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ORGANIC REACTION MECHANISMS 1983

An annual survey covering the literature dated December 1982 through November 1983

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 - 1983

ORGANIC REACTION MECHANISMS 1983

An annual survey covering the literature dated December 1982 through November 1983

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 1985 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

British Library Cataloguing in Publication Data:

Organic reaction mechanisms.-l983 1. Chemistry, Physical organic-Periodicals 2. Chemical reactions-Periodicals 547.1'394'05 OD476

ISBN 0 471 90503 8

Phototypeset by Macmillan India Ltd. Printed at the Pitman Press, Bath, Avon

Contributors

A. ALBERT1 Istituto dei composti del carbonio, Con- tenenti eteroatomi e loro applicazioni, Consiglio Nationale delle Ricerche, Bologna, Italy

Merck Sharp & Dohme Research Laborator- ies, Neuroscience Research Centre, Har- low, Essex

C. CHATGILIALOGLU Istituto dei composti del carbonio, Con-

D. C. BILLINGTON

D. J. COWLEY

R. A. COX

M. R. CRAMPTON

G. W. J. FLEET

A. F. HEGARTY

R. B. MOODIE

C. J. MOODY

A. W. MURRAY

M. I. PAGE

R. M. PATON

J. SHORTER W. J. SPILLANE

C. I. F. WATT

tenenti eteroatomi e loro applicazioni, Consiglio Nationale delle Ricerche, Bologna, Italy

Department of Chemistry, University of Ulster

Department of Chemistry, University of Toronto, Canada

Department of Chemistry, Durham Uni- versity

Dyson Perrins Laboratory, Oxford Uni- versity

Department of Chemistry, University Col- lege, Dublin, Ireland

Department of Chemistry, University of Exeter

Department of Chemistry, Imperial College of Science and Technology, London

Department of Chemistry, University of Dundee

Department of Chemical Sciences, Hudders- field Polytechnic

Department of Chemistry, University of Edinburgh

Department of Chemistry, University of Hull Chemistry Department, University College,

Department of Chemistry, University of Galway, Ireland

Manchester

V

The present volume, the nineteenth in the series, surveys research on organic reaction mechanisms described in the literature dated December 1982 to November 1983. 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 heterogeneous 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.

We welcome two new contributors, Dr. C . I. F. Watt and Dr. W. J . Spillane who have quickly assumed the house style of this now well established series. They replace Dr. J . Brennan and Dr. A. J . Kirby, respectively, to whom we extend our thanks for the major contribution which they have made to the success of Organic Reaction Mechanisms.

Once again we wish to thank the publication and production staff of John Wiley and Sons and our team of contributors whose combined efforts ensure that the standard of the series is sustained. 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 . 15 .

Reactions of Aldehydes and Ketones by M . I . Page ........................ Reactions of Acids and their Derivatives by W . J . Spillane ............... Radical Reactions I by A . Alberti and C . Chatgilialogu ................. Radical Reactions 2 by D . J . Cowley .......................................... Oxidation and Reduction by G . W . J . Fleet ................................. Carbenes and Nitrenes by C . J . Moody ...................................... 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 ..........................

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

Addition Reactions-2 . Cycloaddition by R . M . Paton ..................... Molecular Rearrangements by A . W . Murray ..............................

Carbanions and Electrophilic Aliphatic Substitution by C . I . F . Watt

Addition Reactions-1 . Polar Addition by D . C . Billington ...............

1 33 83

129 165 217 241 263 277 297 323 347 365 381 419

Author Index. 1983 ...................................................................... 511 Subject Index. 1983 ...................................................................... 559

ix

Organic Reaction Mechanisms 1983 Edited by A. C. Knipe and W. E. Watts 0 1985 John Wiley & Sons Ltd.

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

M. I. PAGE

Department of Chemical Sciences, Huddersfield Polytechnic

Formation and Reactions of Acetals and Ketals . . . . . . 1 Hydrolysis and Formation of Glycosides . . . . . . . . 4

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

Reactions and Formation of Nitrogen Bases . . . . . . . 5 Schiff Bases and Related Species . . . . . . . . . 5 Hydrazones, Oximesand Related Compounds . . . . . . 12

Aldol and Related Reactions . . . . . . . . . . 12 Other Addition Reactions . . . . . . . . . . . 16 Enolization and Related Reactions . . . . . . 22 Hydrolysis and other Reactions of Enol Ethers' and Related Compounds. 26 Other Reactions . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . 28

.

Formation and Reactions of Acetals and Ketals

Although it is generally accepted that orbital alignment is an essential requirement for effective overlap the change in energy of a system with deviations from the optimal geometry is not known. For example, the inhibition of resonance in alkoxy carbonium ions has long been of interest but the misalignment of interacting orbitals will cause an unknown decrease in the rate of reactions leading to their formation. The rate of the acid-catalysed hydrolysis of axial 2-aryloxy-trans-1-oxadecalins (1) is about 4 times faster than that of the equatorial isomer. For the spontaneous hydrolysis this ratio is reversed.' Even in the more conformationally locked acetal (2) the equatorial isomer undergoes acid-catalysed hydrolysis 60 times slower and spontaneous hydrolysis 2 times slower than the axial isomer, which in turn is less reactive than a similar acetal without conformational restrictiom2 The axial compound (3) undergoes hydrolysis 200 times faster than the analogous equatorial isomer which does not have a lone pair of electrons on the ring oxygen antiperiplanar to the 4-nitrophenoxide leaving group. Acetal(4) has a fixed geometry which prevents the ring oxygen lone pairs from assisting C-OAr bond cleavage (as shown previously for a chloride leaving group3) and undergoes hydrolysis an estimated 10' times slower than an analogous conformationally flexible acetal.'

