ORGANIC REACTION MECHANISMS 1993 An annual survey covering the literature dated December 1992 to November 1993

Edited by

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

An Inferscience@ Publication

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

ORGANIC REACTION MECHANISMS * 1993

ORGANIC REACTION MECHANISMS 1993 An annual survey covering the literature dated December 1992 to November 1993

Edited by

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

An Inferscience@ Publication

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

Copyright 0 1995 by John Wiley & Sons Ltd, Baffins Lane, Chichester, West Sussex PO19 IUD, England

Telephone: National 01243 779777 International (+44) 1243 779777

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Contributors

W. R BOWMAN

M. R. CRAMPTON

R. G. COOMBES

N. DENNIS

G. W. J. FLEET

S. W. GINN

J. G. KNIGHT

A. C. KNIPE

P. KOCOVSKY

H. MASKILL

A. W. MURRAY

M. I. PAGE

J. SHORTER

W. J. SPILLANE J. H. STEWART

Department of Chemistry, The University of Technology, Loughborough, Leics, UK Department of Chemistry, Durham University, Durham, DHl 3LE, UK Department of Chemistry, Brunel, The University of West London, Uxbridge, Middlesex, UB8 3PH, UK 3 Camphor-Laurel Court, Stretton, Brisbane, Queensland 41 16, Australia Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QT, UK School of Applied Biological and Chemical Sciences, University of Ulster, Coleraine, Co. Londonderry, BT52 lSA, UK. Department of Chemistry, The University, Newcastle-upon- Tyne, NE1 7RU, UK Department of Applied Physical Sciences, University of Ulster, Coleraine, Co Londonderry, BT52 lSA, UK Department of Chemistry, The University of Leicester, Leicester, LE1 7RH, UK Department of Chemistry, The University, Newcastle-upon- Tpe , NE1 7RU, UK Department of Chemistry, The University, Dundee, DD1 4HN, UK Department of Chemical Sciences, The Polytechnic, Queens- gate, Huddersfield, W Yorkshire, UK Department of Chemistry, The University, Hull, HU6 7RX, UK Department of Chemistry, University College, Galway, Ireland School of Applied Physical Science, University of Ulster at Jordanstown, Newton Abbey, Antrim BT37 OQB, UK

V

Preface

The present volume, the twenty-ninth in the series, surveys research on organic reaction mechanisms described in the literature dated December 1992 to November 1993. 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.

There have been two changes of authorship since last year. We say farewell to Prof. R. A. Aitken (Carbenes and Nitrenes) and Dr A. Thibblin (Elimination Reactions) and wish to express our thanks for the expert contributions which they have made to the series over a prolonged period. Their respective chapters have been entrusted to Dr J. G. Knight (University of Newcastle) and Prof A. C. Knipe (University of Ulster).

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

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: Part 1 by W . R . Bowman . . . . . . . . . . . . . . Radical Reactions: Part 2 by S . W . Ginn and J . H . Stewart . . . . . Oxidation and Reduction by G . W . J . Fleet . . . . . . . . . . . . . . . . Carbenes and Nitrenes by J . G . Knight . . . . . . . . . . . . . . . . . .

Carbocations by H . Maskill . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilic Aliphatic Substitution by J . Shorter . . . . . . . . . . . .

by A . C . Knipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nucleophilic Aromatic Substitution by M . R . Crampton . . . . . . . Electrophilic Aromatic Substitution by R . G . Coombes . . . . . . .

Carbanions and Electrophilic Aliphatic Substitution

Elimination Reactions by A . C . Knipe . . . . . . . . . . . . . . . . . . . Addition Reactions: Polar Addition by P. KoEovslj . . . . . . . . . Addition Reactions: Cycloaddition by N . Dennis . . . . . . . . . . . Molecular Rearrangements by A . W . Murray . . . . . . . . . . . . .

