ORGANIC REACTION MECHANISMS 1978 · 2013. 7. 23. · ORGANIC REACTION MECHANISMS 1978 An annual...

ORGANIC REACTION MECHANISMS 1978 An annual survey covering the literature dated December 1977 through November 1978

Edited by

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

An Interscience@ Publication

JOHN WILEY & SONS

Chichester a New York = Brisbane * Toronto

ORGANIC REACTION MECHANISMS - 1978

ORGANIC REACTION MECHANISMS 1978 An annual survey covering the literature dated December 1977 through November 1978

Edited by

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

An Interscience@ Publication

JOHN WILEY & SONS

Chichester a New York = Brisbane * Toronto

An Interscience@ Publication Copyright @ 1980 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 ISBN 0 471 27613 8

Printed in Great Britain by John Wright & Sons Ltd., at the Stonebridge Press, Bristol

Contributors

M. S. BAIRD

C. BROWN

A. R. BUTLER

B. CAPON

D. J. COWLEY

M. R. CRAMPTON

G. W. J. FLEET

I. GOSNEY

M. C. GROSSEL

A. F. HEGARTY

A. J. KIRBY

A. W. MURRAY

D. C. NONHEBEL

J. SHORTER

Department of Organic Chemistry, The University,

Chemical Laboratory, University of Kent,

Department of Chemistry, The Purdie Building,

Department of Chemistry, Glasgow University

School of Physical Sciences, New University of

Department of Chemistry, Durham University

Dyson Perrins Laboratory, South Parks Road,

Department of Chemistry, University of

Dyson Perrins Laboratory, South Parks Road,

Chemistry Department, University College, Cork,

University Chemical Laboratory, Cambridge

Department of Chemistry, University of Dundee

Department of Pure and Applied Chemistry,

Department of Chemistry, University of Hull

Newcastle-upon-Tyne

Canterbury

University of St. Andrews

Ulster

Oxford University

Edinburgh

Oxford University

Ireland

University of Strathclyde

Preface ‘The Road goes ever on and on

Down from the door where it began. Now far ahead the Road has gone,

And I must follow, if I can. Pursuing it with weary feet,

Until it joins some larger way, Where many paths and errands meet.

And whither then? I cannot say.’

The Fellowship of the Ring, J. R. R. TOLKIEN [Published by permission of George Allen & Unwin (Publishers) Limited]

We have little doubt that the above passage will have particular significance for the dedicated team of contributors to Organic Reaction Mechanisms. As editors, we undertake the task of scanning the entire literature of organic chemistry in search of papers of mechanistic interest; we are consequently very milch aware of the manifold development of the subject and of the difficulty in kzeping up with its relentless progress. In keeping with previous volumes we have allocated references to fourteen chapter areas. It has subsequently been the task of each author to provide an expert and comprehensive review of his subject while taking care to highlight those papers of particular interest. Thus, we hope that successive volumes of Organic Reaction Mechanisms will effectively map the major developments in this diverse area while also describing the surrounding fields of activity.

The present volume, the fourteenth of the series, surveys research on organic reaction mechanisms described in the literature dated December 1977 to November 1978. In order to limit the size of the volume we must necessarily exclude or restrict overlap with other publications which review related specialist areas (e.g. photochemical reactions, biosynthesis, electrochemistry, surface chemistry, organometallic chemistry, heterogeneous catalysis). Furthermore, we try to avoid duplication between chapters. Thus, while a particular reference may occasionally be allocated to more than one chapter, we do assume that readers will be aware of the alternative chapters to which a bopderline topic of interest may have been preferentially assigned.

We would once again like to express our particular thanks to our very experienced contributors, to the publications staff of John Wiley and Sons, and to Dr. R S. Cahn whose expertise as technical editor has ensured maintenance of the high standard of presentation expected of this series.

August 1979 A. C. K. W. E. W.

Contents 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Reactions of Aldehydes and Ketones and their Derivatives by B. CAPON . Reactions of Acids and their Derivatives by A. J. KIRBY . Radical Reactions by D. J. COWLEY and D. C. NONHEBEL . Oxidation and Reduction by G. W. J. FLEET

Carbenes and Nitrenes by M. S. BAIRD

Nucleophilic Aromatic Substitution by M. R. CRAMPTON

Electrophilic Aromatic Substitution by A. R. BUTLER

Carbonium Ions by M. C. GROSSEL .

Nucleophilic Aliphatic Substitution by J. SHORTER

Carbanions and Electrophilic Substitution by I. GOSNEY

Elimination Reactions by A. F. HEGARTY

Addition Reactions: Polar Addition by C. BROWN

Addition Reactions: Cycloaddition by C. BROWN

Molecular Rearrangements by A. W. MURRAY .

. .

. .

.

.

Author Index, 1978 . Subject Index, 1978 .

. I

. 29

. 89

. 199

. 249

. 281

. 299

. 313

. 343

. 383

. 429

. 453

. 479

. 509

. 625

. 689

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

B. CAPON

Chemistry Department, Glasgow University

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

.

Non-enzymic Reactions . Enzymic Reactions .

(a) Galactosidases . (b) Glucosidases . (c) Lysozymes . (d) Amylases and Glucamylases . (e) Cellulases . (f) Other Enzymes .

Hydration of Aldehydes and Ketones and Related Reactions Reactions with Nitrogen Bases .

.

Schiff Bases . Enamines . Nucleosides . Hydrazones, Oximes, Semicarbazones and Related Compounds

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

. 1 . 5 . 5 . 6 . 6 . 6 . 7 . 7 . 8 . 8 . 8 . 10 . 10 . 13 . 13 . 14 . 15

. 16

. 18

. 19

. 20

. 21

Formation and Reactions of Acetals and Ketals

There have been reviews entitled “Transition States of Hydrolysis of Acetals, Ketals, Glycosides, and Glycosylamines”,l “Some Mechanistic Studies on the Hydrolysis of Acetals and Hemiacetal~”,~ and “Stereoelectronic Control in Hydrolytic reaction^".^

Hemiacetals have been detected at quite high concentrations in the hydrolysis of some benzaldehyde diethyl acetals by making use of the fact that the hydrolysis of the hemiacetal is base-catalysed but that of the acetal is Addition of sodium hydroxide to a hydrolysing solution of a benzaldehyde acetal, therefore, produces a sharp increase in the concentration of benzaldehyde (and hence UV absorbance) which is proportional to the concentration of hemiacetal present. The p-value for the hydrolysis of benzaldehyde acetals is -3.4 and of hemiacetals is ca. -2; hence

1

2 Organic Reaction Mechanisms 1978

this effect is most noticeable in the reactions of p-methoxybenzaldehyde diethyl acetal. Also, as the hydrolysis of the hemiacetal is base-catalysed and that of the acetal is not, the effect is most noticeable at low pH. Under certain conditions, the hemiacetal is present in a hydrolysing solution of p-methoxybenzaldehyde diethyl acetal to the extent of 40% of the starting concentration.

