ORGANIC REACTION MECHANISMS 1986

An annual survey covering the literature dated December 1985 to November 1986

Edited by

A. C. Knipe and W. E. Watts University of Ulster, Northern Ireland

An Interscience@ Publication

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

ORGANIC REACTION MECHANISMS * 1986

ORGANIC REACTION MECHANISMS 1986

An annual survey covering the literature dated December 1985 to November 1986

Edited by

A. C. Knipe and W. E. Watts University of Ulster, Northern Ireland

An Interscience@ Publication

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

Copyright 0 1988 by John Wiley & Sons Ltd.

All rights reserved.

No part of this book may be reproduced by any means. or transmitted. or translated into a machine language without the written permission of the publisher.

Lihrary of Congress Catalog Card Number 66-23143

British Library Cataloguing in Publication Data:

Organic reaction mechamisms. 1. Organic compounds. Chemical reactions. Mechanisms-Serials 547.13'9

ISBN0471 91724 X

Phototypesot by Macmillan India Ltd. Printed and bound in Great Britain by Anchor Brendon Ltd, Tiptree, Essex

Contributors

R. A. AITKEN

D. J. COWLEY

R. A. COX

M. R. CRAMPTON

G. W. J. FLEET

A. FRY

P. HANSON

A. C. KNIPE

R. B. MOODIE

R. A. MORE O’FERRALL

A. W. MURRAY

M. 1. PAGE

R. M. PATON

J. SHORTER

W. J. SPILLANE

Department of Chemistry, University of St Andrews, Purdie Building, St. An- drews, Fife KY 16 9ST, Scotland

Department of Chemistry, The Uni- versity of Ulster at Coleraine, Cole- raine, Co. Londonderry BT52 lSA, Northern Ireland

Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 1A1, Canada

Department of Chemistry, Durham Uni- versity, Durham DHl 3LE, UK

Dyson Perrins Laboratory, Oxford Uni- versity, South Parks Road, Oxford OX1 3QT, UK

Department of Chemistry and Biochem- istry, University of Arkansas, Fayette- ville, Arkansas 72701, USA

Department of Chemistry, University of York, Heslington, York YO1 5DD, UK

Department of Chemistry, The Uni- versity Ulster at Coleraine, Coleraine, Co. Londonderry BT52 ISA, North- ern Ireland

Department of Chemistry, The Uni- versity, Exeter EX4 4QD, UK

Department of Chemistry, University College, Belfield, Dublin 4, Northern Ireland

Department of Chemistry, The Uni- versity, Dundee DDl4HN, Scotland

Department of Chemical Sciences, The Polytechnic, Queensgate, Hudders-

field, West Yorkshire HD13DH, UK Department of Chemistry, Edinburgh

University, West Mains Road, Edin- burgh EH9 355, Scotland

Department of Chemistry, The Uni- versity, Hull HU6 7RX, UK

Department of Chemistry, University College, Galway, Ireland

V

The present volume, the twenty-second in the series, surveys research on organic reaction mechanisms described in the literature dated December 1985 to November 1986. In order to limit the size of the volume, we must necessarily exclude or restrict overlap with other publications which review specialist areas (e.g. photochemical reactions, biosynthesis, electrochemistry, organometallic chemistry, surface chemistry and heterogenous catalysis). In order to minimize duplication, while ensuring a comprehensive coverage, the editors conduct a survey of all relevant literature and allocate publications 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.

Two changes of author have taken place since last year. We welcome Professor Arthur Fry as author of the ‘Polar Addition’ chapter. This was previously written by Professor Knipe who has now undertaken the chapter entitled ‘Carbanions and Electrophilic Aliphatic Substitution’ in place of Dr Ian Watt, whose valuable contribution to the series is acknowledged.

Once again we wish to thank the publication and production staff of John Wiley & Sons and our team of experienced contributors for their efforts to ensure that the standards of this series are sustained. We are also indebted to Dr N. Cully, who compiled the subject index.

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

vii

Con tents

1 .

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

10 . 11 . 12 . 13 . 14 . 15 .

Reactions of Aldehydes and Ketones and their Derivatives by M . I .

Reactions of Acids and their Derivatives by W . J . Spillane ............ Radical Reactions: Part 1 by P . Hanson .................................... Radical Reactions: Part 2 by D . J . Cowley ................................. Oxidation and Reduction by G . W . J . Fleet ................................ Carbenes and Nitrenes by R . A . Aitken .................................... Nucleophilic Aromatic Substitution by M . R . Crampton ................ Electrophilic Aromatic Substitution by R . B . Moodie ................... Carbocations by R . A . Cox ..................................................... Nucleophilic Aliphatic Substitution by J . Shorter ......................... Carbanions and Electrophilic Aliphatic Substitution by A . C . Knipe Elimination Reactions by R . A . More O'Ferrall .......................... Addition Reactions-Polar Addition by A . Fry ........................... Addition Reactions-Cycloaddition by R . M . Paton ..................... Molecular Rearrangements by A . W . Murray ............................

Page ................................................................................... 1 29 87

129 167 227 247 263 275 289 319 343 361 393 429

Author Index. 1986 ...................................................................... 527 Subject Index. 1986 ...................................................................... 577

ix

Organic Reaction Mechanisms 1986 Edited by A. C. Knipe and W. E. Watts ,c 1988 John Wiley & Sons Ltd.