Following the demonstration that there is a correlation between reactivity

2 Organic Reaction Mechanisms 1983

OAr I

PAr

towards hydrolysis and the length of the C-0 bond to be broken in axial tetrahydropyranyl acetals it has been shown that equatorial acetals (5), which have no lone pair antiperiplanar to the C-OR bond, also show a lengthening of the exocyclic bond. However, unlike the axial series, the C*-O bond length increase^.^

Stereoelectronic effects relevant to the mechanisms of reactions of carbonyl derivatives have been reviewed.6

Primary and secondary isotope effects for the pyridinone-catalysed mutarotation of tetramethylglucose in benzene have been analysed to support a mechanism in which there is considerable coupling between the transferring protons and fission of the ring C-O bond (6). Both hydrogens are in flight in the rate-limiting transition state.'

Using the acid-catalysed hydrolysis of acetals of benzaldehyde as an example it has been shown that kinetic solvent isotope effects can vary from kDl/kH+ = 1.8-3.1 depending on the procedure used for calculation. The source of this variation is attributed to small changes in and solvent isotope effects on the activity coefficient ratios.'

The rate of the acid-catalysed hydrolysis of crown ether acetals (7) is strongly decreased by the addition of alkali and alkaline earth metal chlorides having cations of appropriate size to be complexed by the crown ether. Electrostatic repulsion between the cationic charges on the metal ion and the protonated acetal is attenuated roughly to the extent required by the bulk perrnitti~ity.~

1 Reactions of Aldehydes and Ketones and their Derivatives 3

The condensation of acetophenone with glycerol in a biphasic mixture of toluene and glycerol occurs at the phase boundary; the rate-limiting step is attack of glycerol on the conjugate acid of acetophenone.'O

Isobenzofuran (9) can be formed from the acid-catalysed decomposition of the cyclic acetal (8) by proton loss from the presumed intermediate alkoxy carbonium ion."

The hydrolysis of 9-(nitromethyl)-9-alkoxyfluorenes is thought to proceed through the intermediate formation of an oxocarbonium ion.'*

Acetals and ketals are converted to carbonyl compounds with titanium tetrachloride in diethyl ether. The proposed mechanisms all invohe coordination of TiCI, to the acetal or ketal oxygen. The subsequent steps depend on the structure of the acetal or ketal.',

The reaction of (CO), MnSiMe, with methyl ketals gives methyl vinyl ethers, but with acetals gives manganese acyls. The ketal or acetal oxygen is initially silylated and fission of the carbon-oxygen bond generates the alkoxy carbonium ion which can deprotonate to give the product.14

The interconversion of stereoisomers of polysubstituted 1,3-dioxacyclohexanes can also include the formation of alkene which can be explained by postulating cationic intermediates.'

The thermolysis of some 1,3-dioxolanes (10) gives isomeric tetrahydrobenzo- furans via acid-catalysed rearrangement of the carboxonium ion intermediate. l6

Irradiation of cycloalkanones in methanol gives good yields of the ketal; this is proposed to occur via the protonated ketone although there is little evidence to support this claim."

2-Nitrophenylethylene glycol can act as a photolabile protecting group for aldehydes and ketones by forming an acetal or ketal with the carbonyl group.18

The versatility of quinone bis- and mono-ketals in organic synthesis has been reviewed."

Both aqueous sodium nitrite and tert-butyl hypochlorite in anhydrous carbon tetrachloride convert thioacetals into the corresponding carbonyl compound. The


soft Lewis acids NO' and C1' are thought to attack the soft sulphur of the t hioacetal. O

The hydrolysis of 2-phenyl-l,3-oxathiolan is atalysed by trichloroisocyanuric acid because the latter is hydrolysed to hypochlorous acid, a known electrophilic catalyst for thioacetal hydrolysk2'

Hydrolysis and Formation of Glycosides

Non-enzymic Reactions The rates of acetolysis of permethylated methyl a-glycosides of D - ~ ~ U C O S ~ and D- galactose are greater than those of the correspondingflanomers which is contrary to the behaviour of these substrates towards acid-catalysed hydrolysis. The greater reactivity of anomers with equatorial aglycons (e.g. fl-D) is usually ascribed to their higher ground-state energy caused by dipolar interactions; protonation of the glycosidic oxygen destroys this destabilization, and consequently the concentration of the conjugate acids of D-sugars is greater for fl- than for a-anomers. In the acetolysis reaction stereoelectronic factors are suggested to account for the different behaviour although it is not clear why these effects are not evident in the hydrolysis reaction.22

The rate of alkaline hydrolysis of o-nitrophenyl-fl-D-glucopyranoside, but not that of the galactopyranoside, is largely enhanced by cationic micelles and phenylboronic acid. The reasons for this selectivity are uncertain.23

