Acid-catalysed bromination Acid cleavage

Acetone All ylmercuric iodide Azulene 2-Chloroethanol 2-Chloroethyl vinyl ether 2. Chloropropanol [0-3Hlp-Cresol Cyanoketen dimethyl acetal

Diacetone alcohol Diazoacetic ester

Detritiation Dehydrochlorination (reaction with hydroxide) Acid hydrolysis Dehydrochlorination Detritiation Acid hydrolysis

1

Q

1937 1969

r

1937

a, as

1964,1967

bz 1

1964 1969

u

1966

t

1959

V

1959, 1960 1968

w

ww Acid-catalysed addition of methanol Hydroxide2, Y catalysed depolymerization z Acid decomposition aa Acid hydrolysis

2-Dichloromethylene-1,3-dioxolan Decomposition Dithionic acid Hydrolysis Epichlorohydrin Acid hydrolysis Ethyl formate Ethyl orthoformate Ethyl vinyl ether Ethylene oxide Glucose 1-Iodomercuri-2methoxyethane Isobutene Isobutene oxide Isobutenylmercuric bromide p-Methoxy-amethylstyrene Methyl acetate 2-Methyl-2-butene 1-Methyl-1-cyclopentene 8-Methylglycidol Nitrmide

Reference Date

az bb

x, 9

Unpublished 1938,1959

1938 1956 1938, 1964 1938 1967, 1968 1966 1934,1936 1960

Hydration Hydrolysis Acid cleavage

hh bb

ii

1965 1956 Unpublished

Hydration

rr

1967

Acid hydrolysis Hydration Hydration

X

!.i

1938 1956 1956

Hydrolysis Spontaneous decomposition

bb

kk

Also general catalysis by acetic acid I n methanol solution Conflicting observations

1968

f

3

See Section VIC

1936, 1938

Acid hydrolysis Acid hydrolysis Hydrolysis Mutarotation Acid cleavage

cc, dd bb ee, zz ff, 99

Remarks

1956 1937

At 100°C Conflicting observations

PROTOLYTIC PROCESSES IN H ~ O - D ~ M O IXTURES

297

TABLE2-continued Substrate

Reaction

Nitroethyl anion Nitromethyl anion Phenylboronic acid

Protonation ll El Protonation Protiodoboronation mm in 6.3 M sulphuric acid Hydrolysis 33 Inversion nn,oo Mutarotation PP

Propylene oxide Sucrose a-D-Tetramethylglucose 1,3,5-Trimethoxybenzene Trimethylethylene

Reference Date

Remarks

1968 1968 1960 1956 1936 1966

Protonation

44

1964

Hydration

jj

1956

Derived from hydrogen isotope exchange

a, L a Mer and Chittum, 1936; b, Chittum and La Mer, 1937; c, Brescia et al., 1940; d , Hornel and Butler, 1936; e, Korman and La Mer, 1936;f, Brescia and La Mer, 1938; g, Salomaa et al., 19640,; h, Gold and Lowe, 1968; i, Salomaa et al., 1964b; j,Rule and La Mer, 1938; k, Pentz and Thornton, 1967; I , Orr and Butler, 1937; m, Salomae and Vesala, 1966; n, Schwarzenbach et al., 1936; o, Gross and Wischin, 1936; p, Gold and Lowe, 1963, 1967; q, Batts and Gold, 1969; T, Reitz, 1937; 8, Kreevoy et al., 1964; t , Ballinger and Long, 1959; u, Salomaa et al., 1966; v, Gold et al., 1959, 1960; w, Gold and Waterman, 1968a; x , Nelson and Butler, 1938; y, Pocker, 1959; z, Gross et al., 1936a, 1938; aa, Gold and Waterman, 1968b; bb, Pritchard and Long, 1956; cc, Kresge and Chiang, 196713; dd,Kreevoy and Eliason, 1968; ee, Hamill and La Mer, 1936;j’, Kreevoy and Ditsch, 1960; gg, Kreevoy, 1960; hh, Gold and Kessick, 1965a, b; ii, Kreevoy and Landholm, unpublished; jj, Purlee and Taft, 1956; kk, La Mer and Greenspan, 1937; El, Goodall and Long, 1968; mm, Kuivila and Nahabedian, 1960; nn, Hamill and La Mer, 1936b; 00, Gross et al., 193613; pp, Huang et al., 1966; pq, Kresge, 1964; w, Simandoux et al., 1967; 85, Kreevoy et al., 1967; ww, Gold and Grist, unpublished; xx, Abel et al., 1935; yy, Wynne-Jones, 1936; zz, Moelwyn-Hughes et al., 1934; az,Stamm and Goehring, 1938; bz, Schulze and Long, 1964; cz, Wehry and Rogers, 1966.

B . Some Case Studies 1. The dissociation of acetic acid

The dissociation of acetic acid in aqueous solution is an example of the simplest type of protolytic process. The dissociation constant was one of the first chemical parameters to be studied as a function of isotopic composition of the solvent (La Mer and Chittum, 1936: Hornel and Butler, 1936), and the determinations have been repeated by several groups of workers. Conductivity measurements (La Mer and Chittum, 1936), potentiometry using the quinhydrone electrode (Korman and La Mer, 1936) or glass electrodes (Salomaa et al., 1964a; Gold and Lowe, 1968), and measurements of the rate of a hydrogen-ion

298 V. G O L D catalysed reaction (Brescia and La Mer, 1938) have been found suitable for obtaining precise results. I n addition, Gary et al. (1964a) have performed an accurate determination of the ratio K E / K Dby EM3 measureI

I

I

I

0

0

0

a

0

0

*,do

7 /*

s o Y

a

Y

a

0/OW

i

0

/-

o/@ '0

i'f

e/L

(

/a

@

f I

I

02

0 4

I

06

I

0.8

n

FIQ.2. Dissociation of acetic acid in HEO-D~O.

ments on cells with a hydrogen electrode. The agreement between existing data has recently been examined (Gold and Lowe, 1968). The main sets of results are reproduced in Fig. 2. The solid line represents equation (31) based on the value for K H / R Dby Gary et al. (1964a). The empirical equation of the best curve through the data, of

PROTOLYTIC PROCESSES I N H 2 O - D z 0

MIXTURES

299

Gold and Lowe (1968) and fixed at its extremes by the KH/KDratio of Gary et at. is: p x , - pKH = 0.4630n + 0*0377n2+ 0.0138n3

(119)

A more critical test of the same data is shown in Fig. 3 where the points now represent the difference between determined pK-values and the predictions of equation (119). Generally very satisfactory agreement between the results of the two sets of potentiometric studies with the glass electrode and those of the two conductivity studies is seen to exist. There is virtually a random scatter of all these points about the prediction from equation (119). The kinetic data (Brescia and La Mer, 1938) also fit in reasonably well, although they show some larger deviations and less good reproducibility, especially for large values of n. The predictions of various theoretical equations are superimposed on the experimental data in Fig. 3. Curve A is a plot of equation (as),in logarithmic form, using the experimentally determined (NMR) value 0.96 for the fractionation parameter for acetic acid (Gold and Lowe, 1968) so that pKn-pKH = log[(1- 0*04n)/(l- 0.31n)'I

(120)

Evidently this does not give an entirely satisfactory description of the experimental results, even though the maximum discrepancy between theory and experiment amounts to only ca. 0.05 pK unit. These experiments represent the only existing study where the dependence of a protolytic equilibrium constant on n has been related only to independently measured fractionation parameters. The predictions of equation (31),usingthe accurate value of KHA/.KDA obtained by Gary et al. (1964a), are shown in curve B. Clearly, this simple equation gives a much better fit, but the use of the experimental value of KHA/.KDAguarantees exact agreement at the two extremes and thus renders the success of the theory perhaps somewhat less striking. With the experimental value of KHA/EDA used, curve B is in effect a plot of equation (121): pK, - pKH = log[(1+ 0*074?t)/(1- 0.31n)3]

(121)

Comparison of equations (29) and (121) shows therefore that the former (theoretical) equation would give the same curve if a value of 1.047 were assumed for However, it is not thought that such a high the error limits value is compatible with the NMR determination of of which are unlikely to be appreciably greater than 0.96 -+_ 0-02 (Gold and Lowe, 1968). (However, see also the discussion following equation (137)4

300

V. G O L D 0 01

0 01

00 0

00

.

oc 0

0

+

. .

I

-

0'2 "

-0

*

0

0 I

0

0

+. n P

f

X

.

-

.

I

" 0'4

A

'016

.

c

-0 0

-0 0

-0.0

f-l

-0 0

FIG.3. Dissociation of acetic acid in HzO-DaO. (Results and calculated curves are expressed as differences from the "best-fit " equation ( 1 19).) Experimental points: +La Mer and Chittum (1936); x Chittum and La Mer (1937); 0 Bresoia and La Mer (1938); Salomaa et al. (1964a); Gold and Lowe (1968). Curve A : equation (119); curve B : equation (29); curve C: equation (31) or (121).

+-

PROTOLYTIC PROCESSES I N H z O - D Z O MIXTURES

301

Curve B is also indistinguishable from a plot of equation (122) pK,-pKH

=

log[(1- 0.04n)/0-894n(l- 0 ~ 3 1 n ) ~ I

(122) This expression is obtainable from equations (92) or (94) with the added assumption (Halevi et ul. (1961)) that Y H A = FsA(see Section IVC). The parameters in equation (122) imply the use of 4 L A = 0.96 and F H A = 0.894 for equation (92) or of F H A = 0.894 together with the experimental value of KHA/EDA in the case of equation (94). The mathematical equivalence of equations (92) and (94) with these parameters was selected to reconcile the experimental values follows because FHA through equation (93), i.e. of +LA and KHA/ZDA = 4LAzDA/KEA13

0.96/(3.27 x 0.69)3 = 0.894 The fact that the values of the transfer activity coefficients to be used in equations (92) and (94) are the same is thus in no way remarkable. However, it is worth noting that equations (121) and (122) are algebraically not equivalent and that they nevertheless lead to indistinguishable predictions. These numerical calculations illustrate the difficulty of seeking the theoretical basis for a small discrepancy between experimental data and the predictions of a nearly but definitely not perfectly satisfactory theory. Clearly, a small correction factor which is a function of n is all that is necessary to shift the calculated curve towards the experimental points. It may be observed that curve B is still not the best line that can be drawn through the data (which would be the horizontal line through zero on the ordinate, correspondingto equation (119)). Possible improvements in curve fitting have been looked into (Gold and Lowe, 1968) but it is doubtful that the physical cause of the remaining discrepancy can be found in this way, at least not without even further improvement in the accuracy of the experimental data. It must be pointed out that the analysis here presented for the acetic acid behaviour has made no reference to other possible complications, such as the imperfect validity of the rule of the geometric mean for water and hydrogen ions, which may well become significant in this context (see Gold, 1968b, for some sample calculations of the resultant effect on KH/K,). It would be valuable to have precise measurements on a family of different structurally related acids so that one could attempt to separate the imperfections of theory due to anions from those associated with the other species. =

V. G O L D

302

The foregoing discussion of the success of different theoretical equations has assumed that the experimental curve is very securely anchored at its two ends, i.e. that the accuracy of the ratiOEDA/KHA considerably exceeds that of the points at intermediate isotopic compositions. The assumption is probably justified in the present case, since the EDA/KEA value is based upon work with the hydrogen electrode at the National Bureau of Standards (Gary et al., 1964a),whereas the other points were obtained by use of the glass electrode or other less exact techniques. However, in general it is not true that the results in HzO and DzO are far more accurate than the other data and in such cases EHA/.KDA (or kH/kD) becomes a point of comparable statistical weight to the others. This circumstance generally introduces more latitude into the curve fitting procedure than has been admitted in the above discussion. The theoretical treatment of the data for acetic acid by Gold and Lowe (1968) included a study of the hypothetical assumption of a monoprotic hydrogen ion (Halevi et al., 1961). It was concluded that such a formulation gave a significantly worse agreement with the results. 2. The Jirst dissociation of phosphoric acid, boric acid and periodic acid The case of phosphoric acid was selected by Salomaa et al. (1964a) to exemplify a protolytic equilibrium in which both the acid and base form involved contain more than a single equivalent hydrogen atom. The appropriate form of the general equation (32) is thus

KH= K,

(1-n+n41)3 (l-n++Z)3 (1-n+n+,)2

where relates to L3P0, and +2 to LzPOy. Neither of these fiactionation parameters was determined directly and they were evaluated by insertion of the experimental values for n = 1 and n = 0.5 into equation (123). The solution of these two simultaneous equations gave the reasonable results = 0.77, $, = 0.98 (the value I = 0.67 being used). The corresponding results for the analogous case of arsenic acid were = 0.83, r$z = 0.98. Insertion of the values of r$l and into equation (123) then allows the entire curve to be calculated. Salomaa et al. (1964a) show that there is good agreement between their calculated values and the experimental results. This agreement is hardly surprising for the manner of evaluating (61 and c $ ~ensured perfect agreement at the two extremes and at the midpoint of the curve. This case cannot therefore be claimed to constitute a very severe test of the theory. What is of greater potential interest is that the procedure indicates the use of the theory in the determination of fractionation factors. With this object in mind the experimental data can be deployed more effec-

PROTOLYTIC PROCESSES IN R ~ O - D ~ O MIXTURES

303

tively by using the entire set to find the values of d1 and rpZ which give statistically the best fit to equation (123). It should, however, be noted that fractionation factors evaluated by either of these procedures are subject to uncertainties, set in particular by the neglect of transfer activity coefficients. I n this connection it may be recalled that the evaluation of rpLA for acetic acid from dissociation constants without consideration of transfer led to the value 1.047, as compared with the result 0.96 f 0.02 from NMR data. It should also be realized that the evaluation of several fractionation parameters from experimental determinations of a single equilibrium constant as a function of n may not lead to a very reliable answer, simply because of the nature of the functional connection between K , and fractionation parameters. Thus with the now generally used value E = 0.69 the substantially different values dl = 0.71, rpZ = 0-83 are in good agreement with the experimental results. If these results are accepted it is also possible to evaluate the fractionation factor for the HPOf ion as 0.68, by combination of Rule and La Mer’s (1938) measurements of the second dissociation constant of phosphoric acid in HzO and DzO (K,/K, = 3.62) with the value of &. More recent values of K 2 (Gary et al., 1964b) lead to a much higher fractionation factor for HPOZ-. A different problem arises from the possibility that the exact chemical formulation of the neutralization of an acid by base may sometimes be in doubt. For example, one could ask whether the first ionization of phosphoric acid might conceivably be the reaction OP(OH)3+2H20

-+ H30++OP(OH)4-

(124)

instead of the accepted one OP(OH)s+HzO + H30++02P(OH)z-

In the former case, equation (32) would be

where t#3 would now apply to the four protons of the species OP(OH)4-. and rp3 from the experimental Proceeding as before to evaluate dissociation constants for n = l and n=O.5, one now finds +,=0-80, +,=0-99 (with Z=O-69). These values are closely similar to ones obtained on the alternative model and on the basis of existing knowledge may be considered to be equally reasonable. Similarly (since the calculated curve is bound to give exact fits at n= 0 , n= 0.5 and n= 1) the values of K=/K, calculated on the basis of equation (126) with the above fractionation parameters are in sensible agreement with experiment. It must thus be concluded that a distinction between alternatives

304

V. GOLD

such as (124) and (125) is sometimes difficult on the basis of the dissociation constants in H20-D20 mixtures alone. For the particular example cited the second alternative seems the more credible one but for boric acid, B(OH),, Raman spectra indicate that the product of the first ionization, the borate ion, is to be formulated as B(OH)*(Edwards et a&.,1955). A detailed analysis of the course of the first dissociation constant of boric acid in H20-D20 mixtures (Gold and Lowe, 1968) leads to the unexpected conclusion that of the equations

+ B(OH)4-+H30+ + OB(OH)z--t-HsO+

B(OH)a+ZHzO

(127)

B(OH)s+HzO

(128)

the second alternative gives a significantly better description of the results. However, in view of the independent evidence in favour of the formula B(0H)y for the borate ion, another model was explored and it was found that equation (129), in which the boric acid molecule is taken to be hydrated, also gave an excellent fit to the data.