The ethoxytropylium ion (1) has been detected as an intermediate in the hydrolysis of tropone diethyl ketal, and methoxy- and ethoxy-diphenylcyclo- propenium ions have been detected in the hydrolysis of the acetals (2). However, no intermediate could be detected in the hydrolysis of 4-ethoxyacetophenone dimethyl acetal. Similar experiments were carried out with orthoesters and the intermediate ion could be detected in the hvdrolvsis of trimethvl orthomesitoate : by taking advantage of the rate-decreasing kffect of electrolytes- on the hydrolysis

(3) x = 0 (4) x = s Ph

OMe Me

( 5 ) (6 ) (7)

of carbocations, the intermediate ion could also be detected in the hydrolysis of trimethyl 4-methoxyorthobenzoate and trimethyl or th~benzoate .~ The rate constants for the reactions of these and several other ions with water were also determined, the ions being generated in sulphuric acid solutions. Values of kHzO were obtained by extrapolation to zero acid concentration. It was shown inter alia that the methoxy-substituted cation (3) reacts over 1000 times faster than the methythio-analogue (4) and that the a-amino-substituted ion (5) reacts almost lo9 times more slowly than ion (6). The p+-values for the reactions of ions (7) with water is +2.1.6 This was compared with the p+-value of + 1.6 estimated by Young and Jencks' using a different method as described below.

Young and Jencks studied trapping, by sulphite dianion, of the ions (7) which were generated by hydrolysis of the corresponding acetophenone dimethyl ketals. The fraction trapped increases with increasing sulphite concentration up to a maximum value (f,,,) which increases with increasing electron-releasing power of substituents in the ketal. The overall rate of reaction is unaffected by sulphite. Since the fraction of a-methoxysulphonic acid formed reaches a limiting value with increasing sulphite concentration, sulphite must also catalyse the reaction of water with cations (7) as well as attack them as a nucleophile. General base catalysis of attack of water by acetate was also detected as reflected by a decrease in the yield of a-methoxysulphonic acid with increasing acetate concentration. It was concluded from the low ratio of the rate constant for reaction with sulphite to that with water that the reaction with sulphite was diffusion-controlled. On this basis, on the assumption that the same values apply for the rate constants for reaction of all the ions with sulphite (k, = 5 x lo9 M-l s-l), a series of values for reactions of the ions with water was calculated which, at 25 "C, ranged from 7 x lo6 s-l for

I Reactions of Aldehydes and Ketones and their Derivatives 3

p-methoxy to ca. 4 x lo8 s-l for m-bromo, leading to the value of p+ = 1.6 men- tioned in the last paragraph. The value obtained by McClelland and Ahmad for the p-methoxy ion, by quite a long extrapolation from solutions in concentrated sulphuric acid to water (1.4 x lo6 s-l), was in quite good agreement. A linear plot of these values against the rate constants for reactions of sulphite with the corresponding carbonyl compounds was obtained. When this was extrapolated to isobutyraldehyde, p-nitrobenzaldehyde, and formaldehyde, very high values of rate constants for the reaction of the corresponding ions with water were estimated, e.g. s-l for CH2=6Me. This suggests that reactions which might involve these ions as intermediates, e.g. hydrolysis of the corresponding acetals, probably proceed by SN2 processes.'

The rate constant for nucleophilic attack by water on the stabilized oxonium ion (8) is 8.5 x s-l at 25 "C!

OMe

Oglucose

A discussion of the previously determined solvent deuterium isotope effects and Brernsted a-coefficients for the general acid catalysed hydrolysis of acetals and orthoesters has been given.g In agreement with earlier discussions,1° it was con- sidered that the rate-determining step was the concerted displacement of the alkoxycarbonium ion by the acid catalyst. In addition, however, it was thought necessary to invoke several additional intermediates to explain the difference in solvent isotope effects (and fractionation factors) between these reactions and the general acid catalysed hydrolysis of vinyl ethers.

The spontaneous hydrolysis of acetal (10) with an axial OAr group is 3.3 times slower than that of (9) with an equatorial OAr group.ll This result contrasts with those previously reported which indicated that orthoester (11) should react with preferential cleavage of the axial carbon-methoxyl bond. It is possible that the acetal with an axial OAr group reacts via a half-chair transition state and cation, whereas that with an equatorial OAr group reacts via a boat or twist-boat transition state and cation. If these transition states were of similar energy, the rates of cleavage of axial and equatorial bonds would be similar, as found. With this structure, both the half-chair and boat (or twist-boat) conformations can accom- modate the additional fused six-membered rings without additional strain. With the orthoester (ll), however, the ring fusion is in a different position and a boat conformation would require the other six-membered ring to be fused trans across the base of the boat which is very unfavourable. In an investigation of the tri- cyclic acetals (12) and (13), evidence was obtained that, if the system is made sufficiently rigid, fusion of the axial C(2)-0 bond of a 2-aryloxytetrahydropyran occurs faster than fission of an equatorial one.12 It was found that the acid catalysed hydrolysis of (13) occurs over 3000 times faster than that of (12). The spontaneous hydrolysis of (13) is over 1000 times slower than that of (10); this was explained as


resulting from the intermediate ion in the reaction of (13) undergoing recyclization faster than reaction with water. The rate-limiting step is therefore attack of water on the ion. Consistently, a solvent deuterium isotope effect, kHzO/kDzO = 1.8 at 100°C, was found. On the other hand, (12) appears to undergo a spontaneous hydrolysis in which the rate-limiting step is cleavage of the C-0 bond as - L=*

ArO s (9)

ArO (10)

(11) (12) (13)

kHZO/kDzO = 1.03; this reaction occurs about lo4 times more slowly than that of (9). The important difference between (9) and (12) is that (9) can achieve the boat or twist-boat conformation whereas (12) cannot.