1,4-Dehydration of penitols in acetic acid containing an acid catalyst occurs with inversion of configuration at C(2) or C(4). Acetylated alditols undergo similar processes uia intermediates having free hydroxyl groups. An intermediate ac- yloxonium ion is the cause of the configurational isomerism.24

The rate of the acid-catalysed degradation of acetyl-substituted sucrose derivatives in dimethyl sulphoxide is decreased by 0(1) or O(3) acetylati~n.~'

The incorporation of "0 from solvent H,"O onto the C(1) carbon of the diastereomeric a- and fl-pyranose sugars can be followed by I3C-NMR spectroscopy.26

Iodotrimethylsilane in carbon tetrachloride cleaves interglycosidic linkages in per(trimethylsily1)ated dissacharides to give iodinolysis products that may be readily hydrolysed to component monosaccharides. Unlike acid hydrolysis there is a preferential cleavage of linkages to primary hydroxyl group^.^'

The predominant reaction in the thermal decomposition of sucrose and cellobiose at 150-250" is dehydration.28

Acetylated glycals react with fl-dicarbonyl compounds in the presence of boron trifluoride to give C-glycopyranosides by trapping the intermediate carbonium

The reaction of diazomethane with aldoketoses and diketoses to give ring- expaqded spiro-epoxides has been in~estigated.~'

Enzymic Reactions The mechanism of the hydrolysis of p-o-galactopyranosyl fluoride catalysed by wild-type fl-galactosidase is a three-step one in which a galactosyl enzyme

I Reactions of Aldehydes and Ketones and their Derivatives 5

intermediate can transfer a p-D-galactopyranosyl residue to either water or methanol.” Experimental evolution of the gene coding for the enzyme results in a decrease in the rate of hydrolysis of the galactosyl-enzyme intem~ediate.~~ As the reverse reaction of k,, equation (l), can be estimated from the rate of exchange of 1- 180-galactose with solvent, it can be shown that this is not due to a simple stabilization of transition states or intermediate^.^'

(1)

The inactivation of glycosidases by glycosylmethylaryltriazenes appears to resemble the spontaneous rather than the acid-catalysed hydrolysis of triazenes but a “suicide” mechanism of inhibition is still preferred.34

Based on binding studies of a large number of sugars and alcohols it has been shown that hydroxyls at positions 3 and 4 are important for binding to the galactose site in P-galactosidase. The presence of these hydroxyls is also necessary for efficient catalysis.35

The overall binding specificity of 8-galactosidase at the “galactose” site is determined particularly by positions 3 and 4 and, to a lesser extent, by position 6 of galactose. The wrong orientation at 3 or 4 eliminates binding and catalysis.36

Dextransucrase catalyses the formation of dextran by utilizing sucrose as the D- glucosyldonor substrate. It has now been shown that the enzyme also catalyses the hydrolysis of sucrose. The observations are consistent with the formation of a D- glucosylated intermediate of the enzyme which may be partitioned by D-glucosyl transfer to added acceptors or water.37

The glucose-isomerase-catalysed isomerization of D-glucose to D-fructose occurs without proton exchange with the solvent. The mechanism of action of the soluble and the immobilized enzymes appears to be similar.38

E + PGalX e E.PGalX -+ E . G a l 3 E + PGal-OH

Reactions and Formation of Nitrogen Bases

Schiff Bases and Related Species The solvent deuterium isotope effect kH,0/k40 for the water-catalysed hydrolysis of the dimethylimmonium ion of benzophenone is 2.19. Proton inventory studies in H,O-D,O mixtures indicate that three protons make an equal contribution of about 1.30 to the effect. General base catalysis by water proceeds via a transition state (1 1) in which the immature hydronium ion is solvated by two water molecules. The coupling of proton and heavy atom motions is avoided by consecutive transition states3’


Based on the pH-rate profile and a solvent isotope effect of kH,O/kD,O = 1.6 it is claimed that the hydrolysis of N-salicylidene-2-aminopyridine anion proceeds with intramolecular general base catalysis by the phenoxide ion. There is little evidence to support the claim of intramolecular general base catalysis by the pyridine nitrogen (12). The copperchelated imine undergoes acid-catalysed hydrolysis?'

The rate of the acid-catalysed hydrolysis of Schiff bases derived from diamines and salicylaldehyde decreases with increasing chain-length between the two amino functions?'

