ORGANIC REACTION MECHANISMS 1981 A n annual survey covering the literature dated December 1980 through November 1981

Edited by

A. C. KNIPE and W. E. WATTS, The New University of Ulster, Northern Ireland

A n Intersciences Publication

JOHN WILEY & SONS Chichester * New York * Brisbane Toronto . Singapore

ORGANIC REACTION MECHANISMS - 1981

ORGANIC REACTION MECHANISMS 1981 A n annual survey covering the literature dated December 1980 through November 1981

Edited by

A. C. KNIPE and W. E. WATTS, The New University of Ulster, Northern Ireland

A n Intersciences Publication

JOHN WILEY & SONS Chichester * New York * Brisbane Toronto . Singapore

British Library Cataloguing in Publication Data:

Copyright 0 1982 by John Wiley & Sons Ltd.

All rights reserved.

No part of this book may be reproduced by any means, nor transmitted, nor translated into a machine language without the written permission of the publisher.

Library of Congress Catalog Card Number 66-23143

Organic reaction mechanisms.- 1981 1. Chemistry, Organic-Periodicals 2. Chemical reactions-Periodicals 547.13'9 QD258

ISBN 0 471 10459 0

Phototypeset by Speedlith Photo Litho Ltd., Manchester Printed at the Pitman Press, Bath, Avon.

Contributors

D. J. COWLEY

M. R. CRAMPTON I . R. DUNKIN

G. W. J. FLEET

1. GOSNEY M. C. GROSSEL

A. F. HEGARTY

A. J . KIRBY R. B. MOODIE C. J . MOODY

A. E. MURRAY D. C. NONHEBEL

M. I . PAGE

R. M. PATON J. SHORTER

School of Physical Sciences, New University of

Department of Chemistry, Durham University Department of Pure and Applied Chemistry,

Dyson Perrins Laboratory, South Parks Road,

Department of Chemistry, University of Edinburgh Department of Chemistry, Bedford and Royal

Chemistry Department, University College, Dublin,

University Chemical Laboratory, Cambridge Department of Chemistry, University of Exeter Department of Chemistry, Imperial College of

Department of Chemistry, University of Dundee Department of Pure and Applied Chemistry,

Department of Chemical Science, Huddersfield

Department of Chemistry, University of Edinburgh Department of Chemistry, University of Hull

Ulster

University of Strathclyde

Oxford University

Holloway Colleges, Egham, Surrey

Ireland

Science and Technology

University of Strathclyde

Polytechnic, Huddersfield

V

The present volume, the seventeenth in the series, surveys research on organic reaction mechanisms described in the literature dated December 1980 to November 1981. In order to limit the size of the volume, we must necessarily exclude or restrict overlap with other publications which review related specialist areas (e.g. photochemical reactions, biosynthesis, electrochemistry, surface chemistry, organometallic chemistry, heterogeneous catalysis). In order to minimize duplication, while ensuring comprehensive coverage, the editors conduct a survey of all relevant literature and allocate references to appropriate chapters. While a particular reference may be allocated to more than one chapter, we do assume that readers will be aware of the alternative chapters to which a borderline topic of interest may have been preferentially assigned.

We regret that Brian Capon has found it necessary to discontinue as an author and we wish to acknowledge the major contribution that he made to both the establishment and continuation of Organic Reaction Mechanisms. Brian, in conjunction with his co-editors Charles Rees and John Perkins, conceived and launched the series in 1965; he served as an editor of the volumes dated 1965-1972 but continued thereafter to contribute the chapter entitled ‘Reactions of Aldehydes and Ketones and their Derivatives’. We have no doubt that the international community of chemists who take an interest in the mechanisms of organic reactions will have benefitted considerably from the contribution that Brian Capon made to this series over a period of sixteen years. We hope to maintain the quality and viability of Organic Reaction Mechanisms and to thereby ensure that benefit will continue to accrue from the initiative of the founder editors.

Once again we wish to thank the publication and production staff of John Wiley and Sons and our team of contributors, which has been rejoined by Dr. M. Page. We are also indebted to Dr. N. Cully who compiled the subject index.

A.C.K. W.E.W.

vii

Contents

1 . 2 . 3 . 4 . 5 . 6 . 7 . 8 . 9 .

10 . 11 . 12 . 13 . 14 .

Reactions of Aldehydes and Ketones and their Derivatives

Reactions of Acids and their Derivatives by A . J . Kirby . . . . . Radical Reactions by D . J . Cowley and D . C . Nonhebel . . . .

Oxidation and Reduction by G . W . J . Fleet . . . . . . . .

by M . I . Page 1 23

77

183

Carbenes and Nitrenes by C . J . Moody 239

Nucleophilic Aromatic Substitution by M . R . Crampton . . . . 263

Electrophilic Aromatic Substitution by R . B . Moodie 283

Carbocations by M . C . Grossel . . . . . . . . . . . 299

Nucleophilic Aliphatic Substitution by J . Shorter . . . . . . .

. . . . . . . . .

. . . . .

323

Carbanions and Electrophilic Aliphatic Substitution by 1 . Gosney . . 353

Elimination Reactions by A . F . Hegarty . . . . . . . . . 385

Addition Reactions: Polar Addition by R . M . Paton . . . . . 409

Addition Reactions: Cycloaddition by I . R . Dunkin . . . . . . 433

Molecular Rearrangements by A . W . Murray . . . . . . . 459

Author Index. 1981 . . . . . . . . . . . . . . . . 559

Subject Index. 1981 . . . . . . . . . . . . . . . . 621

ix

Organic Reaction Mechanisms 1981 Edited by A. C . Knipe and W. E. Watts @ 1982 John Wiley & Sons, Ltd.

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

M. 1. PAGE

Department oj Chemical Sciences, Huddersjield Polytechnic

Formation and Reactions of Acetals and Ketals . Hydrolysis and Formation of Glycosides . .

Non-enzymic Reactions . . . . . Enzymic Reactions . . . . . .

. Schiff Bases and Related Species . . . Oximes, Hydrazones, and Related Compounds

Aldol and Related Reactions. . . . . Other Addition Reactions . . . . . Enolization and Related Reactions . . . Hydrolysis of Enol Ethers and Related Compounds Other Reactions . . . . . . . References . . . . . . . .