Hydrolyses of the orthoesters (14) have strong negative entropies of activation and it was suggested that the reaction involved rate-limiting attack of water on a carbonium ion which is formed re~ersib1y.l~

The hydrolyses of 2,2-dialkoxy-tetrahydrofuran and -tetrahydropyran have been shown to be general acid ~ata1ysed.l~

(14) (15)

There have been further quantum-mechanical calculations on stereoelectronic effects in the breakdown of orthoesters and related species.15

Authentic intermolecular SN2 reactions of acetals have been observed by Kirby and his co-workers.16 The compound studied was methoxymethoxy-2,4-dinitro- benzene and the nucleophiles included AcO-, F-, N3-, I-, CO,-, S,03-, H0,-, and HO-. The a-deuterium isotope effect (kH/kD) falls in the range 1.05 to 1.16. It is clear that considerable caution must be used in interpreting a-deuterium isotope in enzymically catalysed reactions of glycosides.

The spontaneous hydrolysis of 2-aryloxytetrahydropyrans has a p- value of 2.7.l’ The effect of metal ions on the rates of hydrolysis of the “Crown Ether Acetals”

(15) has been determined. The effects are slight when n = 0 to 3, but when n = 4


and 5 up to 11-fold rate decreases were observed, presumably as a result of cation binding.18

Halmann and his co-workers have reported further studies of the hydrolysis of phosphonated a~eta1s. l~

The acid-catalysed hydrolysis of p-nitrobenzaldehyde diethyl acetal in micelles of sodium lauryl benzoate has been investigated.20

The use of acetal protecting groups in nucleotide synthesis and their relative rates of hydrolysis have been discussed by Reese.21

Formation of acetals from exo,cis-2,3-dihydroxynorbornane and their sub- sequent equilibration has been studied.22 The three-membered cyclic compounds (16) have been synthesized and tested as substrates for the enzyme epoxide h y d r a ~ e . ~ ~

Ar$ X

X = CH,CO,, CF, CH,O, or F

(16)

NC MeQ:;e

Dithioacetals and oxathiolones may be cleaved by isopentyl nitrite via the S- nitrosyl compound.24 Electrochemical cleavage of 1,3-dithiones has also been in~es t iga t ed .~~

Anodic oxidation of 2,5-dimethylfuran in methanol in the presence of cyanide ion yields a mixture of cis- and trans-isomers (17). The interconversion of these in methanol which contained trifluoroacetic acid was studied and thought to proceed via the cyclic carbonium-oxonium ion.26

Cycloheptatrienone reacts with ethane-1,2-dithiol or propane-l,3-dithiol to yield the products of 1,2-annelation rather than the t h i ~ k e t a l . ~ ~

Other reactions that have been studied include photolysis of acetals,28 reaction of cyclic acetals with ozone,29, 30 homolytic isomerization of cyclic a ~ e t a l s , ~ ~ isomerization of 1,3-dio~olanes,3~ reaction of 1,3-dioxolanes with Grignard acid-catalysed hydrolysis of 2,4-disubstituted 1,3-dio~olanes,~~ hydrolysis of 2-(2,6-dichlorophenyl)-4,6-dimethyl-1,3-dioxane,35 thiolysis of cyclic a ~ e t a l s , ~ ~ neutral hydrolysis of 1,4-dioxaspir0[4,4]deca-6,9-diene-2,8-diones,3~ base-catalysed decomposition of l-(2-hydroxyphenyl)-2-phenyl-3,3-dimetho~ypropan-l-one,~* reaction of 3-methylbut-3-en-1-01 with f~ rma ldehyde ,~~ elimination reactions of acetals to yield vinyl ethers,40 acetal formation?' methanolysis of acetals,42 trans- ke t a l i~a t ion ,~~ hydrolysis of 1,2-O-alkylidene-ar-~-glucofuranoses,~~ acetal formation from 2-deoxyhexitols and aldehydes,45 the reaction of mannose with acetone,46 migration of the benzylidene group of methyl 3,4-O-(R)-benzylidene-P-~-ribopyranoside to yield methyl 2,3-O-(R)-benzylidene-P-~-ribopyranoside and the slower conversion of these compounds into their S - i ~ o m e r s , ~ ~ and condensation of meso- and 2~,3~-dimethylbutane-1,2,3,4-tetraol with f~ rma ldehyde .~~

Hydrolysis and Formation of Glycosides Non-enzymic Reactions The hydrolysis of sucrose in reversed micelles in benzene has been studied.50

It has been suggested that the thermal degradation of sucrose involves intramolecular nucleophilic attack by the hydroxyl group at C(l) of the fructosyl residue on C(2).51

The conformation of 1,3-dioxanes has been studied.49


Base-catalysed formation of 1,6-anhydro-P-~-glucopyranose from phenyl a-D-glucopyranoside has been studied.52 Equilibriu; constants for formation of 1,6-anhydropyranoses from aldoheptoses have been determined.53

The anomerization of 1,2-trans-glycofuranosides with Grignard reagents has been studied.=

Enzymic Reactions (a) Galactosidases. The amino-acid sequence of P-galactosidase from E. coli,

a tetramer of molecular weight 500 000, has been determined.55 Methionine 500 is the site of reaction of the active-site directed irreversible inhibitor, 19-D-galacto- pyranoxylmethyl p-nitr~phenyltriazine.~~

Inhibition of the P-galactosidase of E. coli has been investigated. Four classes of behaviour were found: (i) compounds that affected neither K , not V,,,; (ii) competitive inhibitors that modified K, but not V,; these bind to the free enzyme but not to the ES’ complex; (iii) non-competitive inhibitors that modify V, but not K,; these bind to free enzyme and ES’ complex; (iv) uncompetitive inhibitors that affect K, and V, but the ratio K,/V, remains constant; these bind to the ES’ complex only. It was concluded that there are two binding subsites. It was also shown that there is conformational change when an inhibitor is bound to the en~yme.~’

There have been investigations of the binding of phenyl 1-thio-P-D-galacto- pyranosides to the active site of @-galactosidase from E. cofiS and of the pH- dependence of the kinetic parameters for reactions catalysed by this enzyme.59

There has been a comparison of wild-type P-galactosidase from E. coli and a defective P-galactosidase from deletion mutant strain M 1 5.60

The reaction of glycerol with ~-galactal-Zd catalysed by the P-galactosidase from E. coli, to yield 2,3-dihydroxypropyl 2-deoxy-/3-~-galactoside, occurs by a trans-addition.61 2,6:3,4-Dianhydro-l-deoxy-~-talohept-l-enitol has been used as an irreversible

inhibitor for the P-D-galactosidase from E. c 0 1 i . ~ ~ The bind of Mn2f and Mg2+ to the P-D-galactosidase from E. coli has been

in~es t iga t ed .~~ (b) Glucosidases. Good evidence that an isozyme of the glycosidase from almond

emulsin, which catalyses the hydrolysis of p-D-galactosidase, P-D-glucosidase, and P-D-fucosidase, uses the same active site to do so has been reported by Walker and Axelrod.@ Thus D-glucosylamine, D-galactosylamine, and D-fucosylamine each acts as a competitive inhibitor against each substrate, and each inhibitor has the same Ki value for whichever substrate is used.64