Hydrolysis of 1-arylpyrrole imines occurs with the expected change in mechanism with pH; between pH 4 and 8 the rate-limiting step is addition of water to the protonated imine but above pH 8 it is addition to the free imine?2

In mildly basic media (pH 11) thiamine has been thought to exist in two forms- the cation (13) and the ring-opened thiolate anion (14). It has now been shown that 16 % of thiamine exists as the pseudo-base (15), the tetrahedral intermediate formed by rate-limiting nucleophilic attack of hydroxide ion on the imminium ion, between pH 9.2 and 9.5. The ring-opening reaction occurs by base-catalysed deprotonation of the pseudo-base (15).43

The hydrolysis of 2-alkyl-3-methyl-l,3-oxazolidines proceeds by formation of an acyclic cationic Schiff base (la) formed by 0-protonation and CO bond cleavage. The rate-limiting step is probably breakdown of the carbinolamine (17) formed in a pre-equilibrium step by water attack on (la)?*

The base-catalysed hydrolysis of N-benzyl-5-methylisothizolidinium salts occurs by proton abstraction and ring-opening of the isothiazolidine ring (18) to give a Schiff base which is then hydrolysed to ben~aldehyde.4~

Zinc(I1) and cobalt(r1) complexes with thiourea are catalysts in Schiff base formation between aldehydes and ketones and anilines. Catalysis is thought to involve metal ion coordination to the carbonyl group or to the tetrahedral


I

M e

The reaction of anilines with aroylpyruvic acid anilides is general-acid-catalysed and the effect of substituents has been in~estigated.~’

The kinetics of the cyclization of (19) to the drug alprazolam show a bell-shaped pH-rate profile which is interpreted in terms of a change in rate-limiting step.48

bh

(19) (20)

1,4-Benzodiazepines are important minor tranquillizers. Hydrolysis of the azomethine bond in acidic solution gives the corresponding aminobenzophenone which reversibly cyclizes into the original form in alkali. A kinetic study of triazolam (20) over a wide pH range indicates the formation of carbinolamine intermediates and ring-closure proceeds by rate-limiting acid-catalysed dehydration of the carbir~olamine.~~

As carbinolamines invariably occur as intermediates in non-enzymic interconver- sions between carbonyl compounds and imines it is reasonable to expect that imine- forming enzymes will also produce these intermediates. This has now been shown for the first time with the partial substrate glycolaldehyde phosphate and aldolase by %NMR spectroscopy. The enzyme-bound carbinolamine is presumably stabi-

lized by interactions with amino-acid residues at the active site.” 3,3-Dimethyl-4-dimethylaminobutanal exists as the cyclic free base and its

conjugate acid (21) in aqueous solution; the pK, of the a-ammonium alcohol (21) is 8.70 at 20O.’’

Me Me

Me CH EtO’ ‘Ar

Me


The acid-catalysed hydrolysis of (22) proceeds by carbon-oxygen bond fission to give the intermediate imminium ion.52

Alkaline cleavage of 9-( 1-ethoxyethy1)purines (23) proceeds by nucleophilic attack of hydroxide at C(8) of the purine moiety to give 4,5-diaminopyrimidine and 8- methylpurine. A leaving group at C(6) makes hydroxide ion attack at this position competitive with attack on C(S).’’

X

CH E d ‘Me

RO I

The hydrolysis of diastereoisomeric 1,Zoxazines has been reported.54 N-(Dialkoxymethy1)imidazoles (24) are amide acetals an6 undergo acid-catalysed

hydrolysis by protonation of the imidazole distal nitrogen followed by rate-limiting C-N cleavage to give a dialkoxy cation; unlike previously studied amide acetals C-0 bond fission does not occur, due to the more basic nitrogen available.55

Hydration of the C=N bonds of pteridine (25) has been shown to give the dihydrate (by addition of water at C(6) and C(7)) as well as the previously recognized monohydrate.

The highly reactive bridgehead imine, 2-azabicyclo[3.2.1]oct-l-ene (26) has a C=N stetch at 1585 cm-’, 80 cm-’ lower than normal monocyclic imines. The addition of methanol occurs even at 100 K.57

A concerted reaction is predicted by an ab initio study of the hydration of ketenimine.58 The hydration of ketenimine (27) has been calculated to proceed best with a water dimer but proton transfer to the Barbon does not occur until after the transition state.59

The reduction of imines by the NADH model, 3,5-diethoxycarbonyl-2,6-1,4- dihydropyridine, is catalysed by Mg2 + ions. Substituted benzaldehyde imines generate a Hammett p value of -0.39 which is compatible with hydride transfer to the magnesium-ion-bound imine (28).60


The reduction of the bicyclic iminium ion (29) from the sterically more congested concave a-face (30) occurs probably because of an early transition state so that unfavourable 1,3-diaxial interactions are not fully developed.61

The lithium aluminium hydride reduction of achiral benzil monoimines gives diastereoisomeric amino-alcohols in ratios dependent on subsitutent effects and solvent polarity. The ketone group is reduced first by a reaction pathway (31) favoured by stereoelectronic effects.62

Reduction of the cyclopropylimine (32) with a 1,4-dihydropyridine derivative proceeds without ring-opening; this is consistent with a hydride-transfer mechanism.63

PhNCOEt I

The addition of cyanide ion to the tetrahydropyridinium salt (33) occurs stereospecifically to give trans-diastereoisomers. This may be accounted for by a combination of steric effects and stereoelectronic control.64

Contrary to an earlier report, cyclization of the benzylideneimine of tryptophan methyl ester does not occur in the absence of

Direct transimination occurs for the exchange of ethylamine in pyridoxal 5’- phosphate (PLP) Schiff bases by amino-acids. This pathway is competitive with a mechanism involving the amino-acid and free PLP formed by hydrolysis of the Schiff base. It has been suggested that intramolecular catalysis occurs in direct transimination by facilitating proton switch in the gem-diamine intermediate (34).66