Reactions and Formation of Nitrogen Bases .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

10 12 14 16 17 17

Formation and Reactions of Acetals and Ketals The hydrolysis of substituted benzaldehyde ethyl hemiacetals, generated from the corresponding ethyl salicyl acetal, shows catalysis by hydronium ion, water, and hydroxide ion. The p value for hydronium ion catalysis is - 1.9, in contrast to the value of - 3.25 for the hydrolysis of benzaldehyde diethyl acetal, and hemiacetal breakdown will only be rate-limiting for the latter reaction with substituents in the phenyl ring having CT values < - 0.5. The p value for the pH-independent hydrolysis of the hemiacetals is +0.35 and the solvent isotope effect kHZ0/kDx0 is 2.0 which suggest that proton transfer is important and is consistent with acid-catalysed breakdown of the hemiacetal anion (l).'

G- @t

ArCH

H p* (1 1

The intramolecular addition of an alcohol to an aldehyde (2) to give a cyclic hemiacetal (3) is displaced towards cyclization in basic solution because of hemiacetal ionization. General base-catalysed cyclization occurs with a Br~nsted p

1

2 Organic Reaction Mechanisms 1981

value of 0.62. General acid catalysis is thought to occur by dual mechanisms, viz. general acid catalysis at carbonyl oxygen and specific-acid-general-base catalysis, which is used to account for the observation of different Brmsted CI values for different classes of acids.’

?H

Glycosides with an equatorial leaving group normally hydroiyse faster than those with an axial group. In contrast, the axial anomer of the conformationally rigid acetal (4) hydrolyses 1.5 times faster than the equatorial anomer. Despite the small rate difference, this has been used to support different transition states for the two reaction^.^

The bicyclic hydroxypropyl methoxytetrahydropyran (5) gives only the cis- tricyclic acetal (6) under acid conditions. This is attributed to the development by the intermediate oxenium ion of a lone pair which becomes antiperiplanar to the newly formed C -0 bond (7).4 Acid-catalysed ring-opening of the tricyclic spiro- ketal (8) gives specifically the equatorial bicyclic ether-aldehyde (9) by stereoelectronically controlled hydride transfer to the intermediate oxenium ion (10) because the ether oxygen has a lone pair antiperiplanar to the newly formed C-H bond.5

Cyclization of the intermediate 0x0-carbocation (11) in the formation of dioxolanes is a 5-endo-trig cyclization which is unfavourable by Baldwin’s rules for ring-closure. It has therefore been suggested, with little supporting evidence, that

1 Reactions of Aldehydes and Ketones and their Drrivutiues 3

ring-closure occurs uia the protonated hemiacetal (12).6 The spiro [5.5]undecane ketals exist in conformationally rigid systems (13) which minimize steric effects and maximize anomeric effects.'

Although the environment of a given chiral molecule (it) in the liquid phase will be diastereomeric with, and thus different from, that in the liquid of the racemicmix ture (R,s) there is little evidence to suggest this corresponds to a measurable free-energy difference. For example, the conversions of (s)- and (R, s)-propane-1 ,2-diols into dioxolanes using the diol as solvent proceed at identical rates.*

+

HO

It has long been known that the rate or equilibrium differences among the members of a reaction series, which involves an interconversion of a trigonal carbon and a more crowded tetrahedral carbon, may be correlated with the relative size of the subsituent groups attached to the reaction centre. A calorimetric determination of the enthalpies of hydrolysis of a series of alkyl-substituted dimethyl acetals shows that the enthdpy of the acetal hydrolysis is remarkably insensitive to changes in the substituent alkyl group (approximate slope of acetal AHr us. E, plot = 0.4), suggesting that polar interactions are negligible and that the larger effects seen with the ketals represent true steric effects. As the free-energy changes are well correlated with the E, scale, entropy changes associated with solvation and internal contributions, particularly bond-angle bending, must make important contri- butions to steric effect^.^

Neither the bicyclic ketal(l4) nor its conjugate acid, nor the corresponding fully formed carbocation are severely strained but the geometry of (14) would be such as to inhibit resonance stabilization of the carbocation during its formation. Despite elegant rationalizations of why (14) should exhibit concerted proton transfer and C-0 cleavage, it actually shows no buffer catalysis and a solvent hydrogen isotope effect (kH/kD) of 0.43. A conventional A1 mechanism is proposed."

The rates of hydrolysis of 2-alkoxy-1,3-dioxolanes increase with increasing stability of the 1,3-dioxolenium cation (15) which is compatible with, but not proof

(14) (15)

of, rate-limiting heterolysis of the exocyclic C - 0 bond." The kinetics of the formation and hydrolysis of substituted dioxolanes have been reported.I2 1,3- Dioxolanes give 1,3-dioxolan-2-ylium salts by hydride transfer on treatment with iodine monochloride.13 The bromination of cyclic acetals is slowest for the six- membered ring, shows negative entropies of activation, and is thought to proceed by carbocation f~ rma t ion . '~ Halo-substituted boranes cause ring-opening of cyclic

4 Orgunic Reuction Mechanisms 1981 acetals by rate-limiting formation of an 0x0-carbenium ion which can subsequently be reduced to a hydroxy-ether.” The rate-limiting step in the reaction of triethoxymethane, aniline, and dimedone is solvent-dependent.’ The solvolysis of the thia analogue of methyl chloroformate, MeS2CC1, proceeds by an Shl mechanism in methanol and at a rate faster than that of the oxygen derivative.” Sulphuryl chloride reacts with 1,3-oxathioians and 1,3-dithiolans to give unstable rrans-2,3-dichloro-l,4-oxathians and trans-2,3-dichloro-l,4-dithians, respec- tively.” Acetal formation with carboxamide dialkyl sulphate adducts has been described.’