It has been reported that (20) is a by-product of the hydration of D-glucal catalysed by P-glucosidase. It was proposed that the reaction involved ionization with loss of the 3-hydroxyl group of the glucal (18) to yield an allylic cation (19) which was attacked by 2-deoxyglucose, the main reaction product.65

H O d o H O

LdO CH,OH


6-Bromo-3,4,5-trihydroxycyclohexene-2-t oxide (21) is an irreversible inhibitor for the 13-glucosidase A from bitter almonds. Two peptides were obtained from the tryptic digest in which the inhibitor had become attached to different aspartic acid residues. It seems likely that the inhibitor binds in two different ways to the enzyme.66

(21)

The P-D-glucosidase isoenzymes B from sweet and bitter almonds have been compared.67

There have been investigations of the 13-D-glucosidase from Pyricularia oryeza.68 the undiced p-D-glucosidase from Stachybotrys a t r ~ , ~ ~ and of the P-D-glucosidases from baker's yeast,70 S. carl~bergensis,~~ and sugar beet seed.72

(c) Lysozymes. Details have been published of an investigation by Capon and his co-workers of the hydrolysis of 3,4-dinitrophenyl glycosides of chitin oligosaccharides and of modified chitin oligosaccharides catalysed by HEW lysozyme. In order for these compounds to be substrates, it is essential that the CH,OH group of the residue bound in subsite-D be unmodified; it was concluded that this residue must undergo an important interaction with the enzyme in the transition state and that there was no evidence of any distortion in the ground state of the enzyme- substrate complex.73

A PMR spectroscopic investigation of the bounding of the cell-wall trisaccharide NAM-NAG-NAM by HEW lysozyme indicated that the H( l)-H(2) coupling constant of the reduced NAM residue is unchanged when it is bound in subsite-D. It therefore seems probable that there is no formational change on bonding and hence little strain on bonding in s~bsite-D. '~

There have been several other investigations of HEW l y ~ o z y m e . ~ ~ An electron density map at 2.4 A resolution has been reported for lysozyme from

bacteriophage T4.76 There have been investigations on the lysozymes from Pseudomonas aerugi-

n o ~ a ~ ~ and Streptomyces e r y t h r a e u ~ . ~ ~ (d) Amylases and Glucamylases. Maltotrioses substituted at position 6 of the

non-reducing terminal glucose residue have been synthesized and tested as substrates for Taka-amylase A. They were hydrolysed to glucose and a modified maltose. The relative values of k,/K, for maltotriose and the 6-deoxy-, 6-chloro-, 6-bromo, and 6-iodo-substituted compounds were 1, 0.07, 0.24, 0.19, and 0.22, respectively; this suggests that the 6-hydroxyl group of the terminal non-reducing residue undergoes an important interaction with enzyme in the transition state but that 6-halo-substituents are also able to do this.79

The binding of substrates to Taka-amylase A has been determined by UV- difference spectroscopy.s0

D-Gluco-&lactone and maltobionic-S-lactone have been compared as inhibitors for amylolytic enzymes.s1

The hydrolysis of aryl 13-maltotriosides by sweet potato P-amylase has been investigated.82

Other enzymes that have been studied include the saccharifying a-amylase from


Bacillus subtilis,s3 a-amylase from Thermoactinomyces v u l g a r i ~ ~ ~ and porcine pancreas,a5 Taka-amylase A, 86,87 and the glucoamylase from A . niger.s8

(e) Cellulases. The steric course of the reactions catalysed by two exo-cellulolytic enzymes from T. viride has been determined. A p-glucosidase catalysed the hydrolysis of p-nitrophenyl /%D-cellobioside with retention of configuration and an exo-P-1,4-glucanase-hydrolysed cellopentitol with inversion of conf igu ra t i~n .~~

The cellulolytic enzymes from T. koningii have been inve~t iga ted .~~ (f) Other Enzymes. Other enzymes that have been investigated include p-D-

g1ucuronidase:l dext rana~es ,~~, 93 c~-~-mannosidases,~** 95 P-~-mannosidases,~~ or-L- a r ab ino fu ran~s idases ,~~~~~ / ? - ~ - x y l o s i d a s e s , ~ ~ ~ ~ ~ ~ exo-D-galacturonanase,10’ endo- galacturonanase,lo2 trehalase,lo3 and P-N-acetylhexo~aminidase.~~~

Hydration of Aldehydes and Ketones and Related Reactions Jencks and his c o - w o r k e r ~ ~ ~ ~ have made an important and detailed investigation of the breakdown of the hydrate and of some hemiacetals of formaldehyde (HOCH,OR). Plots of logk,, for the general base catalysed reaction against pK,,, are curves that are convex downwards. The fact that electron-releasing substitutents are rate-enhancing is strong support for a class n mechanism (equation l) rather than a class e mechanism (equation 2); if the reaction involved expulsion of RO-, as in the latter case, no such enhancement would be expected.

L

0 s - B

I R

0- OH

OR OR

/ / HzC, + B HzC, + 6H HzC~, 6 + - HzC=O + B + ROH

O...H...B ( 1 )

6+ O...H...B A 4 OH

OR ‘OR OH

OR OR ’0 R

HZC, 7 H,C, 8- - H,C=O + RO-+ HB+ H,C=O + B + ROH

6- (2) O...H...A

d 4

I I H H s+ OH

OH / /

HzC, + HA HK,+ A- T HzC~,g+ - H,C=O + HA + ROH

(3)

L 4 OH /

HzC, + HA HzC.. 6- - HzC=O + A- + ROH H,C=O

+ OR O.-.H.. .A R

HA + ROH

Also the class e mechanism would require some of the individual rate constants to be larger than the rate constant for diffusion. The general acid catalysed reaction may also proceed by a class e (equation 3) or a class n (equation 4) mechanism. The value of OL increases with decreasing pK, of the leaving group, i.e. aa/ - apKl, = 0.022. This is consistent with both mechanisms but the fact that kHIO+ for cleavage of formaldehyde methyl hemiacetal is 2600 times greater than for cleavage of formaldehyde dimethyl acetal strongly suggests that the removal of the proton has occurred or is occurring in the transition state for the former reaction. Therefore a class e mechanism is most likely. The water reaction appears to be a general base catalysed rather than a general acid-catalysed reaction.lo5