Transimination of the pyridoxal 5’-phosphate in D-serine dehydratase by amino- acids is a multi-step process. Attack of the incoming amino-acid on the Schiff base forms a gem-diamine (35). Stereoelectronic considerations suggest that a conformational change has to take place before lysine can be expelled, for which there is some fluorescence e~idence.~’ The steady-state parameters for decomposition of isomers


R, ,co; -0jPOCHl CH I

I HzN%NHE‘ H PYr H

of serine and threonine indicate that the rate-limiting step changes with substrate and PH.~’

Rate enhancements of less than 100-fold have been attributed to intramolecular general acid-base catalysis by the side-chain in transaminations catalysed by pyridoxamine analogues (36).69

The kinetics of the Schiff base formation from pyridoxal 5’-phosphate and copper (iI)-pyridoxamine complexes are pH-dependent and a consequence of the intermediate formation of a carbinolamine.”

The equilibrium constants for imine formation from pyridoxamine and 2- oxalopropionic acid show a pH dependence with maximum ketimine formation occurring near pH 9; the kinetics of decarboxylation were also determined.71

The conditional formation constants for Schiff base formation between pyridoxamine and 2-oxalopropionic acid are pH-dependent with a maximum near pH 9.”

R (-go- /) N...., f“” : 0-

N Me I H

The equilibrium constants for formation of Schiff bases in aqueous solution from 4dimethylaminobenzaldehyde and substituted anilines increase with electron donation in the aniline. There is a linear free energy relationship between the equilibrium constants and the pK of both the Schiff base and the aniline.73

Pyridoxamine, when attached to the secondary face at C(3) of p-cyclodextrin (37) is an efficient catalyst for the transamination of ketoacids but is only about half as effective as when attached to the primary face at C(6).74

The Schiff base formed from histidine and pyridoxal undergoes an intramolecular cyclization. In reversed micelles imine formation is enhanced while the cyclization is retarded.7s


N-Laurylpyridoxal forms a Schiff base with amino-acids in micelles of cetyltrim- ethylammonium chloride. The equilibrium constant for the formation is about 100- fold more favourable than in the absence of micelle and is increased by hydrophobic side-chains in the amino-acid. The Schiff base undergoes transamination in the absence of metal ions.76

Enzymes using pyridoxal phosphate almost invariably catalyse group-transfer reactions on one face only of a relatively planar pyridoxal-phosphate-substrate complex formed in their active site. However, amino-acid racemases obviously have to operate on both sides of the complex. Conversion of L-a-'H-alanine and L-alanine in D,O into D-alanine shows significant internal return of the a-hydrogen. This supports a single base mechanism for racemization in which the base both abstracts the a-hydrogen and reprotonates the resonance stabilized carbanion (38).77

One of the functions of enzymes using pyridoxal phosphate as a cofactor is to labilize the bond to be broken by orienting that bond perpendicular to the n-system of the Schiff base. Conformations of pyridoxal Schiff bases of amino-acids have been determined using circular dichroism.'*

The effects of isotopic substitution at C(3) of indole, pH, and the presence of indole propanol phosphate indicate that the mechanism of indole condensation with L-serine catalysed by tryptophan synthase, a pyridoxal-5'-phosphate-utilizing enzyme, involves two species of enzyme-L-serine complexes, leading to a branched pathway for the central condensation process. 7 9

Heating optically active a-amino-acids in the presence of aldehydes causes racemization. The intermediate imine generates a 1,3-dipolar species which can be trapped with N-phenylmaleimide.80

Contrary to an earlier claim, the reaction of racemic 2-norbornanone with (+a- phenylethylamine gives not one, but all four, of the expected diastereoisomers of the Schiff base."

The Knoevenagel reaction of malonitrile with cyclohexanone in benzene is catalysed by secondary and tertiary amine bases. Primary amines in the presence of acetic acid give the imine as an intermediate which then rapidly reacts with malonitrile. In the absence of acetic acid a complex rate law is observed and the primary amine acts mainly as a base catalyst."'

Dark-adapted bacteriorhodopsin undergoes a reversible transformation at high pH in which the Schiff base is deprotonated. The "apparent" pK, of the Schiff base is 13.3 and it is suggested that a light-induced pK, change of at least nine units takes place during the photocycle of the rh~dopsin."~

Regioselectivity in deprotonation of carbonyl compounds may be improved by using the corresponding imine. For example, unsymmetrical ketimines derived from butan-2-one undergo deprotonation by lithium dialkylamides with a regioselectivity dependent upon the nitrogen substituent. It is suggested that only the z-imine is dep ro t~na ted .~~

The basic site for protonation of enamino-ketones (39) is the carbonyl oxygen. The pK, of the conjugate acid in water is 2-3."'