Hydrolysis and Formation of Glycosides Non-enzymic Reactions The kinetics of the tautomerization of a-D- and /?-D-galactopyranose in water show that the starting pyranose is simultaneously converted into the anomeric pyranose and into furanoses during the course of mutarotation. Furanose formation is ca. 10 times faster than pyranose formation, and rates of ring-opening of the furanoses are 10-35 times faster than those of the pyranoses.20 Contrary to an earlier report,’l the alkaline hydrolysis of phenyl /?-D-glucopyranoside has been shown to proceed by the commonly accepted SNiCB pathway.22 The rate of mutarotation of N-acetyl-D- neuraminic acid (16) has a minimum at pD 5.4 whereas at pD 1.3 and 11.7 it is too fast to be measured by ‘H-NMR spectroscopy. With no suitable model studies, the rationalization of these observations is premature.23

HO

(16)

In agreement with previous reports, removal of the 2’- or 3’-hydroxyl group enhances the rate of the acid-catalysed hydrolysis of adenosine nucleosides. Other substituent effects in the glycon may be interpreted by the A1 mechanism.24 Anomeric hydroxy groups are protonated faster ( < ten-fold) than non-anomeric hydroxy groups of monosaccharides in DMSO. Anomeric hydroxy groups of ketopyranoses and furanoses are protonated slightly faster than those of aldopyranoses, roughly in parallel with the rates of the acid-catalysed hydrolysis of the corresponding glyc~sides.~’ Glycosyl glycosides may be synthesized with M- stereoselectivity using trifluoromethanesulphonic anhydride as a catalyst.26 4-0- substituted uronic acids, treated with sodium methylsulphinylmethanide, undergo /?-elimination in the ionization step.27 The Hilbert-Johnson silyl nucleoside synthesis with Friedel-Crafts catalysts occurs by reaction ofthe sugar cation with the sily lated base.

Enzymic Reactions Oxygen-1 8 leaving-group kinetic isotope effects are observed for the /?- galactosidase-catalysed hydrolysis of 4-nitrophenyl fl-D-galactoside but not for the 2,4-dinitrophenyl derivative. The latter is thought to hydrolyse by a Shl mechanism to give a galactosyl cation which partitions between a nucleophilic group on the enzyme and water. Substrates with poorer leaving groups hydrolyse by a Sh2

1 Reactions of Aldehydes and Ketones and their Derivatives 5

mechanism to give a covalent galactosyl enzyme.2g The hydrolysis of aryl p-D- glucosidase from Stachybotrys atra proceeds through an intermediate glycosyl- enzyme which may be trapped with alcohols.30 The kinetic a-deuterium isotope effect for the purine nucleoside phosphorylase-catalysed phosphorolysis of inosine is pH-dependent. This is interpreted in terms of a change in rate-limiting step, from one involving C -N cleavage at high pH to give an intermediate 0x0-carbenium ion (17) to an earlier step near ne~tral i ty .~ '

HO OH

(17)

The initial rates of sucrose hydrolysis catalysed by invertase pass through a maximum and then decrease, through two plateaus, with increasing sucrose concentration. This is claimed to be due to increased intramolecular hydrogen bonding with increasing concen t r a t i~n .~~

Reactions and Fonnation of Nitrogen Bases Schif' Bases and Related Species The hydrolysis of the oxazolidine (18) occurs in two separate reaction stages, uiz. reversible ring-opening to the cationic Schiff base (19) followed by a slow formation of the hydrolysis products. The pK, of the protonated oxazolidine is 6.2 and the ratio of this species to the cationic Schiff base is 1 : 19 and independent of acidity. Below pH 5, ring-opening is apparently pH-independent but represents acid- catalysed ring-opening of the neutral oxazolidine. Similarly, in this pH region, apparent general base catalysis in fact represents general acid-catalysed ring- opening of neutral (18) with a Br~nsted a value of 0.70. Ring-opening also occurs by an uncatalysed mechanism above pH 5. The formation of hydrolysis products involves rate-limiting addition of water or hydroxide ion to the cationic Schiff base (19). This intermolecular reaction is much slower than the supposedly unfavourable intramolecular 5-endo-trig r ing -c l~su re .~~

f-7

O X N M e Ar Me

(18)

Ar = p-tolyl (19)

The ring-opening of imidazolidines to give a Schiff base is catalysed by general acids and shows a Br~nsted a value of0.7, indicative of a concerted reaction (20). The latter is attributed to carbocation stabilization and leaving-group effects rather than to the basicity of the ring nitrogen^.^^ Mercury(n) chloride enhances the rate of

6 Organic Reaction Mechunisms 1981

hydrolysis of mono-protonated 9-( 1-ethoxyethy1)purine and adenine but has no effect on the di-protonated species.35 The enhanced rate of mono-protonated diamines reacting with ketones to give imines is attributed to intramolecular general acid-catalysed dehydration of the intermediate carbinolamine (21). Methylation of the carbon atoms between the amino groups generally decreases the reactivity which is rationalized by steric effects in the cyclic transition state.36 Malondialdehyde, a biologically important breakdown product, reacts with the amino group of amino- acids to give enaminal~.~’ Fluoren-9-one-1-carboxylic acid effects the transami- nation of primary amines and amino-acids. Isomerization of the intermediate imine may be facilitated by proton abstraction by the neighbouring carboxyl

H

The chiral diamine (22) stereoselectively dedeuterates labelled acyclic ketones by forming an intermediate Schiff base in which the p r o 3 deuterons are removed preferentially by the intramolecular amino group acting as a general base catalyst. The transition state (23) is of lower energy than that involving removal of the pro-R deuterons because of less unfavourable steric effects. 39

The kinetics of the catalysis of elimination of electronegative substituents from the p-position of a-amino-acids by pyridoxal have been investigated by NMR spectroscopy and the reaction is thought to occur through the di-, mono-, and non- protonated forms of the intermediate Schiff base. In the presence of metal ions, rate enhancements of up to 10-fold are ~bserved.~’ The pyridoxal-catalysed P- elimination (a) and dealdolation (b) of P-hydroxyglutamic acid occur simul- taneously, and in the pD range near the pK, of the 6-carboxyl group decarboxylation follows elimination (24). Protonation of the azomethine and pyridine nitrogens retards expulsion of the hydroxide group but favours d e a l d ~ l a t i o n . ~ ~