1 17 67

103 151 183 201 221 235 263

297 333 355 395 437

AuthorIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

M. I. PAGE

Department of Chemical and Biological Sciences, University of Huddersfield

Formation and Reactions of Acetals, Ketals, and Orthoesters . . . . . . . . . . . . Hydrolysis and Formation of Glucosides, Nucleosides, Oxazines,

and Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions and Formation of Nitrogen Derivatives, Schiff Bases,

Hydrazones, Oximes, and Related Species . . . . . . . . . . . . . . . . . . . . . . . C-C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . . . Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrolysis and Reactions of Vinyl Ethers and Related Compounds . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

3

4 6 8

10 11 12 13

Formation and Reactions of Acetals, Ketals, and Orthoesters

There has long been unequivocal evidence that ring opening during the acid-catalysed hydrolysis of cyclic acetals can be reversible.' Generation of the o-hydroxyalkyloxy carbocations (1) from vinyl ethers of acetophenone shows that trapping the intermediate by water is an order of magnitude faster than intramolecular ring closure. The slower rate of hydrolysis of the corresponding cyclic acetals, compared with their acyclic analogues, cannot be due to reversible ring opening.2

The mechanism of the acid-catalysed hydrolysis of 2-substituted 1,3-dithianes changes from ASE2 for the most reactive thioacetals to A2 for the least reactive. In concentrated acid, the carbocations (2) are generated which react irreversibly with water to give the corresponding benzophenone via the hemithi~acetal.~

The a-deuterium secondary kinetic isotope effect for the uncatalysed hydrolysis of 2- (4'-nitrophenoxy)tetrahydropyran (3) is 1.17, at 46"C, consistent with rate-limiting i~nization.~

The acid-catalysed ethanolysis of substituted di- 1 -azulenyl ketones (4) gives substituted azulenes and ethyl azulene- 1 -carboxylates derived from CCO cleavage. Protonation of the carbonyl oxygen generates a tropylium-like cation and cleavage of the hemiacetal intermediate (5) generates the product^.^

Base-catalysed aced formation from carbohydrate epoxides is thought to occur by intramolecular ring closure of the hemiacetal anion, opening the epoxide (6).6

Organic Reaction Mechanisms I993 Edited by A. C. Knipe and W. E. Watts 01995 John Wiley & Sons Ltd

1

Organic Reaction Mechanisms 1993

There is an inverse relationship between the rates of heterocyclic acetal hydrolysis and their inhibitory effect on the enzyme monoamine oxidase, which is taken to indicate that the enzyme adduct is electronically stabilized by the heterocycles.’

DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) in wet ethyl acetate catalyses the hydrolysis of acyclic acetals by acting as a Lewis acid.8

1,3-Dioxolanes are oxidized by iodine monochloride to the appropriate oxocarbocat- ions (7), which either react with chloride ion to give chlorohydm esters with inversion of configuration or diol monoesters with retention of configuration. The more stable carbocations are susceptible to attack by water on the central carbon.’

A neighbouring hydroxyl group can control the stereoselectivity of spiro ketal formation by magnesium ion chelation.’O The stereoselective reduction of spiro ketals can be achieved by DIBAH and a silane Lewis acid which is attributed to steric hindrance of a-methyl groups at the spiro ketal centre and to vicinal ether oxygens used for bidentate chelation.”

Cyclization of a chiral hydroxy ketone to a hemiacetal occurs stereoselectively, which can be rationalized by steric effects.’*

The stereoselective synthesis of dioxolane-type endo-benzylidene acetals can be performed stereoselectively under kinetically controlled conditions. ’

Bicyclic ketals (8) are precursors of the corresponding diketones and dioximes from which 2,6-disubstituted pyridines can be synthesized. Isotopic labelling identified the presence of the d i~x ime . ‘~

The stereoselective formation of cyclic acetals from pentane-l,3,5-triols relies on attractive van der Waals interactions.15

The acid-catalysed cyclotrimerization of aliphatic aldehydes to give 2,4-6-trialkyl- 1,3,5-trioxanes by heteropoly acids can occur with a phase separation due to the insolubility of the coordinated acid and aldehyde.16

Possible mechanistic pathways have been proposed to explain unexpected products in the acid-catalysed reactions of terpenic ketones and aldehydes with alcohol^.'^ A thiazolium salt is an efficient catalyst for the formation of ketals in alcoholic carbonate solutions.’8 Chiral acetals can be synthesized from the Pd(I1)-catalysed addition of methanol to alkenes.”