Nucleophilic addition-fl-elimination reactions of Schiff bases have been reviewed.86


- O y J H

N H ~ R

Hydrazones, Oximes and Related Compounds Phenylhydrazone formation from 3- and 4-pyridinecarboxaldehydes occurs with rate-limiting carbinolamine dehydration under neutral, acidic and basic conditions. The expected non-linear dependence of the rate on phenylhydrazineconcentration is observed. There is no observable buffer catalysis for 2-pyridinecarboxaldehyde phenylhydrazone formation and a rate enhancement of about 20-fold compared with the isomeric aldehydes is indicative of intramolecular general acid catalysis in rate-limiting carbinolamine formation (40).87

The reaction of sulphuryl chloride with substituted 4-tosylhydrazones gives geminal dihalides, the parent carbonyl compound or a,adichloroaldehydes. The product distribution is very sensitive to structural changes in the tosylhydrazone but can be rationalized by two competing pathways, nucleophilic attack by chloride ion on the C=N bond or sulphination of the N-tosyl atom.88

Oxime formation from 4-heteracyclohexanones is consistent with steric effects inhibiting rate-limiting addition of hydroxylamine to the ketone.8q

Direct attack on nitrogen is thought to occur in the reaction of nucleophiles with 0-(2,4-dinitrophenyl)ohexanone oxime. The Brensted &, is only 0.09 but a polar &&type transition state is favoured.go

The reaction of acetylacetone or benzoylacetone with hydroxylamine hydro- chloride to give isoxazoles is thought to proceed by fast enolization followed by a rate-limiting step with hydr~xylamine.~~

The ring-opening reactions of 3- and 5- non-substituted isoxazoles has been investigated.”

The dehydration of E-aminoacetophenone oximes with mercury EDTA leads to oxynitrones via the n i t r ~ n e s . ~ ~

The previously reported cyclktions of trianions of hydrazides to give 3- indazolinones, or their reaction to give aldehydes, are not reprod~cible.~~

The mechanism of reactions of enamines has been reviewed.95

Aldol and Related Reactions

A new synthesis of eight-membered rings based on a TiC1,atalysed intramolecular aldol condensation of silyl enol ethers with acetals has been reported.96 There is no need for high dilution conditions and the formation of medium rings has been explained by a template effect of titanium.


Silyl enol ethers readily react with aldehydes under pressure and neutral conditions to give adducts which are hydrolysed to the corresponding aldol product. The stereoselectivity is the reverse of similar reactions catalysed by TiCl, and is attributed to a boat transition state at high pressures. At low pressures the stereoselectivity is that predicted from a chair transition state.97

The treatment of aldehyde enol silyl ethers (41) with lead (IV) tetraacetate in methylene chloride gives a-acetoxy-aldehydes, glycolic ester derivatives or enols. The product ratio varies with the structure of (41).98

The Lewis-acid-catalysed aldol coupling of enol silyl ethers and substituted cyclohexanone acetals shows a higher ratio of equatorial attack than the reaction of the parent ketones. The reactions of the enol trimethylsilyl ether of pinacolone and 2-benzyloxyheptanol shows only moderate diastere~selectivity~~ which is in contrast to the reaction of the respective aldehydes.

R

The stereochemical outcome of the cyclocondensation of aldehydes with siloxydienes is subject to considerable influence by changing the Lewis acid catalyst. For example, in tetrahydrofuran with zinc chloride as catalyst virtually complete cis (i.e. erythro)-specificity is observed."' The reaction exhibits all the characteristics expected of the pericyclic mechanism (42); the intermediate immediately formed from (42) has been isolated and no acyclic products are observed.10'

Chiral aldehydes show substantial diastereofacial preferences in their Lewis-acid- mediated reactions with enolsilanes; this has been tetatively ascribed to steric effects. ' O2

Coupling reactions of vinylketene silyl acetals are promoted by titanium tetrachloride to give unsaturated diesters. Bis-allylic dititanium complexes have been proposed as intermediates.'"

Nitrones react with ketene silyl acetals to give /?-siloxyamino-esters. The proposed mechanism involves nucleophilic attack of the nitrone oxygen on the silicon

The extremely high affinity of the fluoride anion toward silicon has been used to catalyse the aldol reaction between enol silyl ethers and carbonyl compounds. It is thought that a naked enolate anion is produced, which undergoes reversible addition to an aldehyde to give the aldol anion (43) which is then trapped by fluorotrimethyl- silane formed in the first step.'"

A variation of the Prins reaction is the Lewis-acidcatalysed reaction of aldehydes with enol ethers. Both geometric isomers of an enol ether give the threo-adduct in their reaction with formaldehyde and trimethylaluminium. The stereoselectivity has

acetai.104


been attributed to a common intermediate (44) which cyclizes to the thermodynami- cally more stable trans-substituted oxetane.lo6

Metal cations of a highly Lewis acidic character are often used in aldol reactions because they are thought to stabilize and tighten the chair-form chelated transition state and enhance the stereoselectivity of the reaction. However, the boat conformation is apparently preferred during aldol reaction of trichlorotitanium enolates. The reasons for this are unclear but the relatively long Ti-0 bond may be important, with secondary orbital interactions favouring the "endo"-arrangement of the reactants being the ultimate cause of the ~electivity;"~ it is not clear either, of course, why the chair transition state is sometimes preferred. The aldol reaction of a- trichlorostannyl ketones with aldehydes and ketones is highly erythro-selective, which is indicative that the reaction does not occur through a chair transition state. O 7

Tris (dialkylamino) sulphonium ions as counter-ions to enolates cause the major products of aldol reactions to have erythro-stereochemistry regardless of the enolate configuration. In contrast to the ordinary aldol reactions of Lewis-acidcoordinated enolates the transition state for this reaction is thought to be an extended acyclic one ( 4 9 ' 0 8