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

M. 1. PAGE

Department of Chemical and Physical Sciences, Huddersjeld Polytechnic

Formation and Reactions of Acetals, Ketals and Orthoesters . . . . . . . . . . 1 Hydrolysis and Formation of Clucosides . . . . . . . . . . . . . . . . . . . . 3

Non-enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Reactions and Formation of Nitrogen Derivatives, Schiff Bases,. . . . . . . . . Hydrazones Oximes and Related Species . . . . . . . . . . . . . . . . . . 5

C-C Bond Formation and Fission; Aldol and Related Reactions. . . . . . . . . 10 Other Addition Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . 19 Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Formation and Reactions of Acetals, Ketals and Orthoesters

The linear relationship observed between bond length and reactivity in unsym- metrical acetals ROCH(R)OX has been shown to hord for variation in R as well as X. The more stable is the anion XO- or the cation ROeHR, the longer is the C-OX bond, as expected from the increasing contribution of the valence tautomer (1). The longer is the C-OX bond, the more reactive is theacetal in reactions involving C-OX bond fission. Crystal structures of hydrogen-bonded 2,6-dioxacyclohexyl acdals have been analysed as models of pre-association complexes for acid-catalysed acetal hydrolysis. Hydrogen-bonding weakens the C-0 bond and the orientation of the hydrogen bond controls the degree of weakening.* The rates of the acid-catalysed hydrolysis of bemophenone crown ether ketals increase rapidly with ring size reaching a maximum in the 17-membered ring, which is attributed to the stable protonated species (2)’

The rates of hydrolysis of acetals and thioacetals of p-(dimet hy1amino)- benzaldehyde are pH-independent between pH 1 and 5 and acid-catalysed above this pH. Apparent general acid catalysis is observed in the hydrolysis of the 1,3-dioxolane and 1,3-oxathiolane derivatives, but for the former the buffer plots are curved indicating a change in rate-limiting step. As shown previously for 1,3-dioxolanes,4 ring-opening may be reversible and the rate-limiting step at low buffer concentration

1

2 Organic Reaction Mechanisms 1986

Ph

is the general base-catalysed addition of water to the oxocarbocation intermediate (3) but becomes ring-opening at high buffer concentration.’ The rates of hydrolysis of acetaldehyde ethyl hemiacetal are greater than those of acetaldehyde diethyl acetal and ethyl vinyl ether. However, a correlation between the rate constants for acidcatalysed acetal and hemiacetal hydrolysis indicates that the latter may become rate-limiting with reactive acetals and vinyl ethers6

Polar and resonance effects of substituents on the rates of formation and hydrolysis of acetophenone dimethyl acetals in methanol containing small amounts of water have been discussed. The rate-limiting step for hydrolysis is water addition to the oxocarbenium ion formed from the hemiacetal intermediateB7 The acid- catalysed hydrolyses of 1,3-dioxanes of substituted benzophenones (4) show a more negative Hammett p-value than that for the corresponding five-membered cyclic acetals.’ There have been further studies of substituent effects on the acid-catalysed hydrolysis of 1,3-dioxolanes and 1,3-dioxanes.’ Cyclic thioacetals and thioketals react with halogen in carbon tetrachloride through a monocationic rather than the previously postulated dicationic species. lo

I Reactions of' Aldehydes and Ketones and their Derivatives 3

Linear free energy relationships for the hydrolysis of acylals and thioacylals in aqueous sulphuric acid give acidity-dependent p-values. The mechanism changes from A2 at low acidities to A1 at high acidity. However, methylene diacetate shows a low-acidity A1 mechanism, which is attributed to intramolecular nucleophilic attack (5), followed by C-0 cleavage to give acetic anhydride and formaldehyde.' ' Glyoxal and other short-chain a-hydroxy-carbonyl and a-dicarbonyl compounds that are unable to form stable intramolecular hemiacetals form complex dimeric and higher- order hemiacetals. The alkaline hydrolysis of aqueous glyoxal dimer (6) shows a complex dependence on hydroxide ion concentration which is not observed for other similar depolymerizations, the mutarotation of fructose, or the dehydration of aldehyde hydrates.' The breakdown of hemiorthothiol and hemiorthothiolate tetrahedral intermediates has been interpreted using stereoelectronic effects.' As expected, the intramolecular proton transfer in (7) has been shown to have a high activation energy in the gas phase.I4

On the basis of X-ray crystallographic analysis, the reaction of ethanolamine with butanedione give a tricyclic hemiketal and not the epoxide as previously reported. An initial 1,Zaddition of ethanolamine to butanedione generates a cis-2,3- dihydroxymorpholine which in turn reacts withanother molecule of butanedione." One diastereoisomer of some chiral acetals reacts faster than the other with triisobutylaluminium and the resulting enol ether is transformed into optically pure ketone. This may be a general kinetic approach to the resolution of ketones.I6 The thermal reactions of cyclopropenone ketals have been described.'

Hydrolysis and Formation of Glucosides

Non-enzymic Reactions The effects of added solutes on the neutral hydrolysis of aldopyranosyl systems are different from those on methoxymethyl derivatives. It is concluded that the reactions of aldopyranosyl derivatives in water are truly S,1 with no pre-association. Kinetic "0 isotope effects in the ring of methyl a- and /?-glucopyranosides iicate there is much more double-bond character in the transition state for /?-glucoside than for a- glucoside hydrolysis. However, the "0 ring effects are small and contrast with other isotope effects which suggest that the exocyclic C-0 bond is largely broken in the transition state. The geometry of the transition states required to explain the kinetic isotope effects is not that predicted by the theory of stereoelectronic control."