1 Reactions of Aldehydes and Ketones and their Derivatives 3

A reversal of the usual reactivity of primary and secondary alcohols towards electrophiles can be achieved by the conversion of 1,2-diols into hexamethylene- stannylene acetak20

Hydrolysis and Formation of Glucosides, Nucleosides, Oxazines, and Related Compounds

Stereoelectronic effects in glycoside hydrolysis have been reviewed and the principle of least motion hypothesis criticized. With little supporting evidence, but many assertions, detailed reaction pathways are outlined including one for the acid-catalysed hydrolysis of cr and p-methoxytetrahydropyrans to explain the 1.5-fold rate difference!21

It is often assumed that carbohydrates cyclize kinetically to five-membered ring acetals but slowly rearrange to the thermodynamically more stable six-membered rings. The acid-catalysed cyclization of 3-substituted-4,5-dihydroxy ketones can give either tetrahydropyran or tetrahydrofuran acetals; syn 3,4-substitution (9) gives the six- membered ring whereas the anti isomer gives exclusively the five-membered ring.22

The equilibrium concentration of the open-chain keto form Of D-fiuCtOSe is 0.8% and almost invariant with pH, as determined by FTIR studies.23

As expected, a p-trimethylammonium substituent decreases the pH-independent hydrolysis of 1 -phenyl$-D-ribofoside compared with a p-nitro ~ubsti tuent.~~

The rate of the acid-catalysed ring opening of b-cyclodextrin is inhibited by guest molecules. The deceleration in rate is directly related to the strength of a~sociation.~~

Eight-membered benzylidene acetals bridging the two monosaccharide components of cr-maltosides are readily formed using cr, a-dimethoxytoluene, but may be selectively hydrolysed by 80% acetic acid at room temperature.

4 Organic Reaction Mechanisms 1993

The reaction of 2-amino-2-deoxy sugars with isocyanates gives initially ureido derivatives which, under acidic conditions, give the trans isomers (10) which consequently ring close to the cis-fused glucofuranoses (1 l).27

The formation of 2-deoxyglycosides proceeds through the intermediate formation of a charge-transfer complex of dimethoxyphenylmethyl glycosides with 2,3-dichloro-5,6- dicyano-p-benzoquinone (DDQ) in the presence of alcohols acting as glycosyl acceptors.28

The different reactivities of ribonolactones with benzaldehyde and acetone in acidic media are associated with relatively minor changes in structure which are difficult to predict.29

The stereo-controlled glycosidation of secondary sugar hydroxyls to give disaccharides containing 1,2-cis-glycoside linkages, using silicon as a tethering step, involves an intramolecular di~placement.~~

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

The 0-acetyl group in (12) is orthogonal to the benzene ring, in the crystal state, which is attributed to dipole repulsion between the imine and the carbonyl group. Tautomerism and isomerization in this system are also disc~ssed.~’

The E-2 thermal isomerization of N-benzylideneanilines (13) can occur through perpendicular or planar conformations. The mechanism adopted is a sensitive function of substituents.

The site of protonation, C or N, in cyclic a-ketoenamines varies with ring size. For example, the cyclohexene derivative is protonated on the heteroatom (14), whereas the seven-membered derivative is also protonated at C(3).33

0 n

H \

IC = N\ Ar Ar

,CH HN

(16)

Me 111.

H \ / ~ H O H

SAr ArCo\ / N = C

\ C1

There have been further reports on the formation and hydrolysis of Schiff bases of pyridoxal 5’-phosphate with hexylamine. The dehydration of the intermediate carbinolamine is assumed to be rate-limiting and catalysed intramolecularly by the phenolic group. The rates of reaction can be correlated with the difference in the pK, of the ammonium ion and the pyridoxal phosphate.34

I Reactions of Aldehydes and Ketones and their Derivatives 5

A theoretical treatment of the pyridoxal-5-phosphate-catalysed transamination reaction has shed little new light on the process.35

There have been fUrther studies on the hydrolysis of Schiff bases of aminobenzoic acids36 and of 1,3-indandione~.~~

The mechanism of the GabrielXolman reaction between pyruvic aldehyde and aminopyrimidinones occurs through the initial formation of Schiff bases such as (15).38 The reductive amination of amido-imines to give enantioselective amido-mines can be achieved using a chiral High enantioselective reduction of imines and ketones can be achieved with chiral oxaborolidines because the re-face is sterically hindered?O