The functionalised (2,5)pyridinophane (25) is slightly more efficient than pyridoxal in the non-enzyme-catalysed racemization of monosodium L-

g l ~ t a m a t e . ~ ~ The rate-limiting step for the liver alcohol dehydrogenase-catalysed

1 Reactions of Aldehydes and Ketones and their Deritutices 7

reduction of aliphatic aldehydes is the dissociation of the enzyme-NAD’ complex which in turn is controlled by a conformational change.43 The Schiff-base mechanism enzyme, 2-keto-4-hydroxyglutarate aldolase, appears to have a non- specific anion binding site in addition to the anionic substrate analogue inhibition site.44 The imidoyl azide structure (26), originally proposed, has in fact the enamine structure (27) which cyclizes to tetrazoles with a bell-shaped pH-rate profile. At low pH, C-protonation of the enimine is rate-limiting and is also general acid-catalysed with a Brransted a value of 0.57. Increase in pH, or high buffer concentration, changes the rate-limiting step to isomerization of the protonated imine. The azide group acts as an efficient intramolecular trap for the imine in which the nitrogen lone pair is cis to the azide, to give the cyclic t e t r a ~ o l e . ~ ~

‘C =N ’ ‘Et N3

CH

/ N3

~ C - N H E ~

A positive p + value for the reaction of aniline with substituted aromatic aldehydes in acetonitrile has been used to suggest rate-limiting attack on the carbonyl group, although pyridine-4-aldehydes show deviations attributable to the influence of carbinolamine d e h y d r a t i ~ n . ~ ~ Acetic acid-catalysed Schiff-base formation from aromatic aldehydes and 2-amino-l,3,4-thiadiazoles involves rate-limiting dehy- dration of the carbinolamine and becomes independent of acid concentration at high concentrations of acetic The condensation of salicylaldehyde and primary diamines occurs within the coordination sphere of copper(r1) and n i cke l ( r~ ) .~~

Schiff-base condensation reactions between 2,6-diacetylpyridine and 3,6-dioxa octane-l&diamine in the presence of Ba(1r) and other metal ions can give complexes of the open-chain derivative formed from one molecule of dicarbonyl and two molecules of diamine.49 These are the probable intermediates in the formation of the 30-membered [2 + 21 macro cycle^.^^ The condensation of 3-methyl-1,Zdiamino- benzene with aromatic aldehydes gives methylben~imidazoles.~’ The reaction of Schiff bases with sodium then ethyl chloroformate gives 1,3,4,5-tetra aryl- imidazolidin-2-ones presumably via the dimeric d i a n i ~ n . ~ ~ The stereoselectivity of the reaction of arylmethanephosphonate carbanions with SchifS bases varies with the cation and anion used to generate the ~ a r b a n i o n . ~ ~ A novel metal carbonyl- catalysed reaction of isocyanates with aldehydes to give imines is thought to occur by insertion of the aldehyde into a preformed isocyanate complex.54 The rate of hydrolysis of substituted 4-(N,N-dimethylamino)benzylideneanilines (28) is acid- dependent below pH 3.5 but pH-independent from pH 3.5 to 6.5. The Hammett p value is positive under both condition^.^^

8 Organic Reuction Mechanisms I981

(29)

The hydrolysis of the imine (29) has been suggested to occur via intramolecular general base catalysis by the phenoxide ion but, because of kinetic ambiguity and lack of data for unsuitable model compounds, this requires more information. Copper(r1) retards the reaction by compiexation with the i m i ~ ~ e . ~ ~ The rate of the acid-catalysed (but not the pH-independent) hydrolysis of imines formed from substituted 2-aminothiazoles and 2-hydroxybenzaldehydes is dependent upon the nature of the s~bstituent.~’ The base-catalysed formation of Mannich bases from 3,5-dimethyl-4-nitroisoxazole proceeds by SN2 attack of the carbanion of isoxazole on N-(hydroxymethyl)amine, whereas in acidic solution the reaction occurs uia the imine

The methanolysis of benzylideneaniline derivatives of the type (30) causes cleavage of the C-MMe3 bond, where M = Si or Sn. The rate of the uncatalysed cleavage is increased by electron-releasing substituents in both aromatic residues. A cyclic mechanism (31) is proposed. The rate of the base-catalysed cleavage is increased by electron-withdrawing groups in the aniline residue. Proton transfer to carbon is thought to lag behind C-SnMe3 bond-breaking, but for C-SiMe3 cleavage, proton transfer occurs to ni t r~gen.~’ Similar proposals have been made for the reactions of l-methyl-2-trimethylsilylbenzimidazole.60 Substituent, salt, and solvent effects on the stereochemistry of the addition of allylic organometallics to Schiff bases have been reported.61

Ar’ ‘N

A reaction involving intramolecular hydride transfer to imines has been described.62 The pH-rate profile for the hydrolysis of hexamethylenetetramine to formaldehyde is sigmoidal, corresponding to water- and acid-catalysed reactions of the conjugate Enamines with a- or P-hetero-atoms (with respect to the amine) have reduced conjugation between the nitrogen lone pair and the double bond. This is attributed to the molecules examined adopting conformations to minimize lone-pair-lone-pair r e p u l ~ i o n s . ~ ~

Oximes, Hydrazones, and Related Compounds Variation in the secondary kinetic deuterium isotope effects in the addition of hydroxylamine to substituted cyclohexanones has been attributed to ring deformation and changes in the angle of approach of the n~c leoph i l e .~~ Large negative values for the entropies of activation for the formation of oximes from adamantyl ketones have been used to suggest rate-limiting dehydration.66 The reactivity of the carbonyl group at various positions in steroids towards

1 Reactions oj Aldehydes and Ketones and their Deriiwtices 9

hydroxylamine has been examined.67 The rate of formation of cyclohexanone oxime and its hydrolysis between pH 1 and 7 has been further studied.68

The cyclization of thiocyanatopropenal with hydroxylamine has been reported.69 The effect of substituents on the barrier to isomerization of ~xirnes ,~ ' and the pH dependence and substituent effects upon the rates of reactions of oximes have been reported.71 Alkoxide substitution of (2)-hydroximoyl chlorides (32) proceeds with >95% retention of configuration, and at half the rate of reaction of the corresponding bromide; the Hammett p value is 1.9. These observations are consistent with rate-limiting formation of a tetrahedral intermediate. It is suggested that stereoelectronically controlled loss of chloride ion from the tetrahedral intermediate (33) is faster than either loss of methoxide ion to regenerate starting material or s t e r eom~ta t ion .~~