Ground-state and transition-state effects have been separated for the acid- catalysed hydrolysis of sucrose in a variety of mixed solvents. The relative catalytic activity of H+ is controlled by its relative sol~ation. '~ An NMR kinetic analysis of the pyranose-aldehyde-furanose equilibrium has yielded the rate constants for the acidcatalysed steps." The concentrations of hydroxide ion and monosaccharide influence the products formed in the alkaline hydrolysis of monosaccharides. The enediol anion species (8) is involved in both isomerization and degradation reactions. There is a rapid equilibrium between C(3) and C(6) saccharides involving aldolization and retro-aldolization. /?-Dicarbonyl compounds, the /?-elimination

4 Organic Reaction Mechanisms 1986

products of (8), undergo benzilic acid rearrangement and a-dicarbonyl cleavage to give a variety of acid products.21

The rates of interconversion of the different tautomers of the 3-deoxy-~-mannose derivative, which exists predominantly in the 8-pyranose form (9), have been determined by 3C two-dimensional NMR exchange data." Treatment of sugar osazones with nitrous acid results in the formation of osone hydrazones by cleavage of the C(2)-N bond whereas the 0-acetylted derivatives give triazoles by cleavage of the hydrazone N-N bond.z3 The photoreaction of aldohexoses in the presence of iron(rI1) chloride induces a selective cleavage of the C(l)-C(2) bond producing 4-0- formyl-waldopentapyranoses. Titanium@) chloride induces a C(5)-C(6) bond- cleavage upon irradiation. It is thought electron-transfer occurs within the iron chelate formed from the 1,2diol system at the C(1) and C(2) positions of the pyranoses (lo), followed by recyclization of the fission product^.'^

HO -CH I

H

C02H

Enzymic Reactions Pure 8-amylase catalyses the hydration of the vinyl ether double bond of maltal to form deoxymaltose with a k,,/K, of 0 x looo M- 's- and with an exceptionally large solvent isotope effect on k,, of 8. Deuteriation of the double bond occurs from a direction opposite to that assumed for protonation of the glycosidic oxygens of

1 Reactions of Aldehydes and Ketones and their Derivatives 5

starch. It is proposed that maltal binds at the active centre of #?-amylase and that the ‘normal’ carboxyl catalytic group functions as shown in (11). This is yet another example which demonstrates that many enzymes have the ability to catalyse different reactions with different s ~ b s t r a t e s . ~ ~

On the basis of molecular dynamics simulation, it has been suggested that the lysozyme-catalysed hydrolysis of oligoglycosides involves endocyclic bond fission (12) rather than the generally accepted exocyclic cleavage. This avoids the required ring distortion and is compatible with most experimental observations except for the effect of substituents on the hydrolysis of aryl glycosides and “0 kinetic isotope effectsz6

The rate of the acid-catalysed anomerization of methyl Dglucopyranosides in CD,OD/DMSO is zero-order in methanol. This observation, and earlier observa- tions on nucleophilic trapping of the presumed oxocarbocation intermediate, suggest that two molecules of CD30D are part of the solvent cage but interacting with the intermediate. An equivalent description would involve solvent sorting induced by the substrate in a mixed solvent mixture.”

The cellulase complex of microorganisms is significant for the hydrolysis of cellulase to fuel, food, and other chemicals. The cellulase complex consists of at least three enzymes, viz. endo- and exo-#?- 1,4-glucanase and #?-glucosidase. The kinetic effects of the individual enzymes in the cellulase multicomponent system have been investigated by selective inhibition.” The enzymic hydrolysis of starches in water is not accompanied by transfer of deuterium to the aqueous medium whereas fermentation involves deuterium transfer from glucose to water and ethanol.”

Reactions and Formation of Nitrogen Derivatives, Schiff Bases, Hydrazones, Oximes and Related Species

Theoretical calculations suggest that the activation energies for the addition of amines to carbonyl compounds become smaller as the reaction becomes more exothermic. However, the addition of NHFz to methanal is an exception which is rationalized by a transition state with more amine-anion character.” Based on Hammett values and structural effects in saturated cyclic ketones, the acid-catalysed dehydration of carbinolamines (13) is thought to involve a predominantly tetrahedral, early transition state. In this respect, decomposition of the tetrahedral intermediate resembles that of cyanohydrins rather than that of bisulphite addition compound^.^

The acetanilide derivative (14), a model for suspected carcinogenic metabolites of phenacetin, decomposes in aqueous solution predominantly into N-acetyl- p-benzoquinone imine which undergoes an acid-catalysed hydrolysis to ben- zoquinone. The acylated carbinolamine (14) is a detectable interrnediate.j2 The amine-catalysed formation of imines by the elimination of HCI from Nchlorobenzylmethylamine shows a kinetic isotope effect kH/kD of 8.8 and a Hammett p-value of 0.96. A symmetrical transition state for the elimination is suggested (15) with little carbanionic character and significant n-bond formation. The kH/k,and p-values first increase and then decrease with increasing base strength

6 Organic Reaction Mechanisms 1986

of the amine catalyst.33 Ring-opening of oxaziridines by nucleophiles can occur at oxygen to give imines, or at nitrogen to give ketones. Base-catalysed attack on the N- alkyl substituent bearing an a-hydrogen (16) is controlled by the oxaziridine stereochemistry and is rate-limiting as indicated by a significant primary isotope effect.34

AcNvH 0

B C

The reduction of benzoquinone Nchloroimines to benzoquinone imines with alcohols is basecatalysed and the rate-limiting step is thought to be breakdown of the tetrahedral intermediate (17).35 Although ringclosure of hydroxy-Schiff bases (18) to oxazolidine tautomers is a supposedly unfavourable 5-endo-trig process, it occurs rapidly, like many other such proce~ses.'~ Bifunctional primary amines with an intramolecular tertiary amino group are effective catalysts for Schiff base hydrolysis. Initial nucleophilic attack by the amine on the iminium ion is rate- limiting. The transimination step is followed by intramolecular general base- catalysed hydrolysis of the intermediate Schiff base.37