+ -

H~O--B(OH)~+HZO+ B(OH)4-+H30+

The required fractionation factors (with 1 = 0-69) are 1.49 for the borate ion and 1.4 for boric acid (the same value was taken for all five positions). However, it must be stressed that these conclusions could not be reached by casual inspection of k,-n curves but only after a least-squares analysis of alternative curve-fitting attempts which may be open to criticism if the role of transfer effects has been underestimated. Analogous problems are met in the dissociation of periodic acid (Salomaa and Vesala, 1966) where the first and second dissociations are thought to involve the following as the main species ~ O ( O H ) S + ~ H+ ~O H30f+104-+3Hz0

+ 2H~O+fIOs(OH)~-

(130)

The solvent isotope effects for the two stages of ionization were measured separately. The analysis of the data in terms of fractionation factors is exceptionally simple in this case because the species IO;, which is involved in both equilibria, does not contain any hydrogen, and therefore does not have to be included in the appropriate forms of equation (32). It follows that there are only two unknown fractionation factors [for IO(OH), and for IO,(OH)i-], and the two results for K,/KH are sufficieni for their evaluation. The course of the K J K , values at all intermediate compositions of solvent may therefore be used as a test of theory. The agreement is not perfect. The character of the data suggests that this may in part be due to experimental difficulties but

PROTOLYTIC PROCESSES IN H z O - D Z O MIXTURES

305

the deviations are too systematic to be attributable to random errors. Salomaa and Vesala (1966) rule out the possibility that the mono-anion may be more extensively hydrated-so that its fractionation factor could be introduced as a disposable parameter to improve the fit. Instead, they attribute the shortcomings of simple theory in the treatment of this scheme to the neglect of the free energy of transfer of the mono-anion. The required adjustment is therefore effected by assuming a suitable value for this term and modifying the calculation in accordance with the procedure set out in equations (86) to (92). The authors suggest that the free energy of transfer is much larger for this unhydrated species than for acids and ions containing hydroxyl groups. This consideration would in part justify the point of view taken in the discussion of the case of boric acid where transfer effects were neglected but where all species involved carry hydroxyl groups. It has previously been pointed out that the main transfer effect can be thought of in terms of fractionation factors (see Section IVC4) and to that extent it may be thought that the distinction is a somewhat semantic one. However, this is not really the case. The conclusion reached by Salomaa and Vesala is more definite in that it argues against the introduction of a fractionation factor for I-OH groupings in the mono-anion, a chemically defined species ; the authors believe to have established by spectrophotometry that the concentration of this species is small. The examples cited above illustrate the difficulties of deciding the state of hydration of the species involved in an equilibrium on the basis of solvent isotope effects. This discussion has certain parallels in problems of reaction mechanism where the degree of involvement of water in the transition state (distinction between A-1 and A-2 reactions) is at issue. By analogy with the conclusions reached for the dissociation of poljybasic acids we may anticipate that it will similarly not be easy to settle such questions by the measurement of rate constants in HzOD20 mixtures. 3. The autoprotolysis of water The fact that the ionic product of DzO is several times smaller than the ionic product of ordinary water was one of the earliest firm results in deuterium chemistry (Abel et al., 1935; Wynne-Jones, 1936; Schwarzenbach et al., 1936). Three recent electrometric determinations (Gold and Lowe, 1963,1967; Covington et at., 1966; Pentz and Thornton, 1967) agree that the difference in pK, values is in the range 0.8600.870 at 25°C; a lower difference (0.809) was reported by Salomaa et at. (1964).

306

V. GOLD

The behaviour of K , as a function of n throws light on the fractionation factor of hydroxide ion and is thus relevant to the study of basecatalysed reactions in HzO-DzO mixtures, as well as being indicative of certain limitations of the chemical model generally used. An added immediate incentive to the first two systematic studies of K, in H20D20 mixtures (Gold and Lowe, 1963, 1967; Salomaa et aZ., 1964s) was to provide a test of the relative merits of the view of the hydrogen ion as a “non-specifically solvated” proton (Halevi et al., 1961) as against the more conventional formulation. The theoretical predictions for the autoprotolysis equilibrium happen to be particularly sensitive to the model chosen, and both investigations conclude unequivocally that calculations based on the monosolvated proton (i.e. equation (36)) give a decidedly better fit to the experimental data than those based on the alternative model. Apart from this agreement about the main controversial point which was settled by these studies, there is some quantitative discrepancy between the two sets of results. More recent investigations (Covington et al., 1966; Pentz and Thornton, 1967) have tended to support the results obtained by Gold and Lowe (1963, 1967) on which the following discussion will accordingly be based. The data can be expressed by the empirical equation (least-squares

fit) ApK = 0.7282n+ 0.0512n2+ 0.0826n3

(131)

from which none of the experimental points deviates by more than 0.010. Equation (36) gives a fairly good theoretical description of the data. Its predictions differ nowhere by more than 0.009 from the empirical equation. However, the two equations do not give coinciding results and Gold and Lowe (1967) note that any one of several minor refinements of equation (36) results in an appreciable improvement of the fit. With the introduction of a single disposable parameter, the predictions of the empirical equation can be reproduced to within 0.001 pK unit over the entire composition range by a modified form of equation (36). Three such modifications may be mentioned. (a) The inclusion of transfer activity coefficients converts equation (36) into

is assumed to be where Fw= (KW)H/(KW)H, and Yw = (xW)H/(KW)H equal to 7%.Equation (132) gives the best agreement with equation (131) if Fwis taken to have the value 0.79. (b) The formula of the hydroxide ion can be modified to include

PROTOLYTIC P R O C E S S E S I N Hp,O-D20 M I X T U R E S

307

hydrogen-bonded water molecules, as in formula 2. If it is assumed that the three hydrogen atoms which are hydrogen-bonded to the negatively charged oxygen atom have a fractionation factor #2 significantly different fiom that of bulk water, then the chemical equation for autoprotolysis becomes SHaO

+ OH-(HzO)a+HsO+

(133)

(The water molecule hydrogen-bonded to the hydrogen atom of the hydroxide group is assumed not to differ from bulk water in fiactionation behaviour, and may therefore be omitted.) The modification of equation (34) corresponding to (133) is therefore

and the equation corresponding to (36) is

The value of d2required to bring equations (131) and (135) into agreement is 0.92. (For independent evidence in favour of a similar formula of the hydroxide ion, see Yagil and Anbar, 1963.) (c) It is possible to take explicit account of the outer water molecules in formula 1 for the hydrogen ion. Designating their fractionation factor by #' we obtain, by entirely analogous arguments, equation (136) : (KW)H

-=

(KW)t8

1 (I-n+nl)'(l -n+n(K,),/(KW)HIS#P)(l

-fi+n43)'

( 136)

The required value of +3 is 0.96. It is obvious that a further equation can be obtained by considering both formulae 1 and 2 to apply, and that it will be possible t o obtain a fit with it. It also follows that the required values of #2 and 43can be much closer to unity than those required for equations (136) and (136). Whether any of these refinements have any basis in reality cannot

308

V. G O L D

convincingly be decided in the light of existing data. There is a need for even more accurate work on this problem. However, it seems that the value cj8 = 0.96 is rather too far from unity to be possible, when it is remembered that other data do not suggest an effect of this size. The equivalent effects of the chemically specific models (b) and (c) and the transfer effect formulation seem to illustrate the point previously made that it is permissible to regard transfer effects as indicative of the involvement of water molecules beyond those represented in the conventional stoichiometric equation for a reaction. Equation (35) allows an evaluation of the fractionation factor for the hydroxide ion on the assumption that the autoprotolysis is adequately described by the simplest equation (i.e. 33). The resultant value is 0-42. This figure does not agree too well with the results of a careful direct study of the fractionation of deuterium between dissolved hydroxide ions and water (Heinzinger and Weston, 1964b), (0.48 at 13.5"C). It is only fair to point out that the low ratio of (KW)H/(KW)D (6.5) obtained by Salomaa et al. (1964a), when substituted in equation (35), would lead to the value 0.47 for doL and would thus largely reconcile the observations. However, as has been discussed, the balance of evidence is at present against this value of (Kw)E/(Kw)D. Attempts to determine dOLby the NMR method have not so far produced results remotely in line with those considered above (Kresge and Allred, 1963; Gold, 1963). This perhaps underlines the need for considering the effect of hydroxide ions on the structure of aqueous solutions. Many questions on this important reaction thus still remain unanswered. 3. Acid-catalysed hydrolysis of ethyl formate This reaction, first studied many years ago by Hornel and Butler (1936), has been the subject of a recent investigation by Salomaa et al. HzO+HCOzEt -+ EtOH+HCOZH

(137)

(1964a) whose results suggest that the earlier measurements were seriously in error. The mechanism of this reaction is often termed A-2, though only in the sense that the transition state contains, in addition to the conjugate acid of the ester, an additional water molecule (or at least one such molecule). The implication of such complicated transition states to reaction rates in H,0-D20 mixtures were first considered in some detail by Swain and Thornton (1961a). Their model is subsumed as a special case in the more general formulation of kinetic solvent

PROTOLYTIC PROCESSES I N H ~ O - D ~ M O IXTURES

309

isotope effects given by Salomaa et al. (1964a) and Kresge (1964). Salomaa et al. discuss the hydrolysis of ethyl formate in terms of the formation of a hypothetical transition state containing a variable number (2m + 1) of equivalent hydrogen atoms, i.e. H@+(?%- 1)HzOtS

=+[SO,H&,+,]*

(138)

They conclude that the assumption m=O (i.e. an A-1 mechanism) is unsatisfactory but that progressively better, though not perfect, fits are obtained for m = 1 and m = 2. The authors cautiously state (with respect to the curve for m= 1) that “it is difficult to say whether the difference is real or experimental”. One may therefore hope that the position may be further clarified by more precise rate measurements. However, it must be borne in mind that the shape of the curve is only slightly changed on going from m = 1 to m = 2. A recalculation of the results with l=O.69 shows that, for n=O.5, the following values of kJkH are predicted for the different models : m = 0, 1.256; m = 1, 1.212 ; m=2, 1.203. The experimental value is 1-18. It would therefore be unrealistic to expect this approach to yield much information also about the structure of the transition state, i.e. to go beyond its stoichiometry. It is, of course, obvious that a model with five equivalent hydrogen atoms is not plausible and must represent an approximation in which an average fractionation factor has to be assumed for non-equivalent positions. However, the measurements and interpretations given by Salomaa et al. (1964a) have removed what was at one time thought to be a case of anomalous behaviour. 4. Hydrolysis of 2-dichloromethylene-1,3-dioxolan (DMD)

This reaction is believed to be typical of a large number of organic reactions in which the rate-determining step is associated with a proton transfer from the aqueous hydrogen ion (or other Brmsted acid) to an unsaturated carbon atom. The rate behaviour of such processes (termed A-SE2 reactions) in H,0-D20 media is expected to conform to the equations set out in Section IIC3. The conversion of 1,3,5-trimethoxybenzene to its conjugate acid (Kresge, 1964) and, more especially, the hydration of olefins (Purlee and Taft, 1956; Gold and Kessick, 1965b; Simandoux et al., 1967), the hydrolysis of vinyl ethers (Salomaa et al., 1966; Kresge and Chiang, 196713; Kreevoy and Eliason, 1968),the protonation of nitroalkyl carbanions (Goodall and Long, 1968) and the hydrolysis of cyanoketen dimethyl acetal (Gold and Waterman, 1967, 1968a) are closely related to the present example and have similarly been studied, in varying depth. A recent review covers a family of

310 V. G O L D A-SE2 reactions (mainly alkylmercuric halide cleavages) which have been investigated by Kreevoy’s group from a similar point of view (Williams and Kreevoy, 1968). The case of 2-dichloro-methylene-1,3dioxolan (3, DMD, for short) (Gold.and Waterman, 1968b) illustrates most of the interesting features of all these examples. The reaction of 3 in aqueous acid results in the formation of the 2-hydroxyethyl ester of dichloroacetic acid, the structure of which is given by either or both of formulae 4 and 5. Depending on which of these formulae is considered, the reaction could be described either as hydrolysis or as hydration of 3. CHz-Ok

I

CH2-0

/c=cc12

(3) CHz-0,

I

HO .CH2. CHzO .COe .CKClz (4)

/OH C

CH2-0’

‘CHClz (5)

(6)

The distinction would not appear to be important to the present discussion. It is sufficient to regard the formation of the ion 6 as the rate-determining step. When the reaction is carried out in D20 as solvent, the atom which becomes attached to carbon to form the new CHCl,(CLCl,)-grouping will be a deuterium atom and, in isotopically mixed media, will be determined by n. and the fractionation factor in the transition state. This expectation is based on the knowledge that hydrogen isotope exchange between the CHC12-groupof the ester and the medium is a comparatively slow reaction. The fractionation factor of the transferred proton in the transition state was determined by comparing the isotopic composition of the CLC1, group of the product with the isotopic composition of the medium. It is the fractionation factor which appears in equation (46a) and others based on it, which relates to this proton-in-transit. Equation (139)defines 41in operational terms. m l-n (139) 41 = c m x n where m is the ratio [CDC12]/[CLC12]. The experimental value of found for this reaction is 0.194 & 0.006. (The inverse of is the product isotope effect T (Gold and Kessick, 196413; 1966a, b.) The rate isotope effect (the ratio of the catalytic coefficient of hydrogen ion in D20 to that in H20)differs from &; its value was found to be 0.39. The rate constants for intermediate isotopic compositions can be fitted t o

P R O T O L Y T I C P R O C E S S E S IN H ~ O - Dz o M I X T U R E S

311

equation (55). The closest fit, according to a least-squares analysis, is obtained if the value a = 0.42 is used, but the kinetic measurements are not precise enough to distinguish between this exponent and values differing from it by as much as 0.1. The reaction exhibits general acid catalysis and the Brransted exponent aA for acetic acid derivatives is 0-49which, in view of the foregoing remarks, is not significantly different from the best value of a. [In the parallel study of cyanoketen dimethyl acetal (Gold and Waterman, 1968a) a similar conclusion was reached (with &A = 0.62 and a in the range 0-5-0-65) and the same is true of the hydration of p-methoxy-a-methylstyrene (Simandoux et al., 1967) and the hydrolysis of ethyl vinyl ether (Kreevoy and Eliason, 1968).] These results can be handled in several ways, according to the point of view adopted. Following Gold and Kessick (1965b), one can combine the product isotope effect with the rate isotope effect kH/kDand solve equation (54) for a without, if necessary, any reference to rate measurements in HzO-D20 mixtures. A suitable adaptation of equation (54) is a =

log ( h E H I k D 1 ) 2 log 1

whence a value a = 0.45 is obtained for the hydrolysis of DMD, in acceptable agreement with the other estimates. Williams and Kreevoy (1968) have shown that there is similar agreement for some other A-SE;2 reactions. It should perhaps be pointed out that Williams and Kreevoy in effect use equation (140) in their evaluation of a (or E ~ as , it is called by them) although their handling of the algebra involves the evaluation of the secondary isotope effect as an intermediate step. Alternatively we can regard the knowledge of kH/kDand a as leading to the evaluation of primary and secondary isotope effects as discussed in the paragraph following equations (70) to (73). According t o the considerations outlined, the primary isotope effect is given by