Benzil mono-oximes react with N-chlorosuccinimide, dimethyl sulphide, and triethylamine to afford a methylthiomethyl n i t r ~ n e . ~ ~ The conversion of benzaldoximes into benzaldehydes with manganese(ni) acetate shows a Hammett p value of -0.57 and is thought to proceed by an electron-transfer mechanism to give an iminoxy radical.74 The heterolytic cleavage of the N -0 bond of 6-methyl-hept- 5-en-2-one oxime produces 6'-pyrrolines by capture of the intermediate nitrilium ion by the alkene.75 At low pHs where the formation of hydrazones usually occurs with rate-limiting formation of an intermediate carbinolamine and exhibits general acid catalysis, the reaction of phenylhydrazine and 2-hydroxybenzaldehyde shows no buffer catalysis. The rate of the pH-independent formation of 2- hydroxybenzaldehyde phenylhydrazone is 200 times faster than that of the 4- hydroxy derivative which is attributed to intramolecular hydrogen bonding (34). This also explains the absence of buffer catalysis.76 It is interesting to note that a 2- hydroxy substituent in acetophenone decreases the rate of carbinolamine formation six-fold.

(34) (35)

The mechanism of indole formation from 2-methoxyphenylhydrazones has been reviewed.77 Thallium(tir) acetate acts as an electrophilic catalyst by reversible coordination to the amino NH of substituted phenylhydrazones, facilitating nucleophilic attack at the methine carbon to give substituted hydrazines as products. By contrast, mercury(i1) irreversibly binds to the imino nitrogen giving osazones as Regioselectivity in ring-closure reactions of hydrazones with thionyl chloride may be rationalized by the greater acidity of methylene

10 Organic Reaction Mechanisms 1981

compared with methyl hydrogens. ’’ 2-Pivaloylindane-l,3-dione (35) reacts with thiosemicarbazide in aqueous base, through two successive retro-Claisen reactions to give 2-acetylbenzoic acid which reacts with semicarbazide to give l-hydroxy-4- met hylpht halazine. O

Aldol and Related Reactions The stereoselectivity of the aldol condensation has been reviewed.81 In slightly basic media, ionization of the gem-diol group of B-bromopyruvate initiates bromide elimination to give P-hydroxypyruvate, which ionizes at pH >13 to give the carbanion enolate and undergoes an aldol condensation.82 The Knorr-Paal cyclo- condensation shows a bell-shaped pH-rate profile, a large negative entropy of activation, a Brransted o! value of 0.25 for the substituted benzoic acid-catalysed condensation, and a Hammett pf value of -0.88, all of which are compatible with an addition-elimination mechanism.83

The sense and degree of stereoselectivity in the deprotonation of ketones can be critical in determining the overall stereoselectivity obtained in electrophilic substitution reactions employing enolate-like intermediates. For example, it usually assumed that the lithio intermediates, of stereochemistry (36) and (37), formed in deprotonations of active methylene-containing compounds are the kinetically formed products, and their formation can thus be rationalized from transition-state structures. However, some of these reactions may be reversible and hence thermodynamic factors need to be considered. Propionaldehyde dimethyl- hydrazone-lithium reagents, formed by deprotonation with lithium diisopropyl- amide, do not equilibrate under the reaction conditions and the ratio of the stereoisomers formed is far removed from equilibrium. In this case, distinct transition states for deprotonation must exist.84

RHx- Lit H Y

“w“ - Li+ R Y

Addition of an enolate to a chiral aldehyde can give two erythru-aldols resulting from attack at either of the diastereotopic faces of the aldehyde. A similar situation exists if the enolate is chiral. Several reagents are now available which give good diastereoselection in the aldol condensation. Double stereo-differentiation can occur if both reagents are chiral or if the solvent is chiral. Cram’s rule predicting the selectivity in the addition to chiral aldehydes may be enhanced by double stereo- differentiation.8s

Under kinetic control z-enolates generally favour erythro-adducts and E-enolates the threo-isomers in aldol condensations. However, titanium enolates derived from ketones react with aldehydes to give preferentially the erythro-adduct which is attributed either to an acyclic transition state or a cyclic one in which chair-to-boat interconversion can occur.86 Lithium enolates of hindred aryl esters condense with aldehydes to give predominantly threo-ald~ls.~’ Lithium enolates react with allylic acetates in a palladium-catalysed alkylation with retention of configuration.88 Reactions of the chiral dianion (38) with aldehyde gives predominantly erythro- aldols. Variation of the erythrolthreo ratios can be rationalized in terms of cyclic us.

1 Reactions qf Aldehydes and Ketones and their Derivatices 11

acyclic transition states. Eryrhro-selectivity may be rationalized by the minimization of steric interactions and maximal separation of negative charge provided by an acyclic anti transition state.89

0 Li

(38) (39)

Boron enolates derived from chiral ethyl ketones show high stereoselectivity in the aldol reaction.” Boron enolates are the suggested intermediates in the aldol condensation of ketones in the presence of dialkylboryl triflates and tertiary amines. Variation of the boron ligands and solvent allow total stereo-control of the conden~ation.~’ High levels of aldol stereo-regulation may be obtained using zirconium enolate~.~’ Chiral boron enolates are also effective in stereo-regulated aldol condensation^,^^ and minimal non-bonded interactions in the pericyclic transition state for the aldol condensation with boron enolates has been proposed to account for chirality tran~fer.’~ Acyclic stereo-selection is also obtained from enolates with tris(diethy1amino)sulphonium cation as the negligibly interacting counter-ion but, interestingly, is independent of enolate geometry. Rather than the normal pericyclic process via the metal-linked six-membered cyclic transition state, an extended geometry (39) is proposed to minimize electrostatic repulsion.95

Triphenyltin enolates undergo a rapid aldol condensation with aldehydes, without the need for the presence of Lewis acids, to give predominantly the erythro- product regardless of the geometry of the starting enolates. This cannot be explained by the conventional cyclic transition state but may be rationalized if the mechanism is ~tep-wise.’~ Other stereospecific reactions of enolates have been reported.”