The di-imine (19), generated in situ from the corresponding phenylenediamine, exhibits a biphasic pH-rate profile for hydrolysis which is attributed to full conversion of (19) into the carbinolamine at high PH.~* The kinetics of the hydrolysis of fluorinated i m i n e ~ ' ~ and other Schiff bases4' have been described. 1,2- Diketone Schiff bases derived from benzoylacetone and 1,Zdiaminobenzenes

1 Reactions of Aldehydes and Ketones and their Derivatives 7

undergo an acid-catalysed dehydration below pH 2.5, but between pH 4 and 5.2 the conjugate acids undergo an acid-catalysed cyclization to 1,5-ben~odiazepines.~’ Buffer catalysis and Hammett plots have been reported for imine formation of 1,3- dicarbonyl compounds?2 A proton-transfer step is rate-limiting in the aminolysis of a-bromodeoxybenzoin in benzene,43

The relative rates of reduction of the imino and carbonyl groups in 1,24mino- ketones varies with the nature of the hydride reducing agent, with consequent control of the stereochemistry of the product amino-al~ohol.~~ Nucleophilic addition to protonated substituted quinonoid dihydropterins (20) does not occur at the 4a carbon of the iminium ion. Methoxylamine reacts at the C(2) position whereas hydroxide ion adds to C(4). Thus, non-enzymatic addition to C(4a) is not a normal reaction course.45 The reaction of nitrous acid with 5-aminopyrimidines produces 1,2,3-triazoles presumably by initial nucleophilic addition of water to C(2) of the ring N=CH-N system followed by an intramolecular reaction of the diazotized 5- amino group.46 The dimerization of quinazoline is catalysed by cyanide ions, and proceeds by initial attack of cyanide on the imine followed by prototropic rearrangement to give a carbanion, analogous to the benzoin ~ondensation.~’

The photochemical isomerization of the 1 1-cis-retinal Schiff base chromophore of rhodopsin to the all-trans retinal form, which is then reduced to all-trans retinal, is the basis of vertebrate vision. As part of the process of dark adaptation, the all-trans retinyl esters are converted back into 1 1-cis-retinal. 1 1-cis-Retinoidsare ap- proximately 17 kJ mol-’ higher in free energy than the all-trans isomer and aromatic amines with a hydrophobic alkyl tail catalyse this conversion through the intermediate formation of Schiff bases.48 The conversion of z-amidines into their E-isomers is so strongly acid-catalysed that,at all pH values below 11, the mechanism involves C-N bond rotation of the protonated species. A pHindependent reaction is observed over a narrow range at high pH and amidines with strongly electron- withdrawing substituents show base-catalysed isomerization, which presumably reflects reversible addition of hydroxide ion?’

5-Aminolaevulinate dehydratase catalyses the dimerization of 5-amino-4- ketopentanoic acid to prophobilinogen (21), the monopyrrolic precursor of haems, chlorophylls, corrins, and other tetrapyrroles. Reduction of the enzyme in the presence of radioactively labelled substrate shows that Schiff base formation occurs between a lysine residue and the substrate ketone.50 The carbonyl acceptor in the lysyl oxidase-catalysed oxidative deamination of lysine residues in polypeptides is not pyridoxal 5’-phosphate.” Lysyl oxidase is a copper-dependent enzyme which catalyses the oxidation of peptidyl lysine in elastin and collagen to peptidyl a-amino- hemialdehyde. Oxidation appears not to occur via an intermediate imine and the aldehyde is produced and released before the binding of oxygen, the second subst rate.52

Schiff bases ofP-hydroxynaphthaldehyde undergo thermal decomposition to give napht hoisoxazole whereas those of salicylaldehyde and Z~hydroxyacetophenone decompose through intermediate benzimidazole derivative^.^^ The activation parameters for the spontaneous and phosphate-catalysed hydrolysis of the iminium salt (22) have been reported.54 The cyclization of guanyl-0-methylisourea hydro-

8 Organic Reaction Mechanisms 1986

chloride with dimethyl formamide dimethylacetal to give 2-amino-4-methoxy-l,3,5- triazine is thought to proceed by the intermediate formation of the imidatonium ion (23). 55

The ring-opening of thiazolium salts (24) in basic solution gives amido enethiolates (25) which reclose upon acidification. The presumed tetrahedral intermediate (26) undergoes reversible general acid-catalysed C-N bond cleavage to give an amino enethiol ester and generalacid-catalysed loss of OH to give (24).56 The sulphoxides and sulphones of the organophosphorus insecticide, phospholan (27), react by nucleophilicattack of water, methanol, and thiols at the imino carbon rather than at pho~phorus.~’

A hydrophobic pyridoxal derivative at the pyridyl nitrogen with a branched alkyl chain having two c16 residues may be embedded in a single-walled vesicle. The transamination of L-phenylalanine with this complex is catalysed by copper(I1) ions. The catalytic activity of the metal ion is so large that the carbanion chelate accumulates as an intermediate in the aldimine-ketimine isomerization. The overall reactivity in the vesicle is greater than that in the micellar phase.” Non-enzymatic transamination reactions by pyridoxamine can be achieved by attaching the