The reaction of ninhydnn with a copper(I1) complex of glycine and alanine involves rate-limiting conversion of the metal-bound amine into the Schiff base.41 The kinetics of the reaction of ammonia with formaldehyde have been further investigated?2 The carbonate-catalysed hydroxymethylation of aminotriazines with formaldehyde shows a Hammett p-value of 1 .6:3 The Hantzch synthesis of novel 1 ,Cdihydropyridines from Schiff bases of o-nitrobenzaldehyde occurs via the imine (16).44

The hydrolysis of phenyl-N-benzoylchlorothioformidate derivatives (17) is thought to occur by unimolecular loss of chloride to form the aza-carb~cation:~

Although boric acid catalyses the rate of oxime formation from salicylaldehyde, there is no evidence of complex formation in the reactants. It is suggested that complexation occurs at the carbinolamine stage so that dehydration is facilitated by Lewis acid catalysis (18).46

Between pH 4 and 13, oxime formation from hydroxylamine and cyclohexanone and bicyclic ketones proceeds with rate-limiting dehydration of the carbinolamine intermediate. The dehydration step occurs by acid catalysis, a pH-independent pathway, and base catalysis with increasing P H ? ~

The pharmaceutically important chiral 1,2-amino alcohols can be formed from the stereo-controlled hydride reduction of a-hydroxy oximino ethers:' Alkenyl-substituted oximes can be cyclized to the corresponding nitrones by treatment with N- bromosuccinimide by trapping the intermediate bromonium ion.49

Theoretical calculations of the mechanism of the Beckman rearrangement of formaldehyde oxime in the gas phase suggest, not surprisingly, that the reaction is ~oncerted.~' The acid-catalysed epimerization of an a-chiral hydrazone occurs faster than that of the parent ketone, as expected on the basis of the different basicities of oxygen and nitr~gen.~' Treatment of 1,2-dihydrazones with N, N'-carbonyldiimidazole results in the formation of the seven-membered ring (19) but the monoacylated derivatives (20) is not converted into (19) by heating.52

Intramolecular nucleophilic attack of a hydrazonyl group on an aldehyde is catalysed by Lewis acids to give substituted py raz~ les .~~ An oxidative method for converting N, N-dimethylhydrazones into nitriles is thought to involve intramolecular general base catalysis.54

Hydrazones can be converted into the corresponding carbonyl compounds by their oxidative cleavage with dioxiranes through the intermediate formation of the N-oxide.55 Tosylhydrazones of vinylogous lactones, on treatment with N-bromosuccinimide, give acetylenic lactones by hydride abstraction to give an intermediate oxonium ion.56

6 Organic Reaction Mechanisms 1993

N , -NPh I I h NH NH Ph’

I N+

HO H HO-&

1 Reactions of Aldehydes and Ketones and their Derivatives 7

Common assumptions about the mechanism of the Grignard reaction have been questioned. It is argued that values of the carbon kinetic isotope effects for the carbonyl carbon of benzophenone of around unity should be taken as proof against, not for, the participation of ketyl as an intermediate which is formed by inner-sphere electron transfer with simultaneous transfer of magnesium.65

Diastereomer differentiation during the 1,2-addition of Grignard reagents to chiral a- keto amides is attributed to complexation of the magnesium to the keto amide which favours particular conformations.66 Arsenic ylides with pyranoses and kanoses give (E)-alkene~.~~ A combination of steric and electronic effects has been used to explain the lack of stereoselectivity in the Homer-Wadsworth-Emmons reaction of phosphonates with aromatic aldehydes.68

The stereo-induction in the hydroxylative Knoevenagel condensation to give a- hydroxy-a, b-unsaturated enoates using chiral a-sulphinyl esters and chiral aldehydes is a function of the absolute stereochemistry of the sulphoxide, the substituent on the sulphoxide, and the amount of base.69

The aldol reaction of hexafluoroacetone and trifluoroacetaldehyde with the boron enolate of the chiral N-acyloxazilidinone causes a reversal of selectivity due to the electron-withdrawing groups preventing coordination to boron leading to an open transition state.7o

The different steric effects of E-Z geometry of the enolate in the transition state for enantioselective aldol coupling using chiral diazaborolidine are responsible for the face selection of the aldehyde c~mponent .~~

Titanium(II1) ions can divert the path of the normal benzoin condensation into thermodynamically less stable products.72

