Organic Reaction Mechanisms: An Annual Survey of Literature, 1995

ORGANIC REACTION MECHANISMS - 1995 ORGANIC REACTION MECHANISMS 1995 An annual survey covering the literature dated Dec...

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ORGANIC REACTION MECHANISMS - 1995

ORGANIC REACTION MECHANISMS 1995 An annual survey covering the literature dated December 1994 to November 1995

Ediied by

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

An Intersciencea Publication

JOHN WILEY & SONS Chichester . New York . Weinheim . Singapore . Toronto

copyright

0 1997 by John Wiley & Sons Ltd,

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Contributors 1. I. BILKlS

Institute of Biochemistry, Food Science and Nutrition, Faculty of Agriculture, The Hebrew University of Jerusalem, Rehovot 76 1 00, Israel Department of Chemistry, University of Warwick, Coventry, A. J. CLARK CV4 7AL, UK Department of Chemistry, Brunel University, Uxbridge, R. G. COOMBES Middlesex, UB8 3PH, UK Department of Chemistry, University of Toronto, 80 St. R. A. COX George Street, Toronto, Ontario M5S IAl, Canada M. R. CRAMPTON Department of Chemistry, University of Durham, Durham, DHl 3LE, UK N. DENNIS Australian Commercial Research and Development Ltd, GPO Box 248 1, Brisbane, Queensland 4001, Australia Dyson Perrins Laboratory, University of Oxford, South Parks G. W. J. FLEET Road, Oxford, OX1 3QY, UK Department of Chemistry, California State University, Fresno, J. R. GANDLER CA 97740-0070, USA Department of Chemistry, University of Newcastle upon Tyne, J. G. KNIGHT Newcastle upon Tyne, NEl 7RU, UK School of Applied Biological and Chemical Sciences, A. C. KNIPE University of Ulster, Coleraine, Co Londonderry, BT.52 ISA, UK Department of Chemistry, University of Leicester, Leicester, P. KOCOVSKY LEI 7RH, UK Departmcnt of Chemistry, University of Dundee, Dundee, A. W. MURRAY DD14HN, UK Department of Applied Science, RTC Tallaght, Dublin 24, B. A. MURRAY Ireland Department of Chemistry, University of Warwick, Coventry, S. M. ROOKE CV4 7AL, UK School of Chemistry, University of Hull, Hull, HU6 7RX, UK J. SHORTER Department of Chemistry, University College, Galway, Ireland W. J. SPILLANE

V

The present volume, the thirty-first in the series, surveys research on organic reaction mechanisms described in the literature dated December 1994 to November 1995. 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 hetcrogeneous 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 several changes of authorship since last year. We say farewell to Prof M. I. Page, Dr W. R. Bowman, Dr D. R. Coghlan, Dr S. W. Ginn and Dr J. H. Stewart, with thanks for their contributions over several years. Their places have becn filled by four authors who are new to the series: Dr B. Murray, Dr A. Clark, Dr S. M. Rooke and Prof I. Bilkis are welcomed as experts on ‘Reactions of Aldehydes and Ketones’, and on ‘Radical Reactions: Parts 1 and 2’, respectively. We regret that late arrival of a chapter caused some delay in publication, but once again wish to thank the 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.w. w.

vii

CONTENTS

.

1

Reactions of Aldehydes and Ketones and their Derivatives byB.A.Murray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Reactions of Acids and their Derivatives by W. J. Spillane . . . . . . . 3 Radical Reactions Part 1 by A . J. Clark and S. M. Rooke. . . . . . . . 4. Radical Reactions Part 2 by I . I. Bilkis . . . . . . . . . . . . . . . . . . . . 5 Oxidation and Reduction by G . W. J. Fleet . . . . . . . . . . . . . . . . . . 6 Carbenes and Nitrenes by J. G . Knight . . . . . . . . . . . . . . . . . . . . 7. Nucleophilic Aromatic Substitution by M . R . Crampton . . . . . . . . . 8. Electrophilic Aromatic Substitution by R . G . Coombes . . . . . . . . . 9. Carbocations by R . A . Cox . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Nucleophilic Aliphatic Substitution by J. Shorter. . . . . . . . . . . . . . 11 Carbanions and Electrophilic Aliphatic Substitution by A . C . Knipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Elimination Reactions by J. R . Gandler . . . . . . . . . . . . . . . . . . . . 13. Addition Reactions: Polar Addition by l? KoEovskf . . . . . . . . . . . 14 Addition Reactions: Cycloaddition by N . Dennis . . . . . . . . . . . . . 15 Molecular Rearrangements by A . W. Murray . . . . . . . . . . . . . . . . Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. .

. . .

. .

ix

1 35 91 123 181 213 231 249 259 279 303 337 363 399 439 555 593

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives B. A . MURRAY Department of Applied Sciences. Regional Technical College Tallught. Dublin. Irelund Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . . . . Hydrolysis of Glucosides and Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . Formation. Hydration. and Hydrolysis of Ketenes . . . . . . . . . . . . . . . . . . . . Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . . . .

Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . lminium Ions and Related Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oximes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrazones, Semicarbazones, and Related Species . . . . . . . . . . . . . . . . . . . C-C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . . . Aldol Rcactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tntramolecuiar Aldols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mukaiyama (Enolsilane) Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Benzoin Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General and Theoretical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Carbon Nucleophiles Containing N, Si, P, or S Substituents . . . . . . Addition of Amine Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Phosphorus Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hydrolysis and Reactions of Vinyl Ethers and Related Compounds . . . . . . . . Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 2 3 4 4 6 1 8 8 8

10 11

12 13 15 15 16 17

18 19

20 20 21 25 26 28 31

Formation and Reactions of Acetals and Related Species An a-diketonc acetal (1a) (cis- 1,6-dimethyl-2,5,7,l0-tetraoxabicyclo[4.4.0]dccanc) undergoes titanium chloride-mediated addition of allyltrimethylsilane diastereoselectively to give the corresponding meso.2,3.diallyl.2,3.dimethyl.l, 4.dioxane (1 b); the two successive substitutions involved are proposed to occur via SN2-like inversions stabilized through an anomeric effect in each case.’ Diastereoselective ring opening of cyclic acetals with hindered Grignards appears to depend on complexation of the magnesium to a remote substrate oxygen.2 Organic Reuctiun Mechanisms 1995. Edited by A . C . Knipe and W. E . Watts 0 1997 John Wiley & Sons Ltd

1

Organic Reaction Mechanisms 1995

2

Dipole repulsions-and not hyperconjugation-have been claimed as the cause of the anomeric effect in 2-methoxyazacyclohexanes,3abut this has been disputed in a theoretical conformational analysis:3bthe effects observed can be explained in terms of back-donation from lone pairs. A wide variety of ‘dimeric’ ring systems (2) have been synthesized from 2-naphthol and various dials, using Friedel-Crafts-type condensations and intramolecular acetali~ations.~ Examples include naphthofuronaphthofuran (rn = n = 0), the corresponding pyranopyran, methano- and propano-dinaphtho[ I ,3]dioxocins (m= 0; n = I , 3), and spiropyrans. Six- and seven-membered hemiperacetals (3; R = R’ = H, n = 2, 3) in HCI-MeOH yield peroxidic products with one, two, or three rings, while the corresponding peracctals (R = Me, R’ = H) give non-peroxidic products, as do persubstituted peracetals (R = R’ =Me), the latter showing skeletal fragmentati~n.~ The results are interpreted in terms of the competing protonation sites in the intermediates arising from each class. Cyclic aryl thioacetals (4) are hydrolysed in a silver-promoted reaction: with electronwithdrawing substituents, this occurs via a 1 : 1 complex, but the p-methoxy compound reacts via a species with two silver ions.6 Hydrolysis rates are > 104-fold slower than with the analogous open-chain species, partly due to lower basicity towards Ag+; the bchaviour is compared with the H+ catalysis. Hydrolyses of cyclic thioacetals of benzophenone and also of its cyclic and open-chain 0,O-acetals are all believed to proceed via an ASE2 me~hanism.~” In contrast, diethyl and diary1 thioacetals, Ph2C(SEt/Ar)2, react via A 1.7b The chemistry of the cr-thio carbocations involved, Ph,C+-SEt and Ph2-SAr, is described.

Fo

Me

OMe

(cH2$A R’ OR

%

CT

CONHL

\

R

HO

Het+

HO X

Hydrolysis of Glucosides and Nucleosides Enzymatic cleavage of glycosides often involves the formation of an enzyme-substrate complex, which is then hydrolyscd via an oxocarbenium ion-like transition state with

I Reactions of Aldehydes und Ketones and their Derivatives

3

acid-base catalysis. Thus, elucidation of the mechanism requires the identification of an active-site nucleophile and the appropriate acid-base residue(s). New methods are described for these tasks, involving a mechanism-based inactivator, and kinetic analysis of candidate acid-base amino acids chosen on the basis of sequence similarities, respectively.' Hydrolyses of (2-deoxy-/?-~-glucopyranosyl)-pyrid~nium and 4soquinolinium salts ( 5 ) in water show first-order rate constants which are independent of pH from 4.4 to 10.1.9aBased on measurements with acetate, halide, and azide, the reaction shows no sensitivity to the nature of the anion. The possible mechanisms are discussed in detail and evidence for the glucopyranosyloxocarbenium ion as a viable intermediate is presented. Its lifetime in water is calculated at > 2.5 x s, slightly higher than the estimate of I x s extrapolated from experimentally measured lifetimes of acyclic oxocarbenium ions.9b The effects of 2'-substitution of the ribofuranosyl ring on the chemical and enzymatic cleavage of the nicotinamide-ribosyl bond for a series of P-NADf analogues (6; X = H, NH2, OH, N3, F; R = H , ADP, 1,p-etheno-ADP) suggest the involvement of the functional equivalent of a diol anion."

Formation, Hydration, and Hydrolysis of Ketenes Rapid, shock wave-induced heating of acetonitrile to 1400-1700 K under pressure gives ketene imine, H2C=C=NH." Ab initio calculations suggest that the ratedetermining step for the reverse reaction is a 1,2-hydrogen transfer from nitrogen to produce vinylnitrene. Acid-catalysed hydration of bisketene (721) shows two steps: rate-determining protonation of Cg, to give an acylium ion, which then reacts with water to give the (monoketeny1)acetic acid (7b),'2a previously proposed as an intermediate in the neutral hydrolysis of (7a). '2b Ring closure then gives cis- and truns-2,3-bis(trimethylsilyl)succinic anhydride (7c). Ab initio calculations for (7a) and the unsubstituted bisketenc clarify the role of the silyl groups in favouring electrophilic attack at C,, as opposed to C,.

The question of the reversibility of the hydration of ketenes to carboxylic acids appears to have been settled by diarylketenes incorporating "0-label from solvent, as shown by NMR, IR, and MS.13 A symmetrical species (with respect to the oxygens) is formed: it is presumed to be the 1,l-enediol; build-up of the acid follows: Ar2C=C=O

Ar2C=C(OH),

4

--t

Ar2CHC02H

Organic Reaction Mechanisms I995

4

Reversibility is seen not only with bulky aryl groups (Me.& 2,4,6-PGC6H2)which stabilize the two ene species relative to the acid, but also for diphenylketene. Inductive and steric effects in hydrolysis of monoalkylketenes have been quantitatively estimated; increasing length and branching of the alkyl group decrease the rate. l4 Kinetics of spontaneous hydrolysis of dialkylketenes in water-acetonitrile shows a sharp decrease in hydration rate connected with a significant non-additivity of substituent effects.'' Formation and Reactions of Nitrogen Derivatives Imines Formation of Schiff bases of pyridoxal 5'-phosphate and polyallylamine proceeds via an ionized carbinolamine which is deprotonated in the rate-determining step, followed by dehydration.16 2-Acetylcycloalkanones of ring size from 5 to 8 have been condensed with simple diamines to examine the preference for Schiff bases with a ring vs a sidechain carbonyl;17 the results are explained on the basis of whether the product enaminone has an endo-double bond (six-membered ring) or two exo-double bonds (five-, seven-, and eight-membered rings). A novel Mannich-type reaction for synthesis of p-amino ketones involves combination of an aldehyde, amine, and vinyl ether in aqueous solution by the action of a lanthanide triflate." The mechanism is proposed to involve initial imine formation followed by combination with the vinyl ether and subsequent hydration to give a pamino hemiacetal. Lithium and zinc dienolates of 3,4-unsaturated carboxylic acid esters give two reactions with imines R'CH=NR2 (R' = 2-Py, Me3SiC-C, R2 = Ph, CHMePh): (i) a kinetically controlled a-coupling (at - 78 "C) to give P,y-unsaturated-$-amino esters, and (ii) a thermodynamically controlled y-coupling (at - 20 "C) to give (E/Z)-a,Punsaturated-E-amino esters.'' The a-coupling product can cyclize to give a P-lactam with a pendant alkene, while the (Z)-y-product can cyclize to a 5,6-dihydropyridin-2one; some of the reactions show high asymmetric inductions. Six-membered cyclic transition states involving a zinc enolate or allylzinc species, respectively, are proposed. 1,2-Asymmetric induction in the addition of n-butyllithium to imine (8; R = SiMe3) (to give the syn- and anti-amines) shows large solvent and temperature dependences, e.g. a switch from a ratio of 28 : 72 at - 90 'C to 78 : 22 at 54 "C, in hexane.20An extension of existing models to incorporate such effects is proposed. At least two selection steps are involved. At low temperature, the stereoselectivitymay be controlled by lithium chelation. N-Substituted lactaldehyde imines (8; R = alkyl) are cyanosilylated to a-aminonitriles (9a, 9b) with syn-diastereoselectivity, regardless of the nature

? OSiBu'Me2

NR

OSiBu'Mel &CN

-

NHR

1 Reactions of Aldehydes and Ketones and their Derivatives

5

(or presence) of Lewis acid catalyst;” it is suggested that silicon coordinates the imine nitrogen. 2-Methyl(benzylimino)cyclohexane (10a) reacts with a$-ethylenic carbonyl compounds to give cyclized adducts with excellent diastereoselectivities.22The reaction is a Michael-type addition via the enamine tautomer (lob), with a chair-like transition state. Use of the (a-1-phenethylamine imine (11) makes it enantioselective as well.23

Schiff bases of 1-tetralone (12a) react with acid chlorides to give spiro-annulated blactams (12b) stere~selectively.’~ N-Benzylideneamino-ethanolsand -propanols undergo a cyclization via an N-bromoiminium cation (13a) to give oxazoles/oxazines (13b).25On lithiation, heteroarylchloromethanes add cleanly and diastereoselectively to imines to give heteroarylaziridines via a Darzens-type reaction.26

R

Ar

Asymmetric hydrogenation of imines catalysed by a chiral titanocene” involves the imine reacting with a titanium hydride in a fast 1,2-insertion step to give titanium amide, which is then slowly hydrogenolysed to amine and regenerated hydride. Mechanisms for the hydrolyses of methyl derivatives of salicylanil in acidic, neutral, and basic media are discussed in terms of steric, electronic, and pK, effeck2* Hydrolysis of N-(2/4-hydroxy)benzylidene-2-aminobenzothiazoles in micro-emulsions has been studied over a wide pH and the rate of acidic hydrolysis of diimines, (RPhCH=N)2(CH2),, in micelles depends markedly on the value of n and the position of the cetyloxy R group.3o Thermochromic reactions of salicylideneaniline and related compounds involve proton transfer between hydroxyl oxygen and imine nitrogen via a six-membered transition state.31

6


Iminium Ions and Related Species f

A series of N-aryliminium ions, ArN(Me)=CH2 (Ar = C6H4X), has been generated in aqueous solution from the solvolysis of the corresponding anilinothioethers, ArN(Me)CH2SR.32Exploiting common-ion inhibition, rate constants for the hydration of the iminium ions were measured, thus affording lifetimes for the cations, varying from 10 ns (X=p-nitro) to 320 ns (X=p-chloro). The dependence of the solvolysis rate on the pK, of the thiolate leaving group yields a value of - 0.93 f0.09 for &, indicating a very late transition state, consistent with a diffusion-controlled cationanion encounter in the reverse direction. The late transition state for cleavage of the C-S bond also involves a large amount of donation from nitrogen: Pdg,= - 0.79 -f 0.06. The significance of the results for the possible intermediacy of an iminium cation (14) in the reaction of N5,N1'-methylenetetrahydrofolate with dUMP to give dTMP is discussed. The method has been extended to produce a simple f alkyliminium cation: CF3CH2N(Me)=CH2 has a lifetime of 55 ns in water.33

+

The lifetime of an a-phenyl-N-nitrosiminium cation, PhCH=N(NO)Me, and its selectivity towards various nucleophiles have been measured directly in aqueous solution.34 Laser flash photolysis of the a-(4-cyanophenyl) ether was used to generate the cation, which has a half-life of about 600 ns in aqueous solution (pH 11, 25 "C). The second-order rate constants for reaction of the species with azide and thiolate nucleophiles are just below the diffusion limit; other values (dm3 mol- s- ') include 2 x 10' (hydrazine), 2 x lo7 (cyanide), 2 x lo7 and 2 x lo6 (hydrogen- and dihydrogen-phosphate), and lo4 (water). Diastereoselective addition of trimethylsilyl cyanide to nitrone (15a) yields syn-ccaminonitrile (15b), useful for making a-amino acids;35 Et2A1CN may be an intermediate. The Westphal condensation of an a-methylcycloiminium ion (16a; X = e.g. C-C02Et or N) with (typically) a symmetrical diketone, RCOCOR, gives a quaternary ammonium bridgehead system (16b). Using the unsymmetrical 1-arylpropane-l,2diones, the regioselectivities are explained in terms of kinetic vs thermodynamic control.36 The latter has the more conjugated intermediate, and is favoured by nexcessive aryls in the diketone. The stereochemical course of the reduction of iminium ions at a bridgehead position, e.g. (17), is examined in terms of its conformational preferences and of the relative steric demands of the two reagents used viz. sodium cyano- and triacetoxyborohydride~.~

'

'


7

The use of an iminium chloride to aminomethylate furan has been compared with the conventional Mannich reaction between ammonia, formaldehyde, and furan, the latter under both neutral and acidic conditions (i.e. H2NCH20Hand H2NCH: as immediate reactant).38 The first two proceed through activated complexes with a four-membered ring structure, with calculated activation energies of 205 and 342 kJ mol-', respectively. In contrast, the acid-catalysed route involves a pronounced product-like transition state which is non-cyclic and has the lowest activation energy (1 13 kJ mol- '), apparently arising from a favourable orbital match on the bondforming carbons. If h a n is replaced with ethylene as the pseudo-acid component, similar results with the same energy order are obtained.39 Oximes

Thermolysis of aryl ketoxime arenesulfonates in refluxing tetralin yields a wide range of products arising predominantly from radicals formed via homolyses of the N-0 and S-0 bonds.40 The substrates also undergo isomerization to imidosulfonates: PhC(R)=NOSOxAr

-+

PhN=C(R)OSOzAr

This proceeds via a 1,2-phenyl migration followed by rearrangement, and leads to amide products. Photolysis gives results similar to thermolysis. A new catalytic method for carrying out Beckmann rearrangements in solution uses tetrabutylammonium perrhenate and trifluoromethanesulfonic acid in a variety of solvents under azeotropic reflux:' the oxime perrhenate (18a) is proposed as intermediate. The optimum solvent is nitromethane, which may favour the reaction by formation of an aci-nitro derivative (18b). Using hydroxylamine hydrochloride, the method has been extended to a one-pot synthesis of lactams and amides from ketones. An unusual ring-opening reaction of tropone' oxime tosylate (19a) by a range of N-, 0-,and C-nucleophiles gives exclusively and stereoselectively 6-substituted (Z,Z,Z)0+/ H;?C N

0 II ,0-Re=O II 0

.

(18a)

d \

-

(18b)

Tsol


8

1,3,5-hexatriene~arbonitriles~~ (19b). Labelling and substitution experiments show that the nucleophile attacks the a-carbon anti to the tosylate. A nitrene intermediate (i.e. N-0 fission before C-C fission) appears to be ruled out by the failure to trap it, and reaction-path calculations favour a concerted route much lower in energy than reaction via the nitrene. Kinetics of aminolyses of N-(2,4-dinitrophenyl)camphor oxime by cyclohexylamine and piperidine have been measured in aqueous a~etonitrile.~~ Mechanisms of cyclo-condensations of aldehydes or ketones with o-aminophenyl ketoximes and aldoximes to yield a variety of quinazolines, oxadiazolines, and aminoindoles have been analysed by molecular-orbital calculation^.^^

Hydrazones, Semicarbazones, and Related Species Reaction of phenylhydrazine with 5-substituted furfurals shows familiar ratedetermining carbinolamine formation at pH < 5, with a switch-over to dehydration of the carbinolamine at higher pH.45 Base-catalysed dehydration is reported for the 5nitrohhral derivative. Acid hydrolysis of phenylhydrazono esters derived from diethyl malonate and ethyl aceto- and cyano-acetates yield half ester, diacid, and reactant, re~pectively.~~ 4-Aminopent-3-en-2-one and its N-aryl analogues (20) couple with benzenediazonium salts at C(3);47 in some cases, the kinetics are independent of both pH and buffer. Substitution in both rings gives linear Yukawa-Tsuno plots. The rate-limiting step is either reactant combination, or else proton loss from C(3) of the intermediate. The possible tautomers and isomers (hydrazo vs azo; intramolecularly hydrogen-bonded species) are also discussed.

p% fA --r

X 0

Me N-N L N H A r '

-

Me Ar

H O

N-N

I

Ar'

Benzaldehyde semicarbazones (21a) are selectively cyclized to 1,2,4-triazolin-5-ones (21b) by copper(I1):' the corresponding oxadiazole system is not formed. The reaction is accelerated by electron-donating substituents, and mechanistic alternatives are discussed. A 1 : 1 substrate-oxidant complex is proposed to account for the kinetics of the oxidation of acetophenone semicarbazones by peroxodisulfate in aqueous acetic acid.49

C-C Bond Formation and Fission: Aldol and Related Reactions Aldol Reactions The use of an 'ansa chain' across a pyridine ring to bring about chiral induction in a pyridoxal/pyridoxamine model has been known for some time: (22a; X = CH2NH2,

1 Reuctions o j Aldehydes and Ketones and their Derivatives

9

R = H) enantioselectively transaminates keto acids in the presence of zinc(II).So"'h Surprisingly, the enantioselective C-protonation to give the amino acid took place from the apparently more hindered side-chain side of the pyridine. The intermediacy of a zinc dimer with the open faces mutually blocking each other was invoked. This type of model has now been used for the enantioselective aldol condensation of glycine with acetaldehyde to give threonine and allo-threonine, using a pyridoxal with pendant amino groups in the chain (2223; X = CHO, R = SCH2C6H4CH2NMe2).50c At low pH the catalyst is enantioselective,with protonation again coming from the bulkier side, but not apparently due to zinc complexation on the open side. And at high pH, the enantioselectivity reverses as the pendant ammoniums deprotonate. The reaction on the (apparently) bulkier side is explained by a stereochemical argument involving puckering of the pyridine ring (22b).

A number of studies of asymmetric aldol reactions involving en01 borinates are reported. A computer model combines an a b initio transition state 'core' (where bonds are being made and broken) with a molecular-mechanics treatment of the rest of the system, i.e. the parts which provide the steric and electronic effects necessary for stereo~electivity.~'This has then been used to develop chiral boron enolates which diastereoselectively add to chiral a-amin~aldehydes.~' Ethyl N-benzyl-N-methylglycinate, PhCH2N(Me)CH2C02Et,gives moderate to good syn-selectivity in reaction with aldehydes to give a-amino-B-hydroxy esters.53 When complexed with boron [i.e. PhCH2h(Me)(BH3-)CH2CO2Et], good to excellent anti-selectivity is achieved. The cause of this complementarity appears to be an equilibration in the boron adduct case (to give the most stable product) vs chelation control (in the lithium enolate) in the case of the free amine, which prevents equilibration. The development of an aldol reaction between lithium enolates of difluoro ketones and non-enolizable aldehydes, to give difluoro aldol adducts in one step, depended on the recognition of the effect of the low nucleophilicity of the difluoro e n ~ l a t e s . ~ ~ 3-Methylpiperazine-2,5-dione derivatives (23a; R = Me) and (23b; R = CH'Ph) participate in stereoselective aldol reaction^;^"^^ (23a) also undergoes stereoselective acy~ations.~' A conference report describes the use of chiral chelated lithium aniides, e.g. (R)-(24), for deprotonation of prochiral cyclic ketones in a variety of reaction types. Stereochemical mechanisms have been developed based on the solid and solution stn~ctures.~~


10

(23a b)

(24)

Aldol reactions are included in reviews of tin(I1) enolates5*(220 references) and of lanthanide and scandium triflate catalysis in aqueous solution59(38 references).

Intramolecular Aldols The absolute and relative electrophilicities of the carbonyl group towards an enolate have been determined.60a Substituted benzaldehyde (25a) has a pendant acetone function which can form an enolate anion (25b), setting up formation of the aldol(25c); subsequent fast steps yield P-naphthol. C-Protonation of the enolate to give back (25a) competes with the cyclization, and was measured by deuterium exchange. Exploiting saturation kinetics with a quinuclidine buffer (due to a switch in rate-determining step from bufler-catalysed enolization to uncatalysed cyclization), the rate constant, k,, for cyclization was found to be 1.6 x lo6 s-'. This compares with a recent estimate of 1.4 x lo6 s-l for aldol adduct formation from benzaldehyde and acetone enolate.60b The carbonyl group of (25b) is a stronger electrophile than water, but weaker than tertiary ammonium ions of pKBH< 13.2.

Evidence for bifunctional acid-base catalysis of an intramolecular aldol condensation by P-cyclodextrins bearing two imidazole groups is seen in a modest rate increase over the control monoimidazolyl or unsubstituted cyclodextrins.61a The reaction is stereoselective, but with only slight enantio-induction: apparently the imidazoles are not optimally placed, compared with other reactions61b3c for which this catalyst has been used. The 1,4-dicarbonyl sugar (26a) has been converted into the enone (26b) via an intramolecular cyclopenta-annulation;" an X-ray crystal structure of the enone is reported.


11

A stereo- and regio-selective synthesis of the A-ring of taxol has been achieved by means of an intermolecular aldol addition and an intramolecular aldol condensation.h3

Mukaiyama (Enolsilane) Aldol Reactions In the Lewis acid-catalysed Mukaiyama aldol and Sakurai allylation reactions, silyl enol ethers and allylic silanes, respectively, couple with aldehydes or ketones (see Scheme 1) to give p-hydroxy ketones and y-hydroxyalkenes, respectively (in silylated form). Acetals and orthoesters can replace carbonyl substrates in both reactions.

SCHEME 1

A possible solution to several conhsing and contradictory claims of enantioselective catalysis is provided by a careful study of three new ‘catalysts:’ T ~ ( C P ) ~ ( O T ~ ) ~ , Ph3COTf, and Ph3CC104.64Trace amounts of water hydrolyse them to produce acids which in turn react with silyl reactant to produce ‘Me3Si+’species, i.e. Me3SiOTf and Mc3SiC1O4. These are the actual catalysts, and the rate and stereoselectivity is dependent on counterion concentration; it is also suggested that this situation pertains in many other systems, as dehydration of the solvent or quenching of the acid produced does not necessarily prevent the formation of these catalysts. Ways of obviating the presence of such species are discussed; many of the successful catalysts and strategies in the literature, it is claimed, work because they contain features which prevent or minimize the incursion of Me3SiX catalysis. A ‘supersilylating agent,’ R3SiB(OTf)4,65aprepared from trimethylsilyl and boron triflates, has been used to achieve high levels of Cram-type stereoselectivitybShin the aldol addition of acetophenone silyl enol ether, PhC(OSiR3)=CH2, to 2-phenylpropanal (27) and 3-phenyl-2-methylpropanal(28). A bulky R group on the silicon is essential for selectivity, though whether it extrts its effect in the silyl ether itself, or in the likely silyloxonium intermediate, R’CH=O-SiR3, derived from combination of catalyst and somewhat hindered silyl triflate, Pr‘’ SiOTf, is interesting in the light of the catalysis by MeXSiOTf reported above.64 The simplest case of the uncatalysed Mukaiyama aldol, addition of enol silane (29a) to formaldehyde to give 3-(silyloxy)propanal, has been studied by ab initio methods.6h

12


The s-cis conformation of (29a) with silicon overlying the double bond is the most stable. A boat-like transition state (29b) was located: the new C-C bond is substantially formed with Si-0 bond breaking and making proceeding asynchronously. The driving force is suggested to be the nucleophilicity of the enol, rather than carbonyl activation by silicon. While an a-stereogenic centre is typically the major determinant of enantioselectivity in nucleophilic addition to carbonyl groups, a series of aldol and allylstannane addition reactions show significant (and sometimes dominant) effects from fi-alkoxy s ~ b s t i t u e n t s ;the ~ ~ cases involved do not arise due to chelate organization. In an attempt to combine the Felkin-Ahn model for a-alkyl substituents with the corresponding 1,3-asymmetric induction model, it is proposed that additions to aldehydes are highly stereo-regular if the a-alkyl and P-alkoxy substituents are in the anti-diastereomeric relationship (i.e. they are mutually reinforcing in their effects), while syn-aldehydes will undergo anti-Felkin addition with dominant stereo-control emanating from the more remote fi-heteroatom substituent. Aldol reaction of (a-0-silylketene-0,s-acetal (30a) (derived from 2-pyridyl thioesters) with benzaldehyde gives enantiomeric fi-hydroxy thioesters6' (30b). The 2-mercaptopyridyl group has several advantages: it is a good leaving group and the sterically demanding pyridine can also coordinate to Lewis acids to give stereo-control. The latter indeed appears to be realized in the switchover from mti- to syn-selectivity on changing from BF3 to Tic& mediation of the reaction, and a switch back occurs when phenyl replaces pyridyl.

Miscellaneous Aldol-type Reactions Molecular-orbital calculations are used to assess an aza-aldof9 (a nitrogen analogue of the boron-mediated aldol reaction) in which an enaminyl borinate forms an ate complex with the aldehyde, which then rearranges to form the new C-C bond via a cyclic transition state. Theory and experiment give disappointing results, apparently because the nitrogen lone pair reduces the Lewis acidity of the boron, a conclusion which should facilitate improvements.

I Reactions of Aldehydes and Ketones and their Derivatives

13

Enantio- and diastereo-selective aldol addition of boron enolates of substituted acetic acids [i.e. R1(R2)C=C(OBL,*)2; L* = isocaranyl] to benzaldehyde yields the corresponding j-hydroxycarboxylic acids,70 PhCH(OH)CR'(R2)C02H. Titaniummediated aldol-type reactions of acetate thioimide enolates with aldehydes proceed with .n-facial differentiation via chelation control to give enantio-pure P-hydroxycarboxylic acids.71 The asymmetric aldolization of the acetate enolate of a chiral carbonyl compound with aldehydes has been achieved with an achiral Lewis acid.72 aSubstituted serines have been prepared dia~tereoselectively.~~ Modifications of mesoporous sieve MCM-41 have been used as acid-base catalysts of aldol and Knoevenagel condensations, Michael addition, and an acetali~ation.~~ Cyclic j-keto esters (31) are converted stereoselectively into cycloalkenones (32) by a y-arylidenation with aldehydes.75 Requiring DBU (1,8-diazabicyclo[5.4.O]undec-7-ene)and methanol, the reaction is initiated by a reversible a-aldol process to give an enolate anion, which reacts irreversibly with aldehyde, followed by dehydration.

6-Aminocaproic acid catalysis of ethyl 2-cyanoacrylate formation from formaldehyde and ethyl cyanoacetate involves rate-determining dehydration of HOCH2NH(CH& CO~H.~~ The Benzoin Condensation In an investigation of antihydrophobic effects, the proportion of aromatic surface shielded from the solvent in the transition state (relative to the totally exposed reactants) has been probed by correlating the effects of co-solvent on rates and s o l ~ b i l i t i e sWith .~~ water as solvent, ethanol lowers the free energy of reactants more than that of the partially stacked transition state, slowing the reaction. The results are related by log(k0lk) = hXlog(S/So), where the subscript refers to pure solvent, S is the solubility, and h is a function of the hydrophobic surface which becomes inaccessible in the transition state. The value of h was found to be ca 0.15-0.20 for 10-20% addition of small alcohols/diols, corresponding to a 3 0 4 0 % coverage of a face of each phenyl group. The mechanism of benzoin condensation catalysed by 3-benzyl- and 3-methylthiazolium ions has been studied in KOBu'-DMSO.'* 2-(a-Hydroxybenzyl)thiazolium ion (33) forms and is stable for long periods, but is converted into benzoin on addition of a trace of protic solvent. The role of this species in the mechanism (together with additional information from '3C-labelled thiazolium and 'H-labelled aldehyde) is discussed. The bis(thiazo1in-2-ylidene) (34) was virtually ruled out as the reactive species which condenses with the aldehyde. However, a kinetic study in the same


14

medium79aclaims that (34) is the authentic catalytic species; it is implicated by the finding that the kinetics are second order in both benzaldehyde and thiazolium cation, contrary to the original Breslow proposal.79b

Thiamine (35) promotes reactions occurring via acyl carbanion equivalents through the formation of (33); in weakly alkaline solutions, (33) can revert to (35) and benzaldehyde. However, under neutral or acidic conditions, the intermediate is 'diverted from catalysis' into an irreversible fragmentation to a pyrimidine (36a) and a phenyl thiazolyl ketone (36b). As the conditions implicate pyrimidine protonation, the N"methyl analogue of the intermediate was prepared and found to hydrolise at all pH values; in D20, the newly formed methyl group in pyrimidine product (36a) had incorporated a deuteron.80 The mechanism involves C(2a)-deprotonation of the substrate to give an enolimine, which tautomerizes to the ylide-like enolate (37), which finally undergoes C -N fission with proton transfer across the (breaking) bond. Me

Me

y 3 2

(35)

.OH


15

N,”-Disubstituted o-phenylenediamines catalyse the benzoin condensations of Nalkylbenzimidazolyl- and benzothiazolyl-aldehydes and hrfiual, via a radical mechanism.81

Other Addition Reactions General and Theoretical In an ub initio calculation of the intrinsic (gas-phase) hydride affinities of carbonyl compounds,82XYCO (X,Y = H, Me, NH2, OH, F), relative hydride affinities, AHRHA represent the enthalpy difference between the following reactions:

XYCO H2CO

+ H+ H-

XYCHO-+ CH30-

--+

Alternatively, they can be viewed as the difference between the isodesmic reaction: XYCO 2CH3 -H HzCO CH3 -X CH3 -Y AHco

+

-+

+

+

and the corresponding reaction for the alkoxide (AHCHO). Significant findings include the following: (i) isodesmic enthalpies are additive: i.e. A f f ~ o ( x Y C 0 = ) AHo(HC0X) AHo(HC0Y)

+

except when both substituents are from the set (NH2, OH, F); (ii) the alkoxides all show such additive behaviour; (iii) electron-withdrawing substituents stabilize both carbonyl groups and alkoxide ions, but stabilize the latter more: this observation conflicts with the more simplistic statement that ‘electronegative atoms activate carbonyl toward nucleophilic attack‘ found in many introductory textbooks; (iv) AHco correlates with charge on oxygen, and the charge on the alkoxide carbon correlates with AHCHO, the latter in an additive fashion; and (v) AHco does not correlate with the bond length of the carbonyl. Other carbonyl systems (a$-unsaturated, cycloalkanones, Lewis acidcomplexed formaldehyde) are also studied. Calculations of nucleophilic additions involving intramolecular proton transfer have been compared and contrasted in the gas phase and solution.83 To rationalize a number of apparently contradictory results in 1,2-asymmetric induction reactions, three rules, supported by model calculations, have been proposed.84 First, in weakly interacting systems the best transition state derives fiom the most stable ground-state conformation of the reactants (rule 1). Second, the best transition state for frontier-controlled reactions has the strongest acceptor anti to the incoming nucleophile (rule 2). Third, the best late transition state derives from the most stable conformation of the product (rule 3). Thus rule 1 requires that the substituents are poor acceptors, while rule 2 may not be obeyed in charge-controlled reactions. If the ‘best’ acceptor is not a sufficiently good electrophile, rule 2 may also be violated: for example, when a methyl competes with hydrogen for the anti position, the results sometimes suggest that the methyl is the ‘smaller’ substituent. The influence of hyperconjugation of allylic bonds, torsional strain, diaxial steric repulsion, and ring deformation on the x-facial selectivity of addition of boron or methyllithium to cyclohexanone has been investigated through calculation of transitionstate geometries and kinetic and equilibrium isotope effects.R5

16


Cram’s rule for predicting the stereochemical course of 1,2-asymmetric additions86a has been incorporated86b into the CAMEO interactive computer program.86c Substituents are designated as small, medium, or large, using an algorithm which calculates Taft E, values. Using sample sequences, the scope and limitations of this predictive tool are discussed. A review (79 references) covers the design of N,N-dialkylnorephedrines as asymmetric catalysts and ligands for use in enantioselective addition reaction^.'^

Addition of Orgunometullics Substituted chloromethyloxiranes (epichlorohydrins) and allylic alcohols have been prepared with high diastereoselectivity from chloro- or iodo-methyllithium and achloro- or a-bromo-ketones or -aldehydes.88In each case, the organometallic reagent is added across the carbonyl group, followed by ring closure with loss of LiX. In the case of the allylic alcohols, the oxirane undergoes iodine-for-chlorine exchange (or lithiumfor-chlorine, depending on reagent), followed by a ring-opening p-elimination. The degree of aggregation in solution of alkyllithiums bearing Lewis base groups, LiCH2Si(Me)2CH2N(CH2X)CH2Y(X,Y = H and/or CH2NMe2), has been correlated with their chemoselectivity (enolate anion formation vs addition) with ketones:89those which exist as monomers deprotonate, whereas the more aggregated ones add. 1Bromo- 1-1ithioalk-1-enes, acting as carbenoids equivalent to -CH20H and -CHO, add to O-protected a- and fi-hydro~yaldehydes.’~Reaction of organolithiums with 1,2dicarbonyl compounds leads to products derived from homolytic C-C bond cleavage induced by electrostatic repulsion of the negatively charged oxygen atoms.91 Enantioselective auto-induction has been observed in the addition of phenyl- or n-butyl-lithium to isob~tyraldehyde.~~ 4,4-Disubstituted cyclohexadienones (38) have been selected as test cases for the study of n-facial selectivity in nucleophilic addition reaction^.'^ Given the distance equivalence of the substituents from the reaction centre and the lack of steric or electronic effects, electrostatic interactions can be studied by varying the combined effects of the substituents on p l , the component of the dipole moment which is perpendicular to the dienone system. The results suggest that dipolar control is dominant, with hyperconjugative orbital stabilization and orbital distortion effects of secondary importance: p I correlates linearly with the logarithm of the selectivity. The point is emphasized by the reversal of selectivity accompanying a reversal of p I achieved by changing R’ from methyl to CF2CF3.


17

Only the E-isomer of 2-(2-methylpropylidene)cyclohexanone reacts with MeMgT.94 Although a homogeneous catalyst’s interaction with the solvent is typically subjected to considerable scrutiny, multiple catalysts present in solution are typically treated independently. For example, an impure enantioselective catalyst is usually assumed to catalyse at the same rate as either pure isomer, and to give an enantiomeric excess corresponding to the linear cancellation of some of the effect of the major isomer by the minor. However, in the fl-amino alcohol-promoted enantioselective addition of dialkylzincs to aldehydes, significant non-linear effects are observed, and are explained in terms of the association of the catalysts, with crucial contributions from both ‘self‘ and ‘non-self’ recognition^.^' An ab initio study of the simplest from of the reaction (addition of dimethylzinc to formaldehyde, with 2-aminoethanol as catalyst) has been carried An amino alcohol with two types of chiral phenethyl substituent (39), with 1,4stereogenic centres, catalyses the enantioselective addition of diethylzinc to aromatic aldehydes.97It is proposed to involve formation of an ethylzinc alkoxide of the catalyst hydroxyl, with the metal also complexing the nitrogen and carbonyl group of the substrate, leading to rate-determining ethyl transfer from a second zinc tethered to the alkoxide. Syn-selective addition of diethylzinc to trans-a,@-epoxyaldehydeshas been achieved via chelation control.98 Stereoselective addition of various zinc species, generated by Pd(0)-catalysed reaction of ally1 esters and diethylzinc, to benzaldehyde occurs via an umpolung of n-allylpalladium involving syn addition with inversion of the allylic stereo-centre.99 Enantioselective addition of methyltitanium and diethylzinc to benzaldehyde has been investigated with new ljgands based on TADDOL (a,a,a’,a’tetraaryl-l,3-dioxolane-4,5-dimethanol). loo Results are correlated with X-ray data and molecular mechanics to identify the precise features for optimum catalysis/enantioselectivity and to refine the mechanism. A stereoselective synthesis of trisubstituted alkenes from ketones uses a tungsten or molybdenum alkylidene initially coordinating to a directing Lewis base (ideally hydroxy) or y to the keto function, followed by intramolecular addition to the carbonyl to give a four-membered oxametallacycle intermediate. lo’ Addition of (E)- and (4-crotyltri-n-butylstannanes to several aldehyde types, mediated by various Lewis acids, gives subtle changes in the degree and direction of enantioselectivity,’” due to the inherent closeness in energy of the synclinal vs antiperiplanar transition states. BF3-promoted additions of chiral y-oxygenated allylic stannanes to diastereomeric enals exhibit a facial bias at the carbonyl group due to conformational effects in the enal.”? Allylstannanes have been added to aldehydes via a bis(n-ally1)palladium complex to give homoallylic alcohols. lo4 Addition of Carbon Nucleophiles Containing N, Si,

or S Suhstituents

Optically active cyanohydrins are valuable starting materials for a variety of asubstituted aldehydes and acids. (R)-Oxynitrilase catalyses an enantioselective transcyanation from racemic ketone cyanohydrins to w-bromoaldehydes.’05 Starting from Br(CH*),CHO (n = 3, 4) and the racemate, (R)-o-bromocyanohydrin,

18


Br(CH,),CH(CN)OH, and the (9-debrominated ketone cyanohydrin, H(CH2), - C(CN)OHCH3, are produced (plus ketone by-product). With BF3, (9-crotylsilanes add selectively to a-alkoxyaldehydes to give homoallylic alcohols.Io6 Diastereoselectivity reverses with TiC14, due to chelation (as in 30a discussed earlier6*),as shown by the use of the non-chelating t-butyldiphenylsilyloxy substituent as a control. The insertion of aldehydes into the C-Si bonds of siliranes (silacyclopropanes) to give oxasilacyclopentanes [e.g. (40) from hexamethylsilirane and benzaldehyde] undergoes a reversal of regio- and stereo-selectivity between thermal and K0Bu'catalysed reactions. lo7 Various silylated nucleophiles form C-C bonds with aldehydes, ketones, and acetals with tetracyanoethylene catalysis, proceeding via a single-electron-transfer mechanism. l o x Wittig reaction of 3-pyridyl X-substituted phenyl ketones with a simple 'nonstabilized' ylid, Ph3P+ -CH(CH2),C02H, typically gives predominantly (3-alkene, but switches dramatically to the E-isomer when a phenylsulfonamido substituent is used.'o9 This is ascribed to interaction between the carboxy and sulfonamide sidechains (either through a hydrogen bond or a salt bridge) in the oxaphosphetane intermediate (41). Removing or N-methylating the sulfonamide, or removing the ylid's o-carboxylate, reverses the selectivity.

n

Me I Me .si-o Me

Ph

Me

Me

O,\'

Y s'o

Ph

trans- 1,3-Dithiane 1,3-dioxide (pK, = 25) adds cleanly and enantioselectively to aromatic aldehydes to give adduct (42) as long as it is delivered as its sodium salt, i.e. under equilibrium control.' l o The adducts show strong hydrogen bonding in the solid state. Addition of Amine Nucleophiles C-Hydroxylation of N-methylanilines by hexafluoroacetone and other polyfluorocarbonyls has been the subject of AM1 calculations."' 9-Aryloxy derivatives, e.g. (43a), of the highly reactive 1,lO-anthraquinone nucleus have been isolated by irreversible photo-isomerization of the 1-phenoxyanthraquinones, and their reactions with methanol and alkyl- and aryl-amines investigated.' l 2 Methanol


19

reacts by I ,Caddition to give an acetal (43b; R = Ar), followed by substitution of the aryloxy group to give another (43b; R = Me). Amines, in contrast, add with immediate elimination of phenol, resulting in an equilibrium mixture of the expected enamin(quin)one, 9-amino-1,lO-anthraquinone (44a), and its enolimine tautomer (44b). This equilibrium, and the influence of the nature of the quinone, and solvent, have been extensively studied by IR, UV, ‘H, 13C and I5N NMR spectroscopy and by quantum-mechanical methods.

Addition of Phosphorus Nucleophiles The presence of two nucleophiles in the synthesis of aminophosphonates by nucleophilic addition of an amine to a carbonyl group and addition of phosphite to the resulting imine sometimes leads to phosphite interception of the carbonyl to give hydroxyphosphonate. The balance of the two routes has been correlated with the hardsoft acid-base properties of the substrates: hard amines react preferentially with hard aliphatic carbonyl electrophiles, while the softer phosphite is more llkely to react with the aryl aldehydes and ketones.’ l4 Diastereoselective phosphonylation of aldehydes using diazaphospholidine reagents, e.g. (45) based on the N,N-bis[ 1-(a-phenylethyllethylene- 1,2-diamine auxiliary, has been achieved in both the Abramov [addition of organophosphoms(II1) ester] and Pudovik [addition of H-phosphonate(V) ester] procedures. l 5

’

H

20


Hydration

A comprehensive ah initio study of the uncatalysed hydration of formaldehyde has yielded thermochemical parameters, vibrational frequencies, solvent isotope effects, and proton inventories for the reaction with a single water molecule, and for clusters containing two, three, and four water molecules.116aIn both the gas phase and aqueous solution, the reaction flux is almost exclusively via an eight-membered ring species containing three water molecules (46), with asynchronous proton transfers. While clearly entropically disfavoured, an enthalpic gain arises from the extra hydrogen bonds achieved relative to, say, the previously proposed' 16b six-membered ring containing two water molecules. In particular, the eight-membered ring allows near-linear proton transfer.116b'c The calculations reproduce accurately a number of experimental parameters, and confirm long-standing theoretical proposals about this reaction. I 16d The kinetics and equilibria of protonation and hydration of 9-acridinecarboxaldehyde (47) have been measured in aqueous solution.'17 It has ca 6% hydrate, vs 70% for the protonated form. The behaviour is similar to 4-pyridinecarboxaldehyde, but both hydration constants are ca 20 times lower, presumably due to crowding. Rateequilibrium relationships for the hydration of both heterocyclic cations match those of neutral benzaldehydes. Hydration of 9-formylfluorene (50; R = H) is discussed later under Enolization and Related Reactions. CHO

Miscellaneous

Benzaldehyde undergoes a Friedel-Crafts-type reaction with benzene in the presence of strong acids to give, inter alia, di- and tri-phenylmethane and triphenylmethanol.1'8The obvious intermediate, 0-protonated benzaldehyde, is, however, a weak electrophile with very low reactivity towards benzene: it has predominantly carboxonium rather than hydroxycarbenium character.' I 9 Instead a super-electrophile, diprotonated benzaldehyde (with both protons on the oxygen) is proposed;"* lack of exchange apparently rules out protonation of the tertiary aromatic or aldehydic carbons, and lack of CO"' or products derived from protonated formyl dication' * tends to rule out @so-protonation. However, ub initio calculations favour C-protonation: relative energies (kcal mol- '1 are 0.0 (ortho- and meta-), 5.1 (para-) and 13.7 (ipso-), vs 20.6 for both the protons being on oxygen."' The o-, m-, and p-structures also show a substantially longer ex0 C-C bond, probably due to the decrease in 71-conjugation between the carbonyl group and the cyclohexadienyl ring: this is also consistent with the greatly increased reactivity in superacid solution.

'

f Reactions of Aldehydes and Ketones and their Derivatives

21

The intramolecular Schmidt reaction, in which azidoalkyl-acyclic and -monocyclic ketones give mono- and bi-cyclic lactams, respectively, has been demonstrated.‘’O It is proposed to occur via initial attack of a ketone activated by a protic or Lewis acid to give an azidohydrin (48), which directly rearranges to product amide and molecular nitrogen. Improvements in the synthetic utility of n-cyclizations of alkenyl- and alkynylcyclopentane-l,3-diones to form a variety of bicyclic ketones have been developed.”’ Contrary to an earlier report, ‘22a the reaction of hydroxide with 2,4-dinitrobenzaldehyde to give 2-nitro-4-nitrosophenol is jirst order in substrate, with the order in hydroxide changing from one to two at high concentrations.’12b The immediate reactant is the hydrate anion, and a mechanism involving a Meisenheimer adduct at the 1position, with subsequent loss of the aldehyde carbon as formate, is proposed. The pseudo-first-order rate constant for reaction of morpholine with carbon disulfide follows the rate law k,,,i,,[amine]2 kw[amine][H20],which is compatible with either a zwitterion mechanism, or a termolecular mechanism previously proposed for C 0 2 and

+

c0s.1~3

Enolization and Related Reactions 3-Hydroxyindene (49a) has been generated by Norrish type I1 photo-elimination of 2methoxyindan-1-one, and the kinetics of its ketonization to indan-1-one (49b) have been studied in aqueous s~lution.’’~ Combination with measurements of rates of the enolization reaction (using halogen scavenging) gives the ketowmol constant (pKE= 7.48) and pK, values of the enol (9.48) and ketone (16.96). Compared with acetophenone (7.96, 10.34 and 18.31), the enol acidity is higher, with the co-planar phenyl better able to stabilize the enolate anion.

OH

0

The enol contents of acetic acid and its methyl ester have both been estimated, coincidentally, as 1 part in 2.5 x using a combination of gas-phase thermodynamic data and calculated free energies of transfer to aqueous solution, together with hydrolysis and vaporization measurements, and the assumption that the free-energy change for the hypothetical hydrolysis of a simple enol ether to its enol is independent of The estimate for the acid agrees with two previous estimates by independent methods. 125b The fluorenyl group dramatically increases enol stability and ketone acidity in 9acylfluorenes (50): values of pKE, p e and p e H for R = Ph in water are 1.91, 9.44


22

and 7.53, respectively.'26 Thus the benzoyl compound has a 106-fold higher enol content than benzoylmethane (i.e. acetophenone; see values above), and is lo9 times more acidic. For the aldehyde, 9-fonnylfluorene (50; R=H), the enol is the predominant tautomer (7 1%), and destabilization of the carbonyl by electron withdrawal also gives a high hydrate content (24%). Trapping with hydrogen bisulfite was used to measure ketonization, while kinetics of enolization required generation of an excess of aldehyde from its hemithioacetal. The tautomeric constant of 2-phenylacetylhran (51a) in water is 5.88 Its pK, value is 14.38, giving p e H = 8.50. Relative to deoxybenzoin ('phenylacetylbenzene' pKE 5.15, pKfiH 9.6), furan enhances enol acidity, but stabilizes the ketone. The former is explained by electron withdrawal by oxygen, whereas the latter (an effect on a neutral equilibrium) is ascribed to resonance (51a) cf (51b).

The precise mechanism of proton transfer in the interconversion of dihydroxyacetone and glyceraldehyde phosphates catalysed by triose phosphate isomerase is discussedI2*" in terms of the putative advantage of an 'internal pK, balance"2Rh in enzyme active sites. A polyazacleft (52) has been designed to recognize enolates of 1,3-dioxo compounds, e.g. cyclohexane-l,3-dione enolate (53), via the formation of four hydrogen bonds as in complex (54).'29 Binding constants of 102-104 dm3 mol-' have been found in acetonitrile. Complementarity is the dominant factor, but for shape-similar enolates, binding correlates with guest basicity. Binding-induced pK, changes are small: (53) is 1 .O unit more acidic in the presence of host. The relevance of the results to enolases and racemases is discussed.

Et02C

+

-b

t

Et02C

0

I

I

H

EtO,C

(53)

(54)


23

Protonation of o,o-dimethylacetophenonesin sulfuric acid is much more sensitive to variation of the para-substituent than the unhindered analogues: p = 5.3 vs l.2.130 a-Heterocyclic ketones such as 2-phenacylpyridine (55a; X = CH), in addition to having an enol tautomer (55b), can also exist as an enaminone (5%): the predominant tautomer varies considerably with solvent. Whereas the keto tautomer is readily identifiable, the other two are difficult to distinguish by UV, IR or 'H NMR spectroscopy. Studies of seven different heterocycles show that the 13Cchemical shift of the 'carbonyl' carbon is more reliably diagn~stic.'~'"Why a particular tautomer predominates with particular heterocycles is discussed.

In contrast to 2-phenacylpyridine, stability in phenacylpyrazine follows keto(imine) (55a; X = N) > enol(imine) (55b) > enaminone (5%); in water the ratio is 99 : 0.89 : 0.004.'32Enolization of the ketone does not occur via the 0-protonation route, but rather by N-protonation followed by proton loss from carbon to give (55c),

which rapidly e n o l i ~ e s . ' ~The ' ~ mechanism depends on binding and activation components of the N- and 0-catalyses, the former being measured by pK, values and the latter by proton-activating factors derived from kinetics: 0-protonation typically activates C-H bond breaking more, but the nitrogen atom generally has an even greater basicity advantage, even in this case x 0.4). N-(5-Methyl-4-isoxazolyl)-4-amino-1,2-naphthoquinone (56a) can enolize to (56b) in what is essentially an enaminone-to-enolimine tautomeri~ation;'~~ subsequent degradation gives 2-hydroxy-1,4-naphthoquinone. Kinetic and thermodynamic parameters have been determined in aqueous alkaline solution at 35 "C;the tautomeric constant is 0.40. Kinetic and thermodynamic acid-strengthening effects of a 0-nitroxyl group have been studied for conformationally restricted ketones.134 Relative rates of deuterium

5

HN

N

(56a)


24

exchange in dioxme-DZ0 for cyclohexanones (57; X = CH2, NOH, NO) are 1.O, 7.0 and 170, and these correlate with (relative) gas-phase ionization enthalpies of 0.0, - 3.6 and - 11.0 kcal mol-'. Hyperconjugation is suggested to play only a minor role in stabilizing the nitroxyl enolates.

The isomeric cycloheptatrienols (58a, b, and c) ketonize by a-protonation in all cases to the corresponding cycloheptadienones (59a, b, and c).13' However, (59c) is unstable relative to (59a): conversion takes place through enol (58a). Rate constants for diazo coupling of the enols (58a and c) (to give a-mono- and a,a'-bis-phenylhydrazones) have been measured; the reactive form in each case is the enolate, which reacts at close to the diffusion limit. In contrast, (58b) isomerizes to norcaradienol(60), which then diazo couples. The results suggest that homoaromatic stabilization in cycloheptatriene must be insignificant, and that the 2-hydroxy group provides a small but effective stabilizing effect on norcaradienol (60).

OH

0

OH

The kinetics of the a-enolization of ketones (61), (62), and (63) have been measured by deuterium exchange to establish the relative roles of homoconjugation and polar effects due to a second carbonyl group.'36 The rate ratio of 76 : 1 for (61) vs (63) is not surprising, but the equivalent value for (62) of 0.0027 is difficult to explain, but may arise from a through-space interaction of the n-systems, and from angle strain. AM1 calculations suggest that only the kinetic acidity of (62) is anomalous. Polar effects are believed to be much more important than homoconjugation, as (61) and (62) show negligible exo- vs endo-selectivity.


O m o

25

Qo

Chiral binaphthalenes (64) have been designed to protonate enolates selectively: one side of the phenolic group is protected by the second na~htha1ene.l~~ In the protonation of metal enolates of 2-alkyltetralones (65), good to excellent enantioselectivities result with magnesium if the counterion is bromide or iodide (but not chloride), whereas with lithium the selectivities are poor, and often with the opposite stereochemistry. These unusual effects may be due to aggregation, or a ‘steering’ effect of a carbamatecomplexed magnesium.

a-Alkoxy and -acetoxy substitution of ketones has been achieved using the appropriate alcohol or acetic acid in an a-umpolung based on the inversion of the thermochemical stability of the keto-enol system upon one-electron oxidation. 38b Enolization is rate determining, followed by oxidation (to the enol radical cation), deprotonation, a second oxidation (to the a-cation of the ketone), and finally attack of the nucleophile. The synthesis relies on the much higher rate of acidcatalysed enolization in ‘ acetonitrile compared with water ( > 1000-fold faster), and indeed the monitoring system used [the oxidant/indicator, iron(II1) phenanthroline] is proposed as part of a novel strategy to measure rates of enolization in anhydrous solvents.

’

Hydrolysis and Reactions of Vinyl Ethers and Related Compounds The a-umpolung of ketones above’38ahas been modified by the use of the silyl enol ether as reactant, allowing a wider range of nucleophiles to be successfully substituted.139 Enantioselective preparation of silyl enol ethers of 3-methylcyclohexanone and related compounds using chiral lithium amide bases involves ‘regiodivergent resolution.”40 An antibody raised against a quaternary ammonium ion, acting as a transition-state analogue modelled on the oxocarbonium intermediate of enol ether hydrolysis, gives high enantioselectivity. I 4 l The best substrates are alkyl enol ethers with a P-alkyl

26


substituent and a 2-double bond. The rate-determining protonation occurs on the re face, giving an S-configured carbonyl product. The enantioselective catalysis includes a contribution from general acid catalysis by a protein side-chain site of pK, 5.2. As part of a search for widely applicable methods for preparing seven- and eightmembered ring systems, [3 41 and [3 51 annulations of bis(trimethylsily1)enolethers with acylsilane dicarbonyl dielectrophiles have been found to proceed with good regioand stereo-chemical control, via a mechanism involving neighbouring-group participation.142 The methoxy group of the trichloroacetyl-activated vinyl ether (66a) is substituted by amines to give (2)-alkyl (or aryl) aminovinyl ketones (66b); the kinetics are first order in amine in polar solvents, but second order in hexane and t01uene.l~~Stepwise addition-elimination mechanisms are proposed, with a zwitterionic enolate (67a) or enol (67b) as intermediate in the respective solvent types.

+

+

OMe

OMe

Oxidation and Reduction of Carbonyl Compounds Hydrogen formation from formaldehyde in basic aqueous solutions is first order in formaldehyde, and tends towards second order in hydroxide at low formaldehyde concentration^.'^^ The role of formaldehyde hydrate and its mono- and di-anion, and the Cannizzaro reactions arising from these species, are discussed. Oxidation of substituted benzaldehydes by peroxodisulfate is first order in reagent, and independent of silver(1).145 Autoxidation oscillating reactions of substituted benzaldehydes and aliphatic aldehydes in aqueous acetic acid are catalysed by cobalt(I1) and bromide;'46 kinetic constraints on the oscillation period were studied, and a mechanism involving 14 elementary reactions proposed. Oxidation of cinnamaldehyde by chromium(V1) in a similar medium involves the chromic acid ester of the hydrated aldehyde.147 Oxidation of ketones by vanadium(V), cerium(IV), chromium(VI), and related reagents has been reviewed (80 reference^).'^' Reduction of formaldehyde by general acid-catalysed hydride transfer has been studied, using three combinations of hydride and proton donor: dihydropyridine-imidazolium, dihydropyridine-ammonium, and methylamine-ammonium. 149 All give similar conclusions with both ab initio and


27

semiempirical methods: (i) proton and hydride transfer occur in roughly perpendicular planes; and (ii) the processes are kinetically coupled (i.e. concerted) but dynamically uncoupled (with proton transfer more advanced in the transition state). The basic geometry seems to be fairly robust: these simple pairs are consistent with more sophisticated models of, e.g., lactate dehydrogenase (see later). The reduction of pyruvate to lactate, catalysed by lactate dehydrogenase, has been modelled semiempirically using NADH as reductant, and two moieties based on relevant amino acids: an imidazole (for His195) and a guanidine (for Arg171).’’0 The starting point (which corresponds to an X-ray structure) consists of a protonated imidazole within hydrogen-bonding distance of the pyruvate carbonyl group, the pyruvate carboxylate itself hydrogen-bonded to the guanidine, and the nicotinamide adjacent to the carbonyl carbon. At the transition state, the proton from imidazole has already been transferred to oxygen along the pre-existing hydrogen bond, and the hydride is almost half-way transferred: the proton and hydride transfers are approximately perpendicular. The stereochemistry of delivery of hydride anion in the reduction of 5fluoroadamantan-2-one (68) switches over from Cieplak-’ ’la to Anh-hyperconjugdtion”lb when the identities of all hydrogen and fluorine atoms are reversed.151CIt is suggested that the periplanar bonds can no longer stabilize the transition state by electron donation, and instead do so by accepting electron density from the incipient bond into the CT* orbitals. These substrates appear to be well suited to this type of study because of their rigidity, and because the substituent, while allowing distinction of the faces, does not obstruct either of them. Ab initio and semiempirical calculations on the transition states for the reduction of 5+ substituted adamantan-2-ones (69; X =N, N-0-, or C-substituent) by aluminium hydride show evidence for hyperconjugative delocalization.lS2 The C(a)-C(p) bond which is antiperiplanar to the incoming nucleophile is lengthened.

Norbornan-7-one (70) has often been used as an isosteric probe of z-facial selectivity. Electrostatic effects appear to dominate in borohydride reduction of 2-endo-substituted and 2,3-endo,endo-disubstitutednorbornan-7-ones, as shown by polar-field susceptibility parameters, and a 13CNMR probe based on the transmission of polar substituent effects.IS3 The diastereo- and regio-selectivity of reduction of bicyclo[3.3.l]nonane-2,9-dione (71) by various hydride reagents has been determined via the product distribution of the four possible hydroxy ketones and four possible diastereomeric diols; steric, stereoelectronic and electrostatic factors are probed by molecular mechanics. lS4

28


Borane complexes of chiral 1-phenethylamines reduce aromatic ketones with moderate to good enantioselectivity in the presence of boron trifluoride etherate; the transition state is proposed to involve hydride transfer from an amine-BF3-BH3 c0mp1ex.I~~ Acetophenone has been reduced enantioselectively with borane using chiral oxazaborolidine catalysts.156 A chiral bis(phospho1ano)ethaneruthenium catalyst brings about highly enantioselective hydrogenation of p-keto esters under mild conditions; the P-hydroxy ester products can in turn be used to make ligand for the catalyst, i.e. the reaction ‘breeds its own chirality.”57 LiBuS,H reduces an acyclic y-sulfenyl-substituted a-enone with 1,4-diastereoselectivity by exploiting conjugation: X-ray analysis shows the sulfbr is approximately orthogonal to the enone plane, and the hydride attacks fiom the opposite side.‘5x Similar results are seen in the corresponding enals, and with y-alkoxy and -siloxy a-enones. Metal hydride reduction of a-seleno ketone, ArCOCH(R)SeR’ (R = alkyl, R’ = Ph, Me), yields mainly threo-8-aryl-P-hydroxyalkyl phenyl (or methyl) selenides,’59 in contrast to the elythro-products found for most other a-heteroatoms: NR2, OH, OR, P(0)Ph2, SR, etc. Cyclopropyl ketones have been reduced diastereoselectively with hydride reagents.160

Other Reactions 8,y-Unsaturated aldehydes typically decarbonylate on photo-irradiation: the formation of a cyclopropyl aldehyde via an oxa-di-n-methane rearrangement has previously only been reported for a rigid aldehyde161aor one with sterically hindered rotation.161bNow aldehydes as simple as (72) undergo the reaction effectively; the phenyl group probably stabilizes the bridging 1,4-biradical intermediate.l 6 l C Although P,y-unsaturated oximes are usually photochemically inert, appropriately substituted acyclic aldoximes (73a) can cyclize in a stereoselective aza-di-n-methane rearrangement to cyclopropyl aldoximes’62 (73b). The reaction has also been extended to an oxime ether and to ketones. The chiral (Z)-oxazolone (74) has been cyclopropanated at the alkene (with modest selectivities) using oxosulfonium methylides, to give four isomeric spiro compounds.‘63 Biphenyls, which are twisted in the ground state, tend to become planar upon electronic excitation. Direct evidence that the singlet (S,) state is extensively polarized in simple substituted biphenyls is seen in the observation that, while 4-phenylphenol (75) undergoes thermal deuterium exchange (in acid) at the 2-position, exchange under irradiation takes place in the 2’- and 4’-positi0ns.l~~ This suggests the intermediacy of quinone methide species, and evidence for them was obtained by irradiating benzylic alcohols (76a) and (77a). Using laser flash photolysis at 266 nm in aqueous solution, both lose hydroxide to give quinone methides, (76b; d,,,=570 nm) and (77b; A, = 525 m). The gas-phase reactions of the hydroxyl radical with P-methyl-substituted ketones have been studied in the presence of NO,; evidence for isomerization of alkoxy radicals, particularly those to the carbonyl, is presented.I6’ When a-alkylcyclohex-


29

Me CH=CH2

Ph

(73a)

Ph

R = H. COMe, COCF3

CH=NOR (73b)

anones such as (78) bear a hydrogen in the y-position (in the side-chain), Norrish type I1 cleavage causes loss of the side-chain, to give (80) as major product. However, with a p-silyl substituent (R2= SiR,Ar,), the reaction switches over to the generally more useful Norrish type I products (79a and b), presumably due to silyl stabilization of a radical intermediate.'66 Carbonylation of chloral (trichloroacetaldehyde) in concentrated sulfuric acid gives cis- and trans-2,5-bis(trichloromethyl)-l,3-dioxolan-4-ones(81), with the ratio


30

dependent on the acid concentration.'67a This in turn depends on the stability of the anti-form o f the protonated aldehyde (82; R = CC13), which predominates in strongly acidic media.167b

When propanedinitrile is reacted in base with an a$-unsaturated carbonyl compound such as (Q-4-phenylbut-3-ene-2-one (83a), a 2-aminobenzene-l,3-dicarbonitrile (83b) is ~btained.'~' This appears to arise from reaction o f three molecules o f dinitrile with enone to give an iminobicyclooctene, which eliminates NaC(CN)3 en route to product (83b). 0

CN

The catalysis o f the thermal spiropyran-to-merocyanine isomerization (84a) + (84b) by a-, /3-, and y-cyclodextrins has been studied at high pressures, yielding data on the volumes o f activation and of reaction and on the nature of the 1 : 1 inclusion complex formed.'69

Halogenation o f aldehydes and ketones by selenium(1V) oxyhalides (generated from SeOz and Me3SiX) involves P-keto selenenyl halides; polyhalogenation is suppressed.170


31

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’ ’ in

l3

l4 l5 I‘ 17

19

2o

” 22

23 24 25

26

’*

27

29

3o

31

32 33

34

35

36 37 38 39 4o 4’

42

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32


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(1995).

CHAPTER 2

Reactions of Acids and their Derivatives W. J . SPILLANE

Chemistry Department. University College. Galway. Ireland CARBOXYLICACIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tetrahedral Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intermolecular Catalysis and Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions in Hydroxylic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b)Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (ii) Transesterification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (iii) Other reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Lactones and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (d) Acids and anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (e) Acid halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (0 Ureas, carbamates. hydroxylamine, and derivatives. . . . . . . . . . . . . . . . (g) Amides. anilides. lactams. and lactims . . . . . . . . . . . . . . . . . . . . . . . (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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Penicillin Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . O ~ e r E n z y m e.s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NON-CARBOXYLIC ACIDS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphorus-containing Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Phosphates. phosphoryl transfer, phosphonates . . . . . . . . . . . . . . . . . . @) Other phosphorus functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enzymic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sulfur-containing Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Sulfur-oxygen compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Sulfur-nitrogen compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Other sulfur compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ReEerences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organic Reaction Mechanism.y 1995 . Edited by A . C . Knipe and W. E . Wans 6 1997 John Wiley & Sons I.td

35

36 36 38 38 38 39 39 40 41 45 45 48 48 50 53 54 56 60 61 67 67 69 69 69 70 70 70 71 71 71 71 75 75 78 78 80 81 84 84


36

CARBOXYLIC ACIDS

Tetrahedral Intermediates Semiempirical molecular orbital (PM3) calculations have been reported for the reactions of m-nitro-, p-nitro-, and 3,4-dinitro-phenyl formates (1) with 18 phenolate anions in the gas phase and in solution (Scheme l).' The mechanistic changeover from rate-limiting formation to breakdown of the anionic tetrahedral adduct (T-) can occur at approximately equal proton affinities (i.e. @A = 0) of the leaving-group phenolates and the nucleophile in the gas phase, particularly for the m-nitro compound. The low stability of T- in solution and stabilization by solvation of the transition state for the breakdown step result in all three formates reacting by a concerted mechanism. Recent evidence from l 8 0 exchange studies in H 2 0 and DzO on the basic hydrolysis of ethyl toluate and isopropyl toluate suggests that the anionic tetrahedral intermediates (2) produced in these hydrolyses equilibriate very rapidly compared with C-OH or C-OR cleavage (Scheme 2).* Oxygen-18 isotope effect studies in the carbonyl oxygen of p nitrophenyl acetate and in the phenolic oxygen atom of the leaving group, together with "N isotope effects in the leaving group indicate that the acyl-transfer reactions of this substrate with various nucleophiles are concerted and do not involve an inte~mediate.~ For the reaction with methoxyethylamine, a stepwise mechanism involving the

XC6H40-

0 II

HCOC6H4Z

+

(1)

__

0-

I

XC6H40-C-OC6H4Z

I

H

1

T-

O II XCbH40-CH

+ -OC6H4Z

SCHEME1

0-

~-M~C~HC-(!-OR

I

OH

__ (2) R = Et, Pr' Scmm 2

OH

I

4-MeC6H4-C-OR

I

0-

2 Reactions of Acids and their Derivatives

37

0

SS II EtO-C-SAr

(7)

II

EtO-C-SAr I+ -NH-

(8)

zwitterionic tetrahedral intermediate (3), with its breakdown rate-determining, is taking place as the crucial step. Cross-interaction constants pxx pyz, and pxz (where X, Y, and Z axe substituents in the attacking nucleophile, the substrate, and the leaving group, respectively) have for some years proved very useful in examining the nature of the transition states in concerted SN2 reactions where pxy < 0, pyz > 0, and pxz > 0 or < 0. Now the crossinteraction constants expected for stepwise carbonyl addition reactions involving ratelimiting breakdown or formation of a tetrahedral intermediate are proposed as p x y > 0, ~ Y 0 and pxY < 0, pyz x 0, and pxz > 0 or < 0, re~pectively.~ Hydrolysis of the major alkaloid securinine (4) from the genus Securinegu, which as its nitrate salt is a stimulant to the central nervous system, involves lactone ring opening and may involve tetrahedral intermediates such as ( 5 ) and (6).5 The aminolysis (secondary alicyclic amines) reactions of 0-ethyl S-aryldithiocarbonates (7) in aqueous ethanol have been r e p ~ r t e d .For ~ ’ ~0-ethyl S-phenyl dithiocarbonate (7; Ar = Ph), plots of kobs (excess amine) vs [amine] showed some upward curvature, but plots of [amine]/k,b, vs l/[amine] were linear. When the amine was 1formylpiperazine, plots of kobs vs [aminel* were linear. A mechanism involving zwitterionic and anionic tetrahedral intermediates is proposed where the aminecatalysed proton transfer from TSto T- is partially rate-determining normally and hlly rate-limiting for l-formylpiperazine.6 Aminolysis of 4-nitrophenyl (7; Ar = 4-02NC6H4)and 2,4-dinitrophenyl [7; Ar = 2,4-(02N)2C6H3]0-ethyl dithiocarbonates gave Brernsted plots which were biphasic with P I = 0.3 (high pK,), p2 = 0.95 (low pK,) for the 4-nitro substrate, and /I1 =0.3 and B2=0.80 for the 2,4-dinitro substrate, respectively. These reactions are seen as being stepwise with the formation of a zwitterionic tetrahedral intermediate (tQ7 The breakdown of a neutral tetrahedral intermediate (9) has been proposed for hydrolysis of methylthiazolium ions8 and the same authors’ now propose that such an intermediate (9) is involved in the hydrolysis of several 3-R-4-methyl- and 3-R-2,4dimethyl-thiazolium ions leading to the enethiolate products (10). Breakdown of (9) is again rate determining.