1 Reactions of Aldehydes and Ketones and their Derivatives 9

coenzyme to fl-cyclodextrin and synthetic macrocycles. Selectivity in the reaction can be achieved by incorporating binding groups. Catalysis can be achieved by attachinga basic group to the pyridoxamine. If this is stereochemically defined, keto- acids may be converted to amino-acids with good stereosele~tivity.~~

The pK, value of the protonated pyridine nitrogen in Schiff bases derived from pyridoxal5'-phosphate and n-hexylamine is 6.1 and independent of solvent polarity in mixtures of ethanol-water. The pK,value of the protonated imine decreases with increasing ethanol concentration. Hydrolysis of the imine with the protonated pyridine is much faster than with the basicform.60 Thecyclization of 0-benzoylated benzamidoximes (28) to 1,2,4-oxadiazoles in aqueous alcohol of pH 2 to 6 generates Hammett p-values of - 1.2 and 1.0 for substituents in Arl and Ar2, respectively. A more polar medium is thought to change the rate-limiting step from proton transfer to nucleophilic addition to the carbonyl group.6'

The reaction of aldoximes with lithium aluminium hydride in hexamethylphos- phoramide gives aldehydes when there is no a-CH, but nitriles when this is present. Dehydration to the nitrile occurs through the cyclic transition state (29). The reductive conversion of ketoximes into ketones is thought to proceed by a similar mechanism following initial hydride transfer to the imine.62 Copper(i1) ions promote the decomposition of the oxime-carbamate pesticide, Aldicarb, by a pathway analogous to that catalysed by acid. The formation of a nitrile is thought to occur through an elimination process in the complex (30). The small amount of aldehyde formed results from nucleophilic attack on the coordinated z - i ~ o m e r . ~ ~

Hydrazine and hydroxylamine react with 1,l-diacetylcyclopropane by opening of the cyclopropane ring to give 1,Zazoles in which the attaching nucleophile is incorporated into the product ring structure. Loss of hydroxyl from the tetrahedral intermediate (31) generates an electrophilic centre sufficient to catalyse cyclop- ropane r ing -~pen ing .~~ Pralidoxime salts (32) are used for the treatment of organophosphate poisoning and are dehydrated by a hydroxide ion-catalysed reaction to the corresponding itri rile.^^

a-Iminium-ketoximes, upon heating with acetic acid-sodium acetate, give imi- dazoles by intramolecular attack of the oxime nitrogen lone pair on the iminium ion.66 The condensation of fl-keto-esters with hydroxylamine gives a mixture of isoxazolin-5-ones and 5-hydroxyisoxazolidin-3-ones which dehydrates in acidic solution to 3-hydroxyisoxazole. The predominant pathway, indicated by "C NMR spectroscopy, involves ring-closure of the hydroxamic acid ir~termediate.~' Sulphinyl chlorides react with oximes to give thermally unstable 0-sulphinyloximes which decompose above 0°C by a homolytic process to give N-sulphonylimines. N M R spectra show strong polarizations in the products, supportive ofa radical-cage mechanism.68

The bell-shaped pH-rate profile for the hydrazinolysis of 5-nitrofurfural is interpreted in terms of rate-limiting formation of the tetrahedral intermediateat low pH with a change to rate-limiting dehydration of the carbinolamine intermediate at high pH. The conclusions were supported by molecular-orbital calculation^.^^ The second-order rate constants for the acid-catalysed formation of benzaldehyde phenylhydrazone in mixtures of ethanol and water are linearly related to the

10 Organic Reaction Mechanisms 1986

(29)

OH

P- ph-vph Br02

(=N-N-CONHz Ar\ I /

reciprocal of the ~iscosity.~' Osazone formation in steroids has been in~est igated.~~ The unusual thermal cyclization of N-alkylhydrazones of benzil to 4,Sdiphenyli-

midazoles is suggested to involve the intermediate formation of a diaziridine by the unlikely ring-closure mechanism (33)." Trichloroacetaldehyde tosylhydrazone undergoes an elimination-addition reaction on treatment with sulphide ion to give an intermediate which cyclizes to a t h i a d i a z ~ l e . ~ ~

The rates of oxidation of semicarbazones by potassium bromate to the corresponding aldehydes or ketones are little affected by substituents or the polarity of the medium. The rate-limiting step is suggested to be the formation of the bromate ester (34) although the addition of bromate ion to the imine conjugate acid cannot be excluded.74

C-C Bond Formation and Fission; Aldol and Related Reactions

The base-catalysed reaction between acetone and (35) involves rate-limiting addition of the acetone enolate anion. Relative rates and equilibria have been compared with

1 Reactions of Aldehydes and Ketones and their Derivatives 11

those for the addition of hydroxide ion and, in turn, a comparison made with the similar reactivities of hydroxide ion and acetone enolate anion with 4-nitrobenzal- deh~de .~ ' A thorough analysis of the structures of barium hydroxide which catalyse the aldol condensation of acetone indicates that the active catalyst is the monohyd- rate.76 The kinetics and the mechanisms of the side-reactions of the aqueous base- catalysed condensation of formaldehyde and acetaldehyde, leading to ethers and acetals, have been de~cribed.~' 2-Azidophenyl alkyl ketones undergo a base- catalysed cyclization by nucleophilic attack of the enolate anion on the azide, displacing nitr~gen.~' There have been several other reports which loosely describe mechanistic aspects of carbanion additions to aldehyde^.'^ There is little evidence to support a vinylogous Cram's rule from studies of nucleophilic attack on a carbonyl group conjugated to a chiral centre."