1 Reactions of Aldehydes and Ketones and their Derivatives 9

Young and Jencks have investigated the breakdown of substituted acetophenone bisulphite compounds (22) and of the corresponding a-methoxy-sulphonic acids (23). The latter compounds are hydrolysed with general acid catalysis and reaction is thought to involve partial proton donation to the leaving sulphite group. The breakdown of the corresponding bisulphite compounds (22) occurs only about

Op", X so,-

(22) (23)

six-fold faster than that of (23) and hence probably proceeds by the same mechanism and not by one involving proton abstraction from the OH group. The variation of a with substituent (X = p-MeO, a = 0.6; X =p-Cl, a = ca. 0.4; X =p-NO,, a = 0.31) is in the opposite sense to that found in the hydrolysis of benzaldehyde methyl phenyl aceta1s.lo6 These results and those for other reactions have been discussed extensively in terms of three-dimensional free-energy contour diagram^.^^',^^ An extensive investigation of the acid-catalysed addition of thiols to ketones in aqueous ethanol has been reported by Lamaty and his co- workers. The results were interpreted in terms of a rate-limiting attack of the thiol on the conjugate acid of the ketone with a relatively late transition state.log

The addition of methyl mercaptoacetate to acetaldehyde shows general acid catalysis but the plots of kobs uersus concentration of catalyst are curves that show a strong dependence of kobs on [catalyst] at low concentrations and a weak dependence at high concentrations. This behaviour suggests that there is a change in the rate-determining step with change in catalyst concentration. It was proposed that, at low concentrations of catalyst, the rate-determining step was trapping of the anionic intermediate (24) which is formed reversibly; at high concentrations of catalyst, formation of this intermediate was rate-determining. In addition, in order

H I

R S - C- 0- I

M e

,/ (24) H H A I

RS-C-OH I

"\ RS- + ,C=O ,

Me Me

to explain the weak dependence of kOb,[catalyst] at high concentrations, it was proposed that there was a general acid catalysed reaction that did not proceed via the anionic intermediate but involved attack of thiolate on the carbonyl group which was hydrogen-bonded to the catalysing acid.ll0~l1l

The rate constants for hydration of 1,3-dichloroacetone in reverse micelles of Aerosol-OT (25) were 1808 to 11 1 times greater than those in aqueous dioxan with the same molar concentration of water. This may arise from a difference in structure between micelle-solubilized water and water in the dioxan-water mixture and/or from general base catalysis by the sulphite head-group of the surfactant.l12

Benzils and ethyl phenyl glyoxylate are very effective inhibitors for chicken-liver esterases as a result of forming hemiacetals with the active-site serine. (E)-Benzil


mono-oxime 0-2,4-dinitrophenyl ether also forms a hemiacetal that undergoes a base-catalysed fragmentation by reaction with the enzyme.l13

Several investigations of solvent effects on the mutarotation of glucose and tetramethylglucose have been

Et

CH,CO,CH,LHBu” I

~ a + -0,s-CHCO,CH,CHBU” I

Et

(25)

Further work on the intramolecular catalysis of mutarotation of glucose 6-phosphate has been re~0rted.l~’

Base-catalysed ring opening of 5-thio-~-glucopyranose and 5-thio-D-xylo- pyranose has been studied118 by trapping the free thiol group with bis-(Cpyridyl) disulphide: it was found that base-catalysed mutarotation of these sugars is 500 times faster than ring opening as measured by this method; it was suggested that there is “a non-covalently bonded intermediate which can undergo ring closure to either a- or P-pyranose (thus causing mutarotation) without ring opening”.l18

The dimerization of tetramethylglucose and 2-pyridone in benzene has been studied by micro~alor imetry.~~~ The equilibrium between 2-hydroxypyridine and 2-pyridone has been investigated further.120

It has been shown by 13C-NMR spectroscopy that D-idose contains 1.6% of a septanose isomer.lZ1 Complexing of carbohydrates with molybdenum has been studied.122

A review123 on “Bifunctional Catalysis” and a monograph124 on “Ring-chain Isomerism” have been published.

Dimerizations of la~ta ldehydel~~ and 3-hydroxy-2,2-dimethylpropana1126 have been studied.

There have been several investigations of the hydration of aldehydes and ke t~nes ,~~’ - l~ l and MO calculations on the hydration of formaldehyde have been r e ~ 0 r t e d . l ~ ~ The chemistry of ninhydrin has been reviewed.l=

The carbonyl hydrate has been detected as an intermediate in the cleavage of dimethylacetylphosphonatelN (see Chapter 2). The cleavage of acylsilanes has been studied.135

A hemia~e ta l l~~ and a hemiacylaP3’ with the bicyclo[3.3. llnonane skeleton have been prepared.

Aldehydes have been shown to inhibit papain through formation of hemi- thioacetals with the active-site thiol group.13*

The reaction of formaldehyde with sodium sulphide has been studied.139

Reactions with Nitrogen Bases140 SchifS Bases Fife141 has extended his work on the hydrolysis of imidazolines to the 2-tert-butyl- N,N’-dimethyl and N-isopropyl-2-p-methoxyphenyl-N’-phenyl compounds (26) and (27). At low pH, the reaction to form compound (28) shows kinetic general acid catalysis and the reaction was thought to involve general base catalysis of the hydrolysis of the intermediate protonated Schiff base which is present at a small concentration. At high pH, there is a pH-independent reaction which may involve


either rate-determining water-catalysed or uncatalysed breakdown of an imidazoline or a hydronium ion-catalysed ring-opening of the imidazoline followed by a rate-determining hydroxide ion-catalysed hydrolysis of the Schiff base. The intermediate Schiff base could be detected in the hydrolysis of (27) was thought to be the N-alkyl compound (29) from its UV spectrum.141

Me

+J I

__f M e O o C H = N \ Pr’

The mode of breaking of unsymmetrical gem-diamines derived from formaldehyde has been studied. They were generated by reduction of the corresponding amidines with borohydride. Throughout the pH range studied (2-1 I), the preferred reaction was expulsion of the less basic amine.142

Pollack and his co-workers have reported further work on the hydrolysis of Schiff bases derived from cyclohexene- 1-carboxaldehyde and amin0-a~ ids . l~~

Cyclization of the imidoyl azide (30) to the tetrazole (31) is slow in inert solvents

Ph Ph \ \ Ph

\c-0 / / \

/c=O /c=*

N \ N p /c=N\

H-C H Hzc)-N/Et I \ \ .:

w\ N, Et

N, Et

(30) (31) (32) Ph

//C-OH \

H-C Et RNH-C=CHCOMe

\ / N=N

I Me

(34)

and in aqueous solution at neutral pH. It shows acid and base catalysis and at p H < 2 acid inhibition; this was explained in terms of stabilization of the diazo- form (32) by intramolecular hydrogen bonding at neutral pH. The base catalysis was thought to arise from proton abstraction which destroys the hydrogen bond and allows rapid isomerization into the reactive form (33); the acid catalysis was attributed to protonation of the nitrogen which disrupted the hydrogen bonding


and allowed rotation to occur. At high acidities, there was complete conversion into the conjugate acid which is unreactive.lU The rate-decreasing effect of the intramolecular hydrogen bond is an example of deceleration due to stabilization of the initial state by interaction with a neighbouring group, and it could be referred to as “anchimeric deceleration”.