38

See also references 37, 39, 41, 48, 73, 80, 84, 94, 104, 105, 110 and 11 1.

Intermolecular Catalysis and Reactions

Reactions in Hydroxylic Solvents (a) General A new set of steric parameters developed by the use of the AM1 semiempirical MO method incorporation MOPAC have been derived using calculated proton affinities (Ap) and methyl ion affinities (AMe).The new parameters, designated 6, have been tested in various ways including the use of kinetic data for the Menschutkin reaction in Scheme 4. For 22 pyridines, the following equation shown was followed: log (k/kH) = 0.656

+ 0.43 PK, - 2.26

with Y = 0.942, s = 0.048, and F= 74.55. This approach is expected to be useful in QSAR studies in biochemistry and medicine. The coefficients in the equation are interpreted as indicating 65% hindrance for the methyl group compared with what it experiences in the methylpyridinium ion; in the transition state, the nitrogen atom is seen as having an effective charge of +0.43."

SCHEME 4

Lee" has reviewed (ca 40 references) the more important aspects of secondary adeuterium kinetic isotope effects involving deuteriated nucleophiles, especially in relation to mechanistic criteria based on cross-interaction constants. Williams'2 examines the topic 'the diagnosis of concerted organic mechanisms' in a short review (ca 35 references). He looks at the energy considerations involved, the exclusion of stepwise mechanisms, and finally some systems under current study. The latter include examples of phosphoryl, sulfonate, and carbonyl group transfer, and a brief look at substitutions at carbon and cyclical and elimination reactions.


39

For reactions involving [2.1. Ilcryptates of organolithium compounds (1 1) as metallating agents during transmetallation, acidity scales of a series of CH acids in a range of solvents have been developed at 25 OC.13 The pK, values lie in the range 10-33. A thermodynamic analysis of the effect of the various solvation interactions on acidity has been undertaken. The energetics of the enol form of acetic acid (12) in aqueous media have been exarnined.I4 The acidities of N-H bonds in 15 carboxamides in DMSO, and the homolytic bond dissociation enthalpies for these bonds, have been derived by Bordwell’s group.’’ The average pKHAfor five aliphatic carboxamides is 25.5, and the average bond dissociation enthalpy is 45 1 kJ mol - I . The use of ethyl trifluoroacetate (13) to protect selectively primary arnines in the presence of secondary arnines, and for mono-hctionalization of diamines, has been described.I6 Intramolecular catalysis is supported by several competition experiments carried out with various secondary mines.

(b) Esters (i) Formation The kinetics of esterification of mono-5-methylheptyl phthalate (14) with 5methylheptanol to give bis(5-methylheptyl) phthalate in the presence of sulfuric acid have been investigated in an isothermal semi-batch reactor. The reaction appears to be first order with respect to (14).” Benzoyl chloride or benzoic anhydnde acylates p nitrophenol in the presence of hexachlorocyclotriphosphazatrieneand triethylamine. * The kinetics of the esterification of terephthalic acid (15) with isooctanol over SnC12type non-acid catalysts were studied.’’ The activation energy for the process was 40.22 kJ mol Scandium trifluoromethanesulfonate, Sc(OTQ3, is a new highly effective acylation catalyst.20It has been shown to be highly effective in the acetylation of octan-2-01 with acetic anhydride to give the ester (16). The acetylation and benzoylation of menthol (17) are greatly facilitated with Sc(0TQ3. Alcohols were protected by esterification with

’

’.


40

C02H

I

Me

I

Me(CH2)s -CH-OAc

acids of the type (18) and the resulting esters could be chemoselectively deprotected.” A review (1 1 references) on the use of iron(II1) chloride in esterification has appeared.22 (ii) Transesterijcation Lipase-catalysed transesterification of w-phenylalkan-1-01s (19) with vinyl acetate (Scheme 5) in organic solvents gives the products (20). R may be phenyl or cyclohexyl and n = 1 4 or 5 for R = phenyl. The most reactive substrate is (19; R = Ph, n = l).23 Transacylation (0-+N acyl transfer) in 1-isopropylamino-3-(1-naphthoxy)propan-2-01 (21; R1 = OAc, R2 =NHPri) to give [21; R’ =OH, R’ = N(Ac)Pr’] proceeds via an anionic tetrahedral intermediate of the type (22). Hydrolysis competes with tran~acylation.~~ The application of iron(II1) chloride in transesterification reactions has been reviewed.*‘ 0 II R(CH2),0H + CH2=CH-O-C-Me

0

__f

II R(CH2),0-C-Me (20)

SCHEME 5

The effectiveness of a series of alkylguanidinium ions containing appended nitrogen bases (23;R = H, CH2CH2NMe2,etc.) and (24) in the transesterification of the RNA model 2-hydroxypropyl p-nitrophenyl phosphate (25) has recently been examined.25 The phosphoryl transfer reaction of (25) gave p-nitrophenol and the cyclic phosphate ester (26). Phosphorus oxychloride-mediated transesterification of alkyl carbamates to aryl carbamates gives reasonable

41

2 Reactions of Acids and their Derivatives R’ I OCH2CHCH2R2 I

H

NHR

NHR (23)

\c””

cNH

MeNHC02R

+ POC13

ArOH

MeNHC02Ar

SCHEME 6

(iii) Other reactions

AM1 semiempirical quantum mechanical calculations using the Langevin dipole solvent model have been made for reaction pathways in the gas phase and in polar solution for the cleavage of phenyl acetate by hydroxide ion and by b-cyclodextrin. Experimental results can be reported using the solvent The question of concerted or stepwise mechanisms in the acyl-transfer reactions of p-nitrophenyl acetate was examined using isotope effects as indicated earlier.3 A mechanistic change from ElcB to BAc2 in the alkaline hydrolysis of aryl 2hydroxycinnamates (27)has been detected from a biphasic Brsnsted type plot with PI = - 1.11 and p2= -0.25 for various phenolate leaving groups in (27). These esters with good leaving groups gave a P value of - 1.11 , consistent with ElcB hydrolysis; at pK,, > 6, the lower Brarnsted slope is ascribed to a BAc2 process.28A kinetic study of the saponification of methyl 2-chloro-4(dimethylaminosulfonyl)phenoxyacetate (28) has been rep~rted.’~ Some saponification studies of industrially important diesters have been rep~rted.~’ The alkaline hydrolysis of ethyl 2-(2’-benzimidazoly1)acetateand ethyl 3-(2’-benzimidazolyl)propionate has been assessed in DMSO-H20 and dioxane-H20

mixture^.^'

The hydrolysis of the a-benzoyloxystyrenes (29; X =Me, H, C1, NOz) in strong acids proceeds by an AAc2 mechanism up to 5.5 M HC104. The evidence includes a Bunnett w parameter of f7.6 and a Bunnett and Olson 4 parameter of + 0 ~ 4 The . ~ k~E 2 o / k D 2 0 ratio is 0.72 and p = -0.6 using CT+ constants. Above 5.5 M HC104, ktr,o/ku,o is 3.32, p is - 1.60, the rate is linear with the Ho function, and the mechanism changes to


42

involve slow olefin protonation. Acid hydrolysis of n-amyl formate, HC02(CH2)4Me, in aqueous DMSO, aqueous propan-2-01, aqueous acetone, aqueous dioxane, and aqueous ethanol has been studied.33 The kinetics and mechanism of acidic, basic, and neutral hydrolysis of 1-aryloxyethyl alkanoates (30) have been examined.34 An AALl mechanism involving an alkoxy carbocation (31) is indicated in acidic media, whereas in basic media attack of HO- at the carbonyl carbon gives a B ~ c mechanism. 2 In neutral media (PH 2.5-8.8), attack of a water molecule on the acyl carbon is rate-determining. Protonated methyl acetate undergoes slow acyl-oxygen cleavage even at - 78 "C (much faster at -20 "C) in FS03H-SbF5-S02 solution to give acetyl cation and methyloxonium ion35 (Scheme 7). The formation of a gitonic dication (32) from 1,ldimethoxyethyl cation (33) is proposed based on studies in deuteriated media. Theoretical calculations at the MP4(SDTQ)/6-3 lG*//MP 2/6-3 1G* level were performed on these mono- and di-activated ester systems.

0 11 RC-OCH(Me)OAr

'OH

II

MeC-OMe

H+

H+

'OH II +

MeC-OMe

H

0 I1 + RC-OCH(Me)

-

SCHEME I

c

MeCO+ + MeOH2


43

The hydrolysis of p-nitrophenyl acetate in aqueous solution (PH 3-8) is accelerated by two orders of magnitude by ultrasonic irradiation. The role of supercritical water in the sonolytic hydrolysis has been assessed and a dynamic heat-transfer model presented.36 The first step in the neutral hydrolysis of bis(4-nitrophenyl) oxalate (34) in aqueous acetonitrile proceeds by a BAc3 mechanism judging from solvent isotope effects and the effects of solvent on rate.37The second step, involving reaction of (35), is much slower owing to the retarding inductive effect of the carboxylate group. Imidazole-catalysed reaction of (34) proceeds with successive release of the two p-nitrophenyl groups and involves the formation and breakup of 1,l'-oxalyl diimidazole (ImCOCOIm) and the tetrahedral intermediate (36). Solvent and substituent effects for the hydrolysis of methyl salicylate and methyl 0-,m-, and p-methoxybenzoates in aqueous organic solvents have been studied.38 Semiempirical MO calculations using the PM3 method have been performed for the reactions of acetate esters with phenolate anions. The mechanistic change from breakdown to formation of the anionic tetrahedral intermediates on the reaction pathway have been examined for the acetates and for formate esters.39 The rates of reaction of the esters 4-nitrophenylbenzoate (37; X = Y =O), S-(4nitropheny1)thiobenzoate (37; X = 0, Y = S), and 0-(4-nitrophenyl)thiobenzoate (37; X = S, Y =0)with alkoxides, aryloxides and thioaryloxides in ethanol at 25 "C have been mea~ured.~' Replacement of Y =O by Y = S in the substrates (37) had little effect, but replacement of X = 0 by X = S in (37) reduced the rate by a factor of 10. Reactivity differences are attributed to polarizability effects. The same workers have recently reported some aminolysis studies (using secondary cyclic amines) with (37; X = 0, Y =0) and (37; X = S , Y=O). The slow step for reaction of (37; X = S , Y=O) depends on the basicity and concentration of amine; it changes from loss of proton from tetrahedral intermediate (38) to give T- (39), to formation of (38) when the amine concentration of becomes high.4'

(35)

(34)

0 0I1 I ArO-C -C -0Ar If ImH

(36)

(37)

Using Hammett, Bransted and cross-interaction constants, novel mechanistic criteria have been derived for various S, reactions including SNl, diss-SN2,concert-SN2,SAN and a ~ s - S ~The 2 . ~same ~ group has looked at the aminolysis (piperidine, Et,NH, and


44

Et3N) of benzoate esters in acetonitrile and propose an enforced SAN mechanism.43 Reaction of diethyl 5-X-2-furoylmalonates (40) with secondary amines (EtZNH, piperidine, pyrrolidine, morpholine and 1-phenylpiperazine) gave products of type (41). No nucleophilic substitution of X by the amines occurred.44 The kinetics of the reaction of imidazole (Im) with 4-nitrophenyl chloroacetate and dichloroacetate (42) in acetonitrile, and acetonitrile with 0.56 mol dmp3 added water, show terms that are first and second order in [Im]. The first term represents nucleophilic reaction by Im and the second is due to general base-catalysed nucleophilic reaction by I ~ . ~ ~ Neutral and anionic forms of hydroxylamine are the strongest known acyl-group acceptors. This conclusion was drawn from a study of the reaction of hydroxylamine

S-

I

S-

+/

I

/

I

\

Ph-C-N

Ph-C-NH I \ OAr

OAr

(38)

(39)

CH2=CHCH2CH(CO*Et)2

(43)

@*&do 0

CH2 =CHCH2C(Me)(CO*Et)PO(OEt)2

1-0

0H

(44)

(45)

0

0

II RC-C(=NOAc)C02Et I R

(46)

(47)

0-


45

with 4-nitrophenyl acetate, p-toluenesulfonate, diethyl phosphate, and diethyl ph~sphonate.~~ The iodo-lactonization of unsaturated carboxylic esters containing a-ethoxycarbonyl and a-diethoxyphosphoryl groups, i.e. (43) and (44), has been studied.47 The oiodosobenzoate (45)-catalysed hydrolysis of a series of benzoate esters occurs by a nucleophilic mechanism in which the rate-limiting step is the collapse of the tetrahedral intermediate (46) which forms by attack of (45) on the ester. FT-IR has been used to detect the presence of the reaction intermediate formed between (45) and the ester.4x Acylium ions form in the decomposition in neat polyphosphoric acid of the aacetoximino keto esters (47; R = Me, Ph, phenylalkyl, cyclopropyl, 3,4,5-trimethoxyphenyl, e t ~ . ) . ~ ~ (c) Lactones and derivatives Di-y-lactone dihydrocanadensolide (48) ring opens in base to give the monolactones (49), (50), and (51) by parallel routes involving hydrolysis to (49) and (50) and a fielimination perhaps via an ElcB mechanism to give (Sl).” The hydrolysis rates are much faster than predicted by models, and an unusual intramolecular interaction which arises froin steric effects is suggested. Further hydrolysis of (50) is normal giving (52) and the hydrolysis of (49) probably proceeds via the &lactone (53). Irradiation in TFE of carboxyalkyl-substituted pyran-4-ones (54) gave reactive oxyallyl zwitterions and cyclization of the pendant carboxyl onto the electrophilic terminus of the oxyallyl system gave the fused bicyclic cyclopentenone lactones (55).5’ The complete mechanistic course of the atropo-selective ring opening of the axially prostereogenic biaryl lactone (56) by a chiral oxazaborolidine-BH3 reagent was investigated by semiempirical AM1 calculation^.^^ The reactions of soft (thiols, acetic acid, bromide) and hard (alcohols, benzylamine) nucleophiles with the 2,3-aziridino-y-lactones (57) and (58) have been studied and the reactivities compared with those of aziridine-2-carboxylic esters with the same nucleophiles. MNDO calculations can predict the regioselectivity of nucleophilic attack on (57) and (58).’? (d) Acids and anhydrides A reasonable correlation exists between gas-phase acidities, calculated by MNDO for 15 aliphatic carboxylic acids, the net atomic charges on the acidic hydrogens in the neutral form, and the net atomic charges and ionization potentials of the anions. There was no correlation between the gas-phase acidities and HOMO and band gaps.54 Theorctical linear solvation energy relationship descriptions have been used to model solute-solvent interactions that influence the acidity of substituted acetic acids [59; X = H , simple alkyl, branched alkyl, OMe, SMe, Ada, %Me3, CbFs, C1, NMe2, CI(CH&, C6H5, CF3, F, Br, CN, CH2=CH, SC6H5, OC6H5, etc.] in different solvents.55 A multilinear regression (MLR) analysis approach is used to generate an equation with the descriptors V,, n,,cB, q - , EA, and q+. Predicted and experimental acidities show good agreement for 25 acids in seven solvents (H20, MeOH, EtOH, iPrOH, DME, EG, t-BuOH). Six monocarboxylic acids (60), (61), and (62) have been


46 Bu I H

H02C

100 ps) of the thiyl radicals. Acctyl and t-butyl radicals formed from the photolysis of pinacolone react with phenolic compounds to form aryl acetates and acylphenols by initial phenolic hydrogen atom abstraction and rec~mbination.~'Hindered phenoxy radicals (27a) and (27b) have been shown to undergo reversible C-C coupling to give bis(cyc1ohexadienes) (28) and (29) (Scheme 17).68The spectra and kinetics of the recombination of alkyl and alkylperoxy radicals originating from di-t-butyl ether have been studied using a pulse radiolysis UV absorption technique.69 A number of thermal reactions have been investigated behind reflected shock waves. The thermal decompositions of buta-1 ,2-diene7' and but-1-yne7*have been investigated at 1 100-1600 K, while the reactions of the methyl radical have been reported at 12242520 K.72 The thermolyses of a number of alkyl and propargyl amines at 380-510 "C


102

+

(28) SCHEME 17

indicate that decomposition occurs via a six-centred cyclic transition state; however, a free-radical mechanism was suggested for the decomposition of diethylcyanomethylamine.73 Thermolyses of a range of di- 1-adamantyl-t-alkylmethanes have been studied and the activation energies correlated with the difference in strain energy between the starting material and the corresponding radicals.74 In addition, an interesting rearrangement of di-1-adamantyl-3-noradamylmethane to 1,2-diadamantyl was reported. Thermolysis of acetophenone and benzophenone oxime arenesulfonates has been postulated to occur via a free-radical mechanism.75 Chloroalkanes, important species in atmospheric chemistry, undergo oxidation mediated by chlorine atoms to give chloromethoxyl radicals which undergo intramolecular elimination of HCl.76 An important reaction in the high-temperature oxidation of benzene is the fragmentation of the phenoxyl radical to CO and 'C5H5. Ab initio calculations indicate that decomposition is likely to take place via an electrocyclic mechanism involving the 6-oxobicyclo[3.1.O]hex-3-en-2-y1 radical.77 The rate constants for decarboxylation of a range of substituted benzoyloxyl radicals have been measured using laser flash photoly~is.~'Ortho-substituted radicals were found to decarboxylate much faster than other isomers. In addition, the rate was found to be heavily dependent upon the solvent used. The significant non-planar geometry of thc ortho-substituted radicals was thought to be responsible for the rate-accelerating effect.

Atom Abstraction Reactions Hydrogen Abstraction by Carbon-centred Radicals The factors which determine the activation energy of radical abstraction reactions have been r e ~ i e w e d In . ~ addition, the activation energies for H-abstractions by a number of radicals have been calculated using bonding and antibonding Morse c u ~ e sValues . ~ ~ were found to be in good agreement with published experimental data. The model used highlights the importance of repulsive forces and requires only bond length, dissociation energy, and TR stretching frequency data for calculation. The abstraction of a hydrogen atom from acetonitrile by the methyl radical has been studied by both the

3 Radical Reactions: Part I

103

ab initio MO and reaction dynamics methods to determine the mechanism at low temperature." It was concluded that quantum mechanical tunnelling strongly affects the reaction rate. Hydrogen atom abstraction by acyl radicals has received some attention. The rate constants for reduction of primary, secondary, and tertiary acyl radicals by (TMS)&H and Bu3SnH have been measured and the KSnHIKsIH values were found to be very similar (12.32-14.45).*' In addition, the rate constants for hydrogen abstraction from Bu3SnD were measured (propanoyl radical, 3 x lo5 1 mol-' s-I) and thiophenol (benzoyl radical, 4.8 x lo7 I mo1-I s - ' ) . ~ ' Radical translocation (intramolecular H-abstraction) has continued to be used to generate radicals which then undergo further reactions such as cyclization. Siliconcentred radicals have been produced by 1,5-H abstraction by vinyl radicals46 or alkyl radicals8* The latter were studied with the aim of developing unimolecular chaintransfer reactions (UMCT). The application of this technique for the mediation of particularly slow bimolecular reactions has proved successful. Reaction of (3 1) with (30) using the conventional syringe pump-high dilution method furnished only starting material (31) and reduced phenyl acetate, whereas the addition to (32) produced the addition product (33) in 71% yield (Scheme 18). Radical translocation has also been used in a translocation-trapping strategy.*3 Barton decarboxylation of the 2mercaptopyridine-N-oxide ester of the acid (34) with Bu'SH followed by fast 1,5hydrogen transfer and trapping with oxygen gave the hydroxylated product (35) (Scheme 19). The rate constant for translocation was found to be 6 x lo6 s-' at 25 "C. The synthesis of oxindoles via a translocation-cyclization strategy, initiated by 1$hydrogen transfer to aryl radicals, has been rep~rted.'~

Bur/ Bur /

OSiBur2H

Bu!

Br


104

SCIIEME I9

The reaction of phenyl radicals with a range of cycloalkanes has been probed by utilization of the cavity-ring-down te~hnique.'~Results were in good agreement with data obtained by the relative rate method. Hydrogen Abstraction by Heteroatom-centred Radicals An analysis of published data relating to polar substituent effects on hydrogen atom abstractions and other radical reactions in terms of perpendicular effects in More O'Ferrall-Jencks diagrams has been discussed. It was concluded that entropic dominance leads to behaviours inconsistent with the reactivity-selectivity principle.86 The rate of H-abstraction from a number of hydrocarbons, fluorohydrocarbons and alcohols by the CF@' has been determined using the relative rate technique and conclusions regarding the fate of the C F Q in the atmosphere have been made.87Habstraction from phenol and t-butyl hydroperoxide by cumyloxyl radicals has been found to be dependent on the solvent." It was postulated that more polar solvents complex more strongly with the reactant hydroxyl group, thus decreasing the rate of hydrogen abstraction. Pulsed radiolysis has been used to determine the absolute rate constants for the reversible H-abstraction reaction from thiols to radicals (derived from alcohols or cyclic ethers).89 Typical values for the forward reaction of radicals with thiols are of the order of 107-10s 1 mol-' s-', whilst the reverse reaction of the hydrogen donors with thiyl radicals were of the order of lo4 times less. R' + R'SH

C RH

+

R'S'

(1)

Kinetic solvent effects for the H-abstractions from a-tocopherol and phenol by tbutoxyl, 2,Z-diphenyl-1-picrylhydrazyl and cumyloxyl radicals have been measured.90 The kinetic solvent effect was found to be almost identical for the same substrate and independent of the radical. This provides a method for predicting the rate constant for the reaction of a radical with a substrate in any solvent providing the kinetic data are available for the reaction of another radical in the same range of solvents. The absolute reaction rate between chlorine atoms and a large number of alkanes has been studied at various temperatures (273-333 K) using the VLPR technique9' and the relative rate m e t h ~ d .In~ addition, ~ , ~ ~ ah initio calculations on H-abstraction by halogen radicals from ethane and propane using UHF, UHF/MP2, and UHFIMP4 (6-31G* basis


105

set) methods have shown that the transition state occurs with the abstracting halogen atom, hydrogen atom and carbon atom c01inear.~~ The kinetics of the reaction between CF3C02H (a potential oxidation product of HFC and HCFCs), H2S, D2S, CH3SH, and CD3SH with atomic chlorine have been The reaction of photo-dissociated CC14 and C12 with H2 at 193 and 35 1 nm, respectively, fbmishes varying amounts of H atoms, with the former producing a much larger con~entration.~~ H-abstraction from a-amino acids by thiyl radicals has been studied at pH 10.5. Radicals were generated from cysteine, homocysteine and glutathione by the azide radical.98 Chiral silanethiyl radicals have been used in an attempt to perform kinetic resolutions. Only low resolutions were obtained in H-abstraction from racemic C(2) symmetric s i ~ a n e s . ~ ~ The kinetics of H-abstraction from secondary amines by 1,Cbenzoquinone monoimine have been reported. loo

Hulogen Abstraction The dissociation energies of the C-X bond in 73 different compounds have been calculated using the corresponding rate constants for halogen abstraction. A diverse range of alkyl, aryl, heteroaryl, and vinyl halides as well as a number of carboxylic acid derivatives were evaluated."' The kinetics of halogen abstraction fi-om a number of halogenated hydrocarbons by various radicals have been studied.'02 In particular, the rates of abstraction by aminoboryl and triethylsilyl radicals have been measured by EPR spectroscopy.I o 3 The rate of abstraction increases with the addition of P-alkoxyl substituents to the organo-halogen radical precursor due to charge-transfer effects operating in the transition state. EPR spectroscopy has also been used to establish that cross-cage interactions exist in 3-substituted bicyclo[ 1.1. Ilpent-1-yl radicals. Io4 During the course of this study the rates of abstraction of bromine atoms from I-bromo-3substituted derivatives were examined. Abstraction from the 1-brorno-3-fluoro derivative was much faster than for the corresponding 3-unsubstituted derivative, indicating a strong polar effect.

Halogenation The addition of HBr across styrene in an anti-Markovnikov manner to give 2bromoethylbenzene has been re-examined both in the presence and absence of 2bromo-2-methylpropan01.'05 A far greater selectivity for the formation of the antiMarkovnikov product was obtained with the additive. The kinetics of chlorination of hexane by various N-chlorosulfonamides have been reported. O6 Competing H-abstraction by C1' or by the sulfonamidyl radical was observed. Addition Reactions

Addition to Alkenes The absolute rate constants for the addition of benzyl, cumyl, cyanomethyl, t-butoxycarbonylmethyl, 07,'Ox and hydro~yrnethyl'~~ radicals to a variety of mono-, 1 , l - and 1,2-disubstituted and trisubstituted alkenes have been measured using

'

Organic Reaction Mech.anisms 199.5

106

time-resolved electron spin resonance. Rate constants were found to vary from 3.3 x lo3 1 mol-' s-' (ethene) to 2.4 x 106 1 mol-' s - ' (1,l-diphenylethene) for the cyanomethyl radical, and from 1.1 x lo4 1 mol-' s-' (ethene) to 1 x lo7 1 mol- s- (1,l -diphenylethene) for the t-butoxycarbonylmethyl radical. Cumyl and benzyl radicals were found to undergo addition to acrylate and styrenes at similar rates. The relative rates and regioselectivity for the addition of a number of electrophilic radicals to pyrrole, furan, and thiophene have been measured.Ito A study of the addition of alkyl radicals to vinylborane derivatives, which investigated the effect of the different boron substituents on the rate and regioselectivity of the reactions, has been reported.' The reactivity of the t-butyl radical with diethyl tartrate-derived vinylboronic ester was found to be similar to that of acrylamide. Theoretical treatments for analysing alkyl radical additions to alkenes have been evaluated.'I2 Ab initio calculations at a range of levels of theory identified UQCISD or UQCISD(T) energies with the 6-3 1 1G**basis set and UHF/6-3 1G* geometries to be best suited. Principal component analysis has been applied to separate polar and enthalpic effects for alkyl radical addition reaction^."^ The rate constant for the addition of the methyl radical to 2-methyl-2-butene has been studied in the temperature range 405444 K.' l 4 The additions of radicals generated from cyclic ethers, alcohols, and alkyl iodides to perfluorenol esters have indicated that these esters are particularly good acceptors of nucleophilic radicals owing to their low-lying LUMOs which allow them to react with radicals which possess relatively high SOMO energies.'I5 2-Substituted vinyl radicals, prepared from the corresponding iodides using either Bu3SnH or TTMSS, add to a variety of alkenes to give (Q-1,2-disubstituted products exclusively. However, the stereoselectivity of the addition of 1,2-disubstituted vinyl radicals was shown to be dependent upon the substituents (Scheme 20). The photoaddition of [60]fullerene to silylketene acetals gives rise to a-fullerene-substituted carboxylic esters instead of the expected 2 2 cycloaddition products.'I7 A mechanism involving a fullerene-ketene acetal radical ion pair was postulated to explain the outcome of the reaction. The relative reactivities of a number of monomers (acrylonitrile, methyl acrylate, methyl methacrylate, and styrene) and dienes (butadiene, isoprene, 2,3-dimethylbutadiene, and 2,3-diphenylbutadiene) with the 1-methyl- 1-(methoxycarbonyl)ethyl radical have been determined. l 9 The data were compared with those obtained from the addition of poly(methy1 methacrylate) radicals to the same acceptors. Results utilizing the monomers showed that the poly(methy1 methacrylate) radical can be modelled adequately by the 1-methyl- 1-(methoxycarbonyl)ethyl radical. Radical allylation has been studied by a number of workers. a-Silyl-a-phenylselenoacetic esters undergo radical allylation with a number of allyltributyltin compounds to hrnish the corresponding a-allyl-a-silylacetic esters, important precursors to di- and tri-substituted THF compounds (Scheme 2 1).I2O A new monoallylstannane radical allylation procedure has been developed which furnishes the desired allylated products in good yield (Scheme 22).12' The stannane (36) is readily available and the organotin by-product undergoes facile hydrolysis and is easily removed from the reaction mixture. The rates of addition of various radicals to a number of allylstannanes have been measured.122 When nucleophilic radicals were used, the best allylating reagent was

' '

'

+

' ' *,'

3 Radical Reactions: Part 1

107

found to be tributyl[2-(trimethylsilyl)prop-2-enyl]stannane, whereas with electrophilic radicals the tributyl(2-methylprop-2-enyl)stannane was superior. BuiSnH

I

R

R‘

SCHEME 20

SCHEME 21

(36)

SCHEME 22

The additions of phenylthiyl radicals to styrene, vinyl acetate, methyl methacrylate, and methacrylonitrile in the presence of the 1,1,3,3,-tetramethy1-2,3,-dihydro1Hisoindol-2-yloxyl radical have been reported. 123 Diphenylphosphinoyl radicals were found to be more nucleophilic than the corresponding dimethoxyphosphinoyl radicals, with the former reacting 10 times faster with acrylonitrile than with vinyl acetate.’24 The additions of a number of phosphorus- and silicon-centred radicals to both diethyl maleate and diethyl fumarate have been studied by ESR.Iz5 Azide radicals can be generated by the addition of TMSN3 to PhIO and The mechanism for the addition of nitrogen dioxide to alkenes has been probed.I2’ The rate constants and Arrhenius expression for the reactions of 1,1-dichloroethene and (E)-l,2-dichloroethene with the nitrate radical, an important oxidant in the troposphere, have been obtained.I2* It was deduced from these data and previous results that elimination of a chlorine atom from the substrates was not an important step. The kinetics of a number of reactions of mono- and di-substituted phenacyl radicals, important intermediates in photo-induced paper yellowing, have been r e ~ 0 r t e d . IThe ~ ~ addition of perfluoropolyether hypofluorites [X(CF20),(CF2CF20),CF2OR; X = OCF3, or OCF20F] to perfluoroalkenes has been studied by EPR and ENDOR technique^.'^^ Products arising from either addition of a fluorine atom or the partner radicals were detected.

Addition to Oxygen-containing Multiple Bonds A tandem process involving cyclization of a primary radical on to an alkene followed by addition to a C=O group and fragmentation has been reported (Scheme 23).131 The product arises from cleavage of bond a, because this cleavage leads to the maximal relief of ring strain. The kinetics of cyclization of aminyl radicals onto aldehydes have been st~~died.~’ For Sex0 cyclization, the rate constant was found to be 5.1 x lo5 s-’, whereas for 6-ex0 cyclization the rate constant was 3.1 x lo4 s-‘. a-Stannyl radicals


108

undergo 5-exo-trig cyclization onto acyl silanes to give cyclic enol e t h e r ~ . 'The ~ rate constant for the addition of primary alkyl radicals to carbon monoxide has been measured (2.7 x lo5 1 mol-' s-' at 50 "Cj and found to be similar to that for secondary r a d i ~ a 1 s . I ~ ~

SCHEME 23

Addition to Nitrogen-containing Multiple Bonds Cyclization of aryl radicals on to the N or C atoms of imines occurs in a 5-exa-trig manner. Minor amounts of phenathridine products were detected and were shown not to have arisen from rearrangement via a cyclohexadienyl radical intem~ediate.~'The kinetics of the association reactions of a series of chlorofluoromethyl radicals with NO have been measured using pulsed laser photolysisitime-resolved mass spectrometry at various pressures and temperatures. 133 The results were analysed by the variational RRKM method. Addition to Thiocarbonyl Bonds Primary and secondary alkyl radicals derived from irradiation of O-acylthiohydroxamates undergo reactions with thionitrile esters to furnish nitroso compounds which dimerize to form trans nitroso d i m e r ~ . ' ~ ~

Homolytic Substitution Aromatic Substitution The cyclization of carbon-centred radicals on to 2-indolylaryl sulfides and sulfoxides occurs via an intramolecular ipso aromatic substitution reaction (Scheme 24j.135 Intramolecular ips0 substitution has also been observed in N-aryl-N-propyl radicals. @so attack was found to be most efficient when the intermediate cyclohexadienyl radical was captodatively stabilized. Intramolecular aromatic substitution of a-amide radicals gives o ~ i n d o l e sThe . ~ ~reactions were carried out at 160 "C in t-butylbenzene


109

using di-t-butyl peroxide as initiator. Possible mechanisms for the re-aromatization are discussed. The reaction of the hydroxyl radical with a number of aromatic compounds has been studied by ab initio molecular orbital calculations. 13' The observed experimental isomeric distribution was adequately explained by comparison with the calculated HOMO orbital coefficients. Coupling of a number of P-dicarbonyl anions with gemchloro-nitro derivatives via S R N 1 reactions produces alkenes, butenolides, or spiro-1nitro-y-butyrolactones, depending on the reactants. 137

SH2 and Related Reactions Ah initio calculations have been used extensively to investigate theoretically a number of SH2reactions. Calculations (MP2, QCISD) into SH2reactions of hydrogen, methyl,

silyl, germyl, and stannyl radicals at sulfur or selenium in methanethiol and methaneselenol indicate that no hypervalent (9-E-3) intermediates are likely.' 38 On the other hand, this type of intermediate was indicated for substitution at tellurium in methanetellurol. Calculations on the SH2reactions of the above radicals at halogens in alkyl and hydrogen halides have also been conducted. 39 Results indicate that no hypervalent (9-X-3) intermediates are formed even for the iodides. Calculations indicate that homolytic substitution at phosphorus in phosphine or methylphosphine by H' or Me' is particularly facile (14-33 kJ mol-' energy In addition, it was concluded that hypervalent phosphoranyl radical intermediates are involved and that they should not undergo pseudorotation before dissociation (10-3 1 kJ mol- '). Intramolecular homolytic substitution of peroxides to give glycidic esters has been accomplished by adding radicals generated fiom alkyl iodides to ethyl 2-(t-butylperoxymethyl)propenoate (37) (Scheme 25).14'

'


110 Reactivity Effects Polarity and Philicity

The relative reactivities for the addition of the electrophilic radicals 'CH2CN, 'CH,CO,Et, and 'CH(CO,Et)2 to pyrrole, N-methylpyrrole, fixan, and thiophene have been measured and found to be in the order N-methylpyrrole > pyrrole x hran > thiophene.' l o In addition, the selectivity for addition at the orand P-positions was shown to be high (al8 ratios > 50). These results were explained by invoking an interaction between the radical SOMO and both the HOMO and LUMO of the substrates. Stability of Radicals The structures of acyl radicals in solution have been studied using time-resolved infrared spectro~copy.~' The carbonyl stretching frequencies for a number of acyl radicals were measured and they were found to be higher than those for the respective aldehydes due to their higher C=O bond order. The preferred conformations of N-alkylN-trialkylsilylmethylaminyl radicals have been probed by EPR spectro~copy.'~~ The preferred conformation is that in which the P-C-Si bond eclipses the singly occupied N-2pn orbital. Hindered rotation about the C-N bond was also observed. In addition, the facile rearrangement of this radical to give 'CH2N(Bu?SiMe3 has been confirmed and is postulated to proceed by an intramolecular 1,2-shifi of the SiMe3 group. The stability and structure of a range of 8-substituted radicals (.'CH2CHXOMe) have been studied using ab initio calculations.143 Rotamer analysis showed an anomeric effect for X = F and NH2. A significant amount of extra stabilization via the anomeric effect was found for 'CH2CF20Me. The activation parameters and radical stabilization enthalpy were determined for the formation of the 1,3-di-t-butylallyl radical by thermolysis of meso- and ( f)-5,6-di-tbutyl-2,2,5,5-tetrmethylde~a-3,7-diene.'~~ Reactions of hydroxamic acid (38) with

4

0

OH


111

potassium hexacyanoferrate(II1) led to the nitroxyl radical (39), which disproportionated to give the nitroso compound (40) (Scheme 26).145The facile disproportionation is thought to occur due to the fixed Z configuration of the nitroxyl radical. The first demonstration of the formation of a-keto-carbon radicals in an enzymatic system based upon pyruvate formate lyase has been r e ~ 0 r t e d . IThe ~ ~ kinetics of the unimolecular decomposition of the 1-chloroethyl radical have been studied as a function of temperature (849-980 K) in He, Ar, and N2.147

Stereoselectivity in Radical Reactions Stereoselectivity in Cyclization High stereo-control has been observed in the 5-exo-trig cyclization of imidoyl radicals (Scheme 27).14* Moderate diastereoselectivities (58-65%) are obtained in 6-endo cyclizations on to imines. The major diastereomers were postulated to arise via a Felkin-Ahn transition state.38Both 1,2- and 1,5-stereo-induction in the cyclization of substituted hex-5-enyl radicals, produced from tosyl radical addition to 1,6-dienes, have been reported (Scheme 28).i49The results indicated that while 1,2-induction was total (trans), 1,5-control was not (predominance of 1,5-cis). The reported results were in good agreement with MM2 calculations.

Y S=C=N

D

M

S

2. I . Ru$nH, SiOz, H 2 AIBN 0

C02Et

H SCHEME 27

79

21

SCHEME 28

Stereoselectivity of Addition to Alkenes Factors which effect the stereoselectivity in radical reactions have been reviewed. A number of studies have indicated that the method chosen for conducting radical addition reactions can have a significant outcome on the stereoselectivity of the process.

112


The addition of radicals (prepared either by the reduction of alkylmercury halides or by Bu$SnH/UV-mediated reduction of alkyl halides) to a series of silyl protected alkyl 2(1 -hydroxyalkyl)propenoates (41) has been probed (Scheme 29). Is' The diastereoselectivity in the addition of 'C6Hll was found to bc dependent on the method of radical formation [41; R', R2 = Me, R3 = Bu'Me2Si; unti :syn = 5 : 1 (Hg), 1 : 1 (Sn)]. Selectivity also increased with the size of the silyl protecting group R3. The addition of alkyl radicals to methylenoxazolidinones (42) has also been shown to be dependent upon the method for radical gencration; however, this time the tin method was superior (Bu3SnH>RHgH).''' In the majority of cases the major product was the trans diastereomer. The diastereoselectivity was also found to be dependent on the size of the radical and the nature of the nitrogen substituent, with carbamate derivatives giving reversed selectivity. Temperature can also have a significant effect on the outcome of a radical process. The diastereoselectivity of addition of chiral acetoxyallyl radicals to methyl acrylate was found to be temperature-de~endent.'~' A temperature dependence was also found for the stereoselective allylation of (1R,1R,4S)-8-phenylmenthyl-N-Boc2-bromoglycinate with allyltributylstannane. Is3 A study on the 1,2-stereochemical induction in the addition of alkyl radicals to y-oxya,/l-unsaturated ester derivatives (43) has indicated that the role of the alkoxy group (R) is important (R=TBDMS, syn:anti=10.2: 1; R=MOM, syn:anti= 15.8: 1). The dioxolane (44) only showed selectivity in the Z series. An explanation based on allylic strain in the transition state was pr~posed.''~ Selective attack from the re-face gave i-ise to syn products preferentially. Efficient 1,2-induction in the addition of radicals to 3hydroxy-1-(methy1thio)-1-(p-toly1sulfonyl)alk-1-eneshas been observed.'" X-ray and NOE studies in solution have identified the preferred ground-state conformation of the substrate, and selectivity is explained by reduction from the least-hindered face in the captodative intermediate. The importance of taking into account both electronic and steric effects when facilitating stereoselective radical additions has been highlighted. 156 Stereoselectivity in the radical allylation of a number of uridine-5'-monoselenoacetals was found to be heavily dependent on the protecting groups at the 2'-0, 3'-0, and 5'-0 positions. Radical reduction or allylation of the alkoxyindene (45) was highly stereoselective ( > 100 : 1) when the free hydroxyl (R = H) was complexed with methylaluniiniumbis(2,6-di-t-butyl)(-4-methylphenoxi~e (MAD) (Scheme 30).'57 Selectivities were very low when bulky R groups were used, whether they were complcxed or not.


113

U L 0qN

R'

\

(re-facc)

.4'

Ph

R'

(si-face)

SC'HEM~J 30

Stereoselectivity of Atom Transfer Lewis acids have been shown to play an important rolc in the stereo-control of many reduction processes. The stereochemistry of deuteriation of stabilized benzylic radicals containing a-alkoxy substituents (46) has been investigated. 58 Bulky substituents gave only modest selectivities (R = ButPh2Si, u : 1= 4.1 : 1); however, these could be enhanced if the reaction was carried out on the free hydroxyl (R=H) after complexation with (MAD) (u : I = 13 : 1) (Scheme 3 1). The sense of stereochemical induction in the deuteriation of 1,2-dioxy-substituted radicals can be reversed when carried out in the presence of bidentate Lewis acid c he la tors.''^ This reversal in selectivity on complexation has also been reported for the butylation of y-substituted-crmethylenebutyrolactones. 160 The use of TTMSS and BuI gave high cis selectivities while the use of Bu3SnH in the presence of bulky diphenoxyaluminium chloride furnished the trans compounds as the major products. Stereoelectronic factors have also been shown to effect the outcome of many reduction reactions. The stereoelectronic effect of a /I-fluorine substituent on the diastereoselectivity of reduction of the 2-fluorocyclopentyl radical by Bu3SnD has been reported.I6l The role of a-donation in the outcome of reduction of a number of oxazolidinones (47a; X = NH, Y = CO), dioxolan-2-ones (47b; X = 0, Y = CO), ylactone (47c; X=CH2, Y=CO), and tetrahydrohrans (47d; X, Y=CH2) has been determined.'62 Examination of the reduction reactions of enolate radicals that contain adjacent polar stereo-centres has indicated that when R = t-Bu (48) there is no effect on the diastereoselectivity on changing the X group [(49) : (50); X = Me, 96 :4; MeO, 95 : 5; F, 98 : 2) (Scheme 32).'63 This is in contrast to recently published results, which indicate a major stereoelectronic effect in related radicals [(49) : (50); R = Ph; X = Me, 46 : 34; MeO, 97 :3; F, 95 : 5).


114

SePh (46)

D A!

D 1

SCHEME 31

Redox Reactions Redox-induced radical C-C bond-forming reactions have been re~iewed.'~The Saveant theory of adiabatic dissociative electron transfer has been tested using the reduction of di-t-butyl peroxide by aromatic radical anions. From the data it was shown that reduction is not adequately described by the SavCant theory and a non-adiabatic dissociative electron-transfer mechanism was proposed.'64 The use of iron compounds to mediate redox reactions continues to be of interest. Oxidation of isopropylbenzene with iron tetraphenylporphyrin in the presence of iodosobenzene has been ~tudied.'~'A significant amount of acetophenone was detected which was shown to arise from reaction of cage-escaped cumyl radical with iodosobenzene. The rearrangement of 1,2,4-trioxane into diol monoesters using Fe"S04 has been reported.'66 A mechanism involving initial reduction to an oxyl radical followed by 1,s-hydrogen transfer and oxidation was proposed to explain the observed outcome (Scheme 33). A number of catalysts for the hydrodiazotization of diazonium salts have been evaluated and the best, Fe"S04, was found to serve as an electron donor. 16' Intermediate radicals were detected by trapping experiments. 9Benzylpurine can be alkylated at the 9-position via radicals generated by the Minisci procedure. The use of Sm12to mediate cyclizations of alkyl and vinyl radicals has been explored. The mechanism of intramolecular cyclization of a number of 1-substituted-6-halo- 1ynes with Sm12 has been probed (Scheme 34).16' The results for the cyclizations of


115

alkyl halides indicate that the major pathway is radical. Cyclization of vinyl radicals generated from vinyl halides and Sm12 have also been studied in great detail4' Cyclization of 3-bromopropenyl 3-(trimethylsily1)propynyl ether (51) furnished a mixture of products including alcohol (52), which may arise from radical (53) by either reduction followed by [2,3]-sigmatropic Wittig rearrangement or by a 5-end0 cyclization and samarium Boord reaction (Scheme 35). R

R

R

R

SCHEME 33

12%

47 %

1%

SCHEME 34

SCHEME 35

Photo-cyclization of vinylmethoxynaphthylenes are catalysed by CU(OAC)~. *" The yield and rate of cyclization were increased when oxygen was present in the reaction, suggesting a singlet-state involvement. Copper catalysis has also been investigated for the BdOzH (TBH)-mediated oxidative addition of alkyl, aryl, and acyl radicals to


116

acrylonitrile (Scheme 36).17' Transfer of the peroxy group was shown to be more selective than the transfer of halides or other pseudohalide groups. The kinetics and mechanism of the oxidation of methyl-a-D-glucopyranosideto sodium methyl-cr-D-glucopyranosiduronateby TEMPO, NaBr, and HOCl have indicated that two mechanisms may operate depending on the reaction condition^.'^^ Radical cyclizations of iodoalkenes facilitated by irradiation in the presence of Pd(PPh3)4 have been shown to proceed via a redox mechanism.53

RH

-

Bu'OzH. CUOAC @CN

Bu'02H + Cu' Bu'O + Bu'02H

R

y

N

O~BU'

-

Bu'O + CU" + -OH

BdOH + Bu'02'

SCHEME 36

(54)

SCHEME 37

Radical Ions Anion Radicals The competition between polar and radical mechanisms in the trimethylstannylation of 1-iodonorbornane has been re-examined and found to be heavily dependent on the choice of counterion (Me3SnLi, radical :polar, 79 : 21; Me3SnNa, radical : polar, 32:68).'73 The study concludes that the use of 1-iodonorbornane as a model to investigate radical nucleophilic substitution reactions is inappropriate and 1haloadamantanes are suggested instead. The photochemically initiated reaction betwecn 1-iodoadamantane and arenethiolate anions has been in~estigated.'~~ Evidence was presented for a non-chain SRNlsubstitution mechanism, with the initial expulsion of an electron from the thiolate. A new SRNl reaction utilizing l-chloromethyl-5nitroisoquinoline and the anion of 2-nitropropane has been reported.'75 Mechanistic evidence includes inhibition by O2 and TEMPO. The reactions of SOT with various azoline nitrogen heterocycles has been explored under a variety of reaction condition^.'^^ In acidic or neutral media the reactions proceed by initial hydrogen abstraction from the NH group to give neutral radicals, whereas in basic solution radical

3 RadicaE Reactions: Part I

anions are formed. No products arising from SO: detected.

117 addition to the C=C bond were

Cation Radicals 2,6-Diarylocta-1,6-dienes undergo a moderately stereoselective ET-induced intramolecular 2 2-cycloaddition via cation radical intermediates.177 The electron-transfer photochemistry of 7-methylnorbornadiene and 7-methylquadricyclane in MeOH has been studied and the products identified.17’ Nucleophilic capture of the initially generated radical cations by MeOH hrnishes radicals which then undergo rearrangement to more stable ally1 radicals. The photo-sensitized valence isomerization of quadricyciane to norbornadiene by dibenzoyltnethanatoboron difluoride shows a CIDNP effect which is reversed when the reaction is carried out in the presence of durene. ‘79 This evidence suggests formation of a triplex which promotes intersystem crossing between the intermediate ion-radical pairs.

+

Peroxides, Peroxyl, and Hydroxyl Radicals Peroxides The thermal decompositions of a range of fluoroalkanoyl peroxides,’” diacyl peroxides,’8 1 and di-t-butyl trioxide’” have been studied and mechanistic conclusions discussed. In addition, the effect of the medium on the rate constants for thermal decomposition of di-t-butyl trioxide has been determined using chemiluminescence.IR3 Studies into the steric and electronic effects of substituents on the rate of decomposition of t-alkyl peroxidesIK4 and p-substituted a-cumyl t-butyl peroxides’s5 have been undertaken. The thermolysis kinetics of t-butyl hydroperoxide have been reported.Ix6 The homolytic cleavage of 9-(t-butylperoxy)fluorene with t-butyl hydroperoxide has been shown to be catalysed by various chromium corn pound^.'^^ Peroxyl Radicals The kinetics for the formation of a number of peroxyl radicals by the addition of O2 to substituted methyl radicals’88 and vinyl radicals’89 have been studied by laser photolysis photo-ionization mass spectrometry. For the addition of substituted alkyl radicals, the reactivity was found to increase with electron-donating substituents (e.g. OMe and NH2) and decrease with electron-withdrawing substituents (e.g. CN). The relative rates of oxidation of a number of cycloalkanes by peroxyl radicals have been determined by competitive oxidation with c ~ m e n e . ” The ~ reactivities of the C-H bonds in five-, seven- and eight-membered rings were found to be much higher than those of six-membered rings. The rate constants for the reactions between peroxyl radicals and a number of flavanoids and catechols, known inhibitors of lipid peroxidation, have been measured using the kinetic chemiluminescence method.”’ The recombination reaction of t-butylperoxyl radicals to give di-t-butyl tetroxide has been studied and the equilibrium constant determined.45The parabolic model has been used to study the kinetic data of the reaction between peroxyl radicals and aromatic

118


amines, thiols, phenols, and alkylhydroxylamines. 192 The one-electron reduction potentials of alkylperoxy radicals have been estimated using thermodynamic data. 193 Hydroxyl Radical

Reactions between the hydroxyl radical and various halogenated alkanes have attracted a lot of attention.194Ab initio studies of the reaction between the hydroxyl radical and trifluoromethane (MP2 level) have been reported.'95 The calculated rate constant was in good agreement with experimental data and a half-life of 65.5 years for CHF3 in the troposphere was proposed. Ab initio studies have also been undertaken on the reactions between the hydroxyl radical and various fluorinated e t h a n e ~ . 'Transition-state ~~ geometries were optimized at the HF/6-31G(d) and MP2/6.31G(dp) levels of theory. It was concluded that 'hydroxyl radicals are the most likely initiators of tropospheric degradation of HCFC, HFC, and CFCs.' The reaction with CF3CH2Fhas been studied in more detail between 255 and 424 K using the discharge-flow resonance fluorescence te~hnique.'~' The kinetics for the reactions between the hydroxyl radical and a number of chlorine- and fluorine-substituted acetates have been reported. '91 In aqueous media the reactivity was found to increase with decreasing halogen substitution, but no reactivity differences were observed for related chloro and fluoro compounds. The mechanism and kinetics for the reaction of the hydroxyl radical with dimethyl ether, diethyl ether, di-n-propyl ether, di-iso-propyl ether, di-n-butyl ether, 199 and t-amyl methyl ethe?" have been determined. Rate constants for the reactions between the hydroxyl radical and methyl glyoxal,201cis-hex-3-en-1-01, cis-hex-3-enyl acetate, transhex-2-enal, linaloo1,2024-methylpentan-2-one and 2,6-dimethylheptan-4-0ne~'~have been determined.

Diazoalkanes The thermal decompositions of a number of para- and meta-substituted 1,4-diamyl-2,3diaza[2.2.l]bicyclohept-2-ene derivatives (54) have been studied in order to probe the electronic effects of this reaction (Scheme 37).204The results indicated the importance of polar effects on the rate of reaction with both radical- and anion-stabilizing substituents enhancing the rate. Analysis of the data by two-parameter Hammett treatment was reported.

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Organic Reuction Mechanisnis I995

Guindon, Y., Slassi, A,, Rancourt, J.? Bantle, G . , Bencheqrous, M., Murtagh, L., Ghiro, E., and Jung, G., 1 Org. Chem., 60, 288 (1995). l h 3 Hassler, C., Batra, R., and Giese, B., Tetrahedron Lett., 36, 7639 (1995). 164 Wcrkntin, M. S., Maran, F., and Wayner, D. D. M., 1 Am. Chem. Soc., 117, 2120 (1995). l h 5 Baciocchi, E., d'Acunzo, E, Galli, C., and Ioele, M., 1 Chem. Soc., Chem. Commun., 1995, 429. 166 Bloodworth, A. J. and Shah, A,, Tetrahedron Lett., 36, 7551 (1995). 167 Wassmunett, F. W. and Kiesman, W. F., 1 Org. Chem., 60, 1713 (1995). lb8 DCsaubry, L. and Bourguignon, J.-J., Tetrahedron Lett., 36, 7875 (1995). 16') Zhou, Z., Larouche, D., and Bennett, S . M., Tetrahedron, 51, 11623 (1995). 170 Kar, S. and Lahiri, S . , 1 Chem. Soc.. Chem. Commun., 1995, 957. Araneo, S., Fontana, F., Minisci, F., Recupero, F., and Sem, A., . I Chem. Soc., Chem. Commun., 1995, 1399. 172 dc Nooy, A. E. J. and Besemer, A. C., Tetruhedron, 51, 8023 (1995). 173 Adcock, W. and Clark, C. I., 1 0%.Chem., 60, 723 (1995). 174 Ahbala, M., Hapiot, P., Houmam, A,, Jouini, M., Pinson, J., and Savkant, J.-M., 1 Am. Chem. Sac., 117, 11488 (1995). Venelle, P., Ralhelot, I?, Maldonado, .I. and , Crozet, M. P., Heterocycl. Commun., 1, 41 (1995); Chem. Abs., 122, 105046 (1995). 176 Shohoji, M. C. B. L., Novais, H. M., and Vicira, A. J. S. C., 1 Chem. Soc., Perlcin Truns. 2, 1995, 2101. 177 Takahashi, Y., Ando, M., and Miyashi, T., 1 Chem. Soc., Chem. Commun., 1995, 521. 17* Weng, H., Du,X., and Roth, H. D., 1 Am. Chem. Soc., 117, 135 (1995). 17' Yang, L., Zhang, M.-X., Liu, Y.-C., Liu, Z.-C., and Chow, Y. L., 1 Chem. Soc., Chem. Commun., 1995, 1055. 18" Sawada, H., Mitani, M., and Molya, Y., Zaiyo Gijutso, 12,290 (1994); Chem. Abs., 122, 105121 (1995). Guo, Q., Liu, P., Li, Y., and Liu, Y., Lanzhou Duxue Xuebao, Ziran Kexueban, 29, 148 (1993); Chem. Abs., 122, 30850 (1995). Khursan, K. L., Shereshovets, V. V., Shishlov, N. M., Khalizov, A. F., and Komissarov, V. D., React. Kinet. Catul. Lett., 52, 249 (1994); Chem. Abs., 122, 55487 (1995). Khalizov, A. E, Makarova, 0. N., Khursan, S. L., and Shereshovets, V V., React. Kinet. Catul. Lett., 54, 427 (1995); Chem. Abs., 123, 32535 (1995). Matsuyama, K., Sugiura, T., and Minoshima, Y., 1 Org. Chem., 60, 5520 (1995). Hendrickson, W H., Nguyen, C. C., Nguyen, J. J., and Simons, K. T., Tetrahedron Let?.,36, 7217 (1995). Batt, L., Kham, M. A., and Mitchell, T. J., Symp. (Int.) Combust. [Proc.], 1994, 793; Chem. Abs., 123, 82678 (1995). lE7 Muzart, J. and Abdelaziz, N. A., 1 Mol. Catal., 92, 141 (1994); Chem. Abs., 122, 9296 (1995). Masaki, A,, Tsunashima, S., and Washida, N., 1 Phys. Chem., 99, 13126 (1995). Knayazev, V. D. and Slagle, 1. R., 1 Phys. Chem., 99, 2247 (1995). Iqu Hamish, R., Lauterbach, G., and Prtizkow, W., J: Prakt. ChemKhem. Ztg., 337, 60 (1995); Chem. Abs., 122,213385 (1995). 19' Belyakov, V. A,, Roginsky, V. A., and Bors, W., 1 Chem. Soc., Perkin Truns. 2, 1995, 2319. Denisov, E. T., Kinet. KataL, 36, 345 (1995); Chem. Abs., 123, 143235 (1995). I q 3 Merenyi, G., Lind, J., and Engman, L., 1 Chem. Soc., Perkin Trans. 2, 1994, 2551. 194 Hsu, K.-J. and DeMore, W B., 1 Phys. Chem., 99, 1235 (1995). Fu, Y., Lewis-Brown, W., and Tyrrell, J., 1 Phys. Chem., 99, 630 (1995). '91 Martell, J. M. and Boyd, R. J., 1 fhys. Chenz., 99, 13402 ( 1 995). '91 Gen-Hou, L. and Yuan-Pem, L., 1 Chin. Chem. Soc. (Taiyei), 41, 645 (1994); Chem. Abs., 122, 55548 (1 995). Iy8 Maruthamuthu, P., Padmaja, S., and Huie, R. E., In?. 1 Chem. Kinet., 27, 605 (1995). 199 Mellouki, A,, Teton, S., and IeBras, G., Int. 1 Chem. Kinet., 27, 791 (1995). Smith, D. F., McIver, C. D., and Kleindienst, T. E., Int. 1 Chem. Kinet., 27, 453 (1995). 201 Tyndall, G. S., Staffelbdch, T. A., Orlando, J. J., and Calvert, J. G., Int. 1 Chem. Kine?., 27, 1009 (1995). Atkinson, R., Arey, J., Aschmann, S. M., Corchnoy, S. B., and Shu, Y., Int. 1 Chem. Kinet., 27, 941 (1995). 2u3 Atkinson, R. and Aschmann, S. M., Int. 1 Chem. Kinet., 27, 261 (1995). '04 Nau, W. M., Harrer, H. M., and Adam, W., 1 Am. Chem. Soc., 116, 10972 (1994).

"' '*

'"'

CHAPTER 4

Radical Reactions: Part 2 I. I. BILKIS

Institute of Biochemistry, Food Science and Nutrition, Faculty ofdgriculture, The Hebrew University of Jerusalem Structure, Stereochemistry, and Stability . . . . . . . . . . . . . . . . . . . . . . . . . Carbon-centred Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nitrogen-centred Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxygen-centred Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitroxides and Spin Trapping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Homolytic Oxidation and Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electron-transfer Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photo-induced Electron Transfers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Electron Transfers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Anions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biradicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thermolysis and Pyrolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photolysis and Radiolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

123 123

123

129 132 133 137 138 138 I45

151

151

157 162 169 171 174

Structure, Stereochemistry, and Stability Carbon-centred Radicals

ESR spectra of alkyl- and fluoroalkyl-C60free radicals'32of general formula CXYZ-C60 (1) have been described, and the structure of the most stable conformer has been established for each particular case. The relative stability of different conformations is determined by the electronegativity of atoms or groups X, Y, or Z, and also by the charge distribution on the surface of C6*. The conformation wherein an electronegative group X resides above the pentagon is the most stable. According to semiempirical quantum-chemical calculations, this is due to a favourable electrostatic interaction between the group and positively charged sites in the pentagon. For systems with two equivalent electronegative groups X = Y, there are two enantiomeric conformations equal in energy. Their mutual transformations occur above 200 K at a rate detectable by EPR. Organic Reaction Mechanisms l Y Y 5 . Edited by A. C. Knipe and W. E. Watts IQ 1997 John Wiley & Sons Ltd

123


124

a;

x = Y = Z = H; b; X = F , Y = Z = H ;

(1) C;

X = OH, Y = Z = H; d; X = CO,H, Y = Z = H;

e; X = Y = F, Z = H; f X = Y = Z = F g; X = Y = H, Z = CH,; h; X = Y = F, Z = CH3; i; X = CF3, Y = Z = H; j; X = CF?, Y = F, Z = H; k; X = CF3, Y = Z = F; I; X = H, Y = Z = CH3; m;X = CFx, Y = H, Z = CHI; n; X = Y = C F ? , Z = H 0; X

= Y = CF3,Z= F

Muonium, which models the chemical behaviour of the hydrogen atom, adds to imidazoline derivatives via positions 2 and 5.3 Interaction of muonium atoms with C7" fullerenes leads to the formation of five isomeric radicals of p-C,,j! Based on calculations and experimental data, an attempt was made to ascribe the muon-electron isotropic hyperfine interaction (hfi) constants to particular isomers. The structure of the tricyclohexylmethyl radical was studied by EPR. A complex hyperfine structure of the EPR spectrum was interpreted using semiempirical quantumchemical calculations within the MNDOAJHF approach. The radical is characterized by the C 3 h symmetry, with the cc-carbon and three fl-carbons lying in the same plane. The temperature dependence of the hfi constants with cc- and fi-protons is attributed to torsional movement of cyclohexyl fragments around the C,-Cp bond.' Internal rotation of methyl groups in the t-butyl radical was studied by EPR. The activation energy of the process was found to be 6 kcal mol-' .6 EPR and ENDOR spectra of radicals trapped during the photo-induced polymerization of trimethacrylate and vinylmethacrylate monomers were reported. Radical decay during post-irradiation heat treatment and dynamic phenomena involving radicals have been interpreted in the light of a dispersive kinetic model.' The 2-@-dimethylaminopheny1)indane-1,3-dion-2-yl radical (an intermediate in the inhibited liquid-phase oxidation of alkylarenes) was prepared at 350 K and ENDOR and EPR spectra of its toluene and diethyl phthalate solutions were described.8 Free radicals resulting from interactions of the t-butoxyl radical with seven terpenes, i.e. a-pinene, b-pinene, a-terpinene, y-terpinene, car-2-ene, car-3-ene, and limonene, were characterized by EPR. Despite the presence of several potentially labile hydrogen atoms, for most systems one prevailing radical species, either substituted cyclohexenyl or substituted cyclohexadienyl radical, was detected.' High-level quantum-chemical calculations have indicated that the free radical HCCCO can be attributed to two minima on the potential-energy surface of its ground electron state, with the minima corresponding to two non-equivalent canonical structures, namely propynonyl(2 j and propadienonyl(3j. In other words, structures (2) and (3) are the real isomers rather than resonance structures.'" The quantum-chemical


125

calculations suggest that multiple minima may be the common feature of several 2A' ground-state free radicals.' In order to find possible stable conformations of the glycine radical in protein structures, a systematic study of the radicals resulting from the corresponding dipeptide was carried out by quantum-chemical methods.I2 The free radicals exhibit slow conformational mobility in comparison with the starting dipeptide. The flat and nearly flat conformations that contribute largely to delocalization of n-electrons are energetically most favourable.

(4)

a; X = H , Y = N 0 2 ; b; X = Y = NOz; c; X = Y = CO2H; d; X = y = co2Me; e; X = Y = COCl; f X = Y = H

A series of inert mono-and di-rnetu-substituted perchlorotriphenylmethyl radicals (4) were synthesized, and their EPR spectra, magnetic susceptibility, and electrochemical behaviour were characterized.l 3 The relative stability of hetero-substituted allyl radicals CH2=CHX (X = Be, BH, NH, 0, Mg, AIH, SiHz, PH, S) was estimated using ab initio and DFT methods. These radicals are stabilized if all atoms forming the allyl skeleton possess comparable electronegativity. In this situation, an unpaired electron is shared between terminal atoms. Tf the electronegativity of the heteroatom is markedly different from that of carbon, stabilization of the radical system is weak and the unpaired electron is predominantly localized on a less electronegative atom.l4 An equation has been suggested for estimating the relative stability of polyenyl radicals of general formula C-(C=C)N: Es(N)

=

-13.2

+ 3.95 -15.8(2)-2"

This equation was used for predicting the stabilities of the weakest C-H, C-C and C-OH bonds in vitamin A and similar compounds.l 5 'Strain-free' stabilization energies were determined for alkyl radical with a-(4-pyridyl) (7.9 kcal mol-'), a(1 -naphthyI) (12.0 kcal mol-'), and a-(2-naphthyl) (8.7 kcal mol-') fragments,I6 different a-carbomoyl substituents (CONR'R2),I7 and two or three a-methoxycarbonyl


126

groups.'* The effect of o-methyl groups on stability of cumyl radicals was discussed." Factors determining the facile formation of diphenyl(2-, or 3- or 4-pyridy1)methyl radicals from the respective dimers were the subject of the study.** The various approaches to the assessment of the relative stability of free radicals (R') produced from amphihydric compounds, such as substituted 9-phenylfluorenes, triphenylmethanols, 9-phenylxanthenes, 2-aryl- 1,3-dithianes, and 2-aryl-1,3-dioxolanes, were discussed.21 Dissociation energies of the C-H bond in acetophenone derivatives with one or two functions of divalent sulfur, i.e. -SCH2COPh and (-S),CHCOPh, were determined. The introduction of one S-substituent decreases the dissociation energy of the C-H bond. The second S-substituent leads to additional weakening of the C-H bond provided that both sulhr atoms are incorporated in a five-, six-, or seven-membered ring.22 The G2, G2(MP2), CBS-4, and CBS-Q models were used to calculate dissociation energies for H-X, CH3-X, CH,=CH-X, CH=C-X, and C H 3 C ( O F X bonds, where X is a first- or second-row substituent. A comparison with available experimental data has shown that the CBS-Q and G2 models yield the best results (the average error is 1 kcal mol-'). There are good correlations between dissociation energies for R-X and H-X bonds. For coordinatively unsaturated substituents X (Li, BeH, NH2, Na, MgH, and AIHZ), the line slopes are similar [cf. 1.20 for CH2-X, 1.20 for CH2=CH-X, 0.91 for CH=C-X, and 0.93 for CH3C(0)-XI. The other group consists of substituents X having unshared electron pairs (NH2, OH, F, PH2, SH, and Cl). In this case, linear dependences between dissociation energies for H-X and R-X bonds have different slopes [cf. 0.75 for CH3-X, 0.85 for CH,=CH-X, 0.46 for CH=C-X, and 1.16 for CH,C(O)-X]. The established correlations have been analyzed in terms of Pauling's electronegativity interpretation of covalent and ionic contributions to bonding.23

Nitrogen-centred Radicals EPR was employed to investigate the structure of aminyl radicals produced via the addition of photochemically generated trialkylsilyl radicals R3Si' (R = Me, Et, Pr') to N-methylene-t-butylamine(H2C=NBut) or via interaction of alkoxyl radicals (R'O') with aminophosphanes (EtO)2PN(R)CH2SiMe3.24 R3Si'+ CH2=NBuf R'O'+ (EtO),PN(R)CHzSiMe3 R

=

-----f

R3SiCH2-fi- But

+

(5) Me3SiCHz-N-R

+ (EtO),POR'

Me, Bu'

The resulting aminyl radicals (5) give preference to conformations (5a) and (5b) in which the B-C-Si bond eclipses the N 2pn orbital formally populated by one electron. Lineshape effects, observed in EPR spectra, indicate a hindered rotation around the R3SiCH2-N bond.