Organometallic carbon nucleophiles generally react with carbon electrophiles with retention of configuration. The only examples in which a carbon electrophile induces inversion of configuration are those reactions where a three-membered ring is being formed. That this is not an anomaly ofcarbon-tin bonds is shown by the fact that a five-membered ring has been formed in an intramolecular electrophilic attack of an aldehyde on a carbon-tin bond with a high degree of retention at the tin- bearing carbon.* ' The stereoselectivity of organometallic additions to aldehydes and ketones with an alkoxy function is usually explained on the basis of a chelation mechanism. This stereoselectivity can be inverted by the addition of crown ethers which complex with the Grignard reagent.82

The chromium salt of but-2-enyl bromide adds to (R)-2,3-isopropylidene- glyceraldehyde with high enantiofacial and low diastereofacial (i.e. Cram) selectivity, whereas dilithium propionate shows the opposite beha~iour.'~ 2-Formylbutadiene may be stabilized as a tricarbonyl(diene)iron complex which reacts with Grignard and other carbanionic reagents. The reaction of the aldehyde complex with organolithium compounds and cuprates proceeds with some dia~tereospecificity.'~ The reactions and mechanisms of metal enolates have been reviewed." MNDO calculations on the stereoselectivity of aldol condensations suggest that

both (E) and (2)-enolates normally give syn aldols under kinetic control (tin, zirconium and titanium enolates, and enol borates). The formation of anti aldols from (Etenolates is due to steric hindrance of the cation.86 The enolate (36) has a highly twisted diene skeleton, as indicated by NMR studies. Aldol reactions of (36) occur exclusively at the distal C(4) position to afford anti geometry via a kinetic process, rather than at C(2),even though "C NMR spectroscopy indicatesa greater electron density at C(2). The role of the lithium counterion appears to be crucial.87

The addition of chiral (a-chloroallyl) boronates (37) to achiral aldehydes gives homoallyl alcohols with 82-92 % enantiomeric excess. Cooperative diastereoface selectivity is observed on addition to chiral substrates. Chiral control is attributed to the cyclic transition state (38)." There have been many other reports of dia- stereoselective aldol additions using boron en~lates.'~ NOE experiments and STO- 3G calculations suggest that EaOl borates prefer the U-conformation (39), whereas the z-derivatives exist predominantly in the extended conformation (40) which is maintained in a chain transition state of the aldol addition. The U-conformation

12 Organic Reaction Mechanisms I986

~ H ~ C O C H ,

(35)

(37)

(39)

makes twist-boat transition states possible. As the E-enolates may exist in both conformations, they may add to aldehydes by two types of transition states of comparable energy and, hence, these reactions may not be stereoselecti~e.~~

The reaction of (trimethy1silyl)allenes with aldehydes and ketones in the presence of titanium tetrachloride gives regiocontrolled homopropargylic alcohols. Reactions involvingchiral allenes proceed with a preference for the formation of the syn diastereomers which is attributed to unfavourable steric effects in the transition state leading to the anti diastereomer."

The enantioselectivity shown by the proline-catalysed aldol reaction is explained by an intramolecular hydrogen bond in an enamine intermediate. Thus, molecular models show that with (S)-proline as catalyst this hydrogen bond involves the pro-R ring carbonyl in the Robinson annulation (41). Although it is claimed this is relevant to aldolase, enamines protonate on carbon and protonated enamines are not good carbon nucle~phi les .~~ Alkylations of the (Rbcamphor imine of tert-butyl glycinate with a variety of alkylating agents give diastereoselectivities ranging from &lo0 %. The results are rationalized by invoking a transition-state interaction between the

1 Reactions of Aldehydes and Ketones and their Derivatives 13

n-system of the alkylating agent and the imine which, for steric reasons, requires alkylation to occur from the pro-R face.93

The reactivities of fldicarbonyl compounds and their enamino-carbonyl anal- ogues in their condensation reaction with heterocyclic amines have been described by their half-lives.94 The reaction of ammonia and benzaldehyde with 1,3- dicarbonyl compounds forms dihydropyridines by the intermediate formation of chalcone. The rate-limiting step is addition of the chalcone to the enamine formed from ammonia and a second molecule of the dicarbonyl compound.95 The addition of enamines to phenyl isocyanate gives mixtures of N-and C-adducts whereas the addition to phenyl isothiocyanate gives only C - a d d ~ c t s . ~ ~

Dianions of cyclic ketoximes react with diphenyl sulphide to give regioselective sulphenylation at the syn a-carbon. This is presumably facilitated by chelation of the dianion to the metal ion.97 There have been many other reports on stereoselectivity in the aldol reaction" and aspects of asymmetric induction in C-C bond-forming reactions.99 A new reaction of the double bond in glycals has been observed which involves ring-cleavage between C( 1) and C(2). The reaction of 3-acetylated pyranoid glycals with trifluoroacetic anhydride and ammonium nitrate gives chiral nitroal- kenes by a Grob fragmentation."' The effect of metal ions on the hydroxide ion- catalysed retro-aldol reaction of hydroxymethyl phenyl ketone has been described."'