Br I

Exceptionally high levels of enantioselectivity are achieved in aldol-type condensations using an optically active sulphoxide containing synthon. A rigid model has been proposed for the transition states wing magnesium enolates (46); chelation of magnesium as shown favours the z-geometry for the amide enolate and the model accounts for the decrease in stereoselection observed on increasing the steric demand of the aldehyde R residue.'OQ

Stereoselective aldol condensations of carboxamides give the erythro-product. The preferred cis-geometry of the precursor amide enolate and a sterically favourable chair transition state are postulated to account for the stereoselectivity.' lo


Erythro-selective aldol condensations occur with quaternary ammonium en- ethiolates generated from N-dialkyl S-trimethylsilylketene S,N-acetals but threo- selectivity occurs in the presence of Lewis acids. A boat-like transition state accounts for the stereoselection.' '

Sterically hindered a-haloisobutyrophenones react with nitroalkane carbanions by competing ionic and free radical substitution leading to different products; e.g., nucleophilic attack at the carbonyl carbon followed by S,i displacement of halogen by the carbonyl oxygen. '''

Contrary to most substituted allylic organometallic reagents, the reaction of carbonyl compounds with crotylmagnesium chloride in the presence of AICI3 gives predominantly products in which the allylic group is attached to the less substituted position. It has been suggested that transmetallation of crotylmagnesium reagent to aluminium reagent occurs by an sE2' process followed by a rapid SE2' reaction of the resulting a-metallylaluminium complex with carbonyl compounds.' '

The regio- and stereo-chemistry in reactions of 1 ,fdisubstituted ally1 anions with aldehydes can be controlled with q3-allyltitanium compounds. The selectivity can be explained by a cyclic six-membered transition state in a chair conformation. l l

The reaction of aldehydes with optically active allylsilanes in the presence of titanium chloride produces optically active homoallylic alcohols of up to 91 % enantiomeric excess. Because the stereochemistry of S,' reactions of allylsilanes is anti (electrophiles enter the double bond from the side opposite to the leaving silyl group), this probably indicates an acyclic linear transition state.' '

Enatiomerically pure a-sulphinyl hydrazones undergo enantioselective aldol-type condensations. The enantiomer formed varies very much with reaction conditions and structure of the reactants.''6

An o-toluate carbanion generated by a chiral lithium amide base undergoes an enantioselective aldol-type reaction with acetaldehyde.' ''

The base-catalysed retro-aldol reaction of 3-methyl-2-butenal to acetone and acetaldehyde proceeds via hydration of the enone with an equilibrium constant of 0.41 for the addition of water to give the fl-hydroxy carbonyl."*

N-Hexadecylthiazolium bromide bound to micelles of hexadecyltrimethylam- monium bromide catalyses the retro-acyloin reaction to give aldehydes from a- ketols. The active aldehyde intermediate formed by C-C bond fission (47) may be trapped by oxidation with flavin.''g

Stereoselectivity in the aldol reaction has been reviewed.12'

:H H


Other Addition Reactions

The importance of directionality in addition reactions of carbonyl compounds has been reviewed and the degree of flexibility in transition states emphasized.12'

A plot of the 'W-NMR shifts of the carbonyl carbon of protonated substituted acetophenones against 6' for the substituent is non-linear.'22

Complexation constants for substituted a,j-unsaturated ketones and acetophenones are correlated with 6' con~tants . '~~

A survey of N-H . . . . O=C hydrogen bonds observed by X-ray or neutron diffraction shows that, in the crystalline state, the bonds are aligned with the conventionally viewed oxygen sp2 lone pairs. 124

The Hammett p value for the equilibrium hydration of aromatic aldehydes is + 1.7. The Bronsted j value for general-base-catalysed hydration is ca. 0.4 but increases slightly with decreasing electron withdrawal in the aromatic ring. The p value for general-base-catalysed dehydration changes from 0.3 for water to + 0.06 for acetate to -0.15 for phosphate dianion. Consideration of a three-dimensional reaction coordinate diagram shows that this is consistent with true general-base- catalysed hydration and specific-base-general-acid-catalysed dehydration (48). ' '

Electron-withdrawing substituents increase the degree of hydration of trifluoroacetophenone; the equilibrium constants are correlated with 6+ and are solventdependent. In mixtures up to 80 mol % DMSO the 4-dimethylamino compound is more highly hydrated than in pure water. However, the extent of hydration of the 4-amino and 4-methylamino derivatives decreases as the water content of the medium is decreased. The different behaviour is attributed to hydrogen bonding between the NH substituent and DMS0.'26

The equilibrium constant for the hydration of the carbonyl group of pyridine aldehydes and their N-oxides decrease as the electron demand on nitrogen increases or as the distance between nitrogen and the carbonyl group increase^.'^^

The gem-diol is the predominant form of 3-bromopyruvic acid at all pH values and hydration of the carbonyl group is general-base-catalysed. The rate constants for the uncatalysed reaction are correlated with the equilibrium constants for hydration which, it is claimed, indicates a product-like transitiod state.'28