127

There is some evidence that the aminyl radicals (5) rearrange to a-aminomethyl radicals ( 6 ) due to an intramolecular 1,2-shifi of the trialkylsilyl group from the carbon to nitrogen atom:

(5)

-+

'CH2N(But)SiR3 (6)

A number of aminyl radicals (7), stabilized by capto-dative interaction of alkoxyl substituent (donor) with a 4-X-2,6-dinitrophenyl substituent (acceptor), were obtained by oxidation of the corresponding mines with lead tetr aa~ etate.The ~ ~ values and signs of the hfi constants of unpaired electron with nitrogen, fluorine, and hydrogen nuclei were determined by ENDOR and TRIPLE resonance spectroscopy. The EPR spectrum

RO-I? NO2

(7) a; R = Me, X = H; b; R = Me, X = NO5 c; R = Et, X = H; d; R = Et, X = NOz; e; R = Pr', X = NOz; f R = Me, X = CF3; g; R = Et, X = CF3; h; R = Me, X = Me; i; R = Et, X = Me

of the 2,6-dinitrophenylaminylradical (7a), observed during oxidation of the respective amine, tends to transform quickly to the spectrum of the 2,4,6-trinitrophenyl derivative (7b). A possible mechanism of the substitution of a nitro group for a hydrogen atom in position 4 of the aromatic fragment is discussed. Aminyl radicals (7) are stable in an inert atmosphere, but in the presence of oxygen tend to transform to the corresponding nitroxides. A number of persistent, isolable, and oxygen-insensitive aminyl radicals (8)--(10) were obtained via reaction of PbOz with the corresponding anilines.26p28The stability of aminyl radicals was found to depend on the nature of substituents in aromatic fragments of both aniline and thiol parts. Specifically, radicals (8) are most stable when X and Y are electron-acceptor groups.26 EPR spectra of radicals (8H10)have been described. The synthesis of partly deuteriated aminyl radicals (9) and (10) made it


128

(8) X = 4-Me, 4-C1,4-Br, 2,4-C12, 3,5-c12, 3-N02, 4-N02; Y = 4-Me, H, 3-C1,4-C1

possible to determine hfi constants and thus get a picture of the spin-density distribution in those There is still no loss of interest in short-lived aminyl radicals and their protonated forms. Researchers' attention was mainly focused on a search for high-level quantumchemical methods for the accurate estimation of spin-density distribution in these species,29 determination of the acidity of protonated forms,30 and characterization of their relative reactivity in (a) addition to the double and (b) abstraction of hydrogen atom.30Thus, multi-reference CI and DFT methods were used to study the geometry and spin-density distribution in the radical cation of azetidine and its deprotonated form, i.e. azetidin-1-yl radicaL2' According to the calculations, the radical cation has a planar geometry, whereas a neutral aminyl radical is puckered with an optimized puckering angle of 22-23". The spin-density distribution in the radicals, calculated by the above methods, was found to be in satisfactory agreement with experimental values. Ab initio investigation" of the addition of aminyl radicals and their protonated forms to the double bond has indicated that the radical-cation form is much more reactive than the neutral form, which is in good agreement with e~periment.~' The experimental data have shown that the radical-cation form is about four times as active as is the free-radical form in addition to the double bond, whereas in the process of hydrogen-atom abstraction their reactivities are ~omparable.~'Several


129

I

Ph SCHEME 1

types of radical clocks based on cyclization or fragmentation reactions of dialkylamine radical cations (Scheme 1) were propo~ed.~' The radical clocks can be used fbrther for the quantitative characterization of different kind of reactivities of the species. However, as indicated3' application of the radical clocks is complicated by the fact that both cyclization and fkagmentation reactions are very pH sensitive (the pK, of dialkylamine radical cations is about 7), and also can be sensitive to the polarity of media.

Oxygen-centred Radicals The absorption spectra and chemical behaviour of 2-alkylbenzoyloxyl radicals have been described. Intramolecular transfer of the hydrogen atom takes place in these radicals, leading to the formation of the corresponding 2-carboxybenzyl radicals32 (Scheme 2).

* O Y O

R%

\

-

H-oYo R

y

\ J

R = H, Me, Ph SCHEME2

A previously proposed simple method for the assessment of energy of homolytic cleavage of A-H bonds in weak AH acids with the use of the pKAHand oxidation potentials of conjugated anions A- was applied to evaluate such energy of 0-H bonds in 18 phenols.32 The theoretical values are in agreement with the experimental values within ca 2 kcal mol-' . The results suggest that introduction of two t-butyl groups in positions 2 and 6 of phenol derivatives decreases the energy of homolytic cleavage of


130

the 0-H bond by 3.6-10.3 kcal mol-'. Such a decrease is caused by destabilization of the initial state due to increasing steric strain in the vicinity of the OH group rather than by additional stabilization of the radical. The same approach was used to evaluate structural effects on the enthalpies for homolytic cleavage of the 0-H bonds in different k e t o ~ i m e s . ~ ~ Geometry, spin-density distribution, and vibrational frequencies and their isotope shifts have been calculated for the phenoxyl radical by taking advantage of different high-level quantum-chemical methods. The results of DFT calculations are in satisfactory agreement with experiment, and also with more expensive UNOCASIICASSCF calculation^.^^ The DFT approach was also used to calculate geometry, spin-density distribution, and vibrational frequencies and their isotope shiRs for biologically important tyrosinylphenoxyl radical (1 1). The results obtained permit a more reliable identification of this radical in biological systems.36 Using t-butoxyl radical and 1,3,5-trimethoxybenzeneas an example, the first spectral evidence for the existence of 7c-complexes between alkoxyl radicals and electron-rich aromatic compounds was obtained.37 Absorption spectra of a series of (arylcarbiny1)oxyl radicals (12H14) have been described.37Different from simple alkoxyl radicals, the radicals (12)-(14) are characterized by strong absorption in the visible region, with Amax ranging from 460 to 590 nm depending on the structure of the (ary1carbinyl)oxyl radical. The substitution of a methyl or phenyl group for benzyl hydrogen atoms, as well as substitution of an electron-donor group for aromatic hydrogen atoms, causes shifts of Amax to the long-wavelength region. Similar dependences are characteristic of the absorption spectra of peroxyl radicals. For example, as distinct from alkylperoxyl radicals with absorption at 250 nm, arylperoxyl radicals Ar02' (Ar = phenyl, 4biphenylyl, 1- and 2-naphthyl, 9-~henanthryl,~' and 2-pyridyI3') absorb in the visible region. Their wavelength depends strongly on the nature of the aromatic fragment and ranges from 490 to 700 nm. The substituents in the aromatic fragment also exert a significant effect?' Specifically, insertion of electron-donor substituents into the pposition of phenylperoxyl radical leads to a strong shift of A,, towards the IR region. Like arylperoxyl radicals, vinylper~xyls~' are characterized by absorption in the visible

'0

WNH2 7' (y -

H

(11)

',,,

%02H

'0

R2

-

(12)

a; R' = R2 = H; X = H, 4-Me, 4-OMe b; R' = R2 = Me; X = H, 4-Me, 4-OMe C; R' = Ph; R2 = H; X = H

d; R ' = Ph; R2 =Me; X = H


131

A, is at 440 nm and is strongly region: for vinylperoxyl radical CH2=CH-02', dependent on the nature of the substituents at the carbon atoms of the double bond. The aforementioned arylperoxyl and vinylperoxyl radicals were obtained by interaction of the corresponding aryl radicals with molecular oxygen. These reactions occur with rates exceeding 2 x lo9 s-' .38241 Unlike alkylperoxyls, both aryl- and vinyl-peroxyl radicals are strong oxidants which are reduced with organic electron donors, such as 2,2'azobis(3-ethylbenzothiazolined-sulfonate ion), chlorpromazine, and 6-hydroxy2,5,7,8-tetramethylchroman-2-carboxylicacid, at very high rates.38339341 Ab initio calculations were applied for modelling the potential-energy surface of interaction of vinyl radical with molecular oxygen.42The results obtained indicate that the process, the final products of which are 'CHO and CH20, follows a complex mechanism that involves cyclization of the first-formed vinylperoxyl radical to the dioxiranylmethyl radical (15) (Scheme 3) rather than the dioxetanyl radical (16) (Scheme 4) proposed earlier.

SCHEME 3

(16) SCHEME 4

The ab initio and DFT calculations for reactions of intramolecular rearrangement of methylperoxyl and ethylperoxyl radicals were published.43 For CH302 ', the main reactions are re-dissociation to CH3 ' 0 2 , dissociation to CH30' + 0, and isomerization producing 'CH200H radical that decomposes hrther into CH20 and 'OH. Ethylperoxyl radical is isomerized due to 8-self-abstraction producing 'CH2CH200H that further undergoes transformation by one of two routes, one of

+

132


which leads to the formation of ethene and H02' and the other to the formation of oxirane and 'OH radical. Experimental and theoretical methods were used to study the thermochemistry and kinetics of the first step of interaction of ol-chloroethyl radical with molecular oxygen.44 EPR and UV-visible spectra of thiylperoxyl radicals in various organic and aqueous matrices have been described. Unlike alkylperoxyls, thiylperoxyl radicals are characterized by absorption within the visible spectral region (A,,, = 560 nm), and also by comparable hfi constants for terminal and inner oxygen. Unusual features of thiylperoxyl radicals have been interpreted assuming the specific nucleophilic solvation of the sulfur atom in polar solvents, which stabilizes the charge-transfer state RS'OO;. To support this assumption, ub initio calculations were applied to a series of systems for which nucleophilic assistance provided by solvent was modelled by interaction of the sulfur atom with anions X- (HO-, F-, SiH3 -). An attempt has been made to relate structural features of thiylperoxyl radicals to their r e a ~ t i v i t yFor . ~ ~aerobic oxidation of malonic acid by Ce(IV), the peroxymalonyl radical was detected by EPR, and the kinetics of its formation from malonyl radical were studied.46

Miscellaneous Radicals UMPYDZP/TZP ab initio calculations were used to examine the geometric structure and spin-density distribution in Si-centred free radicals of general formula Y,SiMe3-, (Y = C1 or SiMe3, n = O-3).47 The calculated values are in satisfactory agreement with the hfi constants for unpaired electron with 29Si [ ~ ( ~ ~ s Noticeable i)]. changes of u ( ~ ~ caused S ~ ) by gradual substitution of the electron-acceptor chlorine atom for a methyl group are due to the electronic effect of the substituent rather than to the change of geometry of the radical centre. In contrast, substitution of the electron-donor trimethylsilyl group for a methyl group makes the radical centre less pyramidal. It has been noted that application of the correlation between a(*'%) and J(29Si-H), as a source of information about geometry of both silyl radicals Y,SiMe3-, and their precursors Y,SiHMe3-,, is correct, in the strict sense, only for a radical family (where the structure of substituent Y is fixed). According to Guerra?' there is no direct unambiguous relationship between hybridization of the rr(Si-H) bonding MO and the SOMO of the silyl radical and the spatial orientation of bonds of the central silicon atom. Of great importance is the electronic nature of substituents, which has a profound effect on hybridization of the above orbitals for a definite geometry of the central fragment. The same is also true for alkyl and phosphonyl radicals.48From the results reported by G ~ e r r a , ~it' follows that geometric interpretation of the influence of the nature of the P-substituent on hfi constants with 8-hydrogen atoms should be used with care. The methods of generation, spectral characteristics, structural features, and reactivities of silyl radicals have been discussed at length in a re vie^.^'


133

Nitroxides and Spin Trapping The synthesis, structure, properties, and applications o f a number of perfluoroalkyl nitroxides have been re~iewed.~’ 2-Amino-substituted quinazolidine-4(3H)-ones (17) are oxidized by p-nitroperbenzoic acid @-NPBA) to produce mainly endo- (18) or exocyclic (19) nitroxide depending on the nature of substituent R in the 2-amino group (Scheme 5). When the Bu‘02H-PbO;! system is used as an oxidant, the main oxidation product is exocyclic nitroxide (19). The nitroxides formed were identified by EPR.”

0’

p-NPBA

(,

X

SCHEME 5

Nitroxides are among the major products resulting from bas :-catalyzed oxidation of secondary aromatic amines with molecular oxygen.52 Mona .yclic biradicals o f the imidazoline series were obtained by treating 1-hydroxy-3-imic fzolidine-3-oxide with alkyl- or phenyl-lithium with subsequent oxidation. Anisotropi, EPR spectra of the biradicals so obtained were ~haracterized.~~ A new series of pH-se. citive nitroxide diand tri-radicals (20) and (21) with a protonated amino group were sy ~ t h e s i ~ eEPR d.~~ spectra of the polyradicals depend on the nature of solvent, temperatui and pH. The spin-spin exchange increases considerably with decreasing pH. Proto,,ation of the central nitrogen atom seems to promote stabilization of those conformations where nitroxyl centres are located most closely to each other. Crystal structures and magnetic properties have been characterized for a number of compounds with one or two nitronylnitroxide (N) or iminonitroxide (I) groups bound to thiophene (22j(26),552,2’-bithienyl (27)-(30),55thieno[3,2-h]- (31), (32) or thieno[2,3-h]-thiophene (33), (34) rings.56

134


I

0' (21)

R = C02Me, p-C6H&02Me, CH20H COzH, P - C ~ H ~ C O ~ H

2-[p-(N-t-Butyl-N-oxyamino)phenyl]-4,4,5,5-tetramethyl-4,5-dihydroimidazo1-3-ox-

ide- 1-oxyl (a stable biradical with a triplet ground state) was ~ y n t h e s i z e dTheoretical .~~ results suggest that not only monomers of nitroso compounds but also their dimers and radical anions can play the role of spin traps, although the last two are less effective. These results should be taken into account for the analysis of kinetic spin-trapping e~perirnents.~~ An alternative route for spin-adduct formation from nitrones in oxidative systems was discussed. Radical cations of nitrones, whose structure was confirmed by EPR and UVvisible spectra, were shown to react readily with nucleophilic reagents yielding nitroxyl radicals (path a; Scheme 6) ('inverted spin trapping'), which formally corresponds to the addition of free radicals from nucleophile to nitrone. Another alternative to the traditional route (path b; Scheme 6) of formation of spin adducts from nitrones and nucleophiles in oxidative conditions is that of addition of nucleophile to nitrone followed by oxidation of the adduct to nitroxide (path c; Scheme 6).59 Photo-induced reactions were used to obtain spin adducts from N-haloimides and four spin traps (2-methyl-2-nitrosopropane, phenyl t-butyl nitrone, N-t-butyl nitrone, and 1,l-di-t-butylethylene).In the case of the first three spin traps, the formation of spin adducts is preceded by intermediate formation of radical cations of the spin traps due to electron transfer from the trap in excited state to N-haloimide.60 As in the previously mentioned work,59 'inverted spin trapping' is discussed. The first examples of solutionstable radical cations of dimeric forms of nitroso compounds were reported.6' Spin adducts of short-lived free radicals from C-H acids were detected in alkaline solutions containing a trap (2-methyl-2-nitrosopropane or phenyl t-butyl nitrone) and C-H acid. Nitroxides were formed upon heating or UV irradiation of the system in the


PhtH-N-Bu' I 0'

I

PhCH=N-Bur

I

0'

4 b-

PhCH-N-Bur

135

U

Y-

b

Y'

C

-e SCHEME 6

*

PhCH-N-Bu' I I Y

136


absence of a special source of free radicals. The mechanism of spin-adduct formation has been proposed.62 Spin trapping made it possible to establish the structure of short-lived radicals formed: (a) by radiolysis of CF2CICF2CI, CFC13, CFC12CH3, CHF2CF2CF2CI, CF9CHFCF3, CC4, and CF2C1CFC12;63 (6) during reduction of CF2C1CFICl and CF21CFC12 by zinc;63 and (c) by sonolysis of aqueous solutions of N,Ndimethylf~rmamide.~~ Interaction of hydroxyl radicals with deoxyribonucleic acid (DNA) (one of the possible reasons for radiation damage of DNA) with its components was studied in the presence of 2-methyl-2-nitrosopropane as a trap. Pynmidine bases, nucleotides, and nucleosides were found to add the hydroxyl radical to the C ( 5 t C ( 6 ) double bond. In some cases for nucleotides and nucleosides, large amounts of other radicals were formed due to abstraction of the hydrogen atom from a sugar fragment. Formation of the two types of radicals (from the base andor sugar fragment) was also observed for purine nucleotides and nucleosides. The results obtained are regarded as evidence for a fast transfer of the radical centre from base moiety to the sugar fragment. According to EPR spectra of spin adducts of DNA and primarily of its low-molecular-weight fragments (obtained by interaction of partly immobilized DNA with enzyme DNase or an acid), pyrmidine bases are the sites of the primary attack in DNA.6s Aryl radicals showed similar behaviour with respect to DNA and RNA.662-Methyl-2-nitrosopropane was also employed to examine another possible route of radiation damage of DNA, whose key step was interaction of radical cations of pyrimidine bases with nu~leophiles.~'The EPR spectra of spin adducts indicate that radical cations of 1substituted uracil attach nucleophiles (H20 or HP0d2-) to position 5 , and radical cations of thymine to position 6, while radical cations of cytosine derivatives undergo opening of the cycle in the course of interaction with nucleophiles. The regioselectivities of hydroxyl radical addition to pyrimidine bases and of water addition to their radical cations are different, although in both cases the same products are formed. The spin adduct formed by addition of hydroperoxyl radical to 5-diethoxyphosphoryl-5-methyl-I-pyrroline-N-oxide (DEPMPO) is more stable than its analogue formed from 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Hence DEPMPO may be regarded as a promising trap for peroxyl radicals.68 EPR spectra have been characterized for ten nitroxide radicals in ten different solvents. The nitroxides can be attributed to addition of hydrogen atom and C-centred radicals (Me', 'But, 'Ph, 'Phd5, 4-FC6H4', 4-CIC6H4', 4-MeC6H4', 2-MeC6H4') to DMPO. The results obtained will allow a more reliable identification of short-lived radicals from EPR spectra of the corresponding spin ad duct^.^^ Also described were the EPR and ENDOR spectra of spin adducts of a series of C- and 0-centred radicals with new spin traps, i.e. 2substituted-DMPO-type nitrones, namely 2-phenyl-5,5-dimethyIpyrroline-N-oxide, 2,5,5-trimethyl- 1-pyrroline-N-oxide, and 2-phenyl-3,3,5,5-tetramethylpyrroline-Noxide. In many cases, data on the aN hfi constant, together with long-range ay-H hfi constants of spin adducts, allow the determination of the structure of short-lived radical precursor.70


137

Homolytic Oxidation and Reduction Dopamine (35) is spontaneously oxidized by molecular oxygen in neutral and slightly alkaline solutions. A detailed kinetic study has shown that abstraction of a hydrogen atom is the rate-determining step. Subsequent reactions yielding dopaminochrome (36) are relatively fast and cannot be examined. Further, dopaminochrome undergoes polymerization producing melanine. The polymerization process is insensitive to pH and oxygen concentration. The second main reaction product is hydrogen peroxide. Metal ions, except for Mn2+, do not affect the rate of aut~xidation.~'

A dramatic effect of molecular oxygen, benzoquinone, and TEMPO on the yield and composition of reaction products of alkane oxidation by dimethyldioxirane suggests that the process follows a free-radical mechanism.72 Additional support for this suggestion comes from radical-trapping experiments: alkyl, a-alkoxyalkyl, and acyl radicals were trapped by protonated 2-methyIq~inolines~~ or CBrC13 and C U C I in ~~~ reactions of alkanes, ethers, and aldehydes with dimethyloxirane, respectively. A free-radical mechanism was suggested for the oxidative deamination of primary amines by benzyl A radical non-branched chain mechanism has been proposed for oxidative decarboxylation of cyclohexanecarboxylic acid induced by hydrogen peroxide.77 The kinetics of thermal autoxidation of all-trans-p-carotene in chlorobenzene were measured at 50°C. For the initiation step, the reaction is first-order with respect to oxygen and p-carotene. The rate constants and activation parameters of this step have been determined. The effect of promoters (azobisisobutyronirile) and inhibitors (atocopherol) on the {&carotene oxidation rate has been characterized.'* The kinetic behaviour and regioselectivity of autoxidation of n-alkanes have been d e ~ c r i b e d . ~ ~ Chlorodifluoromethylbenzene undergoes reductive dechlorination by samarium diiodide in the presence of various alcohols. The reaction mechanism involves intermediate formation of a,a-difluorobenzyl radical and the corresponding anion. The suggestion is supported by data on the influence of radical traps (various alkenes and alkynes) and of carbanion traps (trimethylsilyl chloride, ketones, and aldehydes) on the composition of reaction products." Pentafluorobenzoic acid undergoes reductive defluorindtion in liquid ammonia in presence of sodium and zinc. While reduction with sodium affects a small part of the starting compound, causing extensive defluorination and loss of three (p-and two 0-)or more fluorine atoms, reduction with zinc is complete and is accompanied by removal of one fluorine atom from only the p-position. The reasons why the reductants exert

Orgunic Reaction Mechanisms 1995

138

different effects have been analyzed. The factors responsible for regioselectivity of reductive defluorination have been discussed.” p-Substituted 3-phenylprop-I -yl hydroperoxides are reduced with iron(I1) in the presence of copper(I1) producing p-substituted 3-phenylpropan-l-ols, 3-phenylpropanals, and a mixture of small amounts of 6- and 7-substituted chromans (Scheme 7). The nature of the substituents in the aromatic fragment and the reaction conditions affect the structure and composition of reaction products. Assuming the key role of 3arylpropoxyl radicals, the structure of intermediates leading to cyclic products and the effect of substituents on their relative stabilities have been proposed.82

SCHEME 7

Electron-transfer Reactions Photo-induced Electron Trunsfers Photo-induced electron transfer (PET) between fkllerene c60 and N,N,N’,N’tetramethylbenzidine was studied by laser flash photolysis in polar and non-polar solvents and their mixtures. Electron transfer was found to follow two different mechanisms for polar and non-polar solvents. For solvent mixtures, the two mechanisms occurred sim~ltaneously.~~ Photo-reduction of fdlerene c60 with triethylamine results in the production of cyclic adduct N-ethyl-trans-2’,5’dimethylpyrrolidino[3’,4’:1,2]c60 hllerene. The reaction mechanism involves electron transfer, proton transfer, and recombination of C60H’ and a-aminoalkyl radicals. The resulting adduct with both electron-donor and electron-acceptor fragments transforms to a cyclic adduct by the above sequence of elementary stages.84 Irradiation of bicyclo[m. 1.O]alkanones (rn = 3-6) in the presence of triethylamine and lithium perchlorate causes opening of the cyclopropane ring and the formation of either 3-methylcycloalkanones or ring-expanded alkanones depending on the substituent in position 3 and the size of the cycle.*’ The reaction mechanism involves electron transfer from triethylamine to ketone and opening of the cyclopropane ring in the radical anion of the starting ketone. Regioselectivity of the ring opening is controlled by the relative stabilities of distonic radical anions (Scheme 8). The structure of the primary products formed during irradiation of the dye 5,7diiodo-3-butoxy-6-fluorone (polymerization photo-initiator) in the presence of electron donors, tertiary amines, or borate salts has been established. When tetrabutylammonium triphenylbutylborate was used as an electron-donor, the only intermediate was the


139

R' = H, Bu, COzMe

R=H;n=1,2

R' = H, C02Me. n = 2 R" = H, C02Me. n = 3,4 I R"

radical anion of the starting dye resulting from one-electron reduction of the dye triplet state. However, for N,N-dimethyl-2,6-diisopropylanilinethe neutral radical, which resulted from protonation of the first-formed radical anion, was detected for the first time. Proton transfer from the radical cation of amine to the radical anion of the dye was so fast that could not be detected on the nanosecond time-scale.86 Photo-reduction of m-trifluoromethylbenzoate ester (37) by N-methylcarbazole was used for generation of 5,6-dihydro-5-hydroxythymid-6-yl radical (38) (Scheme 9). Rate constants for the radical-centre transfer to the sugar moiety, as well as those of dehydration for the radical (38), fall within the range of the lowest rate constants of strand scission. Consequently, neither of the processes can be responsible for the strand scission.87 To model the behaviour of the radical pair resulting from thermal electron transfer in aliphatic nucleophilic substitution, photo-reaction of 9-phenylfluorenyl anion with 6iodo-5,5-dimethylhex-l-enehas been studied. Owing to electron transfer, this yields two types of products with acyclic and cyclic alkyl fragments via isomerization of the alkyl radical intermediate (Scheme 0

HO

hv

F

N-methylcarbazole MeCN - H20 ( I :3)

OH

(37)

OH (38)


140

0,. -a,-,P \

+

-

SCHEME 10

The effect of a magnetic field on the recombination of radical ion pairs arising from irradiation of chemically bound donor and acceptor fragments (polymethylene-bound pyrene and N,N-dimethylaniline) was examined in solvents of different polarity. A new model has been proposed to explain the influence of solvent polarity on the effect of magnetic field on the yield of recombination products: exiplexes and pyrenyl triplets.89 Radical cations of diarylalkenes or diarylalkanes are formed via electron transfer from the parent compounds to electron-acceptor photo-sensitizer. The influence of substituents (m-andp-cyano groups, m- andp-methoxy groups) on the reactivity of the radical cations toward nucleophilic addition and cleavage of the C-C and C-H benzylic bonds was chara~terized.~' In the radical cations of aliphatic esters produced by photo-induced electron transfer, either the C-H or the C-C bond is broken. The direction of fragmentation can be predicted from simple thermochemical estimates." Using adamantane, cyclohexane, and 2,3-dimethylbutane as model compounds, it has been shown that alkanes can be functionalized via the primary, secondary, and tertiary C-H bonds as a result of their one-electron photo-oxidation to radical cation followed by depr~tonation.~~ The various donor systems (t-BuX) suitable for generation o f t butyl radical under mild conditions have been characterized. The process consists of photo-induced oxidation of the donor t-BuX by 1,2,4,5tetracyanobenzenethat leads to


141

formation of the radical cation t-BuX+'. The radical cation decomposes easily producing t-butyl radical and an electrophilic leaving group Xf . Further, t-butyl radical can be involved in the interaction with either radical anion of polycyanoarene or electron-acceptor-substitutedalkenesY3Such an approach was employed for generating a-aminoalkyl radicals from a-silylcarbamates by irradiation of these latter compounds in the presence of catalytic amounts of 9,lO-dicyanoanthracene and biphenyl.94 Photochemically excited dicyanoanthracene oxidizes biphenyl to the radical cation that in turn oxidizes a-silylcarbamate, whose radical cation undergoes C-Si bond cleavage into an a-aminoalkyl radical and trimethylsilyl cation. The a-aminoalkyl radical interacted with an electron-acceptor-substituted alkene to yield finally a yacceptor-substituted amino derivative (Scheme 1 1).

A

A = electron-acceptor group

A

SCHEME 11

To examine the effect of homoconjugation on the reactivity of radical cations of substrates having strained rings as well as olefinic moieties in suitable positions, the products formed by irradiation of 7-methy lenenorbomadiene (39) and 7-methylenequadricyclane (40) in the presence of 1,4-dicyanobenzene and phenanthrene were analyzed in detail.95The data obtained indicate that the main reaction of cation radicals (39'') and (40+') is exo-addition of the nucleophile to olefinic carbons in (39+') and cyclopropane carbons in (40+') with subsequent rearrangement of the resulting free radicals (41) and (42) to the intermediate (43) (Scheme 12). Different from radical cation (40+'), the radical cation (39+') is subjected to some extent to endo-attack by the nucleophile. Although exo-methylene groups participate in delocalization of spin density,y6they are not attacked by the nucleophile in either of the radical cations. However, exo-methylene groups affect the reactivity of primary free radicals by stimulating their isomerization to radicals of ally1 type (43) (Scheme 12).y5

142

Organic Reuction Mechanisms 1995

(39+')

(41)

(42)

(40+')

SCHEME12

The electron-transfer-inducedisomerization of two chiral vinylcyclopropane systems, (1R,5R)-( )-sabinene (44) and (1S,5s)-( +)-a-thujene (46), has been described; (44) and (46) transform to less-strained conjugated dienes (s)-( )-B-phellandrene (45) and (s>-( )-a-phellandrene (47), respectively, due to stereoselective sigmatropic rearrangement of the radical cation intermediates (Schemes 13, 14).97 Photo-oxidation of 3,6-diethyl-3,6-dimethyl-1,2-diazocyclohexene(48) by 9,lOdicyanoanthracene yields the distonic radical cation (49), for which a 1,5-shift of the hydrogen atom takes place (Scheme 15). By taking advantage of labelled and optically pure starting compounds, it was possible to determine that this shift occurred stereospecifically and regio~electively.~~

+

+

+

(47)

SCHEME 14

I


143

SCHEME 15

Irradiation of a complex of the diazene (50) with tetracyanoethylene (TCNE) leads to the formation of radical ion pair (51) of distonic radical cation and radical anion of TCNE (Scheme 16). In polar solvents the radical ion pair recombines forming the final bicyclic product (52). In non-polar solvents, an alternative route is prefered. This route involves the back electron transfer from the radical anion of TCNE to distonic radical cation and subsequent addition of the resulting biradical to the double bond of TCNE.99 The mechanism of photo-cycloaddition of tetraarylthiirane with TCNE was investigated.loo The primary radical cation formed upon irradiation of the complex of tetraarylthiirane with TCNE is characterized by localization of SOMO on electrondonor aromatic fragment @-anisyl moiety, for instance). The further opening of the thiirane ring in the radical cation is caused by stereospecific cleavage of the C-C bond. Interaction of the resulting distonic radical cation with radical anion of TCNE yields the cycloaddition product.

x

& NcxCN NC

CN

CN

(52)

;CHEME

16

144


+

The only products of 2 2-photo-cycloaddition of quinones to cis- and transanetholes @-propenylanisole) are oxetanes. Stationary and time-resolved CIDNP experiments, and combined CIDNP detection with photo-induced electron-transfer sensitization, have helped to elucidate the role of radical ion pairs, produced by photoelectron transfer, in the mechanism of formation of final reaction products."' Electrocyclization of 1,2-bis(l -phenylvinyl)benzene (53) to o-xylylene (54) was induced by photo-electron transfer to TCNE or 9,lO-dicyanoanthracene (Scheme 17). Evidence for the formation of o-xylylene was obtained spectroscopically (Ama = 446 nm) and from analysis of the product of its interaction with TCNE (55).'02 Ph

6h

(53)

Ph

Ph

NcxcNl

. NC

CN

Ph

(54)

+

NC

NC

NC Ph

Ph

SCHEME 17

(55)

Irradiation of diphenylphosphinous acid (56) and 10-methylacridinium iodide (57) in an inert atmosphere was shown to result in the formation of diphenylphosphinic acid (58) and 10-methylacridan (59) (Scheme 18). From the data on the effects of medium, atmosphere, and iodide ion and molecular iodine additives on the composition of the reaction products, it was concluded that the excited state gave rise to the radical cation of (56) and 10-methylacridinyl radical.lo3 The role of radical cations of hexamethylbenzene in the formation of products of irradiation of hexamethylbenzene-molecular oxygen complexes is discussed.lo4 The effect of solvent, substituent, and isotopic substitution on the rates of back electron transfer in contact radical ion pairs resulting from irradiation of complexes of CIO with substituted benzenes in aprotic polar solvents has been characterized. Basic difficulties associated with extracting accurate information on the exothermicity of reactions,


145

SCHEME 18

reorganization energies, and electron coupling from measured rate constants have been re~ealed.'~' Other Electron Transfers

In a review'06 of the results of long-standing investigations, it was concluded that, in addition to the classical SN1 and sN2 mechanisms of aliphatic nucleophilic substitution, the mechanism involving electron transfer from nucleophile to substrate should be taken into consideration. The parameters of reacting systems which contribute to the accomplishment of each mechanism have been determined. Interactions of geminal dihaloalkanes (6,6-dichloro-5,5-dimethylhex-l-ene and 6,6diiodo-5,5-dimethylhex-l -ene) with lithium diisopropylamide,lo' sodium diphenylphosphide,Io8 and lithium na~hthalenide"~have been studied. Data on the structure and ratio of products formed in the first two cases were compared with the results obtained for lithium naphthalenide, which usually acts as a one-electron reductant in reactions with alkyl halides. The comparison suggests that 6,6-diido-5,5-dimethylhex-l -ene interacts with lithium diisopropylamide and sodium diphenylphosphide by the electrontransfer mechanism, while the 6,6-dichloro analogue reacts by the mechanism involving electron transfer from only sodium diphenylphosphide. Lithium diisopropylainide behaves as a base with respect to 6,6-dichloro-5,5-dimethylhex1-ene. Investigations of nucleophilic substitution reactions of the SRNl type have continued. The range of substrates and nucleophiles participating in these reactions has become wider, and the synthesis potential offered by this mechanism is being used. It has been shown that, in DMSO, 1-iodoadamantane takes part in S R N l reactions with enolates of acetone, of acetophenone, of propiophenone, and of anthrone."' The anion of nitromethane is inert in this reaction; however, adamantylnitromethane can be obtained if the reaction is carried out in the presence of acetonate ion. Relative reactivities of the above anions towards the adamantyl radical have been obtained. The results have been interpreted on the basis ofpK, data for conjugated acids and on the change of system 71-energy during the coupling reaction. l o The SRNl reaction can be considerably accelerated by introducing a carbonyl group into a- and p-positions of l-chlorobicyclo[2.2. llheptane and 1 -chlorobicyclo[2.2.2]octane, which has been demonstrated for the reaction of 1-chloro-3,3-dimethyl-2oxobicyclo[2.2.1Iheptane, 4-chloro- 1,7,7-trimethyl-2-oxobicyclo[2.2.1Iheptane, and 1chloro-3,3-dimethyl-2-oxobicyclo[2.2.2]octanewith diphenylphosphide anion in liquid


146

ammonia. The carbonyl group considerably decreases the effective activation energy of the reaction due to its mediator role in electron-transfer processes."' It has been demonstrated that sulfonamides are suitable substrates for the accomplishment of the SRN1reaction via the nitrogen atom. Thus, as a result of the SR,l pathway, the interaction of N,N-dibutyl-p-toluenesulfonamidewith diphenylphosphide anion with subsequent oxidation produces the corresponding phosphinic amides (Scheme 19).

"'

Vicinal dinitro derivatives of dioxane can be synthesized by the SRN1reaction either by interaction of geminal chloronitroalkanes with the anion fi-om 5-nitro-l , 1dimethyldioxane or by interaction of the anion from nitroalkane with geminal chloronitrodimethyldioxane. The first provides better possibilities for the optimization of the yield of the target product. ' I 3 2-Chloromethyl-3-nitroimidazo[ 1,2-a]pyrimidine (60) participates in the SRNlreaction with the anion of 2-nitropropane in conditions of phase-transfer catalysis. The C-alkylated products (61) and (62) are obtained in good yields'14 (Scheme 20). The sodium salt of 1,3,6-trimethyI-5-nitrouracilreacts with alkylating agents such as p-nitrobenzyl chloride and 2,2-dinitropropane by the S R N l mechanism to form new

SCHEME 20


147

potentially bioactive 5-nitrouracil derivatives. 1,3-Dimethyl-5-nitro-6-chloromethyluracil can also be involved in the SRNl reaction with the anion of 2-nitropropane."' Conditions have been found in which dichloroarenes yield products of monosubstitution as a result of an electrochemically induced SRNl reaction. Suitable are those nucleophiles which provide the role of electron-donor substituents upon insertion into the aromatic fragment, e.g. phenoxides and enolates. It was specified that electrolysis should be performed with a low current and in the presence of a redox mediator."' To increase the number of vinyl systems capable of participating in SRN 1 reactions, some stilbene derivatives having an electron-acceptor group at the double bond (63), (64) have been synthesized. However, none of the synthesized compounds reacts with pinocolone enolate by the SRN 1 mechanism. The other transformation pathways turned out to be energetically more favourable. Compounds (63) and (64) interact with pinacolone enolate producing diphenylacetylene, most probably due to two successive steps of electron transfer. Compounds (65) and (66) take part in the process of ionic deformylation caused by addition of pinacolone enolate to aldehydic carbonyl. Methylphenylacetylene is formed as end-product of the reaction. Fluorenylidene derivative (67) follows the classical ionic addition-elimination mechanism.'

X

Ph

I

"XY,,# (63)

(64)

a; X = I, Y = NOz b;X=Y=I c;X=Y=Br

NO2 Ph

Br Ph

CHO

-Me

(65)

Ph

Me

P

O

M

e

Br%O (66) -

(67)

An electron-transfer mechanism has been proposed as one of the main pathways of debromination of erythro- 1,2-dibromo-1pnitrophenyl-2-phenylethanein the presence of the anion of 2-nitropropane, leading to the formation of trans-p-nitrostilbene.' l 8 Reductive dehalogenation of 9,lO-dibromo- and 9,1O-diiodo-2-nitro-9,1O-ethano-9,10dihydroanthracene, assisted by a series of tertiary carbanions, has been studied.' l 9 A chain mechanism involving both inter- and intra-molecular electron-transfer steps has been proposed. Quantitative studies have shown that reductive dehalogenation is regioselective. The reduction occurs preferentially at the benzylic bridgehead position para to the nitro group. However, the ratio of para to metu reduction products is only 1.6 : 1, which is much lower (by about two orders of magnitude) than the difference between the dehalogenation rate constants for other p - and m-nitrobenzyl systems. Possible reasons for the differences observed have been discussed.' l 9 A review'20 reports on a possible reductive activation of nucleophilic substitution in aromatic systems containing electron-acceptor groups. The concept of topologically controlled coulombic interactions has been used to choose appropriate model objects.


148

Tetrathiafulvalene (TTF) catalyses the formation of cyclic products from suitable arenediazonium salts (AD) (Scheme 2 1). The reaction mechanism implies electron transfer from TTF to arenediazonium salt, loss of dinitrogen, radical cyclization, trapping of the obtained radicals by radical cation TTFf' via either sulfur or carbon atom, and nucleophilic substitution of TTF. The reactions are catalytic in TTF.'2'.'22

AD

TTF

R+OH R' SCHEM 2 I~

An effective procedure for dealkylative coupling of benzyl alkyl ethers to give the corresponding diarylmethanes has been de~cribed."~The reaction was induced by oxidation of starting compounds to radical cations, either electrochemically or by small amounts of one-electron oxidants. It follows the chain mechanism whose key steps are coupling of the benzyl alkyl ether with its radical cation, rearrangement and fragmentation of thhe resulting distonic radical cation leading to diarylmethane radical cation, and one-electron oxidation of parent ether by diarylmethane radical cation (Schemc 22). It has been found that Diels-Alder addition of trans-stilbene to 2,3-dimethylbuta- 1,3diene,Iz4 and also cyclopropanation of the former by dia~oacetate,"~are catalysed by salts of triarylamine radical cations. These radical cations cause oxidation of transstilbene to its radical cation, which then adds to 2,3-dimethylbuta-l,3-dieneor diazoacetate. The products resulting from interaction of tricyclo[3 .2.0.02,4]hept-6-enes(68) and quadricyclanes (69) with one-electron oxidants (salts of triarylamine radical cations)

x -x-


ArCHzOMe

MeOCHzOMe

149

[ArCH20Me)"

ArCHzAr

[ArCHzAr]"

ArCH20Me

Scmm 22

have been characterized. The key role in the reactions is played by bicyclo[3.2.0]hept-6ene-2,4-diyl radical cations (68+') and quadricyclane radical cations (69+') which yield reaction products via valence and/or skeletal isomerization and final one-electron reduction. Factors that control the influence of substituents R on the direction of structural changes are discussed.Iz6

(68) a;R=Me

(69) a;R=Me b; R = Ph

b;R=Ph

Rearrangement of vinylcyclopropanes to form cyclopentenes is accelerated by salts of triarylamine radical cations of F e ( ~ h e n ) ~The + . rearrangement is a stepwise process that involves one-electron oxidation of the starting compound.127The role of electron transfer in cycloadditions of 1,4-bis(dimethylamino)buta-1,3-diene,12' 2,3-bis(dimethylaminomethylene)bicyclo[2.2.l]heptane, and 2,3-bis(dimethylaminomethylene)bicyclo[2.2.2]0ctane'~~with the various electron-acceptor alkenes has been discussed. In situations where the oxidation potential of the donor component closely matches the reduction potential of the acceptor component, the reaction rate increases markedly, the reactions lose stereospecificity, and EPR spectra of radical species resulting from electron transfer can be observed. The products of electron-transfer-induced4 2-cycloaddition of 2-vinylindoles (70) to p-aminomethacrylates, such as (71), and nitriles (72), or to 1,4,5,6-tetrahydropyridines (73) have been chara~terized.'~~ The results are of synthetic interest because such reactions can be used to build an alkaloid skeleton in high yield. A mechanism involving electron transfer is regarded as a possible path of formation of vinyl fluorides in reaction of vinyltrimethylstannanes with XeF2 induced by silver(1) triflate. 1 3 ' One-electron oxidation of monosubstituted benzenes by nitrogen trioxide is

+

150

a;R=Me b; R = CH2CH20Et


a; R' = CN, R" = H b; R' = C02Me, R" = H c; R' = C02Me, R" = Me

used to interpret the results of nitration of toluene and chlorobenzene by the ternary system NO-N02-02,'3z and anilides and phenyl esters by the binary system NOz03.133

One-electron oxidation of enols by radical cation salts of triarylamines in the presence of nucleophiles leads to carbonyl compounds containing a nucleophilic group in the a-position. The reaction mechanism involves the formation of the radical cation of the enol, its deprotonation, and oxidation of the resulting a-carbonyl radical to carbocation, which, by attaching a nucleophile at the positively charged a-carbon atom, produces the end-product of the r e a ~ t i 0 n . In I ~place ~ of enols, their trimethylsilyl ethers can be used.'35 Proton donors and acceptors speed up electron-transfer reactions that occur with participation of 1-cyanoalkyl and 1,2-dicyanoalkyl radicals-the key intermediates of tbutylation of a$-unsaturated nitriles by t-butylmercury iodides assisted by iodide ion.136 In the presence of proton donors (e.g. NH4'), I-cyanoalkyl radicals are protonated at the nitrogen atom of the cyan0 group, which enhances its one-electron reduction by t-BuHgl2 - and formation of products of reductive alkylation (cyanoalkanes). 1,2-Dicyanoalkyl radicals can be deprotonated by bases such as DABCO, which enhances oxidation by t-BuHgI and the formation of products of oxidative alkylation (dicyanoalkenes). The electron-transfer mechanism has been proposed to explain tetracyanoethylenecatalysed C-C bond formation and reduction in reactions of aldehydes, ketones, and acetals with silylated nucleophiles (trimethylsilyl cyanide, aryltrimethylsilane, aryl methyl ketone, trimethylsilyl enol ethers and triethylsilane). 13' Nitric oxide promotes the aerial oxidation of chlorpromazine and related phenothiazines (74) to the corresponding sulfoxides. The reaction mechanism involves one-electron oxidation of the starting phenothiazine derivative followed by the reaction of the radical cation obtained with nitrate ion. The radical species, attributed to the structure (75a), were detected when triphenylphosphine was mixed with azodicarboxylate.139 The mechanism of radical cation formation consists of electron transfer from triphenylphosphine to azodicarboxylate and subsequent addition of the radical cation of triphenylphosphine to the starting diazo compound. These elementary steps are the key reactions in the new chain-radical mechanism proposed to describe the formation of betaine (75b).'39


151

RCO~-N-~~-O~CR I

Ph3P+

RCO~-N--N-O~CR I

Ph,P+

R (74) a; R = CH2(CH2)2NMe2,X = C1 b; R = CH2(Me)NMe2, X = H

c; R = CH2(CH2)2N(CH2CH2)2NMe2,X = CF3 d; R =Me, X = H e; R = Ph, X = H

Radical Ions Radical Cations The Raman spectrum of trans-stilbene radical cation has been published.140 Unrestricted HF, MP2 and DFT methods were applied to study the potential-energy surface of norbornane radical cation. 14' According to MP2 and DFT calculations, this radical cation is characterized by the C2, symmetry (see below) in the gas phase. MP2 calculations have made it possible to detect two additional minima on the potentialenergy surface, one of which corresponds to C, symmetry and the other to C1 symmetry. A comparison of calculated and experimental hfi constants indicates that the C, structure occurs in CFC13, CF3CC13,and CF2C1CFCl2matrices, and the C,, structure in perfluoromethylcyclohexane and perfluorooctane matrices.

The electronic and geometric structures of radical cations of general formula CsHg +*, namely radical cations of cyclooctatetraene (COTf'), semibullvalene (SBVf'), and bicyclo[3.3.0]octa-2,6-diene-4,8-diyl (BODf') were reported. Quantum-chemical methods were employed to characterize the potential-energy surface that binds these species (Scheme 23). Photochemical induction was used to carry out rearrangements of COT+' to BOD+', the driving force for which is a strong Jahr-Teller distortion characteristic of the second excited state of COT+'. 142 Photo-induced mutual transformations of BODf' and its four isomers, corresponding to different dihydropentalene isomers (DHP+'), have been studied. A set of rules based on frontier


152

BOD+'

COT"

SBV+'

BOD+'

(-Jy+' - (+Jy+* hv

I,5-DHP+'

1,4-DHP+' SCHEME 23

molecular orbitals was developed to describe the photo-rearrangement of DHP+' isomers.143 The formation energy and geometric and electronic structures of radical cations of polycyclic rigid [I. 1.1. llpagodanes (76) and isopagodanes (77), and of corresponding bis(seco)- (78) and seco-dodecahedradienes (79) have been studied by different methods (cyclic voltammetry, EPR, and quantum-chemical calculations).144-146 According to ab initio calculations (PMP2/3-21G//3-21G), a minimum on the potential-energy surface corresponds to the radical cations of each isomer (76)-(79). A comparison of calculated and experimental hfi constants indicates that oxidation reactions of (76) and (78) lead to the same radical species, namely radical cation (78+'). It looks likely that the radical cation of cyclobutane type (76+') can easily rearrange to form the diene isomer (78+'). In the case of oxidation of isopagodane (77) and secododecahedradiene (79), the radical cation of cyclobutane type (77+') is formed. Transition to the homologues [2.2.1. Ilpagodanes (80) and isopagodanes (81) and their corresponding dienes (82) and (83) reverses the The effects of substituents on (a) oxidation potentials of [1.1.1.llpagodanes (76), bis(seco)- (77), seco- (84), and -dodecahedradienes (85) and (b) the extent of conjugative stabilization of the resulting radical cations were described.146 One-electron oxidation of initially planar bicyclopropylidene (86) (D2h symmetry) was found to yield radical cation (86+'), with cyclopropane fragments being turned


153

relative to each other (D2symmetry).'47 Further, this radical cation undergoes a number of transformations whose directions depends on the nature of matrices in which it has been generated. It undergoes opening of the cyclopropane fragments with the formation of distonic radical cation (87+'). In a CF2C1CFCl2 matrix, detachment of H+, producing the ally1 radical (88), is preferential. Azulene radical cation and its alkyl derivatives were generated by UV irradiation of the starting hydrocarbon with mercury(I1) trifluoroacetate in dichloromethane. The hfi constants were determined by EPR, ENDOR, and TRIPLE spectroscopies. Introduction of alkyl groups into the 1- and 3-positions of azulene enhanced considerably the stability of resulting radical cations. In the absence of substituents at least in one of those positions, radical cations of azulene derivatives dimerized, producing finally radical cation 1,I '-biazulenyls. The high reactivity of radical cations of azulene derivatives at positions 1 and 3 is in agreement with high spin density at these

position^.'^^

154


EPR spectra of the products of interaction between hexamethyl(Dewar benzene) and Tl(II1) trifluoroacetate in trifluoroacetic acid under irradiation have been presented. These EPR spectra were compared with those for radical cations of hexamethylbenzene, pentamethylbenzene, pentamethylbenzyl ethers, and pentamethylbenzyl esters. The EPR spectrum registered during oxidation of hexamethyl(Dewar benzene) can be attributed to the radical cation of pentamethylbenzyl trifluoroacetate. These results call for a critical revision of the earlier spectral data for the radical cation of hexamethyl(Dewar benzene). The kinetics of oxidation of hexamethyl derivatives of benzene and of Dewar benzene by TI(II1) trifluoroacetate have been studied, and a reaction mechanism has been proposed. A strong kinetic isotope effect on the rate of oxidation was detected when D was substituted for H in hexamethylbenzene and solvent.'49'' 50 EPR spectra of radical species resulting from oxidation of different dimethyl derivatives of naphthalene, as well as of the corresponding derivatives of binaphthyl and perylene, have been obtained. Except for situations where peri methyl groups can interfere with the dimerization processes, the EPR spectra taken during oxidation of dimethylnaphthalenes are ascribed to radical cations of binaphthyls rather than of perylenes. The proposed reaction mechanism involves the formation of a n-complex between dimethylnaphthalene radical cation and starting arene as the first reaction step.I5' It is r e p ~ r t e d ' ~ ~ -that ' ' ~ 1,1,1,3,3,3-hexafluoropropan-2-ol (HFP) is an excellent solvent to promote generation of radical cations of aromatic compounds in oxidation systems. HFP solutions of radical cations are fairly stable, even at room temperature, which permits recording of highly resolved EPR spectra for these species. HFP slows down the interaction of radical cations with nucleophiles, such as trinitromethanide ion, but exerts no effect on reactivity in radical r e a ~ t i 0 n s . EPR l~~ spectra of radical cations of benzo-crown ethers, generated by irradiation of the starting compounds in CH2C12in the presence of dichlorodicyanoquinone and trifluoroacetic acid, have been described. Trifluoroacetic acid protonates semiquinone anion, thus preventing back electron transfer.'55 The radical cation salts of bis-annulated hydroquinone ethers (89E(91), which are stable in air, were synthesized. Despite their very similar structures, the radical cations have dramatically different reduction potentials. According to X-ray crystallographic analysis, this difference is due to different capabilities of their methoxy groups of participating in delocalization of positive charge spin density.t56 EPR and ENDOR methods were employed to investigate the structures of radical cations of a number of substituted bis-, ter-, and quater-thiophenes. Being free from


155

steric hindrances, oligothiophene radical cations have a planar structure and exist as mixtures of cis and trans conformers; however, a single type of species is formed for sterically hindered non-planar radical cations. 157 The possibility of synthesis of stable radical cation salts based on polyalkoxy derivatives of dibenzothiophene has been examined. It was found that 2,3,7,8-tetramethoxydibenzothiopheneand 2,3:7,8bis(methylenedioxy)dibenzothiophene produce stable salts, which can be isolated as crystals.'58 New radical cation salts were obtained in one-electron oxidation of 4,7disubstituted benzotrithioles (92) by NOfPF6 -. These salts are stable, and their structures in solutions have been confirmed by 31PNMR and EPR methods.'59

R

R (92)

(93)

(94)

a; R = Prl

b; R = OMe

Electrochemical oxidation potentials of 14 p-substituted arylmethyl chalcogenides (sulfur, selenium, and tellurium derivatives)I6' and of ten 0-,m- and p-substituted anilines'6' have been evaluated. Electrochemical oxidation of a homologous series of tris(ary1)phosphines (2,6-disubstituted, 2-substituted or monosubstituted) showed a good correlation between the oxidation potentials and the sum of Hammett of parameters of the substituents carried by the phenyl ring of the phosphines.16' The influence of a- and P-phenyl groups on the electrochemical oxidation potentials of bisN,N-bicyclohydrazines (93) and (94) and on the rate constants of electron exchange between the parent compounds and their radical cations has been examined. 163 EPR and ENDOR spectroscopy were used to study the spin-density distribution in radical cations generated during the oxidation of 3,8-dihydro-l,3,6,8-tetramethylpyrimido[4,5,6-gh]pyrimidine-2,7-( 1H,6H)-dione (95), 1,2:3,6,7,8-hexahydro-1,3,6,8-tetramethylpyrimido[4,5,6-gh]pyrimidine (96), and 3,6,7,7-tetrahydro-l,3,6&tetramethylpyrimido[4,5,6-glz]pyrimidin-2(lH)(97) by radical cations of tris(4-bromophen~1)amine'~~ and of 1,3,5-tris(diarylarnino)benzenes by radical cations of thianthrene. 165 A review of organosilicon radical cations covers such problems as energetics of the formation of these species in the gas phase and in solution, and their spectral characteristics and reactivity. EPR and electron absorption spectra for radical cations of oligosilanes (SinR,+1R~+,;n = 2-6) are similar to those for radical cations of monomeric silanes and indicate absence of delocalization of unpaired electron in radical cations of polymers.'67 By taking advantage of EPR and ENDOR spectroscopy,


156

MeN

1

NMe

(&I$$@ \

MeNn

NMe

MeN

1

NMe

\

MeN-NMe

MeNKNMe

MeN-NMe

0

(95)

(96)

(97)

it was possible to elucidate the structure of radical cations formed from aryltrimethyland tetraaryl-silanes and corresponding organogermanes. 168 As shown by the EPR method, radical cations of furan and M r a n in Freon medium produce sandwich dimeric corn pound^.'^^ Electronic absorption spectra have been characterized for monomeric radical cations of trans- and cis-stilbenes, and also for products of their interaction with starting neutral molecules (71- and a-dimeric radical cations). Formation rate constants for these species have been estimated. Moreover, these species were found to play a key role in cis-trans isomerization of radical cations. The rate constants for interaction of stilbene radical cations with C1- were also dete~mined.'~'The monomolecular channel for cis-trans isomerization of stilbene radical cations becomes important when aromatic fragments of stilbene have methoxy groups in the p-position. This observation and the finding of higher rate constants of interaction of radical cations of methoxy derivatives with molecular oxygen are explained by a stronger separation of charge and unpaired electron localization sites in these radical cation^.'^' Interaction of radical cations with parent neutral molecules, leading to the formation of head-to-head o-dimeric radical cations, is also typical of a wide spectrum of styrene derivatives in non-nucleophilic solvents. This process occurs with almost diffusion-controlled rate constants. At high concentrations of the starting styrenes, trimeric radical cations are formed. In the case of the generation of radical cations of styrene in aqueous solutions, the main channel of their decay is reaction with water, producing p-hydroxybenzyl radicals. 172 Laser flash photolysis was employed to determine rate constants of interaction (addition and/or deprotonation) of the various radical cations of styrene with different nucleophiles (N-, C1-, Br-, MeC02-, CO;!-, CN-, N03-, aliphatic and aromatic amines, and alcohols) in different solutions. Rate constants for cycloaddition of radical cations of styrene derivatives to different alkenes have also been e ~ t i m a t e d . ' ~ ~ High-level quantum-chemical calculations were used to model the interactions of radical cations of alkenes with H20174and NH3.17'Addition of the nucleophile to the radical cation of the alkene yields distonic radical cations (provided the radical cation does not have stabilizing electron-donor groups), and proceeds almost without an energy barrier. 1747175 The possibility of electron transfer fi-om the nucleophile to the radical cation is also discussed. This pathway becomes a competitive if a radical cation


157

fragment and nucleophilic group belong to the same molecule and are separated by a short spacer.'75 Ab initio calculations and valence-bond-mixing modelling were used to develop paradigms permitting prognosis of pathways of nucleophilic s ~ b s t i t u t i o n ' and ~~ electron transfer177in the interaction of nucleophiles (Nu) with a-type radical cations (GI-GZ +'). Depending on charge and spin-density distribution in the transition states, nucleophilic substitution reactions of radical cations fall into two groups.'76 The first group includes 'homopolar' reactions whose transition states are characterized by approximately equal positive charge distribution over nucleophile (Nu), central atom (GI), and leaving group ((32). The second group includes 'heteropolar' reactions where, in the transition states, the positive charge is located predominantly on the central group (GI) bound to Nu and Gz' by dative bonds. For electron-transfer reactions from nucleophile to radical cation, two additional mechanisms, along with the outer-sphere mechanism, have been found.'77 The first is a one-step mechanism according to which the reaction route andor transition state are characterized by a strong binding of a nucleophile to the radical cation ('concerted electron transfer'). The second is a stepwise mechanism according to which the process that formally corresponds to electron transfer occurs through a succession of formation-rupture of chemical bonds, specifically due to a shuttle transfer of atoms or groups of atoms from nucleophile to radical cation. Rate constants for fragmentation of radical cations of trimethylsilyl ethers 17* and acetates179of sterically hindered 2,2-dimesityl-l-R-ethenols were determined by cyclic voltammetry. The reactions result in the formation of an a-carbonyl radical and trimethylsilyl or acetyl cations, respectively. The rate of fragmentation depends on the polarity of the medium and the presence of nucleophiles which, in particular, promote cleavage of the 0-Si bond by stabilizing the resulting trimethylsilyl cation. The methods of quantum chemistry were applied to study the energy of fragmentation of naphthalene radical cation into acetylene and the radical cation of benzocyclobutadiene. Experimental data on the formation of complexes between radical cation of fbllerene and methane, caused by their high-energy collision, are reported. Chemical properties of organosulfur distonic radical cation 'CH2SH2 have been studied.IX2 In the course of interaction with neutral bases (aniline, cyclopentanone, dimethyl disulfide, thiophene, 1,Cdioxane, furan, toluene, benzene, and methyl iodide), 'CH2SH2+ rearranges to give CH3SH+', which further oxidizes neutral base to radical cation.'** Distonic radical cations, which are phenyl radicals with a positively charged substituent at the p-position, have been generated. These radicals are nearly as reactive as neutral phenyl r a d i ~ a 1 . IOxidation ~~ of ketenes with air oxygen, producing succinic anhydrides, is initiated by salts of radical cations of triarylamines which are capable of binding molecular oxygen and activating it with respect to ketenes.Ig4

*'

*'

+

Radical Anions

EPR and ab initio quantum-chemical calculations were used to characterize the electronic and geometric structures of radical anions of azulene and its alkyl derivatives.

158


Spin density is concentrated in positions 6, 4, 8, and 2, which indicates an unpaired electron orbital which is symmetric relative to the symmetry plane that is perpendicular to the molecule plane.'" The principle of similarity of EPR spectra of radical anions and cations of planar alternant hydrocarbons is not valid for the corresponding derivatives of dibenzo[b,h]biphenylene. This phenomenon is interpreted in terms of the Finnegar-Streiwieser model of the Mills-Nixon effect.Is6 Radical anions of the dialkyl ketone series RzCO (R = Me, Et, P i , But) and cyclobutanone were generated in an argon matrix at 4 K. Based on hfi constants with fihydrogen and a-carbon (I3C) atoms, and also on ab initio calculations, a pyramidal structure of the radical centre and preferential conformations of aliphatic fragments were c~nducted."~ The inversion barriers were determined for cyclic fragments in the radical anions of five-,'** six-,'** and seven-memberedIx9 cyclic ketones and thioketones. Interaction of diethyl oxalate with four equivalents of aryl- or hetaryl-lithium compounds yield radical anions of ketones due to addition of organolithium compounds at the carbonyl groups, followed by C-C bond rupture in the dianions formed.''' Similar results were obtained for the reactions of diary1 diketones with two equivalents of aryl- or hetaryl-lithium compounds. 19' Fourier transform ion-cyclotronresonance measurements and ab initio quantum-chemical calculations were employed to characterize carbonyl I3C and deuterium isotopic effects on the electron affinity (EA) of benzophenone in the gas phase. Experimental and theoretical values of isotopic effects are in good agreement [EA(12C)/EA('3C) = 1.03(exp.) and 1.026(calc.); EA(C6Ds)/EA(C6H5) = 1.35(exp.) and 1.32(calc.)] and differ markedly from earlier published data for liquid ammonium solutions of benzophenone.'" EPR, pulse radiolysis, and potentiometric methods were used to evaluate the one- and two-electron reduction potentials of 2-t-butyl-l,4-benzoquinone (one of the metabolites of antioxidants 2- or 3-t-butyl-4-hydroxyanisole)in aqueous solutions. Electron-transfer reactions of this quinone and products of its one-electron (semiquinone) and twoelectron reduction (hydroquinone) with molecular oxygen and superoxide ion were also studied. 192 Oxidation of 4-methylcatechol by molecular oxygen in the presence of hydroxide and methoxide ions was studied by EPR, and the mechanism of formation of primary and secondary semiquinone radical anions was proposed.'93 Hfi constants for radical anions of ubiquinone (98) and the derivative (99), labelled with I3C in different positions, were found using EPR and ENDOR spectroscopy. The spectral parameters of these radical anions in protic and aprotic media were found to be


159

dramatically different. According to AM1, PM3, and TNDO quantum-chemical calculations of hfi constants, the effect of the medium on spin-density distribution is caused by the formation of hydrogen bonds between the solvent molecule and radical anion of the ubiquinones. 94 Radical trianions, resulting from one-electron oxidation of alkaline (NaOH) water-alcohol solutions of 3,3’,4,4’-tetrahydroxybiphenyl by dioxygen, exist as ion pairs with sodium cations. In solutions with high cation concentrations ma+] > 0.02 M, the ion pairs undergo cation exchange. The influence of temperature on EPR spectral parameters and the rate of cation exchange has been ~haracterized.’~~ The interaction of 3-substituted 9,lO-phenanthraquinones with Grignard reagents leads to the formation of radical anions of the starting quinones. The effect of substituents in position 3 on spin-density distribution in these radical anions has been examined.‘96 EPR spectra of radical anions and trianions of benzo[g][ 1,2,5]thiadiazolo[3,4b]quinoxaline-5,lO-dione (100a) and its selenium analogue (100b) have been described. In the radical anions, unpaired electron density is localized mainly on a heterocyclic fragment, whereas in the radical trianion it is localized on the naphthoquinone part.’97

(102) a;X=O b;X=S

An EPR spectrum of a radical trianion of another quinone fused with two sulfur heterocycles, i.e. 2,3,6,7-tetracyanobenzo[1,2-6:4,5-b’]bis-dithiol-4,8-dione (IOl), is presented. 19’ Radical anions of 2,5-bis(tricyanovinyl)-furan (102a) and -thiophene (102b) were generated in solvent mixtures of different polarity and in the presence of different counterions (Lif, Na+, K+, and Cs+). In most cases, radical anions (102a;) and (102b;) are in the form of free ions for which, of the three possible conformations of the radical anion, namely antilanti, antilsyn and synlsyn, the second is energetically the most favourable. The radical anion (102b;) can also exist in the synlsyn conformation when an ion pair with a metal cation is formed. It has been demonstrated that the radical anion (102b;) is highly selective with respect to metal cations provided that ion pairs are formed. The selectivity for the formation of ion pairs depends on the size of the cation and on the distance between two proximate cyan0 groups.’99 Similar behaviour has been revealed by the radical anion 2,5-bis( 1-phenyliminoethyl)pyrazine (103). In the absence of coordinating cations, it exists as an equilibrium mixture of three conformers .s-cisls-cis, s-cisls-trans, and s-transls-trans in acetonitrile or tetrahydrofuran solutions; however, in the presence of cations, the last becomes more prefered. The same paper reported EPR spectra for the radical anion of N-t-butylpyridine-2-

160


carbaldimine (104).200As shown by EPRENDOR measurements, the unpaired electron occupies different orbitals in radical anions of phenanthroline (105a), its 4,7-dimethyl derivative (105b), and its 3,4,7,X-tetramethyl derivative (10%). The first two radical anions have SOMOs of ' h l symmetry. The SOMO of the last is of 'a2 symmetry. The same MOs are occupied by unpaired electron in complexes of these radical anions with dimesitylplatinum.20'

(104)

(105) a; R = R'= H b; R = H, R' = M e c ; R = R' = Me

Radical anions of nitroarenes were detected after mixing arylamines with sodium nitrite and ascorbic acid followed by alkalinization of those solutions. The proposed mechanism involves formation of aryldiazonium salts and their subsequent reduction to aryl radicals. These interact with nitrite ion to produce radical anions of the nitroarenes.2"2 The only EPR spectrum registered during the generation of the radical anion of thiophene in water-alcohol solutions belongs to its protonated form (2-hydrothienyl radical), owing to the high basicity of this radical anion. One-electron reduction of 2bromo- and 2,5-dichloro-thiophene leads to radical anions of the a*-type, characterized by localization of unpaired electron in the C-Br a*-orbital or in one of the two equivalent C-CI a*-orbitals. Experimental data have been compared with the results of PM3 quantum-chemical calculationszo0 Raman resonance spectra of vanadyl and zinc complexes of "N- and D-labelled and non-labelled octaalkylporphyrins have been interpreted in terms of a Jab-Teller static effect.204 The combination of ab initio quantum-chemical calculations and timeresolved Raman resonance spectroscopy has made it possible to describe in detail the electronic structures of products of one-electron reduction of isonicotinic acid and its protonated and deprotonated forms. An extra electron in the isonicotinate radical dianion is localized on the nitrogen atom rather than on the carboxylate group. Owing to this fact, basicity of the nitrogen atom increases by ten orders of magnitude. The radical dianion can be fully protonated at the nitrogen atom even at pH 14.'OS The stoichiometry and mechanism of protonation of alkali metal-benzophenone radical anion salt by weak acids, and their relevance to the base-catalyzed decomposition of benzopinacol, was studied.206 The effect of a substituent on the electron affinity of acetophenone and methyl benzoate has been characterized. The results were treated using Tsuno's correlation


161

approach and compared with the data obtained previously for nitrobenzene, benzaldehyde, and benzonitrile derivative^.^^' The radical anion 'CH2C02 - was generated in the gas phase. Its proton affinity, the energy of its dissociation into CH2; and C02 fragments, and the products of its interaction with NO, NO2, S02, and MeSSMe were determined.208 Kinetic parameters for the reductive splitting of the C-Hal bonds in and t-buty12" halides in polar media have been calculated. The AM1 method was applied to interpret experimental data on the influence of substituent and halogen atom, and their mutual location, on the rate of fragmentation of radical anions of substituted aryl and hetaryl halides. Quantum-chemical calulations were performed assuming that the transformation of the first-formed x-radical anion to the o-radical anion is the ratedetermining step. The intramolecular electron transfer from the n*-SOMO of the aromatic fragment to the o*-orbital of the C-Hal bond occurs through a non-polar transition state. The measured rates of fragmentation of radical anions of halogensubstituted acetophenones and benzonitriles are in good agreement with the calculated values of E (the energy gap between n*-and o*-states of the radical anions); however, this parameter does not always describe differences in rates of halide-ion elimination from m- and p-positions.212A detailed analysis of the effects of medium and of ionic association on the rates of fragmentation of radical anions of aromatic compounds was presented.213A significant difference has been found between the behaviour of radical anions characterized by strong delocalization of a negative charge (haloanthracenes, for example) and that of radical anions bearing electron-acceptor substituents (carbonyl or nitro) on which a negative charge is mostly concentrated. Fragmentation rates of the former systems are almost independent of the counterion and tend to increase slightly upon addition of water, which seems to be due to specific solvation of a leaving group. In contrast, ion-pair formation and specific interactions with proton-donor solvents stabilize the latter systems toward halide-ion elimination. Moreover, addition of protondonor solvents may change the direction of the reaction: reduction of an electronacceptor group rather than fragmentation may take place. These results have been rationalized in terms of rate-determining transformation of first-formed x-radical anion to a-radical anion.213An alternative approach has been described.214The effect of medium on the rate of cleavage of radical anions of aryl halides was rationalized in terms of the key role of the o-radical anion fragmentation step.214Rate constants of C-Cl bond cleavage in radical anions of chlorinated benzaldehydes in aqueous solution were measured by a pulse radiolysis technique.215A theoretical study of the stability of radical anions of polychlorobenzodioxins towards halide-ion elimination has been undertaken.216 Radical anions of silyl-substituted pyrenes and silyl-bridged dipyrenes are unstable and undergo fragmentation of the Si-Si and S i x bonds.217 Transformation of ion pairs of radical anions of furan-2,5-dicarbaldehyde2" and of benzene- 1,4-dicarbaldehyde2I9to radical anions of the corresponding semidiones was observed. Several papers deal with theoretical and experimental investigations of factors controlling the competition between the polar and electron-transfer mechanisms in reactions of radical anions with alkyl halides. Ab initio calculations of the interaction of radical anions of formaldehyde with methyl chloride have shown that the process follows two different mechanisms: x-plane backside attack of the radical anion on

162


methyl chloride leads to the electron-transfer transition state (ET-TS), while oxygen lone-pair backside attack on methyl chloride leads to the transition state for nucleophilic substitution (SUB-TS). An important point is that the ET-TS is characterized by a definite stereochemistry and a high degree of binding of reactants.220 Two similar types of transition states were observed for an intramolecular process involving interaction of ketyi anion and CHzCl fragments that are separated by two or three methylene groups. Since ET-TS and SUB-TS have different steric requirements, the length of the carbon bridge affects significantly the direction of the reaction: whereas for two methylene groups ET is the main route, for three methylene groups nucleophilic substitution becomes energetically preferentiaLz2’ The isotope effects220,221 ~ ~ . I ~ C I / ~ Cor, D ~ respectively, CI ~ C H ~ C ~ / ~ Ccan D ~ Cbe I ,used to discriminate between ET and SUB transition states. The effect of the nature of a leaving group on the ET to SN2 rate ratio has been characterized using the interaction of the radical anion of anthracene with methylating agents MeX (X = -%Me2, I, Br, Cl) as examples. From the data on yields of methylation products and regioselectivity of methyl-group incorporation (at positions 2 and 9 of anthracene), it was concluded that the proportion of the SN2 route increased from 0 to 97% in the above order of alkylating agents.222 The possibility of switching from an &2 to an ET mechanism in the arene radical anion alkylation by introduction of an electron-acceptor substituent into aromatic moiety was demonstrated for the first time.223 Whereas the radical anion of benzonitrile reacts with alkyl halides via an sN2 mechanism, the radical anion of 1,4-dicyanobenzene prefers the ET pathway. Cyclopropylmethyl bromide was used as a test reagent: cyclopropylmethyl radical, formed by the ET mechanism, isomerizes easily to the but-3-enyl radical, leading to the corresponding alkylation products (Scheme 24). Intramolecular electron transfer in radical anions of 9,9’-bianthryl and 10,lO’-dirnethoxy-9,9’-bianthryl has been studied. At 298 K, the rate constants of electron exchange in dimethylformamide were found to be 4.2 x lo7 and 2.2 x lo7 s-’, respectively. The results have been rationalized in terms of the Marcus theory.224The same theory was used to explain a 20% increase in rate constant of electron exchange between naphthalene and its radical anion upon substitution of deuterium atoms for all the hydrogen atoms in arene.225 Radical anion SO4; reacts with imidazolin-2-one, pyrazolin-3-one, and related compounds by hydrogen-atom abstraction fiom the NH group, possibly via oneelectron oxidation followed by deprotonation. The pK, values of the resulting radicals were determined.226 Biradicals A brief analysis of the development of theoretical and experimental methods of investigation of monomolecular reactions involving the formation of biradicals as intermediates was presented.227The femtosecond laser technique, in combination with mass spectrometry in laser beams, was applied to identify biradical species resulting from photolysis of cyclobutane, cyclopentanone, and its 2,2,5,5-tetramethyl derivative. The effect of the structures of biradical species (tetramethylene and trimethylene), their


163

SCHEME 24

energies, and the incorporation of methyl groups into radical sites on the rate of transition-states passage has been characterized.228 CASSCF and CASPT2N quantum-chemical calculations have shown that singlet biradical cyclopentan-2-one-l,3-diyl(107) is more stable than the corresponding bicyclic form bicyclo[2.1.O]pentan-5-one (108). According to calculation, the structures (107) and (108) are characterized by different vibration frequencies of the C=O bond, which allows their experimental d i ~ c r i m i n a t i o n A . ~ ~comprehensive ~ theoretical study of auto-aromatization of (a-hex-3-ene- 1,5-diyne (109) to p-benzyne singlet biradical (1 10) (the Bergman reaction) was performed. The reaction and activation enthalpies and entropy effects were estimated by the CCSD(T) and CASPT2(gl) methods with the use of a wide range of basic sets. The results were shown to depend strongly on both the calculation method and the basis set. Specifically, the difference in reaction enthalpies obtained by CCSD(T) and CASPT2(gl) is 7 kcal mol-'. The difference is somewhat less (4 kcal mol-') for activation enthalpies. Both methods were also used to estimate relative energies for p - , 0-,and rn-ben~ynes.'~' The energy of singlet-triplet splitting has been determined for biradicals of the trimethylenemethane type ( l l l t ( 1 1 3 ) . It is higher than 14 kcal mol-' for planar structures and is only 6 kcal mol-' for structures with mutually orthogonal radical fragments. In all cases, the basic state is triplet.231 Differently, Ullman's nitroxide biradicals, bis[2,2'-(1-oxy-3-oxido-4,4,5,5-tetramethyl-dihydro-1H-imidazoyl](114) and bis[2,2'-( 1 -oxy-4,4,5,5-tetramethyldihydro-1H-imidazolyl](1 15), have a singlet basic state regardless of mutual orientation of radical fiagments, as shown by ab initio

164


calculations of model systems [methyl groups in structures (114) and (115) replacing hydrogen atoms]. The singlet-triplet energy gaps calculated for model biradicals, with reference to the experimental angles between radical fragments, are in good agreement with experimental values for biradicals (114) and (115).232

Data on the isomerization of a cyclopropane fi-agment during photolysis and pyrolysis of 2,4-benzylidenebicycIo[3.1.O]hexan-3-one (116a,b) indicate the formation of a pentamethylenepropane-type biradical intermediate (1 17) or transition state (Scheme 25). Although, in accordance with the quantum-chemical calculations, the energy of the triplet state of pentamethylenepropane-type biradicals is 2 kcal mol-I less than the energy of the singlet state, the attempts made to identify this species were unsuccessful, even at low temperatures.233 The structure and relative formation rates of isomeric triplet biradical intermediates formed by photo-cycloaddition of cyclopent-2-enone and its 2- and 3-methyl derivatives to substituted alkenes CH2=CXY (X = Y = X = Y = F,234 X = H, Y = C02Me23S)have been determined. The composition of products of direct and triplet-sensitized photolysis of syn- and anti-isomers of azoalkanes (118) is in accord with intermediate formation of singlet or triplet biradical, respectively. The triplet biradical has a planar structure; syn- and antiisomers of azoalkanes (1 18) yield the same thermodynamically controlled mixture (96:4) of anti- and syn-housanes (119). Unlike the triplet biradical, the singlet


165

(116a)

(116b)

biradical has a puckered conformation, because direct photolysis of syn- and antiisomers of the parent compound produces housanes that preserve to a large extent the conformation of the precursor. Both triplet and singlet 1,3-biradicals can be effectively trapped by nitroxyl radicals. The generation of triplet biradicals by triplet-sensitized photolysis of azoalkanes (118) has been confirmed by EPR under matrix isolation conditions.236

hv or

Me-N

_t

Me-N

0

0

(118)

0

(119)

a; R = Me, R = R” = H b; R = Me, R’ = Ph, R“ = H (syn-lllb, anti-119b) R = Me, R‘ = H, R” =Ph (anti-ll(lb, syn-119b) c; R = Me, R‘ = R” = Ph d; R = Ph,R’= R” = H SCHEME 26 The ratio of products resulting from photolysis of 2,3-diazabicyclo[2.2.2]oct-2-ene (120) depends on the electron spin state of the biradical intermediate cyclohexane-l,4diyl(l21). The singlet cyclohexane-l,4-diyl biradical in the ‘boat’ conformation (121a) undergoes cyclization forming bicyclo[2.2.0]hexane (122). In the triplet state (121b), this biradical changes its geometry from the high-energy ‘boat’ conformation to the lower-energy ‘twist’ conformation (123b). Its subsequent transformations involve intersystem crossing to the ‘twist’ singlet state (123a), in which the biradical undergoes either ring opening producing hexa- 1,4-diene (124) or ring closure producing bicyclo[2.2.0]hexane (122). The rate ratio of the latter two processes is 7:3. The electronic state of the cyclohexane-l,4-diyl biradical depends on the conditions of photolysis (direct irradiation, singlet or triplet sensitization) and on the probability of intersystem crossing in the primary biradical (125), formed by rupture of the C-N bond in the excited state of the starting diaza compound237(Scheme 27).