The amine-catalysed eliminations of P-hydroxy- and P-acetoxy-ketones show large kinetic isotope effects ( k H / k D = ca. 5) when the axial a-proton is replaced by deuterium. It was estimated (by determining the deuterium contained in the product) that the preference for axial proton abstraction rather than equatorial proton abstraction from the intermediate Schiff base is greater than

The hydrolysis of N-alkyl- and N-aryl-4-aminopent-3-en-2-ones (34) has been investigated: above pH 2 , the rate-limiting step in the reaction of the N-alkyl compounds is base-catalysed attack of water on the substrate protonated at C(3); below pH 2, it is hydration of the carbinolamine. With the N-aryl compounds, base-catalysed attack of water on the protonated substrate is rate-limiting over the whole pH range.146

The effect of acid on the thermochromic system shown in equation 5 has been studied. Acid catalyses equilibration of the environments of the gem-methyl groups. This reaction involves ring opening to give the Schiff base (35) which

Me Me Me Me

11 Me Me

recyclizes. In addition, (35) is converted by a non-acid-catalysed pathway into its trans-isomer which is b1~e . l~’

Labelling experiments have demonstrated that the hydroperoxide formed on autoxidation of the Schiff base formed from 9-aminoanthracene and isobutyraldehyde undergoes base-catalysed decomposition in water-dimethyl sulphoxide via the dioxetan as shown in equation (6).Im

It appears that a-proton abstraction from the Schiff bases formed from pyridoxal and amino-acids is partly controlled by stereoelectronic factors; Schiff bases in which a C(a)-H(a) bond is orthogonal to the n-system are especially reactive.149

Pyridoxal 5’-phosphate reacts with mixed micelles of hexadecyltrimethyl- ammonium bromide and dodecylamine hydrochloride to form a Schiff base


which has similar spectral characteristics to the Schiff base formed by pyridoxal 5’-phosphate with glycogen pho~phory1ase.l~~

The rate constant for Schiff base formation with pyridoxal-pyruvate trans- aminase and 5-deoxypyridoxal is 1.79 x lo7 M-l s-l. It was suggested that the rate-determining step in imine formation is production of the ES c0mp1ex.l~~

There have also been investigations of the template effect in Schiff base forma- t i 0n ,1~~ Schiff base hydrolysis,153 the effect of micelles on Schiff base hydrolysis,154

Me

MG Me

/ A r N + g --+ A ~ N H + ~ ~ ~ + ArNHCHO -t o=c,

0-0 HO-0

( 6 )

H H

condensation of methyl benzoylpyruvates with aniline,155 alkaline hydrolysis of 3-(substituted phenylimino-~xindoles,~~~ hydrolysis of “Etazolate h y d r ~ c h l o r i d e ” , ~ ~ ~ reaction of a-amino-acids with phenalene-l,2,3-trione hydrate,158 reaction of acetyl- and formyl-ferrocene with acetone cyanohydrin and amines to yield FCCR(CN)NHC,H,R’,~~~ hydrolysis of methyl (a-acetoxybenzyl)nitrosamine,lm ketimine-enamine tautomerism,lel reaction of phthalaldehyde with ammonia and a r n i n e P and with thiols and primary a m i n e ~ , l ~ ~ transamination reaction between a-amino-acids and phthalaldehydic acid,164 reduction of a pyridoxal 5‘-phosphate Schiff base,165 pyridoxyl-catalysed y-elimination of a-amino-acids,166 and E-Z isomerization of i m i n e ~ . l ~ ~ , 168

Enamines There have been investigations of the protonation of e n a m i n e ~ , l ~ ~ l ’ ~ and of the reaction of cyclohexanone enamines with diacyl di-imides.l’l MO calculations on vinylamine have been r e ~ 0 r t e d . l ~ ~

Nucleosides Cordes and his co-workers have reported a-deuterium isotope effects for the hydrolysis of several nucleosides and related compounds. The a-deuterium isotope effects for the hydrolysis of unprotonated, monoprotonated, and diprotonated inosine and of deprotonated adenosine (kH/kD = ca. 1.2 in each case) were interpreted in terms of rate-limiting unimolecular decomposition^.^^^

The a-deuterium isotope effects for the hydrolysis of ,&NAD+ and p-NMN (1.103 and 1.1 35, respectively) also indicate unimolecular processes.174 However, the enzymically catalysed hydrolysis of p-NADf by the NAD-glycohydrolases from pig-brain and Neurospora crassa are 0.985 k 0.021 and 1.003 & 0.002, respectively, and it was concluded that, alternatively, (i) substrate binding to these enzymes is irreversible, (ii) C-N bond cleavage is not involved in the rate- determining step, or (iii) C-N bond cleavage occurs with participation of a nucleophile. Of these, (ii) was preferred and it was thought that a conformational change was the rate-determining step. In contrast, for the hydrolysis of /3-NMN catalysed by the same enzymes, the a-deuterium isotope effects are 1.132 and 1.100, respectively. With this substrate, therefore, there appears to be a different rate- determining step which is probably one involving formation of a carbonium ion.174

The phosphorylation of adenosine and inosine by calf spleen purine nucleoside phosphorylase was also studied. Conditions were used where the measured isotope effect was for binding of the nucleoside to the enzyme. Values of k,/k, = 1.04-1.05


were obtained and interpreted as arising from distortion of the ribose ring in bonding to the enzyme.175

Hydrazones, Oximes, Semicarbazones and Related Compounds The solvent isotope effect for the general acid catalysed reaction of p-methoxybenzaldehyde and methoxylamine varies from ca. 1 for catalysis by formic acid and cyanoacetic acid to ca. 3 for NCCH,CH,NH3+ and O(CH2CH2),NH2+, and is 2 for MeOCH,CH,CH,NH,+ and CH,CH,CH,NH,+. The results were interpreted in terms of a mechanism that involved rate-limiting protonation of the zwitteronic intermediate (36). In this process, it was proposed that the rate- limiting step changed from formation of the encounter complex with the strong