The intramolecular pinacol coupling of diketones to cyclic 1,2-diols is induced by titanium and the stereochemistry of the reaction can be predicted by molecular- mechanics calculations of the steric effects.73

Cyclic a-carbonyl-substituted cyclopentanones react with a, P-unsaturated aldehydes in a cascade of processes involving Michael addition, regioselective aldol cyclization, followed by a reverse Dieckmann reaction to give substituted cycloheptanes catalysed by potassium carbonate in methanol.74

The carbanion addition of nitriles to cinnamaldehyde occurs by both 1,2- and 1,4- addition pathway^.^' The kinetics and mechanism of the acid-catalysed condensation of acetone with phloroglucinol have been reported. 76

There have been numerous reports on the selectivity of carbon-carbon bond-forming reactions, including a review on the mechanism and stereochemistry of the Wittig reaction77 and original papers.78 There has been a theoretical study of the Reformatsky reaction.79

The most common carbanions studied have been Sn80 and Si8' derivatives with numerous reports involving B complexes.82 Other Lewis acids have included Ti,83 Al,84 Fe,85 Li,86 Zqg7 and lanthanides.g8

Diastereoselectivity in CC formation can be controlled by an a,p-epoxy group adjacent to the carbonyl under attack.89

Carbon-carbon bond cleavage and formation catalysed by transketolase with its cofactor thiamine diphosphate involves at least three proton-transfer steps. Possible

8 Organic Reaction Mechanisms I993

functional groups involved in these processes have been suggested on the basis of the three-dimensional structure of the

Other Addition Reactions

A simple model to explain x-facial selectivity in the nucleophilic addition reactions of ketones continues to be sought. It is suggested that electrostatic interactions between anionic nucleophiles and the substrate are generally more important than orbital interactions.”

Electrostatic interactions are thought to control the stereochemistry of nucleophilic additions to substituted 7-norb0rnanones.~~ Other calculations suggest that the preference for axial nucleophilic attack on 4-axially-substituted cyclohexanones is due to the large barrier for equatorial attack. There is no transition state stabilization for axial a t ta~k.9~

Cyclohexenones generally show high stereoselectivity in 1,2-nucleophilic additions favouring axial addition compared with cyclohexanones. This appears to be the case even for hindered em-cyclohexenones with sterically demanding nucleophiles. The intrinsically higher axial selectivity is attributed to orbital overlap.94

Calculated ground-state and transition-state structures for the addition of hydride ion to carbonyl compounds show that electrostatic, electronic, and steric interactions, in addition to conformational energies, are important in determining product f~rmation.’~ n-Facial stereoselectivity can also be shown to be dominated by electrostatic effects.96

The LiAlH4 reduction of cyclohexanones which are axially substituted with methyl, methoxy, and hydroxy groups at the 2-position gives, predominantly, products formed from axial attack. It is claimed, not very convincingly, that this supports Cieplak’s model of orbital control in the transition state.97

The enantioselective reduction of ketones with borane using proline or prolinol as chiral auxiliaries is attributed to the intermediate formation of a chiral oxazaborolidine as the reducing agent9*

The R (23) and S isomers of the NADH model reduce carbonyl and imine groups with good enantioselectivity under conditions of ternary complex formation with magnesium ions.99 The reduction of ketones with uranium borohydride complexes gives stereoselectivities which can be related to the stereochemistry of the metal complex. loo

The highly enantioselective formation of cyanohydnn from aromatic aldehydes and cyanide catalysed by the cyclic dipeptide cyclo-(S)-phenylalanyl-($)-histidine is thought to be due to complexation of the aldehyde with the dipeptide. However, there is no NMR or IR evidence for this, although calculations suggest some interaction between HCN and the imidazole of histidine. The fundamental problem is, of course, that the reaction is heterogeneous.101

The addition of cyanide with dimethyldicyanosilane to P-hydroxy ketones occurs with high diastereoselectivity. The syn configuration of the 0-hydroxycyanohydnn product is compatible with intermolecular addition of cyanide through a chair-like six- membered transition state. ‘02

I Reactions of Aldehydes and Ketones and their Derivatives 9

125) (26) 127)

The cyclic chiral diketopiperazine derived from (9-phenylalanine and (+histidine catalyses the enantioselective addition of HCN to aldehydes and is thought to occur by an initial covalent interaction between HCN and the cata1y~t. l~~