Organic Reaction Mechanisms f 995

166

Donor-acceptor substitution exerts very little effect on intersystem crossing rates in 1,3-diarylcycIopenta-1,3-dienyl triplet biradicals (126). The lifetimes for substituted and unsubstituted systems are comparable.238 The effect of an external magnetic field on CIDNP in biradicals produced by photolysis of large-ring cyclic ketones (cycloundecanone and cyclododecanone) was studied at different concentrations of CBrC13 used as a radical scavenger. This approach has allowed the elucidation of different channels of intersystem crossing in biradicals in low magnetic fields, the evaluation of the kinetics of recombination in biradical systems, and the determination of rate constants for interaction of biradicals with CBrC13.239The effect of external magnetic field and of magnetic isotopes on the

\ / [ * = . I m - [ou-] I

3

Li

Li

(126) a; X = Y = OMe b; X = Y = NO2 c; XIY = OMe/NO2 d:X=Y=H

(127)


167

lifetimes of biradicals obtained during the photolysis of benzophenone derivatives, resulting from intermolecular transfer of a hydrogen atom, has been examined.240The biradical intermediate (127) formed in reaction of 2-alkylbenzotriazoles with lithium diisobutylamide was identified by EPR.241 The generation of biradical intermediates during 1,2- and 1,Ccycloaddition of buta1,3-diene to the exo-double bond in 3-substituted 5-methylene-2(5H)-fones is suggested.242 1,4-Dehydronaphthalene biradicals, generated by thermolysis of enediynes (128), are trapped by nitroxyl radicals producing finally 1,4-naphthaquinones243(Scheme 28).

G

Q

?

0 ' I

R 0

(128) a; R,R' = H b; K,R'= Me c; R,R' = OMe d; R-R' = OCH20 e; R-R' = (CH& f R = Me, R' = Et

SCHEME 28

Biradicals play a key role in processes of formation of naphthalene derivatives by irradiation of silicon-tethered phenylalkynes (129)244 and of anthracene and phenanthrene derivatives during exposure of 6,7-benzobicyclo[8.3.O]trideca-6,10diene-3,8-diyne-l,Sdiols (130) to mesityl chloride in the presence of triethylamine, followed by treatment with water.245 Irradiation of 5s-5-0-t-butyldimethylsiloxymethylfUran-2(5H)-one (131) in acetonitrile leads to dimerization of the starting compound with the formation of C2-symmetric bis(1actone) (132), along with intramolecular photo-cycloaddition with the formation of bicyclic product (133).246 The mechanism of formation of the bicyclic product involves intermolecular transfer of the hydrogen atom from the t-butyl group to the biradical formed primarily as a result of irradiation of the starting compound (Scheme 29).

168


ASiPJPh Y

'

O

X Ph

SCHEME 29


169

An enthalpy profile for the equilibrium between dispiro[2.2.2.2]deca-2,4-diene(134) and two biradical intermediates (135) and (136) has been characterized. The possibility of a non-concerted path for the equilibrium (134) (136) is being discussed.247 Interaction of polyfluorinated cyclopropanes with halogens leads to the opening of the ring accompanied by the formation of 1,3-dihalofluoropropane derivatives. It is postulated that the reaction involves the formation of a biradical intermediate due to C-C bond cleavage in polyfluorocyclopropane.248

Thermolysis and Pyrolysis Possible pathways of monomolecular decomposition of CH30F have been studied by ab initio methods. Of four pathways leading to the formation of CH20 and HF, the most preferential are the following two. The first occurs via a synchronous one-step elimination of HF, and the second via formation of methoxyl radical and atomic fluorine in the first step and subsequent interaction between them to yield the final reaction product. The two pathways are characterized by nearly the same free energies of activation (ca 38 kcal m ~ l - l ) . ~ ~ ~ Thermal decomposition of CF2C12 was investigated over a wide temperature range (1446-2667 K) at different concentrations of the starting compound in Kr diluent. The rate constants for following reactions have been determined: CFzC12 'CF2Cl

+M +M

4

-+

'CF2Cl + 'C1 (+M) CF2 'C1 (+M)

+

A one-step elimination of molecular chlorine with the formation of difluorocarbene is not accomplished. Enthalpies of formation of CFzCl and fragmentation of this radical via C-CI bond rupture have been estimated.250 A kinetic study of the formation of ethane through homogeneous pyrolysis of propane at 500°C has been reported, and the rate constant of initiation of this reaction has been measured.25' The mechanism for the thermal decomposition of trunsazoisopropane has been studied using ab initio quantum-chemical approaches.252Rate constants and activation parameters of elementary reactions that occur during thermal decomposition of azoisopropane in the presence of trans-but-2-ene were measured over a wide temperature range from 489 to 540°C.253 The ab initio method was applied to evaluate two possible mechanisms of thermal decomposition of pyridine, pyrimidine, pyrazine, and ~ y r i d a z i n e .One ~ ~ ~ of the mechanisms involves intermolecular rearrangement of hetarenes to the bicyclic Dewar isomer followed by its decomposition into acetylene and HCN. This mechanism is hardly probable since the associated critical energy parameters for most hetarenes exceed markedly experimental values of activation barriers. The only exception is pyridine. The second mechanism is the chain-radical pathway that involves rupture of the C-H bond (at the position ortho to the nitrogen atom) in the initiation stage. Subsequently, the hetaryl radical decomposes yielding the CN radical as one of the products. This radical, along with the hydrogen atom, is responsible for the continuation of the chain. The calculated energies of the most important steps of the

170


radical pathway coincide with experimental values within the limits of 10 kcal mol-’ , which led the authors to give preference to this mechanism. A chain-radical mechanism has been proposed for cracking of phenethyl phenyl ether (137) at 330425°C that models thermal behaviour of lignite and low-rank The process occurs via two competitive pathways (Scheme 30), the rate ratio of which depends on the regioselectivity of interaction of phenoxyl and benzyl radicals with the starting compound. The first pathway leads to styrene and phenol, whereas the second affords toluene and benzaldehyde. Styrene and phenol result from p-scission of a free radical of benzyl type (138) into styrene and phenoxyl radical, which transforms to phenol via abstraction of the hydrogen atom from the starting compound. Toluene and benzaldehyde are produced via transformation of the a-phenoxyalkyl radical (139), which undergoes a 1,2-shift of a phenyl group from oxygen to carbon and P-scission producing benzaldehyde and benzyl radical. The latter abstracts a hydrogen atom from the starting compound with the formation of toluene. The reaction is initiated by the scission of the CH,-OPh bond in the starting compound and can be accelerated by adding free-radical sources.*” The products and mechanism of pyrolysis of ethynylben~ ene~ ~ ~and ~ ’~ 1,4’ diphenylbut-l-en-3-yne2” have been studied in detail. In both cases, the composition of products depends on the nature of the carrier gas and the temperature at which the process is performed. Pyrolysis of ethynylbenzene2’6 at 700°C in a nitrogen atmosphere brings about the formation of 1- and 2-phenylnaphthalenes, 1-methylene-2-phenyl-lHindene, 1-methylene-3-phenyl-IH-indene, and 5,1O-dihydroindeno[2,1-a]indenc. However, at higher temperatures ethynylarenes, as well as benzene, naphthalene, acenaphthylene, biphenyl, pyrene, fluoranthene, and the other CI6HIOisomers, are formed. As hydrogen is used as a carrier gas, the main products are styrene and benzene. It is assumed that the process follows a radical mechanism.256Major radical intermediates were scavenged with dimethyl d i ~ u l f i d eThese . ~ ~ ~were phenyl, 0-,m-, and p-ethynylphenyl, 2- and 1-phenylvinyl, 1- and 2-naphthyl, methyl, hydrogen atom,

I

(139)

Ph

PhCH2’ SCHEME 30

+

PhCHO


171

and radicals resulting from the addition of ethynylphenyl and phenyl radicals to the triple bond of the parent compound. Small amounts of carbenes, e.g. phenylvinylidene, were also detected. Based on the analysis of the concentration profiles of radicals and the main products of pyrolysis, a well justified scheme of pyrolysis of ethynylbenzene has been proposed. In the presence of suitable donors of hydrogen atoms, pyrolysis of 1,4-diphenylbut-l-en-3-yne, or its fluoro derivative, is controlled by radical processes; however, if the system is deficient in hydrogen atoms, the key role is played by vinylidenecarbene species.25x Thermal and photochemical cyclization reactions of perfluorohepta-1,6-dienehave been studied. In both cases, cyclization occurs by a stepwise mechanism with the formation of a biradical intermediate (Scheme 3 1). However, in a thermal process, the biradical intermediate is characterized by a six-membered ring (140) and in a photochemical process by a five-membered ring (141). Thermal treatment of perfluorohepta-l,3,6-triene leads to the formation of two types of products: (a) the kinetically more favourable allylcyclobutene (142) via reversible four-electron pericyclic process; and (b) the thermodynamically more favourable bicycloheptene (143) via a stepwise mechanism involving a biradical intermediate (144) (Scheme 32). The ratio of the products changes in favour of bicycloheptene (143) with increasing temperature of the process.259

major product

Fq:

major product

(141)

SCHEME 31

Photolysis and Radiolysis Photolysis of perfluoroazooctane (145) in the presence of cycloalkanes C,H2, (n = 5 , 6, 7) leads to the formation of the corresponding perfluorooctylcycloalkanes CsF17CmH2m-I(m = 5, 6 , 7) (Scheme 33). The reaction mechanism involves intermediate formation of perfluoroalkylazocycloalkane CXHI7N=NCmH2,,-, (146) whose photolysis produces the end-product with a quantum yield close to unity. It is postulated that azo compound (145) is transformed to azo compounds (146) due to


172

SCHEME 32

photo-induced cleavage of one C-N bond resulting in perfluorooctyldiazenyl (147) and perfluorooctyl radicals. The latter remove the hydrogen atom kom the solvent (cycloalkane) with subsequent formation of cycloalkyl radical that recombines with perfluorooctyldiazenyl radical (147).260 Irradiation of a-brominated xylenes in benzene, isooctane, and benzene-cyclohexene mixture results in the formation of xylenes containing either fewer or more bromine atoms than in the parent compound. Possible mechanisms of reaction product formation are discussed.26' The mechanism of the photolysis of 2-hydroxypyridine-2-thione derivatives (148), which have been widely used as a source of free radicals in recent years, was studied. The starting compound in its excited state undergoes N-0 bond cleavage producing 2-pyridylthiyl radical and acyloxyl (RCO;) or carbon-centred radicals (R') depending

f

n = 0 , 1,2

(146)


173

on the structure of R. The reactivity of R' towards molecular oxygen, methyl methacrylate, cyclohexa-l,3-diene, and benzhydrol has been characterized. An additional chain route of RC02' and R' formation, involving interaction of the starting compound with the radical R' (Scheme 34), has been found.262 A new method of transformation of alkyl halides to oximes has been suggested. Irradiation of alkyl iodides in the presence of m y 1 nitrite and hexabutylditin leads to the production of high yields of the corresponding alkyloximes. This reaction may be also valid for benzyl bromides. Interesting results were obtained with the use of alkyl iodides, which produce cyclizable free radicals upon irradiation. The oximes formed contain a cyclic fragment, provided that the system is capable of forming a fivemembered ring. In other situations the main reaction products are acyclic ~ x i m e s . ' ~ ~ The 193 nm photolysis of vinyl methyl ketone leads to the formation of methyl and vinyl radicals. The combination of two vinyl, vinyl and methyl, or two methyl radicals yields butadiene, propylene, and ethane, respectively. Disproportionation of two vinyl radicals results in the formation of ethylene and acetylene. A comparison of data on the ratio of the products of photolysis of vinyl methyl ketone and its perdeuteriated analogue has shown that the isotopic effect occurs in only disproportionation of two vinyl radicals.264 Using pulse radiolysis, it was possible to generate alkyl radicals from cycloalkanes (C, to Clo) and normal alkanes (c6to CI7).Rate constants of interactions between alkyl radicals and their reaction with molecular iodide have been determined.265

O ,0 dR

R' 0

OKR 0

SCHEME 34

+ CO2

174


As shown by pulse radiolysis, bromine-centred radical cations of starting haloalkanes are formed via interaction of hydroxyl radical with 1-bromo-n-chloroalkanes in strongly acidic aqueous solutions. These radical cations are stabilized due to interaction of the positively charged bromine atom either with uncharged bromine atom of the other molecule (via formation of the intermolecular 3e-2c bond) or with the uncharged chlorine atom of the same molecule (via formation of the intramolecular 3e-2c bond). For n = 2, 5, and 6, stabilization occurs via an intermolecular path, whereas for n = I , 3, and 4 it is via both inter- and intra-molecular paths. Experimental data are in good agreement with AM1 estimates of the strength of 3e-2c bonds.266Radical cations of brombenzene were detected during interaction of hydroxyl radical with the starting arene in strongly acidic aqueous solutions.267Hydroxycyclohexadienyl radical, formed in the first step, undergoes acid-catalysed dehydration. The redox potential of radical cation C6H5Br+' was determined. This radical cation was shown to oxidize Br- and SCN- anions, and also organic sulfides, at high rates. Pulse radiolysis was employed to estimate rate constants of interaction of hydrox yl radical with hydroxymalonic acid in solutions at various pH values. In oxygencontaining solutions, the addition of the a-hydroxyalkyl radical to dioxygen is followed by removal of H 0 2 or 02.Ketomalonic acid is the main product of radiolysis (along with H202) in aqueous acidic solutions (pH 3); however, in alkaline solutions (pH lo), it undergoes oxidation producing finally oxalic peracid and C02.*@ To establish the mechanism of nitroarene action as a radiosensitizer, radiolysis of N20-saturated aqueous solutions of I ,4-dioxane, 1,3-dioxane, tetrahydrofuran, and dimethyl ether, which model the sugar moiety in the DNA molecule, was carried out in the presence of 4-nitrobenzonitrile. a-Monoalkoxyalkyl radicals, formed via abstraction of a hydrogen atom from the above compounds by hydroxyl radical, add to the oxygen atom of nitro group to give N-alkoxy nitroxides, ArN(0')OR. In contrast to amonoalkoxyalkyl radicals, a,a-dialkoxyalkyl radicals (1,3-dioxan-2-y1), with stronger electron-donor properties, cause reduction of 4-nitrobenzonitrile to its radical anion. Subsequent transformations of N-alkoxy nitroxides have been characterized. These radicals undergo either homolytic cleavage via the N-OR bond, producing nitroso compounds and alkoxyl radical RO', or heterolytic cleavage via the NO-R bond producing the radical anion of nitroarene (ArN02;) and carbocation R+. Finally, in the presence of appropriate reductants (e.g. ascorbic acid), the N-alkoxy nitroxides can be reduced to the corresponding hydroxylamines. Radiolysis of 1,4-dioxane in an oxygencontaining medium leads to the same products (although in different ratio) as in its radiolysis in the presence of 4-nitrobenzonitrile. This is accounted for by the key role of alkoxyl radicals RO' formed in the both cases in the formation of final products.269

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*

'' ''

176


Bentley, J. and Madden, K. P., 1 Am. Chem. Soc., 116, I 1397 (1994). Zubarev, V. E. and Brede, 0..1Chem. SOC.,Perkin Trans. 2, 1995, 2183. 6n Eberson, L., Lind, J., and Merenyi, G., 1 Chem. Sac., Perkin Trans. 2, 1994, 1181. 61 Greer, M. L., Sarker, H., Mendiciano, M. E., and Blackstock, S., 1 Am. Chem. Soc., 117, 2467 (1995). Lagercrantz, C. and Ebereson, L., Acta. Chem. Scand., 49, 399 (1995). Gille, L. and Stoesser, R., 1 Fluorine Chem., 69, 191 (1994). 64 Misik, V, Kirschenbaum, L. J., and Ricsz, P., 1 Phys. Chem., 99, 59 (1995). 65 Davies, M. J., Gilbert, B. C., Hazlewood, C., and Polack, N. P, 1Chem. SOC., Perkin Trans. 2, 1995, 13. 66 Hazlewood, C., Davies, M. J., Gilbert, B. C., and Packer, J. E., 1 Chem. Soc., Perkin Trans. 2,1995,2167. 67 Hildenbrand, K., 1 Chem. Soc., Perkin Trans. 2, 1995, 2153. 68 Tuccio, B., Lauricella, R., Frejaville, C., Bouteiller, J.-C., and Tordo, P., 1 Chem. Soc., Perkin Trans. 2, 1995, 295. 69 Janzen, E. G., Zhang, Y.-K., and Haire, D. L., Magn. Reson. Chem., 32, 71 1 (1994). 70 Janzen, E. G., Zhang, Y.-K., Haire, D. L., Kotake, Y., and Payne, M., Appl. Magn. Reson., 6, 51 1 (1994); Chem. A h . , 123, 198166 (1995). 71 Herlinger, E., Jameson, R. F., and Linert, W., 1 Chem. Soc., Perkin Trans. 2, 1995, 259. 72 Bravo, A,, Fontana, F., Fronza, G., Mele, A., and Minisci, F., 1 Chem. Soc., Chem. Commun., 1995, 1573. 73 Minisci, F., Zhao, L., Fontana, F., and Bravo, A,, Tetrahedron Lett., 36, 1895 (1995). 74 Minisci, F., Zhao, L., Fontana, F., and Bravo, A,, Tetrahedron Lett., 36, 1697 (1995). 75 Ali, M. M., Fahmy, A. M., Gaber, A. M., and Atalla, A. A., 1 Indian Chem. Soc., 338, 1139 (1994); Chem. Abs., 122,213401 (1995). 76 Ali, M. M., Fahmy, A. M., Gaber, A. M., and Atalla, A. A., Bull. Fac. Sci. Assiut Univ., 23B, 185 (1994); 3 . 5 x 108s-'. 0

Photolysis of matrix-isolated cyclopropanecarbonyl chloride gives rise to cyclopropylidene ketone (87).79Irradiation of the ketene (87) gives chlorocyclopropane and propa- 1,2-diene, suggesting the intermediacy of cyclopropylidene (88). Kinetic data showed that the rate of rearrangement to allene was roughly twice that of reaction with HC1. Ah initio calculations on the reaction of HNC with H2C=SiH2 show that the primary cycloadduct (89; X =NH, Y = CH2) rearranges to the more stable silaziridine (89; X = CH2, Y =NH) via the cyclic carbene (90)."

A kinetic study of the 1,2-Si shift of the disilacyclobutane (91) to give (92) revealed that log A = 12.48 and the activation barrier is 54.09 kcal mol-1.81 Ah initio calculations predicted that the transition state was late and corresponded to the carbene (93). Borylmethyleneboranes [94; All = (Me3Si)&=C=CR] were found to isomerize by 1,2-carbon-to-boron followed by 1,2-boron-to-carbon migration, via diborylcarbenes (95)." An ab initio investigation of the concerted ring expansion of singlet cyclopropyinitrene gave a barrier height of 38.89 kJ r n ~ I - ' . * ~The pyrolysis of 3azido-3-phenylazetidinesgave rise to products of heterocyclic ring expansion of the intermediate nitrene~.'~ Irradiation of (aminoalky1)phenyl azides (96; R = H or Et) gave rise to bicyclic azepines (97) in good yield even in the presence of diethylamir~e.~~

226


Nitrenium Ions Flash photolysis and product analysis of 4-azidobiphenyl (and 2-azidofluorene) indicated that the initially formed singlet nitrene is protonated in water to form the nitrenium ion (98).'6 The results suggest that the acid dissociation constants for these nitrenium ions are less than Nucleophiles and Electrophiles Time-resolved LFP techniques have been used to study the mechanism of photodecomposition of 2-methoxy-1,2-diphenyldiazoethane in methan01.~' The results are consistent with thermal equilibration between the singlet and triplet states, followed by reaction of the singlet with methanol to form an ether. The reaction of diarylcarbenes, Ar2C:, generated by photolysis of the corresponding diazo compounds, with alcohols was studied by picosecond absorption spectroscopy." Protonation to form the contact ion pair (99) was observed to occur with rate constants between 0.4 x lo9 and 4.7 x lo9 dm3mol-' s-I. No evidence for nucleophilic attack by the alcohol was seen. The carbomethoxyarylcarbene (100) formed from the diazo compound, was protonated by HC104 to give a benzyl cation with a rate constant of 3.5 x lo9 drn3 mol-' s - ' . ' ~ The stable carbene (101), generated by reaction of the corresponding 2(3H)-thione with potassium, has a pK, value of 24 in (CD3)$30.90Reaction of the carbene with 2bromopropane gave an elimination : substitution ratio of 20 : 80, comparable to that obtained with the commonly used base DBN. The reaction of Ph(Cl)C:, generated by photolysis of the diazirine, with alkyl azides was studied by LFP9' The bimolecular rate constants were found to be (1.5-3.8) x lo7 M-' s-', comparable to the rate of reaction with alkenes. The reaction with benzyl azide has a barrier of 0.04 kcal mol-' and entropy of activation of - 25.7 & 1 eu. The results are consistent with initial attack on N(l) of the a i d e to form a zwitterion. Photolysis of diazo compounds (102; n = 1,2) in chloroform led to products resulting from trapping of the intermediate carbenes by the dimethylamino group to form ammonium ylides (103).92The electrophilicity of lithium carbenoids, caused by metal-

227

6 Carbenes and Nitrenes

assisted ionization, enables intramolecular nucleophilic substitution to occur (104) to produce benzofurans, thianaphthenes, and indoles (105; X = 0, S, NH).93 Me

Bromodifluoromethylimides (106; X = Br) were formed diastereoselectively by reaction of the imide enolates with Br2CF2.94The reaction was proposed to occur via attack of the enolate on in situ-generated F2C: to produce an anion (106; X = Li) which abstracted bromine from Br2CF2 to form the product and regenerate F2C:. The enantioselective formation of ylides (107; X = S, Se) was achieved by chiral copperand rhodium-catalysed reaction of the allylic sulfides (or selenides) with ethyl d i a z ~ a c e t a t e .The ~ ~ ylides (107) underwent 2,3-sigmatropic rearrangement to give products in up to 41% ee. DBN was found to react with the phosphinophosphoniocarbene (108; R=NP?!) to give the tricyclic adduct (109).96 Initial attack by N(5) of DBN on the phosphino phosphorus was proposed.

Silylenes and Germylenes A high-level ab initio study of 1-silavinylidene H2C=Si: corrects the previously large discrepancy between experimental and calculated harmonic vibrational freq~encies.~' The regioselective addition of hindered silylene (1 lo), generated by photolysis of a trisilane, to C70 (which has eight distinct types of C-C bond) was reported.98 The adduct Ar2SiC70was formed as a 2 : 1 ratio of isomers with selectivity controlled by HOMO(silylene)-LUMO(C70) interactions. The pentacoordinate ethoxydisilane (11 1;

228


X=NMe2) was found to be thermally unstable, losing EtOSi(Me)zPh to generate a silylene at 110 0C.99The corresponding tetracoordinate disilane (111; X = H) was stable up to 200 "C. The extremely hindered disilenes (112) underwent dissociation at 70 "C to produce the divalent silylene which was trapped by a range of species.'" Reaction of the silylene with benzene and naphthalene gave 1 2-adducts which were characterized by X-ray structure determination.

+

High-level ab initio calculations on the dimerization of silylenes Y(H)Si: (Y =OH or NH2) predict that bridged structures (113) are more stable than the disilenes Y(H)Si=Si(H)Y.''' Reaction of a lithium phosphide with a germanium dihalide gave rise to the diphosphanyl-substituted germylenes (1 14).'02 The corresponding diarsanylsubstituted germylenes, and diphosphanyl- and diarsanyl-substituted stannylenes and plurnbylenes were synthesized in a similar manner. H I &.Y.,,, SiG ,Si

Y I H (113)

PR~R~

/ :Ge \

PR~R* (114) R' = SiArzF, R2=P@i

References

' Mansuy, D. and Mahy, J. P., Catal. Met. Complexes, 17, 175 (1994);

*

lo

"

12

l3 l4

l5 l6

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''

''


230 68 h9

70 7'

72

73 74

75

76 77 78

79

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** 83

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y9

Tamao, K., Nagata, K., Asahara, M., Kawachi, A,, Ito, Y., and Shiro, M., 1 Am. Chem. Soc., 117, 11592

97

1995, 1529.

(1995).

loo

I"' lo'

Suzuki, H., Tokitoh, N., and Okazaki, R., Bull. Chem. SOC.Jpn, 68, 2471 (1995). Apeloig, Y. and Miiller, T., 1 Am. Chem. SOC., 117, 5363 (1995). Driess, M., Janoschek, R., Pritzkow, H., Rell, S., and Winkler, U., Angew Chem., Int. Ed. Engl., 34, 1614 (1995).

CHAPTER 7

Nucleophilic Aromatic Substitution MICHELR. CRAMPTON Department of Chemistq University of Durham General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The SNAr Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heterocyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meisenheimer and Related Adducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzyne and Related Intermediates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23 1 233 239 24 1 243 244

General There has been a review of the preparation and reactivity of arenediazonium ions.' Theoretical studies of the nature of C-N bonding in diazonium ions indicate that the electron-density distribution is consistent with a dative bonding model; the benzenediazonium ion can best be thought of as a carbenium ion closely associated with an internally polarized N2 group.* The structures and reactivities towards both gaseous and liquid nucleophiles of free arylium cations, formed by dediazoniation,have been in~estigated.~ Electrospray mass spectrometric study of 4-substituted-2-nitrobenzenediazonium ions shows a surprising stability of the intact ions to collisionally activated loss of nitrogen. This contrasts with the behaviour of monosubstituted benzenediazonium ions. The 2-nitro-substituted compounds may experience loss of the 4-substituent or substitution of the nitro group by water.4 Iron(I1) ions have been shown to be efficient catalysts in hydrodediazoniation reactions (replacement of the diazo group by hydrogen) in dimethylf~rmamide.~ The catalyst acts as an electron donor to initiate the sequence shown in Scheme 1. Replacement of a diazonium group by fluorine (the Balz Schiemann reaction) has been investigated in [2.2]metacyclophane derivatives. The 8,16-dimethoxy compound carrying a single diazonium group is unusual in that a difluoro derivative is formed, probably by a mechanism involving radical^.^ The Sandmeyer reaction involves homolysis of a diazonium ion followed by copper-catalysed substitution. Absolute rate constants have been estimated for the Fe2++ ArN2+ ArN2'

-

Ar'+ solvent ---+

Fe3++ ArN2' Ar'+Nz ArH

SCHEME 1 Organic Reaction Mechanisms 1995. Edited by A. C . Knipe and W. E Wans 0 1997 John Wiley & Sons Ltd

23 1


232

transfer of chloride ligands from Cu(I1) to the 2-benzoylphenyl radical, and relative rate constants for the transfer of chloride and water ligands to other substituted phenyl radicals have been obtained.' A key step in the SR,l chain reaction is the unimolecular fragmentation of a radical anion. A theoretical study by the AM1 method has been reported of haloaromatic radical anions. Intramolecular electron transfer between the 7c* and the CT* antibonding C-Hal orbital is thought to be the rate-determining step in the cleavage of these species and a good correlation was found between the energy difference between these orbitals and experimental fragmentation rates.' The dual photo- and electro-chemical activation of m-halonitrobenzenes in acetonitrile has been reported. The process involves light absorption by the radical anions, (Ha1C6H4NO2)', followed by fragmentation by halide loss. The resulting nitroaryl radicals form nitrobenzene. The dual activation is successful only with halide loss, and the groups CN, NO2, SOR, and S02R cannot be similarly lost.' An mechanism has been proposed for the photochemically activated alkoxycarbonylation of aryl halides using carbon monoxide in the presence of a cobalt catalyst." The feasibility of monosubstitution of 1,4-dichlorobenzene and of dichloropyridines in electrochemically initiated S,, 1 reactions has been investigated. It was found that monosubstitution can be observed only when the nucleophiles act as electron-donating substituents, which, interestingly, is the reverse of the behaviour found using photochemical initiation." Paired electrosynthesis has been used to effect the nucleophilic substitution of hydrogen by lH-tetrazoles in 1,bdimethoxy- and 1,3,5trimethoxy-benzenes;l 2 reaction between anions of the nitrogen heterocycles, generated at the cathode, and radical cations of the electron-rich aromatics, generated at the anode, yield products such as (1). H

N

I

OMe

I

F

(1)

of electrochemical studies of the reactions with There has been a further nucleophiles of p-dinitrobenzene, p-nitrobenzonitrile and polyfluoronitrobenzenes. The results are not compatible with the s,&!mechanism, which involves nucleophilic attack on a radical anion. The reductive activation which is observed may be due to an enhanced rate of cleavage of zwitterionic intermediates such as (2). Possible competition between SNand ET pathways has been observed in the reactions with cyclopropylmethyl bromide of the radical anions of benzonitrile and 1,4dicyanobenzene. The former radical yields benzylcyclopropane so that direct S N attack on the cyclopropylmethylbromide is indicated. The latter yields products derived from the ring-opened alkyl halide, indicating that the initial step is electron transfer to give the cyclopropylmethyl radical.l5

7 Nucleophiiic Aromatic Substitution

233

The SNAr Mechanism Theoretical studies, by the MNDO-PM3 method, have been reported of nitro-group substitutions in 1,3,5-trinitrobenzene and 2,4,6-trinitrotoluene by methoxide16 and phenoxide” nucleophiles. The calculations support an addition-elimination mechanism for the reactions in polar solvents. There has been a theoretical study, using SCF and MP2 methods, comparing the substituent effects of nitro and nitroso groups in aromatic systems.18 There is continued interest in the mechanism of base catalysis in substitutions by amine nucleophiles. IOnetic studies have been reported of the reactions of phenyl aryl ethers with aliphatic amines in DMSO. It was arguedI9 that here general base catalysis is the result of rate-limiting proton transfer from initially formed zwitterionic adducts (3), followed by rapid uncatalysed loss of phenoxide from the anionic intermediates (4). This contrasts with the behaviour of alkyl aryl ethers where the rate-limiting proton transfer is to the leaving group (the SB-GA mechanism). In non-polar media, association phenomena between reagents is likely and may contribute to catalytic effects. A study by 19FNMR spectroscopy in [2H8]tolueneas solvent has identified the association of nitrofluorobenzenes and of 2-fluoropyridine with primary amines2’ The relative probabilities of amine catalysis in non-polar solvents by stepwise, dimeric, and cyclic mechanisms has been considered.21 PhO ,

+NHR‘R2

.__I

O z N O N o 2 \

I

-

+R~R~NH

+ + R1R2NH2

slow

/

J 02N@N02

+ R1R2NH + PhOH

NO2

It has been reported that the reactions in DMSO of 1-fluoro-2,4- and -2,6dinitrobenzene with N,N-dialkylamines in the presence of potassium carbonate, which yield dinitrophenyl N,N-dialkylcarbamates such as (5), probably involve the prior formation of carbamate ions.22The reaction of the dichlorodiphenylethylenederivative (6)with N,N-dimethylformamidein the presence of sodium hydroxide gives a product in which both the ring chlorine atoms have been replaced by NMe2 groups.23


234

There have been hrther reports of the reaction under high pressure of mono-, di-, and tri-chloronitrobenzenes with N-substituted cyclic amines. Substitution of chloride yields quaternary ammonium salts such as (7), which may undergo dealkylation or ring ~pening.’~’’~ Reaction, also under high pressure, of 2,3,5,6-tetrachloronitrobenzene with ethylenediamine gave a 1 : 1 substitution product and a bridged 2 : 1 product by substitution of a nitro group and/or a chlorine atom. However reaction with N,N‘dimethylethylenediamine gave cyclized products through successive substitutions of an ortho-chlorine atom and the nitro group.26 There have been kinetic studies of the reactions of picryl chloride with 2,6-diamin0pyridine*~and with 3-amino-l,2,4triazole.28

It has been reported that substitution of 1,2-dihal0-4,5-dinitrobenzenewith primary or secondary amines proceeds by nitro-group replacement, to give products in which the halogen substituents are available for further reaction cherni~try.’~ Displacement of a nitro group is also observed in the reactions of 1,2- or 1,4-dinitrobenzene with electrogenerated aryl sulfide ions or aryl disulfide ions in N,N-dimethyla~etamide.~’ A convenient synthesis of 4-fluoro-1-naphthaldehyde (8) has been r e p ~ r t e d ; fluoride ~ is readily displaced from (8) by a variety of nucleophiles in DMSO. Am I

Am I

H Am

7 Nucleophilic Aromatic Substitution

235

A kinetic study of the hydrolysis of 1-pyrrolidino-, 1-piperidino-, and 1-morpholino2,4-dinitrobenzenes to yield 2,4-dinitrophenol has shown catalysis by both hydroxide and by amine. The catalysis is due to the formation of a-adducts (9) and (lo), respectively, by nucleophilic attack at an unsubstituted ring position. The addition of the nucleophile favours displacement by causing rotation of the 1-substituent from the ring plane hence decreasing conjugation with the n-system of the aromatic ring3* Kinetic study of the reaction of 2,4-dinitrobenzaldehydewith hydroxide ions in water has led to the mechanism proposed in Scheme 2. Initial attack of hydroxide at the carbonyl function yields the hydrate anion (11). Attack of hydroxide at the 1-position leads to displacement of formate, and the final step is loss of hydroxide to give the nitroso function. The final product is in equilibrium with its hydroxy o - a d d ~ c t . ~ ~

?” No,

HO’

N ‘0-

SCHEME 2

There is evidence from kinetic and equilibrium studies of 4-nitrosoanisole and 4nitrosophenyl phenyl ether in aqueous acid that hydrolysis involves nucleophilic attack by water at the ring carbon bearing the alkoxy or aryloxy substituent of the protonated substrate.34Kinetic and spectroscopic studies of the hydrolysis in water or in DMSO of bis(2,4-dinitrophenyl ether)s of poly(ethy1ene glycol) show that hydroxide attack may occur at the C(1) position.35 There has been a report of pronounced solvent and cation effects in the nucleophilic coupling of alkali metal 2-naphthoxides with 1-bromo-2-naphthols; halogen exchange between reacting partners may occur c onc ~rre nt ly.3-Bromoazulenequinone ~~ (12) has been shown to undergo substitution with a range of nucleophiles to give the 3substituted product; however, reaction with butanethiolate yields the 2,3-bisbutylthio deri~ative.~~

236

a


0

0

Br

No2

There is current interest in mechanisms of the substitution of ring hydrogen atoms by nucleophiles. Replacement of a ring hydrogen by a methylamino group in 1,3dinitrobenzene and some of its monosubstituted derivatives may be achieved38 by reaction with liquid methylamine containing potassium permanganate; there is NMR evidence for the intermediacy of methylamino a-adducts such as (13). There has been a report of the vicarious nucleophilic substitution of hydrogen in nitro- 1,6-methano[lO]annulenes (14) by a variety of carbanions including those derived from halomethyl aryl s ~ l f o n e s .Treatment ~~ of nitroarenes with the carbanion derived from 1(phenylsulfonylmethy1)benzotriazole (15) yields products of vicarious substitution. However, unexpectedly, it is the phenylsulfonyl group rather than the benzotriazole which is cleaved. Small quantities of products resulting from the oxidation of initially formed a-adducts are also pr~duced.~’ It has been demonstrated that the initial attack of carbanions derived from phenylacetonitriles on nitroarenes occurs at unsubstituted ring positions and may lead to the products of vicarious substitution of hydrogen. Contrary to a previous report, it was shown4’ that the phase-transfer-catalysed reaction of phenylacetonitrile with 4-chloro-3-(trifluoromethyl)nitrobenzeneproduces the benzisoxazole derivative (16) rather than the straightforward substitution product (17). Reaction of (pentachloropheny1)lithium with a-lithio-a-arylacetonitrilesresults in displacement of the halogen at the 4-position to give a-aryl-cc-(2,3,5,6-tetrachloropheny1)acetonitriles; a four-centred transition state (18) was proposed.42

Ph

Q” PhyHCN

NO*

(17)

Li I


237

A theoretical study using SAM1, AM1, and PM3 methods has been reported of the halogen exchange and fluorodenitration reactions of 2,4-dichloronitrobenzenewith free fluoride ion and with tetramethylammonium fluoride (TMAF). A key role in the reaction with TMAF is the association of the tetramethylammonium ion with the nitroaromatic structure.43An inexpensive form of potassium fluoride with high surface area, which shows enhanced activity in nucleophilic aromatic displacements, has been prepared44 by recrystallization from methanol by slow evaporation of the solvent followed by drying at 100 "C. Acetophenones labelled at the 4-position with '*F have been produced4' by reaction of 4-haloacetophenones with an ['*F]fluoride-cryptandoxalate system; the relative efficiency of halogen replacement was F > C1> Br > I. A quantitative treatment has been reported of micellar effects on nucleophilic substitution of 2-chloro-3,5-dinitropyridineby hydroxide and azide ions in the presence of cetyltrimethylammonium halides. The anionic concentrations at the micellar surface depend upon both specific and non-specific coulombic interactions, which were calculated by solving the Poisson-Boltzmann equation.46The substitution of 1-chloro2,4-dinitrobenzene by glutathione in reverse micelles has been used as a model system to assess the transition-state stabilization in glutathione transferase-catalysed conjugat i ~ n . ~ ~ Intramolecular nucleophilic substitutions of fluoride or chloride, activated by orthoor para-nitro groups, to yield biaryl ether bridges have been used in syntheses of model ring systems for the antibiotic tei~oplanin.~*-~' Two intramolecular aryl-aryl coupling reactions of 2'-bromoreticulines have been described. The regioselectivity depends on the cyclization method; palladium catalysis gives a salutaridine derivative whereas a photochemically induced SRN 1 reaction gives the aporphine ~keleton.~' The intramolecular Smiles photo-rearrangement shown in Scheme 3 is subject to general base catalysis.52A Brsnsted plot shows classic Eigen behaviour with a break at pH 6 consistent with the pK, value expected for the intermediate (19). Study of the photo-reactions of 2,6-difluoro-4-nitroanisolein the presence of nucleophiles shows that one fluorine is replaced by hard nucleophiles and the methoxy group by softer nucleophiles. Little reduction occurs and one fluorine atom is not replaced so that the reagent my be useful as a biochemical p h ~ t o - p r o b e . Irradiation ~~ of 1,2,4,5tetracyanobenzene in the presence of aliphatic ethers results in electron transfer and may yield products in which a cyan0 group is substituted to give alkyltricyanoben~enes.'~

(19)

SCHEME 3

238


Coordination of arenes with tricarbonylchromium results in activation towards nucleophilic attack. It has been shown that reaction of Cr(C0)3-complexed oalkylanisoles with carbon nucleophiles may result in tele-substitution of the methoxy group.55 The deprotonatiodsilylation of methoxy- and (1,2-dimethoxybenzene)Cr(CO), derivatives may yield silylated products with high enantioselectivity when a chiral lithium amide is used as base.56 (Haloary1)copper nucleophiles have been prepared from active copper and the corresponding haloiodobenzene; cross-coupling of the reagents with alkyl and acyl halides yields the respective alkyl-substituted haloarenes and haloaryl ketones.57 Copper(1) has been shown to catalyse the reactions of iodoarenes with sodium arenesulfinates yielding unsymmetrical diary1 ~ u l f o n e s .The ~ ~ nickel-catalysed substitution of the sulfonyl group in aryl t-butyl sulfones has been reported in reactions with aryl Grignard reagents which lead to the formation of biaryls. This reaction may be used in conjunction with the powerful ortho-lithiating effect of the 1-butylsulfonyl group to prepare unsymmetrical ortho-substituted b i a r y l ~ . ~ ~ There has been a report of the catalysis by a combination of copper cyanide and palladium of the coupling of aryl iodides and a-lithioamines to yield 2-aryl-substituted amines.60Palladium catalysis is also effective in the synthesis of arylamines by reaction of aryl halides with secondary amines in the presence of silylamide base.61The Heck reaction, in aqueous media, has been used to produce styrylamino acids from arenediazonium salts derived from phenylalanine and tyrosine.62 There has been a report of the selective hydrodehalogenation of halogenated aromatic ketones by hydrogen in the presence of palladium on carbon.63This catalyst may also be effective in the Stille reaction, the palladium-catalysed cross-coupling of aryl halides or triflates with organostannanes; it was found that the yield and reaction rate are enhanced by the addition of copper iodide as co-catalyst and triphenylarsine as l i g a ~ ~ d . ~ ~ It has been reported that the initially formed intermediate in the Stille reaction resulting from oxidative addition of Pd(0) into the aryl halide may undergo aryl-phenyl exchange with triphenylphosphine ligand leading to mixtures of biaryl products.65 Pd(0) in combination with lithium chloride has been used to promote the cross-coupling of trimethyl(4-pyridy1)stannane with polybromoarenes to yield poly(4-pyridyl)-substituted aromatic compounds.66There have been reports of the palladium-catalysed reaction of organostannates with aryl halides in aqueous media,67and of the solid-phase synthesis of biphenyls by heterogeneous cross-coupling of trialkylphenylstannanes with aryl ele~trophiles.~~ The Pd-catalysed cross-coupling of pyridyl triflate with aryl bromides in the presence of hexamethylditin is thought to involve the intermediacy of a labile pyridyl~tannane.~~ The Suzuki reaction, the Pd-catalysed reaction of aryl halides with boronic acid derivatives, has been used to produce arylboronic esters from the pinacol ester of diboronic acid.70 The Pd-catalysed intermolecular cross-carbonylation of aryl iodides with dihydrofbrans may be achieved by reaction with carbon monoxide in the presence of a tertiary a m i ~ ~ eThe . ~ ' Pd-catalysed coupling of allylic cyclic carbonates with iodobenzene was found to give phenyl-substituted allylic alcohols; however, arylation without reductive ring opening was achieved using diphenyliodonium tetraflu~roborate.~~ There have been reports of Pd catalysis in the intramolecular cyclization of an iodoaryl


239

n i t r ~ a l k e n eand ~ ~ in the reactions of substituted aryl iodides with allenes, which may yield bicyclic products enantio~electively.~~

Heterocyclic Systems There have been fill reports of interesting studies of the nature of the transition states in substitutions in 1,3,5-triazinederivatives. Substitution of 4-nitrophenolate ions from 2(4-nitrophenoxy)-4,6-dimethoxy-1,3,5-triazine by substituted phenolate ions in aqueous solution obeys a linear Brmsted-type equation over a range of pKa values both greater and less than the pKa value of the leaving The absence of curvature is consistent with a mechanism involving the single transition state (20). By contrast, the pyridinolysis of 1-(4,6-diphenoxy-1,3,5-triazin-2-yl)pyridinium chloride with substituted pyridines shows a non-linear Brernsted plot with a break-point when the pK, of the pyridine nucleophile equals that of the leaving group; this result is consistent with a traditional two-step mechanism involving the intermediate (21). The results indicate that there is negligible coupling between the bonding changes in the two steps, and substituent effects show that bond formation is about half complete in the addition step.76

Kinetic studies have been reported of the substitution reactions of the thiophene derivatives (22: L = Br, OPh, OC6H4N02;Y = CONH2,C02Me) with aliphatic amines in benzene. Base catalysis was observed with the compounds containing phenoxy or nitrophenoxy leaving groups, and the effects of the ortho-like Y substituents were discussed.77Reactions of 3-bromo-2-nitrobenzo[b]thiophene(23) with amines in N,Ndimethylformamide yield the expected substitution products, the 3-amino derivatives, together with the isomeric 2-amin0-3-nitrobenzo[b]thiophenes.~~


240

There have been reports of base catalysis in the reactions of 2-alkoxy-N-alkylpyridine salts with piperidine in a ~e toni tril eand ~~ of the effects of acid and base catalysts on the reaction of 4-chloroquinoline with 1,2,4-t1iazole.~~Kinetic studies of the piperidinodechlorination of 2,4-diamino-6-chloropyrimidine(24; R = H) in DMSO show the absence of base catalysis, indicating that piperidine attack at the 6-position is rate limiting. The corresponding N-(3)-oxide (25; R = H) is slightly more reactive towards nucleophilic substitution. A much more marked increase in reactivity was found in the N-acetyl derivative (24; R = COMe). However, the reactivity of (25; R = COMe) was reduced since it was converted into an anionic form by piperidine.81There has been a kinetic study of the relative rates for successive displacement of the three chlorine atoms in 2,4,6-trichloro- 1,3,5-triazine (cyanuric chloride) by butylamine in Nmethylpyrrolidine and by morpholine in propan-2-01.~~ Oligomeric porphyrins have been prepared by the stepwise nucleophilic substitution of aminoporphyrine monomers on to cyanuric chloride.83 The reactions of cyanuric chloride with dialkylamines have been used to prepare both symmetrical and non-symmetrical trisubstituted triazines; NMR experiments indicate that rotation about Ar-N bonds may be r e ~ t r i c t e d .An ~~ attempt has been made to correlate reactivity to substitution in heterocyclic compounds with chemical shifts in their I3C NMR spectra.85

NHR

(24)

The reaction of 2-chloro-3,5-dinitropyridinewith hydroxide yields the pyridine derivative by the ANRORC mechanism as shown in Scheme 4; there has been a study86 of solvent effects on the rates of formation and disappearance of the ring-opened intermediate (26). It has been reported that in alkaline solution 3,Sdiacetyl- and 3,5dicyano- 1,2,6-trimethylpyridinium salts are converted by recyclization into N,5dimethylanilines and 2-methylaminopyridines, re~pectively.~~ Reaction of 1,2,3triarylbenzo[h]thiophenium ions with alkoxide results in ring-opening with retention of configuration.88

SCHEME 4


24 1

There have been several reports of the vicarious nucleophilic substitute (VNS) of hydrogen by carbanions containing leaving groups, and the method has been applied to nitro derivatives of thiophene, furan, and pyrr~le.~’ It was reported that 5- and 6nitrobenzoxazoles (27) undergo nucleophilic attack at the 2-position resulting in ringopened products. However, when the 2-position is blocked VNS may occur in the carbocyclic ring.” The VNS reaction of 2-substituted-5-nitrobenzoxazoleswith 4chlorophenoxyacetonitrile resulted in the formation of 4-cyanomethyl derivatives and was used in an attempted synthesis of tetrahydropyrroloquinoline alkaloids.” It has been shown” that a phenylmethylsulfonyl group may be introduced regiospecifically at the 4-position of 3-substituted pyridazines by VNS reaction of the pyridazinium dicyanomethylides (28). In all these reactions the initial step is nucleophilic attack at a ring-carbon carrying hydrogen. Similarly, in the unusual substitution reactions of 3trichloromethylpyridine (29) and its derivatives, the first step is attack at the unsubstituted a-position and this is followed by loss of chloride and hydrogen migration to the ~ide-chain.’~

Meisenheimer and Related Adducts There has been a major review rationalizing the regioselectivity of anionic addition to nitro-activated arenes and noting the importance of stereoelectronic stabilization in C( 1) a d d ~ c t sThe . ~ ~use of anionic o-adducts in organic synthesis has been reviewed,95 and a spectrophotometric method has been reported for the determination of some phenolic drugs. This involves nitration followed by the formation of strongly coloured Janovsky adducts by reaction with acetone in alkaline ~olution.’~ Alkylation of adducts formed by carbanion addition to 9-nitroanthracene may ultimately yield 1O-substituted-9anthroxime~.’~The reaction of 1,3,5-trinitrobenzene with tetrahydroborate gives the trihydro adduct (30), which yields 1,3,5-trinitrocycIohexaneon acidif icati~ n.Kinetic ~~ studies of the hydrogen isotope effect, kHlkD, have provided evidence for proton tunnelling in the reactions with tertiary amines of 2,4,6-trinitrotoluene, 2,4,6trinitrobenzyl chloride, and hexanitrobibenzyl.” Kinetic and equilibrium data have been reported for the reaction of carbanions derived from 12 ring-substituted benzyl cyanides with 1,3,5-trinitrobenzene, to give (31), and with 4-nitrobenzofuroxan. With increasing carbanion reactivity, rate constants approach a limit of ca lo9 dm3 mol-’ s-’, and the results were used to measure the intrinsic reactivities of the carbanions in these a-adduct-forming reactions.loo Reactions of carbanions derived from nitroalkanes with 4,6-dinitrobenzofuroxan (DNBF) yield

242


the adducts (32). Rate and equilibrium measurements in water indicate that these adducts have stabilities 105-108 times greater than those of the corresponding cradducts from 1,3,5-trinitrobenzene, emphasizing the extremely high electrophilic character of DNBF. Reaction of adducts (32) with base results in the b-elimination of nitrous acid to give alkenes (33) which were characterized by NMR.'" b-Elimination reactions have also been observed on treatment with potassium fluoride in acetonitrile of the adducts (34) formed from DNBF with sulfonium ylides.''* The reactions of methoxide ions with 7-methyl-4-nitrobenzofuroxan result in rapid attack at the unsubstituted 5-position followed by isomerization to give the thermodynamically preferred 7-methoxy-7-methyl adduct (35). The unusual preference for the latter process over proton loss from the methyl side-chain was ascribed to the absence of steric strain at the 7-position (allowing methoxide addition) and to the high intinsic barrier expected for deprotonation.Io3

base

(32)

(33)

It is reported that reactions of dinitrophenyl crown ethers with alkali metal hydroxides in aqueous DMSO may lead to the concerted formation of anionic 0adducts and complexes with the metal cation^.''^ The hydroxide adduct (36) of a triazolotriazine has been prepared and its crystal structure dete~ mined. '~ Spiro ~ adducts containing 1,3-dithiolane and 1,3-0xathiolane rings at the 8-position of 5,7dinitroquinoline have been prepared and characterized.Io6 Crystallographic studies of the spiro adducts (37; R = H, NO2) have been reported and their thermal decomposition pathways determined.lo7 There have been spectroscopic studies of the salts formed

243


R

I

(341

(35)

from (37; R=NOz) with a variety of metal cations,"* and solvent effects on the electronic spectra of a series of a-adducts have been examined."'

Benzyne and Related Intermediates Theoretical studies have been reported of C6H4X- anions (X = F, C1, Br) which may, in the gas phase, show characteristics of benzyne-halide complexes. Ab initio calculations predict a dramatic decrease in binding energy from C6H4F- to C6H4Cl- and to C6H4Br- (226, 96, and 60 kJ mol-'). In agreement with experiment, the C,&Brion is calculated to undergo a bromide transfer rather than hydrogen abstraction when reacting with methanol."0 Calculations at the MP2, MP3, and MP4 levels established two structures, with a low energy barrier, for C6H&-: (a) a bromophenide ion and (b) a bromide-benzyne complex where the bromide ion straddles the ortho- and metahydrogens of the ring."' An experimental study of the ion-molecule reactions of hydroxide and methoxide ions with bromobenzene indicates benzyne formation initiated by proton abstraction followed by loss of halide. Experiments with monodeuteriated bromobenzenes suggest that reactions with hydroxide are the result of long-lived complexes in which extensive scrambling of hydrogen-deuterium occurs. Reactions of amide ions with bromobenzene result in the formation of all the isomeric bromophenoxide ions without isotopic scrambling indicating weak binding in the collision complexes.' "


244

It has been shown that phenyl[o-(trimethylsilyl)phenyl]iodonium triflate (38), which may be readily prepared from o-bis(trimethylsily1)benzene and the hypervalent iodine reagent iodobenzene diacetate, is a useful precursor of benzyne.'I3 A study of the decomposition of 1-(2'-carboxyphenyl)-3,3-dimethyltriazene (39) and its tetrahaloanalogues has identified the arenediazonium-2-carboxylates as intermediates in aryne formation.' l4 A re-investigation of the decomposition of benzenediazonium-2carboxylate in mixed nucleophilic solvents indicated the operation of a number of mechanistic pathways. In addition to benzyne, products derived from 2-carboxyphenyl cations and 2-carboxyphenyl radicals were observed; benzyne formation is favoured in halogenated solvents and occurs by concerted loss of nitrogen and carbon dioxide."' Reaction with borates and borinates of zirconocene complexes (40) of substituted benzynes leads to the regioselective formation of heterodimetallic compounds, which may be converted into halophenols.' l 6 The relative reactivities of 4-substituted benzynes towards methanol, ethanol, and propan-2-01 have been examined. l7

'

OTf

R

The regioselective cycloaddition of an a-alkoxybenzyne with an angularly hsed CIsiloxyfuran has permitted the synthesis of benz[a]anthraquinone derivatives. There have been reports of the intramolecular Diels-Alder reactions of an aryne and an azadiene to give lycorine alkaloids' l 9 and of benzyne with an acyclic diene.'*'

''

References

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Broxton, T.J., Colton, R., and Traeger, J. C., 1 Phys. Org. Chem., 8, 351 (1995). Wassmundt, F. W. and Kiesman, N. F., 1 Org. Chem., 60, 1713 (1995). Tsuge, A,, Moriguchi, T., Mataka, S., and Tashiro, M., 2 Chem. Res. (S), 1995, 460. Hanson, P., Hammond R. C., Gilbert, B. C., and Timms, A. W., 1 Chem. Soc., Perkin Trans. 2, 1995, 2195.

10

11

Pierini, A. B. and Duca, J. S., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1821. Compton, R. G., Dryfe, R. A. W., Eklund, J. C., Page, S. D., Hirst, J., Nei, L., Fleet, G. W. J., Hsia, K. Y., Bethell, D., and Martingale, L. J., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1673. Marchal, J., Bodiguel, J., Fort, Y., and Caubere, P., 1 0%.Chem., 60, 8336 (1995). Amatore, C., Combellas, C., Lebbar, N.-E., Thiebault, A., and Verpeaux, J.-N., 1 Org. Chem., 60, 18 ( 1995).

l2 l3 14

Hu, K., Niyazymbetov, M. E., and Evans, D. H., Tetrahedron Lett., 36, 7027 (1995). See Organic Reaction Mechanisms, 1994, Chapter 7. Marquet, J., Casado, F,, Cervera, M., Espin, M., Gallardo, I., Mir, M., and Niat, M., Pure Appl. Chem., 67, 703 (1995).

l5

Panteleeva, E. V, Vaganova, T. A,, Shteingarts, V D., and Bilkis, I. I., Tetrahedron Lett., 36, 8465 (1995).

7 Nucleophilic Aromatic Substitution 16

245

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67

'" "'


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I08

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'I2

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CHAPTER 8

Electrophilic Aromatic Substitution R. G. COOMBES Department of Chemistq Brunel University, Uxbridge General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkylation, Acylation, and Related Reactions. . . . . . . . . . . . . . . . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

249 249 250 252 256 256

General A valence-bond study' of benzene, phenol, and benzonitrile, and the arenium ions formed by them on protonation, has shown that, although the spin-coupled wavefunctions for the aromatics can be interpreted in terms of valence-bond structures, the charge delocalization in the ions is achieved through a single spatial configuration of semi-delocalized orbitals. The form of a spin-coupled wavefunction for the ions demonstrates clearly the effect of the substituents. Rates of nitration of monosubstituted benzenes2 from MNDO calculations have been related to substrate ionization potential. The interaction of solvent with the transition-state structures for some reactions including Friedel-Crafts substitution has been discu~sed.~ A correlation between the regioselectivity of substitution in some heterocyclic compounds with 13C NMR chemical shifts has been e ~ p l o r e dRecent .~ criticism, reported last year, of the use of the reactivity ratio of mesitylene to durene as a probe of transition-state structure in many substitutions and its use to distinguish between conventional ionic and electron-transfer pathways has been firmly rebutted as a general propo~ition.~ The importance of the involvement of dicationic species as the effective electrophiles in Gatterman, HoubenHoesch, and Friedel-Crafts reactions of unactivated benzenes has been demonstrated.6 + For example, N,N-diprotonated hydrogen cyanide (HE=NH,) is effective in the Gatterman reaction of benzene with cyanide and protonated acyl cations are effective in, for example, the acetylation of benzene by MeCOSbF6 at high acidities (see also references 34-36).

Halogenation Formic and sulfuric acids have been shown to promote electrophilic fluorination by elemental f l ~ o r i n esuggesting ,~ that it may indeed be possible to use fluorine as a viable Organic Reaction Mechanisms 1995 Edited by A. C. Knipe and W E Watts 0 1997 John Wiley & Sons Ltd

249

250


reagent in organic synthesis. 4-Fluorobenzoic acid is, for example, converted smoothly and cleanly into 3,4-difluorobenzoic acid in 66% yield at room temperature in formic acid and pentafluorobenzoic acid can be formed from 2,4-difluorobenzoic acid in concentrated sulfuric acid, again at room temperature. There is the possibility of hypofluorite intermediacy. Chlorination of phenol with sulfuryl chloride (S02C12) is catalysed by primary and secondary amines in non-polar solvents and under these conditions reaction to give monochlorinated products is rapid and highly regiospecific for ortho substitution (olp > 4).' The high regioselectivity is attributed to in situ N-chloroamine formation, the N-chloroamine attacking the ortho position of phenol, facilitated by intramolecular hydrogen bonding. Regioselective para bromination of anilines occurs on reaction with bromine and nitrosonium bisulfate in concentrated sulfuric acid, the nitrosonium salt being essential for reaction.' A route involving the appropriate aniline radical cation is suggested (cf. reference 26). The orienting effect of the 1-0-(2,3,4,6-tetra-O-acetyl-j3D-glucopyranosyl) group in aromatic bromination by bromine in dichloromethane has been described" and also, when used in conjunction with hydroxy andor methoxy groups, a number of high-yield regioselective brominations of potential synthetic utility have been achieved. The iodination of phenols in free ortho and para positions is readily achieved in dichloromethane solution using bis(sym-collidine)iodine(I) hexafluorophosphate (1).l 1 With aniline and N,N-diethylaniline, however, regioselective para iodination in excellent yield was observed. A convenient new procedure for the direct iodination of unreactive aromatic compounds has been reported.I2 The procedure involves passing fluorine diluted with nitrogen at room temperature through a mixture of iodine, concentrated s u l h c acid, and the substrate. Nitrobenzene is converted into 3-iodo- 1nitrobenzene in 70% yield under these conditions. The mechanism may involve the intermediacy of iodine fluoride, a hypervalent iodine species, or a hypofluorite derived from sulfuric acid.

Nitration Studies of reactions which do not have the conventional mechanism of electrophilic aromatic substitution continue. Two further substrates have been studied in the photochemical nitration reaction with tetranitromethane, which has importance in mechanistic arguments. In the case of 1,2,3,4-tetramethylben~ene,'~ the structure of a

8 Electrophilic Aromatic Substitution

25 1

nitro-cycloadduct has been determined by X-ray crystallography. In the case of 1meth~xynaphthalene,'~ evidence is presented that the products, including 1-methoxy-4and 1-methoxy-2-nitronaphthalene result from highly labile nitro- or nitritotrinitromethyl adducts, including (2). N-Nitrosuccinimide (3) has been used" as the reactant in a related reaction to produce a range of products from very electron-rich aromatics (e.g. N,N-dimethyl-p-toluidine). The photolysis with tetranitromethane has been used in related studies as a method of preparation of methyl-substituted naphthalene radical cations.l 6 A report has a p ~ e a r e d of ' ~ measurements by Raman spectroscopy of the variation with temperature of the concentration of nitronium ions in nitric acid-sulfuric acidwater mixtures. Conclusions drawn, however, concerning kinetic behaviour at low nitronium ion concentrations merit further discussion. The nitration of some alkylbenzenes, catalysed by mercury(I1) acetate, has been studied in a number of solvents." With toluene a mercuriation-nitrosodemercuriation sequence, giving a change in product isomer ratio from the normal, was identified in nitric acid-acetic acid and dilute nitric acid. Isomer proportions of 0- 30%, m- 6% and p- 64% could be achieved. Further evidence has been adduced for the operation of nitrogen trioxide (NO;) as the electrophile involved in electron transfer in ozone-mediated nitrations with nitrogen dioxide (kyodai nitration).l 9 The ratios of dinitrobenzenes and of nitrophenols formed as side-products in the nitration of benzene are significantly different from those formed under conventional conditions. Cyclic acetals of aromatic carbonyl compounds (4) can be nitrated smoothly under kyodai conditions in the presence of magnesium oxide as an acid scavenger.20o- and p-Nitro-compounds, in addition to significant proportions of m-nitro derivatives, are formed, the acetal ring remaining almost intact. The ternary mixture NO-N02-02 has been found to be more effective than NOT02 as a nitrating agent for non-activated aromatic compounds and again nitrogen trioxide is implicated as the reactive species.21This observation is related to one made previously.22Kyodai nitration of anilides and aryl esters gives a mixture of ortho- and para-nitro derivatives in which the former isomers p r e d ~ m i n a t e .Intermediacy ~~ of (5) or (6) formed by reaction of NO2 with the appropriate radical cation is suggested to explain the ortho predominance. The use of dinitrogen pentaoxide in liquid sulfur dioxide as a nitrating agent has been explored. Reaction with benzene and monosubstituted derivatives at - 11 "C gave

(4)


252

results similar to those obtained from mixed acid nitration.24Results from competition experiments and the nitration of bibenzyl indicated reaction at a rate faster than mixing. A number of heterocyclic compounds including pyrimidine did not react, but reaction with pyridine and a number of its derivatives was successhl. Further investigation of the nitration of pyridine has led to the suggestion25of the intermediacy of two species. First, a pyridinium-S02-N205 complex (7) was formed and then, on addition of water, a 1,Cdihydropyridine complex was formed which decomposed by a first-order process to give mainly 3-nitropyridine.

(7)

(8) a; X = H

b; X = N 0 2

Reaction of aniline with nitrosonium bisulfate followed by nitric acid in concentrated sulfuric acid to give nitrophenyldiazonium ions involves nitrosonium ion-catalysed nitration in the para-position with normal meta- and para-nitration followed by diazotization on dilution with water.26Mixed-acid nitration of 6,6-dimethylbenzosuberone (8a) at 25 "C gives the unexpected rearrangement product (9).27 The unrearranged nitro-compound (8b) is only formed at 0 "C and rearranges to (9) in acid solution at 25 "C, a process for which the presence of the nitro group is necessary.

Alkylation, Acylation, and Related Reactions Treatment of porous support materials (e.g. silica having a 70 average pore diameter) with aluminium chloride in solution produces an entirely heterogeneous form of aluminium chloride, which is highly active in the liquid-phase alkylation of aromatics using alkenes and chloroalkanes.28 Selectivity towards monoalkylation is improved over homogeneous reactions and the supported reagent catalysts are re-usable and easily recovered by filtration. A review29 in Chinese includes comment on the application of iron(II1) chloride in Friedel-Crafts reactions. A semiempirical study3' of the mechanisms of alkylation of arylamines has been carried out. Calculations on the acid-catalysed ortho-alkylation by an alkene support a mechanism similar to that of the ene reaction, i.e. involving (10). An alternative route for alkylation of aromatics with alkenes in the gas phase has been demonstrated from a radiolytic study of the reaction of benzene and propene in methyl fluoride containing oxygen and dimethyl ether.3' Alkylation occurs within an ion-molecule complex formed upon addition of an arenium ion to the alkene.


253

The Y-type zeolite HZZ-360 has been shown to be an effective catalyst for the electrophilic monoalkenylation of a range of aromatic compounds by phenylethyne in 1,2-dichlorobenzene at 110 O C 3 ’ Reaction is believed to occur on the external surface of the catalyst particles. Vinylation is also achieved33 by reaction of alk-1-ynes, phenols, tin(1V) chloride, and tributylamine in refluxing acetonitrile, when orthoalkenylphenols are formed. 1,2-Dicarbonyl compounds react with benzene in the presence of trifluoromethanesulfonic acid to give high yields of gem-diphenylated ketones.34Involvement of 0,Odiprotonated 1,2-dicarbonyl species [e.g. 1,2-dihydroxyethene dication (1l)] as the initial electrophiles is suggested. Under superacid conditions benzaldehyde reacts readily with benzene to give a high yield of triphenylmethane and there is evidence for the involvement of diprotonated be n~a l de hydeAb .~~initio calculations suggest that the latter species is the O,C(aromatic)-diprotonated dication (12). In contrast, other workers36suggest that 0,O-diprotonated benzaldehyde (13) is the reactive intermediate in the reaction of benzene with benzaldehyde in the presence of, for example, trifluoromethanesulfonicacid to give initially triphenylmethane. Here NMR deuteriumexchange experiments seem to rule out (12).