= 3.56 or, With a = 0.45 and k E / k D= 2-55, we thus obtain kg80/3kg2Do by employing the value of aA in this calculation, 3.67. The (inverse) secondary isotope effect on proton transfer from the hydrogen ion per D-atom is given by la; the values corresponding to a = 0.45 and 0.49 are 0.85 and 0.83, respectively. The possibility of deriving a value of a either from the best fit of the k, - n curve to equation (55) or from rate measurements in carboxylate buffers ( a = aA)suggests the use of the data in conjunction with equation

11

312

V . GOLD

(114) to derive an estimate of the transfer effect. Using the definition of dl in equation (139), we can cast equation (114) in the form

The value of H* corresponding to a = a A = 0.49 is 0.97 ; for the curvefitting result a = 0.42 one obtains B* = 1-02. Both results suggest that the transfer effect is small in this reaction. The inference is not unexpected, in view of the fair agreement between a-values derived by different routes, one of which (equation (54) or (133)) assumes the total absence of a transfer effect. Williams and Kreevoy (1968) have pointed out that there is similar agreement for different estimates of a in other reactions studied by Kreevoy and his collaborators, and Gold and Waterman (196813) have tabulated the corresponding estimates of F*, all of which are close to unity. It is important to note that the absence of transfer effects on these reactions does not imply the total absence of transfer effects. Solubility measurements on DMD show that g D M D = 1-17. It also seems possible that values of Pi close to unity are more especially associated with reactions in which the substrate is electrically neutral and the transition state is a mono-cation, The analysis of acid dissociation of acetic acid in H20-D20 mixtures (Gold and Lowe, 1968; see Section VB1) and the study of proton transfer to nitromethyl and nitroethyl anions (Goodall and Long, 1968) suggest that transfer effects are much more significant for equilibria (or pseudo-equilibria for the formation of a transition state) in which a neutralization of electric charge occurs. . All these conclusions are somewhat dependent on the assumption that the other possible complications of the analysis mentioned in Section IV are absent. The success of the analysis in the cases studied so far (Williams and Kreevoy, 1968) is some justification of the value 1 = 0.69 and the conclusions about the approximate cancellation of effects due to the imperfect validity of the rule of the geometric mean. The limitations of these somewhat optimistic inferences can only be settled by further, more accurate, experiments. VI. CATALYSISBY SPECIES OTHER THAN HYDROGEN IONSIN AQUEOUS SOLUTION

A. Carboxylic Acids The possibility of detecting an isotope effect on proton transfer from an undissociated acid only arises for the A-SE2 mechanism. The

PROTOLYTIC PROCESSES IN H ~ O - D ~ O MIXTURES

313

theoretical prediction is unambiguous. The appropriate form of equation (56) for the rate constant of the reaction S+LA

+

SL++A-

(143)

is

k, k,

-

-

l-n+n+* l-n+n+,,

(144)

whence equation ( 5 7 ) is obtainable by the usual steps. Because a single exchangeable hydrogen atom is concerned, the numerator and denominator in this fraction are linear expressions in n. For acetic acid the fractionation factor is close to unity (0.96) and the prediction of equation (57) for acetic acid is therefore a practically linear dependence of Ic, on n. This point has only recently been experimentally confirmed for the hydrolysis of cyanoketen dimethyl acetal (7) (Gold and Waterman, 1967, 1968a; cf. Goodall and Long, 1968). Distortions of the shape of MeO, MeO’

c=c

,CN ‘€I

equation (57) are expected if there is a significant transfer effect and, in-any case, because of the imperfect validity of the rule of the geometric mean as a consequence of which the two fractionation factors are themselves slightly dependent on n. Gold and Waterman (1968a) considered the small discrepancy between their experimental points and the predictions of equation (57) in terms of the transfer effect alone. Equation (144) was modified to give

where

H*

= gSgHA/gH*

and Y * , defined in a corresponding manner, is taken as (F*),. Equation (145) is the analogue of equation (113) for proton transfer from the hydrogen ion and is derivable by the same steps. - Equation (145) gave the best fit t o the data for the assumption of Y* = 0.96, i.e. quite a small transfer effect. However, this calculation by Gold and Waterman (1968a) disregarded the deviation from the rule of the geometric mean. I n the case of hydrogen ion-catalysed reactions we have remarked that a correction for this effect is hard to evaluate because of its unknown size for the hydrogen ion. I n the 11*

314

V. G O L D

present instance this unknown parameter for the hydrogen ion does not enter into the problem and it is a simple matter to recalculate the fractions kJkH by use of the experimental value K = 3-76 for the equilibrium constant of reaction (4). The fractionation factors in equation (144) can be expressed in the form

4

(147)

= 404rel

where +o is the value applicable as n+O. Values of the function have been calculated (Gold, 1968b) and selected values are reproduced in Table 3. Since the experimentaI determination of +LA ( = 0.96) applies TABLE3 Theoretical Variation of Fractionation Factor with n for K = 3.76 (4 = 40+re~)

0.1 0,994

0.2 0.988

0.3 0.981

0.975

0-6

0.7

0.964

0.958

0.8 0.953

0.9 0.946

1.o 0.940

n

0

+re1

1.000

n 4r-21

0.4

to the limit n+l, it follows that the corresponding value of 1-02. Instead of (145) we thus obtain equation (148):

0.5

0*97@

(+O)LA

is

Table 4 compares the predictions of equations (57), (145) and (148) with the experimental values. It is evident that the case for the inclusion of a small transfer effect now becomes even less strong. The predictions of equation (148) are virtually indistinguishable from equation (145) and, at their worst, differ by no more than 2% from the experimental value. It is of questionable validity to pursue the analysis beyond this degree of agreement at the present stage. Again, the calculation in Table 4 with and without consideration of the breakdown of the rule of the geometric mean (i.e. by equations (57) and (148)) should place the importance of this factor in perspective. The case considered here is one in which this effect can be properly computed and is also one in which it exerts a particularly large influence because the ratio kH/k, is large. Even so the difference between the predictions of equations (57) and (148) is small compared with the accuracy normally attainable in all but the most exact kinetic studies.

PROTOLYTIC

315

PROCESSES I N H ~ O - D ~ M OI X T U R E S

As the last column in Table 4 shows, the experimental values of kn/kH follow a nearly linear dependence on n ; so do all the predicted values. However, this does not provide a line of evidence for distinguishing between the two common mechanisms of general acid catalysis. TABLE4 k,/k-Values

for Acetic Acid Catalysis of Hydrolysis of Cyanoketen Dimethyl Acetal

A(knhi) An

kn/kE 12

(Expt.a)

(Ca1c.b)

(Ca1o.C)

(Ca1c.d)

0 0.2 0.3 0.4

1.000 0.832 0.745 0.662 0.589 0.506 0.438 0.352 0.271 0.187

1.000 0.843 0.763 0.683 0.602 0.519 0.437 0.354 0.271 0.187

1.000 0-837 0.756 0.675 0.593 0.512 0.431 0.349 0.268 0.187

1*000 0.836 0.756 0.675 0.595 0.515 0.435 0.353 0.271 0.187

0.5

0.6 0.7 0.8 0.9 1.0

(Expt.)

0.84

0.87 0-83 0.73 0.83 0.68 0.86 0.81 0.84

Gold and Waterman (1968a). Equation (57). CEquation (145) with H* =0*96. d Equation (148) (R=3.76).

a b

Either equation (143) or equations (149) to (150) (with (150) as the rate-limiting step) represent reaction mechanisms compatible with the observation of general acid catalysis (Bell, 1941b). 1

SH+L30+

++

-1

LSH++LzO

LSH++A- + LS+HA

(149) (150)

I n these equations the hydrogen atoms written before and after the symbol S are not equivalent and the latter is not rapidly exchangeable with the solvent. Applying equation (56) to the composite scheme, one apparently obtains equation (151), which differs from equation (144) for the single-step mechanism.

316

V. GOLD

However, this procedure would be incorrect. It is possible, for the purpose of representing kinetic orders, to write equation (149) as the first step of the scheme, but we may do so only because the ratio [LA]/ [A-] is proportional to the concentration of hydrogen ion. However, this concentration is much smaller than that of LA, and the relevant pre-equilibrium which is disturbed by the isotopic solvent changes is thus the protonation (deuteronation) of SH by LA and not by L,O+. I n many cases the ambiguity can convincingly be resolved by considering the size of the isotope effect (Long and Bigeleisen, 1959). An equilibrium problem related to the kinetic Scheme (143) is presented by the basicity constants of anions (i.e. equilibrium constants of reactions of the type of (152)) A-+HzO

=: =+OH-

(152)

calculated by Pentz and Thornton (1967). Here too the departure from the rule of the geometric mean is reflected in fractionation factors of the single-proton solute species H A and OH- and therefore without the need to consider the rule of the geometric mean in relation to any species other than water. Some of the other problems associated with these equilibria have already been mentioned (see Section VB3). B. Hydroxide Ions The critical treatment of studies of hydroxide catalysis in HzO-D20 mixtures is handicapped by the comparative uncertainty of the value of the fractionation factor +oL for the hydroxide ion (or, perhaps, doubts about the proper formulation of the aqueous hydroxide ion), as was discussed in Section VB3. The most probable mechanisms to be considered are slow proton transfer from the substrate and a two-step mechanism. These two schemes are in a sense the respective analogues of A-S,2 and A-1 processes. If the hydroxide ion is taken to be simply OL-, the formation of the appropriate transition states can be represented by the equations SH+OLSL+OL-

e (S---H---OL-)*

=: s-+LzO

?+

(s-)*+LZo

I n equation (153) the proton in SH is not in isotopic equilibrium with the solvent and therefore does not contribute to the solvent isotope effect (which is entirely a secondary isotope effect in this instance), although its replacement by deuterium prior to the kinetic experiment would result in the observation of a primary isotope effect.

PROTOLYTIC PROCESSES IN H ~ O - D ~ M OIXTURES

317

The theoretical solvent isotope effects obtained by the appropriate substitutions in equation ( 5 6 ) are, for equation (153),

- -n

+ n+OLkD/kH

1 -n+n+,,

(an equation essentially derived by Nelson and Butler in 1938) and, for equation (15 4 )

-

1 ( 1 - n +nkH/kD+OLw - n + n h )

(158)

The substitution leading from (155) to (156) is a prerequisite to application of the theory for the case of mechanism (153) but it may be noted that equation (157) is itself entirely predictive, since the fractionation factor of the substrate, +sL, is in principle amenable to measurement (e.g. by isotopic equilibration in an acidic medium if the reaction is not also subject to acid catalysis). Equations related to the above and additional ones for other mechanisms (a total of twelve) involving hydroxide ions were discussed by Swain and Thornton (1961b). Many of these are practically identical in their predictions. Somewhat surprisingly, the literature does not appear to contain a single convincing study of the solvent isotope effect for the otherwise well-studied mechanism (153). An example of mechanism (154) is the reaction of 2-chloroethanol with hydroxide ion to form ethylene oxide. Various lines of evidence, including the actual size of the solvent isotope effect (Ballinger and Long, 1959; Swain et al., 1959), indicate the sequence (159) to ( 1 6 0 ) as the reaction mechanism CHzCl.CHzOH + OHCHzCl .CH20-

CHzCl. CHz0- 4 HzO __f

(159)

-

CHz CHZ ‘ 0 ’

with reaction ( 1 6 0 ) as the rate-limiting step. Reaction (160) does not formally involve any exchangeable hydrogen nucleus, and one would therefore expect the solvent isotope effect on the rate of the overall reaction to be similar to the solvent isotope effect on the equilibrium

318

V. G O L D

constant of (159). Ballinger and Long (1959) reported measurements of this equilibrium constant in both H20 and D20 as solvent. These measurements present some difficulties because of the concurrent dehydrochlorination of the alcohol and there was therefore quite a spread in the individual determinations. Nevertheless, Ballinger and Long (1959) concluded that the difference between the ratio of equilibrium constants (K,/KH= 1.35) and the ratio of rate constants ( k D / kH = 1.54) was real and corresponded to a medium effect of 15% on the rate constant for reaction (160). If, for the sake of argument, we do not follow Ballinger and Long’s conclusion but assume that the latter ratio is accurate and that the medium effect is absent, then it is possible to calculate the rate constants k, from equation (158). The calculated curve is convex towards the n-axis, as predicted, but the quantitative agreement (with +oL = 0.47) is not perfect ; the calculated rate is ca. 5% too low near the middle of the curve. The depolymerization of diacetone alcohol is another reaction which is usually thought to follow the mechanism of equation (154) or, specifically, of equations (161) to (163) (CHB)ZC(OH).CHZ.CO.CH~+OH+ (CH3)2C(O-).CHz.CO .CH3+HzO (161) (CHs)zC(O-).CHz.CO.CH3 + (CH~)ZCO+-CHZ.CO.CH~ -CHz.CO .CH3 + HzO

+ (CH3)zCO+OH-

(162) (163)

with reaction (162) as the rate-limiting process (see, e.g. Ingold, 1953). On the basis of their observation that the rate of the reaction depended linearly on the deuterium content of the medium, and also of a primary isotope effect, Nelson and Butler (1938) advanced a different scheme, of the general type of equation (153) in which the rate-determining step was the heterolysis of a C-H bond in diacetone alcohol. Pocker (1959) briefly announced experimental results contradicting Nelson and Butler’s findings: he found a curved relationship between k, and n and the absence of a primary isotope effect. However, it is also worth noting that Nelson and Butler’s theoretical reasoning was ill-founded. Neither of the two general schemes, (153) and (154), predicts a linear dependence of k, upon n. In fact, the theoretical predictions (equations (156) and (158)) are very similar for the value k,/k, = 1.50 to which most experimental results refer and the possibility of distinguishing between the two mechanisms on this basis is-at least-debatable. To illustrate the point, Table 5 gives calculated results for the two alternative schemes. There is an appreciable difference between equations (156) and (158) with kD/kH= 1, but this is a somewhat improbable value for either mechanism.

PROTOLYTIC PROCESSES IN H ~ O - D ~ M O IXTURES

319

TABLE5 Calculated Values of k,/kH for Hydroxide Ion Catalysis by Different Mechanisms and k D / k H = 1.5 and 1.0 ( # 0 ~ = 0 . 4 7 ) -___ knlh

n 0 0-1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

C.