OH 0- H A ArCHO + CH,ONH, e, I + I +

Ar C -NH,OCH, A r c -NH,OCH,

(36)

acid to proton transfer with NCCH,CH,CH,NH,+ and O(CH,CH,),NH,+ and was starting to change to separation of the products with the weaker acids (cf. Ref. 177 and Chapter 2).176

The Brsnsted coefficient for catalysis by phosphonate buffers of the dehydration of the intermediate carbinolamine in semicarbazone formation from substituted benzaldehydes is independent of the substituent (a = 0.80 rt: 0.02; acv/aa = 0) and also the p-constant (- 1.9) is independent of acid strength (ap / - BpK,, = 0). On the other hand, the Bronsted a-coefficient increases as the leaving group becomes more basic; this apparent imbalance of the transition state has been discussed.178

The kinetics of the addition of nitrogen base to pyruvic acid have been studied by line-shape analysis of the PMR spectra of a flowing reaction mixture.179

The reaction of hydrazine with ethyl acetoacetate has been investigated by flow NMR methods. A time-averaged spectrum of the ethyl acetoacetate and carbinolamine was observed in addition to the spectra of the trans-hydrazone and 3- methylpyrazol-5-one which is the product of intramolecular displacement on the ester group by the NH, group of the hydrazone. The cis-hydrazone was not detected, so the trans-hydrazone must isomerize more rapidly than it cyclizes. In addition, cyclization probably takes place at the carbinolamine stage.lsO

The pH-rate profile for the formation of the phenylhydrazone of 2-hydroxy- acetophenone shows a plateau in the pH-range 5-7. Under these conditions, formation of the carbinolamine is rate-limiting but no general acid catalysis by external acids was detected. It was suggested that the reaction involved intramolecular general acid catalysis by the hydroxyl group of the phenol.181

The kinetics of both steps in the formation of pyruvate oxime have been measured by continuous-flow microcalorimetry.182

The 2,4-dimethylsemicarbazones of some aromatic aldehydes exist as ring forms in deuteriotrifluoroacetic acid.ls3

The imine (38) has been detected (13C NMR spectroscopy) as an intermediate in the Fischer indole synthesis of indomethacin (39) from the hydrazone (37).le4 Other investigations of the Fischer indole synthesis have also been d e s ~ r i b e d . ~ ~ ~ . ~ ~ ~

Other reactions which have been investigated include hydrolysis of a-nitrobenzaldehyde phenylhydra~onel~’ and of erythromycin oxime,ls8 formation of semicarbazones from heterocyclic ketones,189 iodine-promoted cyclization of


y, &unsaturated ketones,lgO reaction of ketoximes with phenyl i so th i~cyana te ,~~~ , lg2

condensation of o-phthalaldehyde with urea and thiourea,lg3 the Hoch-Campbell reaction,lg4 formation of pyrazoles from 4,4-dimethoxybutan-2-one and methyl- hydrazine,lg5 and the E-2-isomerization of azineslg6 and oximes.lg7~ 19*

CH,COOH

Meo*:e MeoQ N-N=C, , 4

CH,CH,COOH

M e NH I C

OH \Ar I

(37) Ar = p-CIC,H,

I C

0” \Ar

(39)

Hydrolysis of Enol Ethers In a further attempt to find an enol ether whose hydrolysis involves a rapid and reversible protonation, Kresge and ChwanglS9 have studied the hydrolysis of 1-cyclopropylvinyl methyl ether. However, hydrolysis of this compound showed all the characteristics of a reaction that involves a slow proton transfer (e .g . general acid catalysis and kHsO+/kDzO+ = 4.51). It was also shown that cis- and trans-2-arylvinyl ethers are not interconverted during hydrolysis;200 therefore, with these compounds too, the rate-determining step is protonation of the carbon- carbon double bond. It is interesting to note that it has been suggested that, under certain conditions, hydrolysis of ketene S-ethyl phenyl monothioacetal does involve the reversible proton transfer sought.201

An a-phenyl group has a smaller rate-enhancing effect in vinyl ether hydrolysis than an or-methyl group. This probably arises from the fact that the a-phenyl group is conjugated with the double bond and thus stabilizes the initial state as well as the transition state.202

The isotope effects of the hydronium ion catalysed hydrolysis of vinyl ethers have been discussed in terms of Marcus rate theory.203

Acid-catalysed hydrolysis of the enol ether (40) yields (inter a h ) compound (43). This was thought to be formed by protonation and bromine participation to yield the bromonium ion (41) which then underwent attack from the exo-face to yield the hemiacetal (42) which subsequently reacted with neighbouring methoxyl participation as shown,204

Tracer studies have shown that the biosynthetic enol ether cleavage of thebaine to form codeinone involves methyl-oxygen bond cleavage and not the normal type of enol ether hydrolysis.205

The reactions of cyclic enol ethers (including glycals) with organopalladium compounds have been studied.206


1

143) Mk

There has been an extensive investigation of the 13C-NMR spectra of vinyl ethers.207

Enolization and Related Reactions There have been reviews on “Bifunctional Catalysis of a-Hydrogen Exchange of Aldehydes and Ketones”208 and “Studies of Amine Catalysis via Iminium Ion Formation”.209

Details have been published of Bruice and Bruice’s demonstration that the enolization of oxaloacetic acid does not proceed by a concerted general acid general base catalysis.210 It was found that tertiary amines with pK,>8 show a special type of kinetic behaviour : the intercept of the plot of log k versus [Me,N] does not lie in the pH-rate profile, determined by using other buffers. It was proposed that these tertiary amines catalyse the reaction through formation of a carbinolamine (equation 7).210 Similar behaviour was reported for diethyl oxalo- acetate.211 The keto-enol tautomerism of oxaloacetic acid has also been investigated by PMR spectroscopy.212

OH I

I +NR,

0- 0 I II + NR, -OOC-C-CH,COO- ~ - 0 0 C - C - C H 2 C 0 0 -

-0OC- C- CH,COO- I +NR,

0- OH I c I

-OOC-C=CHCOO- 7 -OOC--C=CHCOO-

Enol pyruvate has been generated by the treatment of phosphoenol pyruvate with phosphorylase. Tritiated phosphoenol pyruvate yielded the triply labelled pyruvate in D,O. This was racemic when no other enzyme was present but was the (3s)-enantiomer when the reaction was carried out in the presence of pyruvate kinase. This was the same isomer as was formed in the presence of pyruvate kinase alone ; hence these results are consistent with the reaction, catalysed by pyruvate


kinase, proceeding via enol pyruvate since it was shown that pyruvate kinase catalyses the conversion of enol pyruvate into p y r u ~ a t e . ~ ~ ~