Two sequential and regioselective Friedel-Crafts reactions of gem-dihalocyclopropanecarbonyl chlorides with substituted benzenes have been rep~rted.~’ (E)-3-Aryl-2,2dihalocyclopropanecarbonyl chlorides [e.g. (14)] afforded 4-aryl-3-halo-1-naphthols [e.g. (15)], while 2,2-dichlorocyclopropanecarbonyl chlorides 1e.g. (16)] gave 4-aryl-lnaphthols [e.g. (17)] with benzene or p-xylene. A cyclialkylation strategy has been used to make hydr~phenanthrenes.~~ The annulations occur in synthetically useful yields if the aromatic ring is electron rich and if conformational effects favour cyclization. Compound (18a), for example, does not cyclize in the presence of BF3.Et20, whereas (18b) forms (19). Trifluoromethane-


254 OH

OH

sulfonation of the allylic alcohol of a piperonylated conduritol (20) induces intramolecular electrophilic alkylation of the aromatic ring.39 The prevalence of substitution ovtho or @so to the CH20 bridge is controlled by the nature of the ring substituent Z. @so attack is followed by 1,2-alkoxymethylmigration. 1,l'-Biphenyl-2yl isocyanide dihalides (21) undergo novel Lewis acid-catalysed c y c l i ~ a t i o n sto~ give ~ the hitherto difficulty accessible 6-chloro- and 6-bromo-phenanthridines. The thermolyses of N-mono- and N,N-di-substituted benzyl derivatives of 2-aminopyridines have been studied41 to investigate their possible roles in the ring benzylation reaction. The formation of 2-benzylamino-5-benzylpyridiniumchloride occurs by rearrangement of N,N-disubstituted benzyl derivatives only. A complementary MNDO study of electrophilic substitution in 2-aminopyridines was performed. The Gatterman-Koch formylation reaction has been compared with other electrophilic substitutions in super acid^.^^ Formylation has priority over the other reactions under conditions where most of the substrate is protonated, because the formyl cation is formed close to the substrate, in particular by protonation of carbon monoxide by the protonated substrate. An efficient mild procedure for the acylation and perfluoroacylation of activated aromatic substrates (e.g. 1-methoxynaphthalene) has been reported.43 The reagent system is (RC0)20-Me2S-BF3 in dichloromethane and it is believed that dimethylacylsulfonium salts (RCO'SMe2 RC02BF3) are the active acylating species. Hafnium trifluoromethanesulfonate has been found44 to be an extremely efficient catalyst for the acid anhydride acylation of a range of reactive aromatics. Anisole has been regioselectively acylated in the para position by reaction with carboxylic acids at > 150 "C over H-ZSM-5 zeolite.45 Substitution at the ortho and meta positions was not observed but ester formation was significant and dominant at lower temperatures. The full results4' of the investigation of the mechanism of the bisacylation of aromatics with 0-phthaloyl dichlorides in the presence of aluminium chloride to give anthraquinones has indicated the importance of the asym-dichlorides (22), which react initially with the aromatic compound to give o-benzoylbenzoic acid pseudochlorides (23), which then undergo cyclization. In unexpected contrast to benzenoid aromatics, which are alkylated, N-methylpyrrole undergoes acylation on reaction with lactones in the presence of aluminium chloride in chloroform solution at 60 "C, the reaction being most efficient with y- and a - l a c t o n e ~ . ~ ~ Annulation reactions are possible, for example the formation of mainly (24) from the lactone of 4-hydroxypentanoic acid.


255

@ @ /

x x

(18) a; X = H b; X = M e

Me

Me (19)

(21) X,Y = C1, Br combinations


256 Other Reactions

The arenium ions from simple aromatics (e.g. benzene) have been studied by UVvisible and 'H NMR spectroscopy at room temperature in AIC13/Br3-Me3SBr-HBr melts.48 This allows, for example, the positive charge distributions on the five sp2 carbons of the pentamethylbenzenium ion to be confirmed by 'H NMR studies. AM1 calculations have been carried out on polyfluorobenzenes and their related protonated forms.49Proton affinities of the former have been estimated as have activation energies for 1,2-hydrogen shifts in the latter. The sulfonations of biphenyl and various activated derivatives by sulfur trioxide in dichloromethane have been studied and indication of the positions of successive reactivity obtained." The sulfonation of dimethoxynaphthylenes has been investigated.51 A linear-free-energy relationship has been demonstrated for substituent effects in the Reimer-Tiemann reaction of a number of phenols.52Vilsmeier reaction of, for example, N,N-dimethyl-4-methylaniline with N-formyl-N-ethylaniline in phosphoryl chloride results in initial ortho substitution to give (25).s3 This is followed by a 1,5-sigrnatropic hydrogen shift to give an iminium ion (26) in which electrophilic attack on the adjacent aromatic ring occurs to give a dibenzo[b, f ][ 1,5]diazocine.

I

Me, +, NO S

I

The reaction of anisole with NO+ AlCI, in SO2-CD2CI2 at - 70 "C has been demonstrated by 'H, 13C, and "N NMR spectroscopy to give the n-complex (27).54In contrast, the reaction of thioanisole, which was studied by similar methods, gives the complex (28). Results of MIND0/3 calculations are in agreement with these observations. References

'

'

Raos, G., Gerratt, J., Karadakov, E? B., Cooper, D. L., and Raimondi, M., 1 Chem. Soc., Faraday Trans., 22,401 1 (1995). Games, A. M. E. A. N. F., Bo1.-Soc. Porf Quim., 49, 16 (1993); Chem. A h . , 122, 238968 (1995). Bertran, J., Lluch, J. M., Gonzalez-Lafont, A., Dillet, V, and Perez, V, ACSS'mp. Ser, 568, 168 (1994); Chem. A h . , 122, 9264 (1995). Ding, J., Daxue Huaxue, 9, 51 (1994); Chem. A h . , 122, 30782 (1995). Baciocchi, E. and Galli, C., 1 Phys. Org. Chem., 8, 563 (1995). Sato, Y., Yato, M., Ohwada, T., Saito, S., and Shudo, K., 1 Am. Chem. SOC.,117, 3037 (1995). Chambers, R. D., Skinner, C. J., Thomson, J., and Hutchinson, J., 1 Chem. SOC.,Chem. Commun., 1995, 17. Gnaim, J. M. and Sheldon, R. A., Tetrahedron Lett., 36, 3893 (1995). Gorelik, M. V, Lomzakova, V I., Khamidova, E. A., Shteinian, V Y., Kuznetsova, M. G., and Andrievsky, A. M., Mendeleev Commun., 1995, 65.

8 Electuophilic Aromatic Substitution 10

257

Mabic, S. and Lepoittevin, J.-P., Tetrahedron Lett., 36, 1705 (1995). Brunel, Y.and Rousseau, G., Tetrahedron Lett., 36, 8217 (1995). 12 Chambers, R. D., Skinner, C. J., Atherton, M., and Moilliet, J. S., 1 Chem. SOC.,Chem. Commun., 1995, 19. 13 Butts, C. P., Eberson, L., Foulds, G. J., Fulton, K. L., Hartshom, M. P., and Robinson, W. T., Acta Chem. Scand., 49, 76 (1995). 14 Butts, C. P., Eberson, L., Hartshom, M. P., Persson, O., and Robinson, W. T., Acta Chem. Scand., 49, 253 (1995). 15 Calvert, J., Eberson, L., Hartshom, M. P., and Svensson, J. O., 1 Chem. Soc., Perkin Trans. 2, 1995, 645. 16 Eberson, L., Hartshom, M. P., and Persson, O., 1 Chem. SOC.,Perkin Trans. 2, 1995, 409. 17 Zaman, M. B. and Hanson, C., Bangladesh 1 Sci. Ind. Res., 29, 143 (1994); Chem. Abs., 123, 111324 (1995). I8 Greenop, M. W. and Thomas, C. B., 1 Chem. Soc., Perkin Trans. 2, 1995, 1595. 19 Suzuki, H. and Mori, T., J: Chem. Soc., Perkin Trans. 2, 1995, 41. 20 Suzuki, H., Yonezawa, S., and Mori, T., Bull. Chem. Sue. Jpn, 68, 1535 (1995). 21 Suzuki, H. and Mori, T., 1 Chem. Soc., Perkin Trans. 1, 1995, 291. 22 Ross, D. S. and Blucher, W. G., Report 1980, ARO-13831.3-CX, Order No. AD-A085324, Avail. NTIS; from Gov. Rep. Announce. Index (US.), 1980, 80(20), 4255; Chem. Abs., 94, 120451 (1981). 23 Suzuki, H., Tatsumi, A., Ishibashi, T., and Mori, T., 1 Chem. Soc., Perkin Trans. 1, 1995, 339. 24 Bakke, J. M., Hegbom, I., Ovreeide, E., and Aaby, K., Acta Chem. Scand., 48, 1001 (1994). 25 Bakke, J. M. and Hegbom, I . , J Chem. Soc., Perkin Trans. 2, 1995, 1211. 26 Gorelik, M. V., Lomzakova, V. I., Khamidova, E. A., Shteiman, V. Y., and Kuznetsova, M. G., Mendelem Commun., 1995, 64. 27 Garcia, J. G., Enas, J. D., Fronczek, F. R., and VanBrocklin, H. F., 1 Org. Chem., 59, 8299 (1994). 28 Clark, J. H., Martin, K., Teasdale, A. J., and Barlow, S. J., 1 Chem. Soc., Chem. Commun., 1995, 2037. 29 Yu,S., Huaxue Shiji, 16, 257 (1994); Chem. Abs., 122, 213188 (1995). 30 Chaka, A. M., Int. 1 Quantum Chem., 53, 617 (1995); Chem. Abs., 122, 159855 (1995). 31 Aschi, M., Attina, M., and Cacace, F., Angew. Chem., Int. Ed. Engl., 34, 1589 (1995). 32 Sartori, G., Bigi, F., Pastorio, A,, Porta, C., Arienti, A,, Maggi, R., Moretti, N., and Gnappi, G., Tetrahedron Lett., 36, 9177 (1995). 33 Yamaguchi, M., Hayashi, A,, and Hirama, M., 1 Am. Chem. Soc., 117, 1151 (1995). 34 Yamazaki, T., Saito, S., Ohwada, T., and Shudo, K., Tetrahedron Lett., 36, 5749 (1995). 35 Olah, G. A,, Rasul, G., York, C., and Prakash, G. K. S., 1 Am. Chem. Soc., 117, 11211 (1995). 36 Saito, S., Ohwada, T., and Shudo, K., . I Am. Chem. Soc., 117, 11081 (1995). 37 Nishii, Y. and Tanabe, Y., Tetrahedron Lett., 36, 8803 (1995). 38 Majetich, G., Liu, S., and Siesel, D., Tetrahedron Lett., 36, 4749 (1995). 39 Doyle, T. J., VanDerveer, D., and Haseltine, J., Tetrahedron Lett., 36, 6197 (1995). 40 Currie, K. S. and Tennant, G., 1 Chem. Soc., Chem. Commun., 1995, 2295. 41 Kowalski, P., Bull. Soc. Chim. Belg., 104, 97 (1995). 42 Tanaka, M., Fujiwara, M., and Ando, H., 1 Org. Chem., 60, 3846 (1995). 43 Kiselyov, A. S. and Harvey, R. G., Tetrahedron Lett, 36, 4005 (1995). 44 Hachiya, I., Moriwaki, M.. and Kobayashi, S., Tetrahedron Lett., 36, 409 (1995). 45 ' Wang, Q. L., Ma, Y., Ji, X., Yan, H., and Qiu, Q., J: Chem. Soc., Chem. Commun., 1995, 2307. 46 Sartori, G., Bigi, F., Tao, X., Porta, C., Maggi, R., Prdieri, G . , Lanfranchi, M., and Pellinghelli, M. A,, J: Org. Chem., 60, 6588 (1995). 47 Harrowven, D. C. and Dainty, R. F., Tetrahedron Lett., 36, 6739 (1995). 48 Ma, M. and Johnson, K. E., 1 Am. Chem. SOC.,117, 1508 (1995). 49 Borisov, Yu. A. and Kurbanbaev, R. M., lm Akad. Nauk, Ser Khim., 1993, 1878; Chem. A h . , 123,255954 (1995). 50 Cerfontain, H., Yousi, Z., and Bakker, B. H., Phosphorus Sulfur Silicon Relat. Elem., 92, 231 (1994); Chem. Abs., 122, 160028 (1995). 5 1 Lin, J. and Zou, Y., YingyongHuuxue, 12, 51 (1995); Chem. Abs., 122, 238972 (1995). 52 Min, H. and Lubing, Y., Liaoning Shfan Duxue Xuebao, Ziran Kexueban, 17, 131 (1994); Chem. Abs., 121,280090 (1994). 53 Meth-Cohn, 0. and Taylor, D. L., 1 Chem. Soc., Chem. Commun., 1995, 1463. 54 Borodkin, G. I., Podryvanov, V. A,, Shakirov, M. M., and Shubin, V G., 1 Chem. Soc.. Perkin Trans. 2, 1995, 1029. 11

CHAPTER 9

Carbocations ROBINA. Cox

Department of Chemistg University (f Toronto, Cunudu Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OpenSystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzyl Cations and Related Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzhydryl, Trityl, and Related Systems . . . . . . . . . . . . . . . . . . . . . . . . . Oxocarbenium and Related Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitrenium Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Destabilized Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatic Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arenium Ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vinyl, Aryl, and Related Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CyclicSystems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bicyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bridged Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

259 260 26 1 262 263 263 265 266 266 267 269 269 27 1 273 275

Introduction

A number of reviews of different aspects of carbocation chemistry have been published. George Olah in his Nobel lecture address has reviewed much of his career work on carbocations, particularly those stabilized by superacid media.’ A review on the reactivities of short-lived carbocations prepared by flash photolytic methods has appeared,’ and the stabilizing effects of silicon on carbocations are included in a general review of silicon in organic chemi~try.~ Tertiary carbenium ion stabilities and rates of formation are discussed in the light of an empirical MM2 force-field method for calculating steric or strain ener gie~Other .~ calculations reproduce experimental data such as heats of formation, bond dissociation energies, gas-phase acidities and proton affinities for a considerable number of molecular, radical, anionic, and cationic specie^.^ The thermodynamics of C-H bond breaking by proton transfer and hydride-ion transfer provide a useful criterion for carbocation and carbanion stabilities.6 The matrix isolation of unstable carbocations and their examination by IR spectroscopy has been summarized.’ Carbocation rearrangement mechanisms can be elucidated by making use of the ICAR computer program.8 A new method for making Organic Reaction Mechanisms 1995. Edited by A. C . Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

259

260


carbocations in ambient-temperature molten salt media has been described.' The DielsAlder reactions of carbocations have been reviewed."

Open Systems Two calculational studies of CHf are reported.' ' , I 2 The hydrogen-bridged structure for the ethyl cation is calculated to be 6-8 kcal mol-' more stable than CH3CH;, and an unusually small JCHof 13 Hz is predicted for this ~pecies.'~ Protonated acetylene is also bridged, with three hydrogens permuting cyclically among the possible positions. l2 High-level calculations on R3Sif indicate that these cations interact more strongly with solvent than do the corresponding carbocations, in which the charge is hyperconjugatively and inductively delocalized.l4 At high levels of theory CH,SiH; is reported to be the only minimum on the SiCHf potential energy surface, although SiH3CHl is also a minimum at lower levels." Semiempirical and ab initio calculations on protonated allylic and diallylic alcohols indicate that the ally1 cation structure is considerably stabilized with respect to the protonated alcohol, and that reactivity differences in these alcohols may be related to protonation-dehydration energy differences in addition to structural differences. l 6 Rate constants observed for the reaction of n nucleophiles with carbocations are at least eight orders of magnitude greater than those calculated for a single-electron-transfer mechanism, meaning that the polar reaction in which charge transfer is associated with C-C a-bond formation is favoured. Trimethylsilylazide is an efficient carbenium ion scavenger in the gas phase, trapping the ions within s of formation by displacing Me3Sif; intermediate carbocation structures can be inferred from the resulting stable RN3.18 The gas-phase reaction of Me3C+ with 2,2-dimethylbutane is pressure dependent, and the pressure dependence of reaction efficiency is proposed as a criterion for the recognition of anchimeric assistance in hydride transfers. l 9 Me3C+ attacks the unlabelled ring of C6H5(CH2)2C6Ds 1.5 times faster than the labelled ring, but (C6H5CH2)2 and (C6D&H2)2 are both attacked at the same rate.2o However, Me3%+ reacts 1.5 times faster in both cases, and a collision complex is inferred to play a role in this process.20 In solution, the Me$+ cation is a proposed intermediate in the solvolysis of 2-methyl2-propanesulfonyl chloride, which cleaves to Me&+ and ClSO; in aqueous solution over a wide range of P H . ~ '

Some acyclic 1-hydroxy-, 1-amino-, and 3-hydroxy-pentadienyl cations have been characterized by low temperature NMR spectroscopy, and computationally; the 3hydroxy cations cyclize to 1-hydroxycyclopentenyl cations.22 Activated aziridines (1)

26 1

9 Curbocations

N3

++-a (4)

ring open in acidic alcohol media.23The resulting cations, (2) and the rearranged (3), may lose a proton to give allylamides, homoallylamides, or enamides, may be externally trapped to ethers, or, if of suitable structure, ring close to oxazolines and dihydr~xazines.~~ Amines (5) can be synthesized by an intermolecular Schmidt reaction, using aliphatic azides and carbocations (4) derived from benzylic or tertiary alcohols.24The cationic polymerization of several vinyl ethers has been the subject of a mechanistic in~estigation.~~

Benzyl Cations and Related Systems The barrier to carbocation-nucleophile combination reactions, primarily those involving benzyl cations, has been the subject of a comprehensive review.26It appears that resonance interactions are expressed to a smaller extent than polar interactions in the transition state for formation of the combination product, and that the opposite applies to its reaction.26

c 6 H

X

+

N3

X

I

fast

H&3

A

6 X

X

The ci-azido group stabilizes an adjacent carbocation centre by resonance,


262

(8) Z = o-Me, rn-Me, m-Bur, H

for instance in (6)." Benzaldehydes (7) are the only products; the p values show that the magnitude of electron donation by a-N3 and a-OMe to a benzyl carbocation centre is similar, much larger than for a-meth~l.~' Micelle-induced changes in reaction rate and solvation for two benzyl cations have been investigated; substitution with retention of configuration is enhanced and substitution with inversion is decreased in anionic miceiles.28 The most hindered benzyl cation yet observed as a stable species is (8), prepared by treating the parent alcohol with FS03H-S02C1F at -78 0C.29 Two crown ethers incorporating stable carbocations, (9) and (lo), have been ~repared.~'Benzyl group transfer in (E)-arylmethanediazoates and aryldiazomethanes in aqueous solution can take a benzyl cation or a benzyldiazonium ion route, qepending on the substituent in the aryl ring.3' The kinetics of the reactions between PhCHX (X = F3BO-, Cl,BO-, p MeOC6H4, MeO) and allylsilanes and alkenes have been studied.32 The reactivity varies strongly with the substituent X, but it is almost independent of the allylsilane or alkene. Benzhydryl, Trityl, and Related Systems

-

(11)

NCCPh2

NCCPh2

(12)

(13)

The 2-cyano-l , 1,2,2-tetraphenylethyI cation (1l), prepared from the corresponding chloride with AgSbF6 or SbFS in CH2CI2, is stable and long-lived below -55 0C.33 However, when prepared using AlC13 in benzene, it ring closes at above -78 "C to (12), leading to (13). The equ'valent cation with OMe instead of CN simply undergoes a 1,2-phenyl shift to Ph3C- APhOMe.33 Substituent effects in the reactions between benzhydryl cations and nucleophiles are mainly enthalpic in origin, AS: remaining constant as long as an enthalpic barrier remains.34 When the barrier is gone, hrther

9 Carbocations

263

decreases in the electron-donating ability of ring substituents cause an increase in reactivity due to an increase in A difision clock for determining carbocation reactivities has been used to obtain electrophilicity parameters for benzhydryl cations.35 Several highly stable azulenyl trityl cation species have been prepared as PF; salts, viz. (14),36 (15)," and (16) and its di- and mono-azulenyl mono- and di-phenyl

R = H, Me, C02Me

R', R2 = H, Me, C02Me, CMe3

analogues.37pKR+values in the 11-12 range are reported,37and the ring flips occumng in these species have been studied.36337 Some triarylcarbenium salts have been prepared from the corresponding alcohols by treating them with acid in bulky alcohol solvents.38

Oxocarbenium and Related Ions

0

The pinacol-type rearrangement of protonated ethers (17) provides a novel route to substituted cyclopentanones (18).39 The hydrolysis of three (2-deoxy-P-D-glucopyranosy1)pyridinium salts permitted the estimation of > 2.5 x lo-" s for the lifetime of the glucopyranosyloxocarbenium ion in aqueous s~lution.~' Appropriate sulfoxides can be transformed into sulfides, dithioacetals, and vinyl sulfides, by way of sulfurstabilized carbocations, by treating them with magnesium a m i d e ~ . ~ '

Nitrenium Ions Arylnitrenium ions (20) in the singlet state are generated when the precursors (19) are flash photolysed; these are trapped by the alcohol or water reaction solvent with rate constants in the 106-109 M p l sC1 range.42 The reaction rates of substituted + arylnitrenium ions (ArNY, Y = H, Me, Ac) do not correlate with the o+ values of the aryl substituents, unlike the corresponding dimethyl carbocations, which is taken to mean that in the nitrenium ions the positive charge is largely in the aryl ring rather than on the nitrogen.43

Organic Reaction Mechanisms 199.5

264

Nu-

NHAc

NHAc

I-H+

(Ar =

H

C6F5,

3-NO2Ph

OCOAr

t NHAc

VHAc

9 Carbocations

265

O-Aroyl-N-acetyl-N-(2,6-dimethylphenyl)hy~oxylamines give products of the Nacetylarylnitramine, but the mechanism is not clear; at least three cationic intermediates seem to be involved, some of them with exceedingly short lifetimes.44N-Acetyl-N-(4biphenyly1)- and N-acetyl-N-(2-fluorenyl)-nitreniumions can be selectively trapped at a diffusion-controlled rate by 2'-deoxyguanosine in aqueous solution.45 O-Aroyl-Nacetylhydroxylamine (21) gives a variety of meta- and para-substituted 2,6dimethylacetanilide products in aqueous acid as shown; however, none of them involve nitrenium ion precursor^.^^ Destabilized Carbocations

y' oNCMe3 Ph-C-C

Me

N-OMe

1

4

dl

\H

Ph-C-C

-c1-

H

Ph

Me

\+

f-F Ph

/--OMe

H

-

Me \

I

&CMq

Ph

1

t

Me

\

IN-oMe

Ph

(25)

t

The a-imino- and a-oximino carbocations (23) and (26) have been ~tudied.~' Chloride (22) solvolyses in methanol faster than does 1-chloro-1-phenylethane, and the resonance contributor (24) apparently makes a substantial contribution to the stability of the intermediate carbocation (23). Both (27) and (28) are important contributors to the stability of (26), derived fiom (25); this compound solvolyses in methanol faster than does 2-chlor0-2-phenylpropane.~~ Calculations show the stabilizing effects of agroups in carbocations of this type to be in the order CH=NOCH3 E CH=CH2 > CH=NHCH~> CH=S > CH=O = H > CN > ~ 0 ~ . 4 7 The effect of the cr-carbomethoxy group in (29) has been ~tudied.~' With a 4-methoxy group in the aryl ring the cation can be detected in water, but the p-tolyl and phenyl cations can only be detected in HFIP. Overall the solvolysis reactions are much slower


266

than those of the a-unsubstituted benzyl cations.48A number of 7-(perfluoroalkyl)-7bicyclo[2.2. llheptyl derivatives have been prepared.49 The extent of delocalization in the cations resulting from their solvolysis was obtained by comparing the solvolysis rates of the a-H and a-(perfluoroalkyl) derivatives, the former being faster by factors ranging from 8 to ca lo4; the a-CF3 group slowed the reactions relative to the a-C2FS group by factors between 1.1 and 8.0.49 The products revealed a general trend of destabilization of both localized and delocalized carbocations by perfluoroalkyl groups.49 High-level calculations have been carried out on several a-thioformamidyl carbocations, and the circumstances under which the bridged and open forms are preferred have been delineated.50Highly reactive a-carbonyl cations are suggested as intermediates in the skeletal rearrangements observed during the N02BF4 nitrations of some a$-unsaturated ester^.^' Aromatic Cations CpIf-N-C-Ph I

1

3 mol MeOH

v

toluene

(Ar = C hF5)

The stable cyclopropenylium betaine (30) has been the subject of an X-ray crystal structure d e t er m i n ati ~n.~~ Detropylation of N-tropylacetamide in acid apparently involves an N-protonated amide or other high-energy intermediate; the process is general-acid-catalysed and the products are tropylium cation and a ~ e t a m i d eRate . ~ ~ and equilibrium constants for the detropylation of N,N-dimethyltropylamine have been determined in aqueous HC1 and various buffer media.53Some electrophilic reactions of the dibenzo[a,&ropylium ion have been studied, and an electrophilicity parameter for it e~tab l i s h ed The .~~ crown ether (10) with a pKR+of ca 3.8 is rep~rted.~'

Arenium Ions Two possibilities have been suggested for protonated benzene, the edge-protonated ccomplex Wheland intermediate structure (3 1) and the face-protonated x-complex structure (32). Calculations suggest that (31) is the more stable of the and it

9 Curbocations

267

appears to have that structure in solution,56but experimental evidence that (32) is the more stable structure in the gas phase has been ~btained.'~ A theoretical study of the C 12H17+ energy surface in the 2,3-dimethyl-3-phenyl-2-butyl cation region suggests that this cation is not likely to be a reaction intermediate; the most favoured isomer is (33), but the phenonium ion (34) is only 0.29 kcal mol-' above it in energy.57The Cram phenonium ion (37) is observed when (35) is protonated, the presumed intermediate (36) not being ~ b s e r v a b l e .Carehl ~~ study showed that (37) has the structure shown and that it is not non-classical; neither is (38), which was also observed.58 Treatment of trialkylsilanes with Ph&+(C6F5)4B- in the presence of benzene derivatives only gives silylated Wheland intermediates and not long-lived trisubstituted silicenium cations, according to a comparison of experimental and ub initiolIGL0 29Si NMR re~ults.'~ The persistent arenium ions formed when various benzopyrenes are protonated in superacid have been studied.60 Vinyl, Aryl, and Related Cations Calculations on the allene dication H&C=&I give singlet electronic-state energief in agreement with measured values.61The C2H21+potential-energy surface has H2C=C-I as a global minimum, although the symmetrical iodine-bridged species is very close to it in energy, according to an ab initio study.62 Photolysis of benzenediazonium salts at low temperature can give either triplet or singlet aryl cations, depending on the ring substituent, although most of the observed reaction products are singlet-deri~ed.~~ The arylium ions XC6H4+ (X =NO2, CN, C1,

Organic Reaction Mechanisms 199.5

268

Br, OH, OMe), formed from multi-tritiated XC6H5 by tritium decay, react with methanol in the liquid phase and with methanol and methyl halides in the gas phase to give the unrearranged 40% ortho, 40% meta and 20% para ratio of products.64 The observed reactivity is compared with calculated values.64

(40)

R=Me,H

(44)

(43)

(42)

(45)

(X = Br, I, OTf)

The phenyl iodide group in (39) is a 106-fold better leaving group than is triflate ion.65 The solvolysis reactions of the resulting vinyl cation have been studied and evidence for internal return from an intimate ion-molecule pair was obtained.65The /?silyl group effect in vinyl cations such as (40) and (41) has been evaluated in terms of hyperconjugative stabilization and geometrical distortion by an experimental and computational comparison with suitable vinyl cations without silicon.66 lt has been found that the selectivities of the less stable carbocations (42) and (43), and the two vinyl cations (44) and (45), towards the nucleophiles Mg12 and MgBrz in aprotic solvents are all nearly the same, although the reaction rates differ by more than three orders of magnitude; a theoretical explanation in terms of the constant selectivity principle is offered.67 OEt

I

=C -C -0Et I H (Z = S, Se)

PhZ-C

BF3-Et20

PhZ-C

+/ OEt

-C -C,

(46)

R -C 3 C -N2+X-

H (47)

The prop-2-ynyl cations (46) do not rearrange to allenyl cations when treated with mild nucleophiles, simply giving direct substitution products.68Bis-silylated ynamines do not give the ethynyl cation precursors (47) when treated with nitrosating agents; the

9 Carbocations

269

only products are those of attack at the P - ~ a r b o n .The ~ ~ hydrolysis of N(benzenesulfony1)-C-(N-methylani1ino)imidoyl chlorides in 50% aqueous methanol has been the subject of+ an extensive kinetic study; the reaction involves the azocarbocation PhSOzN=CNMePh below pH 9.70 Cyclic Systems

The cycloaddition reactions of the cyclopropylcarbinyl cation (48), for instance to give (49) with ethylene and to give a cyclooctenyl cation with buta-1,3-diene, have been characterized the~retically.~~ A high-level MO study of the cyclization of (50) to (51) is reported.72 The AJ equation has been applied to the 13C-lH coupling constants observed for the dicyclopropylcarbinyl cations (52)-(55) in superacids; the positive charge was found to be delocalized into both cyclopropyl rings.73 Theoretical calculations relevant to the molecular rearrangements of (-)-a-cedrene observed in superacids are reported.74 Bicyclic Systems The bridgehead bicyclo[ 1.l.l]pent-1-yl cation (57) is an intermediate, or perhaps a transition state, in the reactions of (56); the products are (58) and (59).75The rearranged cation (60) is implicated as a reaction intermediate but (61) is not. The cations (62) and (63) were also studied; changing the aryl group substituents in (63) led to a Hammett p

270


value of - 1.7.75 A series of 5-substituted bicyclo[3.1. llheptyl bromides has been solvolysed in alcohol solvents.76 Direct replacement of the bromine by an alkoxy group, presumably via the bridgehead carbocation, accounts for about one third of the product for the H and CHzCl substituents, and nearly two thirds when the substituent is CO;Na+; however, little or none was found for 11 other sub~tituents.~~

9 Carbocations

27 1

Bromination of (64) and its endo isomer involves cations such as (65) and (66), both of which are classical.77Semiempirical calculations on proton addition to these systems show a thermodynamic preference for the formation of (67) from both isomers, and enable detailed stereochemical predictions to be made.78 Unsymmetrical phenyl bridging favours (68) over (69) for the cation derived from 2-t-cumyl-2-adamantanol and 2-isopropenyl-2-phenyladamantanein magic acid solution, according to experimental and theoretical results.79 The stereoselectivity of secondary adamantyl carbocations attributed to a-participation is effectively suppressed by charge-stabilizing methyl or phenyl groups at C(2) in the tertiary cations (70), which are classical.80

Bridged Systems The recently obtained X-ray crystal structures of several carbocation species stabilized by bridging or by hyperconjugation have been the subject of a review." The accuracy of ab initio geometries at several theoretical levels has been obtained by comparison with these crystal structures, and by comparing theoretical and experimental NMR chemical shifts and vibrational frequencies; agreement is fairly good now, and improving.82

KCH20H SbFs

SiMe3

S02CIF-SO2F2 -130 "C

*

The 1-(trimethylsilyl)bicyclobutonium ion (71) has been the subject of an experimental and theoretical study.83The results are consistent with a set of degenerate, interconverting bicyclobutonium cation structures, with no ring inversion occurring and no evidence of any contribution from cyclopropylmethyl structures.83The homocubyl triflate (72) is pressure-sensitive; at 10 000 atm pressure the deuterium label becomes totally scrambled, presumably via structures like (73).84 Cation (74) with a

272


pentacoordinated carbon atom is ‘remarkably stabilized compared to its parent compound,’ according to calculations, representing a ‘missing link’ between the bicyclo[3.2.O]hept-3-yl and 7-norbornyl cations.85

Several studies relevant to norbomyl cation chemistry are reported. A combined ab initio-Monte Carlo study showed that the classical norbomyl cation structure is not significantly more stabilized than is the non-classical structure in water, the nonclassical structure being the only stable form both in the gas phase and in solution.86 Cyclopropyl participation is apparent in the bridged norpinyl cation (76), formed from (75); some direct solvolysis product (77) is found, but rearrangement to (79), presumably via (78), predominate^.'^ Cation (79) can also be formed from (80) directly; the solvolysis product is (81) in endo and ex0 isomers, primarily ~ x o . ’However, ~ the unsubstituted norpinyl cation (82) is 16 kcal mol-’ less stable than is the norbornyl cation (83), which is responsible for most of the observed products, and it is formed much more slowly than is (84) under the same conditions.88This norpinyl-norbomyl rearrangement has also been studied by product analysis,” and the effect of the presence of the destabilizing substituents CN and CF2CF3 in the substrate on the

9 Curbocutions

273

reaction and its products has been examined.89Nitroxylation of (85) gives a product mixture from which the presence of (86) is inferred."

Dicatioas An X-ray crystal structure of the ditriiodide salt of (87) is reported; the central bond has a 53" twist, in agreement with PM3 calculation^.^^ The crystal structure of [5.5]bis(cyclopropenylium)ophane (88) is also reported.92 Dications such as (90), formed from (89) and similar compounds in superacid, may consist of two antiaromatic


274

cations linked by a single bond, cross-hyperconjugation being a factor in their ~tability.’~

-

Ph& hP: Ph

S02CIF FS03H

OH

~Ph,=.~~

-78 OC

OH

Ph

2’

Ph

0

II

+C

I

R

(92)

(93)

No evidence was found for ‘Y-aromatic’ stabilization in the (hexaphenyltrimethylene)methane dication (91), which is stable to -20 0C.94The entire n-system is twisted, and all six phenyls must be present or intramolecular allylation to indenyl cations occurs. The analogue (91; Ph =p-CF3C6H4) was also observed, but this is only stable at -90 0C.94Dications (92) are stable in superacid at -80 “C when R = Ph or Me, but not when R = cy ~l o p r opyl .~~ The diacylium species (93) has also been obser~ed.’~

-

MeS + FC-N-OH MeS (95)

MeSFN02 MeS

(94)

MeS

N-OH

5 MeS+< MeZ

X

(96)

ZMe Z = S, 0;X = MeS, F, Ar

MeZ

M ~ S N

‘0

,KO-

(97)

HF-SbFS

Me=Me

Me

9 Carbocations

275

Dication (95) is formed when (94) is treated with CF3S03H or HF-SbF5 at 0 "C or below, as determined by NMR spectroscopy; treatment with nucleophiles can give either (96) or (97).96Diprotonation of a$-enones such as (98) in superacid leads to dications such as (99); the methyl derivative shown is reported to undergo rearrangement and intramolecular cyclization to

References

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l2 l3 l4 16

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27 28 29 30

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38 39

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276 4L 42 43 44

45 46

47 48

49 50

52 53

54

55 56

57

58 59

6o

61

62

63 b4 65

66 67

68 69

70 7’

72

73 74 75

76

77 78 79

8o

8’ 82

83 84 85

86 87 88


Kobayashi, K., Kawakita, M., Kouichi, Y., Mannami, T., Yamamoto, K., Morikawa, O., and Konishi, H., Bull. Chem. SOC.Jpn, 68, 1401 (1995). Robbins, R. J., Yang, L. L.-N., Anderson, G. B., and Falvey, D. E., 1 Am. Chem. SOC.,117, 6544 (1995). Novak, M., Kahley, M. J., Lin, J., Kennedy, S. A,, and Swanegan, L. A., 1 Am. Chem. SOC.,116, 1 1626 (1 994). Fishbein, J. C. and McClelland, R. A,, 1 Chem. SOC.,Perkin Trans. 2, 1995, 663. Novak, M. and Kennedy, S. A,, 1 Am. Chem. SOC.,117, 564 (1995). Fishbein, J. C. and McClelland, R. A,, 1 Chem. SOC.,Perkin Trans. 2, 1995, 653. Creary, X., Wang, Y.-X., and Jiang, Z., 1 Am. Chem. Soc., 117, 3044 (1995). Schepp, N. P. and Wirz, J., 1 Am. Chem. Soc., 116, 11749 (1994). Nelson, D. W., O’Reilly, N. J., Speier, J., and Gassman, P. G., 1 Org. Chem., 59, 8157 (1994). Bertone, M., VuckoviC, D. L. J., Cunje, A,, Rodriquez, C. F., Lee-Ruff, E., and Hopkinson, A. C., Can. 1 Chem., 73, 1468 (1995). Hewlins, S. A,, Murphy, J. A,, and Lin, J., Tetrahedron Lett., 36, 3039 (1995). Erker, G., Ahlers, W., and Frohlich, R., 1 Am. Chem. SOC., 117, 5853 (1995). Palou, J., Robinson, P. M., and Wan, C. I. F., 1 Chem. SOC., Perkin Trans. 2, 1995, 1999. Henninger, J., Mayr, H., Patz, M., and Stanescu, M. D., Liebigs Ann. Chem., 1995, 2005. Glukhovtsev, M. N., Pross, A,, Nicolaides, A,, and Radom, L., 1 Chem. SOC.,Chem. Commun., 1995, 2347. Mason, R. S., Williams, C. M., and Anderson, P. D. J., 1 Chem. SOC.,Chem. Commun., 1995, 1027. Stoelting, D. T. and Fry, J. L., 1 Ox.Chem., 60, 2835 (1995). Olah, G. A,, Head, N. J., Rasul, G., and Surya Prakash, G. K., 1 Am. Chem. Soc., 117, 875 (1 995). Olah, G. A., Rasul, G., Buchholz, H. A., Li, X.-Y., and Surya Prakash, G. K., Bull. SOC.Chim. Fr., 132, 569 (1995). Laali, K. K., Hansen, P. E., Houser, J. J., and Zander, M., 1 Chem. Soc., Perkin Trans. 2, 1995, 1781. Andrews, S. R., Parry, D. E., and Harris, F. M., J. Chem. Soc., Faraday Trans., 21, 1 181 (1 995). Campos, I? J. and Rodriguez, M. A., 1 Chem. Soc., Chem. Commun., 1995, 143. Gasper, S. M., Devadoss, C., and Schuster, G. B., 1 Am. Chem. Soc., 117, 5206 (1995). Filippi, A,, Lilla, G., Occhiucci, G., Sparapani, C., Ursini, O., and Speranza, M., 1 Org. Chem., 60, 1250 (1995). Okuyama, T., Takino, T., Sueda, T., and Ochiai, M., 1 Am. Chem. SOC.,117, 3360 (1995). Siehl, H.-U., Pure Appl. Chem., 67, 769 (1995). Garcia Martinez, A,, Alvarez Martinez, R., Teso War, E., Garcia Fraile, A,, Osio Barcina, J., and Subramanian, L. R., Tetrahedron, 51, 7077 (1995). Yoshimatsu, M., Shimizu, H., and Kataoka, T., 1 Chem. Soc.. Chem. Commun., 1995, 149. Martinez Alvarez, R., Hanack, M., Schmid, T., and Subramanian, L. R., 1 Phys. Org. Chem., 8, 191 (1995). Kwon, K.-S. and Song, Y.-Y., 1 Korean Chem. Soc., 39, 650 (1995); Chem. Abs., 123, 255923 (1995). Cramer, C. J. and Barrows, S. E., 1 Org. Chem., 59, 7591 (1994). Mann, M. and Fabian, J., 1 Phys. Org. Chem., 8, 536 (1995). Kelly, D. P., Banwell, M. G., Ryan, J. H., Phyland, J. R., and Quick, J. R., 1 0%.Chem., 60, 165 1, 5364 (1995). Polovinka, M. P., Korchagina, D. V, Shcherbukhin, V V, Gatilov, Y. V, Rybalova, T. V, Zefirov, N. S., and Barkhash, V A,, Tetrahedron Lett., 36, 8093 (1995). Wiberg, K. B. and McMurdie, N., 1 Am. Chem. SOC., 116, 11990 (1994). Della, E. W. and Elsey, G. M., Aust. 1 Chem., 48, 967 (1995). Bumtt, A,, Coxon, J. M., Steel, P. J., and Whittington, B. I., 1 Org. Chem., 60, 2812 (1995). Bumtt, A,, Coxon, J. M., and Maclagan, R. G. A. R., Tetrahedron, 51, 11557 (1995). Stoelting, D. T., Forsyth, D. A,, and Fry, J. L., J Org. Chem., 60, 2841 (1995). Henmann, R. and Kirmse, W., Liebigs Ann. Chem., 1995, 699. Laube, T., Acc. Chem. Rex, 28, 399 (1995). Schleyer, P. v. R. and Maerker, C., Pure Appl. Chem., 67, 755 (1995). Siehl, H.-U., Fuss, M., and Gauss, J., 1 Am. Chem. SOC.,117, 5983 (1995). Spitz, U. P. and Eaton, I? E., Angew Chem., Int. Ed. Engl., 34, 2030 (1995). Szabo, K. J. and Cremer, D., 1 Org. Chem., 60, 2257 (1995). Schreiner, P. R., Severance, D. L., Jorgensen, W. L., Schleyer, P. v. R., and Schaefer, H. F., 1 Am. Chem. SOC., 117, 2663 (1995). Henmann, R. and Kirmse, W., Liebigs Ann. Chem., 1995, 703. Bentley, T. W., Norman, S. J., Kemmer, R., and Christl, M., Liebigs Ann. Chem., 1995, 599.

9 Cavbocations 89

90 91

92

93 94

95 y6

97

277

Fendel, W., Kautz, C. B., Kirmse, W., Klar, M., Siegfried, R., and Wonner, A., Liebigs Ann. Chem., 1995, 1735. Krasutsky, F’. A,, Likhotvorik, I. R., Dubinina, T. V, Nesterenko, V V, and Jones, M., Tetrahedron Lett., 36,3079 (1995). Bock, H., Nather, C., and Havlas, Z., 1 Chem. Soc., Chem. Commun., 1995, 1111. Gleiter, R., Merger, M., Oeser, T., and Imgartinger, H., Tetrahedron Lett., 36,6425 (1995). Malandra, J. L., Mills, N. S., Kadlecek, D. E., and Lowery, J. A., J: Am. Chem. SOC., 116,11622 (1994). Head, N. J., Olah, G. A,, and Surya Prakash, G . K., 1 Am. Chem. Soc., 117, 11205 (1995). Heagy, M. D., Wang, Q., Olah, G. A,, and Swya Prakash, G. K., 1 Org. Chem., 60,7351 (1995). Coustard, J.-M., Tetrahedron, 51, 10929 (1995). Koltunov, K. Y. and Repinskaya, I. B., Zh. 0%.Khim., 30, 90 (1994); Chem. Abs., 122, 30783 (1995).

CHAPTER 10

Nucleophilic Aliphatic Substitution J. SHORTER School of Chemistry, University of Hull, Hull HU6 7RX Vinylic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Allylic Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Polycyclic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epoxide Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Small Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Substitution at Elements Other than Carbon. . . . . . . . . . . . . . . . . . . . . . . Intramolecular Substitution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anchimeric Assistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ambident Nucleophiles and Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . Isotope Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gas-phase Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medium Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phase-transfer Catalysis and Other Intermolecular Effects . . . . . . . . . . . . . . Structural Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hammett Equation and Other LFERs . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilicity and Leaving-group Effects . . . . . . . . . . . . . . . . . . . . . . . . Kinetic Studies (Miscellaneous) . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

280 280 281 282 286 287 289 290 290 29 1 291 293 294 296 297 297 297 298 298 298

Vinylic systems Rappoport’s work has continued.I4 Rate constants of elementary steps in the additionelimination mechanism of nucleophilic vinylic substitutions (SNV) have been determined for the reactions of a-nitro-p-X-stilbenes (1) and (2) (X = OCH2CF3, OMe, or NO2) with various nucleophiles in 50% v/v DMSO-H20.’ When X = OCH2CF3 and the nucleophile is HOCH2CH2S-, the reaction intermediate accumulates to detectable levels, and when X =OMe and the nucleophile is CF3CH20-, the intermediate actually constitutes the ‘product,’ since the loss of MeO- is too slow to be observed. Interesting structure-reactivity relationships were observed with the various leaving groups and nucleophiles. The reactions of P-methoxy-a-nitrostilbene with methoxyamine and with Nmethylmethoxyamine are the first examples of SNVsubstitutions by amine nucleophiles in which the anionic intermediate (formed by deprotonation of the zwitterionic intermediate) accumulates to detectable levels.2 The above nucleophiles show the Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

279


280

enhanced reactivity expected for a-effect nucleophiles. A series of stilbene halides bearing one electron-withdrawing substituent on the double bond has been studied in an attempt to encourage vinylic substrates to undertake an SRNl-likeroute of nucleophilic substitution, a process that requires acquisition of one ele~ tron.The ~ attempt was not particularly successful and it was concluded that competition by other routes hampers the occurrence of the SRNlprocess. Ph

NO2

c, =c\

\

/

X

Ph

Ph

/C =c \ X NO2 \

Ph

I

(2)

(1)

Z

E

(3)

Label incorporation and Z -+ E isomerization in the reaction of 3-azidomethylenedihydro-(3H)-furan-2-one (3) with NaI5NNz in 1 : 1 acetone-H20 have been measured as a probe for internal clockwise versus anticlockwise rotation in the intermediate ~arban i o n .~ The energies of the lowest vacant orbitals of a series of model vinylic systems with substituents differing in electron-withdrawing power have been computed at the 321G*//3-21G*, 6-31G*N3-21Gt, or 6-31 IG*l/3-21G* level^.^ When the first vacant orbitals with cr and n symmetry at the carbon centres are separated by > 0.01 hartree, an almost complete correspondence is found between the symmetry of the lowest orbital and the stereochemical outcome of nucleophilic substitution on the corresponding real substrates. Allylic Systems

Chiral p-phosphinocarboxylic acids, e.g. (4), available by conjugate addition of lithium diarylphosphides to chiral cr,fl-unsaturated carboxylic esters, form chelate complexes with Pd.6 These will catalyse allylic substitutions of cyclic substrates, giving up to 99% enantiomeric excess, the S configuration being preferred, e.g. (5). Substitution reactions of ally1 alcohol derivatives with diethylamine, phenol or dimethyl malonate are efficiently catalysed by Ni(dppb)2 (dppb = 1,2-diphenylphosphinobutane), ammonium salts, or bases being added as promoters or ~o-reagents.~ Nucleophilic substitution, in the gas phase, on 0-protonated but-1-en-3-01 and transbut-2-en-] -01 by methanol, proceeds via a concerted sN2' mechanism in competition with the SN2mechanism' (&2' = allylic substitution with rearrangement).

I0 Nucleophilic Aliphatic Substitution

28 I C02R

* f y c o * R n-4

S

n = 5 , 6 or 7 X = OAc or C1

(4)

R = Me or Bur (5)

Ab initio MO calculations have been carried out for the non-identity ally1 transfer processes X-

+ C H ~ = C H C H ~ Y ~ C H ~ = C H C H+ ZY-X

where X = H, F, or C1 and Y = H, NH2, OH, F, PH2, SH, or Cl.9 The Marcus equation applies well. 'The transition state (TS) position along the reaction coordinate and the TS structure are strongly influenced by the thermodynamic driving force, whereas the TS looseness is originated from the intrinsic barrier.'

Miscellaneous Polycyclic Systems Sulfonate esters (triflates, mesylates, or tosylates) of a series of compounds related to 7perfluoroalkyibicyclo[2.2.l]heptan-7-ol(6t(12) have been solvolysed in various solvents to examine the competition between destabilization of the carbocationic intermediates by perfluoroalkyl groups and stabilization by neighbouring-group participation." The former effect was measured by comparing the rates of solvolysis of the 7-H and 7-RF compounds: the k7-Hlk7-RF ratios range from 8 to about lo4, depending on the extent to which anchimeric assistance can compensate for the inductive destabilization by RF.The CzF5group exerts a slightly smaller retarding effect than CF3; k7 - c,F, lk7 - CF, varied between 1.1 and 8.0. For the Ag(1)-catalysed methanolysis of the N-chloro derivatives of 7-azabenzonorbornadienes, the relative ability of substituted aryl rings to participate in selective reaction of the anti-invertomers (13) has been estimated qualitatively.' Rates of solvolysis in 80% EtOH-H20 have been measured for a series of 5substituted bicyclo[3.1.l]heptyl bromides (14).12 The substituent X acts mainly in accordance with its g I value, but the parent and the 5-OMe derivative deviate from the appropriate plot. The enhanced rate for the former is attributed to nucleophilic solvent assistance, while the deviation of 5-OMe is attributed to anchimeric assistance. Rates of solvolysis in various solvents have been determined for l-chlorospiro[adamantane-2,2'-adamantane] (otherwise 1-chloro[ lldiadamantane) (1S).l3 This substrate is about lo8 times more reactive than 1-chloroadamantane, and the solvolysis rate, even at 0 "C, can only be measured in solvents less ionizing than 80% EtOH-H20. The high reactivity is attributed mainly to F-strain arising from steric interactions between the Cl- leaving group and the closest CH2 hydrogen atoms. MM2 calculations support this idea. Nucleophilic attack on the aminoaziridinium cation (17) [derived from the sesquidiazabicyclooctane dication (16)] by PhS-, NC-, MeCO;, or F- results in

'

282

x x


C-N+ bond cleavage with inversion at carbon.l4 For attack by MeCO; or F only the axially substituted derivatives (18) are produced, but with PhS- and NC-, 40% and 15%, respectively, of the em-substituted derivatives (19) are initially formed. ~

Epoxide Reactions

A long series of papers on the regiochemical control of the ring opening of 1,2epoxides by means of chelation involving metal ions has been extended to oxirane systems derived from cyclopentene, bearing a polar substituent, CHzOBn or C02Me, in a homoaliylic relationship to the oxirane ring.I5 As found previously for other systems, chelate bidentate species participate in the ring-opening process under appropriate conditions. In a further paper the work is extended to mono- and di-functionahzed

283

10 Nucleophilic Aliphatic Substitution

aliphatic systems, bearing the heterohnctionality OR in a homoallylic and/or allylic relationship to the oxirane ring. l6 A chemoselective reaction of amidines or guanidines (21) with a-cyan0 epoxides (20) leads to 4-amino-5-carbethoxy-, 4-hydroxy-5-cyano-, or 4-carbethoxy-5-awl-imidazoles." Depending on the steric hindrance of the epoxides, the nucleophile reacts on either the nitrile or the ester group. The reaction medium is also important in governing the chemoselectivity. In contrast to the solvolyses of cyclic allylic epoxides, the acid-catalysed solvolysis of optically pure 1,2-epoxybut-3-enein water or an alcohol as solvent shows a high degree of inversion of configuration.l 8 Titanium and zirconium complexes of bis(pico1inic) amides catalyse the ring opening of cyclohexene oxide by trimethylsilyl azide.'' The product, 1-azido-2-trimethylsilyloxycyclohexane,was obtained with up to 7 1YO enantioselectivity when a catalyst prepared from (S,S)-N,N'-bis(2-pyridinecarboxamide)- 1,2-diphenylethane and zirconium tetra-t-butoxide was used. NH2

R3-N=C

/

\

R4

(21)

a; R3 = R4= Ph b; R' = Ph, R4 = NHPh

284


The reactions of oxiranes with carbon disulfide can lead to various products.’’ When alkali metal halides are used as catalysts, high yields of 1,3-0xathiolane-2-thiones(22) are obtained at room temperature. Lithium bromide is the best catalyst and THF is the best solvent for high selectivity. Ab initio MO calculations (MP2/6-3 1 G**//MP2/63 1 G*)have been carried out for the gas-phase reactions of methyloxirane with HOand of methylthiirane with HO- and HS-.21 With HO- as nucleophile, elimination is slightly favoured over addition, but with HS- addition is easily preferred.

+

+

S

An experimental and theoretical (molecular mechanics and semiempirical MO) study of the methanolysis of dicyclopentadiene diepoxide (23) has been presented.22 With NaOMe, chemo-, regio-, and stereo-selective opening of the epoxycyclopentane fragment occurs, but in the acid-catalysed reaction both epoxy groups are attacked. The selectivities of the reactions of 0,O’-dialkyldithiophosphoricacids with epichlorohydrin (24) have been studied.23 Under the alkaline conditions used, epichlorohydrin is converted into the corresponding thiirane and the ultimate reactions are nucleophilic displacements of C1- by thiophosphate anions. Detailed kinetic studies have been made of the catalysis of the reaction of 0-cresol with epichlorohydrin by quaternary ammonium and phosphonium salts containing various alkyl groups and anions.24 The kinetics and mechanism of esterifications of acetic acid by oxirane or epichlorohydrin have been in~e st iga te d.~~ The reactions are base-catalysed by acetates of alkali metal, quaternary ammonium, or Cr(II1). Regio- and stereo-selectivity have been studied for the ring opening of hryl- and thienyl-glycidates (25) with benzylamine or trimethylsilyl For (25a), attack on C(2) is overwhelmingly predominant, with the former reagent favouring anti and the latter syn ring opening. These and other results are rationalized through AM1 calculations. The presence of a trans-acetonide group in 1,2 : 5,6-dianhydro-3,4-0-isopropylideneD/L-hexitol has been found to exert a dramatic influence on the selectivity of the reaction of the substrate with b e n ~ y l a m i n e The . ~ ~ opening of the two epoxide rings leads exclusively to a 7-endo-tet-type cyclization process, achieving the synthesis of 3,4,5,6-tetrahydroxyazepanein good yield.


285

(25)

-

2-fury1 b R = 2-glycidyl

a; R

The stereospecific acetolysis of threo- and elythro-2-aryl-2-[1-(methylthio)ethyl]oxiranes has been studied.’* It is suggested that the various products are generated from thiiranium ionic intermediates, because they all completely retain the configuration of the initial oxiranes. Several series of fluorinated epoxy ethers (26) have been found to react with Lewis acids to give different ring-opening products, depending upon the structure and the experimental condition^.'^ Both nucleophile-assisted and stepwise processes can occur. In all cases, except when a phenyl group stabilizes the Cp secondary carbenium ion [i.e. R = P h in (26)], the C,-0 bond is broken, leading to addition, transposition, or cyclization products. A kinetic study has been carried out of the ring opening of phenyl glycidyl ether by 4-dodecylbenzenesulfonicacid.30The reaction is inhibited by water. Ring-opening reactions of optically pure 2-aryl-3,3-dimethyloxetaneshave been studied in strongly protic or Lewis acidic condition^.^^ For hydrolysis or alcoholysis catalysed by sulfuric acid, ring opening occurred at the benzylic position and partial inversion of configuration was observed. In other reactions studied, attack occurred at the least-hindered carbon and the configuration of the asymmetric centre was unaffected. The SN2reactivity and product distribution were determined for the reactions of six dioxetanes (27) with m ~ r p h o l i n eThe . ~ ~ overall reactivity and product distribution are strongly dependent on the nature of X and Y. Thus, reactivity is enhanced by electronattracting substituents X (e.g. Cl) and the product is almost entirely the adduct (28). Reactivity is also increased by electron-attracting substituents Y (i.e. NOz), but diminished by electron-releasing substituents Y (i.e. OMe). The effects of such substituents on product distribution are to increase and to decrease, respectively, the proportion of fragmentation product (29).


286 Other Small Rings

A long series of papers on regiochemical control of the ring opening of epoxides by means of chelation involving metal ions has been extended to cis- and trans-aziridines (30) and (31) derived from 4-(benzyloxy)~yclohexene.~~ The regioselectivity for the trans substrates was largely in favour of C(l) product, but that for the cis substrates varied with reaction conditions. Certain cis substrates changed from almost complete C(1) selectivity under some conditions to almost complete C(2) selectivity in the presence of metal ions. The role of chelate bidentate intermediate structures involving metal (or sometimes proton) was postulated. The regio- and stereo-selectivity of the ring-opening reactions of the 3-arylsubstituted aziridines (32) and (33) have been studied.34 The regiochemical outcome appears to be determined by a balance of electronic activation at C(3) by Ph and the chelating effects of the C( 1) oxygen functionality, which can direct nucleophiles intramolecularly to C(2) or C(3).

6

6

x

2,

2X

'

\" '

(31) trans

X = NH, NCOZEt, or NTs

Ts

Ts

I

I

Ph

I

(32)

(32)

R =H or Bn

2 R'

I

R'

I

Phu PhN=C=S N

NaI

+

(34)

,c=s

Ph

I

Ph

R' = SO*Ph, S02C6H4Me-4, or S02C6H4CI-4

Substituted N-(arylsulfony1)aziridines have been found to give a cycloaddition reaction with aryl or alkyl isothiocyanates in the presence of sodium iodide as catalyst,


287

e.g. reaction (34).35In the case of reaction (34), it is suggested that the catalysis involves ring opening by attack of I- at the C to which Ph is attached. The reactions involving alkyl isothiocyanates seem to have a different mechanism. The same research group has studied the reactions of N-arylsulfonylaziridines with dimethylsulfoniumethoxycarbonyl methylide, -CH(CO,Et)SMe,f, to give 1-arylsulfonyl-2-ethoxycarbon y l ~ e t i d i n e sThe . ~ ~ reactions are both regio- and stereo-selective. Aziridines containing an allylsilane moiety at the end of a polymethylene chain, (CH,), or (CH2)4, may undergo Lewis acid-catalysed cyclization to form cyclopentane and cyclohexane derivatives, respectively, e.g. (35H37).37In the cyclopentane case the cis isomer (36) predominates, but in the corresponding reaction leading to cyclohexane derivatives, the trans isomer is formed primarily. Possible transition states were discussed, but no explanation of the above difference in stereoselectivity was achieved. SiMe3

/

(35)

(36) cis

(37) trans

The reactivity of 2,3-aziridino-2,3-dideoxy-~-lyxono-y-lactone derivatives (rigid analogues of aziridine-2-carboxylic esters) towards soft nucleophiles and hard nucleophiles has been studied.38 The main matters of interest are the control of lactone versus aziridine ring opening and C(2) versus C(3) regioselectivity. Soft nucleophiles gave products of aziridine ring opening, whereas hard nucleophiles gave products arising from initial attack of the lactone ring. The stereochemical outcome and diastereoselectivity of the reactions of racemic lithiated methyl phenyl sulfoxide with two equivalents of racemic oxaziridines have been determined.39A possible transition state was suggested. The intervention of an aziridinium ion intermediate has been suggested in connection with the following reactions: the hydrolysis of chlorambucil (a nitrogen mustard) and chlorambucil-spermidine conjugate in aqueous buffer solutions:' and the decomposition of N-phosphorylated nitrogen mustards4' (see also related work by the same group4'). The reactions of 1,2,3-triarylbenzo[b]thiopheniumsalts (38) with alkoxide anions leads to the exclusive formation of (a-alkoxy-substituted alkenes (39).43This indicates that the nucleophilic ring opening proceeds with complete retention of configuration.

Substitution at Elements Other than Carbon This section is entirely concerned this year with substitution at silicon. The work of Eaborn and his colleagues has continued.44345In the reactions of (Me3Si)3C[Si(CD&I] with silver salts AgY in non-hydroxylic solvents, unrearranged

288


NaOR(2eq.) ROH

,c=c

(38)

'ArI

Ar2

Ar', Ar2 = Ph or anisyl X = Br or C1O4 R = Me, Et, Pr' or Me3CCH2

OR

(39)

products (Me3Si)3C[Si(CD3)2Y]usually predominate over the rearranged products (Me3Si)2C[Si(CD3)2Me](SiMe2Y), revealing the inadequacy of the simplest mechanistic picture in which a methyl-bridged cationic intermediate (40) has two bridged silicon centres that are equally available for attachment of a n ~ c l e o p h i l e .Various ~~ alternative possibilities were considered. The relative reactivities of a series of compounds related to the crowded (Me3Si)2(Ph2MeSi)CSiMe21 towards silver salts or IC1 have been studied.45The results support the proposal that for the above substrate, and also for (Me3Si)2(PhMe2Si)CSiMe21, the rate-determining step involves generation of a Ph-bridged cation (41), and so anchimeric assistance by a Ph group to the departure of I-.

(41) R = Phor Me

(42) R = M e or H

The consecutive reactions of diethoxydimethylsilane and triethoxymethylsilane with MeO- in MeOH have been followed by FT-IR monitoring.46 The consecutive rate constants for the former are 1.93 irO.12 and l.OOiz0.12 1 mol-' s-' at 295 K, while those forthe latter substrate are 1.12f0.09, 0.82f0.10, and 0.51 50.06 1 mol-' s C 1 at 295 K. The results for the diethoxy compound are considered to show a statistical 2 : 1 relationship, within the limits of experimental error, but those for the tiethoxy compound do not show a 3 : 2 : 1 relationship, owing to the intervention of steric and inductive effects. The reactions of the pentacoordinate silicon compounds (42) with nucleophilic reagents such as lithium amides, alkyllithiums, and Group I metal alkoxides have been studied.47 The results are complex, depending on the nature of R and of the nucleophile, the reaction conditions and stereoelectronic factors. When R =H, hydride transfer is important.


289

Intramolecular Substitution The relative rates of cyclization of the phosphinate anions BrCH2CH2(CH2),CH2(Ph)P(0)O- in dichloromethane are 4.3 : 1 for n = 0 and 1, giving five- and six-membered ring products, re~pectively.~~ The corresponding values for ClCH2CH2(CH2),CH2(Ph)P(S)Oin cyclization via sulfur are 30 : 1. These values are surprisingly small for ease of formation of five-membered rings compared with sixmembered rings. Ab initio MO calculations at MP2/6-3 1 G**//MP2/6-3 1 G* level have been used to examine the potential-energy surfaces for the ring closures of HSCH2CH2S-, HSCH2CH2CH2S-, and HSCH2CH2CH2CH2S- to give thiirane, thietan and tetrahydrothiophene, re~pectively.~~ The activation barriers are 19.2, 29.4, and 23.1 kcal molrespectively, i.e. the formation of the three-membered ring has the lowest barrier, even lower than that for an analogous sN2 reaction, e.g. 25.0 kcal mol-’ for MeS- EtSH. An explanation is offered. The cyclization of allenic amines leading to seven-membered and larger azacycles may be effected by using iodine as the electrophilic trigger.” These reactions have been studied in detail for the allenic sulfonamides (43), giving first the diiodides (44), which may then form either the smaller ring (45) or the larger ring (46).5’ While the sulfonamide (43) with n = 1 gave predominantly the corresponding pyrrolidine (45), in all other cases (n = 2-5) the larger ring (46) was either the major or the exclusive product. Thus path (b) involving attack of a primary site by N in an sN2 process is usually preferred to path (a), which involves an sN2’ process.

+

+

’,

+

‘m

/I

NaH.DMPU

/

(45)

The products and stereochemistry have been studied for various reaction systems essentially involving internal nucleophilic attack by 0 - in an SN’displacement of Brfrom an enolate, e.g. (47) giving (48).52The cyclization of the substrate (49) to give the pyrrolidine (50) is said to be the first reported case of intramolecular nucleophilic substitution on nitr~gen.’~ Yields of product diminished as the bulk of the substituent R’ was increased.


290

-

:

+

Br-

(49)

Anchimeric Assistance The acid-catalysed hydrolysis of the methyl ether linkage in (51) proceeds at least 1700 times faster than the corresponding reaction of the reference compound (52).54This was attributed to participation involving the neighbouring amide group in (51). The compound PhSCD2CH2Cl reacts with 1- in dry acetone to give PhSCD2CH21 through an SN2process.55 The iodo compound then undergoes anchimerically assisted ionization (53) to give product with the deuterium label scrambled. In further work, rates of displacement of halide ions by halide ions showed the expected nucleophilicity order C1- > Br- > I- and normal leaving-group order I- > Br- > CI-.

,

0

YNL (51)

Ambident Nucleophiles and Electrophiles There appear to be no studies of ambident nucleophiles to report this year. Second-order rate constants have been measured for the reactions of N-methyl-Nnitrosotoluene-p-sulfonamide(MNTS) and of 2-ethoxyethyl nitrite (EEN) with oxygen


29 1

nucleophiles, sulfur nucleophiles and I-.56 For MNTS, soft nucleophiles react at the nitroso group, whereas hard nucleophiles react at least in part at the sulfonyl group. A complicated situation was found for EEN. The application of the nucleophilicity scales N+ and n was discussed. N-Nitrosoiminium cations are ambident ele~trophiles.~~ Azide ions may either trap such cations by attack at C or lead to denitrosation through attack at NO. Isotope Effects Secondary kinetic isotope effects (KIEs) involving deuteriated nucleophiles have been reviewed by Lee58with respect to the theory of secondary a-deuterium KIEs, the crossinteraction constants of the forms of Hammett equation much applied by this author and his co-workers, and transition-state variations for associative and dissociative SN2 reactions. The 11C/14CKIE has been used to investigate steric hindrance in Menshutkin reactions of various substituted amines with labelled methyl iodide.59This KIE is about 1.2, and increases slightly as the nucleophile becomes more sterically hindered. Thus it is 1.220 f0.009 for 2,6-lutidine, compared with 1.189 f0.012 for 2,4-lutidines, in acetonitrile at 30 "C. A water-promoted, concerted E2 reaction of 9-(l-X-ethyl)fluorene (54) in 25 vol.% acetonitrile in water yielding 9-( 1-ethylidine)fluorene (55) has been found to compete with stepwise substitution and elimination reactions via the ion pair which lead to 9(1 -hydroxyethyl)fluorene (56), 9-(1-acetamidoethyl)fluorene (57), and 9-vinylfluorene (5tQ60 The evidence includes a detailed study of the various KIEs for the rate coefficients characterizing the various processes. Extended basis set calculations with electron correlation have been carried out for reactant and transition state properties of the gas-phase SN2 reactions: X-

+ MeY + MeX + Y-

(X = C1, Y = Br; X = C1, Y = I; and X = Br, Y = I).61Rate constants for these reactions and their perdeuteriated analogues have been calculated. KIEs and their temperature dependences were calculated and analysed. The KIEs for the first two reactions were in fair agreement with experimental values, but the third reaction showed a marked discrepancy. Gas-phase Reactions In the gas-phase ion-molecule reactions of C1- or I- with MeBr or Me1 at elevated collision energies [studied by guided ion beam and selected ion flow drift tube (SIFDT) techniques], dihalide products have been observed, i.e. the products of processes of the type62

X-

+ RY + XY- + R:

The details of the study led to the conclusion that such products arise from collinear attack of X- at the halogen in RY and this is supported by ab initio calculations at the MP2LANLlOZ level.

292

q


Y CY3

(54)

X = Br or I L = 'H or 2H Y = ' H or 2H

Y CY3

Transition-state structures have been found in ab initio calculations of identity reactions of LiF, LiC1, or NaCl with MeF or MeC1, as a p p r ~ p r i a t e .The ~ ~ retention transition state can be considered as an SNitype in which Me+ interacts with a metal halide triple ion, MX;. The inversion transition state, which can also be considered as an ionic assembly, is highly bent from the rectilinear X 1. . C . . .X of the ionic analogues. Definitive ab initio predictions have been made for the SN2 identity exchange reaction64 F-

+ MeF + FMe + F-

Calculations have employed a range of basis sets and include accounting for electron correlation. The final predictions for the complexation energy and for the intrinsic activation barrier are - 13.6 k 0.5 and 12.8 d= 1.5 kcal mol-', respectively, placing the net SN2barrier 0.8 kcal mol-' below the separated reactants. High-level ab initio calculations have also been carried out for the above reaction and for the corresponding reactions of the other halide ions and methyl halides.65The ionmolecule complexation energies in the order F, Cl, Br, and I are - 57.1, - 43.7, - 40.5, and - 35.3 kJ mol-' at 298 K, respectively, the central bamers are 46.1,

293


53.5,45.0, and 40.8 kJ mol-' at 298 K, respectively, and the overall barriers relative to the reactants are therefore - 11.0, 9.8, 4.5, and 5.5 kJ mol-' at 298 K, respectively. The same research group has also carried out a high-level computational study for the gas-phase identity reactions of halide ions at neutral nitrogen?

X-

+ NH2X

--+

XNH2

+ X-

The results are compared with those for the analogous reactions at saturated carbon (see earlier). The central barriers are surprisingly similar: in the order F, C1, Br, and I 58.2, 58.5, 46.9, and 39.1 kJ mol-', respectively. Computer simulations and animations of the motions of atoms as a chemical reaction proceeds give a detailed picture of how the reaction occurs at a microscopic level. Applications to SN2 reactions have been reviewed.67 The same research group has carried out statistical rate theory calculations for the reaction6' C1-

+ MeBr -+ ClMe + Br-

Three different statistical theoretical models and three different potential-energy surfaces were used to calculate the rate constant as a function of temperature, translational energy, and H(D) isotopic substitution. Overall, there is poor agreement between calculated and experimental results. Ab initio studies at the HF and MP2 levels using 6-3 1 + G** basis sets have been made on the SN2identity (mainly allyl) exchange reactions69

+

RCHzX

+ X-

+ X-

+ RCH2X

For R = CH2=CH, X = H , NH2, OH, F, PH2, SH, and C1, and for R = M e or CH=C, X = C1. The activation barriers are closely related to the electronegativities of R and X. The same group has also carried out ab initio MO studies on the identity gas-phase nucleophilic substitution reactions of CH2=CHCH2X by X- with X = H, F or C1, using 6-3 1 G** basis sets, including electron correlation at the MP2 level.70When X = H (the weakest nucleofuge), reaction occurs by a stepwise sN2' mechanism, whereas when X = C1 (the strongest nucleofuge), the concerted SN2 reaction is favoured. For X = F there is competition between various pathways. Transition-state structures for gas-phase SN2 reactions of substituted pyridines with MeCl, MeBr, or Me1 have been localized by the AMPAC program using the AM1 H a m i l t ~ n i a n .The ~ ~ activation barriers are ca 70 kcal mol-'. The order of leavinggroup abilities is I- < Br- < C1- and the C-N bond length in the transition state increases in the same order. Substitution by electron-withdrawing groups in the para position has very little effect on the structure of the transition state, but bulky groups in the ortho position lead to looser and earlier transition states. The concept of a transition-state structure is well defined in the gas phase, but it needs clarification for reactions in solution.72The problem has been discussed for various types of reaction, including SNland Menshutkin reactions.