(Equation (156))

(Equation (158))

1.000 1.025 1.054 1.084 1.119 1.160 1.207 1.262 1.326 1.404 1.500

1.000 1.014 1.032 1.057 1.088 1-125 1-172 1.231 1.301 1.389 1.500

"

1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

1.000 0.949 0.913 0.888 0.875 0.870 0.875 0,888 0.913 0.949 1.000

Water-Catalysed " Reactions

Appreciable solvent isotope effects can arise in reactions in which the solvent acts as an acid or base, either in a pre-equilibrium or in the rate-determining step. An endless variety of schemes can be imagined and the following remarks will be restricted to two different examples which have actually been studied. They are the decomposition of nitramide (La Mer and Greenspan, 1937) and the hydrolysis of acetic anhydride (Batts and Gold, 1969). For both reactions, the rate is smaller in D20 and the k,-n curves show a curvature in the opposite sense to that for those acid catalysed reactions in which k, > k, (Fig. 3). The general character of the curves is reminiscent of that for K,, also indicated on the same figure. This qualitative similarity suggests that the transition states resemble the products of the ionization of water, but with less complete charge separation. To put this general inference curves have into somewhat more specific mechanistic terms, the nk, been calculated for reasonable transition state models conforming to it. Not too much should be deduced from the fact that agreement between experimental and calculated results can be obtained in this way. There is no doubt that other equally successful models can be devised. For the spontaneous decomposition of nitramide (NH2NOz) the transition state is assumed to have formula 8, on the supposition that the rate-limiting step is base-catalysed removal of a proton from the (less stable) aci-tautomer (NH:NO,H). This suggestion is made in the

320

V . GOLD

light of the known acidic nature (pK- 7) of the substrate, the ready exchangeability of both its hydrogen atoms (La Mer and Hochberg, 1939), and a kinetic order of unity with respect to added base. There is no direct evidence in support of the implied concerted transfer of 2

L L’

\

3

I

0 - - - L ---N.NO---OL

proton 1 and the detachment of the OL- group, but the possibility seems attractive. Following the reasoning suggested by Kresge (1964) for the treatment of slow proton transfer from the hydrogen ion, we assume $ 2 to be related to the degree of proton transfer in the transition state (p). Complete proton transfer (p=1) would imply & = I ; the opposite situation (,!I=0) would correspond to cP2= 1. For an intermediate ,!I, $2 = 18. Analogously, the fractionation factor $3 for p= 1 would be that of the fully formed hydroxide ion, and, to facilitate the calculation, we assume that p = O would imply $3=1 for hydroxylic Since the predominant form of hydrogen. Accordingly, $3 = nitramide in solution is H,N*NO,, the formation of the transition state can be written as

gL.

LzO+LzN.NOz

+

8

(164)

and it will also be assumed that the hydrogen atoms in nitramide show no significant isotope fractionation with respect to water. This particular assumption could be tested by direct experiment. According to equation (56), we therefore have - = (1-n+nz~)2(1-n+n&L)(1-n+n$l) k, kH

The parameter

dl can now be related to k,lkH

in the usual way, i.e. we again assume that p can be equated to the exponent in the Brnrnsted catalysis law, Ic,Jk, can now be evaluated for the isotopically mixed solvents. With p= 0.75, the value applicable to electrically uncharged bases (Bell, 1941a), the calculated curve shown in Fig. 4 is obtained. The shape of the curve is not sensitive to the value of p selected. In particular, almost the same results are obtained by using ,!I = 1 (although complete proton transfer in the transition state is ruled out by the observation of general catalysis). The case p = O results in a straight line joining the extreme points of the curve and is thus clearly incompatible with the evidence.

~ 1 = k D / k H ~ 2 ~ & L . If

P R O T O L Y TIC PROCESSES IN H,O-D,O

MIXTURES

321

For the spontaneous hydrolysis of acetic anhydride we consider a transition state structure 9, which can be regarded as a generalized

0

I

I

I

I

0.2

0 4

0.6

0.8

0

n

FIG.4. k,/k= for spontaneous reactions. (Open circles are experimental points for nitramide, filled circles experimental points for acetic anhydride. The respective curves are calculated from equation (165) with 8=0.75 and from equation (166) with a=0-5. The bottom curve reproduces equation (131) for the ionic product of water.)

representation of the various transition states envisaged by Jencks and Carriuolo (1961) and Butler and Gold (1962). In this case the approxi0-

1

2

I

R-C- - -0.CO .CH3- - -H-- -OH2

I

OH 3 9

mation + 3 = 1 and +z=Z1-a seems appropriate, where Q! is the degree of proton transfer from H30+ to the acetic anhydride moiety. The fractionation factor is again obtained from the ratio k,llc, (since k,lk,

322

V. GOLD

= +&). Although the reaction is known to be general base-catalysed, the value of ct is known but vaguely (Butler and Gold, 1961). The isotope effect is given by

_ k, -- ( 1 - n + n + l ) ( l - n + n + z ) 2 k, and the assumption 01 = 1 is therefore clearly unacceptable since it would lead to a linear dependence of k, upon n. For lower values of a,the calculation is once again not sensitive to the precise value chosen. From Fig. 4 the experimental results (Batts and Gold, 1969) are seen to be in good agreement with a calculated curve based on o! = 0.5. VII. SOLVENTS OTHERTHANWATER

A. Water-Dioxan Mixtures The addition of a non-aqueous component to water usually has a much more profound effect on the values of rate and equilibrium constants than has the isotopic change from H20 to DzO. I n other words, quantitative studies in ternary solvent systems such as dioxan-HzODzO are difficult if minute changes in the dioxan content can produce effects which outweigh the isotope effect. The dissociation of acetic acid and the autoprotolysis of water have been examined in dioxanH,O and dioxan-D,O systems up to dioxan mole fractions of 0.25 and 0.45, respectively (Gold and Lowe, 1964). I n both cases the equilibrium constants change rapidly with dioxan content but the isotope effects vary but slightly over the same composition range, and these findings suggest that fractionation factors likewise do not undergo a dramatic change. Measurements of the fractionation factor for the hydrogen ion in aqueous dioxan by the NMR method (Gold and Tomlinson, unpublished measurements) tend to confirm this conclusion. The value of 1 increases from 0.70 in water to 0.81 in aqueous dioxan with a dioxan mole fraction of 0.86. If one applies equation (35) to these resuIts it is possible to evaluate +oL; the value of this fractionation factor is found to stay constant at 0.42 from 0 to 20 mole percent of dioxan (see, however, Section VB3 for possible shortcomings of equation (35)). The evaluation of these basic fractionation parameters provides a basis for the study of dioxan-HzO-DzO mixtures with a constant proportion of dioxan but varying relative amounts of the isotopic waters. No significant measurements in such systems or on systems with a non-aqueous component other than dioxan appear as yet to have been reported. Hine and Haworth (1958) have successfully studied the

PROTOLYTIC PROCESSES IN H , O - D ~ O MIXTURES

323

hydroxide ion-catalysed benzilic acid rearrangement in dioxan-H,O and in dioxan-D,O and, since in this instance the effect of changes in the dioxan content of the medium is not large, this would appear to be a suitable case for the investigation of the ternary solvent system. On the other hand, Steffa and Thornton (1967) have encountered additional experimental difficulties for other reactions involving hydroxide ions in ternary systems with dioxan.

B. Methanol The formula of the monosolvated hydrogen ion in methanol solution is assumed to be MeOHg. This is a two-proton species, compared with the three-proton species H,O+ considered for aqueous solutions. Similarly the methanol molecule itself contains one exchangeable proton less than water. As a result, the characteristic equations of the theory based on the general equation (32) change in form for the MeOH-MeOD system. If we consider the dissociation of a weak acid, for example, HA+MeOH

+ MeOHZ++A-

(168)

and if we take the symbol Z to apply to deuterium fractionation between the methanolic hydrogen ion and methanol, then equation (32) becomes

The fractionation factor correspondingly refers to the deuterium distribution between the acid and methanol (&A = (D/H)LA/(D/H)MeOL). From the expression for the limit n+l, we obtain t$LA

= z2KEA/KDA

and hence

Equations (169) to (171) are the analogues of (29) to (31) for aqueous solutions and are different from them. These expressions put in more explicit form the suggestion (Gold, 1960) that the study of acid-base phenomena in non-aqueous isotopic solvent mixtures can give information concerning the formula of the dominant form of Brmsted acid present. Precise measurements of acid-base equilibria, in MeOH-MeOD mixtures, of the type of equation (168) do not appear to exist, and it must be admitted that the attainment of the requisite accuracy may 12

324

V. GOLD

be a matter of some difficulty. A few basicity constants in MeOD have been determined (Schowen and Latham, 1967). There are no comparable difficulties about the measurement of rate constants of acid-catalysed reactions in MeOH-MeOD and the results obtained (Gold and Grist, unpublished) support the basic assumptions outlined above. The success of these measurements (which extends to the determination of CL by isotopic variation of the solvent) for a general acid-catalysed reaction is of some practical interest, because the detection of general acid catalysis by studies with buffer solutions is not an easy procedure for methanol solvent. The use of MeOH-MeOD thus becomes of direct usefulness in the diagnosis of reaction mechanism. The para,meter 1 for methanolic hydrogen ions has been measured by the NMR technique (Gold and Grist, 1968). The available information about the effect of metal salts on the hydroxyl proton signal of methanol throws additional light on the significance of this type of determination. The considerations may have some relevance to the interpretation of I-values also for aqueous solution and will therefore be explained in a little detail. The effect of a dissociated electrolyte solute in low concentration on the position of a solvent proton signal is the sum of cation and anion contributions into which it cannot normally be separated. For 1:1-salts these shifts are usually much smaller than those of the corresponding acids but they are not vanishingly small. Nevertheless they are assumed to be absent in the usual calculation of I from NMR results. The basis of the measurement is the idea that the position of the collapsed hydroxyl hydrogen signal is a concentration-weighted average of the positions of hydrogen-ion and solvent signals. I n a partially deuteriated system of the same stoichiometric concentration of hydrogen ion the position of the signal is changed because the ratio of acidic to solvent protons will not be the same if deuterium and protium are not randomly distributed between solvent and hydrogen ions. The quantitative application of this idea generally assumes that this is the only effect to be considered and, especially, that the position of the collapsed signal is not also in part determined by the presence of the anion. The procedure is partially justified by the observation of practically the same value of 1 for aqueous perchloric and hydrochloric acids (Gold, 1963;Gold and Kessick, 1965a). When magnesium perchlorate (and some other salts) are dissolved in methanol, two hydroxylic proton signals are observed at low temperatures; one of the signals can be attributed to methanol molecules co-ordinated to the magnesium ion (six molecules per ion) and the other to “free” methanol (Swinehart and Taube, 1962; Swinehart et al., 1963).

PROTOLYTIC PROCESSES IN H ~ O - D ~ M O IXTURES

325

It has been noted that the position of the latter signal is not the same as in pure methanol. It was also suggested that this shift reflects the effect of anions and that this effect can accordingly be evaluated (Butler et al., 1968). Strictly speaking the “anion” shift contains not only the effect of anions but also that of cations on methanol molecules beyond the first co-ordination shell of six molecules. However, if one assumes that this secondary effect of the magnesium ion is small then it is possible to subtract from the measured shift of theX@ollapsed)proton signal of an acid solution the anion shift and thus to evaluate the effect due solely to the hydrogen ion in solution. The determination of the fractionation factor by studies of the effect of an acid in MeOH and in MeOD could therefore also be divorced from the anion contribution. With the aid of several additional assumptions, necessitated by the paucity of available data, Gold and Grist (1968) applied these considerations to the determination of 1 for methanol and noted that the inclusion of the correction changed the value of l from 0.63 to 0.60. These results must be regarded as preliminary but they point a way to a better defined understanding of 1 and an approach that may ultimately be applicable also to aqueous solutions. More O’Ferrall (personal communication) has recently studied solutions of sodium methoxide in MeOH and MeOD (with a little MeOH) by the NMR method and has derived a fractionation factor for the methoxide ion which must, of course, be due to methanol molecules associated with the solute. This factor is quite far from unity (0.72) and thus emphasizes the importance of lyate-solvent hydrogen bonds, and adds plausibility to the hypothesis of the importance of hydrogen bonding to the aqueous hydroxide ion in connection with hydrogen isotope fractionation in the hydroxide ion. However, it has not yet been shown that the methoxide fractionation is independent of the nature of the cation, and detailed analyses based on this number may be premature. It will be evident that secure knowledge of this parameter and of the fractionation factor of the methanolic hydrogen ion will in due course allow prediction of the ionic product of MeOD relative to that for MeOH and also of K,,/K,, ratios for some acids in methanol from the measured isotope effects on basicity constants (Schowen and Latham, 1967). VIII. Speculative Generalities It is hard to summarize the present state of development of the subject and harder to predict probable lines of development. It is easier to point out a few things that ought to be done. On the achievement side it is probably fair to state that we have an

326

V. GOLD

understanding of the reasons for the curvature of certain kn-ngraphs and that all the main phenomena can satisfactoriIy be explained in terms of exchange effects. One of the chief factors to be considered is the different discrimination between hydrogen isotopes of different molecules, i.e. the isotope fractionation between solvent and solutes. Another important factor is the precise formulation of solute species and an important reason for the characteristic shapes of various curves lies in the fact that the solvated hydrogen ion contains more than a single hydrogen atom with a significant isotope fractionation relative to water. This model is adequate in first approximation for all reactions and appears to be especially satisfactory for the family of A-S,2 reactions where preservation of cation charge during the formation of the transition state is likely to minimize secondary effects due to further interactions between solute and solvent that do not find expression in the conventional chemical formulations. For these reactions, rate and product measurements in H20-D20 mixtures provide mechanistic information not deducible from experiments in H20 and D20 alone. Several obstacles still stand in the way of a fuller exploitation of the information potentially available from this source. I n the f i s t place, our knowledge of fractionation factors for ordinary molecules is very fragmentary and a good deal of systematic collection of data is required before one can make confident extrapolations to other structures. There is, secondly, a need for systematic work on transfer effects. I n principle, the thermodynamic measurements required are simple, but generalizations may be slow to emerge. However, with the increasing interest in all problems associated with water structure and interactions in solution, one may hope for real progress in this field in due course. We must include here also the transfer effects which complicate the determination of fractionation factors of ionic solutes and on which there has been a certain amount of progress. A third, as yet more elusive problem is that of the degree to which the rule of the geometric mean fails in the case of the aqueous hydrogen ion. Whilst it seems realistic to expect a definitive answer to the corresponding problem for the water molecule, the experimental problems standing in the way of a direct approach for H30+are formidable. Mass spectrometry of gaseous H30+or model calculations on the isolated H,O+ species may here give some guidance in the future. However, it should be borne in mind that the further interaction of H30+with water molecules (i.e. the problem of transfer or secondary solvation of the hydrogen ion) will bedevil the reliability for aqueous solutions of any answer derived for H,O+ in the dilute gas phase. Fourthly, it would seem that there is a need for further improvement

P R O T O L Y T I C P R O C E S S E S I N H ~ O - D Z OM I X T U R E S

327

in the standard of accuracy of rate and equilibrium measurements. It may indeed be true to say that all refinements of theory beyond the first approximation are as yet premature and that the first need is for the recognition that the data to be analysed ought to be more precise than is considered satisfactory in other applications of kinetic studies. The writer does not exclude himself from the strictures implicit in these remarks. There are two areas in which it seems that substantial advances could be made even on the basis of first-order theory. These are the field of “spontaneous ” react,ions where isotope effects are sometimes large and where the existence of many closely related systems makes it likely that a useful framework of generalizations could be found. The second field is that of strictly non-aqueous solvent systems where a comparison of solvent isotope effects with those in aqueous solution is likely to throw light on essential differences in chemistry. As a mechanistic tool in the investigation of acid- or base-catalysed reactions in aqueous solution, the measurements in isotopically mixed solvents are most useful for reactions where a certain amount is already known about the mechanism. I n particular, the study of mixed solvents is also a good deal more informative whenever it is possible to measure product isotope effects in addition to rate isotope effects. In such cases (and A-S,2 reactions spring to mind as a good example) solvent isotope effect studies can add considerably to the detailed picture of a transition state. The phenomena are as yet less suited to the ab initio assignment of reaction mechanism, such as the decision between weak nucleophilic participation of water in an acid-catalysed reaction and an A-1 mechanism, when no information beyond the k,-n relation is available. For these reasons it is likely that mechanistic investigation by this method will increasingly be directed towards systems where both rate and product isotope effects are obtainable. The whole area is thus pregnant with challenging problems and interesting possibilities, an assessment which is reflected in the remarkable growth in the volume of work published and in progress over the past few years. ACKNOWLEDGMENT The author’s thanks are due to Drs. E. M. Arnett, M. M. Kreevoy, A. J. Kresge, F. A. Long, R. A. More O’Ferrall, and M. Wolfsberg for advance information on unpublished work. REFERENCES Abel, E., Bratu, E., and Redlich, 0. (1935). 2. physik. Chew. A173,363. Albery, W.J. (1967). Progr. Reaction Kinetics. 4, 353. Arnett, E. M., and McKelvey, D. R. (1969). “Solvent Isotope Effects on Thermodynamics of Nonreacting Solutes.” To be published. Ballinger, P., and Long, F. A. (1959). J. Am. Chern. Soo. 81, 2347.