Despite the small differences in activation energies which may account for the relative proportion of isomeric alkenes formed in the Wittig reaction, changes in the steric course of the reaction with solvent have been used to support the equilibrium formation of betaine and oxaphosphetan intermediates.” The &/trans ratio of the alkenes formed in the Wittig reaction of ylides from benzyltriaylphosphonium salts increases as the steric crowding at phosphorus increases.” An efficient silicon- mediated alkene synthesis from ketones produces almost exclusively (z)-alkenyl derivatives, which is attributed to the diastereoselective addition of the a-silyl carbanion to the carbonyl cornpound.lo0 Reaction of a-silylated ester magnesium enolates with aldehydes gives only one diastereoisomer (of two possible /?- hydroxysilanes) which yields E-unsaturated esters on acid work-up.”’

The reaction of 3-chloroaffyltrimethylsilane with aldehydes in the presence of Lewis acids gives methyl ethers of homoallyl alcohols.”’ Double stereo- differentiation using a chiral a- [(trimethylsilyl)oxy ]ketones in an aldol reaction with chiral racemic aldehydes gives high diastereoface ~electivity.”~ Silyl enol ethers, in the presence of TiC14, alkylate exo-2-norbornyl halides with retention of onf figuration."^ The selectivity of the alkylation of cyclopropyl alkyl ketones depends on substituents attached to the carbonyl carbon and on the ring.Io5 Solid hexamethylphosphotriamide can be used to control C- or 0-alkylation with different metal ion enolates, presumably by interacting with the cations.’06 The

12 Organic Reaction Mechanisms 1981

influence of substituents, solvents, temperature, and concentration on the ratio of 0- to C-methylation of enolate anions has been examined.'''

Metallo enamines, as enolate equivalents, have introduced the possibility of a chiral environment and hence the control of the direction of eiectrophilic attack to give a novel asymmetric C -C bond-forming reaction. Thus, chiral imines may be prepared from cyclic ketones and chiral amines; formation of the lithioenamine and then alkylation gives, after hydrolysis, 2-alkylcycloalkanones in 87-100 % enantiomeric purity.' '* Thioenolates generated from thioamides have the z- configuration and selectively give the erythro-isomer in aldol condensations.' O9 The two-phase kinetics observed for the retro-aldol cleavage of pent-3-en-2-one to acetone and acetaldehyde are attributed to initial reversible hydration followed by C-C bond cleavage."' The formation of xanthyrones and glaucyrones from a "melt reaction" between pyrones, methyl methoxymethyleneacetoacetate, and dry sodium methoxide proceeds by Michael addition of the pyrone anion to the a,F- unsaturated ketone. The proportion of products results from competitive protonation and the leaving-group ability of the carbanion."' The product of the Perkin reaction of benzaldehyde and acetic anhydride in the presence of potassium acetate is, before hydrolysis, potassium cinnamate and K+ (OAc, Ac0H)- and not the commonly accepted mixed anhydride.' l 2

Other Addition Reactions In contrast to the cyclic transition-state structure proposed for the hydration of 1,3- dichloroacetone in water-dioxane, an acyclic structure is suggested for the reaction in micelles of bis(2-ethy1hexyl)sodium sulphosuccinate (AOT) with the number of associated water molecules depending on the water-surfactant ratio. From labelling experiments, the linear dependence of the rate constant upon atom fraction of deuterium indicates that only one proton is moving in the transition state. ' ' Solvent effects on the equilibrium constants for hydration of pyridine-4- carboxaldehyde have been reported.' '

Theoretical models suggest that addition of a water molecule to formaldehyde in the gas phase gives a zwitterion of no finite life-time and the addition is therefore "enforced" to be concerted. Conversely, initial protonation of formaldehyde or addition of hydroxide ion are favourable processes.'15 The rates of the base- catalysed dehydration of oxalacetate hydrate are faster than those for enolization of oxalacetate,; however, the converse holds when the reactions are catalysed by tertiary amines at high buffer concentration, but not at low concentrations. There is thus a rate cross-over with increasing concentration of tertiary amine which had led earlier workers to suggest the formation of a carbinolamine intermediate.' However, tertiary amines still show enhanced activity compared with other bases; the reason is not clear but electrostatic factors may be important.' ' The rates of addition of sulphite ion to aromatic aldehydes have been measured.' '' Analysis of structure-reactivity relationships for benzaldehyde cyanohydrin formation by the Taft and Yukawa-Tsuno dual-parameter equations indicate a product-like transition state.' Asymmetric addition of hydrogen cyanide to benzaldehyde catalysed by the cyclic dipeptide cyclo(L-phenylalanyl-L-histidine) gives an enantiomeric excess of 90 % but the optical yield decreases with increasing reaction time. ' 2o

Ketols (M), in equilibrium with their hemiketals, undergo isomerization by base- catalysed intramolecular hydride transfer from the alcohol function to the carbonyl

1 Reactions of Aldehydes and Ketones and their Drriuatiues 13

group.'" The intramolecular Cannizzaro reaction of phthalaldehyde to 2- (hydroxymethy1)benzoate ion is a slow process because it proceeds via the cyclic hydrate dianion (41) which must undergo unfavourable ring-opening to (42) before intramolecular hydride transfer can occur.' 22

The rate of addition of anionic nucleophiles to carbonyl compounds may be affected by metal-ion complexation with either the nucleophile or the carbonyl oxygen. In the reaction of benzaldehyde with acetonitrile anion in THF, lithium ion facilitates the reaction by coordination to the carbonyl oxygen but potassium ion retards the rate by coordinating to the anion. Carbonyl complexation is favoured by electron-releasing substituents in the aldehyde but electron-withdrawing sub- stituents encourage coordination to the n~c leoph i l e . ' ~~ The unusual reactivity of constrained cage ketones has been reviewed.'24 It is generally agreed that nucleophilic addition to cyclohexanone, proceeding through an early reactant-like transition state, is directed into the equatorial position by steric hindrance but the reasons for the preference of some nucleophiles for a more hindered axial approach are uncertain. It has been suggested that transition-state stabilization, resulting from electron donation of the oCH bonds of cyclohexanone into a low-lying vacant o* orbital, associated with the o-bond being formed in the reaction, favours the axial appr~ach . '~ ' According to SCF perturbation theory, the directional nature of nucleophilic attack on carbonyl groups is dependent upon closed-shell repulsion, electrostatic interaction, and charge transfer. The frontier-orbital description of the charge-transfer term is therefore inadequate.'26 Attack of a reagent at an unsaturated site occurs such as to minimize anti-bonding secondary orbital interactions between the critical frontier molecular orbital of the reagent and those of the vicinal bonds.127