The photochemical retro-aldol-type reaction of Cnitrobenzyl derivatives in aqueous solution is thought to proceed by C-C bond-cleavage to generate the nitrobenzyl carbanion.'02 Treatment of the kinetic data for the Wittig reaction of substituted phosphoranes and benzaldehydes by linear free energy relationships indicates that the rate-limiting step is breakdown of the betaine intermediate to the product alkene. Entropies of activation are also consistent with this interpret- ation.lo3 The Wittig reactions between substituted benzaldehydes and phosphorus ylides show volumes of activation in the range -20 to - 30 cm3 mol- ', which are consistent with rate-limiting breakdown of the intermediate betaine. There is no evidence of a change in rate-limiting step with change in substitutents or s~lvent. ' '~ The mechanism of the Wittig reaction at the solid-liquid interface has been discussed. lo'

The ratio of cis- and trans-oxaphosphetanes does not always correspond to the Z/E alkene ratio in the Wittig reaction. This 'stereochemical drift' has been attributed to the reversibility of oxaphosphetane formation, competitive with their decompo- sition to alkenes. There is a large effect of the concentration of lithium ions on the stereochemical outcome of the Wittig reaction which isattributed tocoordination of the metal ion to the aldehyde or ylide.'06 The cis-oxaphosphetanes undergo reversal to ylide and aldehyde more readily than the trans isomers.'07

The first step in the Petersen reaction, the addition of a silyl carbanion to a carbonyl compound, determines the ratio of cis to trans alkenes formed, because the breakdown of the adduct is stereospecific. This is a major difference from the Wittig reaction. The stereochemistry of the addition step can be rationalized by the minimization of steric effects and the analysis is considered to be generally applicable to carbanion additions in which chelation is insignificant. lo'

14 Organic Reaction Mechanisms 1986

The elimination of silicon from fl-silyl-fl-stannyl oxides derived from the condensation of a-silyl-a-stannyl ester enolates with carbonyl compounds has been used to prepare vinylstannane~.'~~ Stereoselectivity in the Wittig reaction using silyl-phosphoranes has been discussed.' l o The Horner-Wittig reaction with the diphenylphosphinoyl (Ph2PO) group is erythro selective while reduction of the a- Ph2PO-ketones (42) with sodium borohydride gives threo intermediates and hence E-alkenes by stereospecific elimination of Ph2P02 - . The addition of cerium(1n) chloride reverses the selectivity to favour the erythro isomer, presumably due to chelation altering steric effects.' "

The introduction of an ortho-substituent in the phenyl residues of (a4ithiobutyl)diphenylphosphane oxide (43) increases the diastereoselectivity in the Horner-type reaction with benzaldehyde.' " By contrast, the a-lithiated alkyldiphe- nylarsane oxides react extremely diastereoselectively. ' ' The carbanion (44) reacts with aldehydes and ketones more slowly than the analogous P=O derivative, probably because the oxaphosphetane intermediate is more stable with oxygen than with sulphur in the apical position.' l4 The volume of activation for the ene reaction between ketones and an activated carbonyl is similar to the reaction volume which suggests a product-like transition state (45) for this [4 + 21-type cycl~addition."~

Other Addition Reactions

There has been an excellent review on the elucidation of effective charges on atoms in the transition states of organic reactions."6 The use of linear free energy relationships in elucidating transition-state structures has been reviewed. Included is the general acid- and base-catalysed addition of nucleophiles to the carbonyl group.' ' '

A theoretical treatment of the addition of nucleophiles to carbonyl compounds shows the activated complex to have a four-membered-ring structure. Heavy-atom reorganization is more advanced than proton transfer in the activated complex.' '* Semiempirical and ab initio calculations on the geometry and stability of nucleophilic-addition derivatives of carbonyl compounds have been compared for the gas phase and solution.'"

The benzaldehyde/boron trifluoride adduct adopts the anti configuration (46) as shown by X-ray crystallography and heteronuclear Overhauser experiments. ''O In the gas phase, the conversion of hydroxide ion and methanal into the tetrahedral intermediate is strongly exothermic. Upon hydration, a significant energy barrier is introduced and the theoretical treatment indicates that it is the strength of hydrogen bonds rather than their number which is primarily responsible for the solvent- induced activation barrier.' '

The reaction of a-sulphonoxy ketones (47) with methanolic potassium carbonate gives only a-hydroxy dimethyl acetals. Apparently the inductive effect of the sulphonoxy group activates the carbonyl group towards nucleophilic attack so that other potential reactions do not compete. Acetal formation is presumed to occur by the intermediate formation of an epoxide, whereas the reaction of amines with (47) yields a-amino ketones from the intermediate aziridine (48).' 22

1 Reactions of Aldehydes and Ketones and their Derivatives 15

OS02Ar

(47)

2-Chloro- and bromo-3-pentanone react wit.. solutions of alkoxide ion in alcohol in a highly stereoselective manner to give hemiacetals of cis-2,3- dimet hylcyclopropanone. The reaction occurs by ring-closure of the enolate (49) to expel halide and form an intermediate cyclopropanone. ’ 2 3 a-Halogenated ketimines react with cyanide in various solvents to give a-cyanoaziridines, presumably through formation of the intermediate (50) prior to ring-closure. l Z 4 The 2-halogenoethoxide ion, generated from halide ring-opening of ethylene oxide, reacts with electron-rich benzaldehydes slower than its ring-closure to oxirane; with electron-deficient benzaldehydes the rate-limiting step becomes ring-opening of ethylene oxide.’ 2 5

Glyoxal(51), the simplest a-dicarbonyl, is highly reactive in aqueous solution and under mildly basic conditions irreversibly forms glycolic acid anion (52). Contrary to the conclusion of a previous study, there is not a second-order dependence on hydroxide ion concentration. The rate-limiting step involves intramolecular hydride transfer from the mono- and di-anions of the glyoxal monohydrate (53).lZ6 The conversion of hemithiolacetals, formed from 2-mercaptotethanol and a series of substituted arylglyoxals, into thiolesters is general base-catalysed and shows a Hammett p-value of + 0.9. The rate-limiting step is thought to be deprotonation (54) to give an enediolate anion which is reprotonated at CP.l2’