++

Radical Processes The possible contribution of non-chain electron transfer (ET) to nucleophilic aliphatic substitution has been surveyed and explored in This may be the rate-

294


determining step when the nucleophile is a good electron donor and steric hindrance in the transition state excludes the classical sN2 mechanism. When a reaction appears to have some characteristics of ET and some of S N ~the , authors favour interpretation in terms of an intermediate transition state, rather than a competition between two reaction paths. The 9-phenylfluorenyl anion does not react with neopentyl iodide, but on irradiation it undergoes efficient reaction to form the products of nucleophilic aliphatic s~b s t i t u t i o n With .~~ the sterically analogous cyclizable molecule 6-iodo-5,5-dimethylhex-1 -ene, no ground-state reaction is observed, but both cyclized and uncyclized products of substitution are produced upon irradiation. 'Thus photoproducts clearly involving electron-transfer-induced radical intermediates can result without accompanying free-radical cyclization. These results suggest that, although the observation of cyclized products in the reaction of a cyclizable radical probe with a nucleophile is evidence of a radical intermediate, the absence of such cyclized products does not require the absence of radical intermediates.' p-Bromophenacyl bromide reacts with tetrabutylammonium bromide in cumene at 100 "C for 66 h to give a 47% yield ofp-bromoa~etophenone.~~ It is claimed that this supports a SET mechanism for the identity reaction of the substrate with Br-, i.e. the cumene scavenges the radical anion intermediate and reduces the radicals to pbromoacetophenone. Other evidence is also given. The photo-stimulated reactions of 1-iodoadamantane with various carbanions (anions from acetone, acetophenone, propiophenone, anthrone, nitromethane, or fluorene) in DMSO have been ~tudied.'~ Product analyses were interpreted in terms of an SRNl mechanism.

Medium Effects Grunwald-Winstein treatments of the rate constants of solvolysis of a series of secondary and tertiary benzylic toluene-p-sulfonates, p-nitrobenzenesulfonates, chlorides, and bromides are nearly all improved by including an h1 term, where h is the sensitivity towards changes in the (recently developed) aromatic ring parameter I.77 The value of h is increased by a second aromatic ring at the a-carbon, on introduction of an electron-withdrawing a-CF3 group or by introducing an electron-releasing aromatic ring substituent. The solvolysis of 4-bromobut- 1-ene proceeds by an sN2 mechanism in a wide range of solvents, as indicated by sensitivity of the rate to solvent nucleophilicity, and other evidence." There is a minor SN1 component in 97% TFE, and this becomes dominant in 90% HFIP. Solvolysis rates of p-nitrobenzyl and 3,5-bis(trifluoromethyI)benzyl p-toluenesulfonates have been determined in a wide variety of solvents.79 The 2-adamantyl YoTs parameter by itself gave poor results in correlation analysis of these data. The introduction of a solvent nucleophilicity term effected a considerable improvement in the correlations. The same research group has also studied solvent effects on the anchimerically assisted solvolyses of threo-2-aryl-1-methylpropylp-toluenesulfonates.80 As above, yo^, by itself gave poor results in correlation analysis. The


295

introduction of a parameter Y A , based on solvolysis of 2-@-methoxyphenyl)-2methylpropyl p-toluenesulfonate, led to considerable improvement. The same parameter has also found considerable application to the solvolyses of benzyl ptoluenesulfonates containing electron-donating substituents.'l Solvolyses of monosubstituted benzhydryl bromides have been found to give excellent linear correlations of log k with CT+ constants, but solvent effects do not correlate well with YBnBror YB,.82Correlation analyses involving the use of log k values for a-t-butyl-2-(2-naphthyl)methylbromide in the appropriate solvents provided evidence for the importance of different extents of solvation in the delocalized transition states and for nucleophilic solvent intervention in solvolysis of benzhydryl systems. Rates at several temperatures in acetonitrilemethanol mixtures have been measured for the reactions of ethyl and 2-phenylethyl benzenesulfonates with aniline or benzylamine, and activation parameters have been ~alculated.'~Transfer enthalpies were measured for the nucleophilic reagents in the same solvents and used in the interpretation of the activation enthalpies. 180-scrambling studies were carried out for the solvolyses of a-(t-buty1)benzyl tosylates in several solvents.84 Extensive ion-pair return, comparable to product formation, was found. Similar studies were also carried out for benzyl tosylates, substituent and solvent dependence of ion-pair return being examined for this 'borderline' s o l v o l y ~ i s Ion-pair .~~ return is decreased significantly by more electronwithdrawing substituents and in more nucleophilic solvents. A picosecond kinetic study has been carried out for the formation of contact ion pairs by the heterolysis of the C-C1 bond in benzhydryl chloride, the solvents being MeCN and EtCN.86 The activation energies for collapse of the ion pair are 3.2 and 2.8 kcal mol- ', respectively. It was concluded that ion-pair recombination occurs in the 'polarization caging regime.' In a long series of papers on the kinetics and mechanism of unimolecular heterolysis of industrial organic halides, rate constants have been determined for diphenyldichloromethane heterolysis in 11 protic and 17 aprotic solvent^.^' The rate was governed mainly by the polarity and electrophilicity of solvents, with a negative effect of nucleophilic solvation being observed for protic solvents. Activation parameters were determined for the reaction of methyl iodide with triethylamine in eleven acetone-ethanol mixtures.88Rate constants were correlated with the Dimroth-Reichardt ET(30) parameter. Rate constants of the Menshutkin reaction between triethylamine and iodoethane have been measured at 3 13 K in seven primary and secondary alkanols at various pressures.89Calculations of volumes of activation by several model-based equations are compared and procedures for dissecting intra- and inter-molecular contributions to the volume of activation are discussed. A semiempirical study has been made of the solvent effect on the reactions of MeX (X=CI, Br, or I) and NH3.90 A 'multicavity self-consistent reaction field' was employed and two dielectric media corresponding to hexane and water were modelled. The potential-energy surfaces for the three reactions are similar in different media, indicating broad similarity of reaction mechanism. However, the details thereof depend substantially on the solvent employed e.g. in hexane the

296


ion pair MeNH:Xis formed, whereas in water the reaction results in free ions. Rate constants and activation parameters were measured for the reactions of carboxylate ions with ethyl iodide in acetonitrilemethanol mixtures.” Enthalpies of solution were measured for the tetraalkylammonium salts of the relevant nucleophiles. ‘An empirical correlation incorporating nucleophiles and transition-state anions has been found between the derived quantities, namely the specific interaction enthalpies for anions and the number of methanol molecules participating in hydrogen bonding with the anions.’ The kinetics of the reaction of iodide ion with methyl p-toluenesulfonate have been studied at five temperatures in several hydroxylic or non-hydroxylic solvents, and in acetone-water mixtures.92The expected ct-proton abstraction step in the reaction of 4trifluoromethylbenzyl chloride in alkaline dioxane-water media does not take place.93 Instead, an SN2 reaction followed by an etherification step, forming bis(4trifluoromethylbenzyl) ether, occurs. These consecutive reactions were studied kinetically in several dioxane-water media at various temperatures. Molecular dynamics computer simulation has been used to relate the thermodynamic properties along the reaction coordinate to microscopic solvation for the SN2 reaction of C1- with MeCl in supercritical water as a function of temperature and density.94 In a long series of papers on the kinetics and mechanism of unimolecular heterolysis of organic halides, the nature of the lithium perchlorate salt effect during ionization of benzhydryl bromide in 6-butyrolactone has been in~estigated.~~ The effect of verdazyl indicators on the salt effect was examined. The effects of added trifluoroacetate, triflate, and tosylate salts on the trifluoroacetolysis of 1-(4’-tolyl)-2,2,2-trifluoroethyltosylate have been studied, including reactions of 180-labelledand optically active substrate^.'^ The salt effects on the solvolytic rate constant hv,the polarimetric rate constant k,, and “0 scrambling were examined in detail and the results interpreted in terms of ion-pair formation and disappearance by competitive return and reaction with solvent or salt.

Phase-transfer Catalysis and Other Intermolecular Effects The nucleophilic substitutionreactions of n-octyl sulfonates are catalysed by complexes of alkali metal salts MY with polyethers (PEGs, crown ethers, or cryptands; M = Li, Na, or K, Y = I or Br) in low-polarity solvents (chlorobenzene, o-dichlorobenzene, or toluene) at 60 0C.97With complexes of PEGs and crown ethers, rate constants for a given substrate increase in the order Kf < Na+ < Li+, but such effects diminish with increasing nucleofugality of leaving group. For cryptate complexes the rate constants are virtually independent of the cation. The addition of the non-ionic surfactant dodecyl(dimethy1)phosphineoxide (CI2PO) to aqueous cetyltrimethylammonium bromide (CTABr) inhibits the micellar-mediated reaction of Br- with fully bound methyl naphthalene-2-sulfonate (MeONs).” Reaction in the micellar pseudophase depends on the concentration of Br- in the interfacial surface region. On addition of CI2P0, [Br-] is decreased by increases in both the fractional micellar ionization and the volume of the micellar pseudophase.


297

The first examples of surface-catalysed SN2 reactions have been reported.99 These involve the dehydrative coupling of alcohols to form ethers over the zeolite HZSM-5 or the fluorocarbon sulfonic acid resin Nafion-H, either at 100 "C under about 10 atm total pressure, or in concentrated sulfuric acid solution at 100 "C and ambient pressure.

Structural Effects The role of ion pairs and ion-molecule pairs in solvolytic substitution, elimination, and rearrangement reactions has been reviewed. O0 Relative reactivities have been studied for the aminolysis reactions of alkyl alkanesulfonates and sundry interesting observations have been made,'" e.g. the greater reactivity of N-methylbutylamine than N-methylaniline is due to differences in entropy of activation rather than differences in activation energy. C12H25S03Meis considerably more reactive than MeSO3CI2H25. Nucleophilic substitution reactions of 3-trichloromethylpyridine, its N-oxide, and 3,5-bis(trichloromethyl)pyridine occur in most cases by way of attack at ring C, followed by hydrogen migration to the side-chain, although attack at the trichloromethyl C has also been observed.'02 Hammett Equation and Other LFERF Lee' O3 has reviewed recent advances in the application of cross-interaction constants. He has also reviewed the subject in Korean.lo4 and p - and The relationship between the signs of the Hammett p values pi(,,), the validity of the reactivity-selectivity principle (RSP) has been discussed"' (the symbols are for Lee's extended Hammett equation, involving the combined effect of two substituents in different benzene rings). The RSP is said to be valid when W = pi(o)p,(~)lpiiis negative. About 100 reaction series were analysed and various mechanistic significances of the RSP were derived. The kinetic data for six reactions of Y-phenylalkyl or Y-phenacyl Z-arenesulfonates with X-anilines or X-benzylamines have been re-analysed.lo6 It was concluded that in five of the six cases the errors associated with the cross-interaction term pxyz are large and the contribution this makes to the overall analysis is probably statistically insignificant. The rates of Menshutkin-type reactions of R2C6H40S02C6H4R1with substituted pyridines in acetonitrile at 35 "C have been measured by the conductometric method, and the second-order rate constants were analysed by means of the Hammett equation.lo7 Rate constants and activation parameters have been determined for substitution reactions of P-substituted bromoethanes and bromopropanes with thiourea in various solvents. O8 Isokinetic and Taft relationships were applied. Nucleophilicity and Leaving-group Effects The anilino thioethers 3- or 4-02NC6H4N(Me)CH2SC6H4-2-CO~undergo concerted bimolecular nucleophilic substitution with various nucleophiles in aqueous solution at 25 OC.lo9Attack is on CH2 and the leaving group is -SC6H4-2-CO;. In Swain-Scott


298

correlations the two substrates show low and approximately equal sensitivities to the nature of the nucleophile, i.e. s z 0.4. The rate constants for 41 compounds bearing a C=S function reacting with MeX (X = I or Tos) span seven orders of magnitude"' (the solvent was acetone, acetonitrile or methanol). The photoelectron spectra of the nucleophiles show two low-energy peaks, corresponding to the n,-s bonding orbital of C=S and the lone-pair orbital ns. Various correlations between rate data and PES data were attempted. The best one involves In k versus the inverse of the energy EB of the sulfur lone pair (r = 0.96 for about 40 points). Solvolysis of 9-(1-X-ethyl)fluorene (X=I, Br, C1, OTs, or OBs) in 25 vol.% acetonitrile in water gives the elimination products 9-( 1-ethylidene)fluorene and 9vinylfluorene and the substitution products 9-( 1-hydroxyethyl)fluorene and 9(1-acetamidoethyl)fluorene.' Added strong nucleophiles open up a competing SN2 pathway. The importance of this route is leaving-group-dependent. This 'synergism' between nucleophile and leaving group favours SN2 reaction with 1- > Br- > C1- > TsO-, BsO- leaving groups. Additional experimental work on rates of solvolysis of highly reactive methanesulfonates, together with literature data, are the basis for updating the scale of leavinggroup effects for SNl reactions of 1-phenylethyl substrates in 80% ethanol-water at 75 oC.112The scale covers a range of 10l6 in relative rates, from 5 x l o p 8 for MeCO; to 1.1 x lo9 for CF3SOT (C1- is the standard at 1.0).

Kinetic Studies (Miscellaneous) Kinetic studies have been made for the following reactions: the methanolysis of certain amines of trivalent phosphorus (phosphonites), with a view to finding cases of intramolecular catalysis;''3 the hydrolysis of 2-bromomethyl-3,5,6-trimethylpyrazine over the pH range 1-1 1;l14the acid-catalysed hydrolysis of t-butyl phenyl ether;'" and the first-order ethanolysis of benzhydryl chloride as a model reaction for exploring links between the theoretical rate law and the experimental response surface.16

Acknowledgement The hospitality of the University of York, UK, during the writing of this chapter is gratefully acknowledged.

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Hu, W.-P. and Tmhlar, D. G., 1 Am. Chem. Soc., 117, 10726 (1995). Cyr, D. M., Scarton, M. G., Wiberg, K. B., Johnson, M. A,, Nonose, S., Hirokawa, J. H., Tanaka, H., Kondow, T., Moms, R. A,, and Viggiano, A. A., 1 Am. Chem. SOC.,117, 1828 (1995). 63 Harder, S., Streitwieser, A,, Petty, J. T., and Schleyer, I? v. R., 1 Am. Chem. Soc., 117, 3253 (1995). 64 Wladkowski, B. D., Allen, W. D., and Brauman, J. I., 1 Phys. Chem., 98, 13532 (1994). 65 Glukhovtsev, M. N., Pross, A,, and Radom, L., 1 Am. Chem. SOC., 117,2024 (1995). 66 Glukhovtsev, M. N., Pross, A,, and Radom, L., 1 Am. Chem. Soc., 117, 9012 (1995). 67 Hase, W. L., Science, 266, 998 (1995); Chem. Abs., 122, 30793 (1995). 68 Wang, H. and Hase, W. L., 1 Am. Chem. Soc., 117, 9347 (1995). 69 Lee, I., Kim, C. K., and Lee, B.-S., 1 Phys. Org. Chem., 8, 473 (1 995). 70 Park, Y. S., Kim, C. K., Lee, B.-S., and Lee, I., 1 Phys. Chem., 99, 13103 (1995). 71 Berg, U., Chanon, M., Gallo, G., and Rajzmann, M., 1 Org. Chem., 60, 1975 (1995). 72 Bertran, J., Lluch, J. M., Gonzalez-Lafont, A,, Dillet, V., and Perez, V,ACS Symp. Ser, 1994, 568; Chem. Abs., 122, 9264 (1995). 73 Lund, H., Daasbjerg, K., Lund, T., and Pedersen, S. U., Acc. Chem. Res., 28, 3 13 (1995). 74 Tolbert, L. M., Sun, X.-J., and Ashby, E. C., 1 Am. Chem. Soc., 117, 2681 (1995). 75 Haberfield, I?, 1 Am. Chem. Sac., 117, 3314 (1995). 76 Rossi, R. A,, Pierinin, A. B., and Borosky, G. L., 1 Chem. Soc., Perkin Trans. 2, 1994, 2571. 77 Kevill, D. N. and D'Souza, M. J., 1 Chem. Soc., Perkin Trans. 2, 1995, 973. 78 Kevill, D. N. and Abduljaber, M. H., 1 Chem. Soc., Perkin Trans. 2, 1995, 1985. 79 Fujio, M.,Susuki, T., Goto, M., Tsuji, Y., Kim, S. H., Ahmed, G. A.-W., and Tsuno, Y., Bull. Chem. SOC. Jpn, 68, 673 (1995). 80 Fujio, M., Saeki, Y., Nakarnoto, K., Yatsugi, K., Goto, N., Kim, S. H., Tsuji, Y., Rappoport, Z., and Tsuno, Y., Bull. Chem. SOC.Jpn, 68, 2603 (1995). 81 Fujio, M., Susuki, T., Yatsugi, K., Saeki, Y., Goto, M., Kim, S . H., Tsuji, Y., Rappoport, Z., and Tsuno, Y., Bull. Chem. SOC.Jpn, 68, 2619 (1995). 82 Liu, K.-T., Chin, C. I?, Lin, Y.-S., and Tsao, M.-L., Tetrahedron Left., 36, 6919 (1995). 83 Huh, C., Lee, H. W., and Lee, I., Bull. Korean Chem. Soc., 16, 52 (1995); Chem. Abs., 122, 132349 (1995). 84 Tsuji, Y, Yatsugi, K., Fujio, M., and Tsuno, Y., Tetrahedron Lett., 36, 1461 (1995). 85 Tsuji, Y., Kim, S. H., Saeki, Y, Yatsugi, K., Fujio, M., and Tsuno, Y., Tetrahedron Left.,36, 1465 (1995). 86 Deniz, A. A., Li, B., and Peters, K. S., 1Phys. Chem., 99, 12209 (1995). 8i Dvorko, G. F., Cherevach, T. V., Kulik, N. I., and Ponomareva, N. E., Zh. Obshch. Khim., 64,979 (1994); Chem. Abs., 122, 186811 (1995). 88 Nevecna, T. and Bekarek, V., Acta Univ. Palacki. Olomuc., Fac. Rerum Nat., 112, 77 (1993); Chem. Abs., 121, 300427 (1994). 119 Viana, C. A. N., Calado, A. R. T., and Pinheiro, L. M. V., 1 Phys. Org. Chem., 8, 63 (1995). 90 Maran, U., Pakkanen, T. A., and Karelson, M., 1 Chem. SOC.,Perkin Trans. 2, 1994, 2445. " Kondo, Y., Sugitani, W., Tokui, M., and Takagi, T., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1049. 92 Bao, B. andHu, K., Hangzhou DuxueXuebao, Ziran Kexueban, 21,422 (1994); Chem. Abs., 122, 186712 (1995). 93 Riad, Y., Gundermann, K. D., and Bardan, A. A. El, Egupt. 1. Chem., 37, 123 (1994); Chem. A h . , 122, 238955 (1995). 94 Flanagin, L. W., Balbuena, €? B., Johnston, K. P., and Rossky, I? J., 1 Phys. Chem., 99, 5196 (1995). 95 Dvorko, F., Golovko, N. N., Pervishko, T. L., and Ponomareva, E. A., Zh. Obshch. Khim., 64, 1281 (1994); Chem. Abs., 122, 132417 (1995). 96 Allen, A. D., Fujio, M., Tee, 0. S., Tidwell, T. T., Tsuji, Y., Tsuno, Y., and Yatsugi, K., 1 Am. Chem. Soc., 117, 8974 (1995). 97 Gobbi, A,, Landini, D., Maia, A,, and Secci, D., 1 0%.Chem., 60, 5954 (1995). 98 Blask6, A., Bunton, C. A,, Toledo, E. A., Holland, P. M., and Nome, F., 1 Chem. Soc., Perkin Trans. 2, 1995, 2367. 99 Sun, Q., Herman, R. G., and Klier, K., 1 Chem. Soc., Chem. Commun., 1995, 1849. 100 Thibblin, A,, Spec. Publ. R. SOC.Chem., 148, 415 (1995); Chem. Abs., 123, 111257 (1995). 101 Roberts, D. W., Ward, R. S., and Hughes, P. J., 1 Chem. Res. (S), 1995, 70. lo' Cartwright. D., Ferguson, J. R., Giannopoulos, T.,Varvounis, G., and Wakefield, B. J., Tetrahedron, 51, 12791 (1995). lo3 Lee, I. Spec. Publ. R. SOC. Chem., 148, 361 (1995); Chem. Abs., 123, 111254 (1995). Io4 Lee, I. C., Hwahak Sekye, 34, 204 (1994); Chem. Abs., 122, 9166 (1995). Lee, I., Lee, B.-S., Koh, H. J., and Chang, B. D., Bull. Korean Chem. Soc., 16, 277 (1995); Chem. A h . , 122, 264860 (1995). 61

62

10 Nucleophilic Aliphatic Substitution Io6 lo' lo'

'09 111

I12

Kevill, D. N. and D'Souza, M. J., J. Chem. Soc.. Perkin Truns. 2, 1994, 2427. Cheong, D.-Y., Park, J.-H., Kweon, J.-M., Yoh, S.-D., and Shim, K.-T., 1 Koreun Chem. Soc., 38, 915 (1994); Chem. Abs., 122, 105054 (1995). Ryazantsev, G. B., Sukhov, L. L., Lys, Ya. I., and Fedoseev, V M., Vestn.Mask. Univ., Serr 2: Khim., 35, 502 (1994); Chem. Abs., 122, 132336 (1995). Eldin, S. and Jencks, W. P., 1 Am. Chem. SOC.,117, 9415 (1995). Arbelot, M., Allouche, A., hrcell, K. F., and Chanon, M., 1 Org. Chem., 60, 2330 (1995). Meng, Q. and Thibblin, A,, 1 Am. Chem. Sac., 117, 9399 (1995). Bentley, T. W., Christi, M., Kemmer, R., Llewellyn, G . , and Oakley, J. E., 1 Chem. Sac.. Perkin Truns. 2, 1994, 2531.

'I4 'I5

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301

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Lajunen, M. and Tanskanen-Lehti, K., Actu Chem. Scand., 48, 861 (1994). Axelsson, A.-K. and Carlson, R., Actu Chem. Scund., 49, 663 (1995).

CHAPTER 11

Carbanions and Electrophilic Aliphatic Substitution A. C . KNIPE

School of Applied Biological and Chemical Sciences, University of Ulster, Coleraine Carbanion Structure and Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MO Calculations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organolithiums . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatic and Other Delocalized Anions . . . . . . . . . . . . . . . . . . . . . . . . . Carbanion Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enolates and Related Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heteroatom-stabilized Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organometallic Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proton-transfer Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Aliphatic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

303 303 305 306 308 308 321 323 328 330 332 332

Carbanion Structure and Stability

MO Calculations For 166 molecules, radicals, anions, and cations, the CBS-4, CBS-Q, G2(MP2) and G2 energies have been calculated and found to reproduce experimentally determined heats of formation, bond dissociation energies, gas-phase acidities, and proton affinities with an average error of only 1 kcal mol-'.' A Gaussian-2 ab initio study of the rearrangements of ethyl, ethenyl, and ethynyl anions and of the stabilities of these anions towards spontaneous electron loss has been reported;2 the ethyl anion is predicted to lose an electron spontaneously whereas the ethenyl and ethynyl anions will not. Barriers for 1,2-hydrogen shift for ethynyl, ethenyl, and ethyl anions are calculated to be 85, 228 (syn) or 234 (anti), and 200 kJ mol-', respectively. The gas-phase acidities associated with deprotonation at the two different sites of buta- 1,3-diene have been determined, under relatively low-pressure conditions in a Fourier transform ion cyclotron resonance mass spectrometer, by proton abstraction using strong anionic bases; the corresponding conjugate anions have been identified by means of a probe reaction with nitrous oxide.3 The 1-butadienyl anions are found to be ca I0 kJ mol- less stable than the 2-butadienyl anions and this is confirmed by highlevel ab initio calculations which predict a planar charge-localized structure for the former (in which the butadiene n-system is still intact) but the attainment of additional

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stabilization of the latter by 100 O rotation of the central C-C bond, thereby achieving allylic charge delocalization and a structure with two nearly orthogonal n-systems. Ab initio calculations, using Gaussian 92, have also been used to establish that the ion CSH- has a ground-state triplet structure with a nearly linear carbon skeleton but with the terminal H at a marked angle to the carbon backbone! Anions C,H- are of interest since the neutral hydrocarbons C,H ( n = 2-6) have been detected in circumstellar gas. The AM1 method has been used to calculate the geometric structure, charge distribution, and heats of formation of 9-R', 10-R2-9,10-dihydroanthracenes (R' = R2 = H, Me, Ph; R' = Me, Ph or CN R2 = H) and of their mono- and di-anions formed on deprotonation at positions 9 and There is a correlation between the nelectron densities and the change in I3C chemical shift upon anion formation from the neutral species and the resulting pattern of negative charge distribution is similar to that for substituted diphenylmethanes. The hybridization of the deprotonated carbon is nearly sp2, the dianions being somewhat more planar than the monoanions, and the thermodynamic stabilities estimated for the gas phase follow the pattern of first and second acidity constants reported for substituted 9,lO-dihydroanthracenes in the liquid phase. Ab initio calculations of the structure and bowl-to-bowl inversion barriers of corannulene and its dianion and tetraanion have established that the barriers decrease from 14.2 kcalmol-' for neutral corannulene to 7.9-9.2 kcalmol-' for the dianions and to 3.2kcalmol-' for the tetranion; the curvature flattens with introduction of negative charge but a bowl-shaped geometry still prevails for the tetraanion, for which the charge distribution is not consistent with an anion-within-a-trianion model;6 however, see also reference 22. The AM1 method has been found to have practical advantage for predicting the CH acidity of fluoroorganic compounds in gas phase and in solution; calculated proton affinities of the carbanions have been compared with the corresponding pK, values and kinetic acidities, and the influences of ionic association and solvation have been addres~ed.~ Ab initio calculations of the structure and stabilities of gas phase C6H4X- (X = F, C1 and Br) anions have lent support to an earlier suggestion that C6H4Br- and C6H41p display the characteristics of halide-benzyne complexes.8 The calculations predict that the binding energy of the donor-acceptor complex decreases dramatically on going from C6H4F- to C6H4C1- and to C6H4Br- (226, 96 and 60 kJmol-', respectively) as a consequence of the decrease in orbital overlap with increase in size of the halogen; the prediction that C6H&r- will therefore undergo bromide ion transfer, rather than hydrogen abstraction, on reaction with methanol is consistent with experimental reports. AM 1 calculations of the gas-phase stabilities of enolates formed on deprotonation of bicyclo[2.2.2]octane-2,5-dione,bicyclo[2.2.2]octane-2,6-dione~1-hydroxy-4-0x02,2,6,6-tetramethylpiperidine, 4-0~0-2,2,6,6-tetramethyIpiperidine-l-oxyl, 9-hydroxynorpseudopelletierine, and norpseudopelletierine-9-oxy110 have been correlated with measurements of the corresponding rates of enolization in 60 : 40 (v/v) dioxaneD20. Ab initio geometry optimizations at the MP2/6-3 1 + G* theoretical level have been applied in a study of the effects of the cyano, aldehyde, and nitro groups on the acidity

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'

of methane, propane, and cyclopropane. The experimental gas-phase acidities are well reproduced and the trends observed have been explained with reference to the degree of charge transfer from the carbanion (Me M Pf > cyclopropyl) to the substituent (NOz= CHO > CN > NC). Thus, whereas cyclopropanecarboxaldehyde and nitrocyclopropane are ca 10kcalmol-' less acidic than their isopropyl counterparts, only small differences apply in the case of the corresponding nitriles and isonitriles. AM1 calculations of excess charge density in nitromethyl anions reveal the predominant contribution of resonance form HzC=Nf(O-)2; the influence of heteroatomic a-substituents and of solvation on the proton affinities of anions of aliphatic and alicyclic nitro compounds has also been probed. l 2 A theoretical study of the structure of acetonitrile and its anion CH3CN- has been reported.13

Organolithiums Results of a study of Lewis base (LB) complexation, aggregation and reactivity of three a-organolithiums suggest that for RmLim.nLBsystems: smaller coordinatively saturated aggregates lose LB more easily, because they contain more LB to provide assistance; fractional reaction orders of RLi are indicative of aggregate-substrate complexes; and predissociation of tetramer to dimer could be a prerequisite of complex formation for substrates that are weak donors, but may not be needed for strong donor ~ubstrates.'~ 13CNMR lineshape analysis of the monomeric aryllithiums (la) and (lb) in THF has revealed the mechanism of 7Li relaxation, the dynamics of intermolecular bond exchange, and the mechanism of rotation around carbon-lithium bonds; the asymmetric nature of the tridentate complex formed between (lb) and pentamethyldiethylenetriamine has also been established. Li Li+

R

(1) a; R = But

b;R=Me

(4)

The (2-THF& structure of the THF-solvated dimer of dilithiated 1-di-t-butylhydroxymethyl-3,3-dimethylcyclopropene(2) has been shown by X-ray analysis to feature tetracoordinate carbons (R'R2CLiz fi-agments)approaching planarity and unusual C-C bond lengths in the cyclopropene ring.I6 A combination of 'H and 13C NMR techniques has been applied to determine the structure of sulfur-stabilized lithiated allylic carbanions (3) and (4).17The structure of lithiated 0 - 1-(t-butylthio)but-2-ene (3) is described as a transoid carbanion in which

306


allylic carbon atoms C( l), C(2), and C(3) have intermediate sp2-sp3 hybridization; the Bu'S group plays no significant role in carbanion stabilization. In contrast, lithiated (Ql-(phenylthio)but-2-ene (4) exhibits cis geometry about the C( 1)-C(2) bond and the phenylthio group participates in stabilization of the allylic charge. By monitoring the coalescence of signals of diastereotopic groups in the 'H NMR spectra of secondary benzyllithium compounds in THF it has been possible to determine the effects of benzylthio, benzylseleno, and isopropyl(methy1)amino asubstituents on the barrier to racemization; in each case breaking of the carbon-lithium bond with formation of a solvent-separated ion pair or larger dipole is likely to be the rate-limiting step of the racemization, as evidenced by the negative activation entropies which have been determined for reaction in THE" Interest in the synthetic application of the ambident dianionic nucleophiles obtained on deprotonation of unsaturated carboxylic acids by two equivalents of lithium dialkylamide has prompted a theoretical modelling of solvated lithium dienediolate of but-2-enoic acid." The chemical reactivity and I3C NMR spectral data are consistent with the s-trans dienediolate structure proposed and semiempirical ab initio calculations have revealed that in taking account of dianion solvation by a discrete number of solvent molecules it is important to use ether rather than water molecules when a conformational equilibrium is possible. Semiempirical PM3 calculations have been performed on the complexes formed between the chiral ligand (R,R)-2,3-dimethoxy-1,4-bis(dimethylamino)butane and several organolithium compounds.20 The nature of the ligand binding, by oxygen atoms, nitrogen atoms, or both, has been found to depend on the aggregation state of the organolithium. While the complex with t-BuLi exists as a monomer, those formed with other organolithiums studied are primarily dimeric in character. For aldehyde alkylation by BuLi, reaction via a monomeric precomplex has been shown to have a smaller activation barrier than for that via the dimeric complex. Spectroscopic studies of a series of silicon- and sulfur-substituted chiral organolithium reagents have probed the interplay of chelation and solvation by THF and HMPA in determining their ion pair structure, solvation and configurational stabilities2' Aromatic and Other Delocalized Anions Superaromaticity is considered to arise when the benzene units of a benzenoid molecule are annealed in such a way that all benzene units form a macrocyclic system, whereas aromaticity arises from cyclic conjugation alone. The difficulties in quantifying superaromaticity have been addressed and three alternative hardness indices, which differ in the way in which their reference hardnesses are defined, have been applied in order to determine the degree of superconjugation in kekulene, coronene, and corannulene tetraanion.22Each of the hardness indices, which are more sensitive than resonance energy indices, predict that the structures are superaromatic, and lend support to the suggestion that the corannulene tetraanion structure may be viewed as an annulene-within-an-annulene(as suggested by NMR data); however, see also reference 6.

1I Carbanions and Electrophilic Aliphatic Substitution

307

A full report on the formation, chemistry, and structure of the tribenzacepentalene dianion (6) has included comment on the structure and reactions of 4,7tribenzodihydroacepentalene derivatives (7) which are readily formed by its reaction with electrophiles (R'X) and feature an extremely out of plane C( l)=C( 10) double bond which is correspondingly of increased reactivity.23 The formation of (6)-K2 on treatment of (5a-d) with Lochmann-Schlosser base (BuLi-KO'Pen) is believed to proceed via the mono- (8) and di- (9) anions (which can be observed in most cases) followed by eliminative loss of RH,presumably via a short-lived trianion (10). The relative abundances of (6)-K2 versus the combined relative abundances of (8) plus (9) correlate with the relative stabilities of the expelled anions, i.e. H- >> Bn- > Me- > Et- and can be adjusted by limiting the amount of base used. The structure of (6)-Li2 crystallized from DME was found to feature layers of dianions (6) alternating with layers of DME-complexed lithium counteranions; each lithium cation is chelated by three DME molecules; the central acepentalene fragment adopts C3 symmetry and is bowl-shaped, although each indan subunit is planar.

Hexane

___)

LSB

1

"\

-H+

(7)

R= a H;b Me; c Et; d Bn

-R-

I

H

K'

(9)

(10)

Further investigation of the effects of nitro groups on acidic and homolytic bond dissociation enthalpies of the acidic C-H bonds in carbon acids and their radical anions has been reported.24 The increase in C-H heterolytic bond dissociation energies (acidities in DMSO) effected by nitro substitution of methane on the a orpara positions of toluene (ca 50, 40, and 30 kcal mol-', respectively) is in contrast with the corresponding small decrease in homolytic bond dissociation energies (BDEs) (ca 7.6, 2.8, and 1.5 kcal mol-', respectively). While nitro groups stabilize radicals by delocalizing the odd electron, they also exert a destabilizing influence by inductive electron withdrawal; both effects are stabilizing in the case of carbanions.

308


BDEs have also been determined25 for a number of malononitriles, 2-substituted dialkyl malonates, alkyl 2-cyanoacetals, and related compounds by combination of measurements of equilibrium acidities (pKHA)and oxidation potentials [Eox(A-)] of the corresponding conjugate anions in DMSO, according to the relationship BDE = 1.37pKHA 23.1EOx(A-) c. The pKHAvalues of dialkyl malonates increase from 15.9 to 16.4 to 18.4 as the dialkyl groups are changed from dimethyl to diethyl to di-t-butyl, yet the BDEs (95.3 z t 0.3 kcal mol- ’) remain unaffected. Introduction of methyl, ethyl, isopropyl and t-butyl groups to position-2 of diethyl malonate causes the BDE value to decrease by 4.4, 3.7, 2.5, and 0.8 kcal mol-’ and the PKHA value to increase by 2.0, 2.4, 3.8, and 8.0 units, respectively, whereas a phenyl group weakens the acidic C-H bond by 10 kcal mol-’ but has no effect on acidity. The marked acid weakening effect of the 2-t-butyl group (to which BDE is insensitive) can be ascribed to steric hindrance to anion solvation; the marked reduction of BDE by a 2-phenyl group is a consequence of radical stabilization by conjugation, yet for the anion this is apparently precluded by a chelating effect of K+, which confines the phenyl group to an orthogonal position relative to the chelate ion plane. NMR-based charge mapping and metal ligand properties of carbanions derived from bispyridyl- and bisquinolyl-methanes have been explored.26

+

+

Carbanion Reactions Enolates and Related Species The synthetic scope, asymmetric induction, and diastereoselectivity of aldol, Michael, and related reactions of tin(I1) enolates have been reviewed.27 BF3.0Et2-promoted addition of allyl- and p-methallyl-stannanes to aldehydes (lla) and (14a) have been found to follow opposite stereochemical paths; this is in keeping with the stereochemical dichotomy found for aldol addition of enol silane to anti-substituted aldehydes (lla) and ( l l b ) versus syn-substituted aldehydes such as (14a) and (14b).28 For (lla) and (1 lb) preferential formation of the Felkin/l,3-anti-diastereoisomer (12a and 12b, respectively) is favoured since those factors that control u- and pstereoinduction are mutually reinforcing; for (14a) and (14b) the carbonyl face selectivity changes from Felkin to anti-Felkin as the size of the enolsilane substituent R is decreased (from Bu‘ to Me), since the diastereofacial bias imposed on the carbonyl moiety by u and fl substituents are now non-reinforcing. Thus, it is clear that carbonyl addition reactions of unhindered trigonal nucleophiles that proceed through polar transition states may be influenced by p-heteroatom substituents. This is believed to be the first report of anti-Felkin selectivity for Mukaiyama aldol reactions performed under conditions which preclude chelate organization. A firther study of Lewis acid-mediated aldol reactions of enol silanes has revealed that silylketene acetals (17) derived from 2-pyridylthioester react with benzaldehyde in the presence of Tic& to give exclusively the syn-aldol product (19) whereas the BF3mediated reactions afford the corresponding anti-adduct (18) as the major pr~duct.’~ This is the first report of syn-selectivity for reaction of the silyl ketene acetal of achiral thioesters with achiral simple aldehyde; this has been explained with reference to a transition state in which the coordination of titanium ion with both benzaldehyde

I I Carbanions and Electrophilic Aliphatic Substitution OP O H c p p r l

Me

OH

309 OH

OP

R

Nu

BF3.0Et2 CHZC12

OP Pri

Me

Me

(12) Felkin

(12) anti-Felkin

(15) Felkin

(16) anti-Felkin

a; P = PMB b; P = TBS

carbonyl and pyridine nitrogen of the silyl ketene acetal completes the formation of a cis-octahedral complex, thereby reducing conformational freedom of the system. The degree of threo-selectivity (22 > 24) observed on aldol reaction between the lithium enolate of 2,6-dimethylcyclohex-2-enone(20) and aromatic aldehydes or 2- and 3-furaldehyde has been found to exceed that for analogous reactions of 2,6dimethylcyclohexanone and 2,2,6-trimethylcyclohexanone.This has been ascribed to a repulsion or non-bonding interaction between the cyclohexenic double bond and the .n-aromatic system of the aldehyde (cf. 21 and 23); aromatic ring substituents on the aldehyde exert only a modest influence.”

anti

d

OTBS PhCHO

(17) R = Me, Et, Bu, Hex, Pr‘

YF3.OEtz

syn

phI(LsJQ R

The diastereoselectivity displayed in an aldol-type reaction used for asymmetric synthesis of cr-substituted serines from achiral aldehydes has been shown to depend on


310

Ar

2.ArCHO

\

the Lewis acid-base or the cationic lithium-base combination chosen to promote the double chiral recognition process.31 Results of a kinetic study of the intramolecular addition of enolate ion (26) to its neighbouring carbonyl group have shown that the electrophilic reactivity of the benzaldehyde-type carbonyl group is comparable to that of weakly acidic tertiary ammonium ions.32 In water, the conversion of (25) to (28) occurs by rate-limiting formation of (27), which undergoes subsequent fast reaction; the rate of deuteroxide ion-catalysed exchange of deuterium into (25) to give (25-D) is slower than the formation of (28), since kHoH < k,, but in 3-quinuclidinone buffer (0.1 M) the exchange occurs faster than aldol addition (kBD[BD+] > k,. With increasing concentration of 3quinuclidinolbuffer (50% fi-ee base, pH = 10.1) the apparent second-order rate constant for the conversion of (25) to (28) approaches a limiting value with a change from ratedetermining buffer-catalysed deprotonation of (25) (k, > kHoH ~ B H [ B H + to ] ) ratedetermining uncatalysed cyclization of (26) when k B ~ [ B H > f ]k,. The estimate of k, = 1.6 x lo6 s-' is remarkably close to the rate constant previously reported for conversion of a bimolecular encounter complex, between the enolate of acetone and benzaldehyde, to the aldol adduct and consistent with an effective molarity of approximately unity for the intramolecular enolate addition reaction. Values of kB and kBH/kcfor a series of 3-substituted quinuclidine buffers have also been determined and correlated with pKBH to give Brnnsted slopes of /?=(IS3 and -a=-0.48, respectively; the hypothetical quinuclidine corresponding to log(kBHlkc)= 0 has P K B H = 13.2. The interplay between complementarity and basicity and the use of hydrogen bonding to lower the pK,s of guest molecules has been explored for molecular recognition of enolates in a~etonitrile.~~ By use of polyazaclefts (29) and (30) (illustrated in idealized binding models with hexa- 1,3-dienone enolate) as the receptors

+


31 1

for a range of methylene compounds, in an attempt to model the enolase and racemase enzymes, it has been established that complementarity of the guest to host is the dominant factor in enolate binding although binding will increase with basicity for enolates of the same shape and hctionality. Only a small fraction of the large pK, shifts found for enolase and racemase enzymes can be ascribed to effects of hydrogen bonding analogous to those reported in this study.

Carbonates (32a-c) derived from l,l'-binaphthalene-8,8'-dio1(31) have been used as chiral proton sources in order to achieve enantioselective protonation of enolates (32ac); the ee values are insensitive to R but much higher for protonation of magnesium enolates than for lithium e n ~ l a t e s . ~ ~


312

(31) R = H (32) R = CONR'2

(33)

(34)

a; R' = Me b; R' = Et c; R' = Pr'

The enantioselectivity observed on deprotonation of 2-r-butyl-2-methyl-1,3-dioxan5-one and tropinone with chiral lithium amide bases is enhanced if one or more equivalents of LiCl are present; in some cases the opposite enantiomer, formed on reaction with an electrophile, may be caused to p r e d ~ m i n a t e Chiral . ~ ~ chelated amide bases have also been used for enantioselective deprotonation of prochiral cyclic ketones, regioselective deprotonation of optically active 3-keto steroids, kinetic resolution of 2-substituted cyclohexanones, enantioselective aldol reaction, and enantioselective alkylation of achiral ketones.36 The desymmetrization of 2,4-dimethylbicyclo[3.2.l]octan-3-oneby enantioselective deprotonation with a variety of chiral amine bases has also been studied37and catalytic asymmetric C-C bond formation reactions of lithium enolates have been reviewed.38 Novel sulfonyl electrophiles have been used to trap ketone enolates in an attempt to develop CD ring synthons of relevance to vitamin D3.39 An unusual enantioselective aldol-type reaction between aldehyde and the 9-BBN enolate of camphor-derived N-acetyloxazolidinethione (a chiral thioimide) has been explained with reference to a boat-like transition structure.40 The stereoselectivity of aldol addition of chiral boron enolates, R1R2C=C(OBL:)2 of mono- and di-substituted acetic acids to benzaldehyde has been found to depend strongly on the type of chiral ligand used, to the extent that the enolate may be directed to add predominantly to either the re or si face of the aldehyde, where L* = 2-%r or 4-dIcr, respectively (Icr = di-4-isocaranylchloroborane).4' Chiral boron enolates which have previously been found to induce enantioselective synthesis of aldols have now been used for stereoselective aldol reactions involving chiral N,N-diprotected a-aminoaldehyde~.~~ Acyclic diastereofacial selectivity in the Baylis Hillman reaction, whereby ambident vinyl a-anions derived from acrylic esters and methyl vinyl ketone add to protected chiral a-hydroxy- and a-amino-aldehydes under the catalytic influence of tertiary amines, has been investigated; the preference for anti-selectivity for these nonchelation-controlled aldol-type additions has been interpreted in terms of the Felkin model and the Anh-Eisenstein proposals for 1,2-asymetric induction.43 High n-facial differentiation has been reported for titanium-mediated chelationcontrolled aldol-type reactions of acetate thioimide enolates with representative aldehydes.44 For non-chelation-controlled aldol bond formation reactions of acetate

I I Carbanions and Electrophilic Aliphatic Substitution

313

imide enolates a switch in n-facial selectivity can be achieved by alternation of either the imide enolate ligand or the geometry of the boryl catalyst. It has been shown by NMR assignments that the effect of ( 3 4 - and (3S)-3-benzyl substituents, respectively, on the stereochemistry of aldol condensations of the lithium enolates of 1,4-bis[(S)-1-phenylethyl]piperazine-2,5-dionederivatives with benzaldehyde, acetaldehyde, and acrylaldehyde is to induce prevalent cis-induction; this is not the case for reaction with rnetha~rylaldehyde.~~ Stereochemical control in formation of p-lactams by zinc-mediated ester enolateimine condensation reaction has been explored.46247 The cisltrans ratio of lactams (37) formed on reaction of the chlorozinc enolate (35) with imines (36) in THF is increased in the presence of strongly coordinating co-solvents (HMPA, DMPU, TMU, or NMP), which apparently favour a transition state for reaction via (E)-enolate; furthermore, the high asymmetric induction ( > 98% ee) observed on formation of cis-/I-lactams from (35) with chiral imine [36; R' =Et, R2 = (R)-PhCHMe], suggests that the transition state is highly ordered and features (a-enolate aligned with (4-imine. All of the results have been interpreted with reference to relative stabilities of transition states (38a) and (38b), together with the presence of a fast (E)-(2)-enolate equilibrium. Metal counterion, temperature, and substituents have been shown to influence the distribution of products obtained on reaction of dienolates of but-3-enoic, 3-methylbut2-enoic, pent-3-enoic, and 4-phenylbut-3-enoic methyl esters with imines (36);47 reaction at the 2-position of the dienolate occurs reversibly at low temperature (-78 "C)

OZnCl

OEt

(35)

a; X = H, Y = Me,Si,

r - 73 M e - r N

(a-enolate

I

n b; Y = H, X = Me*Si, .SiMez N

I

(E)-enolate

3 14


to give the a-coupling product, a 8-amino ester, whereas y-coupling at the 4-position occurs at ca -20 "C to give the corresponding a,P-unsaturated ester. The C-C coupled products may subsequently undergo irreversible ring closure to form p-lactams or 5,6dihydropyridin-2-ones, respectively, which may exhibit high asymmetric induction when a chiral amine such as [36, R' = 2-pyridy1, R2 = (R)-PhCHMe] is used. P-Lactam formation is favoured by the use of zinc dienolates, 4-substitution of the dienolates, non-aromatic imine N-substituents, and low reaction temperature. a-Coupling and preferential formation of trans-8-lactams are believed to occur by reaction of the zinc dienolate in its Z-conformation. The diastereoselective y-coupling reactions have been interpreted with reference to a six-membered cyclic transition state in alternative boat and chair (cf. 38) forms. A study of enolate protonation by chiral amines has established, for example, that the naproxen amide (42) can be obtained with an enantiomer excess of77% on treatment of a 1 : 1 : 1 mixture of enolate (39), amine (40), and lithium amide (41 with BF3.0Et2;the enantioselective protonation reaction proceeds by internal proton return (ipr) within a mixed aggregate containing the enolate and the chiral amine.48Direct proton transfer to an enolate may occur when the pKaDMSO of the amine is lower than that of the enol, otherwise BF3.OEt2 is necessary to activate the N-H bond and facilitate ipr to amide, ester, lactam, or lactone enolates. It seems that direct proton transfer requires the minimum number of bond-breaking and bond-forming events while BF3.OEtz-induced ipr in an enolate-amine complex involves prior cleavage of at least one of the bonds between lithium and a nitrogen electron pair.

(40) M = H, R = CH2CH2NMe2 (41) M = Li, R = CH2CH2NMe2

(42)

A revised model for five-membered ring enolate alkylation, based on steric and stereoelectroniceffects, as well as ring conformations, has been proposed to account for unexpected contrasteric formation of (43) rather than (45) on reaction of (44) with methyl iodide (EI) when R2 = R3 = OR.49


315

Factors which may influence the asymmetric alkylation of amide enolates having pseudoephedrine or ephedrine as chiral auxiliaries have been highlighted5' and a marked effect of HMPA on the diastereoselectivity of the condensation reaction between the enolate dianion of diethyl (5')-malate and imines, to give 2-pyrrolidinone derivatives, has been rep~rted.~' The formation of ethyl 2-cyanoacrylate, on reaction of ethylcyanoacetate with formaldehyde catalysed by 6-aminocaproic acid, has been shown to involve dehydration of the intermediate HOCH2NH(CH2)5C02Hin the rate-determining step; the reaction is of first order in HCHO and 0.5 order in ethyl ~yanoacetate.~~ Rate and equilibrium measurements have been reported for formation of o-adducts (49) on reaction of benzyl cyanide anions (48) with 1,3,5-trinitrobenzene(46) (and with 4-nitrobenzofuroxan) in methanol.53Values of K1 for deprotonation of benzyl cyanides (47) by methoxide ion, and of hMe for addition of MeO- to (46), have been used to obtain k2K1,kL2,and hence K2, from the rate of equilibration of (46) and (49) for which kobs= (k2Kl[RC6H4CH2CN][MeO-])/(1 hMe[MeO-]) k-2). Values of K1K2, which were also obtained by direct observation of the extent of conversion of (46) to (49), are insensitive to ring substituents R, since increases in the value of K1 with increasing electron withdrawal by R are exactly balanced by corresponding decreases in the values of K 2 this ; implies that the negative charge is completely transferred to the trinitrosubstituted ring of (49). With increasing reactivity of the benzyl cyanide anions (48) the very high values of k2 (consistent with a poorly delocalized anion) approach the limit of just under lo9 dm3 rnol-' s-l and values of kW2 decrease steadily. By

+

+

o*NTNo2 +

MeO-

+

MeO-

KOMe

TNEL-MeO-

NO2

(46)

CHzCN

I

RQ (47)

NO2

/


316

extrapolation to log K2 = 0 the value of the intrinsic rate constant for the C-C bond forming reaction, log b = 2 . 5 f 0 . 5 , is obtained; thls is 1.5 units lower than that for proton transfer to a nitrogen acid, with consequent location of negative charge on N, and may again be influenced by delocalization on to the trinitrobenzene ring. Alkylations of nitrile anions by a range of tertiary a-halo ketones and nitriles have been inve~tigated~~ in an attempt to detect fiuther occurrence of the SRNlmechanism which has already been established for reaction of resonance stabilized carbanions with tertiary benzyl halides; the alkylations of [NCC(Me)C02Et]- and [NCC(Me)CN]with p-02NC6&COCX(Me)2 were found to take place by the SRNlprocess, as evidenced by the inhibiting effect of (But)2NO'. It has been shown previously that ammonium benzylide salts (50, R f H ) , when treated with a weak base, afford isomeric products (52) and (55) derived from ylides (51) and (54), respectively, by [2,3]- and [ 1,4]-sigmatropic rearrangement. It has now been confirmed through isotopic labelling that both rearrangement manifolds apply in the case of (50a)for which it would otherwise be impossible to determine the origin of the product (52)= (55).55The [2,3]-rearrangement accounted for 44, 85, and 100% of the rearrangement product obtained from (50a) on reaction in DMSO, DMF, and CH2C12, respectively, while for (50b) the corresponding percentages were 33, 54, and 100%. A [1,2] (Stevens) rearrangement of both (50a) and (Sob), to give diastereoisomers of 4-RC6H4(CHCN)2NMe2,is favoured when solid NaHC03, rather than K2C03, is used in DMF.

*CN

R'

barelsolv~

R

ayN MeSOd-

\

baselsolvenl

a;R=H b; R = C1

*FN

*FN

R

The kinetics of reaction of malononitrile with alkyl nitrites in aqueous basic medium have been explored in order to determine the probable mechanism of this C-nitrosation reaction, which is believed to proceed via the carbanionic form of the nitrile.56 The kinetics of formation of the corresponding oxime, HON=C(CN)*, were consistent with


317

pre-equilibrium formation of the nitrile anion, followed by its reaction with nitrite in a rate-limiting step:

CH2(CN)2 -CH(CN)2

+ RON0

&

ka

-CH(CN)2

+

H+

HON=C(CN)2

+ ROH

Consequently, the reaction is inhibited by acid at high acidity and unaffected by general acid-base catalysts. Correlation of the values of log k2, obtained for various alkyl nitrites, with the corresponding Taft o* values gives a high positive value of p* = 3.49, which reflects stabilization of the incipient alkoxide leaving group and a decreased selectivity for nitrosation of this highly reactive nucleophile. Quantitative antihydrophobic effects, as a probe for transition-state structure, have been discussed with particular reference to the benzoin condensation reaction between benzaldehyde cyanohydrin anion and benzaldehyde.” For reaction in water (ko)the free energy of the starting materials is lowered by the effect of added ethanol on the exposed phenyl groups and the same effect on the transition state is to be expected unless some fraction (h) of the hydrophobic surface is hidden. For reaction in presence of various co-solvents the dependence of rate constant k on benzaldehyde solubility S is given by log (k&) = hC log (S/So), with h = 0. I 9 (attributed to ca 40% shielding of a hydrophobic face of each phenyl group). It has been argued that the carbanion orbital overlaps n* of the carbonyl by back-side approach, such that the phenyl rings are only partly occluded (Scheme 1). These results have been compared with those for displacement reactions involving a phenyl group on each reactant.

’H,CN

0- OH

SCHEME 1

A semiempirical MO study (MNDO and PM3) of the transition states for Michael addition reactions of the lithium (2)-enolates of N-alkylideneglycinates to a$unsaturated esters has attributed the exclusively high anti-selectivity to the attractive MO interaction between the imine moiety of the donor and the a-carbon of the acceptor.58 The potential for asymmetric synthesis has prompted the first stereochemical investigation of 1,Cconjugate addition reactions of readily available chiral and racemic P-keto sulfoxides and P-keto sulfones with highly stabilized Michael acceptor^.^^


318

Reactions with arylidenemalononitriles and benzylidenecyanoacetates were investigated since the 1P-addition is followed by O-ring closure to give an amino-4H-pyran ring amenable to analysis of the extent of asymmetric induction at the electrophilic carbon during the nucleophilic addition process; the results reveal that the type of functional residue attached to the sulfur moiety does not affect the stereochemical course of the Michael addition. Cyclopentyl-substituted dienone and trienones have been synthesized by Michael addition of y-methoxy allylsulfonyl anions to mono- and bi-cyclic cyclopentenyl phenylsulfones followed by hydrolysis of the intermediate adducts to give 6-sulfonylsubstituted enones which undergo eliminative formation of dienyl ketones.60 The chemistry depicted in Scheme 2 is illustrative of the transformations involved.

PhS02 HMPA, THF

Me0

Me0

n = 5-7 ca -65 "C

I

-Li02SPh

SCHEME 2

The lithium enolate of p-(phenylsulfony1)isobutyrophenone has been shown to exist mainly as a dimeric aggregate in THF at 3 x l o p 3 M.61 Spectroscopically distinct monomer and dimer can be detected on dilution to 5 x l o p 5 M, thereby allowing the determination of the dimerization constant Kd= (5 f0.1) x lo4 M-' and monomer pK = 14.69. The kinetics of reaction with p-t-butylbenzyl bromide reveal that alkylation occurs via the monomeric ion pair even in the presence of a large excess of dimer, The mechanisms of reaction of sodium hydroxide with 2-, 3-, and 4-nitrobenzyl sulfones, to give azoxybenzene derivatives, have been explored.62 The carbon-bonded a-adducts (59a-d) obtained on reaction of nitroalkane anions (58a-d) with 4,6-dinitrobenzofuroxan (57) can be isolated as crystalline alkali metal


319

salts63and have been shown by rate and equilibrium measurements to be 105-10s times more stable than the analogous a-adducts of 1,3,5-trinitrobenzene. For (59a-d) in DMSO the addition of base (MeO-, CF3CH20-, NEt,) promotes formation of (60ad) by base-catalysed 8-elimination of nitrous acid, there being no evidence of deprotonation at C(a) to form the corresponding dianion in the case of (59a-c), where R' = H. The anioas (60a-d), which are the conjugate bases of the corresponding 7-R4,6-dinitrobenzofuroxans,have been characterized by N M R spectroscopy. Thus, the overall reaction constitutes a nucleophilic aromatic substitution of hydrogen, assisted by the departure of a vicarious nitro group from the nucleophile. Structural features of the diastereomeric a-adducts (59b,c) formed on reaction of (57) with (58b,c) have been discussed.

It has been shown that 4-substituted-5,5-dimethyloxazolidin-2-ones are effective chiral auxiliaries for stereoselective enolate alkylations and conjugate additions of attached N-acyl moieties, as illustrated by the high degree of asymmetric induction achieved for reactions depicted in Schemes 3 and 4.64 The auxiliaries are readily available from cc-amino acids and can be recycled following efficient removal by hydrolysis (LiOH, THF-HzO, 0-20 "C). Intramolecular Michael addition reaction between 8-keto ester and enol moieties has featured in studies of formation of 14-membered macro cycle^.^^ Diastereoselective bromination of lithium and boron enolates derived from 2-acyI-2ethyl-l,3-dithiane-l-oxideshas been achieved with limited success using NBS as the source of electrophilic halogen.66 Results of normal anionic polymerization of methylmethacrylate promoted by 9methylfluorenide as a nucleophilic catalyst have been compared with those for an analogous group transfer polymerization which occurs if a silyl ketene acetal initiator, 1-methoxy-1-(trimethylsiloxy)-2-methylprop-1-ene, is also present;67 it is concluded that the ester enolate anions are propagating intermediates in each case. Tetrabutylammonium salts of carbon acids (malonic acid diesters and diamides, nitropropane, phenylacetic and phenylpropionic acid esters and 9-ethylfluorene) have been found to initiate polymerization of acrylates and methacrylates at room temperature.68 Narrow molecular weight distributions can be achieved but the side reactions observed suggest that the growing polymer chain does not feature the naked


320

81-97% de from (61)

75-95% de from (62)

(i) LDA, 0 "C (ii) PhCH2Br (iii) Me1 R = Me, Ph, Bu, Pr' SCHEME 3

95% de from (63)

92% de from (64)

(iv) CuBr, (Me)2S/PhMgBr, THFhle2S (2:l) (v) CuBr, (Me)zS/MeMgBr

SCHEME 4

anion expected of a true living polymerization process, possibly as a consequence of hydrogen bonding between the anion and metal-free action. Photostimulation has been shown to induce reaction of 1-iodoadamantane with a range of carbanions in DMSO. The SRNlmechanism has been proposed and the following reactivity order of carbanions towards 1-adamantyl radicals in the first propagation step has been determined by competition experiments: acetone enolate ion (1 .O) < acetophenone enolate ion (1 1) < nitromethane anion (32) < anthrone anion (80); the carbanion reactivity in the photostimulated electron transfer increases with the pK, of the corresponding conjugate acids.69 A 'H, I3C, and 29Si NMR spectroscopic analysis has established that 2-bromo-l(trimethylsi1oxy)ethylene (65) is converted exclusively into the carbanionic species (66) on addition to t-BuLi in Et20.70In contrast, when THF is used, the initially formed (66) undergoes complete transformation to the enolic structure (67) over a period of 8 h by an intramolecular 1,3-rnigration of the trimethylsilyl group. The results are consistent


32 1

with product distributions previously reported for reaction of electrophiles with (65) in various solvents following bromine-lithium exchange. Novel intramolecular attack at the a-carbons of cyclopropanone-Favorskii intermediates by enolate ions has been shown to provide a route to functionalized tri- and tetra-cyclic systems.71A linear steric energy correlation has been established for a cyclic condensation of alkyl acetoacetates with 1,3,5trinitrobenzene in presence of base.72

Heteroatom-stabilized Species Reviews of regioselectivity and stereoselectivity of heterosubstituted carbanions have highlighted the role of silylallyl anions in organic synthesis73aand the influences of counterion, solvent, and heteroatom on coupling reactions of charge-delocalized car bani on^.^^' The chemistry and thermochemistry of silicon-containinganions in the gas phase have also been reviewed.74 a-Silyl effects on the acidities of carbon acids and on the corresponding homolytic bond dissociation enthalpies have been reported. Introduction of a Me3Si group into the 9-position of fluorene or the methyl group of PhS02CH3 increases the acidity by 2 and 4.2 kcal molrespectively; likewise, incorporation of the Ph3Si group causes increases of 5.9 and 10.5 kcal molre~pectively.~~ In contrast, corresponding increases in the BDEs are small and indicative of destabilizing effects on radicals adjacent to silicon. The acidity increases have been attributed to a combination of (a) anion stabilization through polarizability effects of the silyl groups and (b) relief of steric strain on deprotonation of the substrate. a-Silyl carbanions have been implicated in the synthesis of thiophenes from allenyl s u l f o n e ~and ~ ~from ~ a-silylallenepho~phonates;~~' in each case the anions, generated by heteroconjugate addition, reacted with SO2 to form intermediate ap-unsaturated sulfines which underwent subsequent rearrangement. Kinetic and mechanistic studies of enantiomerization of a-thio-, a-seleno- and atelluro-substituted alkyllithium compounds have been rep~rted.'~ Dimesitylphenylboranes (68) have been found to form corresponding dianions in THF on reduction with Na-K or K mirror; the spectral data suggest that the dominant canonical structure is (69) rather than (70).78

',

',

Scheme 5 is believed to account for the formation of imine (78) from dimethylvinylsulfonium iodide and (71) since reaction of intermediate anion (74) by an alternative 1,2-hydride shift with displacement of dimethyl sulfide would proceed without loss of deuterium from the product.79


322

It SCHEME 5

A full report of the high diastereoselectivity found for reaction of the anion of trans1,3-dithiacyclohexane 1,3-dioxide with aromatic aldehydes has been published.80 The stereochemistry of addition is highly selective only when the reactions are under equilibrium control; this can be achieved using the sodium salt whereas for other metals (Li, Mg, Al, Ce, Ti) poorer selectivity results. It has been argued that preferential complexation of the metal alkoxide with the axial sulfoxide results in a conformation in which the equatorial sulfoxide electronically repels the aromatic ring and thereby disfavours one of the two possible diastereoisomeric products. Lochmann-Schlosser base has also been applied in a study of the relative rate and stereochemistry of formation of carbanions derived from 1,3-dioxanes bearing methyl and/or phenyl substituents at C(2) or C(4).81. It has been concluded that while two adjacent oxygen atoms mildly stabilize equatorial carbanions, the stereoelectronic effect of the lone pairs is to prevent the resulting carbanion from becoming planar, and there is a very large ratio of relative kinetic acidities for equatorial and axial hydrogens at C(2). Thus, 2-phenyl- 1,3-dioxanes can be deprotonated to give a pyramidal anion (similar to that for 2-phenyl- 1,3-dithianes and reprotonated stereoselectively from the equatorial side) provided that the phenyl group occupies an axial position, whereas either equatorial or axial hydrogen can be removed from 4-phenyl-l,3-dioxanes to give the benzylic carbanion which is planar and therefore similar to the phenylcyclohexyl carbanion.

I 1 Carbanions and Electrophilic Aliphatic Substitution

323

Asymmetric induction has been reported for reaction of prochiral electrophiles with the configurationally stable sulfoxide carbanions derived from dithioacetal sulfoxides which incorporate the thiacyclopentane ring.82 Tricarbonyl(styrene)chromium(O) has been shown to react with sulfur and phosphorus ylides (and a-chloro organometallics) to give tricarbonylchromium(0) complexes of mono-, di- and tri-substituted cyclopropane~.~~ Reaction mechanism and synthetic applications of the Wittig-Horner reactions have been reviewed84and the origin of the stereoselectivity exhibited in Wittig reaction of aromatic ketones has been addressed.85The high E-stereoselectivity found for reaction of arylsulfonamido-substituted phenyl 3-pyndyl aromatic ketones with non-stabilized carboxyphosphonium ylides [Br-Ph3P+(CH2)n+lC02H,n = 2-71 has been ascribed to stabilization of a trans-oxaphosphetane intermediate through interaction of the sulfonamido and carboxylate groups by either hydrogen bonding or salt bridge formation; removal of either of these groups results in preferential (4-alkene formation. The conclusions are supported by semiempirical conformational analysis of the four uncharged diastereomeric oxaphosphetane intermediates in each case. The nitrile imine HCNNH (80), an isomer of diazomethane (79), has been formed in the gas phase by a cation beam experiment and shown to exist as a stable molecule; theoretical calculations on the interconversion of (79), (80), and (81) have been reported.86

Organometallic Species Means of lithiation of fluorinated benzenes and fluorinated bromobenzenes have been explored.87Lithium diisopropylamide (LDA) in THF-hexane causes clean removal of the most acidic proton, whereas butyllithium in diethyl ether-hexane can be used to achieve clean bromine-lithium exchange. The lithiated intermediates so formed were identified either by trapping with acetone or by thermal conversion to the corresponding benzyne, which was then trapped by Diels-Alder addition. Results of a study of the directed lithiation of unprotected benzoic acids, using standard conditions (Bu'Li-TMEDA-THF, -90 "C) followed by reaction of the lithiated product with electrophiles, have aided development of routes to benzoic acids contiguously tri- and tetra-substituted with a variety of functionalities.88Although the carboxylate group directs ortho-lithiation of the parent acid, it is only of intermediate directing ability, as evidenced in intramolecular competition with methoxy, chloro, fluoro, or diethylamido groups in ortho- and para-substituted benzoic acids. Further investigation of the orientation of lithiation of 1- and 2-alkylbenzotriazoles has revealed that the 2-isopropyl derivative reacts only at the a-CH of the isopropyl group whereas the 1-isopropyl derivative is lithiated mainly at three positions of the

324


benzene ring; the l-methyl and 1-ethyl derivatives undergo predominant a-CH lithiati~n.'~ A report of a PM3 and MNDO study of the mechanism and the regioselectivity of the lithiation of lithium methyl-l- and methyl-2-naphthylcarbamate, lithium 1,2,3,4tetrahydroisoquinolinecarbamate, toluene, and phenol has cautioned that regioselectivity predicted by semiempirical methods may be erroneous when two differently hybridized carbon centers of the substrate are in c~mpetition.'~ In contrast with the exclusive formation of 3-lithio-2-methoxypyridine(83) and the high yield of 1,4-adduct (84) already reported for reaction of 2-methoxypyridine (82) with LDA and n-BuLi, respectively, it has been found that a 1 : 1 aggregate of BuLi with Me2N(CH2)20Li induces predominant formation of (85) by metalation at C(6).91

The reactivity of methyllithium with bridgehead nitrogen imidazoheterocycles has been e~plored.'~ The well established regioselective ortho-deprotonation of arene chromium tricarbonyl complexes bearing a-electron-withdrawing or chelating substituents has been extended to include regioselective ortho-substitution of diphenylsulfoxide chromium tri~arbonyl.'~The sulfoxide substituent can induce regio- and stereoselective ortho-deprotonation and can subsequently be removed to give its @so anion. The mono- and di-anions derived from diphenylsulfoxide chromium tricarbonyl and lithium diisopropylamide show complementary stereoselectivities in their reactions with electrophiles (D+, MeI, Me3SiC1). Ortho-deprotonation of (1s)-1 -phenethyl (phenyl chromium tricarbonyl) ether with marked stereoselectivity has been exploited in asymmetric synthesis of homochiral diarylcarbinols from the resulting ~ a r b a n i o n . ~ ~ Intramolecular coordination of lithium ion with the penultimate 2-pyridyl group of 1lithio-1,3-bis(2-pyridyl)butane is believed to account for the stereoselective formation of meso-like products of its alkylation, silylation, and other electrophilic reactions conducted in THF at -78 0C.95 Unprecedented 1,6-nucleophilicaddition of organolithiums (in pentane at -78 "C) to aromatic aldehydes and ketones (Scheme 6) has been promoted, in high yield, by initial complexation of the carbonyl compound with aluminium tris(2,6-diphenylphenoxide) (ATPH).96 Primary, secondary, and tertiary alkyllithiums can be introduced and the distribution of aromatization to dearomatization products can be influenced by choice of solvent and quenching method. Highly diastereoselective non-chelate-controlled 1,2-addition of 1-bromo- 1-1ithioalk1-ene carbenoids to O-protected a- and P-hydroxyaldehydes has been used to introduce


325

SCHEME 6

the synthons -CH20H and THO?' A method for the diastereoselective preparation of substituted epichlorohydrins by reaction of a-bromo- or a-chloro-carbonyl compounds with chloro- or iodo-methyllithium, respectively, has been reported;98the epichlorohydrins have been used for regioselective preparation of ally1 alcohols. Electron-withdrawing groups (R = COZEt, COMe) have been found to induce unusual 1,4-addition of MeMgI to benzoco~marins.~~ On exposure of a mixture of and (Z)-2-(2-methylpropylidene)cyclohexanone to MeMgI the Z-isomer remains unreactive and the E-isomer forms two stereoisomers of 1-methyl-2-(2-methylpropylidene)cyclohexanol, preferentially with the hydroxyl group in the equatorial position.loo Highly diastereoselective ring-opening reactions of chiral acetals, derived fiom I ,4-di-t-alkoxy-(2S,3S)-butane-2,3-diols and ArCHO, by secondary or sterically hindered Grignard reagents are believed to proceed with bidentate complexation of magnesium with acetal and t-alkoxy oxygens."' The enantioselective addition of diethylzinc to arylaldehydes, to give optically active 1-arylpropanols, can be achieved in good yield and with enantiomeric excess of up to 88% by use of the optically active N-1-phenylethyl derivatives of (lR)-2-amino-lphenylethanol as chiral auxiliaries.' 0 2 The auxiliary features stereogenic centres in 1,4positions, whereas the most common promoters of the asymmetric addition of EtzZn to aldehydes are chiral at adjacent positions. Twenty new ligands, all analogues of TADDOL (86a), have been evaluated as titanium ligands for catalysis of asymmetric addition of methyltitanium and diethylzinc reagents to ben~aldehyde."~The ligands featured replacement of the dioxolane ring of the TADDOL by cyclobutane, cyclopentane, cyclohexane, cyclohexene, bicyclo[2.2.1]heptane, bicyclo[2.2.1Iheptene, bicyclo[2.2.2]octane and bicyclo[2.2.1Ioctene; replacement of the aryl groups by H or alkyl was also explored. It was found that both axial and equatorial aryl groups are necessary for ligand-accelerated catalysis of these reactions and that TADDOL (86b) is superior to all other ligands. Enantioselective addition of dialkylzincs to benzaldehyde to give enantiomerically pure secondary alcohols can be achieved under the catalytic influence of certain chiral P-dialkylamino alcohols. It has now been established that non-linear effects on the rate and stereoselectivity of such reactions arise when stereochemically, or chemically,

(a-


326

OH

R

OH

O

(86) a;R=H b; R = Me, Ar = Ph

impure catalyst is used; the influence of (2S)-3-exo-(dimethylamino)isoborneoland its stereoisomers and also achiral 2-(dimethylamino)-l , 1-dimethyl ethanol has been explored systematically.lo4 The expectation that enantioselectivity of a reaction may vary linearly from 100% S to 100% R as a h c t i o n of the ratio of the S and R catalyst is no longer valid when the catalyst enantiomers interact in the reaction system. Thus, for reaction of diethylzinc with benzaldehyde in toluene in presence of racemic amino alcohol (87) the reaction proceeds 13 times slower than in presence of the enantiomerically pure S or R catalyst; furthermore, although racemic (87) promoted the formation of racemic product, the ee values were not otherwise directly related to the ratio of the catalyst enantiomers used. It has been concluded that the reaction is catalysed by the tricoordinate ethylzinc aminoalkoxide (88, R = Et), formed fiom diethylzinc and [(S)-XI- or [(R)-X]-(87),which is in equilibrium with its dimer (89). When both enantiomers of the catalyst are present, the alternative homochiral or

heterochiral diastereomeric dimers (89) may be formed from the monomers (88) by self-recognition or non-self-recognition, respectively. The heterochiral dimer has been found, by cryoscopy, to be overwhelmingly more stable than the homochiral dimers, thereby ensuring that most of the minor enantiomer is incorporated in heterochiral dimer whereas the excess of the dominant enantiomer exists as homochiral dimer in equilibrium with the corresponding monomer which promotes enantioselective alkylation. This accounts for the marked chiral amplification observed when partially resolved (87) is used as catalyst and for attainment of a rate minimum when racemic (87) is used as catalyst.