On the other hand, hydrolysis of Z- and E-phosphoenol-2-oxobutyrate by pyruvate kinase yields 2-oxobutyrate only in a stereoselective manner. It was suggested that protonation of the enol occurred partly through a non-enzymatic pathway.214&

It has been demonstrated that ionization of both enzyme and substrate con- tributes to the form of the pH-rate profiles for the interconversion of D-glyceraldehyde 3-phosphate and dihydroxyacetone phosphate catalysed by triose phosphate isomerase from chicken m u ~ c l e . ~ ~ ~ b

Phosphomannose isomerase, which catalyses the interconversion of D-mannose 6-phosphate and D-fructose 6-phosphate, uses p-D-fructose 6-phosphate as its substrate.214c

Enolization is the rate-determining step for release of p-nitrophenol from 4-(p-nitrophenoxy)butan-2-one and base ; the latter reaction is therefore easily studied with this substrate. Rate constants were measured for the reaction with 30 bases with pK, values 4.70 to 15.75; the Brarnsted plot, which was curved, was discussed in terms of a modified Marcus theory in which the curvature was ascribed to a variation of w,.215 Similar curvature was found in the reactions of pivalate esters.216

Carboxypeptidase A has been shown to catalyse deuterium exchange, presumably via an enol or enolate, of the substrate analogue 3-p-methoxybenzoyl-2- benzylpropanoic acid-3,3-d2 (44). This reaction was inhibited by i- -benzyl- succinic acid which is an inhibitor of hydrolyses, catalysed by carboxypeptidase A.217

As part of an extensive investigation of the volumes of activation of proton- and hydroxide-transfer reactions, Brower and Hughes2I8 have determined the volume of activation for dedeuteriation of acetophenone-2,2,2-d3 by hydroxide ion to be -1 ml mol-l. This result was interpreted in terms of a late transition state. The AV* for the Cannizzaro reaction was also determined. This was -27 ml mol-l which was thought to be made up of ca. - 12 ml mol-1 for the initial addition of HO- and of ca. - 15 ml mol-I for the transfer of H-.21e

(44) (45)

The a- to a'-rearrangement of a-halo-ketones may proceed by two mechanisms : (i) dehalogenation-rehalogenation, or (ii) via 2-hydroxyallylic cation (45). The former may be detected by carrying out the reaction in the presence of 2-naphthol which traps the halogen, and the latter by allowing a bromo-ketone to rearrange in the presence of HC1 when halogen exchange can occur. By using these and other tests, it was found that, in acetic acid containing anhydrous hydrogen chloride, 2,2-dibromocholestan-3-one rearranges by mechanism (i) ; on the other hand, l-bromobicyclo[5.3.l]undecan-ll-one and 1-chloro-1-phenylbutan-2-one rearrange by mechanism (ii). 1-Bromo-1-phenylbutan-Zone rearranges by both mechanisms.219


The effect of 18-crown-6 and of cryptand12.2.21 on the alkylation of potassium ethyl acetoacetate has been studied.220&

Hammett correlation of the acidities of m- and p-substituted acetophenones has been reported.220b

The rate of deuterium exchange of 4-substituted camphors (46) increases with increasing electron-withdrawing power of the substituent. The ratio of the rate constants for exchange at exo- and endo-positions decreases with increasing size of the substituent and a linear correlation was obtained between log k2-ero/k2-endo and the A-value of the substituent; this was rationalized in terms of a steric interaction between the substituent and deuterium oxide in the transition state for exo-protonation of the enolate anion.221a, Werstiuck and his co-workersB2lb have investigated deuterium exchange of norbornanones substituted in other positions ; they also found that the rate of exchange at the 3-exo-position is more sensitive to the substituent than that at the 3-endo-position; the plot of logk,,, versus logk,,,, has a slope of 1.67.221b

Proton exchange of norbornane-2,5-diones occurs over 100 times faster than that of the corresponding monoketones. This enhancement was attributed partly to inductive and strain effects and (by a factor of 13 to 32) to “homoenolic assis- tance”.222

a-Thioenolization of thiocamphor occurs faster than enolization of camphor as determined by deuterium exchange. The exo- and endo-rates are, respectively, 23.2 and 12.3 times faster for the thioketone than for the ketone.223

Twistan-4-one, i.e. tricycl0[4.4.0.0~~~]decan-4-one, undergoes exchange of one CH,CO 270 times faster than that of the other. Examination of models shows that one C-H makes an angle of about 90” with the double bond of the carbonyl group while the other makes an angle of ca. 30”; presumably the former undergoes rapid exchange and the latter slow exchange.224

The conversion of phenylglyoxal into mandelic acid is catalysed by glutathione, which forms a hemithioacetal, and a base. Reaction proceeds with proton abstraction from the hemithioacetal via an enediol intermediate.225

Yeast enolase is inactivated by butanedione through reaction with its essential arginine residue.226

Other enzymes investigated include muscle pyruvate k i n a ~ e , 2 ~ ~ yeast hexo- kinse,228 and A5-3-oxosteroid i ~ o m e r a s e . ~ ~ ~

Other reactions that have been investigated include photoenolization of croton- aldehyde,230 amine-catalysed ionization of dihydroxyacetone phosphate,231 isomerization of pentoses and 3-deoxyhe~oses,~~~ interconversions of glyceraldehyde and d ihydroxya~e tone ,2~~ ,~~ interconversion of D-glucose and D-fructose catalysed by sodium a l ~ m i n a t e , ~ ~ ~ epimerization of 2-acetamid0-2-deoxyhexoses,~~~ catalysis by 238 iodination of ace top hen one^^^^ and of pyruvic acid,240 base- catalysed enolization of ~yclopentanone,2~~ keto-enol tautomerism of d dike tone^,^^^ P- thio~o-ketones,~~~ phenol radical anion,244 and 3-acetyl-5-isopropylpyrrolidine- 2,4-di0ne,~~~ alkylation of e n o l a t e ~ , ~ ~ ~ and the gas-phase 1,3-hydrogen shift of the enol of acetic

MO calculations on keto-enol tautomerism have been reported.248

Homoenolization The interconversion of the ketones (47) and (48) through homoenolization occurs 100 times faster than with the saturated analogues.249 The compound (48) also

ORGANIC REACTION MECHANISMS 1978 · 2013. 7. 23. · ORGANIC REACTION MECHANISMS 1978 An annual...

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