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AUTHOR INDEX Numbers in italics refer to the pages on which references are listed at the end of each article.

A

B

Aalto, V., 284, 309, 330 Babad, H., 175,203 Bachman, B. L., 196, 205 Abe, R., 233,254 Backer, H. J., 931,108 Abe, T., 218,220,234, 254 Bader, R. F. W., 189, 203, 260, 317, 330, Abel, E., 261, 284, 297, 305, 327 331 Abraham, D. J., 7, 60, 80,114 Badiger, V. V., 79, 110 Abramovitch, R. A., 240, 254 Bahner, C. T., 8, 26,113 Adams, G. E., 119,121,123,127,129,130, Baldwin, J. E., 200, 203 148,149 Ballinger, P., 297, 317,318,327 Adams, J. H., 18, 20, 22, 24, 25, 27, 113 Bamford, C. H., 193,203 Adhikari, P., 10, 113 Bamford, W. R., 172, 203 Aguiar, A. M., 45, 46, 59, 108 Bannister, W., 77, 114 Ainscough, J. B., 217, 247, 254 Bantysh, A. N., 71,108 Akatsuka, M., 239, 254 Barash,L., 155,164,165,166,167,178,203, Albery, W. T., 281, 295, 327 209 Alfassi, Z. B., 129, 130, 131, 142, 149 Bard, C. C., 223, 255 Allen, A. O., 125,150 Baronowsky, P., 201, 208 Allen, C. R., 223, 254 Barr, J. T., 26, 113 Alles, B. J. P., 104, 108 Barrow, R. F., 161, 202,206 Allred, A. L., 266, 282, 283, 308, 329 Barton, G. W., 285, 330 Amrich, M. J., 117,202 Bartulin, J., 113 Anastassiou, A. G., 189, 195, 202 Anbar,M., 117,118,119,120,121,122,123, Bass, A. M., 160, 161, 203 124, 125, 126, 127, 128, 129, 130, 131, Rates, R. G., 261, 262, 287, 298, 299, 302, 303,305,306, 328 132, 134, 135, 136, 139, 140, 142, 145, Batts, B. D., 297, 319, 322, 328 146, 147, 148,149,150, 307, 331 Ando, W., 193,197, 205 Bauer, V. J., 45, 54.55, 110 Baum, 192,205 Andrews, E. B., 161,202,206 Baxendale, J. H., 123,135, 145,148,149 Andrews, L., 161, 163, 202, 203 Bayless, J., 173, 175, 208 Anet, F. A. L., 189, 203 Bayless, J. H., 173, 175, 203, 204 Angeletti, E., 41, 42, 43, 47, 50, 108 Beachem, M. T., 29,114 Anselme, J. P., 171, 177, 207 Beck, G., 123, 131,149 Applegate, L. E., 83, 84, 112 Behohlav, L. R., 20,22,111 Arai, S., 129, 130, 149 Bell, J. A., 154, 177, 202, 203 Archibald, T. G., 46, 59, 108 Bell, R. P., 261, 263, 315, 320, 328 Armbrecht, F. M., 185, 208 Bellobono, I. R., 44, 52, 64, 71, 108 Armstrong, D. A., 127,149 Beltrame, P., 5, 11, 43, 44, 52, 53, 64, 65, Arnett, E. M., 290, 327 68, 71, 72, 92, 93, 108, 109 Ashitaka, H., 169, 187, 207 Asmus,K. D., 123, 128, 130, 131, 135, 149 Beltrame, P. L., 5, 11, 43, 64, 68, 108, 109 Bemasconi, C. F., 244, 254 Autenrieth, W., 46,47, 108 Benesi, H. A., 242, 254 Ayscough, P. B., 124,149 333

334

AUTHOR I N D E X

Ben-Naim, A., 260,328 Benson, R. E., 9,111 Benson, S. W., 154, 188, 190, 194, 204 Benson, W. R., 1, 43, 44, 45, 46, 109, 113 Beranek, E., 224,225, 255 Berger, R., 9,113 Bergman, E., 27,113 Bernheim, R. A., 164,203 Bernstein, H. J., 79,111 Bertrand, M., 200, 203 Bethell, D., 155, 156, 171, 175, 180, 185, 191, 193,203 BBzaguet. A., 200,203 Bigeleisen, J., 266, 316, 328, 330 Bikales, N. M., 43,109 Binsch, G., 176, 205 Birchall, T., 238,241,254 Birum, G. H., 73,109,110 Blake, J. A., 234, 254 Blanchard, E. P., 155, 185,203,208 Block, H., 267, 328 Boag, J. W., 123,148 Bockris, J. O’M., 295,328 Bohler, F., 15,111 Boll, W. A.. 172,204 Bolot, P., 178, 203 Bonhoeffer, K. F., 297, 330 Boos, W. F., 211,256 Bordhag, A. E., 180,205 Bosch, N. F., 171, 172, 204 Bott, R. W., 98, 109 Bottini, A. T., 82, 94, 96, 109 Boudakian, M. M., 77, 78, 80, 114 Boularand, G., 59, 90,109 Boulton, A. J., 241,254 Bowden, K., 234, 254 Bowen, R. E., 242, 256 Braams, R., 120, 121, 127, 131, 132, 133, 139, 140, 147,149 Bradley, J. N., 170, 171, 172, 192,203 Brady, D. G., 65,114 Braendlin,H.P., 18,20,22, 111 Brandon, R. W., 162, 203 Brasen, W. R., 180,205 Bratu, E., 261,284, 297,305,327 Bregman-Reisler, H., 129, 130, 131, 142, 149 Brescia, F., 297, 298, 299, 300, 328, 330 Briegleb, G., 214, 223, 225, 226, 251, 254 Broadbank, R. W. C., 260,328 Brensted, J. N., 279, 328 Brook, A. J., 223, 254 Brown, K. C., 175, 185,203 Brown, N. E., 241,255 Brueck, B., 10,113 Buck, W., 146,150

Buckley, N. C., 98,113 Buncel, E., 213,224,226,234,255 Bunnett, J. F., 10, 33, 72, 109, 214, 251, 255 Burlitch, J. M., 155, 184, 186, 208 Burnelle, L., 161,204 Burnett, R. M., 7, 60, 80, 114 Burr, J. G., 202, 203 Burske, N. W., 27,110 Burton, D. T., 26, 27,109 Busch, M., 227, 228, 255 Butler, A. R., 321, 322, 328 Butler, J. A. V., 262, 263, 278. 283, 286. 297,308,317,318,329 Butler, R. N., 325, 328 Buttery, R. G., 169, 204 Byme, W. E., 235,236,237,239,244,246, 248,255,256

C Cadogan, J. I. G., 154,203,267, 328 Cairns, T. L., 1, 7, 13, 15,109, 111 Caldin, E. F., 217, 223, 234, 247, 254, 255 Callahan, J. J., 240, 256 Callister, J. D., 171, 191, 193, 203 Campagni, A., 12,65,66,109 Canback, T., 238,255 Cantner, M., 223, 226, 251, 254 Capon, B., 156, 203 Carboni, R. A., 1,109 Carr, R. W., 188,205 Carrh, S., 11, 92, 108 Carriuolo, J., 321, 329 Casson, J. E., 193, 203 Castro, C. E., 155, 156, 203 Catchpole, A. G., 2, 109 Cattania, M. G., 11, 64, 65, 72, 109 Caveng, P., 216, 218, 220, 236, 237, 240, 244,245,255,257 Cawley, J. J., 181,203 Cercelr, B., 134, 149 Chaimovich, H., 201,203 Chambers, K. W., 118,149 Chambers, R. D., 1, 109 Chang, T. L., 260,328 Charlesby, A., 127, 149 Chaudhuri, N., 169,204 Chesick, J. P., 192, 203 Chiang, Y.,286,297,309, 329,330 Chierici, L., 9, 43, 109 Chinoporos. E., 154, 203 Chirkov, N. M., 64,69,111

335

AUTHOR INDEX

Chittum, J. P., 297, 300, 328, 330 Chu, T.-C., 260, 328 Chutny, B., 130,149 Ciereszko, L. S., 202, 203 Ciganek, E., 178,204 Claisen, L., 9, 109 Clark, H. C., 155, 185, 204 Clarke, P., 173, 204 Clause, A. O., 84,112 Clayton, A. B., 30,109 Clifford, D. P., 241, 254 Clopton, J. C., 173, 174, 208 Closs, G. L., 154, 162, 171, 172, 181, 182, 183, 196, 198, 199,200, 203, 204 Closs, L. E., 172, 181, 196, 204 Cockerill, A. F., 155, 180,203 Coffey. R. S., 196,205 Coffman, D.D., 1, 7, 13, 15,109,111,112 Collinson, E., 118,149 Conway, B. E., 295, 330 Cook,E. W., 44,50, 51,109,112 Cook, F. B., 173,175,203 Cottis, S. G., 9, 109 Couch, M. M., 176,177,204 Coussemant, F., 297, 309, 311,330 Covington, A. K., 262,305, 306, 328 Cowan, D. O., 176, 177,204 Cowell, G. W., 170, 171, 172, 203 Coyle, J. J., 182, 198, 199, 204 Crain, D. L., 20,22,111 Crain, R. D., 20,22,111 Cram, D. J., 227,257 Crampton, M. R., 213, 215, 216, 218, 220, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 244, 248, 249, 250, 251, 252, 253, 254,255 Crawford, R. T., 176, 209 Crelier, A. M., 84, 112 Cross, R. J., 185, 208 Crumbliss, A. L., 182, 183, 205 Csapilla, J., 100,110 Cseh, G., 98, 100,110 Cullen, W. R., 25, 26, 27, 109 Cullis, C. F., 118, 149 Curtin, D. Y., 3, 38, 79, 98, 109 &%a, F., 224,225,226,255 Cvetanovib, R. T., 189, 204

D Daigle, D., 45, 59, 108 Dainton, F. S., 118, 123,149 Damico, R., 11,111

Damraver, R., 192, 208 Danen, W. C., 181,208 Darragh, K. V., 186, 205 Dauben, W. G., 172,204 Davis, C. O., 295,329 Davis, J-V., 117, 120, 138, 139, 150 Dawson, D. S., 26, 109 Debye, P., 146,150 Degani, C., 33,36,56,113 de la Mare, P. B. D., 2,110 De Maayer, L., 117,150 DeMore, W. B., 154, 188, 190, 194,204 Destro, R., 216, 245, 255 Dev, V., 96,109 Dewald, R. R., 117,150 Dewar, M. T. S., 246, 255 Dhabanandana, S., 260,328 Dhaliwal, P. S., 26, 27,109 Dick, J. R., 15, 20, 24, 25, 27, 112, 113 Dickeson, J. E., 236, 237, 240, 244, 245, 255 Dickinson, C. L., 7, 13, 15, 110 Dietrich, H., 176, 206 Dietrich, M. A., 31, 110 Di Nunno, L., 50, 65, 67, 71, 86, 89, 110 Ditsch, L. T., 297, 329 Dixon, S., 30,110 Doering, W. v. E., 169, 178, 191, 193, 196, 197, 199,204 Dolbier, W. J., 154, 181, 184, 192, 205 Doleib, D. M., 180, 204 D o l h i , J. E., 55, 110 Dolman, D., 241,255 Dorfman, C. R., 129,149 Dorfmann, L. M., 117, 130,149,150 Dowd, S. R., 184,186,208 Dowell, A. M., 193, 205 Dreier, F., 20, 110 Drischel, W., 182, 206 Duchesne, J., 161, 204 Duddey, J. E., 98, 113 Duncan, F.J., 189,204 Duncan, J. H., 173, 174, 189, 208 Duncan, W., 20,110 Durett, L. R., 155, 207 Dvoretzky, I., 156, 189, 206, 207 Dyall, L. K., 215, 236, 237, 240, 244, 245, 255 Dye, J. L., 117, 150

E Eaborn, C., 98,109 Earle, R. B., 212, 206

336

AUTHOR INDEX

Eaton, P. E., 76, 84,110 Ebert, M., 120, 130, 134, 139, 149, 150 Eddy, R. D., 260,328 Edwards, J. O., 304,328 Eglinton, G., 93, 110 Eigen, M., 117,150, 282, 328 Eliason, R., 297,309, 311, 329 Eliel, E. L., 33, 79, 110 Emmons, W., 43,45,48,110 Emslie, P. H., 218, 220, 231, 236, 237, 239, 256 Engberts, J. B. F. N., 171, 172,204 Engel, R. R., 198, 208 Engelhardt, V. A., 1 , 9 , 15,109, I l l , 112 Engelsma, J. W., 192, 204 England, D. C., 31, 110 Epprecht, A., 297,305, 330 Erb, L., 238,256 Erickson, K. L., 92, 110, 201, 204 Erlenmeyer, H., 297, 305, 330 Etter, R. M., 157, 176, 182, 191, 198, 199, 204, 208 Etzemuller, J., 178, 203 Evans, D. E. M., 30,110 Evans, D. F., 261, 331 Evans, M. J. B., 234,254 Eyring, H., 285: 331

F Fahey, R. C., 98,110 Fainberg, A. H., 100,114 Fainzil’berg, A. A., 154, 156, 208 Fanshawe, W. J., 45, 54,55,110 Farmer, R. C., 228, 229, 255 Farnum, D. G., 171,209 Farr, J. D., 254,255 Farusaki, A., 216, 245, 257 Favini, G., 11, 64, 65, 72, 108, 109 Feast, W. J., 28, 30, 110 Feldmann, C. H., 117, 150 Fendler, E. J., 235, 236, 237, 239, 244, 246, 248,255, 256 Fender, J. H., 235,236, 237,239, 244,246, 248, 255,256 Fenton, D. M., 100,110 F&e, A., 44, 52, 64, 71, 108 Ferran, J., 161, 206 Fick, R., 225, 254 Fielden, E. M., 119, 120, 121, 122, 124, 147, 150 Fikentscher, L., 193, 204 Finn, F., 201,208 Fischer, E-O., 156, 204