Theoretical calculations of the gas-phase hydration of formaldehyde indicate that the mechanism is a termolecular concerted one with a cyclic transition state. However, a step-wise mechanism may occur in aqueous solution because the solvated zwitterion (49) is stabilized by s o l ~ a t i o n . ' ~ ~

The reaction of the sterically hindered 2,6-dichlorobenzamide with o-

0-

H I H

i A\

7 ,NHCOR

0

I Reactions of Aldehydes and Kerones and their Derivatives 17

phthalaldehyde gives an isoindoline instead of the expected phthalan. These two products result from either aldehydic oxygen or amide nitrogen attack on the adjacent aldehyde in the initially formed adduct (SO). It has been suggested that the electron-withdrawing orthochlorines enhance ionization of the NH group and hence favour isoindoline formation.'30

The kinetics and activation parameters for the addition of peroxide salts to butyraldehyde in methanol and benzene have been determined.' 31

Although generally thiols do not add to ketones, whereas aldehydes readily react, the former is a common biological reaction. Thiol addition is at least 4 kcal mol- ' more favourable than hydration in the case of aldehydes but only 2-4 kcalmol-' more favourable for ketones; thiol addition is subject to greater steric effects than is water addition.' j2

Free energies of transfer suggest that aldehyde solvation effects have negligible influence on secondary isotope effects for their reactions. For example, acetaldehyde and acetaldehyde-1-d show the same distribution between D20 and the vapour phase.'33

Binding a chloromethyl ketone, which is a specific inhibitor, to the serine protease enzyme trypsin causes an upfield shift of > 100 ppm in the I3C-NMR resonance of the carbonyl carbon. This has been interpreted as evidence for formation of a tetrahedral adduct with the serine hydroxyl of the enzyme.'34

Phase transfer of carbonyl-containing compounds from water to organic solvents shows that aqueous solution impedes hyperconjugation of the 8-CH electrons into the carbonyl group, i.e. desolvation decreases the force constants of the 8-CH bonds and causes a normal 8-deuterium isotope effect. This may explain some of the small inverse or normal secondary isotope effects observed for enzyme-catalysed reactions in which an sp2 carbonyl carbon is converted to

The equilibrium constants for the single addition of oxygen nucleophiles to acetaldehyde are similar in water and chloroform whereas those for nitrogen, sulphur and carbon nucleophiles are more favourable in water. These observations indicate that favourable hemiacetal and thiohemiacetal formation of some aldehydes with serine and cysteine proteolytic enzymes is not due to a lowering of the microscopic dielectric constant at the active site.136

The degradation of chromones in alkaline medium is inhibited by hydroxide ion because ring-opening produces the dianion (51)."'


9-[Substituted carbonyl-l-naphthyllfluorenes exist in two conformations up (52) and sp (53) with a high energy barrier to their interconversion (- 25 kcalmol-I). The lower stability of the ap form is attributed to the twisting of the carbonyl plane from that of naphthalene. Additions to the carbonyl occur smoothly in the sp conformation but they do not occur to a detectable extent in the up conformation if X is larger than hydrogen.13*

N-Nitrosoamines react with thiocarbonyl compounds in acidic solution to give the corresponding carbonyl analogues. It is suggested that the soft NO+ ion coordinates to the soft sulphur followed by nucleophilic attack of water (54).13’

The transformation of thiocarbonyl compounds into carbonyl derivatives with 5- butyl hypochlorite is thought to occur by attack of the soft chlorinium ion, Cl’, on the soft sulphur of the thiocarbonyl. The intermediate carbocation is then attacked by 5-butoxide ion (55) with elimination of elemental sulphur and hydrogen ch10ride.I~’

The reduction of substituted a,a,a-trifluoroacetophenones by N-(fl-methyl- thioethyl)-l,4-dihydronicotinamide (56) exhibits a Hammett p value of 2.62 in the absence of magnesium ions and a non-linear plot (p changes from 1.50 to 0.77) in their presence. The kinetic isotope effect k , / k , increases with increasing electron withdrawal in the ketone. These observations are not seen with the N- propyldihydronicotinamide. An unconvincing argument based on differences in entropies of activation is used to substantiate an electron-transfer mechanism which is retarded by s ~ 1 p h u r . l ~ ~

Retardation of the rate of reduction of a,a,a-trifluoroacetophenone by N-propyl- 1,4-dihydronicotinamide in acetonitrile with increasing amounts of water is probably due to hydration of the ketone. However, the acceleration brought about by the addition of magnesium ions is independent of the amount of water. The relative catalytic efficiencies of hydrated and unhydrated magnesium ions are not clear. 142

The reduction of aldehydes by NADPH-dependent aldehyde reductases requires the binding of substrate and coenzyme. Pig liver aldehyde reductase I requires NADPH to bind first before the substrate pyridine-3carboxaldehyde; however, when 4-carboxybenzaldehyde is the substrate binding is random.143

The horse liver alcohol dehydrogenase-catalysed reduction of cage-shaped ketones proceeds according to the “quadrant rule” which states that hydrogen attack from the lower quadrants is most favoured for the C,-1 quadrant ~r ien ta t ion . ’~~

The mechanism and stereochemistry of the borohydride reduction of ketones has

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