The configuration of cr-cyanohydrins can be inverted under Mitsunobu esterification conditions through the intermediate formation of an 0-triphenylphosphonium-activated cyanohydrin followed by &2 attack of an oxygen nucleophile.‘04

The relative rates of the acid-catalysed addition of H i 8 0 to the carbonyl group in conformationally rigid ketones can be rationalized by larger steric effects with the substituent synperiplanar to the nucleophile. Antiperiplanar electronic effects are minimal. The abnormal behaviour induced by the monoaxial methoxy substituent is due to hydrogen-bonding when the methoxy group is synperiplanar.loS

Fast protonation of 1-azaadamantones is followed by slow hydration of the carbonyl group. Protonation of the nitrogen increases the equilibrium constant for gem-diol formation by three orders of magnitude for the diketone (24).lo6

Theoretical calculations suggest that a second water molecule acts as a bihctional catalyst in the gas-phase addition of water to formaldehyde. lo7 Theoretical calculations on the addition of trichloroacetic acid to carbonyl groups suggest that intramolecular proton transfer and oxygen addition occur concurrently (25).’08

Pyruvic acid and acetaldehyde react with substituted nitrosobenzenes to give the corresponding N-phenylacetohydroxamic acids. The pH dependence, a Hammett p- value of 1.97 for substituted nitrosobenzenes, and an inverse solvent isotope effect of 0.41 have been used to suggest a mechanism involving intramolecular proton transfer (26) in the case of pyruvic acid.Io9

Formaldehyde reacts with substituted nitrosobenzenes to give the corresponding N- phenylhydroxamic acid. Initial addition of the nitroso group to the carbonyl gives a zwitterionic tetrahedral intermediate. Subsequent proton transfer gives the nitrosocar- binolamime which then undergoes rate-limiting proton transfer from carbon to give the hydroxamic acid.”O

2-Iminooxetanes (27) undergo a variety of electrophilically initiated ring-opening reactions to y-amino alcohols with lithium aluminium hydride, hydrolysis to p-hydroxy amides, and conversion into p-lactams with lanthanum(II1). ‘ l 1

10 Organic Reaction Mechanisms 1993

peri-Interactions in the reactions of quinones have been reviewed.' l2 Enantioselective addition to one of the carbonyl groups of 1 ,Zdiketones can be achieved by conversion of one of the carbonyl groups at a cyclic acetal with a chiral auxiliary.''3 Natural products containing the 2-methoxytropone residue undergo reversible nucleophilic addition to the 2-p~sition."~ The formamidine (28) reacts with benzaldehyde in the presence of base to give (29), where the oxygen is thought to arise from the aldehyde.

A theoretical treatment of the addition of nucleophiles to thiocarbonyl emphasizes the importance of the first and second HOMO and the energy of the sulphur lone-pair orbital.' l 6 Thiols react with thioaldehydes to give unsymmetrical disulphides.'" Electron-poor selenoaldehydes react with thiols in the presence of triethylamine to give selenyl sulphides.' l 8

Enolization and Related Reactions

The amount of enol in aqueous solutions of 2-phenacylpyridine is more than 250-fold more than that in the 4-isomer, which is attributed to stabilization by intramolecular hydrogen bonding (3O).ll9 In 1-phenacylpyrihnium ions (31), proton loss from carbon can be used to measure the effect of the positive charge on the stability of the azomethine ylide. The proton-activating factor is 5 x lo3 for reaction with hydroxide ion, which is significantly lower than the equivalent effect (lo9 - 1O'O) on proton loss from oxygen.120

Theoretical calculations predict that the en01 form of 3-hydroxyisoxazole (32) is the predominant form in solution, whereas the 0x0 form (33) is found in the 5-is0mer.'~'

(31) (32) (33)

The absorption of thermal energy by a molecule is usually assumed to be rapidly partitioned between translational, rotational, and vibrational energy. There should therefore be no kinetic difference between microwave-irradiated reactions and conventionally heated reactions, which has been shown to be the case for the acid- catalysed isomerization of carvone. 122