Fischer, P. B., 216, 220, 236, 237, 240, 244, 245, 257 Fisher, I. P., 168, 204 Flemon, W., 175,203 Flory, K., 182, 206 Flynn, J. Jr., 79, 110 Fogelzang, E. N., 15, 30, 31, 114 Foltz, R. L., 175, 204 Foreman, M.I.,218,220,225,231,236,237, 239,256 Foster, R., 215, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 231, 235, 236, 237,239,252, 255, 256 Fowler, J. S., 43,44, 45,46, 50, 55, 58, 111 Francis, J. M., 118, 149 Frank, A. W., 29,110 Frank, W. C., 25,112 Frankham, D. B., 155, 180,203 Franzen, V., 155, 192, 193, 200, 204 Frazza, E. J., 8, 41, 44, 47, 50, 54, 57, 84, 113 Freeman, J. P., 43, 45, 48,110 Prey, H. M., 154, 174, 177, 188, 189, 193, 204,205 Fried, J. H., 15, 107, 112 Friedman, Lester, 153, 173, 175, 203, 204, 205,208 Friedman, Lewis, 284, 328 Fritze, P., 82, 114 Funakubo, E., 196,205 Fydelor, P. J., 127, 149 Fyfe, C. A., 215, 216, 217, 218, 219, 220, 222, 223, 225, 226, 227, 231, 235, 236, 237, 239,240, 252, 255, 256

G Gafni, A., 46, 59, 110 Gal, A., 99, 113 Garbiseh, E. W., Jr., 10,109 Garner, A. Y., 199, 208 Garrison, W. M., 121, 124, 150, 151 Gary, R., 261, 287,298, 299, 302, 303, 328 Gaspar,P. P., 156, 158, 188, 189,195,205 Gazzolo, F. H., 212, 256 Gelin, R., 9, 110 Generosa, J. I., 189, 203 Gerstl, R., 198, 199, 207 Geuther, A., 177, 205 Ghariani, M., 233, 251, 255 Ghersetti, S., 45, 54, 85, 88, 110 Ghosez, L., 176, 205 Giacin, J. R., 189, 205 Gibbons, W. A., 155, 182, 205,209

337

AUTHOR I N D E X

Gibson, J. D., 26,113 Gidvani, B. S., 46, 60,110 Giese, B., 76,110 Gilbert, G. P., 135, 149 Gitis, S. S., 215, 234, 235, 237, 238, 239, 256 Glaz, A. I., 215, 256 Goehring, M., 297, 330 Goh, S. H., 171, 204 Gold, V., 32, 110, 156, 203, 213, 215, 216, 218, 220, 222, 223, 224, 226, 228, 229, 231, 232, 233, 235, 236, 237, 238, 243, 244, 245, 246, 248, 249, 251, 252, 255, 256, 262, 263, 266, 267, 269, 271, 273, 274, 275, 277, 280, 281, 282, 283, 285, 286, 290, 292, 297, 298, 299, 300, 301, 302, 304, 305, 306, 308, 309, 310, 311, 312, 313, 314, 315, 319, 321, 322, 323, 324, 325, 328 Goldstein, M. J., 154, 181, 184, 192, 205 Goldwhite, H., 15, 107, 112 Golstein, J. P., 198, 208 Gompper, R., 9, 15,60, 110 Goodall, D. M., 290, 297, 309, 312, 313, 329 Gorbarty, M. L., 45,54,55,114 Gordon, M. E., 184,186,205,208 Gordon, S., 117, 118, 121, 122, 123, 124, 125, 130, 131, 132, 134, 143, 150 Gosselink, E. P., 155, 206 Gottich, B. P., 1, 9, 46, 111 Gramaccioli, C. M., 216, 245, 255 Gramas, J. V., 164,203 Grassmann, D., 176, 206 Green, A. G., 227, 256 Green, S. A., 155, 205 Greenspan, J., 297, 319, 330 Greenzaid, P., 7, 13, 15, 113 Grev, D. A., 129,149 Greyson, J., 261,329 Griffin, C. E., 235, 236, 237, 239, 244, 246, 248, 255, 256 C a n , G. W., 155,206, 207,209 Griffiths, W., 117, 138, 150 Grist, S., 297, 324, 325, 328 Grob, C. A., 98, 100,110 Groppeli, G., 22, 25, 113 Gross, P., 262, 273, 278, 297, 329 Groten, B., 77, 114 Gruendmann, E., 15,111 Grunwald, E., 100,114 Guarino, J. P., 130,150 Gudkova, A. S., 60,62,110,112 Guella, F., 11, 64, 65, 72, 109 Gunning, H. E., 201, 209 Gutsche, C. D., 196, 205

H Halberstadt, M. L., 189, 205 Halevi, E. A., 282, 287, 301, 302, 306, 329 Hamill, W. H., 130,150,263,297,329 Hamilton, G. A,, 189,205 Hammick, D., Li.,215,223,255, 256 Hammond, G. S., 166, 158, 176, 177, 188, 189, 195,204,205,206 Hanna, S. B., 155, 180,205 Hantzsch, A., 211, 224, 234, 256 Harborth, G., 81,114 Harris, E. E., 3, 109 Harris, J. F., Jr., 9, 15, 76, 110 Harris, R. F., 198,208 Hart, E. J., 117, 118, 119, 120, 121, 122, 123, 124, 125, 127, 128, 129, 130, 131, 132, 134, 136, 142, 143, 145, 146, 147, 149,150 Hartenstein, J. H., 171, 207 Hartzler, H. D., 201, 205 Hasse, E., 9, 109 Hassler, J. C., 193, 208 Hatch, M. T., 180, 209 Hauser, C. R., 180, 205 Hawes, B. W. V., 243,256 Haworth, H. W., 322, 329 Hayon, E., 125,150 Hazenberg, J. F. A., 31, 108 Heberling, J., 80, 112 Heckert, R. E., 1, 7, 13, 15, 109, 111 Heicklen, J., 155, 205, 208 Heilbronner, E., 216, 220, 236, 237, 240, 244,245,257 Heine, R. F., 77, 114 Heininger, S. A., 73, 109, 110 Heinzinger, K., 266, 282, 283, 308, 329 Hellin, M., 297, 309, 311, 330 Henderson, W. A., 199, 204 Hendry, D. G., 169,208 Henglein, A., 123, 128, 130, 131, 135, 149 Henry, R. A., 225,256 Hepp, P., 211,224,256 Herold, B. J., 156, 205 Herzberg, G., 160, 163,205 Herzog, B. M., 188,205 Higuchi, J., 162,164,166,205 Hildebrand, J. H., 242,254 Hill, D. L., 248, 256 Hill, H. E., 77, 114 Hine, J., 27, 110, 154, 177, 186, 193, 205, 322,329 Hine, M., 27, 110 KO,K. E., 248,256

338

AUTHOR I N D E X

Ho, S.-Y., 155, 188, 205 Hoberg, H., 185, 186, 205 Hochberg, S., 320, 330 Hodgkins, J. E., 181,205 Hoeg, D. F., 182, 183,205 Hoffmann,R., 158, 159,166,170,177,178, 195,205 Homer, J. B., 168, 204 Horlein, G., 15, 113 Horn, K., 172, 177, 206 Hornel, J. C., 262,297,308,329 Horowitz, A., 7, 13, 15. 113 Hoz, S., 49,113 Hruby, V. J., 155,205 Huang, H. H., 297, 329 Huber, H., 76,110 Huett, G., 33, 110 Hughes, E. D., 2,109,110 Huisgen, R., 76, 110, 155, 176, 205, 214, 257 Hummel, K. F., 193,197,205 Humphrey, J. S., Jr., 91, 113 Hutchison, C. A., 162, 166, 168, 203, 204, 205

I Ide, J., 43, 45, 49, 110 Iglehart, E. S., 62,114 Illuminati, G., 240, 256 Ingold, C. K., 2, 109,262, 318, 329 Iskander, Y., 155, 180,204, 205 Itoh, K., 165,166,167,207 Ivaschenko, A. A., 200,207 Iwai, I., 43, 45, 49, 110

J Jackson, C. L., 211, 212, 256 Jacobs, T. L., 100,110 Jacox, M. E., 161, 163, 177, 206, 207 Jakobsen, H. J., 10, 113 Janaka, J., 216,245, 257 Janovsky, J. V., 238,256 Janzen, E. G., 214, 234, 236, 257 Jencks, W. P., 321,329 Jennen, J. J., 190,205 Jibril, A. O., 240, 256 Johns, J. W. C., 160, 163, 205 Johnson, A. W., 155,205 Johnson, G. E., 242, 256 Johnson, G. R. A,, 126,150

Johnson, H. W., Jr., 3,109 Johnson, R. L., 26,27,109 Johnson, S. L., 51,110 Johnston, H. L., 295,329 Jolley, P. W.. 15, 26, 31,110, 156, 205 Jolly, W. L., 238, 241, 254 Jones, D. E., 33, 39, 42, 44, 47, 50, 64, 71, 96,110,111 Jones, E. R. H., 93,110 Jones, M., 156, 193, 196, 197, 204, 205 Jones, W. M., 11, 98,111 Jortner, J., 145, 150 Joschek, H. I., 155,204 Josey, A. D., 15,111 Jula, T. F., 192, 208

K Kamat, R. J., 98,113 Kaminskii, A. Y., 234, 235, 237, 238, 256, 256 Kamlet, M. J., 9, 111 Kampmeier, J. A., 98, 109 Kankaanperii, A., 297, 330 Kantor, S. W., 180,205 Kapicak, L. A., 46, 59,108 Kaplan, F., 201, 205 Kappa, M., 176,206 Kassinger, R., 43, 49, 60, 79, 80, 114 Kataev, E. G., 45, 59,111 Kaufman, G. M., 172,206 Kawata, M., 238, 256 Kay, R. L., 261,331 Kayser, W. V., 279, 297, 329 Keene, J. P., 127, 149 Kempf, R. J., 164, 203 Kerber, R. C., 181, 206 Kerr, J. A., 168,206 Kessick, M. A., 274, 280, 282, 283, 297, 309, 310, 311, 324, 328 Kessler, H., 176, 207 Ketley, A. D., 317, 331 Kevan, L., 123, 143, 147,150 Keyes, C. T., 241, 255 Kibby, C. L., 188, 206 Kiesel, R. J., 191, 208 Kimura, K., 162, 169, 187, 207 Kimura, M., 224,238,241,256 King, B. J., 96,109 King, T. J., 239, 256 Kingerley, R. W., 263, 287, 329 Kirk, A. G., 202, 206 Kirmse, W., 154, 156, 172, 175, 176, 177, 181, 193,206

AUTHOR I N D E X

Kirshenbaum, I., 260,329 Kissel, H., 211, 224, 234, 256 Kistiakowsky, G. B., 188,206 Klar, R., 297,330 Klein, H. G., 77, 114 Klein, J., 46, 59,111 Knight, V., 155, 205 Knox, L. H., 191,204 Knunyants, I. L., 26, 31, 111 Kobrich, G., 155, 156,182, 201, 206 Kochetkov, N. K., 1, 9, 46, 64, 69, 111 Kogel, W., 228, 255 Kohler, B. E., 162, 204 Kohvakka, E., 247,257 Kon, G. A. R., 46,60,110 Kondo, K., 191,207 Kopecky, K. R., 176, 177, 189,204,206 Kopp, P. M., 127,149 Koremura, M., 9, 111 Korman, S., 297,329 Kornblum, N., 181,206 Krauss, F., 297, 329 Kray, W. C., 155,156,203 Kreevoy, M. M., 274, 279, 280, 281, 295, 297,309,310,311,312,329, 331 Krescheok, G. C., 260, 329 Kresge, A. J., 266,269,270,271, 273, 274, 275, 280, 282, 283, 286, 297, 308, 309, 320,329,330 Kretchmer, R. A., 274, 329 Kristinsson, H., 155, 206, 209 Krohn, W., 76,114 h e , R. B., 77,114 Kudo, K. I., 7, 15, 16,111 Kudryashov, L. J., 1,9,46,111 Kudryavtseva, T. A., 64,69,111 Kuivila, H. G., 297, 330 Kulozycki, A., 155,197,205 Kuntz, I., 33, 113 Kupperman, A., 136,150 Kuryla, W. C., 80, 111

L Labes, M. M., 223,256 Lecher, J. R., 18, 19, 20, 24, 25, 26, 28, 29, 112,113,114 Lafferty, R. H., 26,113 La F l a m e , P., 197, 204 Lagrange, R., 161,206 Laird, R. K., 161,206 Lajunen, M., 297,330 Lambert, R. W., 297,328

339

LaMer, V. K., 261,263,284,287,295,297, 298, 299, 300, 303, 319, 320, 328, 329, 330 Land, E. J., 130,150 Landgrebe, J. A., 186,192,202,206 Landholm, R. A., 297,329 Landini, D., 41,47,111 Langford, P. B., 27,110,186,205 Latham, K. S., 324, 325, 330 Laughlin, R. G., 169,204 Laughton, P. M., 262,274, 330 Laursen, R., 201,208 Lavanish, J. M., 175,209 Law, D. C. F., 9,111 Lawesson, S. O., 10,113 Leech, W. A., 33,113 Lebreton, J., 161, 206 Ledednova, V. M., 73,114 Ledwith, A., 154, 170, 171, 172, 175, 176, 180,184,192,203,206 Lee, D. J., 98,110 Lee, E. K. C., 189,206 Lee, W. G., 90,112 Leermakers, P. A,, 189, 206 Leftin, H. P., 107,114 Leis, D. G., 80, 111 Leitch, L. C., 79,111 Lemal, D. M., 155,206 Letsinger, R. L., 98,111 Levitzky, A., 140, 150 Levy,A., 77,114 Lewis, G. N., 222,256 Libby, W. F., 198,209 Lide, D. R., 161,163,207 Linn, W. J., 9,111 Lmsey, R. V., Jr., 31,110 Liptay, W.,223,224,225,226,251,254,256 Little, E. L., 1, 15, 109,112 Littrell, R., 193, 208 Lobry de Bruyn, C. A., 211,221,256 Logan, S. R., 125, 142,150 Long, F. A., 269, 270, 271, 282, 287, 290, 295, 297, 300, 301, 302, 306, 308, 309, 312, 313, 316, 317, 318, 322, 327, 329, 330 Long, G., 234,255 Lossing, F. P., 168,204,208 Lovelock, J. E., 129,150 Lowe, B. M., 262, 269, 271, 277, 282, 290, 297, 298, 299, 300, 301, 302, 304, 305, 306,312,328 Lucas, J. M., 96,109 Lugli, G., 45,54,110 Lusk, D. I., 182,183,205 Luz, Z., 142,150 Lwowski, W., 197, 206

340

AUTHOR INDEX

M Maasbol, A., 156,204 McBee, E. T., 18,20,22,27,111 Macchi, P., 11,92,108 McConaghy, J. S., 197,206 McElvain, S. M., 181, 206 McGeer, E. G., 1,109 McGhee, H. A., 160,206 McGregor, S. O., 155, 206 Mach, K., 124,149 McKelvey, D. R., 290, 327 Mackie, R. K., 215,218, 220,223, 224,226, 255,256 McKnight, C., 189, 206 McKusick, B. C., 1, 7, 13, 15, 109, 110, 111 McManimie, R. J., 77, 114 McMullen, C. H., 54, 55,111 McMurtry, R. J., 24, 27, 29, 30, 62, 112, 113 McNaughton, G. S., 123, 127, 148 McNesby, J. R., 189, 205 Maioli, L., 5, 12, 42, 44, 47, 48, 50, 65, 66, 67, 68, 89, 111 Makula, D., 9, 110 Malrnberg, C. G., 261, 330 Mamantov, A., 200, 207 Manakov, M. N., 200,207 Mango, F. D., 156,206 Mann, D. E., 160, 161, 163, 177, 203, 206, 207 Mansfield, G. H., 93,110 Marchese, G., 11, 43, 47, 64, 88, 89, 111 Margrave, J. L., 168,206 Mariella, R. P., 240, 256 Marsigny, L., 161,206 Martin, D., 15,111 Martin, E. L., 111 Martin, J. M., 155,207 Martin, W. J., 160, 206 Marzo, A., 93, 109 Mataga, N., 165, 166, 167, 207 Matesich, M. A., 98, 112 Matheson, M. S., 117, 150 Mathis, R. D., 186, 192, 206 Mathews, C. W., 161, 163, 206 Matthews, D. B., 295, 328 Meek, J. S., 43, 44, 45, 46, 50, 55, 58, 111 Megson, F. H., 29,114 Meiboorn, S., 142, 150 Meier, R., 15, 111 Meisenheimer, J., 212, 224, 239, 257 Melby, L. R., 31, 110 Melloni, G., 45, 54, 110