The Hammett p value for the reaction of methylmagnesium chloride with l-aryl- 2-phenylpropanones is 0.53.' 2 8 Evidence supporting the single-electron-transfer mechanism in the reaction of Grignard reagents with ketones comes from the observation of an EPR spectrum during the reduction of aromatic ketones by p- hydrogen transfer from the alkyl group of the Grignard reagent.'29 The stereochemistry of the addition of phenyl- and methyl-magnesium bromide to chiral carbonyl compounds has been studied as a function of solvent polarity. In some, but not all, cases there is a correlation between stereoselectivity and the ET solvent parameter.I3' The invariability of asymmetric induction as a function of substituent in the addition of CH,MgBr to 1-aryl-2-phenylpropanones and the Hammett p value of 0.24 for the ratio of the rate constants have been used to substantiate a four- centre pericyclic concerted rne~hanisrn.'~' The formation of diols from reactions of benzylic Grignard reagents with aldehydes proceeds by nucleophilic addition of the aromatic ortho-carbon to the aldehydes.' 32

The reaction of tert-butyl isocyanide and trifluoroacetic acid with aldehydes and ketones to give an a-(acy1oxy)carboxamide (Passerini reaction) is catalysed by

14 Organic Reaction Mechanisms I981 pyridine acting as a general acid The reaction of benzaldehyde with C13C- in the presence of benzylquininium chloride as a phase-transfer catalyst gives 5.7 % enantiomeric excess (R)-P~CH(OH)CCI, .' 34

Volumes of activation have been used to suggest a concerted mechanism in the ene reaction of hex-1-ene with dimethyl mesoxalate.' 35 A primary deuterium kinetic isotope effect (k , /k , = 2.16) for the addition of dimethyl mesoxalate to alkenes has been used to suggest a non-linear transition state for hydrogen transfer (43).136

E = C0,Me

(43 )

Enolization and Related Reactions Vinyl alcohol, the simplest enol, has been generated from several precursors and kept in solution below ca. - 10" for several hours. Vinyl alcohol is converted into acetaldehyde ca. 100 times faster than is ethyl vinyl ether which, again, contradicts earlier assumption^.'^^ The rates of iodination of fl-piperidinopropiophenone and its N-methyl derivative are similar and up to 4000 times larger than those for suitable model compounds. This is attributed to intramolecular electrostatic stabilization of the developing negative charge on the carbonyl oxygen in the transition state (44).13*

An unnecessarily complicated argument has been used to show that the pH- independent enolization of acetone represents water catalysis rather than the kinetically equivalent hydroxide-ion attack on the conjugate acid.' 39 The equilibrium constants for tautomerism may easily be determined, because at low halogen concentration the rate of the acid-catalysed halogenation is first order in halogen and the rate-limiting addition of halogen to the enol is diffusion-controlled. Cyclohexanone contains 20 times more enol than does cyclopentanone. Contrary to previous suggestions, it has been shown that ketonization rate constants do not equal those for methyl enol ether hydrolysis and their ratio varies between 15 and 150, depending on enol structure. The transition state for acid-catalysed enolization has the proton less than half-tran~ferred.'~' Variation in the rates of iodination of substituted acetophenones have been attributed to different degrees of resonance between the carbonyl group and the s~bs t i t uen t . ' ~~ A very small (<twice) rate enhancement is observed for the micellar-catalysed enolization of acetone. lJZ

Glyoxalase I catalyses the conversion of glutathione and a-keto-aldehydes into

1 Reactions of Aldehydes and Ketones and their Derivatives 15

the glutathione thiol ester of the corresponding a-hydroxy-acid. a-Keto-aldehydes react non-enzymically with glutathione to form hemithioacetals of which only one of the diastereoisomers binds to the enzyme.'43 The rearrangement of hemithioacetals (45) to a-hydroxythiol esters (46) is almost completely inhibited by the addition of flavin, a good trap for carbanions. This is indicative of an enediol intermediate (47) rather than the expected 1,2-hydride shift me~han i sm. '~~

0 OH

The kinetics of the enolization of cyclic ketones by amino-acids has been studied.'45 The kinetics and mechanisms of iodination reactions have been reviewed.'46 The rate of the acid-catalysed bromination of 2,4,6-trimethylaceto- phenone in 50 % aqueous acetic acid is first order in bromine but is overall a rapid reaction. The reaction of the enol with bromine to give the bromonium ion is rate- limiting because of unfavourable non-bonded interaction^.'^^ Activation parameters and Brsnsted p values for the iodination of cyclic ketones have been r e p ~ r t e d . ' ~ ~ Cuprous iodide catalyses the acid-catalysed zero-order iodination of a~et0ne.l~' The effect of the medium on the iodination of acetone has been discussed with reference to selective intermolecular forces.' The heterocyclic base-catalysed iodinations of acetophenone and acetonaphthones show Brsnsted j3 values of

Halogens react rapidly with a$-unsaturated ketones either by addition to the en01 or by initial attack on the carbonyl oxygen, rather than by expected attack at the C=C bond.' 5 2 The non-free-radical chlorination of ketones in methanol favours substitution at the least substituted carbon LY to the carbonyl group. This is consistent with the formation and chlorination of the least hindered enol ether.' 53 The gas-phase kinetic isotope effect, k H / k D , for the reaction of acetone with RO- decreases in the order R = Me3C > Br > Et > Me > H.lS4