1 I Carbanions and Electrophilic Aliphatic Substitution

327

The fl-dialkylamino alcohol-promoted reaction of dialkylzincs with aldehydes has also been modelled by an ah initio MO study, using 2-aminoethanol, dimethylzinc, and formaldehyde.lo5 The methylzinc alkoxide (90), formed from dimethylzinc and 2aminoethanol by elimination of methane, has been confirmed as the actual catalyst and shown to exist in equilibrium with stereoisomer dimers (anti>syn) (cf. 89). The catalyst is bifunctional and sequentially coordinates dimethylzinc and formaldehyde (in either order) to give a complex (91) which undergoes intramolecular alkyl migration to give (92); tetramer (93) is obtained from (92) by reaction with either formaldehyde or dimethylzinc. Although addition of dimethylzinc to formaldehyde is highly exothermic, the alkylation reaction does not occur in absence of an amino alcohol, or when 100 mol% of the amino alcohol is added.

H2

[

"ZnMe O/

H2

H2

(MeZnOEt)4

I

I

MeyZn -. Me

Me

The effect of a Lewis acid catalyst on nucleophilic ring opening of vinyloxiranes by organocopper reagents has been fiuther explored.'06. The reaction of methyl (E)-4,5epoxypent-2-enoate (94) with arylcopper reagents (such as PhCu and Ph2CuLi) has been shown to proceed primarily with formation of (95); the effect of BF3 is to increase the yield and reverse the regioselectivity, in favour of the apparent SN2'product (96). It has been concluded that (94) reacts with all phenylcopper reagents via an S N ~ mechanism but that the effect of BF3 is to promote initial SN2 reaction with LiBr (if present from generation of the phenylcopper reagent) to give bromo alcohol (97) and its regioisomer which is converted into (96) by a subsequent sN2' reaction. It is not clear why the sN2 product (95) predominates, without formation of (97), on reaction with Ar2CuLi.BF3when o,o'-disubstituted (Me, Me or Me, OMe).

Ar

Ar

(94)

(95)

(96)

+ QH


328

A synclinal transition state in which the CH2SnBu3group is gauche to oxygen has been proposed to account for the effects of alkene geometry on the stereoselectivity of BF3.EtzO-mediated addition of crotylstannanes to achiral aliphatic, aromatic or ct,Punsaturated aldehydes; reactions with ct-alkoxy- and P-alkoxy-aldehydes have also been investigated.'07.

Proton-transfer Reactions Efficient catalysis of proton transfer by antibodies generated in response to rationally designed model compounds has been discussed"* and the role of His 95 in promoting intramolecular proton transfer reactions of triose phosphate isomerase has been recon~idered.'~~ Amphihydric compounds (RH) are those for which all three of the species Rf, R' and R- are sufficiently stable to be generated in solution. The thermodynamics of the corresponding C-H bond breaking by transfer of H-, H' or H+ and for interconversion of the species by electron transfer have been reported (e.g. for 9-arylxanthene and 2aryl- 1,3-dithiane series) and relationships between these properties have been discussed.' l o AM1 calculations of the gas-phase stabilities of enolates formed on deprotonation of bicyclo[2.2.2]octane-2,5-dione, bicycl0[2.2.2]octane-2,6-dione,~, 1-hydroxy-4-0~02,2,6,6-tetramethylpiperidine,4-0~0-2,2,6,6-tetramethylpiperidine-l-oxyl, 9-hydroxynorpseudopelletierine and norpseudopelletierine-9-oxyl'ohave been correlated with measurements of the corresponding rates of enolization in 60 :40 (v/v) dioxane-D20. For the acid series GCH2COMe, GCHzCO,Et, GCHZCONMe2 it has been shown that for seven sets of data [G = H, Ph, PhS, C-(CHZ)~S~CH, Me3Nf, Ph3P+, or MeCO] the homolytic BDEs of the acidic C-H bond increase progressively with the change from ketone to ester to amide, in line with the + R effects of the groups Me < OEt < NMe2. This is further illustration of the general conclusion that for weak acids decreases in ground-state energies tend to increase the BDEs of the acidic A-H bonds, and vice versa. The equilibrium acidities of these carbon acids in DMSO and the oxidation potentials of their conjugate bases have also been measured for the seven sets. For each set a progressive increase in PKHA and a smaller progressive cathodic shift of E,,(A-) accompanies the progressive small increase in BDE of the acidic C-H bond. BDEs and equilibrium acidities in DMSO have also been determined for the N-H bonds of 15 carboxamides; the average PKHA is 25.5 and the average BDE is 108 f 2 kcal mol-I. Gas-phase acidity measurements, using proton transfer kinetics in a flowing afierglow/selected-ion flow tube, have yielded values of AGacid/kcalmol- (in parentheses, f2-5 kcal mol- ') for CHz=C=CH-H (372.8), H-CH,C=CH (374.7), CH3C-C-H (373.4), and CH,=C=C'H (364), Erom which the respective values of AHa&kcal mol-l (381.1, 382.7, 381.1, and 372) were calculated using ASacicid. ' I 2 Measurements of electron affinities have been combined with values of AHacidin order to obtain the corresponding bond dissociation energies (88.7, 90.3, 130.2, and 100 kcal molrespectively). Problems associated with determination of

'"

',

1 I Carbanions and Elech-ophilic Aliphatic Substitution

329

gas-phase acidity values by proton transfer reactions for systems which may isomerize are discussed. Isotope, solvent, steric, and temperature effects which govern the rates of proton/ deuteron transfer reactions of 2,4,6-trinitrotoluene, 2,2',4,4',6,6'-hexanitrobibenzyl (HNBB) and 2,4,6-trinitrobenzyl chlorides (TNB)with tertiary amines in DMSO and CHzC12 have been e~plored.''~The upward curvature of Arrhenius plots at low temperature for TNT and TNB is indicative of tunnelling and the observed rate constants agree well with those predicted by application of Bell's theory. A study of the ionization and enolization of 2-phenylacetylfuran has revealed (by comparison with deoxybenzoin) that the effect of the oxygen of the furan ring is to (a) enhance the acidity of the enol and (b) stabilize the keto relative to the enol tautomer."4 Rate constants for enolization (measured by iodination) and of ketonization (measured by quenching the enolate and monitoring enol) of 2-phenylacetylfuran were combined to give KE=[enol]/[ketone]= 1.32 x (pKE=5.88); pK,= 14.38 was also determined and used with pKE, to give PK,"~= 8.5 for the enol tautomer. For deoxybenzoin the values pKE= 5.15, and pK?" = 9.6 have already been reported. The kinetics of deprotonation of 2-nitroethanol (98) and 2-nitropropane-1,3-diol(99) by hydroxide ion, water, amines, and carboxylate ions have been studied in order to examine the potentiaI effect of H-bonding in the nitronate ion on the thermodynamic and kinetic acidities of (98) and (99).'15 The pK2" values for (98), (99) and CH3N02 are 8.60, 7.68, and 10.22, respectively, and the acidifying effect of the CH20H groups is believed to be a consequence of inductive electron withdrawal and hyperconjugative stabilization of the nitronate ion which may also be stabilized by intramolecular Hbonding. The increase in rate of proton transfer on substituting nitromethane with one CH20H group indicates that the Brmsted tl value is positive and in contrast with the abnormal behaviour found previously for deprotonation of nitromethane, nitroethane, and 2-nitropropane by HO-; it is argued that the deprotonation transition state is nonetheless imbalanced in each case. The acid dissociation constants (pK,OH = 13.33 and 12.60, respectively) determined for the alcoholic hydroxyl groups of (98) and (99) are consistent with an earlier correlation of RCH20H acidities with o*. 02NCH2CH20H

HOCH2CHCH20H

I

N02

(98)

(99)

Bromine or chlorine substitution has been found to increase the gas-phase acidities of benzene and naphthalene by 13-14 kcal mol-', primarily by an inductive effect which decreases by 2.5-3.5 kcal mol-' per bond separating the acidic site from the halogenbearing carbon; larger effects are caused by fluorine substitution.'I6 The acidities were determined by a flowing afterglow technique using the silane cleavage method; linear correlations between meta and para position acidities of halobenzenes with those for corresponding rn- and p-haiophenols, -haloanilines, and -halotoluenes were found. Ab initio calculations have been used to define five stationary points on the potential energy surface for proton transfer between methane and amide anion in the gas


330

phase.’ l 7 Theoretical studies have also addressed: tunnelling contributions to the dynamics of tautomerization in gas-phase formamidine and its monohydrated complex (a hydrogen-bonded system);’ bifurcation of tunnelling trajectories of two-proton transfer reaction^;''^ and proton and heavy atom motions during tautomerization of oxalamidines.120 Errors inherent in studies of the tunnelling mechanism of liquid phase proton transfer based on kinetic isotope effects have been highlighted. A study of the deprotonation of intramolecularly hydrogen-bonded monoanions of phenylazoresorcinols (100) has been extended to include determination of the effects of substituents R’-R’ on the rate coefficient kf and equilibrium constant K.‘” The values of K increase with increasing electron-withdrawing ability of R3, such that log K = 0 . 5 5 ~ ~2.29, in 90% (v/v) DMSO-H20. Electron-withdrawing substituents R’ and R’ cause a remarkable reduction in the rate of removal of the hydrogen-bonded proton by hydroxide ion (via an open intermediate) and permit the reactions to be followed over a period of minutes.

’”

+

OR2 RI j

I

+

HO-

1:91-.2 N

NO

+

H20

A nearly temperature-independent kinetic isotope effect for the reverse proton transfer of 7-hydroxyquinoline has been confirmed, and rationalized in terms of associated solvent reorganization.”’ The kinetics of proton transfer from the N-H acid 1,8-bis(4-toluenesulfonamido)-2,4,5,7-tetrani~onaphthalene to various N-bases in acetonitrile have been interpreted with reference to the structure of the transition state.lZ4

Miscellaneous A bimolecular E2cB /?-elimination mechanism has been suggested for the transfer of hydride ion from carbanion salts RM (M = Li, MgBr) and R2N-Li+ to tetrasubstituted activated alkenes of type ArzC=C(CN)C02R (R = Me, Et);’25 the reaction occurs in competition with Michael addition and is favoured by a benzyl substituent at C(/?) of RM or a small size of RM.


331

The mechanism of benzoin condensation of benzaldehyde in dry DMSO, using tBuOK as base and catalysed by 2-I3C-labelled 3-benzyl and 3-methylthiazolium salts, has been probed using a-I3C- and w2H-labe1ledbenzaldehyde.126 A stable intermediate 2-(a-hydroxybenzyl)thiazolium ion is formed, by nucleophilic addition of the C(2) carbaniodylide to the carbonyl carbon, without rearrangement of the benzaldehyde C(ajH and subject to the expected inverse isotope effect kH/kD = 0.83. The intermediate is rapidly converted to benzoin once even a trace of water or methanol is added to the solution. These results are in contrast with the conclusion that for benzoin condensations promoted by thiazolium cations in mild basic conditions the actual catalytic species are bis(thiazo1in-2-ylidene)~;a second-order kinetic dependence on both aldehyde and thiazolium cation has been found.12' The activity of 3,3'polymethylene-bridged thiazolium and benzothiazolium salts as base catalysts of the benzoin condensation depends strongly on the methylene bridge length and suggests that, in aprotic medium, bis(thiazo1in-2-y1idene)s rather than thiazolin-2-ylidenes are implicated.12* For other discussion of benzoin condensation, see reference 57. Sequential base-induced addition, elimination, and cyclization steps have been proposed to account for the cycloaddition products (pyrroles) formed on reaction between tosylmethyl isocyanide or (t-butoxycarbony1)methyl isocyanide, (XCH2CN), to 1,Cdisubstituted 2,3-dinotrobuta-1,3-dienes.129 Reactions of arylazosulfones (ArN=NS02Tol-p) with active-methylene compounds (CH2XY; X,Y = CN, C02Et) have been found to proceed by successive condensation processes to form tetrasubstituted ethylenes, such as ArNHCX=CXY.I3O Diastereoselective addition of the dianion of 4-(phenylsulfonyljbutanoic acid to a chiral a-benzyloxymethyl imine has been studied.I3' Catalytic antibodies capable of promoting Dieckman cyclization and related carbanion reactions have been generated in response to bifunctional five-membered ring haptens which feature a sulfone group, to represent the transition state(s) associated with the tetrahedral intermediate, and an amino group, to encourage formation of a general base.'32 Internal clockwise versus anticlockwise rotation of the carbanion formed on addition of I5NN; to an electrophilic vinyl azide, 3-azidomethylenedihydroro-(3H)-furan-2-one, has been probed by monitoring label incorporation and Z to E is~merization.'~~ Despite the relatively low nucleofbgality of azide, N; expulsion occurs more rapidly than complete equilibration of the carbanion conformers. Nonetheless, the percentage of label incorporation on starting from the E, relative to Z, isomer indicates that incorporation and isomerization are connected; competition between 60 a and 120 rotations has been discussed. The products of reaction of 1-hydroxyprenyl monoanion with Br(CH2),Br (n = 2-4) form by alkylation at position 3a or 5, followed by deprotonation and intramolecular alkylation.134 It has been reported that 2- and 3-nitro-l,6-methano[l0]annulenesand their 11,lldifluoro derivatives undergo vicarious nucleophilic substitution of hydrogen (ortho or para to the nitro group) on reaction with a carbanion bearing a leaving group X at the carbanionic centre; this involves nucleophilic addition, base-induced p-elimination of HX, and p r ~ t o n a t i o n . ' ~ ~ O

332


cl-Lithio conjugated enyne sulfones have been found to form 2,4-diynols in high yield on reaction with carbonyl compounds; the reaction proceeds by a carbonyl addition, syn-dehydrosulfonylation sequence. 36 Stereoselective additions of a-sulfinyl ester enolate to benzaldimine~l~'and of organolithium reagents to chiral imines derived from erythro-2-amino- 1,2-diphenylethan01'~' have been reported.

Electrophilic Aliphatic Substitution Results of a study of the kinetics of reaction of N-bromosuccinimide to amines and amino acids suggest that the electrophilic transfer of Br+ from nitrogen to nitrogen occurs via a concerted reaction in which the unprotonated amino group of the substrate attacks the NBS bromine. 139 The corresponding second-order rate constants increase with increasing basicity of the amino substrate; the activation enthalpies for these fast processes are small and the large negative entropies of activation are indicative of a highly solvated transition state. The kinetics of chlorination of a m i n e ~ ' ~ ~and ' ' ~ N' rnethyla~etamide'~~ in aqueous hypochlorite have also been interpreted. An SN2-type mechanism is believed to apply for fluorination of a range of nucleophilic substrates (metal enolates, silyl en01 ethers, 1,3-dicarbonyl compounds, o-metallated aromatics, RLi and RMgX) by N-fluoro-o-benzenedisulfonimide or o-benzendisulfonic acid. 143 Results of a study of the solvent dependence of the kinetics of nitrosation of ureas by nitrous acid in THF-water and DMSO-water mixtures suggest that only at high THF concentrations ( > 80%, wlw), when catalysis by chloride ion can be observed, does the mechanism differ from that in pure water.'44 Ab initio calculations have revealed that the two viable pathways for reaction of ethane with NO+ are in contrast with the generally discussed mechanisms for electrophilic substitution of alkanes and lead to (a) the nitrosomethylene cation and methane through C-C bond cleavage and (b) protonated nitrosoethane via abstraction of a hydride followed by addition of HNO to the ethyl cation; the respectively activation energies (33.5 and 31.1 kcal mol-') and small primary H/D isotope effects (2.6 and 2.9) for attainment of the non-linear transition structures are ~ o m p a r a b l e . ' ~ ~ The complex situations which arise when an ambident nucleophile reacts with a nitrosating agent, perhaps bearing two electrophilic centres, have been discussed'46 and the kinetics of nitrosation of dibenzylamine by NaN02 in aqueous buffers have been reported. 147 Remote conformational bias effects on diastereofacial selectivity in SE2' additions of 8-oxygenated allylic stannanes to chiral enals have been interpreted.14'

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”’

CHAPTER 12

Elimination Reactions J. R. GANDLER Department of Chemistry, California State University, Fresno, CA 93 740-0070, USA Mechanisms of Elimination Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . ElcB and Related Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E2 Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eliminations via Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyrolytic Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions of Carboxylic Acids and Related Reactions . . . . . . . . . . . . . . . . .

Nitrogen Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alkyl Halides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclo-eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theoretical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E2 and Related Eliminations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclo-eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyrolytic Eliminations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eliminations via Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elimination Reactions in Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

337 337 34 1 344 344 344 346 347 348 349 349 351 352 353 353 357 360

Mechanisms of Elimination Reactions ElcB and Related Mechanisms The base-promoted hydrolyses of a series of aryl N-(arylsu1fonyl)carbamates (1) in aqueous solution have been reported.' The products in these reactions are the corresponding benzenesulfonamides, phenols and COz. The Hammett p value (using Hammett r Y substituent constants) for changes in substituents in the leaving aryloxide ion is large and positive ( p = 2 . 9 3 ) , consistent with rate-limiting expulsion of the aryloxide ion in an ElcB mechanism, rather than direct rate-limiting nucleophilic addition to the carbonyl group. Further support for this mechanism includes a Hammett p value of - 0.66 for substituent changes in the benzene ring of the arylsulfonyl group. This is consistent with increasing rates of expulsion of the aryloxide ion from the conjugate base of the substrate that is favoured by electron-donating substituents (the substrates are largely or completely ionized at the pH values used to determine the Hammett p value). The logarithm of the rate constants for expulsion of phenoxide ions from the conjugate bases of substrates of the type m C 0 2 P h , where R =Me, H, Ph, p02NC6H4, MeCO, PhCO, Cl,CCO, and PhS02, against the pK, of these substrates, is Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

337


338

impressively linear and extends over ca 15 pKa units of substrate acidity (slope = 0.74). Rates vary over lO”-fold. This result extends the relationship first reported by Williams and co-workers.

0

ArSO2NH-4

O

K,

\

ArSO2N KOAl

OAr

(1) ArS02NH2+ C 0 2 + ArOH

H20,

HO-

C--

ArS02N=C=O

+ ArO-

Rate constants for expulsion of CF3CH20- and MeO- from (2) and (3) have been reported as part of a continuing study of nucleophilic vinylic substitution reactions in which the overall reaction is analysed, and rate constants for all the elementary steps determined.2Relative leaving-group abilities of the two alkoxide ions from these stable and strongly delocalized carbanions show a strong dependence on their pK, values. For example, values of PI, (the slope of a plot of log k against the pK, of the leaving group) are near - 1, suggesting extensive cleavage of the C-0 bond in the transition state for leaving group expulsion. Steric acceleration of the loss of CF3CH20- contributes somewhat to these large (3, values.

Nucleophilic vinylic substitution reactions of P-methoxy-a-nitrostilbene (4) with methoxyamine and N-methylmethoxyamine have been r e p ~ r t e d .The ~ intermediate nitronate ion is detectable in these reactions, but not in reactions with more basic amines, because expulsion of methoxide ion from the intermediate carbanion is more strongly dependent on the pKa of the amine (owing to the ‘push’ of the amine’s nonbonded electrons) than is nucleophilic addition to the substrate. As a result, loss of methoxide is slowed to an extent that the intermediate nitronate ion is detectable. Significant amounts of the intermediate can be generated, even with the less basic amines, at pH values where deprotonation of the zwitterion intermediate helps drive the equilibrium towards the carbanion.

12 Elimination Reactions

339 RR~NH+

Ph'

Ph

Ph'

(4)

RR'N

Ph

The hydroxide-promoted hydrolyses of aryl o-hydroxycinnamate esters (5) have been studied in dioxane-water (20 : 80, v / v ) . ~Nine phenoxide leaving groups ranging in leaving-group ability from 2,6-dinitrophenoxide ion (pK1, E 3.7 1) to 4-cyanophenoxide ion (pKl, = 7.95) were studied. A change in mechanism is suggested to occur from an ElcB mechanism, via the o-oxoketene intermediate (6), for leaving groups whose pK, is less than 6, to an addition-elimination mechanism for substrates with more basic leaving groups. The change in mechanism is supported by a break in a Brsnsted plot of the logarithm of the apparent second-order rate constant for reaction against PICl,, the pK, of the leaving group. For weakly basic leaving groups Plg= - 1.11, consistent with rate-limiting expulsion of a phenoxide ion via the ElcB mechanism. For more basic phenoxide ion leaving groups, Blg = -0.25, consistent with rate-limiting addition of hydroxide ion to the carbonyl group. An ElcB mechanism is also supported for the reaction of 2,4-dinitrophenyl-2'-hydroxycinnamate,based on a rate constant calculated from the Hammett equation that is 330 times greater than expected for the associative mechanism, and on entropies of activation that are 40 cal mol-' K-' larger than for the BAc2 reaction of 2,4-dinitrophenylcinnamate.

?H

Q-

340


For the amine- and substituted pyridine-promoted decomposition of a variety of ozonides, a 1,2-eliminationvia an ElcB mechanism has been suggested, although an E2 mechanism seems more likely, rather than direct nucleophilic attack on oxygen.’ For example, when 1-phenylcyclopentene reacts with ozone, it forms (7). With tertiary amines and substituted pyridines, (7)reacts to give 5-0x0-5-phenylpentanoic acid (S), the product of 1,2-elimination. On the other hand, if breakdown of (7) proceeded via nucleophilic attack on oxygen, 5-0x0-Sphenylpentanal would have been produced instead. The authors show that, for the reaction of a wide variety of alkenes, ozonolysis followed by work-up with triethylamine is faster and results in better yields than a traditional work-up with dimethyl sulfide.

The aminolysis and hydrolysis reactions of several sulfamate esters (RNHS020Np, where R=PhCH2, Ph, 4-MeC&, 3-MeC6H4, 4-FC6H4, 4-C1C6H4, and H, and ONp =p-nitrophenoxide) have been studied in an acetonitrile-water solvent mixture (50 : 50).6 The products of the reactions are RNHS02NHR and RNHSO; RNH,f. The results are consistent with an ElcB elimination, via a sulfonylamine intermediate (RN=S02), with rate-limiting formation of the intermediate from the conjugate base of the substrate. The base-promoted elimination reactions of the sulfoxides and sulfones of sulfur mustard (2-chloroethyl ethyl sulfide) have been studied in aqueous s ~ l u t i o n Unlike .~ sulfur mustard, where the major reaction is substitution (via a cyclic episulfonium ion), for the sulfoxides and sulfones the only observed reaction is elimination of HCl to form alkenes. The mechanism is likely to be either ElcB, or E2 via a carbanion-like transition state. The base-promoted reactions of several ally1 ethers (9) (1-ethoxybut-2-enes, 1methoxybut-2-enes, 1-ethoxyprop-2-ene) have been studied experimentally in the gas phase by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry* and theoretically by density-functional theory. A variety of bases were employed, including H2N-, Ph-, Me2N-, HO-, MeO-, EtO-, and F- ions. The major reaction pathway is 1,Celirnination to give, presumably, buta-l,3-diene, and the detectable ionic products, viz. the alkoxide ion either free (RO-) or solvated by the conjugated acid of the base (RO- HB). Proton-transfer reactions (from the 6 carbon), 1,2-eliminations, aliphatic SN2, and SN2’ reactions also contribute, although to a small extent, to the overall reaction of these substrates. The 1,Celimination reaction is suggested to follow an ElcB mechanism that may proceed through either single-, double- or triple-well pathways.


341

R = Et, Me

E2 Mechanisms Elimination reactions in acetonitrile-water mixtures of (E)-O-p-nitrophenyl-2,4dinitrobenzaldoxime (10; R = H) promoted by triethylamine in triethylaminetriethylammonium (1 : 1) buffer solution have been r e p ~ r t e d .The ~ mechanism is suggested to be E2, with syn elimination, despite the presence of a strongly activating 2,4-dinitrophenyl group and a moderate aryloxide leaving group. The evidence for the E2 mechanism includes the observation of general base catalysis by triethylamine and a significant leaving-group effect: the 2,4-dinitrophenoxide/4-nitrophenoxideleavinggroup rate ratio is 33 in water-acetonitrile (95 :5 ) , a ratio that appears too large for a mechanism involving rate-limiting proton transfer.

&R

0"

+

O2N

NO,

(10) R = H, NO2

A water-promoted concerted E2 mechanism in acetonitrile-water (25 : 75, v/v) has been suggested for the reactions of 9-(1-X-ethyl)fluorene (ll),where X = Br or I. An E2 elimination reaction yielding 9-( 1-ethylidene)fluorene (12) competes with stepwise elimination (yielding 9-vinylfluorene) and substitution reactions that proceed via an ion pair." For the iodide and bromide, 95% and 69%, respectively, of the product is (12). The reaction promoted by solvent takes place with a significant primary kinetic isotope effect, kH/kD= 2.0 and 3 .O, for the bromide and iodide substrates, respectively, consistent with a concerted E2 mechanism, rather than a stepwise mechanism via a free or ion-paired carbocation. This elimination reaction is promoted by substituted acetate


342

ions, giving rise to a Brsnsted value for general base catalysis of 0.42 and 0.41 for the bromide and iodide substrates, respectively. Water shows a ca sevenfold negative deviation from the Brsnsted correlation line. If the previously studied reaction of 9(chloromethy1)fluorene follows an E2 mechanism, as has been proposed based on structure-reactivity studies, it is likely that the compounds studied in this work do also. In a closely related paper,' the reactions of (11) were investigated with X = chloride, tosylate, and brosylate leaving groups. Evidence is presented that the tosylate derivative undergoes elimination via an ion-pair mechanism rather than by the E2 mechanism. The authors suggest that, unlike SN2/SN1 substitution reactions, in these systems the concerted E2 mechanism is not enforced by the short lifetime of the ion-paired carbocation intermediate. Rather, it is concluded that both the stepwise and concerted mechanisms may proceed simultaneously by two parallel competing pathways. The hydroxide-promoted reaction of 2-(4-nitrophenyl)ethyl bromide was studied12 in the presence of cationic chemo-degradable surfactants, [2-alkyl(1,3-dioxalan-4-y1) methyl]trimethylammonium bromides (13). Rate enhancements of up to 50-fold were observed relative to the hydroxide ion-promoted reaction in the absence of surfactants. The authors conclude that the major source of the rate enhancement is increased reactant concentration in the micellar reaction volume.

'

RXH Me3N+

Br-

The carbanions of nitromethane, nitroethane, 1-nitropropane, and 2-nitropropane add to the very strongly electrophilic 4,6-dinitrobenzofuroxan (14) to form stable carbonbonded a-adducts, similar to Meisenheimer or anionic a-cornplexe~.~Addition of base (in Me2S0 solution) does not result in deprotonation of the adducts (this would give rise to dinitronate ions), but instead results in elimination of HN02 to give an alkene (15) via an E2 or ElcB mechanism.


343

Reactions of 1-(2-chloroethyl)-3-alkyl-3-acyltriazenes(16) with isopropylamine, npropylamine, diethylamine, and pyrrolidine (in the amine as solvent), and with hydroxide ion in aqueous solution, result in dehydrohalogenation to give 1-vinyl-3alkyl-3-acylt~iazenes(17). The authors favour an E2 mechanism for the reaction with a transition state that has significant carbanion character.l4 For several of the substrates the initial product undergoes subsequent deacylation. There is no hydrogen-deuterium exchange into the substrate during the course of the reaction as determined by ‘H NMR. Direct SN2substitution andor deacylation rather than elimination were observed under reactions conditions that favour these mechanisms.

(16)

(17)

R = Me, benzyl Acyl = N-methylcarbamoyl, acetyl, carboethoxy

Treatment of threo- and erythro-1-methyl-2-phenylpropyl tosylate with butyllithium at room temperature results in stereospecific syn elimination; the threo isomer yields (@-2-phenylbut-2-ene, whereas the erythro isomer yields (Z)-2-phenylbut-2-ene, in 98% and 94% isomeric purity, respectively.” Evidence is presented that suggests the elimination involves o-lithiation of the tosyl group followed by syn elimination via the o-lithiated intermediate.


344

The kinetics of the debromination reactions of erythro-dl-1-aryl-1,2-dibromo-2nitropropanes by secondary amines in acetonitrile have been reported. The reactions are stereospecific (anti elimination) resulting in the formation of (E)-1-aryl-2nitropropenes. The rate law consists of terms that are both first and second order in amine. Correlation with Hammett CJ values (rather than 0- values) suggests that the reaction is initiated by attack on the Br that is M to the nitro group. Based on Hammett p values, Brernsted p values, and the bromide/chloride leaving-group rate ratio (the element effect), an E2 mechanism with a carbanion-like transition state is proposed for the reactions of these substrates. The dehydrohalogenation reactions of N-(2,3-dibromo-3-chlorobutyl)trimethylammonium bromide by alcoholic potassium hydroxide have been reported. Dehydrobrominations of a series of 1,2-dibromo-l-diaryl-ethanesand -propanes have been reported in CCl4 solution promoted by the following solid catalysts; powdered NaBr, LiC1, Fe', FeBr;?,FeBr3, and silica gel.''

'

Eliminations via Carbocations A review with 20 references has been published on ion pairs and ion-molecule pairs in solvolytic substitution, elimination, and rearrangement reactions.l 9 The reaction of 2-methyl-2-propanesulfonylchloride has been investigated in aqueous solution over the pH range 3.5-13.0.*' Reaction apparently proceeds via ionization to the t-butyl carbocation, which gives rise to products of both substitution (tbutyl chloride, t-butyl alcohol, and, at high pH, 2-methyl-2-propanesulfonate ion) and elimination (isobutene). The reactions of alkyl vinyl ethers and alkyl vinyl sulfides with trifluoroacetic anhydride in CC14 solution (in the absence of added base) has been reported.;?' 'H NMR and IR spectra show that addition of trifluoroacetic anhydride to the double bond results in the formation of stable adducts (18), which undergo slow elimination of trifluoroacetic acid to give trifluoroacetylated alkenes. Depending on substrate structure, the elimination step is suggested to proceed by the Ei, E2, or El mechanism.

CH,=CHXR

(CFK0)20

OCOCF3

I

CF3COCH2CHXR

slow

(18)

CF3COCH=CHXR

X = 0 (trans product) X = S (cis and trans product)

Pyrolytic Eliminations Reactions of Carboxylic Acids and Related Reactions Rate constants for the gas-phase pyrolysis of a series of N-benzoyl- (19) and N-acetylpropanamides (20), and N-benzoyl- and N-acetyl-2-methypropanamideshave been


345

measured.22Reactions proceed via a six-membered transition state that is favoured (up to a factor of 12) by methyl substitution at the j3-position (the site at which the proton is removed). Two modes of elimination are possible for the N-acetyl compounds, via transition states (21) and (22). Since acetamide is not formed in the reaction, but RIRzCHCONH2 is, (where R1 and Rz are either H or methyl), the reaction is suggested to proceed via loss of one of the N-acetyl methyl protons, via (22).

R'

R2

0&YH PhCONHCOCHR'R2

'

---+

NY0

(19)

b; R1 = H, R2 = Me c; R' = R2 = Me

(20)

NH2COPh

+ R1R2C=C0

Ph

a; R I = R* = H

MeCONHCOCHR'R*

-

(21)

-

0

-

1.

R'R~CH

0'

i .H

CHzCO

+ NH2COCHR'R2

(22)

The kinetics of gas-phase pyrolysis of chloroacetic acid, 3-chloropropionic acid, 2chlorobutyric acid, 3-chlorobutyric acid, 5-chlorovaleric acid,23 and 2-bromo-3methylbutyric acid24have been studied in a static reaction vessel, seasoned with ally1 bromide, in the presence of the free-radical inhibitors cyclohexene or toluene. The reactions were studied at temperatures ranging from ca 300 to 400 "C. Products are formed via several reaction channels. However, for the dehydrohalogenation reactions of a-halo acids, a reaction via a polar five-membered transition state giving rise to an alactone (23) intermediate appears to be the most probable mechanism. For example, chloroacetic acid gives rise to HCl, CO, HzCO?~2-chlorobutyric acidz3 gives rise to propanal (80%) and but-2-enoic acid (1 5%) (but-2-enoic acid is apparently formed by dehydrohalogenation via a four-membered transition state), and for the reaction of 2bromo-3-methylbutyric acidz4 the major products are isobutyraldehyde, CO, and HBr. The gas-phase elimination reactions of 2-hydroxy-2-methylbutyricacid and 2-ethyl-2hydroxybutyric acid also presumably proceed by the same mechanism, via an a-lactone, in which the carboxyl hydrogen assists loss of OH.25On the other hand, for the reaction of 3-chloropropionic acid, acrylic acid, ethylene, C02, and HCl are prod~ced.'~ Acrylic acid is formed by dehydrohalogenation via the four-membered transition state, whereas ethylene is suggested to form via breakdown of an intermediate 8-lactone (24). In the reaction of 3-chlorobutyric acid23 the major products are propene (63%) (via a B-


346

lactone) and but-2-enoic acid (28%). Smaller amounts of but-3-enoic acid are also formed (9%). Finally, 5-chlorovaleric acid reacts to give d-valerolactone.

ClCH2CH2C02H

CH2=CH;?

+

CO;?

CH2=CHCO;?H

Unimolecular rate constants and Arrhenius activation parameters have been reported for the gas-phase elimination reactions of pentane-2,4-dione, methyl and ethyl acetoacetate, 3-phenylhydroazopentane-2,4-dione, and ethyl 3-0x0-2-phenylhydrazonobutyrate at temperatures ranging from 500 to 783 0C.26 Rate constants and activation parameters for the gas-phase elimination of methanesulfonic acid from but-3-ene-1-methanesulfonate and 3-methylbut-3-ene-1 methanesulfonate at temperatures ranging from 290 to 300 "C have been rep~rted.'~

Nitrogen Compounds The thermal dealkylation at 250 "C of a series of 2-(N-t-alkylamino)-4,6-dichloro-striazines has been reportedF8 The pyrolyses reactions of allylcyanomethyl-, diallylcyanomethyl-, diethylcyanomethyl-, and diethylpropargyl-amines have been studied in a stirred-flow reactor at 380-510 "C at pressures of 8-15 Torr using toluene as a carrier gas.29 The pyrolyses reactions of N-(t-buty1thio)allylamine (25) and N-(t-buty1thio)diethylamine (26) have been studied in a stirred-flow reactor at temperatures ranging from 3 10 to 410 "C and pressures between 8 and 15 Torr, using toluene as the carrier gas.30For the reaction of N-(t-butylthio)diethylamine, the major products are isobutene and N,N-diethylthiohydroxylamine, Et2NSH, consistent with a unimolecular fourmembered cyclic transition state for the elimination reaction; N-(t-buty1thio)allylamine gives rise to N-allylthiohydroxylamine,and isobutene and propene, in a 3 : 1 ratio. Propene is suggested to result from decomposition of N-allylthiohydroxylamine, CH2=CHCH2NHSH (a product formed in the elimination reaction of the substrate) via a cyclic six-membered transition state (a retro-ene reaction with 1 3 hydrogen-atom


347

transfer). Arrhenius parameters are reported and are consistent with the mechanistic assignments.

The thermal decompositions of 2-pyrrolidinone and 2-pyrrolidinethione have been studied in a flow system by following changes in UV photoelectron spectra.” The reactions of 2-pyrrolidinone and 2-pyrrolidinethione yield largely CO, ethylene, H2, and HCN, and pyrrole and HzS, respectively. MO calculations at the PM3 and 6-3 1G levels of theory of the transition-state structures in the two reactions show significant differences that are a result of the change from a carbonyl to a thiocarbonyl group. A continuous-wave (cw) COz laser has been used as a heat source to promote the vacuum pyrolysis of 1,2,3-benzotriazine (27; R = H) and 4-methyl-l,2,3-benzotria ~ i n e . The ~ * UV photoelectron spectrum (PES) of 1,2,3-benzotriazine at a laser power of 40 W results in changes that are consistent with the formation of l-azabenzocyclobutene (benzazete) (28). Peak assignments in the PES were made with HAM/3, using optimized geometries calculated with Gaussian 92 at the HF/6-31G** level of theory. At a laser power of 54 W further changes in the PES are noted, including the formation of HCN. The changes in the PES are consistent with formation of benzyne via elimination of HCN from the diradical intermediate (29).

R

R

I

-

(27) R=H,Me

Alkyl Halides

The vacuum pyrolyses of 6,6-dibromobicyclo[3.1.O]hexane, 6,6-dichlorobicyclo[3.1.O]hexane, and exo-6-bromo-endo-6-chlorobicyclo[3.1 .O]hexane have been studied by using a 50 W cw COz laser as a directed heat source.33The reactions were monitored by photoelectron spectroscopy. Compounds (30a) and (30b) eliminate HX (rather than Xz as observed in solution) to yield 2-halocyclohexa-1,3-dienes, whereas (30c) selectively loses HC1. The results are consistent with a concerted 1,3-elimination of HX.


348

(30) a; X = Y = Br

b; X = Y = CI c; X = CI, Y = Br

Cyclo-eliminations The thermal decomposition of 3,4-dihydro-2H-pyran (31) has been studied by two methods: by a shock wave laser-Schlieren technique at 900-1500 K (at 110-560 Torr), and in a flow tube at 663-773 K at a pressure 0.5 Torr above atmospheric pressure. In the latter method, the decomposition of ally1 ethyl ether was used as an internal standard.34 The reaction, a retro-Diels-Alder reaction, gives rise to ethylene and acrolein under all reaction conditions. RRKM theory is used to fit the laser-Schleiren data. The Arrhenius parameters derived from both methods are in good agreement and are consistent with most, but not all, of the data reported previously for this reaction.

In the conrotatory electrocyclic ring-opening reactions of cyclobutenes (32) to give butadienes, substituents on the 3-position of the cyclobutene ring may twist either inwards or outwards during ring opening (referred to as the torquo-selectivity of the reaction). Theoretical studies of the thermal ring-opening reactions of cyclobutenes fused to cyclohexenes have been reported, and compared with previously reported experimental data, in order to understand better the electronic and steric factors that influence the course of these reaction^.^' Relative activation energies for ring opening with outward and inward rotation of the ethoxyearbonyl group (see below, for example) were determined by carrying out a single-point MM3* force-field calculation of the ab initio transition-state geometry (obtained at the HF/3-2 1G level of theory; higher level calculations gave results that were in agreement with results obtained with RHF/3-21G calculations). The electronic component of the reactions, corresponding to the interaction of the r~ and r ~ * orbitals of the breaking C-C bond and the p or 71 orbitals of the substituent at the 3-position of the cyclobutene ring, was determined by comparing relative activation energies for inward and outward rotation determined by ab initio and MME* force-field calculations (the latter takes only steric factors into account). The difference between the two represents the inherent electronic component of the torquo-selectivity. In this way good agreement between the calculated and experimental data was obtained.


8” O

K

349

)I--I

In a related paper, reactions of seven 3,3-disubstituted cyclobutenes (33) show that only substituents that are strongly electron-withdrawing can cause inward rotation.36 For example, the formyl group (CHO) strongly favours inward rotation. The results are in good agreement with the preferences derived from relative activation energies determined by HF/3-2 1G calculations. A table of these rotational preferences is included in the paper for seven substituents (relative to hydrogen).

When heated, 1,4-0xathiine-S-oxides, such as (34), undergo a retro-Diels-Alder elimination reaction to form a,a’-dioxosulfine (35).37 The dioxosulfine is a reactive intermediate which can be trapped; it can act as both a diene and dienophile in Diels-Alder reactions.

Theoretical Studies E2 and Related Eliminations

+

Ab initio calculations, at the MP2/6-3 1 + GI* and MP2/6-3 1 G* levels of theory, of the potential-energy surfaces for gas-phase reactions of HO- and HS- with methyloxirane and methylthiirane have been rep~rted.~’ When HO- is the nucleophile, E2 elimination (attack at the methyl group) is slightly favoured over SN2substitution, consistent with experimental findings. The importance of ring strain in the substitution reactions was assessed by comparing the reactions of the cycliccompoundswith their acyclic analogues, i.e. the reactions of HO- with ethyl methyl ether and ethyl methyl sulfide,and the reaction of HS- with ethyl methyl sulfide. Surprisingly, a large amount of the ring strain (75% in the reaction of methyloxirane) is released at the transition state despite the fact that the transition state occurs early along the reaction coordinate. For the anti elimination reaction


350

of methyloxirane, reaction proceeds through a transition state in which the 0-C1 -CB-H dihedral angle is 160 '. This twisted conformation for anti elimination is apparently favoured in order to avoid eclipsing interactionsbetween the methyl group and the C1-C2 bond of the oxirane ring that are present in the antiperiplanar conformation. For the same reason, a dihedral angle of 28 rather than 0 O is observed for the syn elimination reaction. As expected from previous work, the transition state for syn elimination has more carbanion character (a shorter C1-0 bond length) than for anti elimination, but is 4.4 kcal mol- less stable. This result contrasts with the result for this same reaction in solution, where the syn elimination pathway is favoured. This is consistent with ion pairing in solution that stabilizes the transition state for syn elimination. For the syn elimination reaction of methylthiirane with hydroxide ion, an H-Cp-C1 -S dihedral angle of 38 O is observed. Syn elimination is 6.2 kcal mol-' less favourable than anti elimination for this reaction and proceeds through a more carbanion-like transition state. Compared with the hydroxide ion-promoted eliminations, transition states for the HS- promoted elimination reactions of methylthiirane are more central (synchronous), have more double-bond character, have greater C- S bond cleavage, and react through conformations that are nearly periplanar. The reaction barriers, however, for HS - promoted eliminations are high so that S Nsubstitution ~ is the favoured pathway. High-level ab initio and DFT calculations have been reported on the fluoride-induced elimination of HF from ethyl fluoride.39The G2 method (which uses large basis sets and extensive electron correlation corrections) and DFT calculations using a basis set with diffuse fhctions (aug-cc-pVDZ) gave consistent results. Significant discrepancies with previously reported DFT calculations are noted and discussed. The results show that anti elimination is favoured over substitution, because of a smaller reaction barrier and a reaction that is entropically favoured. Two theoretical papers, published simultaneously, report on the decarboxylation of 3carboxybenzisoxazole (36). In the first paper, the reaction in aqueous solution was investigated via a combined Monte Carlo quantum mechanical and molecular mechanical simulation method.40 The method is presented as an automated procedure for simulating reactions in solution. The calculated and experimental free energies of activation are in excellent agreement (26.1 and 26.3 kcal mol-', respectively). An analysis of solute-solvent interactions is discussed. In the second paper, the reaction is investigated in detail by ab initio method^.^' The effect of water on transition-state geometries (the effect is dramatic) was investigated by including one or two water molecules in the calculations. 13C isotope effects are calculated and are in good agreement with experimental values for the reaction carried out in water. Solvent effects are also estimated in several solvents (chloroform, acetonitrile, tetrahydrofuran, methanol, and ethanol) using Monte Carlo free-energy perturbation calculations. O

'

+

35 1


Calculations at the MP2/6-3 lG* level of theory of transition-state geometries, and primary and secondary kinetic hydrogen and heavy-atom isotope effects for several intramolecular syn elimination reactions have been reported.42The unimolecular Cope and ylide elimination reactions (37), (38), and (39) shown below were studied.

+

CH3CH2NH20-

120 "C

CH2=CH2

+ HONH2

Agreement between experimental and calculated isotope effects are reasonable, although differences are expected, because the experimental values are based on reactions (in some cases carried out under different reaction conditions) of substrates whose structures are in many cases significantly different (e.g. j-phenylethyl systems, for which a large amount of reliable isotope effect data is available) than those for which the calculations were done. Nevertheless, the results do support the value of calculations of transition-state geometries at this level of theory. The reaction dynamics of thermal, gas-phase decomposition reactions of vinyl bromide have been reported. The calculations use classical trajectory methods on a global potential-energy surface generated via ah initio calculations and experimental thermochemical, spectroscopic, and structural data.43Ah initio calculations, including electron correlation corrections, were carried out using 6-3 lG(d,p) basis sets for carbon and hydrogen, and Huzinaga's (4333143314) basis set augmented with split outer s andp orbitals and an f orbital for Br. Cyclo-eliminations The conversion of bicyclo[ 1.1.O]butane into buta- 1,3-diene has been studied using multi-configurational based wavef~nctions.~~ The isomerization reaction is predicted to occur via the concerted conrotatory mechanism, consistent with experimental observations. The calculated barrier for the concerted conrotatory mechanism is 42 kcal mol--', within 1 kcal mol-' of the experimental value. The less-favoured concerted disrotatory and stepwise mechanisms have calculated barriers of 56 and 116 kcal molrespectively. Semiempirical calculations of activation energies underscore the importance of orbital overlap in thermal reverse homo-Diels-Alder and intramolecular reverse ene reactions.45 Calculations were carried out for the reactions of cis-3,6-dimethyl-3,6dihydropyridazine (40), diazabicycloalkenes (41), and stereoisomers of cyclopropanes

',

(42).


352

+

The [2s 2a] thermolysis of azetidine to produce ethylene and methylenimine has been studied by semiempirical and ab initio SCF MO (3-21G and 6-31G*) methods.46

(42) R = H,C1, Me

Pyrolytic Eliminations The potential-energy surfaces for the unimolecular thermolysis of 1,2-dioxetane (and the dimethyl and trimethyl derivatives) have been studied via semiempirical calculations using the PM3 and AM1 Hamiltonions with multielectron configuration intera~tion.~' The calculated activation barrier (18 kcal mol- ') for 1,2-dioxetane decomposition occurs on the ground-state surface (it is thermally activated), consistent with experimental results. On the ground-state surface, the 0-0 bond stretches and abruptly breaks at a bond length of 2.55 P\, corresponding to extensive stretching of the 0-0 bond and consistent with a diradical mechanism. The triplet state is degenerate in energy with the ground-state surface for bond distances between 2.0 and 2.55 A, allowing intersystem crossing and the formation of some formaldehyde in the triplet state. Multiconfigurational self-consistent-field calculations, using a polarized basis set, of activation energies and transition-state structures for the gas-phase unimolecular decomposition of acetic acid have been reported.48 The results suggest that decarboxylation via a four-centred transition state is the favoured pathway (resulting in formation of CH4 and COz) and proceeds with an activation barrier of 71.8 kcal mol-'. The dehydration reaction, which produces H20 and CH2=C=0, is suggested to proceed via a two-step mechanism: 1,3-hydrogen migration to give the enediol, followed by elimination of water, with an overall activation barrier of 73.1 kcal mol- The results are consistent with previously reported experimental activation energies which range from 67.5 to 72.5 kcal mol-' and from 64.9 to 72.7 kcal mol- for the dehydration and decarboxylation reactions, respectively. In a related paper, the potential-energy surface for the thermal decomposition of acetic acid was re-examined using ab initio MO calculation^.^^ The results are consistent with the results noted previously. Ab initio calculations have been carried out on the unimolecular elimination reactions of cis- and trans-dichloroethane, 1,l-dichloroethane, and trichloroethane. Reactions involving three- and four-centred HCl eliminations, H2 and Clz eliminations, and H and C1 migration reactions are disc~ssed.~'

'. '


353

Ah initio (HF/3-21G) and AM1 calculations have been reported for the pyrolysis of 2-haloacetic acids. The calculated reactivity decreases in the order F > C1> Br.” Semiempirical calculations using the AM1 method have been reported for the thermolysis of alkyl acyloxyformatess2and for the thermolysis of t-butyl ethers.53For the latter reaction, activation energies were calculated. The results indicate that elimination occurs via a four-centred cyclic transition state that results in the formation of butylene. Semiempirical calculations, using the AM 1 method, of the thermal elimination reactions of carbonic acid and carbonic acid esters have been rep~rted.’~ Classical trajectories for the four-centred elimination reaction of vinyl fluoride have been calculated at the HF/3-21G level of theory. At this modest level of theory, qualitative agreement is noted between calculated and experimental results.5s The RHF/6-3 1G**method with MP2 quantum chemical energy correction was used to calculate activation barriers for 1,l- and 1,2-eliminationsof HF from ethyl fluoride.s6 Calculations on the thermal elimination of RC(0)OON02, using the AM1 method, have been reported, where R = Me, CH2=CMe and Ph.57

Eliminations via Carbocations Theoretical studies, using the AM1 method, have been carried out for the acid-catalysed dehydration reactions of 15 arene dihydrodiols (43).’* The substituted o-phenol products are favoured both kinetically and thermodynamically, because the intermediate carbocation leading to these products can be stabilized by electron-donating, ringactivating substituents X. The electron-withdrawing substituents, PhSO and CF3, deactivate the ring, thus favouring formation of the corresponding m-phenols.

Elimination Reactions in Synthesis A study of stereoselectivity in the Wittig reaction of aromatic ketones (aryl 3-pyridyl ketones) (44) with carboxyphosphonium ylides has been rep~rted.’~ For the reactions of a variety of 3-substituted phenyl 3-pyridyl ketones, the (Z)-aryl-3-pyridylalkenoic acid (45) is favoured over the E-isomer by factors ranging from 1.5- to ca 4-fold. However, when the substituent at the 3- or 4-position on the phenyl ring is a (benzenesulfony1)amino group (NHS02Ph), the product is the (E)-alkenoic acid, formed (with one exception) in greater than 90% yield. Semiempirical calculations at the AM1 level of

3 54

Organic Reaction Mechanisms 1995 0 Bu'OK

(44)

b

'X

x (45) E and Z

theory suggest that the increase in stereoselectivity is a result of a hydrogen bond or salt bridge between the (benzenesulfony1)amino group and the carboxylate group that stabilizes a trans-oxaphosphetane intermediate. This intermediate then breaks down to give the (E)-alkenoic acid. This conclusion is also supported by experimental results which show 'normal' EIZ ratios (slight preference for the Z-isomer) when either the carboxyl group of the phosphonium ylide group, or the acidic hydrogen of the (benzenesulfony1)amino group of the aryl ketone, is removed and replaced with a methyl group. N,N-Disubstituted hydroxylamines (46) connected to vinyl groups by three or four carbon atoms yield pyrrolidine and piperidine-N-oxides by a concerted reverse-Cope elimination reaction." The reaction of (46), as shown, is an example of pyrrolidine ring formation. The reactions are reversible and proceed via stereospecific syn addition, consistent with a concerted mechanism (a reverse-Cope reaction). The results are not consistent with a free-radical mechanism. The scope and synthetic utility of this reaction is discussed. Phenyl[o-(trimethylsilyl)phenyl]iodonium triflate (47) and several derivatives have been prepared as precursors for benzyne. The compound (47) is a crystalline solid, and can be stored for extended periods.61Renzyne is generated by reacting the compound, dissolved in CH2C12, with Bu4NF dissolved in THE Reactions with a variety of dienes yield Diels-Alder adducts in high or quantitative yields.

OTf I

(46) a; R = CH2CH=CHPh

b; R = CH2CH=CHMe

c; R = CH2CH=CMe2 d; R = CH2C(Me)=CH2

I

1Me a; R ' = CH2Ph; R2 = H

b; R' = Et; R2 = H

c; R ' = i-Pr; R2 = H d; R' = R2 = Me

(47)


355

(R)-l-t-Butyl-4-ethylidenecyclohexane (48) ( z 98% of the desired isomer) has been synthesized from 4-t-butylcyclohexanecarboxylic acid via the optically active plactone.62 Decarboxylation of the Ij-lactone proceeds, as expected with retention of configuration.

Buf

0

Bur

(48)

A novel ring-opening reaction of tropone oxime tosylate (49), promoted by a variety of nucleophiles, results in the formation of substituted (352)-hexa- 1,3,5-trienecarbonitriles (50).63 This contrasts with previously studied nucleophilic and electrophilic reactions of troponoid compounds in which the ring skeleton is normally retained. Nucleophiles that promote this reaction include secondary amines, alkoxide ions, and Grignard reagents (methyl- and phenyl-magnesium bromides). PM3 calculations suggest that ring opening proceeds via formation of a tetrahedral intermediate (similar to a Meisenheimer complex) that results from nucleophilic attack at C(2). The intermediate is then suggested to break down via concerted C(l)-C(2) and N-0 bond cleavage. "OTs N nucleophile

H

(49)

H H

(501

H

Elimination reactions of methiodide derivatives (51) of isoxazolidines have been studied.64 The reactions are promoted by a 10% sodium hydroxide solution at reflux. The cis-isoxazolidines eliminate to yield tetrahydro- 1,3-oxazines (52) and a$-enones (53), whereas, the trans-derivatives (54) yield only a,P-enones. The mechanism of 1,3oxazine formation is suggested to involve abstraction of an N-methyl hydrogen yielding a 0-hydroxyiminium intermediate, which then undergoes cyclization with ring expansion. This reaction shows a product isotope effect of 2.5 when the hydrogens of one of the N-methyl groups are replaced with deuteriums. Formation of a$-enones is suggested to proceed via initial abstraction of a hydrogen a to the isoxazolidine oxygen. For the trans-isomer, enones are presumably formed because the antiperiplanar arrangement of the C-H and 0 - N bonds is stable. On the other hand, for the cisisomer, because of steric interactions between substituents on C(3) and C(5), the antiperiplanar arrangement becomes energetically unfavourable so that this mode of elimination is no longer favoured.


356

Quinoline-4(lH)-thiones (55) have been synthesized via pyrolysis of enamino-thioesters (56). The reaction presumably occurs via the formation of an imino-thioketene intermediate (57), formed via 1,4-elimination, which then undergoes c y ~ l i z a t i o n . ~ ~ Compound (58) reacts with SOC12 at -18 "C to give (59) via a Beckmann fragmentation reaction.66A possible mechanism involving a cyclic six-membered N - 0 sulfite intermediate is proposed. Ph

R'

6xR2 S

I

Q

41O-47O0C,

~

R'

XEt

R2

(56)

x=s,o R' = alkyl

(57)

S

&R2

I H (55)

R'


357

Other Eliminations The elimination of I2 from (60) yields (61), 3,7-dimethyltricyclo[3.3.0.03~7]oct-1 (5)ene, a highly strained, ‘pyramidalized’ alkene, that is identified by trapping, via DielsAlder cycloaddition with 1,3-diphenylisobenzofuran and 11,12-dimethylene-9,10dihydro-9,lo-ethan~anthracene.~~ r

-l

-

Diels-Alder adducts

fi-Lactones undergo two types of reactions when treated with anhydrous MgBr, in diethyl ether solution: ring enlargement and fi-elimination.68These competing pathways were investigated for the reactions of (62) and (63), and the related compound (64) in which a five-membered ring replaces the six-membered ring. For (62) and (64), R1 and Rz are H and methyl, H and isopropyl, or H and t-butyl. Both epimers were investigated. Compounds (62) and (64) undergo ring expansion: e.g. compound (62) forms (65). On the other hand, (63) undergoes p-elimination to give (66). A rule is proposed that pelimination will occur only if C(4) is tertiary and both C(5) positions are secondary. The C(4) position corresponds to the spiro-carbon in these systems. Interestingly, the regioselectivity of the elimination reaction is high: > 95% of the product is accounted for by (66). The high regioselectivity is rationalized in terms of a steric effect in which the carboxylate oxygen is complexed by MgBrz (after ring opening) and that this moiety is rotated away from the phenyl or alkyl substituent and toward the smaller hydrogen. This favours removal of the syn 5-hydrogen leading to (66).

5 ’ 1

(63)

4

R = Ph, t-Bu, Me, SPh


358

When 1-(2'-carboxytetrahalogenophenyl)-3,3-dimethytriazenes (67) are heated, tetrahalogenobenzynes are formed.69 The benzynes are apparently formed via a twostep process in which dimethyamine is first eliminated producing benzenediazonium-2carboxylates, which then break down to the benzynes via apparent synchronous loss of N2 and C02. The benzynes were trapped via Diels-Alder cycloaddition using 2,5dimethylfuran, p-xylene, m-dimethoxybenzene, and N-methylpyrrole. The reaction in the presence of N-methylpyrrole produces (68).

xGGN-N\ /

CHClZCHC12, heat

\ /

X

N-methylpyrrole

I

~

X X

C02H

(68)

(67)

X = C1, Br, H

The kinetics of the reaction of triphenylphosphoniocyclopentadienides (69) with tetrafluoro-p-benzoquinone (fluoranil) in methylene chloride solution have been rep~rted.~' Reaction proceeds with substitution by an addition-elimination mechanism, and yields both mono- and 2,6-di-substituted products (only the disubstituted product is isolated). For the reaction leading to both products, the rate is independent of added base (quinuclidine), and there is no isotope effect when the tetradeuteriated ylide is employed. The results are consistent with rate-limiting addition of the ylide. It is suggested that loss of HF from an intermediate a-adduct occurs via a concerted fourmembered transition state and is not base-catalysed. Carbon-13 kinetic isotope effects have been reported for the decarboxylation of oxalic acid in sulfuric and phosphoric acids7'

0

+ F

F 0

2,6-disubstituted product

I 2 Elimination Reactions

359

Ethane- 1,2-disulfonic anhydride and 2,2-dimethylisothiazolidinium-l, 1-dioxide fluorosulfate react with triethylamine via direct displacement at sulfur rather than by an elimination-addition mechanism via the ~ulfene.~' Compound (70) undergoes reaction by three parallel routes in basic solution: the main reactions are hydrolysis of each lactone group, and a p-elimination reaction to give (71); the latter reactions accounts for only 6% of the product, however. Rate and equilibrium constants and activation parameters are reported.73 Bu

0

Me

*

Me O

Y C02H B U

The reactions of triflamides (72) with alkyllithium reagents have been studied. Reaction can proceed via either p-elimination to give an imine and the triflinate ion (the imine is then subsequently alkylated via addition of the alkyllithium reagent), or by direct substitution of the CF3 group by the alkyllithium reagent.74Steric hindrance and substrate acidity are factors that determine the reaction mechanism.

Several alkyl- and aryl-substituted buta-l,2,3-trienes (74) have been ~ y n t h e s i z e dvia ~~ a tetrabutylammonium fluoride induced 1,4-elimination reaction of the corresponding acetate esters of silyl propynylic alcohols (73). Simple alkyl derivatives of (74) polymerize readily, whereas phenyl- or 1-butyl-substitutedderivatives may be stored in hexane solution at -30 "C for days.

(73)

(74)

E- and Z-isomers

Reaction of tris(trimethylsilyl)germyllithium-3THF with 2-adamantanone (75) in hexane at - 78 "C yields after work-up the I ,2-digermacyclobutane (76);76 (76) is

360

Organic Reaction Mechunisms 1995

presumably formed via the germene (759, which is suggested to be formed via a Peterson-type elimination reaction. This is the first reported example of a germene with silicon substituents on germanium; (76) is apparently also the first reported example of a 1,2-digermacyclobutane (1,3-digermacyclobutanes are known). Further evidence for the formation of (77) was provided by carrying out the reaction in the presence of buta1,3-diene, in which case the expected Diels-Alder reaction takes place.

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lo

” l3

l4

l6

17

‘*

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CHAPTER 13

Addition Reactions: Polar Addition PAVELKOCOVSKY Department of Chemisty, University of Leicestel; Leicester LEI 7RH, UK Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Additions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Halogenation and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions of ArSX, ArSeX, and Related Reactions . . . . . . . . . . . . . . . . . . . Additions of Hydrogen Halides and Other Acids . . . . . . . . . . . . . . . . . . . . Addition of Electrophilic Carbon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Electrophilic Nitrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions Initiated by Metals and Metal Ions as Electrophiles . . . . . . . . . . . . Hydroboration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Electrophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions to Multiple Bonds Conjugated with C=O . . . . . . . . . . . . . . . . . . Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups . . Additions of Organometallics to Activated Double Bonds . . . . . . . . . . . . . . . Miscellaneous Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

363 363 364 368 368 368 370 371 378 379 382 382 387 392 393 396

Reviews The main protagonists of the mechanism of alkene bromination have summarized their work in reviews focused on new mechanistic insight into the electrophilic bromination of alkenes,’ fates of bromonium ions in solution with regard to the short lifetime and competing reaction pathways; and stereo-, regio-, and chemo-selectivity of bromination of ethylenic compound^.^ Other reviews published during the coverage period of this chapter, include the stepwise electrophilic additions with novel synthetic ramifications of an old ~ o n c e p t electrophilic ,~ cleavage of bicyclo[ 1.1 .O]butanes,’ the utilization of tin(I1) enolates in Michael and related reactions,6 control of asymmetry through conjugate addition^,^ and the regiochemistry of nucleophilic additions to C60.8

Electrophilic Additions The remote substituent effect on the electrophilic additions to 1,3-dienes has been studied with the aid of model compounds such as (1)9 Organic Reaction Mechanisms 1995 Edited by A C Knipe and W E Watts fu 1997 John Wiley & Sons Ltd

363


3 64

n

X

Halogenation and Related Reactions The stereochemistry of electrophilic additions (Br2, NCS, or NBS) to methylenecyclohexanes (2) to give products (4) has been shown to be consistent with the Cieplak model, involving axial attack by the electrophile, (2) -+ (3). The corresponding epoxidation is less stereoselective, presumably owing to the more crowded transition state, which renders the axial approach more difficult.l o

A full account on the large inverse deuterium kinetic isotope effect (IDKIE), observed for the electrophilic bromination of 7-norbornylidene-6'-norbornane (5), has now appeared.' The reaction kinetics and product distribution in the bromination of (5a) and its perdeuteriated analogue (5b) were studied in AcOH and MeOH as a function of added Br-. In all cases a significant IDKIE on the rate constant of bromination has been observed. Thus, in AcOH, the IDKIE effect (kD/kH) is 1.56 and 1.83 at [Br-] = 0 and 0.040 M, respectively. Apparently, added Br- causes a significant retardation, indicating the intervention of a reversibly formed bromoniumion intermediate. Four kinds of products have been isolated, namely the normal dibromide (7) and the P-bromo solvate (8), and two others, namely (11) and (13), that originate from capture of the a-bromo cation (10) arising via a Wagner-Meenvein rearrangement of the originally formed bromonium ion (6). In AcOH, adding Brresults in increasing the amount of the normal dibromide (7) at the expense of the solvent-intercepted and rearranged products. By contrast, in MeOH the dibromide (7) is never an important product at any [Br-] investigated, the two major isolated products being the normal methoxy bromide (8) and the rearranged ketone (13). Little isotope effect has been observed on the product distribution. Further evidence for the Brf transfer from the bromonium ion of adamantylideneadamantane to reactive alkenes (e.g. cyclohexene, w-alken- 1-ols, and pent-4-enoic acid) has been accumulated.l 3 Bromination of alkenes (e.g. ally1 alcohols, but-2-enone, etc.) and akynes (e.g. PhCECH) with bis(dimethy1acetamide) hydrogen bromide, i.e., [AcNMe2. . . H+ . . .