Meloy, G. K., 201, 205 Melquist, J. L., 297,329 Menzies, A. W. C., 260, 328, 330 Merer, A. J., 161, 163, 206 Meyer, E., 155,207 Meyer, V., 211, 257 Meyerstein, D., 134, 139, 149 Michael, B. D., 119,121, 123, 127, 129, 130, 148,149 Middleton, W. J., 1, 9, 15, 109, 111,112 Miginiac, P., 154, 206 Mill, T., 20, 110 Millauer, H., 15, 113 Miller, A. L., 216, 220, 236, 237, 240, 244, 245,257 Miller, F. W., 98, 111 Miller, J., 248, 256, 257 Miller, R., 223, 234, 257 Miller, S. I., 32, 33, 35, 44, 51, 64, 71, 76, 78,90,110,112 Miller, W. T., Jr., 15, 107, 112, 182, 206 Milligan, D. E., 161, 163, 177, 206, 207 Mills, 0. S., 156, 207 Minasz, R. J., 184, 186, 208 Minh, T. D., 201,209 Mitsch, R. A., 161, 163, 177, 199, 207 Mobbs, R. H., 1,109 Modena, G., 5, 11, 12, 42, 43, 44, 45, 47, 48,50,54,64,65, 66, 67,68,71, 74, 85, 86, 88, 89, 109, 110, 111, 112 Moelwyn-Hughes, E. A., 297, 330 Montanari, F., 9, 41, 42, 43, 47, 50, 74, 90, 108,109,111,112 Montgomery, L. K., 81, 83,84, 112 Moore, C. B., 177, 207 Moore, D. R., 113 Moore, W. R., 112 Moorthy, P. N., 123,150 Morcom, K. W., 260,328 More O’Ferrall, R. A., 171, 172, 243, 257 Moritani, I., 162, 165, 166, 167, 169, 187, 196,205,207 Moriuti, S., 176, 207 Morris, C. J., 96, 109 Morris, J. W., 215, 216, 220, 256 Morris, R. O., 33, 39, 42, 44, 47,50, 64, 71, 96,111,112 Morrison, G. C., 304, 328 Morton, C. J., 27, 111 Moss, R. A., 154, 171, 177, 182, 183, 196, 198,199,200,204,207 Mower, H. F., 7, 13, 15,111 Mui, J. Y.-P., 155, 184, 186, 192, 208 Mulder, R. J., 201, 209 Muller, E.. 176, 207 Mdliken, R. S., 214,257

341

AUTHOR I N D E X

Mullikin, J. A,, 96,109 Munch, J. H., 202, 209 Murehashi, &-I., 162, 165, 166, 167, 169, 187, 196,205,207 Muraour, H., 234,257 Murray, R. W., 162,164,166,167,207,209 Murto, J., 216,247,257

N Nachod, F. C., 297,328 Nagai, T., 196, 205 Nahabedian, K. V., 297,330 Nair, R. M. G., 155, 207 Nakadate, M., 238, 256 Nakano, M., 191,207 Naso, F., 11, 43, 47, 64, 88, 89, 111 Nazy, J. R., 98,111 Nefedov, 0. M., 200, 207 Negrini, A., 42, 43, 47, 112 Nelson, W. E., 263, 283, 297, 317, 318, 330 NQmethy, G., 260, 330 Nesmeyanov, A. N., 9, 10, 16, 43, 60, 65, 73,74,112,113 Neta, P., 118, 122, 123, 124, 126, 127, 134, 135, 142, 148,149 Neunhoeffer, O., 239,257 Newall, A. R., 193, 203 Newall, C. E., 239, 256 Newbury, R. S., 285,330 Newman, D. D. E., 104,112 Nickon, A., 173,207 Nishida, S., 196, 205 Nishino, M., 162, 165, 166, 167, 207 Noonan, 261,284,287,330 Norris, A. R., 213, 224, 225, 226, 241, 250, 251,255, 257 Norris, N. P., 226, 234, 257 Novikov, S. S., 154, 156, 208 Noyce, D. S., 98,112 Noyes, R. M., 78,112, 145,150 Noyes, W. A., 155, 188,205 Noyori, R., 172, 176, 207 Nozaki, H., 172, 176, 191, 207

0 O’Connor, B. R., 98,109 O’Donnell, J. P., 227,257 Oftedahl, E. N., 98,111 Oksengendler, G. M., 234, 235, 239, 256 Olsen, R. E., 96,109 Onwood, D. P., 280,330

Orr, W. J. C., 262, 278, 285, 297, 330 Osmundsen, J., 241, 257 Overberger, C. G., 171, 177, 207 Oversby, J. P., 124, 149 Owen, L. N., 102, 103,104,112

P Papenmeier, G., 173, 204 Parcell, R. F., 94,113 Parham, W. E., 80,112 Park, J. D., 18, 19, 20, 22, 24, 25, 26, 27, 28, 29, 30, 44, 50, 62, 112, 113, 114 Parker, A. J., 72,113, 251, 253, 257 Parr, J. E., 45, 54, 55 Paskovich, D. H., 171, 209 Pastour, P., 236,243,244,257 Patai, S., 2, 3, 7, 33, 35, 56, 63, 113 Paul, M. A., 282,287, 301, 302, 306, 329 Pearson, R. G., 190, 207 Pederaen, K., 279, 328 Pentz,L., 262,271,285,297,305,306,316, 330 Perekalin, V. V., 73, 113, 114 Perkins, M. J., 154, 156, 203 Perrot, R., 9,113 Perry, D. R. A., 28,110 Perry, F. M., 7, 28, 60, 80, 114 Pervova, E. Y., 26, 31,111 Peterson, P. E., 98, 112,113 Petroveanu, M., 101,114 Pettit, R., 156, 205 Pfister, K., 102,113 Phillips, G. O., 117, 138, 150 Phillips, L., 175, 176, 184, 206 Phillpott, E. A., 325, 328 Pickles, V. A., 236,237, 240,244,245, 255 Pimentel, G. C., 177, 207 Piseckg, J., 226, 255 Pitea, D., 64, 68, 71, 93, 109 Pizey, J. S., 41, 42, 47, 48, 113 Pocker, Y., 297,330 Pohland, A. E., 1, 43, 44, 45, 46, 109, 113 Pollard, C. B., 94,113 Pollitt, R. J., 213, 226, 235, 236, 237, 238, 239,252,257 Pottie, R. F., 168, 207 Poulton, G. A., 240,254 Powell, F. X., 161, 163, 207 Powell, J. W., 172, 173, 201, 207 Prinzbach, H., 171, 207 Pritchard, J. G., 297, 330 Prokai, B., 185, 208 Proudlock, W., 224, 234, 255

312

AUTHOR INDEX

Pruess, H., 54, 76, 114 Pruett, R. L., 8, 26, 113 Pruitt, K. M., 10, 109 Purlee, E. L., 263, 273,283, 284, 285, 287, 295,297,309,330 Putnam, W. E., 155,207 Pyper, J. W., 285, 330

R Raap, R., 43, 49, 113 Rabani, J., 120, 121, 133, 147,150 Rabinovitch, B. S., 188, 191,192,207,208 Rackow, S., 15,111 Raisin, C. G., 262, 329 Ralea, R., 101, 114 Randall, R., 175,204 Rapp, K. E., 26,113 Rappoport, Z., 2,3,7,13,15,33,35,49, 56, 63, 99,113 Redhouse, A., 156,207 Redlich, O., 261,284,297,305, 327 Reed, R. I., 126,150 Rees, C. W., 154, 156, 203, 207 Reich, P., 15,111 Reimlinger, H., 171,207 Reitz, O., 262, 297, 330 Rekasheva, A. F., 113 Remud, D. J., 178, 209 Rettig, K. R., 197, 205 Reusch, W., 173, 204 Reutov, 0. A., 60,112 Riad, Y., 155, 180, 205 Richard. J. T., 119, 123, 129, 130, 149 Richardson, D. B., 155, 189, 207 Richey, H. G., Jr., 98, 113 Rickborn, B., 227, 257 Ridd, J. H., 243, 257 Riedel, A., 156, 204 Ring, D. F., 188,207 Ring, R. N., 113 Ritter, A., 192, 209 Robert, A., 49, 113 Roberts, E., 77,114 Roberts, J.D., 81,94,109,112,113 Robertson, R. E., 262,274, 330 Robinson, C. A., 102, 113 Robinson, R. A., 261, 262, 287, 298, 299, 302, 303,305, 306,328 Robinson, R. R., 297,329 Robson, J. H., 190,201, 207 Rochester, C. H., 215, 218, 220, 222, 226, 228, 233, 236, 238, 241, 243, 244, 245, 246, 248, 249,251, 256, 257

Rogers, L. B., 297, 331 Rogers, T. E., 324,331 Ross, S. D., 33, 113, 214, 223, 256, 257 Ross, V. F., 304, 328 Rossman, M. G., 7, 60, 80, 114 Rothberg, I., 155, 180,208 Rowe, F. M., 227,256 Rowland, F. S., 189, 199, 206, 208, 209 Roy, A. K., 124,149 Roylance, J., 30, 109 Rozantsev, G. G., 154,156,208 Rule, C. K., 263,297,303,330 Russell, G. A., 169, 181,208,214,234,236, 257 Russell, K. E., 213, 226, 234, 254,255 Russell, R. L., 189, 208 Rybin, L. V., 65,73, 74,112,113 Rybinskaya, M. I., 2, 9, 10, 16, 43, 66, 73, 74,112,113

S Sachs, W. H., 155,205 SaEr, S. R., 45,54,55,110 Sakabe, N., 216,245,257 Salomon, M., 295, 330 Salomaa, P., 269, 210, 271, 282, 284, 297, 300, 302, 304, 305, 306, 308, 330 Samchenko, I. P., 113 Sandwick, P. E., 98,114 Sangster, D. F., 125, 129, 130, 150 Sargeant, P. B., 202,208 Sarkar, I., 155, 209 Satchell, D. P. N., 267, 297, 328 Sauer, J., 214, 257 Sauers, 8. S., 191, 208 Saunders, B. C., 213, 226, 235, 236, 238, 239,252,257 Saunders, D., 156, 208 Savory, J., 62,114 Sayers, D. R., 30,109,113 Scardiglia, F., 81, 112,113 Schaal, R., 227,236,243,244,257 Schaleger, L. L., 269, 270, 271, 282, 297,300,302,306,308,309,330 Schear, W., 82, 109 Scheibler, H., 47,113 Scheiner, P., 195, 208 Scheraga, H. A., 260,329,330 Scherer, O., 15, 113 Schiavelli, M. D., 98, 112 Schmidt, K., 146,150 Schmitz, E., 155, 177,208

295, 309,

237,

295,

AUTHOR INDEX

Schmitz, R., 225, 257 Schneider, H., 260, 329 Scholes, G., 118, 141, 150 Schowen, R. L., 324,325, 330 Schroll, G., 10,113 Schultz, J. W., 304, 328 Schulz, L., 178,203 Schulze, J., 297,330 Schwartz, G. M., 198,204 Schwartz, K. €I., 15,111 Schwarzenbach, G., 262,297,305, 330 Schwarzenbach, K., 175,185,209 Scorrano, G., 50, 65, 67, 71, 86, 89, 110 Scotti, F., 8, 41, 44, 47, 50, 54, 57, 64, 113 Scribner, R. M., 1,109 Seaborg, G. T., 222, 256 Seddon, W. A., 118,149 Sergeev, A. P., 15,30,31,114 SeNk, K. L., 214,216, 218, 220, 228, 229, 231,232,248,249,257 Setser, D. W., 193, 208 Severin, T., 10,113,225, 257 Seyferth, D., 155, 184, 185, 186, 192, 205, 208 Shafer, J., 201, 208 Shalygin, V. A., 71,108 Shapiro, J. S., 168, 208 Shrtpiro,R.H., 173, 174, 175,208 Shrtrrah, M. L., 29,112 Shaw, P., 141,150 Shearman, R. W., 260,330 Shechter, H., 153, 172, 173, 175, 190, 201, 202,203,204,205,206,207,208 Sherman, W. V., 129,147,150 Shih-Lin, Y., 180,206 Shiner,V. J., Jr., 91,113,284, 328 Shoosmith, J., 160, 205 Shvo, Y., 113 Sighinolfi, O., 6, 11, 64, 68, 109 Silversmith, E. F., 6, 11, 64, 113 Simandoux, JX., 297, 309, 311, 330 Simic, M., 118, 126,150 Simmons, H. D., 184, 186,208 Simmons, H. E., 155,184, 185,203,208 Simmons, M. C., 189,207 Simms, J. A., 77,114 Simonetta,M., 5,11,64,68,71,92, 93, 108, 109,216,245,255 Simons, J. P., 208 Simons, J. W., 192, 208 Sisido, K., 172, 207 Skell, P. S., 157, 164, 176, 177, 180, 182, 189, 191, 192, 194, 196, 197, 198, 199, 200,203,204, 205, 208, 209 Skovronek, H. S., 157,182,191,204

343

Slaugh, L. H., 27, 113 Slaymaker, 5. C., 156,207 Smith, D., 6, 11, 64, 113 Smith, H. A., 8, 113 Smith, J. A,, 172, 173, 175, 203, 206 Smith, R. A., 200,203 Smith, R. D., 155, 184, 185, 208 Smithen, C. E., 154,207 Smolinsky, G., 162, 209 Snow, C. M., 19,24,112 Somade, H. M. B., 103,112 Sommer, L. H., 192,209 Songstad, J., 190, 207 Sopova, A. S., 73,113,114 Spector, M. L., 107,114 Sprung, J. L., 198,209 Srinivasan, S., 295, 328 Stamm, H., 297,330 Stefani, A. P., 27,111 Steffa, L. J., 323, 330 Stegel, F., 240, 256 Steiner, E. G., 3,109 Steiner, H., 262, 278, 297, 329 Steinwand, P. J., 279, 297, 329 Stephens, R., 28,30,109,110,113 Stephenson, D. L., 181,205 Sterlin, R. N., 26, 111 Stern, E. W., 107,114 Steudel, R., 161, 209 Stevens, G., 193,203 Stevens,I. D. R., 174,177, 204 Stevens, T. S., 172, 203 Stewart, R., 227, 234, 241, 254, 255, 257 Stirling, C. J. M., 54, 55, 76, 93, 94, 111, 114 Stockdale, J. A., 125,150 Stockel, R. F., 29,114 Stoffer, J. O., 18,111 Stone, F. G. A., 15,26,31,110 Strating, J., 31, 108, 210, 209 Straub, T. S., 297, 329 Strauss, M. J., 225, 256 Strausz, 0. P., 201, 209 Strom, E. T., 214,236,257 Stubbs, C. E., 76,84,110 Sturtz, G., 98,114 Styan, G. E., 25,26,109 Suess, H., 262, 278, 297, 329 Sullivan, R., 24, 26, 27, 28, 29, 30, 113, 114 Sultanbawa, M.U. S., 103,104,108,112 Swain, C. G., 180, 209, 260, 273, 308, 317, 330, 331 Swallow, A. J., 118, 120, 139, 149,150 Swenson, J. S., 178, 209 Swinehart, J. H., 324, 331

344

AUTHOR INDEX

Symons, E. A., 213,255 Tsubomura, H., 162,169,207 Symons, M. C. R., 325,328 Turner, J.J., 27,111 Szutka,A., 117,118,121,124,131,132,150 Tyuleneva, V. V., 26,111

T

U

Taddei, F., 12,66,67,112 Ueda, H., 216,245,257 Taft, R. W., Jr., 297,309,330 Ulland, L. A., 192,209 Tamberg, N., 224,256 Unger, I.,188,205 Tang, Y. N.,189,199,209 Urey, H. C., 285,331 Tantasheva, F. R., 45,69,111 Urry, G. W., 181,206 Tarrant, P., 30,31, 62,114 Tatlow, J.C., 30,109,110,113 Taube, H., 324,331 V Taylor, D. R., 93,114 Vainionpaa, J., 247,257 Taylor, E. C., 113 Van Bekkum, H., 128,151 Terrier, F., 236,243,244,257 Van der Auwera, A.-M., 189,203 Tesoro, G. C., 113 Van der Kerk, G. J. M., 185,206 Theobald, C. W., 1, 109 Theron, F., 11, 41,42,47,48,50,64, 69, Van der Stouw, G. G., 172,206 VanDine, G. W., 158,159,166,205 74,76,89,90,91,97,105,107,114 Van Leent, F. H., 211,221,256,257 Thewalt, K., 239,257 Van Leusen, A. M., 201,209 Thoma, M., 241,256 Thomas, J.K., 117,118,121,122,123,124, van Oosten, R.P., 9,108 125,126,130,131,132,134,143,149, Vaughan, R. J.,210,203 Venkateswarlu, P., 161,209 150,151 Verkade, P.E., 128,151 Thompson, W. L., 15,114 Thornton, E. R., 155,180,208,209,262, Vernon, C. A., 33,39,42,44,47,50,64,71.