1 Reactions of Aldehydes and Ketones and their Derivatives 11

The conjugated muconate enol (34) is a stable dienol generated by the bacterial catabolism of 4-hydroxyphenyl acetate which ketonizes to the keto acid (35) by enzymatic and non-enzymatic pathways. The enol(34) is initially rapidly converted into the isomeric ketone (36). Enzymatically the ketone (36) is converted into (35) via the intermediate enol (34). 123 The enzyme 4-oxalocrotonate tautomerase catalyses this allylic rearrangement by a one-base mechanism as isotopic and stereochemical studies suggest a suprafacial process.124

On the basis of inhibition of the enzyme phenylpyruvate tautomerase by stereoisomeric substituted cinnamates, it has been concluded that the enzyme produces the thermodynamically less stable (I?)-enol via a syn tautomerization transition state. 125 The acid-catalysed deuteriation of phenalenone (37) occurs at the enolic carbon in strong acid but elsewhere at lower acid concentrations.126

As expected, the gegenion has a large effect on the calculated energy and charge distribution of enolate anions but, unexpectedly, there is little variation among the various alkali metal cations, despite great differences in their ionic radii.'27 Homo- enolization is facilitated by the benzo group, which can stabilize the carbanion. 128

The reaction of dithiol with 1,3-dichloroacetone, catalysed by caesium carbonate, gives good yields of macrocyclic ketones. The mechanism appears to involve an unusual rearrangement involving enolate carbanion attack on sulphur to displace an enolate by CS bond ~1eavage.I~~ Epoxide formation occurs by ring closure of the enolate anion of tx-substituted ketones in the gas phase with no C-alkylation to give cyclopropanones. I3O

Hydrolysis and Reactions of Vinyl Ethers and Related Compounds

The pH-rate profile for the antibody-catalysed hydrolysis of the en01 ether (38) indicates an important ionizable side-chain with pK = 5.2 which is thought to be a

12 Organic Reaction Mechanisms 1993

carboxyl group. The small kinetic solvent isotope effect of kH/kD = 1.75 is taken to indicate general acid catalysis by the antibody (38).13'

The solvolysis of polyenol ethers in acidic media can be thought of as a competition between ionic and electron-transfer reaction pathways. For highly conjugated systems, electron transfer occurs for the neutral species but is not feasible if the side-chain is protonated on the 8-hydroxy

c

The hydration stability of acylketenes (39) depends largely on substituents, but the reactivity of (39; R' = OEt, R2 = But) is unique in that the rate of hydration is fast and independent of the solvent composition in water-acetonitrile mixtures. This is interpreted as evidence for an intramolecular cyclic non-polar transition state (40). 133

The intramolecular trapping of a ketene by a pyrazole group leads to the betaine (41).'34 Mercury(I1) iodide acts as an exceptionally mild catalyst for the aldol condensation of silyl ketene acetals with aldehydes. '35

0 0 - - H

c=c=o / /

// 1.. 'I R'-C \ EtO - c: -c;" - H R2 Bur 0 (39) (40)

Other Reactions

The acid-catalysed decomposition of u-diazocarbonyl compounds is thought to occur by rate-limiting protonation of the diazo carbon. The hydrolysis of (42) shows a kinetic

1 Reactions of Aldehydes and Ketones and their Derivatives 13

isotope effect, kH+/kD+ = 3.1 and a Bronsted CI exponent of 0.7. However, the product is the rearranged acid (43). Although there is no direct evidence of a rate acceleration, it is suggested that the 1,2-shifl of the methylthio group occurs during the rate-limiting step. 136

The oxidation of aldehydes by horse liver alcohol dehydrogenase occurs with a pronounced lag at low enzymehigh aldehyde concentrations, during which dismutation into the corresponding alcohol and acid is ~bserved.'~'

The oxidation of aliphatic aldehydes by pyridinium hydrobromide perbromide occurs by hydride transfer from the aldehyde hydrate.138

Chromium(I1) chloride converts CI, P-unsaturated aldehydes into the corresponding cyclopropanols. 139 The cobalt(I1)-catalysed reaction of alkenes with aliphatic aldehydes and molecular oxygen to give P-hydroxy ketones occurs through a radical rea~ti0n.l~'

A kinetic study of the high-temperature pyrolysis of formaldehyde in shock waves has been r e~0r t ed . I~~ A mechanism for the chain decomposition, based on calculations and measurement of hydrogen atom abstraction, has been proposed. 142

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CHAPTER 2

Reactions of Acids and their Derivatives

w . J . SPtLLANE Chemistry Department. University College. Galway. Ireland

CARBOXYLJCACIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tetrahedral Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Reactions in Hydroxylic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

@)Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(ii) Transesterification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(c) Lactones and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Intermolecular Catalysis and Reactions . . . . . . . . . . . . . . . . . . . . . . . . . .