16 Organic Reaction Mechanisms I986

The kinetics of the decomposition of hexachloroacetone in DMSO are consistent with rate-limiting breakdown of the gem-diol hydrate of the ketone (55) into trichloroacetic acid and trichloromethane anion.' 28 Chloromethyl ketones are effective inhibitors of serine proteases and, classically, this is attributed to direct nucleophilic displacement of chloride by imidazole, forming a covalent C-N bond. An alternative mechanism involves hemiketal formation with the serine which then forms an epoxide by displacing chloride (56). The epoxide could then become the electrophilic trap for imidazole. The observed Ki value for peptide chloromethyl ketones and human leukocycyte elastase is at least 10-fold lower than that for structurally related substrates. It has been suggested that the hemiketal intermediate

"22'"""' (49)

(57) in fact accumulates and that direct displacement of chloride by imidazole occurs at this stage.'29 Substituent effects are also compatible with the formation of (57) with other serine pro tease^.'^' "C NMR studies of the inhibition of the cysteine protease papain by peptide

aldehydes suggest that a thiohemiacetal(S8) is formed. The hydroxyl of (58) does not point towards the oxyanion hole and it is concluded that stabilization of the oxyanion of a tetrahedral intermediate may not be possible in papain-catalysed

1 Reactions of Aldehydes and Ketones and their Derivatices 17

reaction^.'^' The enzymic oxidation of aldehydes often occurs by the intermediate formation of a thiohemiacetal using the dehydrogenase enzyme's cysteine residue (58). Hydride transfer to NAD' produces an acyl-enzyme intermediate. Hydro- lysis of the NADH-containing acyl-enzyme of cytosolic aldehyde dehydro-genase has been shown to release the carboxylic acid product after hydride transfer.' 32.

The effects of solvent composition on the kinetics and equilibria for the hydration of 4-formylpyridine in mixtures of dioxan-water have been described,' 33 as have those for aliphatic aldehydes of pyruvic acid.'34 The anthocyanin pigments are basically flavylium ions (59) which undergo a rapid and reversible hydration to produce pseudobases that reversibly ring-open to chalcones. The hydration equilibrium is favoured by 3-methyl substitution (59; R = Me) so that more acidic solutions are required to maintain 3-methylflavylium ions in their coloured forms. This destabilization is attributed to loss resonance due to unfavourable steric effects.'

Dialkylhaloboranes reduce benzaldehyde faster than do trialkylboranes. A cyclic mechanism with a boat-like transition state (60) is proposed, which can account for the major differences in the rates of r e d ~ c t i 0 n . l ~ ~ The asymmetric reduction of prochiral dialkyl ketones with dimeric (R,R)-2,5-dimethylborolane (61)13' is unusual because alkenes isostructural with (61) undergo hydroboration with insignificant asymmetric induction. This behaviour is rationalized by the monomeric borane attacking the complexed ketone from the sterically favoured direction.' 3*

The heats of hydride addition to carbonyl compounds in the gas phase may be correlated with residual electronegativity, which reflects the ability of atoms to stabilize charge by inductive effects, and effective polarizability which reflects stabilization through induced dipole interactions. The hydration equilibrium of ketones and aldehydes and the pK, values of the gem-diols in aqueous solution can also be quantified by the same electronegativity parameter.' 39

There is exclusive 1,Zreduction of the conjugated cyclohexenone systems (62) in alkaline solutions of 1:l waterdioxan. Hammett p-values suggest a late transition state for hydride transfer. 140 The asymmetric reduction of ketones using alcohol dehydrogensase produces R-alcohols with smaller substrates whereas the larger ketones form the S-enantiomer. 14' Asymmetric induction in the addition of hydrogen cyanides to aromatic aldehydes incorporated into the cavity of fl- cyclodextrins is attributed to a preferred mode of inclusion and the unlikely general acid base-cataiysed mechanism (63).'42

The irreversible 1,4addition of sulphite ion to p-benzoquinone is preceded by the reversible formation of the intermediate carbonyl bisulphite adduct. Both this and the free quinone undergo Michael addition of sulphite ion.'43 The pH-dependence of the rate of addition of bisulphite to substituted benzaldehydes has been r e ~ t u d i e d . ' ~ ~ The rate and equilibrium constants for the addition of cycloalkyl hydroperoxides to cyclic ketones to form hemiperoxy ketals are controlled predominantly by the size of the ketone ring.14' Anisyldithiophosphinic anhydride, (CMeOC6H4)~P2S4, is the most widely used reagent for the thiation of carbonyl compounds. The mechanism of this interesting reaction is thought to involve

18 Organic Reaction Mechanisms 1986

I

(57)

H

R Enz- &OH

I

(58)

H

nucleophilic attack of the anhydride monomer on the carbonyl group to form the intermediate (64).'46

Nucleophilic addition to 5-substituted adamantanones is favoured in the syn direction for electron-withdrawing substituents which is attributed to interaction between the antibonding carbonyl n-orbital and the s~bstituent.'~' Longibornane- 3,4-dione derivatives with a leaving-group at C( 12) undergo nucleophilic attack initially at a ketonic group, followed by displacement of the leaving-group by the oxygen of the tetrahedral a d d ~ c t . ' ~ * The effect of an axial substituent, at C(3) and C(4) relative to the carbonyl group, on the axial/equatorial product ratio of nucleophilic addition to cyclohexanones varies with the reaction condition^.'^^

There have been reports on the stereoselective reduction of cyclohexanone derivative^.'^^ Steric effects in the nucleophilic addition to ketones"' and stereoselection in these reactions have been reviewed,' 5 2 as have the reactions of