96,110,111,112 271,273,285,297,305,306,308,316, 317,323,330,331 Vesala, A., 297, 304,305,330 VessiAre, R.,59,90,105,109,114 Thrush, B. A,, 161,206,209 Vidulich, G. A., 261, 331 Thurman, D.E., 192,206 Vivarelli, P., 45,54,85,88, 110 Tieckelmann, H.. 9,109 Voisey, M. A., 193,205 Tishler, M., 102,113 Voss, J., 47,113 Tobey, S. W., 9,111 Todesco, P. E., 12,42,43,44,45,47,48,54, 65,66,67,68,71,85,88,89,109,110, 111,112 W Toepfl, W., 9,15,60,110 Wagner, P. J., 156, 209 Tomita, K., 9,43,45,49,110 Walker, D. C., 117,151 Tomlinson, C., 322,328 Waller, F. J., 155,205 Tonti, S.,44,45,54,65,66,68,71,112 Welsh, A. D., 158,209 Topley, B., 285,331 Walton, D.R.M., 98,109 Torck, B., 297,309,311,330 Ward, H.R., 112 Trapp, H., 182,206 Wardley, A., 223,256 Travis, D. N.,161,163,206 Warner, D. A., 30, 31,114 Treiber, A. J. H., 184,186,208 Washbume, S.S., 192,208 Trofimenko, S., 9,114 Wassennan,E., 162,164,165,166,167,178, Trost, B. M., 155,181,209 203,207,209 Trozzolo,A.M., 155,162,164,165,166,167, Waterman,D.C.A.,277,297,301,309,310, 205,207,209 311,312,313,315,328 Truce, W. E., 7,41,42, 43,45,47,48,49, 50,54,55,60,76,77,78,79,80,110, Watkins, K. W., 188,207 Wayne, R.P., 193,203 113,114 Webster, 0.W., 9,111,114 Trunov-Krosovskii, V. I., 235,256

345

AUTHOR I N D E X

Wedel, B. G. v., 181, 206 Wehry, E. L., 297, 331 Weintraub, P. M., 10,114 Weiss, J. J., 123, 150, 214, 257 Wepster, B. M., 128,151 Werstiuk, N. H., 173, 207 Wescott, L. D., 189, 192,196, 198, 208,209 West, R., 9, 111 Westheimer, F. H., 181,201,203, 208 Weston, R. E., Jr., 266, 282, 283, 285, 308, 329,331 Weyna, P. L., 181, 206 Whalen, D. M., 182, 206 Wheland, G. W., 223, 255 White, R. F. M., 33, 39, 42, 44, 47, 50, 64, 71,96,111,122 Whiting, M. C., 93, 110, 172, 173, 201, 204, 207 Whitlock, H. W., Jr., 98 Whittaker, D., 171, 191, 193, 203 Wiberg, K. B., 175, 209 Wideman, L. G., 180,205 Wigger,A., 123, 128, 130, 131, 135,149 Wilcott, M. R., 192, 203 Wiley, D. W., 7,13,15,110, 171,209 Wilkins, V. G., 127,149 Wilkinson, F., 118,149 Willey, F. G., 172,204 Williams, J.M., Jr., 280,281,295,310,311, 312,331 Willis, C. J., 155, 185, 204 Will&, R. L. S., 124,151 Wilmot, P. B., 125, 142,150 Wilson, C. L., 262, 329 Wilson, L. H., 24,25,113 Wilson, R. C., 141,150 Winberg, H. E., 1, 109 Wingler, F., 184, 185, 209 Winstein, S., 100, 114, 198, 209 Winterfeldt, E., 54, 76, 114

Wischin, A., 262,297,329 Wittig, G., 81, 82, 114, 175, 184, 185, 209 Wolfsberg, M., 284, 331 Wolinsky, J., 92,110,210,204 Wood, J., 234, 255 Wood, J. B., 175, 203 Woodward, R. B., 195, 205 Woodworth, R. C., 194, 197,200, 208 Woodyard, J. D., 181,205 Wright, C. R., 46, 60, 110 Wynne-Jones, W. F. K., 223, 234, 257, 295,297,305,331

Y Yager, W. A., 155, 162, 164,165, 166, 167, 178,203,207, 209 Yagil, G., 307, 331 Yakubovich, A. Y., 15, 30, 31, 114 Yamamoto, Y., 165, 166, 167,207 Yarkova, E. G., 45,59,111 Yates, P., 171, 176, 209 Yonan,P. K., 32,33,35,44,51,64,71,112 Yoshimine, M., 180,209 Yurchenko, 0. I., 73,113,114

Z Zahler, R. E., 33,109, 214, 255 Zech, B., 176,207 Zeiss, G. D., 158, 159, 166, 205 Zel’venskii, Y. D., 71, 108 Zimmerman, H. E., 171,202,209 Zimmerman, W., 239,257 Zollinger, H., 165, 209, 216, 218, 220, 236, 237,240,244,245, 255 Zugravescu, I., 101, 114 Zwanenburg, B., 171,172,204 Zwolenik, J. J., 161, 209

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CUMULATIVE INDEX OF AUTHORS Anbar, M., 7, 115 Bell, R. P., 4, 1 Bethell, D., 7, 153 Brand, J. C. D., 1,365 Brown, H. C., 1, 35 Collins, C. J., 2, 1 Crampton, M. R., 7,211 Ferguson, G., 1,203 Fielda, E. K., 6, 1 Frey, H. M., 4, 147 Gilbert, B. C., 5,53 Gold, V., 7,259 Greenwood, H. H., 4,73 Johnson, 5.L., 5,237 Kohnstam, G., 5, 121 Kreevoy, M. M., 6 , 6 3 Long, F. A., 1 , l Maccoll, A., 3, 91 McWeeny, R., 4 , 7 3 Miller, S. I., 6, 185 More O’Ferrall, R. A., 5,331 Norman, R. 0. C., 5 , 5 3 Olah, G. A., 4, 305 Parker, A. J., 5,173 Perkampus, H.-H., 4,195 Pittmann, C. U., Jr., 4, 305 Rappoport, Z., 7 , l Reeves. L. W., 3, 187 Robertson, J. M., 1,203 Samuel, D., 3, 123 Schaleger, L. L., 1, 1 Scheraga, H. A., 6,103 Shatenshtein, A. I., 1, 156 Silver, B. L., 3, 123 Stock, L. M., 1,35 Symom, M. C. R., 1,284 Turner, D. W., 4, 31 Whalley, E., 2, 93 William, J. M., Jr., 6, 63 Williamson, D. G., 1, 365 Wolf, A. P., 2,201 Zollinger, H., 2,163 zuman. P., 5, 1

347

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CUMULATIVE INDEX OF TITLES Acid solutions, strong, spectroscopic observation of alkylcarbonium ions in, 4, 305 Acids, reactions of aliphatic diazo compounds with, 5, 331 Activation, entropies of, and mechanisms of reactions in solution, 1, 1 Activation, heat capacities of, and their uses in mechanistic studies, 5, 121 Activation, volumes of, use for determining reaction mechanisms, 2, 93 Aliphatic diazo compounds, reactions with acids, 5, 331 Alkylcarbonium ions, spectroscopic observation in strong acid solutions, 4, 305 Ammonia, liquid, isotope exchange reactions of organic compounds in, 1, 156 Aromatic substitution, a quantitative treatment of directive effects in, 1, 35 Aromatic substitution reactions, hydrogen isotope effects in, 2, 163 Aromatic systems, planar and non-planar, 1,203 Arynes, mechanisms of formation and reactions at high temperatures, 6, 1 A-Sx2 reactions, developments in the study of, 6, 63 Base catalysis, general, of ester hydrolysis and related reactions, 5, 237 Basicity of unsaturated compounds, 4, 195 Bimolecular substitution reactions in protic and dipolar aprotic solvents, 5, 173 Carbene chemistry, structure and mechanism in, 7, 153 Carbon atoms, energetic, reactions with organic compounds, 3,201 Carbonium ions (alkyl), spectroscopic observation in strong acid solutions, 4, 305 Catalysis, general base and nucleophilic, of ester hydrolysis and related reactions, 5, 237 Carbonyl compounds, reversible hydration of, 4, 1 Conformations of polypeptides, calculations of, 6, 103 Conjugated molecules, reactivity indices in, 4, 73 Diazo compounds, aliphatic, reactions with acids, 5, 331 Dipolar aprotic and protic solvents, rates of bimolecular substitution reactions in, 5, 173 Directive effects in aromatic substitution, a quantitative treatment of, 1, 35 Electron spin resonance, identification of organic free radicals by, 1, 284 Electron-spin resonance studies of short-lived organic radicals, 5, 53 Electronically excited molecules, structure of, 1, 365 Energetic tritium and carbon atoms, reactions of, with organic compounds, 2,201 Entropies of activation and mechanisms of reactions in solution, I, 1 Equilibrium constants, N.M.R. measurements of, as a function of temperature, 3, 187 Ester hydrolysis, general base and nucleophilic catalysis, 5, 237 Exchange reactions, hydrogen isotope, of organic compounds in liquid ammonia, 1, 156 Exchange reactions, oxygen isotope, of organic compounds, 3, 123 Excited molecules, structure of electronically, 1, 365

Free radicals, identification by electron spin resonance, 1, 284 Gas-phase heterolysis, 3,91 Gas-phase pyrolysis of small-ring hydrocarbons, 4, 147 General base and nucleophilic catalysis of ester hydrolysis and related reactions, 5,237 349

350

CUMULATIVE INDEX

H~O-DZO Mixtures, protolytic processes in, 259 Heat capacities of activation and their uses in mechanistic studies, 5, 121 Heterolysis, gas-phase, 3,91 Hydrated electrons reactions of, with organic compounds, 7, 115 Hydration, reversible, of carbonyl compounds, 4, 1 Hydrocarbons, small-ring, gas-phase pyrolysis of, 4, 147 Hydrogen isotope effects in aromatic substitution reactions, 2, 163 Hydrogen isotope exchange reactions of organic compounds in liquid ammonia, 1, 156 Hydrolysis, ester, and related reactions, general base and nucleophilic catalysis of, 5,237 Ionization potentials, 4, 31 Isotope effects, hydrogen, in aromatic substitution reactions, 2, 163 Isotope exchange reactions, hydrogen, of organic compounds in liquid ammonia, 1. 150 Isotope exchange reactions, oxygen, of organic compounds, 3, 123 Isotope and organic reaction mechanisms, 2, 1 Kinetics, reaction, polarography and, 5, 1 Mechanism and structure in carbene chemistry, 7, 153 Mechanisms, organic reaction, isotopes and, 2, 1 Mechanisms, reaction, use of volumes of activation for determining, 2,93 Mechanisms of formation and reactions of arynes at high temperatures, 6, 1 Mechanisms of reactions in solution, entropies of activation and, 1, 1 Mechanistic studies, heat capacities of activation and their uses in, 5, 121 Meisenheimer complexes, 7, 211 N.M.R. measurements of reaction velocities and equilibrium constants as a function of temperature, 3, 187 Non-planar and planar aromatic systems, 1, 203 Nuclear magnetic resonance, 8ee N.M.R. Nucleophilic catalysis of ester hydrolysis and related reactions, 4, 237 Nucleophilic vinylic substitution, 7, 1 Oxygen isotope exchange reactions of organic compounds, 3, 123 Planar and non-planar aromatic systems, 1, 203 Polarizability, molecular refractivity and, 3, 1 Polarography and reaction kinetics, 5, 1 Polypeptides, calculations of conformations of, 6, 103 Protic and dipolar aprotic solvents, rates of bimolecular substitution reactions in, 5, 173 Protolytic processes in HaO-DaO mixtures, 7,269 Pyrolysis, gas-phase, of small-ring hydrocarbons, 4, 147 Radicals, organic free, identification by electron spin resonance, 1, 284 Radicals, short-lived organic, electron spin resonance studies of, 5, 53 Reaction kinetics, polarography and, 5, 1 Reaction mechanisms, use of volumes of activation for determining, 2, 93 Reaction mechaniems in solution, entropies of activation and, 1, 1 Reaction velocities and equilibrium constants, N.M.R. measurements of, as a function of temperature, 3, 187 Reactions of hydrated electrons with organic compounds, 7, 115 Reactivity indices in conjugated molecules, 4, 73 Refractivity, molecular, and polarizability, 3, 1 Resonance, electron-spin, identscation of organic free radicals by, 1,284 Resonance, electron-spin, studies of short-lived organic radicals, 5, 53 Short-lived organic radicals, electron spin resonance studies of, 5, 53 Small-ringhydrocarbons, gas-phase pyrolysis of, 4, 147

CUMULATIVE INDEX

361

Solution, reactions in, ent.ropies of activation and mechanisms, 1, 1 Solvents, protic and dipolar aprotic, rates of bimolecular substitution reactions in, 5, 173 Spectroscopic observation of alkylcarbonium ions in strong acid solutions, 4, 305 Stereoselection in elementary steps of organic reactions, 6,185 Structure and mechanism in carbene chemistry, 7, 153 Structure of electronically excited molecules, 1, 365 Substitution, aromatic, a quantitative treatment of directive effects in, 1, 35 Substitution reactions, bimolecular, in protic and dipolar aprotic solvents, 5, 173 Substitution reactions, aromatic, hydrogen isotope effects in, 2, 163 Temperature, N.M.R. measurements of reaction velocities and equilibrium constants a function of, 3, 187 Tritium atoms, energetic, reactions with organic compounds, 2, 201 Unsaturated compounds, basicity of, 4, 195 Volumes of activation, use of, for determining reaction mechanisms, 2, 93

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