(a)General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(i) Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(iii) Other reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(d) Acids and anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (e) Acid halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (0 Ureas, cafbamates. and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . (g) h i d e s , anilides. and lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . (h) Non-heterocyclic nitrogen centres . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Other heterocyclic nitrogen centres . . . . . . . . . . . . . . . . . . . . . . . . .

Reactions in Aprotic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Catalysis and Neighbouring-group Participation . . . . . . . . . . Association-prefaced Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metal-ion Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Decarboxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enzymic Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serine Proteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metallo- and Acid Proteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OtherEnzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catalytic Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

NON-CARBOXYLIC ACIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphorus-containing Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

Enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sulphur-containing Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(a) Phosphates. phosphoryl transfer. phosphonates . . . . . . . . . . . . . . . . . . (b) Phosphinates and other phosphorus compounds . . . . . . . . . . . . . . . . .

18 18 20 20 20 21 21 21 22 24 25 28 28 30 32 33 34 35 36 40 43 44 44 44 46 47 47 49 50 50 50 50 52 53 54

Organic Reaction Mechanisms 1993 Edited by A . C . Knipe and W . E . Watts 0 1995 John Wiley & Sons Ltd

17

18 Organic Reaction Mechanisms 1993

Other Acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

CARBOXYLIC ACIDS

Tetrahedral Intermediates

Recent work' on the calculation of pKa values for tetrahedral intermediates has refined and extended the original work of Fox and Jencks2 The equation

has been used very successfully for these calculations. A p 1 value of -9.1 f 0.4 for the effect of a substituent X on the pKa of Y in X-C-Y and of -4.4 f 0.4 when the system is of the type X-C-C-Y is proposed. The problem of 01 values for charged substituents is also addressed in this work.

Carbon and oxygen isotope effects suggest that the alkaline hydrolysis of methyl formate is stepwise, with rate-determining formation of the tetrahedral intermediate. Carbonyl carbon (k12/k13), and both carbonyl oxygen (k16/k'*) and nucleophilic oxygen (kI6/k'*) effects have been mea~ured.~ Water, with general base assistance from HO-, may be the attacking nucleophile.

The butyl- and methylbutyl-aminolysis of 4-nitrophenylacetate in chlorobenzene is catalysed by glymes, H(CH2OCH:!),H; values of kcatlo, (where 0, is the number of oxygens in the catalyst) increase for the butylaminolysis up to an oligomer length with n = 4 and then plateau; for methylbutylaminolysis, however, glymes with n = 2 4 have the sane effect4 These differences arise from differences between the zwitterionic tetrahedral intermediates (1; R = H, Me). The glyme with n = 3 catalyses butylaminolysis by forming two bifurcated H-bonds. This suggested structure defines the size of the ammonium ion and is a method of 'fingerprinting' ammonium ions in transition states.

A review (33 references) in Russian considers the rearrangement of the tetrahedral intermediate arising in the alkaline hydrolysis of aryl esters of N-substituted benzimidic acids5 For N-ethyl-N-(trifluoroethy1)toluamide (2; R' = CH2CF3, R2 = Et) and N- toluoyl-3,3,4,4,-tetrafluoropyrrolidine [2; R' R2 = CH2 (CF2)2CH2], the rate of carbo- nyl oxygen-18 exchange in basic media exceeds that of hydrolysis, and it has been possible to obtain k,,, and khyd constants since the paths are kinetically isolated.6 For "0 exchange, the slow step is the addition of hydroxide to give an anionic intermediate; for hydrolysis, the slow step is the breakdown of this intermediate. Activation parameters have been measured and are discussed in terms of solvent restriction in the transition states.

Anionic (3), dianionic (4), and zwitterionic (5) tetrahedral intermediates are proposed in the mechanisms of hydrolysis of isatin (6; R' = R2 = H), its carboxymethyl derivative (6; R' = CH~COZH, R2 = H), and their 5-nitro-substituted derivatives (R2 = NO2).' These intermediates may break down to products via HOP-, H3O+- and