The enolization reaction of alkyl mesityl ketones with alkylmagnesium bromide is first order in each reagent. Kinetic isotope effects (k& = 2.6-3.1) with a-deuterio- substituted ketones have been used to support a step-wise mechanism, uiz. pre- equilibrium coordination of the Grignard reagent to the carbonyl oxygen followed by rate-limiting hydrogen abstraction.' ' Triethylamine catalyses the enolization of ketones in the presence of Grignard reagent^.''^

Monomeric metaphosphate anion reacts with ketones to give enol phosphates and, in the presence of aniline, promotes Schiff-base formation. It is suggested that biosynthetic phosphorylations that require ATP may proceed through monomeric metaphosphate anion.' 5 7 Silyl phosphites react with a-halocarbonyl compounds to give not only the enol phosphates (Perkow reaction) but also 1 : 1 carbonyl addition products and 2-0x0-phosphonates; the proportion of products depends upon substituents. The Perkow reaction probably proceeds via an initial attack of phosphite on the carbonyl carbon.158 The powerful electrophile, 4,6-dinitrobenzo- furoxan, reacts with monoketones and j3-diketones, in the absence of added base, to

0.9-1 .O.' '

16 Organic Reaction Mechanisms I981

give a-adducts. Reaction presumably occurs via the en01 of the ketone. With fl- diketones both enolic and ketonic adducts are formed.' 5 9 Allylation of acetals with allylsilanes is catalysed by iodotrimethylsilane to give the corresponding homoallyl ethers, with regiospecific transposition of the ally1 group.' 6o

The rates of tautomerization of di-n-alkyl fl-diketones in mixed solvents compared with water have been analysed by consideration of the free energies of transfer of the transition states.16' The degree of enolization of fl-keto-esters of azines is greater than that of analogous benzoylacetates.' Ketones react with diethoxycarbenium fluoroborate in the presence of N,N-diisopropylethylamine to give a-(diethoxymethyl) ketones through, it is suggested, intermediate formation of the en01 ether.'63

Hydrolysis of Enol Ethers and Related Compounds Hemiorthoesters, from hydration of ketene acetals, have been detected by 'H- and ' 3C-NMR spectroscopy. Their hydrolysis shows an acid-, base-, and water- catalysed reaction. The latter probably involves rate-limiting ionization of the hydroxyl group rapidly followed by breakdown of the mono-anion and hydronium ion within the first-formed encounter complex.' 64 The mechanism and kinetics of reactions of ketenes have been reviewed.' 65 The acid-catalysed hydrolysis of phenylketene acetals 0,O- (48) and 0,s- (49) acetals involves rate-limiting protonation of the double bond. A non-linear dependence of the rate upon formate buffer concentration is thought to be not attributable to a change in rate-limiting step as the rate is unaffected by the addition ofmer~aptoethanol.'~~ However, as this thiol is not significantly ionized at low pH it may not be able to effectively compete with water attack on the intermediate carbocation.

Ph OMe Ph ,SMe

H/C=C\OMe H OMe

\ / \ ,c=c \

The rate of hydration of ketene to give acetic acid is pH-independent between pH4 and 10 with a rate constant of 44s-' and shows kHZ0/kDzO of 1.9. This is compatible with rate-limiting uncatalysed addition of water to the ketene.I6' Dichloroketene reacts with dimethylketene dimethyl acetal to yield the cyclobutanone regiospecifically, but the reaction of methylchloroketene and ketene diethyl acetal yields an acyclic product, an acylketene acetal. This is consistent with a two-step mechanism involving a dipolar intermediate which can either lose a proton or cyclize.'68 The perfluoroacylketene (S), the first acylketene to be isolated, a related perfluorovinyl ketone (51), and the analogous sulphur derivatives have been prepared from a dimer of hexafluoropropene. The acylketene reacts as a diene to give adducts that are hydrolysis products of the vinyl ketone ad duct^.'^'

Kinetic solvent isotope effects (kH30+/kD30+ < 1) and CQ. 100% deuterium incorporation during the acidic hydrolysis of ketene selenoacetals indicate that a rapid and reversible protonation at the olefinic fl-carbon occurs. The rate-limiting step could then be hydration of the carbocation or the breakdown of the

1 Reactions of' Aldehydes and Ketones und their Derivutives

/ CF3 ,CF3 F2C=C

\ o=c=c

\ c=o c = o I I c2 F5 c2 Fs

17

(50) (51)

intermediate hemior th~es te r . '~~ The rate of the acid-catalysed hydrolysis of 9- methoxyoxacyclonon-2-ene (52) is 500 times faster than that of 2-methoxy-2,3- dihydropyran. The nine-membered ring compound exhibits non-linear buffer plots, compatible with reversible protonation and rate-limiting decomposition of the intermediate hemiacetal.' 7' The effect of P-alkyl substitution in vinyl ether hydrolysis is not cumulative.' 7 2 The acidic hydrolysis of dioxenes (53) occurs by 0- protonation and rate-limiting ring-cleavage.' 7 3

Other Reactions The effect of solvent on the kinetics of the oxidation of cyclohexanone have been investigated.' 74 The rate of the ruthenium(n1)-catalysed oxidation of aromatic aldehydes by alkaline metaperiodate is independent of metaperiodate concentration and shows a Hammett p value of + 1.66. This has been interpreted in terms of a change in mechanism from hydride loss in acid medium to proton loss in alkaline medium.'75 The oxidation of benzaldehyde to benzoic acid by acidic bromate occurs by slow formation of an intermediate bromate ester:' 76 3-Nitrobenzylidene dibromides and dichlorides decompose in base to give the aldehyde, but the difluorides give a-chloro-4,4'-dinitrostilbene oxide.' 7 7

The red colour produced in the Fujiwara reaction of gem-polyhalogen compounds with pyridine is due to the formation of a conjugated benzamidine.' 7 8

The Hammett p value of - 1.67 for the addition of substituted diaryldiazomethanes to chloranil indicates the development of a large positive charge on the diazo carbon in the transition state.' 79 The reaction of two moles of an aromatic aldehyde with methyl thiocyanate in the presence of tributylphosphine gives both S- methylthiobenzoates and phenylacetonitriles probably by a novel disproportio- nation reaction.'"

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18 Organic Reaction Mechanisms 1981

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