',"

13 Addition Reactions: Polar Addition

365

(5) a;L=H b;L=D

H20

work-up

0


366

AcNMez]Br3, afforded the corresponding dibromides [e.g. BrCH2CH(Br)CHz0H, BrCH2CH(Br)COMe, and cis- and trans-PhC(Br)=CHBr, respectively] in good yields. Cyclohexene gave stereoselectively the trans-dibromide (77%).l4 The reactions of PhCH=CHCHzOH with NBS in 50% aqueous Bu'OH at 35 "C, giving PhCH(OH)CH(Br)CH,OH, exhibits a large positive dielectric effect and follows the rate equation dmBS]ldt= (2.2 x 10V2[alkene] 2.7 x 10-6/[H'])~BS].'5 Bromination of exo-ethylenic acetals, such as (14), has been reported to yield either the cis- or the trans-dibrominated derivatives. When R = alkyl, the cis-isomer is obtained and can be isomerized to the trans-product. By contrast, aryl-substituted acetals (R = aryl) afford the trans-isomer, except when there is an electron-withdrawing group on the aryI.l6

+

Kinetic and spectral studies of iodofluorination of CFz=CFz, CF3CF=CFz, and CF30CF=CF2 by the Iz-IF5SbF3 system revealed that the reaction is initiated by the 1: attacking the double bond. l 7 A study of the iodofluorination of the lactams (15) and (16) revealed an interesting dependence on the N-protective group. Thus, the BOC-protected lactam (15) is iodofluorinated to give mainly (17), whereas its henzyl-protected counterpart (16) favours the formation of the rearranged product (18). This behaviour has been attributed to the different nucleophilicities of the nitrogen atoms in (15) and (16).18

0

R=BOC

F

0

0

(15) R = BOC (16) R = PhCH2

Tetrahydrodianthracene (19) has been reported to react with halogens to give transannular (20) and ring-opened (21) products, the ratio being remarkably dependent on the solvent. Thus, transannular addition is favoured in solvent of medium polarity, whereas preferential ring opening has been observed both with increasing and decreasing polarity. For instance, Clz in toluene gives ca 100% of (21), in CH2CI256%


367

of (20), and in CF3CH20H again ca 100% (21). The authors suggested three different mechanisms to rationalize these findings. l 9

The mechanism of iodolactonization of CH2=CHCH2CH(C02Et)2 and CH2=CHCH2C(Me)(C02Et)PO(OEt)2 has been formulated. Large amounts of iodine and higher reaction temperatures led to increased yields.20 The hydroxy bromination of HCsCCH20H with NBS in aqueous acidic medium has been found to be first order with respect to NBS, propargyl alcohol, and Ht, and inverse first order with respect to succinimide. The kinetic results point to solvated bromonium ion as the reactive species.21 The iodination of a-allenic alcohols (22) has been found to proceed via a radical-type isomerization of the initially formed mixture (ca 1 : 1) of E and Z-isomers, affording predominantly the Z-product (23).22

Bromination of ArCH=CHCsCCH=CHAr' in Et20 or AcOH in the LiBr gave a mixture of four types of products corresponding to (dibromocumulenes), addition to the triple bond (dibromostilbenes), (dibromoallene), and tetrabrominated derivatives. The electronic effects position have some control over the reaction outcome.23

presence of 1,6-addition 1,Caddition in the para

368


Additions of ArSX, ArSeX, and Related Reactions N-Phenylthiophthalimide and N-phenylselenophthalimide, combined with pyridine.9HF or Et3N.3HF complexes, allow the formal addition of PhSF or PhSeF, respectively, across C=C or C=C bonds. A strongly acidic reagent, such as pyridine.9HF, is required to polarize the C-N bond sufficiently to allow the reaction to occur. On the other hand, selenium adducts can also be obtained in good yields using the less acidic Et3N.3HF (avoiding, e.g., acetal cleavage or isomerization). The addition to propargylic alcohols is entirely regioselective. Steroidal alkenes, such as (24), proved to afford mainly diequatorial products (27) and (28) owing to the thermodynamically driven equatorial cleavage of the intermediate sulfonium ions (25) and (26) (note that the usual axial cleavage is rever~ible!).’~

\I

PhS+

(26)

J

Additions of Hydrogen Halides and Other Acids The FeC13-catalysed hydrochlorination of vinylidene chloride is characterized by the induction period, which appears to be due to the formation of the inactive anionic complex of the catalyst with HCl in the presence of small amounts of water. A decrease in water content results in an increase in the concentration of the catalytically active forms of FeC13 and, finally, in the auto-acceleration of the hydrochlorinati~n.~~ The kinetics of the addition of arenesulfinic acids to 4-substituted 2-nitroethenylarenes have been studied by means of UV spectrophotometry. The effects of para substituents in benzenesulfinic acids and the change in the reactivity of the nitroethylene system (due to electron-withdrawing groups) have been assessed. The substituent effect fits Hammett’s equation, the p-value being - 1.12 (at 298 K).26

Addition of Electrophilic Carbon The reaction of electron-rich alkenes, such as vinyl ether (29a) and vinyl sulfide (29b), with (CF&0)20 in cc14, CHC13, or CHZC12 has been elucl ‘ated by NMR


369

spectroscopy. The initial formation of the addition products (30) has been found to occur via a stepwise mechanism. The latter intermediates then undergo a self-catalysed Ei, E2, or E l reaction, depending on the stability of the intermediates to give the products (32a) and (32b), respectively.

i29)

a;Z=0 b;Z=S

(32) a;Z=0 b;Z=S

o-Phenylenediamine (33) has been reported to afford via intermediate (34) two types of products on reaction with aqueous formaldehyde and cyclopentadiene in THFMeCN, namely (35) and a mixture of (36) and (37); the latter two predominate if an excess of CH20 is employed.**

A Homophthalic anhydride (38) has been reported to afford cyclo-condensation products (40) on reaction with I-aza-l,3-dienes (39).29

370

Organic Reaction Mechanism I995

The kinetic studies of the polymerization of Pr'OCH=CH2 and ClCH2CH20CH=CH2, initiated by HI in CH2C12 in the presence and absence of Bu4N+I- as common anion salt, revealed that the reaction proceeds directly through the carbon-iodide termini without any necessary electrophilic activator. In accord with the previous observations, it has now been found that the addition of small amounts of the salt (0.5-10% with respect to the initial [HI], depending on the monomer) dramatically reduces the polymerization rate and leads to living-type polymerizations. Higher amounts of the salt have no W h e r influence. This general behaviour, observed for all the vinyl ethers studied, suggests a common-ion salt effect and, therefore, an ionic polymerization mechanism involving ion pairs and free ions. In the absence of the salt, both ion pairs and free ions of higher reactivity participate in the propagation, whereas only the ion pairs contribute to the propagation in the presence of a commonion salt. According to this scheme, the living character of the polymerization can be assumed to result from a propagation reaction governed by non-dissociated ionic species.30 Addition of Electrophilic Nitrogen (PTAD) (41) and MeOH to cis- and The addition of 4-phenyl-l,2,4-triazoline-3,5-dione trans-but-2-ene, 1-methylcyclopentene, and (@-2-methylbut-2-ene-1,1,1-d3 gives pure anti-addition adducts, e.g., (42). On the other hand, partial loss of stereochemical integrity was observed with substituted inde ne ~.~Aziridinium ' intermediate (43) has been directly observed by NMR spectroscopy on reaction of (41) and transcyclooctene. *

Ph

N=N

MeOH

0

4 NH N/

OMe

Aziridination of allylic alcohols with 3-acetoxyaminoquinazolinones,such as (44), is known to occur with similar (if not better) stereoselectivity than the corresponding

I3 Addition Reactions: Polar Addition

371

A transition state (46) for the aziridination of epoxidation with peroxy electron-rich allylic alcohols, e.g. (45), has now been proposed.35

I

products

Pyridinium imides (47), as well as 3-acetoxyaminoquinazolinones (44) from which they can be prepared, have been reported to aziridinate alkenes as diverse as styrene and diethyl f i ~ m a r a t eSimilarly, .~~ the corresponding triethylamine imide gives aziridines on reaction at - 30 "C. The reactivity of the aziridinating intermediate is consistent with its formulation as an azaimide ( N - ~ ~ i t r e n e ) . ~ ~ The cyclic 8-dicarbonyl compounds (48) and silyl enol ethers (50) undergo aziridination with (44) to produce the corresponding cc-(oxoquinazoliny1)amino ketone derivatives (49) and

Additions Initiated by Metals and Metal Ions as Electrophiles The mechanism of the ruthenium-catalysed rearrangement of acyclic alkenes, e.g. (52) -+ (53), has been studied with the aid of a model system consisting of 3phenylpropene-3,3-d2 (52) and [Ru(H~O)~]+ in different solvents. The latter reaction turned out to yield stereospecifically trans-phenylpropene with deuterium content on all carbon atoms of the propyl chain (53)-(57). A kinetic isotope effect kHlku=2.3 has been observed (compared with the reaction of the non-deuteriated 3-phenylpropene). A competition experiment revealed an intermolecular deuterium transfer. The results are

372

Organic Reaction Mechanisms 1995 0

0

OSiMeq

0

consistent with a stereospecific syn-l,2-addition~elimination of an intermediate metal hydride, arising predominantly from attack of the metal on position 2 (58).39

phDq -MD

Ph

-MH

(52)

& ’,

Ph

I . +MD 2.-MDw

Ph

M

(53)

Ph (54)

(52)

1. +MD 2. -MD

D (56) 1. +MH 2. -MD

(55)


373

The deuterioformylation (2H, CO) of hex-1-ene, catalysed by rhodium coordinated to chelating diphosphines, has been elucidated in order to shed more light on the mechanism. The reaction gives rise, nearly exclusively, to a mixture of regioisomeric aldehydes Me(CH2)$HDCH2CD=0 and Me(CH2)3CH(CD=O)CH2D,with deuterium label at the B-carbon and at the carbonyl carbon. Very little deuterium was incorporated into the recovered hexene. These results established that the regiochemistry of aldehyde formation is dictated by an essentially irreversible addition of a rhodium hydride to coordinated hex-1-ene to produce an alkylrhodium intermediate that is committed to aldehyde f~rmation.~' Increased a-selectivity of the Rh(1)-catalysed hydroformylation of methyl acrylate in favour of (59) rather than (60) has been attained by adding bis(dipheny1phosphino)butane (dppb) as the ligand.41

Formation of an inclusion complex of dec-1-ene with cyclodextrin has been proposed to account for the remarkably regioselective hydroformylation (61) -+ (62).42 In addition to the well established MOP (63), a new monodentate ligand (64) has been introduced into hydrosilylation chemistry and shown to effect high asymmetric induction in the Pd-catalysed hydrosilylation of substituted styrenes (65) -+ (66) with 89-96% ee.43

Cyclohexene

(63) X = OMe (MOP) (S) (64) X = H (H-MOP) ( R )

The Pd-catalysed cyclization of aryl iodides on to a proximal allene moiety (67)has been reported to occur at the central atom of the allene system, generating the 71-ally1


374

intermediate (68). The latter species can then be attacked by secondary mines such as (69); the regioselectivity of this process is sensitive to added inorganic base, steric effects, and the nature of the adjacent h e t e r ~ a t o m . ~ ~

+AMe

0

0

(68)

QNMe 0

0

Studies on alkene epoxidation, catalysed by ruthenium(T1I) Schiff bases, have demonstrated the superiority of bidentate ligands. When camed out in the presence of surfactants (e.g. Triton X- loo), the reaction is believed to occur via carbocationic

intermediate^.^^

A comparison of the course of catalytic osmylation of steroidal alkenes in the presence and absence of a complexing amine showed that, in the absence of the amine (Et,N), the reaction is significantly slower and gives substantial amounts of allylic byproducts (Scheme 1). The results were interpreted in terms of a stepwise, non-concerted Sharpless mechanism. The co-oxidant may determine the formation of some products; thus, interaction of the osmate ester with But-OOH in the absence of the complexing amine leads to the formation of an a-hydroxy ketone (Scheme Z).46 A highly enantioselective catalytic dihydroxylation of p-methoxyphenyl ethers of homoallylic alcohols, such as tvans-RCH=CHCH*CH*OC6H4oMe, has been reported.47 Farnesyl acetate (70) has been dihydroxylated with 120 : 1 positional selectivity, using the mechanistically designed bis-cinchona alkaloid ligand (71),

375

I3 Addition Reactions: Polar Addition 0,

-c-c=c HI O T

+o

0€4

/

;

1 1 '

3

c-c-

I

/ ib

products

,o [ \'o

bo=os'

I

J

SCHEME 1

/O 0sO>'O H-C-C- I O,\

r'

I 1

pOBut

-

OH

SCHEME 2

instead of the common PHAL; the usual M e 0 group in the alkaloid moiety (Q) was replaced with the bulkier Pr2CH0 group.48 Catalytic, regio- and stereo-selective nickel(0)-catalysed addition of Grignard reagents to allylic ethers can now be achieved (Scheme 3), provided that a Lewisbasic, coordinating group is present in the substrate molecule (72). In the absence of such a group, no reaction occurs. The reaction proceeds catalytically in the presence of (Ph3P)NiC12, presumably via the corresponding q3-comp1ex (73). The bidentate complexes, such as (dppe)NiC12, are ineffective, apparently owing to their lower dissociation ability, which precludes the crucial coordination to the pendant phosphine in (72).49


376

J Pent,.,

MeMgCl

Me

H

\

-Ni(O)

Me

I

Me

i

PentPPhz (74) SCHEME 3

A study of the regio- and enantio-selectivities of the organolanthanide-catalysed alkene hydrosilylation revealed that, e.g. for a-alkenes, the turnover and the 2,lregioselectivity can be enhanced by openness of the metal ligation sphere and increasing the Ln3+ radius. For substituted styrenes, complete 2,l -regioselectivity (i.e. Si delivery to the benzylic position), rate enhancement by a para-electron-donating substituent, and turnover fiequencies as high as 400 h-' (at 60 "C) have been observed. For hex-1-ene, 2,l -addition regioselectivities are as high as 76% and turnover frequencies > 1000 hFor 2-phenylbut-l-ene, (R)-Me2SiCp[(- )-menthyl-

'.

377


c~lSrnCH(SiMe~)~ and (S)-Me,SiCp[( - )-menthylCp]SmCH(SiMe3)2 have been shown to effect hydrosilylation with 68% and 65% ee, respectively (at 25 “C). The The mechanism has former reaction obeys the rate law v = k[Sm]1[alkene]o[PhSiH3]1. been discussed in terms of a hydride-alkyl cycle involving rapid, exothermic alkene insertion into an Ln-H bond followed by turnover-limiting Si-HLn-alkyl transposition (delivery of the alkyl group to Si).” The trans-hydrostannylation of alkynes (Scheme 4) can now be effected in the presence of Lewis acids (ZrC14 or H~Q).~‘ RC3CH Bu3SnH

+

-&

ZrC14

,C1, BU~S~’,: , ~ r ~ 1 3 H’

Bu3SnH

H

H

SCHEME 4

Elucidation of the mechanism of titanocene dichloride-catalysed hydromagnesation of alkynes with alkyl Grignard reagents confirmed the individual steps as illustrated in Scheme 5.52

I

2Pr’MgCI

R

H

Cp2TiH PriMgCl

RCrCR H

TiCp2

SCHEME 5

The kinetics and mechanism of the oxidative chlorination of acetylene in solution of CuCl and CuC12 have been reported; optimum conditions for the formation of CH2=CC12 have been identified.53


318

Several ruthenium complexes, such as (PhOMe)(Ph3P)RuC12, (p-cymene)(Ph3P)RuC12, @-cymene)(Bu3P)RuC12,and CpRu(COD)Cl, have been shown to catalyse the ene addition of unactivated alkenes to unactivated alkynes, the latter complex exhibiting the highest conversions and regioselectivities. Monosubstituted alkenes are required while both terminal and internal alkynes react. A mechanism involving the formation of a ruthenacyclopentene has been proposed.54 Rhodium-catalysed, intramolecular silylformylation of an acetylenic bond has been found to be dominated by the exo-dig ring closure: (75) -+(76)”

(75) n=1,2

Hydroboration Facial selectivity in the hydroboration of allylic alcohols has been studied with the aid of steroidal model compounds (77) and (78). The hydroxyl group apparently tends to direct the reaction to occur from the anti-face. Thus, the 3b-hydroxyalkene (77) gives the 4a-alcohol (79), whereas the 3a-epimer (78) favours the formation of the 4P-isomer


379

The reaction of B3H7 with acetylene has been studied theoretically, with geometries computed at the MP2/6-31G(d) level and relative energies estimated at the [MP4/63 11 G(d,p)] level. The initial reaction of B3H7 C2H2 has been found to give an addition product with little or no barrier. Loss of H2 leads first to cyclic C2B3H7 carboranes and then, through two methyleneborane intermediates, to the known nidoC2B3H7.Two pathways have been identified for the loss of H2 from the latter species, one synchronous and the other asynchronous, to the final product 1,2-C2B3H5.57

+

+

Miscellaneous Electrophilic Additions Benzothiazole (81) adds to aliphatic, open-chain and cyclic alkenes at 80 "C under p TsOH catalysis. Terminal alkenes give Markovnikov products. If a large excess of acid is used alkenes have been found to isomerize partly prior to the reaction so that mixtures of products are ~btained.~'

RL?3 ,0SiMe3 027

380


The product analysis in the reaction of a,P-unsaturated esters with NO$F; at - 16 "C suggests the intermediacy of highly reactive ci-carbonyl cation^.'^ Sulfonation of allylsilanes such as (82) with SO3 at -60 to 25 "C in CH2C12(with a 1.5 molar excess of dg-dioxane over SO3) has given various adducts, which can rearrange to more stable compounds (83) or (S4).60 The Richter reaction (85) -+ (87) has been revisited and the mechanism refined. The elucidation of the reaction course has led to the interception of the intermediate halide (86) that can now be obtained in a preparative procedure.6'

Acid-catalysed cyclopropane ring opening in (88) with methanol has been found to occur via both 'corner' and 'edge' protonation.62By contrast, bromination of the exoand endo-isomers (88) and (89) turned out to be initiated at the double bond; both isomers are preferentially attacked from the exo-face of the C=C bond. The stationary points on the potential-energy surface that result from the bromine addition have been identified by semiempirical methods. The non-classical bromonium ions appear to be less stable than the classical structure^.^^ Mercury(I1)-mediated cleavage of cyclopropane ring in (90) has been revisited and shown to be highly regioselective in the case of n = 1 or 2 and less regioselective for n = 0. In all three cases, the main product arises via the cleavage between the least- and the most-substituted carbon of the three-membered ring; the nucleophile enters preferentially at the carbon more distant from the electron-withdrawing OH group (in consonance with the cleavage of analogous epoxy alcohols). The reaction reflects the variation in nucleophilicity. Thus, if carried out in methanol with (CF3C02)*Hg,the product obtained is the methoxy derivative (91; R=Me), reflecting the poor nucleophilicity of the CF3CO; ion. With other mercury salts, such as Hg(NO3)2 or ( A C O ) ~ Hthe ~ , corresponding nitrate (91; R =NO2) or acetate (91; R = Ac) are obtained, re~pectively.~~


381

It X = Br (1 1 %) X = OMe (29%)

+

X = Br (1 1%) X = OMe (49%)

X X = Br (4%) X = OMe (37%)

X = Br (17%) X = OMe (31%)


382 Nucleophilic Additions

Additions to Multiple Bonds Conjugated with C=O The cation (Kf or Naf) in 2,6-di-t-pentylphenolates(ArOK or ArONa) has been found to affect the kinetics of their Michael addition to CH2=CHC02Me. It has been suggested that this effect is associated with the ability of ArONa to replace the cation with H+ originating from the product.65 The intramolecular Michael addition of sulfur anion generated from (92) has been reported66to give preferentially the cis-substituted heterocycle (93) in accordance with the Cieplak (9 : 1 to 1 : 1);66the Felkin-Ahn-t~pe~~ product (94) is formed in minute amounts.66By contrast, the analogous 0-nucleophile, published p r e v i o ~ s l y , ~ ~ ~ ~ ' prefers the Felkin-Ahn model. The difference has been rationalized in terms of differences in orbital stabilization.66Unfortunately, there are several serious errors in the original paper66 so that it is difficult to read.

c-'

H C02Me

He C O i M e I

Cieplak model

(93)

SAC

(92)

R = Bu'MeZSi or Me

H Felkin-Anh model

(94)

As expected, the reaction of trans-chalcone PhCH=CHCOMe with primary amines RNH2 (R = Pr, Bu, C6H13) in heptane or benzene has been found to exhibit a decrease in the reaction rate constant with increased solvent basicity (due to the solvation of ammonium ions).72A similar effect has been observed for the addition of piperidine to benzylidenemalonic ester (i.e. the final step in the Knoevenagel c~ ndensation). ~ ~ The kinetics of the reaction of I , I , I -trichloro-4-methoxypent-3-en-2-one (95) with various aliphatic and aromatic amines at 25 "C in H20, Me2S0, EtOH, CHC13, toluene, or hexane have resulted in the formulation of an addition mechanism. The preferential 2-geometry of the product (96) is dictated by an intramolecular hydrogen bonding.74


383

A study of diastereocontrol in the Lewis acid-catalysed Michael reactions of 4siloxycyclopentenone (97) with ketene silyl acetals (98) has demonstrated a competition between the stereoelectronic and steric effects. Thus, the sterically disfavoured syn preference (to the d o x y group) has been observed for the acetals with small steric demands (99), whereas sterically bulky acetals give rise to the reversal of diastereoselection

b

TBSO

(97)

Rx0siR3 \ 2’

TBSO‘

+

R

G,

‘’

--CO*R’

(99)

OR’

A

R=Me

(98)

Michael-type additions of 2-methyl(benzylimino)cyclohexane, reacting as its secondary enamine tautomer (101), to methyl methacrylate, methyl crotonate, and maleic anhydride has been found to proceed with excellent diastereoselectivity, which apparently originates from the chair-like transition state.76

w

Me H

P m / C02R

-MeOH

0

I

-Ph

Dilithiated P,y-unsaturated secondary amides (102) undergo diastereoselective

( 5 95 : 5) conjugate addition to cyclopentenone; the stereoselectivity has been

rationalized via the transition state (103).77 MNDO and PM3 calculations indicate that the lithium (2)-enolates, derived from Nalkylideneglycinates (104), react with a,,&unsaturated esters through a stepwise mechanism, including the initial anti-selective formation of Michael adducts. The second step consists of the stereoselective ring formation or a 1,3-dipolar addition. The energy difference between individual transition states reflects the steric hindrance


384

caused by the alkylidene moiety: bulky alkylidene substituents prefer the formation of Michael adducts, whereas the small substituents favour 1,3-dipolar adducts. The high anti-selectivity observed in the first step has been attributed to the attractive MO interaction between the imine moiety of the donor molecule and the C, of the acceptor.78

R4NnC02Me

(104)

+

Me

-CIO,Me

base

MeOZC,

CfMe "'T02Me

H

The Michael-type addition of heteroaromatics, such as furans (105), indoles, and thiophenes to a,S-unsaturated ketones (including methyl vinyl ketone) can now be carried out in the presence of BF3.Etz0.79

R = H (79%) R = Me (80%)

Mono- and 2,6-di-substituted quinones (108) and (109) have been obtained from the reaction of the tetrahalo-p-benzoquinones (106) and triphenylphosphoniocyclopentadienide (107) as a result of two parallel, irreversible second-order reactions, which are well separated in time. The rate of formation of the monosubstituted product was determined using the stopped-flow technique and its half-life was found to be in the millisecond range. Kinetic data for the mono- and di-substitution products indicate that both reactions proceed in two steps involving rate-limiting addition to form a polar betaine intermediate followed by El elimination of hydrogen halide.80 Mere eight-fold acceleration has been demonstrated for the conjugate addition of pyrrolidine to a,B-unsaturated lactones in the presence of the catalytic amounts (0.1 equiv.) of the guanidinium salt. The effect has been attributed to selective hydrogen bonding (110).81 The first antibody-catalysed Michael addition of CN- to a,S-unsaturated ketones has been reported.*'


385

Whereas the reaction of the vinyl chloride (111) with ethyl a-thioacetate gives the expected product of vinylic substitution (112) that can be isolated, further treatment with a strong base (e.g. NaH) triggers an intramolecular Michael addition to give, eventually, (113).83 An interesting Michael-type macrocyclization of (1 14) has been successfully executed with the cis-isomer; the corresponding trans-isomer, as well as the analogous acetylene derivative, proved to prefer an intermolecular reaction.84 Michael addition of DBU to dimethyl acetylenedicarboxylate, followed by intramolecular condensation of the adduct, afforded the tricyclic derivative (1 15)? Polyfluoroalk-2-ynoic acids (116; R = CHF2, CF3, or CHF2CF&F2) readily undergo an intermolecular Michael addition, followed by a Michael-type cyclization, with a variety of bifunctional nucleophiles, such as (117; X = NH, NMe; Y = NH, S, 0, NMe) or o-phenylenediamine, to give the corresponding imidazolidine, thiazolidine, and oxazolidine derivatives (118) in moderate to good yields.86


386

7yF35F3 -

It

f-

Ph

C02Et

I

MeOzC-COzMe

Ph

Ph

C02Et

S-

C02Et

5

387


Rf-CGC-CO2H

(116)

+

-

HX WYH (117)

RfXCH2c02H xuy (118)

Rf = CHF2, CF3, CHF2CF2CF2

x, Y = s, 0

Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups

The AdN-E and sN2-V mechanisms in bimolecular nucleophilic substitution at vinyl carbon (Scheme 6 ) have been assessed, in particular with regard to the relevance of the LUMO symmetry of the electrophile (Figure 1). To this end, the lowest vacant orbitals of a series of vinylic compounds with substituents of different electron-withdrawing power (X = RSH+, Ph+, C1, TfO, F, MeI+, MeCl+, etc.) have been computed at the 321G*//3-21G*, 6-31G1;//3-21G*, or 6 3 1 1Gt//3-21G* levels (Figure 2). In substitutions where the first vacant orbitals with (T- and n-symmetry at the carbon atoms are separated by >0.01 hartree, an almost complete correspondence has been found between the symmetry of the lowest orbital (LUMO) and the stereochemical outcome of nucleophilic substitution on the corresponding substrates. This finding is in accord with the assumption that the interaction of the approaching nucleophile with the orbital of TCsymmetry directs the attack orthogonally to the molecular plane (AdN--!?mechanism, leading either to retention or inversion of configuration (Scheme 7; route a), while interaction with the a-symmetrical orbital dictates the attack in the molecular plane (SN2-Vmechanism, leading to inversion of configuration; route b). The situations where this correlation fails are related to substrates where either the energy gap is smaller or for which other mechanisms (non-concerted or steered by pre-coordination) have been proposed; route c.~? The silyl enol ethers derived from cyclohexanone and cyclopentanone (119) undergo a 1,4-addition to p-nitro- and P,P-dicyano-styrenes (120) (but not to a,fl-unsaturated carbonyl compounds) in 5 M LiC104-Et20 at room temperature to afford the corresponding Michael adducts (121) in good yields and with moderate stereo-

SCHEME 6


388

Nu

SCHEME 7

FIGURE 1

selectivity (1.3 : 1 to 3.5 : 1). The experimental evidence has suggested the involvement of transfer of the silyl group to the Michael acceptor.88Similar Michael additions of pketo sulfoxides and P-keto sulfones (122) have also been reported.89

b

OSiMe3

+

Y

EtzO, r.t.

13 Addition Reactions: Polar Addition Nucleophile

Transition state

3 89 Electrophile

FIGURE 2. Orbital correlation diagram in nucleophilic substitutions. Reprinted with permission from Lucchini, V., Modena, G., and Pasquato, L., J. Am. Chem. Soc., 117,2297 (1995). Copyright (1995) American Chemical Society.

Rate constants for the elementary steps in the addition-elimination of nucleophilic vinylic substitutions (SNV)have been determined by studying the reactions of stilbenes (124) and (125) with HO-, CF3CH20-, piperidine, and HOCH2CH2S- in Me2SOH20 (1 : 1) at 20 "C. In the reaction of (124) with HO- and piperidine, and also in the reaction of (125) with HO-, piperidine, and HOCH2CH2S-, the SNV intermediate, whose formation is the rate-limiting step, does not accumulate to detectable levels. By contrast, in the reaction of (124) with HOCH2CH2S-, the intermediate (126) was directly observable, which allowed a kinetic determination of all steps involved in the reaction. The structure dependence of the various rate constants has been rationalized in terms of an interplay of electronic, steric, resonance, and anomeric effects. The observed dependence of the rates of the departure of the alkoxide ion (MeO- vs CF3CH20-) from the intermediates on the pK, of the respective alkoxide ion suggests a large amount of C-0 bond cleavage in the transition state."

"'HX Y

Ph

(124) X = NO*, Y = CF3CHzO (125) X = Y = NO2

Ph

I

I

,Ph

CF~CU~O-C-C+

N02SCHzCH20H

(126)


390

Another kinetic and spectroscopic study, namely that of the reactions of NHzOMe and MeNHOMe with /3-methoxy-a-nitrostilbene(127) in MeS02-H20 (1 : l), has also led to the direct observation of the intermediate in nucleophilic vinylic substitution. Thus, with MeNHOMe, the reaction of the latter stilbene gave rise to the expected enamine substitution product (128). With NH20Me, the product at high pH is the anion (129), while at low pH it is the imine form (130) rather than the enamine. On the other hand, at high pH and high amine concentrations, the concentrations of the S N V intermediates (131; R = H or Me) rise to detectable levels, which allowed their spectroscopic and kinetic characterizations. These reactions represent the first examples of a nucleophilic vinylic substitution by amine nucleophile in which the intermediate is directly observable. The structure-reactivity comparisons between the MeNHOMe reaction and the reaction of (127) with piperidine and morpholine, reported previously, are consistent with a relatively weak dependence of the nucleophilic addition step ( k l ) on the amine basicity (Pnuc= 0.25) but a strong dependence of the leaving-group expulsion step (k2) on the amine pK, (ppush = 0.71). This explains why the intermediate is observable in the reaction with the relatively weakly basic NH20Me and MeNHOMe but not with more strongly basic amines. Steric effects appear to play a major role in the MeNHOMe reaction. One type of steric effect has been attributed to crowding in the intermediate, which reduces the rate and equilibrium constants for intermediate formation and enhances leaving-group departure. The other type is steric hindrance to n-overlap in the product and the preceding transition state, which reduces the push by the nitrogen lone pair of the intermediate and hence decreases k2 for leaving-group expulsion; the latter effect seems to be stronger than the former.”

MeNHOMe

Me0

Ph

Ph MeNOMe (128)

NH20Me

Ph

NO2

phHNo2hcH:

MeON

Ph

MeON

Ph

Ph I MeO-C-C,

p 0 2 -

I

dOMe

ph

(131)

The reaction of aqueous acids with the product of addition of CF3CH20- to (124), i.e. (132), has been found to lead almost exclusively to the corresponding acetal (134) by carbon protonation. By contrast, the CH30- adduct (133), arising from (127), leads almost exclusively to the recovery of (1 27) by acid-catalysed expulsion of MeO-.92 The addition of arenesulfinic acid to 4-(2-nitroethenyl)toluene, giving aryl 2-nitro-1(p-tolylethyl)sulfones, has been shown to be an overall second-order process. The rate-

I3 Addition Reactions: Polar Addition

(124)

CF3CH20-

Ph

39 1

I

+NO1

H30+

I

Ph

(R=CF&Hz)

RO-C-C, RO

Ph

I

CF~CHZO-C-CH,

I

CF3CH20

,Ph NO2

MeO-

(132) R = CF3CH2 (133) R = M e

(127)

determining step is the addition of the sulfinate anion to the olefinic double bond of 4(2-nitroethenyl)tol~ene.~~ The addition of PhCH2NHMe (MBA) to styrene (St), catalysed by PhCHzN(Li)Me (LMBA), has been found to follow kinetics expressed by the equation v = l@t][LMBA]o.5[MBA]; the calculated activation entropy is - 1.7 x lo2 J K mol-'. The mechanism has been shown to be different from that for the Et2NH addition (catalysed by Et2NLi). Dimer formation of LMBA and strong solvation of the activated complex have also been d e m ~ n s t r a t e d . ~ ~ Addition of the lithium enolate of dioxanone (135) to (a-P-bromovinyl sulfone has been reported to give the corresponding product of vinylic substitution (136) with high stereoselectivity. On the other hand, addition to the Z-isomer proved to be poorly stereoselective, producing a 1.6 : 1 mixture of (137) and (138), respectively. Nevertheless, in both cases the geometry of the double bond was hlly preserved. Reactions of the corresponding (tJ-P-bromoacrylate follow the same pattern.95

1. LHMDS THF, -78 "C 2' BrdfiS02Ph

0

I.

e

S02Ph


392

Conjugate addition of nucleophiles to the nitroalkene (139) followed by in situ ozonolysis, results in the formation of a-substituted thioesters (141), having in most cases the 'unexpected' syn relative configuration, which is in sharp contrast to the addition to cQ-unsaturated esters.96

Stereoselective, intramolecular carbolithiation of vinyl sulfides, such as (142), has been reported.97

P Meh

G

R Sph

~

I . BuLi, THF

phM

2. MeOH

Me Me

SPh

Additions of Organometallics to Activated Double Bonds Competition between 1,2- and 1,4-addition, an evergreen in organometallic chemistry, has been investigated with the aid of model compounds for which the latter reaction is disfavoured by severe steric hindrance, e.g. with wootkatone (143) and other enones. The best 1,2- to 1,4-ratio in favour of the latter (up to 1 :4.5) has been found for Me3Al in the presence of a catalytic amount of (acac)2Ni. Other reagents, such as cuprates, favour 1,2-additi0n.~~

2-(2-Methylpropylidene)cyclohexanone has been reported to give a 1,4-addition product with MeMgI in the presence of C U C ~ . ~ ~ Facial selectivity in lithium dialkylcuprate addition has been elucidated with the aid of substituted endo-tricyclo[5.2.1.02'6]decadienones(144). The results (Scheme 8) have been interpreted in terms of steric and stereoelectronic effects.loo

I 3 Addition Reactions: Polar Addition

(144)

393

endo

exo

X

exo; endo

H C02Et OMe SPh SePh S(0)Ph

-100: 0 86: 14 2 3 ; 77 0 : 100 0 : 100 0 : 100

SCHEME 8

The novel sulfonylalkyne (145) has been reported to favour 'normal' Michael addition (146) when treated with cuprates. By contrast, other nucleophiles give rise to 'anti-Michael' products (147). Attempts have been made by the authors to rationalize this behaviour in terms of MO theory.'"

TsqSePh - =I RZCuCNLiz

R

Ts

SePh

Nu

(N, 0, S, Se)

Nu

SPh

Miscellaneous Nucleophilic Additions Trimethylsilyl cyanide has been reported to add to the nitrone (148) with essentially complete stereoselectivity. This outcome has been rationalized by the favoured transition state (149).'02 y-Methoxy sulfonyl anions (150) undergo conjugate addition to mono- and bi-cyclic cyclopentenyl sulfones. The primary adducts (151) tend to cyclize to spirocyclic cyclopropane derivatives (152), which can be hydrolysed to afford 6-sulfonylsubstituted enones (153).'03 Several pathways in the reaction of cyclohexanone enamines with a,p-unsaturated acid chlorides and 2- and 3-chloropropionyl chlorides have been reported. The actual choice of the preferred reaction channel is dependent on the reaction condition^."^ In accord with the expectation, the addition of nucleophiles to RC6H4N=C=0 (R = H, Me, Br, C1, NH2, NO*) has been shown to correlate with the positive charge located at the carbon atom of the NCO group. The charge was calculated using the EHMO method. '05

394


on S02Ph

S02Ph

I

____)

Me0

-78 "C THF, HMPA

(151) PhSOzLi -65 "C

S02Ph

SOzPh

H20

silica

f--

THF reflux

Me0

Primary aliphatic amines add across the triple bond of ClCrCCl to give various products, depending on the reaction conditions. O6 Investigation of the alleged 6(O)"-endo-digcyclization of (154) revealed an unusual acid-catalyzed rearrangement of the benzofuran (155), initially formed by the 5(0)"exo-trig ring closure (!), to afford (156) as the final prod~ct."~

'


395

The competition between the Michael addition and Diels-Alder reaction of avinylpyrrole and dimethyl acetylenedicarboxylate has been studied at the PM3 semiempirical level. It has been found that substituents dramatically influence the orbital level and, consequently, the reaction preference.log The reactivity of the bridgehead-substituted bicyclobutanes (157) towards nucleophiles has been compared with that ofthe analogous vinylic compounds (158). Ab initio calculations suggest that electron-withdrawing substituents (EWG) exert nearly the same energetic effects on the ground state of the two systems. The observed difference in reactivities must, therefore, stem from the different nature of the corresponding transition states."'

The stereochemistry of the anionic polymerization of 2-vinylpyridine and related vinyl monomers has been reported to depend on subtle steric interactions between the prochiral anion and the alkyl group of the reagent (ROLi2)+ 'counterion.' This effect shifts the equilibrium between the diastereoisomeric pro-meso and pro-rac ion pairs in favour of the latter species, which reacts with the monomer in syn fashion to produce meso sequences. It has been argued that a helical conformation of the growing chain can be expected to favour such a pro-meso species, leading to rapid, isotactic chain growth."' The tetrabutylammonium salts of CH-acidic compounds [malonic diesters and diamides, MeN02, PhCH2C02R, PhCH(Me)C02R, and 9-ethylfluorene] have been reported to serve as inexpensive initiators for the anionic polymerization of acrylates and methacrylates at room temperature. Molecular weights of 1500-25 000 can be reached, with the distribution being fairly narrow (D= 1.1-1.4 in optimized cases). The X-ray analysis of the tetrabutylammonium salts of PhCH2C02R, PhCH(Me)C02R, and MeCH2CH(Ph)C02R showed that anions and cations interact with one another via hydrogen bonding. Therefore, the initiators cannot be considered to be naked anions."' The role of the enolate anions in the silicon-mediated polymerization (group-transfer polymerization, GTP) of CH2=C(Me)C02Me (MMA) has now been investigated using Cs+, Bu4Nf, and Li+ salts of 9-methylfluorenide as the nucleophilic catalysts. The results of normal anionic polymerization of MMA using these carbanion salts were compared directly with the analogous GTP processes carried out in the presence of the silyl ketene acetal initiator 1-methoxy-1-(trimethylsiloxy)-2-methylprop-1-ene (MTS). In the absence of MTS, these reactions are characterized by low conversion (14-25%), no control of Mn, and broad molecular-weight distribution. By contrast, in the presence of MTS, controlled MMA polymerization is observed. The authors concluded that the results are consistent with an associative GTP mechanism only if it is postulated that the chemistry and stereochemistry of a pentacovalent siliconate anion are the same as those of an ester enolate anion intermediate.lI2

396


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''

'"

398 91

92 93 94

95 96 97

98

99 100 101

I02 103 104 105

I Oh 107

I08 109

I10 Ill 112


Bemasconi, C. F., Leyes, A. E., Eventova, I., and Rappoport, Z., 1 Am. Chem. SOC.,117, 1703 (1995). Bemasconi, C. F., Schuck, D. F., Ketner, R. J., Eventova, I., and Rappoport, Z., 1 Am. Chem. Soc., 117, 2719 (1 995). Alexiev, D. I. and Ivanova, S . M., Zh. Org. Khim., 30, 720 (1994). Hamana, H., Hagiwara, T., and Narita, T., Saitama Kogyo Daihgu Kiyo, 3, 22 (1 994); Chem. A h . , 122, 159887 (1995). Bmncko, M. and Crich, D., 1 Org. Chem., 59, 7921 (1994). Barren, A. G . M. and Rys, D. J., 1 Chem. Soc., Perkin Trans. I , 1995, 1009. Krief, A,, Kenda, B., and Remade, B., Tetrahedron Left., 36, 7917 (1995). Kabbara, J., Fleming, S., Nickisch, K., Neh, H., and Westermann, J., Liebigs Ann. Chem., 1995, 401. Cuza, O., Caravaniez, D., and Zavoianu, D., Rev. Chem. (Bucharest), 45, 368 (1994); Chem. Abs., 122, 80508 (1 995). Zhu, J., van der Hoeven, J., Slief, J.-W., Klunder, A. J. H., and Zwanenburg, B., Tetrahedron, 51, 10953 (1995). Back, T. G. and Wehrli, D., Tetrahedron Lett., 36, 4737 (1995). Merchan, F. L., Merino, P., and Tejero, T., Tetrahedron Lett., 36, 6949 (1995). Jin, 2. and Fuchs, P. L., 1 Am. Chem. Soc., 117, 3022 (1995). Butkus, E. and Bielinyte-Williams, B., Collect. Czech. Chem. Commun., 60, 1343 (1 995). Zhang, S. and Jing, Ch., Huaxue Shijie, 34, 275 (1993); Chem. Abs., 122, 30781 (1995). Pielichowski, J. and Czub, P., Bull. SOC. Chim. Belg., 104, 407 (1995). Weingarten, M. D. and Padwa, A., Tetrahedron Lett., 36, 4717 (1995). Domingo, L. S., Jones, R. A,, Picher, M. T., and Sepulveda-Arques, J., Tetrahedron, 51, 8739 (1995). Azran, C. and Hoz, S., Tetrahedron, 51, 11421 (1995). Hogen-Esch, T. E., Jin, Q., and Dimov, D., 1 Phys. Org. Chem., 8, 222 (1995). Reetz, M. T., Hiitte, S., and Goddard, R., 1 Phys. Org. Chem., 8, 231 (1995). Quirk, R. P. and Kim, J.-S., 1 Phys. Org. Chem., 8, 242 (1995).

CHAPTER 14

Addition Reactions: Cycloaddition N. DENNIS

Australian Commercial Research and Development Ltd, GPO Box 2481, Brisbane, Queensland 4001, Australia

+ + +

2 2-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4-Cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Cycloadditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

399 403 413 427 433

A practical guide to photochemical cycloadditions has been published.'

2

+ 2-Cycloaddition

+

+ +

Factors determining the outcome of competing 2 2- and 2 4-cycloaddition reactions are discussed.2 The stereo- and regio-selectivity of 2 2-photo-cycloadditions of alkenes have been investigated by PMO and FMO method^.^ Semiempirical MO theory has shown that fluorine andor amine substituents reduce the potential-energy barrier of the 2 2-cycloaddition reactions of ethylene with formaldehyde? Global potentialenergy contour plots have been developed for reactions involving stepwise concerted addition of two alkenes to form cy~lobutane.~ Kinetic studies of the zwitterionic 2 + 2cycloaddition of TCNE and bis(4-methoxycinnamyl) ether decisively exclude an ET mechanism in favour of a polar mechanism.6 The thermal reaction of hnctionalized cyclobutenes (1) with 1,l-dimethoxyethene yields the expected 2 2-adducts, bicyclo[2.2.0]hexanes (3) and new 4 2-adducts, bicyclo[4.2.0]octenes (4) via the intermediate (2) (Scheme l).' The photo-sensitized intramolecular 2 2-cycloaddition reactions of 2,6-diarylocta1,6-dienes are potentially stereoselective via a 1,4-cation radical intermediate.8 The photo-induced intramolecular ortho cycloadditions of 2-substituted 4-(3-methylbut-3en- 1-oxy)acetophenones (5) itre 100% regioselective syn, yielding initially adduct (6) which is converted into the stable cyclobutene (8) via the cyclooctatriene (7) (Scheme 2).9 Also, the photochemical cycloaddition of silicon-tethered enynes (9) produces substituted cyclobutenes (10) with high regiospecificity in high yields (Scheme 3)." Ab initio calculations on the photo-cycloadditions of triplet cyclohexenones with alkenes show that the origin of the regioselectivity is in the bond-forming step." Triplet 1,4-biradical intermediates in the photochemical 2 2-cycloaddition reaction between cyclopenten-2-one with methyl acrylate and ethyl vinyl ether have been trapped with

+

+

+

+

+

Organic Reaction Mechanisms 1995. Edited by A. C. Knipe and W. E. Watts Q 1997 John Wiley & Sans Ltd

3 99


400 OMe &OMe

($:

OMe

+

SOTCHCI3

Rl

R'

COR2 (1) R1 = H, C02Me, COPh; R2 = OMe, Ph

-

R1

C02Me OMe OMe (3)

(F.\

Me0

+

O OMe (2)

R' = H, COzMe

I

P h O C g ; Me0

OMe (4)

SCHEME 1

hv

*

-

MeO

hv

c--

A

\ / o

O

Mk

(7)

R = Me,CF3, OMe SCHEME 2

O

14 Addition Reactions: Cycloaddition

Bu'zSi

,O--WPh

40 1

1. hv, MeCN

____)

2. NH4F

HO

R

(9)

R = H,Ph, C02Me, SiMe3

SCHEME 3

hydrogen selenide.l 2 N-Alkenoyldihydropyridinones (11) and 3-acetyl-N-alkenoyltetrahydropyridines undergo diastereoselective intramolecular photochemical cycloaddition to yield cyclobutaquinolizidones (12) and cyclobutaindolizidinones,respectively (Scheme 4).13

The Paterno-Buchi reactions of methacrylonitrile with 5-substituted adamant-2-ones exhibit n-face ~electivity,'~ which can be reversed by inclusion in P-cyclodextrin.l5 An extensive review on the 2 2-cycloadditions of ketenes has been presented.l6 A kinetic study of the cycloaddition of t-butylcyanoketene with styrenes indicates a concerted asynchronous mechanism involving a transition state with some degree of charge ~eparati0n.l~ The first example of stereospecificity in the aryne-alkene cycloaddition between benzyne and ketene silyl acetals has been reported.'* Both MgBr2.Et20I9 and methylaluminium bis(4-bromo-2,6-di-t-butylphenoxide)zohave been successfully used in the stereoselective 2 2-cycloaddition reaction of trimethylsilylketene with aldehydes. Ab initio calculations predict that electrostatic solute-solvent interactions are critical in the control of the stereoselectivity of keteneimine cycloaddition reactions.21 5H, 7H-Thiazolo[3,4-c]oxazolium-1-oxides react as ketenes with imines to produce spirocyclic b-lactams and lH,3H-imidazo[1,5c]thiaz~les?~ Dichloroketene reacts with 1,3,5-tri-t-butylcyclopentadiene(13) to yield the expected 2+2-cycloadduct (14), but in the presence of zinc a complex rearrangement yields the 'abnormal' adduct (15) (Scheme 5).23 The aminium saltinitiated reaction of ketenes produces succinic anhydrides via a formal 2 + 2 dimerization of the ketenes with the incorporation of an additional oxygen atom.24 PM3 calculations of the addition of allenes to imines indicate that the reaction proceeds via a non-concerted two-step mechanism where the allene attacks towards the

+

+


402

C1~CCOCl

Zn

____)

I

t

IB"' *M e

+

lone pair of the imine nitrogen atom.25The intramolecular 2 2-cyclization reaction of phenylsulfonyl-substituted allenes with unactivated alkenes proceeds across the C(l)-C(2) double bond of the allene with complete stereoselectivity.26 1-Seleno-2-silylethenes react with methylenemalonate esters in the presence of a Lewis acid to form 2 2- and 2 + 1-cycloadd~cts.~~ Bis(trimethylsily1)admantylidenegermene (16) spontaneously dimerizes in a head-to-head fashion to produce the single dimer (17) (Scheme 6).28

+

SCHEME 6

403

I 4 Addition Reactions: Cycloaddition

+

qr

A 2 2-cycloaddition is involved in the conversion of 4-methyldithieno[3,4-b : : 3’,2’-d]pyridinium iodide (18) into the cycloadduct (19) on treatment with 2 equiv. of DMAD (Scheme 7).29

DMAD

DMAD

H

R

H

R

I

R

Me

A

I

R R

-S

f--

Me R

H

Me

(19)

R = C02Me SCHEME 7

2

+ 3-Cycloaddition

For the photochemical 1,3-dipolar cycloaddition of ethylene to benzene, the semiempirical MO method, SINDO1, favours the reaction mechanism involving a prefulvene intermediate rather than one involving an exciplex intermediate.30 AM1 calculations of the BF3-catalysed 1,3-dipolar cycloaddition of azide anion to nitriles confirm a stepwise mechanism.31v32Second-order rate constants were determined for the cycloaddition of phenyl azide to norbornene in aqueous solutions and these show large reaction rate increases in aqueous media.33 2-Azido-5trimethylsilylthiophene cycloadds with trimethylsilylacetylene to yield a single triazole cycloadduct, whereas 2-azido-5-methylthiopheneyields a mixture of regioisomeric triazole c y c l o a d d ~ c t s .The ~ ~ asymmetric 1,3-dipolar cycloaddition reactions of acylnitrenes have been inve~tigated.~~


404

A review of stereo- and regio-control of 1,3-dipolarcycloaddition reactions of imines with nitrile oxides by metal ions has been published.36The 1,3-dipolar cycloaddition of nitrile oxides to sugar nitroalkenes and @,/?-unsaturatedcarbonyl sugar derivatives yields sugar isoxazolines as single diastereoi~omers.~~ y-Alkoxyvinyl sulfones react with benzonitrile and acetonitrile oxides to produce isoxazolines with complete regioselectivity and moderate anti stereo~electivity.~~ The stereochemical outcome of 3 + 2-cycloadditions of nitrile oxides to Baylis-Hillman adducts can be explained by the ‘inside alkoxy effect.’39A new dispiroacetal-protected but-3-en- 1,2-diol undergoes regiospecific and diastereoselective addition to nitrile oxides.4o Perturbational analysis shows a strong H O M O ~ i o ~ o ~ ~ d e ~ y d e interaction -LUMOn~~o as the principal reason for the high thione reactivity in 1,3-dipolar cy~loadditions.~”~~ The 3 + 2-cycloaddition of nitrones with cinnamates proceeds with high endo selectivity ( > 99% ee) in smectic liquid crystalline solvent (BPCD).43 The regioand stereo-selectivity of the reaction of aldonitrones of 3-imidazoline-3-oxides with monosubstituted alkenes depend mainly on the substituent on the dip~larophile!~ Intramolecular cycloaddition of nitrones (20) with lithium enolate furnished 4-hydroxy4-methyl-3-oxa-2,7-diazabicyclo[3.3.0]octanes (21) with high diastereoselectivity (Scheme 8).45 A single stereogenic centre a to the oxime moiety can control the diastereoselectivity of 1,3-dipolar cycloadditions. Thus the aldoxime (22) derived from L-threose reacts cleanly with divinyl sulfone to yield an intermediate nitrone (23), which cycloadds to yield a single isomeric cycloadduct (24) (Scheme 9).46The intramolecular 1,3-dipolar cycloaddition of propylidene nitrones produces cycloadducts which rearrange to 5-azahydr1ndan-8-ones.~~ The 1,3-dipolar cycloadditions of cyclic nitrones with (4-y-hydroxy- and ( 8 - y alkoxy-a,/?-unsaturatedesters yield adducts derived from endo-transition states with antifacial approach.48 a,/?-Unsaturated y-lactams derived from (4-pyroglutaminol readily undergo 1,3-dipolar cycloaddition with N-methylnitr~ne!~Regiospecific 1,3-

R

\ I

0-

q

8” /

N

Me (20) R =Bu‘,Bz,Me

T

0

?z

LDA, THF,

-78 “C

SCHEME 8

R,&pyk,q/ I

0-

Me

O-Li+

I 4 Addition Reactions: Cycloaddition OH

/

R

+x

405

R

I

Ph2SiO

0-

A + PhMe, 24 h

(22)

R = Bu' R

SCHEME 9

dipolar cycloaddition of C-aryl-N-alkylnitrones to chiral dipolarophiles produces 5substituted isoxazolidines which can be converted into polyhydroxylated piperidine~.~' CJV-Diphenylnitrones also react with vinyl sulfoximines to produce 4-sulfonimidoyli~oxazolidines.~'A mechanism has been proposed for the dramatic change in regioselectivity observed in the Mg and Zn ion-mediated nitrone cycloadditions with ally1 alcohols.52 Ab initio and semiempirical PM3 calculations of the 1,3-dipolar cycloadditions of pyridine-N-oxides and isocyanates provide theoretical evidence of concerted and nonsynchronous mechanisms with zwitterionic ~ h a r a c t e r2,2-Dimethyl-3,4-dihydro-2H.~~ pyrrole-N-oxide undergoes intramolecular 1,3-dipolar cycloaddition with optically active cQ-unsaturated esters to yield isoxazolidines whose stereochemistry support an exo-transition state.54 The asymmetric 3 2-cycloaddition between 2,3,4,5-tetrahydropyridine-1-oxide and (2)-@)-vinyl sulfoxides to yield the isoxazolidines (25) and (26) has been utilized in the efficient synthesis of enantiomerically pure piperidine alkaloid, (+)-sedndine (27; R = Me) (Scheme lo)? The 1,3-dipolar cycloaddition of benzonitrilium N-phenylimide with 4-arylmethylidene-3-phenylisoxazol-5(4H)-ones (28) produces 5-aryl-1,3-diphenylpyrazole-4-carboxylic acids (29) by the elimination of benzonitrile from the initially formed cycloadduct (Scheme 1l).56 The 3 2-annelation of allylidene(tripheny1)phosphoranes with 1,2-diacylethylenes produces substituted cyclopentadienes but no cycl~hexadienes.~'A novel phosphinecatalysed 3 2-cycloaddition of buta-2,3-dienoates(30) or but-2-ynoates with electronefficient alkenes yields cyclopentene derivatives (31) via the mechanism outlined in Scheme 12." Intramolecular palladium-catalysed 3 2-cycloadditions of methylene-

+

+

+

+

406


I

SCHEME 10

phtc N,O

0

+

+

Ph-CZN-G-Ph

(28) Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 3-BrC6H4, 3-thienyl

1

-PhCN

SCHEME 11

cyclopropanes with acetylenic esters provides an entry into bicyclo[3.3.0]octane and bicyclo[4.3.O]nonane systems.59 The 1-pyrazoline (33) derived from 5-diazo-10,ll -dihydro-SH-dibenzo[a,dIcycloheptene (32) and 2,5-dimethyl-l,4-benzoquinoneundergoes thermal 1,3-dipolar cycloreversion to produce the cyclopropane (34) in competition with nitrogen extrusion (Scheme 13).6096' Lewis acid-catalysed 1,3-dipolar cycloaddition of 2H-chromenes with 1,4-benzoquinone mono- and bis-imides (35) provides a new synthesis of azapterocarpans (36)(Scheme 14).62


407

PPh3

-

* PhH, Nz, r.t. i C02Et (30)

1

diethyl fumarate

C02Et

c

+PPh3

C02Et

SCHEME 12

-

+ Me

r.t. a 50 "C

0

Me Me 0

SCHEME 13

(34)

408

a

Me0

Organic Reaction Mechanisms 1995 ___) BF2.0Et2

+

S02Ph

CH2C12, -78 "C

(35)

/

(36)

OMe

SCHEME 14

The 1,3-dipolar cycloaddition of 1-(phthalazin-1-yl)pyridinium-3-olate with 27~electron addends produces the expected substituted 8-axabicyclo[3.2.l]oct-3-en-2ones.63 However, the reaction of 3-dimethylamino-1-methyl-1,2,4-triazinium-5-olates (37) with DMAD did not produce the expected 3 +2-adduct (38) but the tetrahydropyrrol0[3,4-~]pyrazole derivative (39) via the rearrangement shown in Scheme 1 5.64 3-Aroylaziridines react with diphenylcyclopentenone to produce anhydro-3-hydroxy-2,4-diphenyl-6-aroylpyrylium hydroxides (40), which undergo stereospecific 1,3-dipolar cycloaddition with dimethyl cyclobut-1-ene- 1,2-dicarboxylate to produce exo- and endo-cycloadducts (41) and (42) (Scheme 16).65 Base treatment of 5-aminothiazolium chlorides (43) yields mesoionic thiazoles (44), which undergo 1,3-dipolar cycloaddition with DMAD and methyl propiolate followed by extrusion of isothiocyanate to provide substituted pyrroles (45) in good yield (Scheme 17).66 The intramolecular 1,3-dipolar cycloadditions of N-(phenylmethy1ene)benzenesulfonamide with the munchnones (46) are highly regiospecific, producing 2,5disubstituted imidazoles (47) as outlined in Scheme 18.67 The effect of high pressure on the transition metal-catalysed cycloaddition of trimethylenemethane-PdLz to coumarin is to decrease the reaction rate and to invert the regioselectivity.68 Under solvent-free conditions, azomethine ylides from imidates of a-amino-esters react with imino alcohols to produce new imidaz~lones.~~ Non-stabilized azomethine ylides have been shown to undergo 1,3-dipolar cycloaddition with P-nitrostyrenes to yield trans-3-aryl-4-nitr0pyrrolidines.~~ Menthyl acrylate undergoes asymmetric 1,3dipolar cycloaddition with metallo-azomethine ylides (49) derived from imines (48) in the presence of LiBr or AgOAc to give homochiral cycloadducts (50) (Scheme 19).71,72 Substituted 5-phenyl-3,4-dihydro-2H1,4-oxazin-2-ones are precursors of azomethine ylides which react with N-phenyl- and N-methyl-maleimidesyielding exclusively exoN'

Me

(37)

Me

0

(38)

R = H, Me, Ph

SCHEME 15

409


- rn

(43)

R’ Ph Ph Me Me

(44)

T2

’6

Ph

R2 Me CH2Ph CHzPh CH2C02Et

R3

But But Bur Bu‘

R4 Ph NMe2 NMe2 NMe2

R2 SR‘ ;R3NCS

R * 4

E

(45)

E

NR3 17 SCHEME

c y c l o a d d ~ c t s[60]Fullerene .~~ readily undergoes 1,3-dipolar cycloaddition with imines of cr-amino acid esters to produce two isomers of fidlerene-fused proline derivative^.^^ 5R-(1‘R,2’S,S’R-Menthyloxyl)-2(SH)-kanone and N-acetyl-5R-isopropoxy-2(5H)pyrrolone undergo asymmetric 1,3-dipolar cycloaddition with metallo-1,3-dipoles derived from both aryl and aliphatic imines from a-amino esters in the presence of A~OAC-DBU-THF.~~ Metallo-azomethine ylides also undergo facile stereospecific and regiospecific cycloaddition with ethyl (E,)-4,4,4-trifl~orobut-2-enoate~~ and chiral


410

I

Me (46)

R' = R2 = Ph R1 = Ph; R2 = Me R' = Me; R2 = Ph

J-co2 Ph

Ph

R'

I

I

Me

Me SCHEME18

AgOAc, NEtl

\

0

/

P

DMSO, 1 h

3

AcO-Ag -0

(50)

R' = 2-naphthyl, R2 = menthyl SCHEME 19

en one^.^^ In the exo-diastereoselective 1,3-dipolar cycloaddition of azomethine ylides also derived from a-amino acid esters to (2R)-3-benzoyl-4-methylene-2-phenyloxazolidin-5-one, LiBr-DBU-THF was found to be especially effective.78 The intramolecular 3 2-cycloaddition of the nitrone (51) derived from 2-( 1,2propyny1oxy)benzaldehyde and N-methylhydroxylamine yielded the expected 4isoxazoline (52) as a transient intermediate which rearranges to the only characterizable product, 4-methyl-2,5-endo-oxo-2,3,4,5-tetrahydro[ 1,4]benzoxazepin (53), via the mechanism outlined in Scheme 20.79

+


41 1

PhH

95 "C. 4.5 h

(53) R = Me,Bu'

SCHEME 20

1-Acetoxy-2-hydroxycyclohexa-3,5-diene reacts with diazomethane to b i s h 3 + 2cycloadducts showing complete syn-facial selectivity.80The cycloaddition of chiral a$unsaturated y-alkoxy or y-amino ketones with diphenyldiazomethane affords conjugated A*-pyrazolines with high diastereofacial selectivity.81 Again, 2 equiv. of diphenyldiazomethane react with acyl isothiocyanates to give 4,5-dihydro-l,3-oxazole4-spiro-2'-thiiranes (54), which isomerize to the thietan-3-imines (55) (Scheme 2 In the presence of an Ag(1) catalyst, acetylenic a-diazo ketones (56) bearing gem-

R = CCl,, C02Me, Ph, OEt, Bu'

(54) SCHEME 21


412

dimethyl substituents undergo intramolecular 1,3-dipolar cycloaddition to produce bicyclic pyrazole derivatives (57) in 47-55% yield rather than the normal Wolff rearrangement (Scheme 22).83 0

0

/acc1 +: "&/ II

-E

10 mol% Ag20 EtOH, 78 "C, 1 h

J

L SCHEME 22

+

Carbonyl oxides readily undergo 3 2-cycloaddition with imines to afford the The corresponding 1,2,4-dioxazolidines with high degrees of ~tereoselectivity.~~ photolysis of benzofuro-annulated oxanorbomadiene (58)in the presence of CC and CN dipolarophiles yields propellanes (60) via the intermediate carbonyl ylide (59) (Scheme 23).85The thermal decomposition of 2,5,5-trimethyl-2-trimethylsilyloxy-A3-

E = C02Me, R = (NC)CH=C(Bu')

I

SCHEME 23


413

1,3,4-oxadiazoline produces a reactive carbonyl ylide which can be trapped with DMAD.~~ Intramolecular 3 2-cycloaddition of an azoxy group and an adjacent parallel olefinic bond in a cage compound (61) produces the so far unknown 1,2,3oxadiazolidine (62) (Scheme 24).87,88

+

& & 0

150T

___)

O

h

PhH, 2 h

(61) SCHEME 24

2

+ 4-Cycloaddition

(62)

+

A theoretical study of the aromatic character of the transition states of allowed 271 471and forbidden 2n + 2ncycloaddition has been reported.89 Ab initio MO calculations provide evidence for the dominant role of secondary orbital interactions in determining the endolexo product ratio of Diels-Alder reactions of cyclopropene with dienes.” At levels of theory up to MP2lcc-pVDZ, the gas-phase cycloadditions of ethylene and buta- 1,3-diene with cyclopropylcarbinyl cation are asynchronous but c~ncerted.~’ DFT methods have been used to study the Diels-Alder reactions of ethylene with buta-l,3diene and cycl~pentadiene.~~ The cycloaddition of 1,4-dioxabuta-1,3-diene with ethylene and vinyl alcohol has been investigated using ab initio MO calculation^.^^ The photo-sensitized electron-transfer intramolecular cycloaddition of 1,1,8,8-tetraphenylocta-l,7-diene (63) yields a single 4e 2e-adduct (64) (Scheme 25).94 Electron transfer has been demonstrated spectroscopically in the Diels-Alder reactions of 2,3bis(dimethylaminomethy1ene)-bicyclo[2.2.llheptane and -bicyclo[2.2.2]octane with electron-deficient alkenes such as TCNE.95,96The formal transfer of a substituent from a dienophile to a diene via a Diels-Alderlretro-Diels-Alder tandem reaction has been investigated by AM1 semiempirical MO methods.97

+

Ph Ph

Ph Ph

hv MeCN-PhH (3: 1)’ CbH4(CN)2- 1.4


414

The dimerization of (E)-l,3-diphenylbuta-1,3-diene follows a concerted pathway and not a diradical mechanism as previously assumed.98 Diels-Alder dimerizations of various spiro[2.4]hepta-4,6-dieneshave been studied theoretically and e~perimentally.~~ The effect of substituents on the 4+2-dimerizations of acylketenes has been investigated using semiempirical Ah41 calculations.Io0 N-Arylamino-l,3-diazabutadienes undergo 4 2-cycloaddition with ketenes to yield pyrimidinones."' The reactions of pent-3-ene-2-thione with ethyleneIo2and of thiochalcone with alkeneslo3 have been investigated by AM 1 calculations of the transition-state structures. Chiral titanium reagents catalyse the enantio- and endo-selective Diels-Alder reactions of (E)- 1-phenylsulfonylalk-3-en-2-ones with ~yclopentadiene."~The reactivity of a$-unsaturated dimethylhydrazones in 4 +- 2-cycloaddition reactions has been studied using AM 1 semiempirical calculations.lo5 N-Acylthioformamides react as dienophiles in Diels-Alder reactions.lo6The 4 2-cycloaddition reactions of diarylselenoketones with trans,trans- and cis,trans-hexa-2,4-dieneproceed stereospecifically.lo7 Competition kinetics of the tris(4-bromopheny1)ammonium salt-catalysed DielsAlder additions of stilbenes to 2,3-dimethylbuta-1,3-diene provide evidence for a cation radical mechanism.Io8Rate enhancement of Diels-Alder and ene reactions have been investigated in several inorganic perchlorateeorganic solvent solutions. Small rate accelerations are the result of increases in the medium internal pressure while large rate enhancements are consistent with a catalysis of the metal ion behaving as a Lewis acid.lo9 The effect of solvents on the Diels-Alder reactions of cyclopentadiene and isoprene with electron-deficient dienophiles has been analysed by AM1 and PM3 calculations.' l o Small quantities of Lewis acids (Cu2', Ni2+, Ca2+, Zn2+) can efficiently catalyse Diels-Alder reactions in water.' A pseudo-dynamic analysis of the rate acceleration of Diels-Alder reactions in water provides evidence that the rate enhancement is due to hydrogen-bonding stabilization of the polarized activated complex and to the decrease of the hydrophobic surface area of the reactants during the activation p r ~ c e s s . " ~ ~ " ~ Electronic and nuclear polarization effects in aqueous solution are crucial factors in the diastereofacial selectivity of Diels-Alder reactions.' l 4 Quantitative antihydrophobic effects have been used as probes for transition-state structures in Diels-Alder reactions.' l 5 A catalytic enzyme, Diels-Alderase, isolated from cell-free extract of Alternariu solani, has been shown to catalyse the intramolecular 4 2-cycloaddition of prosolanapyrone 111 (65) to the exo-adduct solanopyrone A (66) (Scheme 26).'16 For the first time, an antibody-catalysed hetero-Diels-Alder cycloaddition between trans-piperylene and a nitroso dienophile has been re~0rted.l'~ Methodology has been presented for the preparation of antibody catalysts for the Diels-Alder reaction by using flexible haptens.' I8 fi-Cyclodextrin exhibits a catalytic effect on the Diels-Alder reaction of cyclopentadiene and electron-deficient dienophiles. This effect has been explained by a molecular model involving 8-cyclodextrin transition structures.' l9 Aqueous solutions of fi-cyclodextin can control the regioselectivity in Diels-Alder reactions between 1,4benzoquinones and the dienes, isoprene and penta-1 ,3-diene.I2' High pressure has been shown to accelerate the Diels-Alder reaction between cyanoacetylene and cyclohexa-1,3-diene.I2' The high-pressure intramolecular Diels-

+

+

+

415


OMe

OHC

Diels-Alderase

30 "C, 10 min

Alder reaction of 1-oxobuta-1,3-diene exhibits a pressure-induced increase in diastereoselectivity.y.'22The effect of pressure, temperature, and catalyst on the diastereofacial selectivity in Diels-Alder reaction of (5S)-(E)-5,6-O-isopropylidenehex-3-en-2-one with cyclopentadiene has been investigated.lZ3 The first example of a highly enantioselective catalytic Diels-Alder reaction of an achiral dienophile, N-arylmaleimide, with an achiral diene, 2-methoxybutadiene, has been reported. 124 Also, chiral 2-alkoxy- 1,3-butadienes undergo 4 2-cycloaddition with PTAD, NPM and TCNE with moderate to high face ~e1ectivity.l~~ Chiral openchain dienols possessing 1,3-allylic strain due to the presence of a cis-substituent produce highly like-selective 4 2-adducts with maleic anhydride, N-phenylmaleimide, and 4-phenyl- and 4-methy1-1,2,4-tria~oline-3,4-dione.'~~ (Phenyl)[o-(trimethylsilyl)phenyl]iodoniu triflate is a new and efficient precursor of benzyne under mild and neutral condition^.'^^ The first example of an intramolecular Diels-Alder reaction of a benzyne with an acyclic diene (67) to produce a cycloadduct (68) has been reported (Scheme 27). The course of the reaction is dependent on the diene geometry.128

+

+

OMe

OMe

SCHEME 27

Ab initio and PM3-CI calculations were used to study the transition structures for Diels-Alder additions of hetero-dienophiles to butadiene'29 and cyclopentadiene.'30 The Diels-Alder reaction of unsubstituted 2-aza- 1,3-dienes with trans-diimide was studied using semiempirical AM1 calculation^.'^ The intermolecular hetero-Diels-

'

416


Alder reaction of enamino ketones with ethyl vinyl ether exhibits a high pressuredependent increase in diastereoselectivity in favour of the trans adducts.I3' The formal hetero-Diels-Alder reactions of N-arylamines (69) produce tetracyclic decahydro7,7,11-trimethylindolizino[3,4-b]quinolines(70) and (71) in a ratio which is dependent on the coordination number of the acidic catalyst (Scheme 28).'33

-

n

Lewis acid

CH~C12,42h

+ Me

Me

H

Me

,Me

SCHEME 28

Semiempirical calculations (AM1 and PM3) were used to explain the stereodivergent facial differentiation of the intermolecular hetero-Diels-Alder reaction of chiral l-oxabuta-l,3-dienes in the presence of TMS-OTf or Me2A1C1.'34 4Acetoxyazetidin-2-one reacts with 2-(t-butyldimethylsilyloxy)buta-1,3-diene to form Diels-Alder adducts, carbacephem~.'~~ The first example of the 4 2+-cycloaddition of a thienium cation with a 1,3-diene has been rep01-ted.l~~ Multiple-stage mass spectrometry has been applied to the study of polar 4 2+ Diels-Alder cycloadditions of nitrilium and immonium ions in the gas phase.' 37 N-Methyl-4H-pyrazolium cation (72) behaves as an electron-deficient diene in the 4+ + 2-cycloadditions with cyclic alkenes to form the cationic cycloadduct (73), which rearranges to the phthalazinecarboxylate (74) (Scheme 29).13' The intramolecular polar 4+ 2-cycloadditions of cationic 2-azabutadienes with various dienophiles provides a facile synthesis of 1,2,3,4-tetrahydroquinolinespossessing high regio- and diastereo-selectivity. 39 Ab initio calculations indicate the reactivity of thiophene with acrylonitrile is similar to that of butadiene with eth~1ene.l~' The AM1 semiempirical method has been used to predict the reactivity of benzo[b]- and benzo[c]-thiophenes as dienes in Diels-Alder reactions'41 and to predict that thiophenes are best activated towards Diels-Alder reactions by conversion into the corresponding S-methylthiophenium anions.142 The photochemical Diels-Alder reaction between thiophene derivatives bearing electronwithdrawing substituents and phenylacetylenes provides o-substituted biphenyls.143 Ab initio calculations of the cheletropic and Diels-Alder reactions of sulfur dioxide with 1,3-dienes have been completed'44 and results suggest that 1-methoxycyclohexa1,3-diene should react with SOz to produce a sultine in preference to a ~ u lf o le n e . The '~~ retro-Diels-Alder reaction of 1,4-oxathiine-S-oxide (75) generates up'-dioxosulfine (76),which cycloadds with dienophiles and dienes (Scheme 30).146

+

+

+

'

417

I4 Addition Reactions: Cycloaddition

A, MeCN

Me0

Me0

N

Ph (74)

E = C02Me

SCHEME 29

(75)

(76)

SCHEME 30

A

0

418


MO calculations for the reaction of ethylene with nitrosoethylene in the presence of BH3 showed that the reaction is an inverse-electron-demand Diels-Alder cycloaddition in which boron is an effective catalyst. 147 Electron-poor 2-azadienes undergo inverseelectron-demand Diels-Alder reactions with trans-cyclooctene and cispuns-cyclooctadiene to produce trans-cycloalkanotetrahydropyridines.148 AM1 calculations have been used to study the Diels-Alder reaction between buckminsterfullerene (C60) and 2,3-dimethylidenebicycl0[2.2.2]octane.'~~ The photochemical reaction between N-ethoxycarbonylazepine and [60]fillerene produced two photo-cycloadducts by formal 4 + 2- and 6 2-cycloaddition reactions.'50 The reaction of [60]fullerene with the nickel phthalocyanine (77) yields a green Diels-Alder adduct (78) which exhibits multiple reductions (Scheme 3 l).15'

+

mcN . @ :J$R

+

3 @

CN

WAch

CN

N-Ni-N

DBU, pentanol, reflux

R

R = heptyl

RN \ E/

R

(77) Cm. PhMe,

reflux

SCHEME 31

Ab initio MO calculations were used to investigate the transition structures for heterodienophile addition to 1,3,4-0xadiazole'~~ and 4 H - p y r a ~ o l e ~the ' ~ ~tautomer most suitable as a diene in Diels-Alder reactions.lS4 MP3 semiempirical calculations have

419


been used to investigate the Diels-Alder reactions of pyrr~le,’~’ oxazole, and isoxazole with a l k e n e ~ . ”4-Nitro-3-phenylisoxazole ~ reacts as a dienophile with open-chain and cyclic carbodienes.”’ Indole-2,3-dienoate (79) undergoes facile 4 2-cycloaddition with a variety of dienophiles to produce substituted carbazoles (80) (Scheme 32).’58 Bicyclic anhydro-4-hydroxy-2-0x01,3-thiazinium hydroxides undergo 4 2-cycloaddition with dienophiles to yield 1,4-cycloadducts which can extrude COS to form bicyclic pyridin-2-0nes.”~

+

+

OLi I

Me (79)

!

E-CLC-E E = C02Me

N

I

I

Me

Me

(80)

SCHEME 32

The thermolysis of olefinic benzocyclobutenes (81) yields o-quinodimethanes (82) which undergo intramolecular Diels-Alder addition, The stereochemical course of the addition is influenced by the nature of the protective group and the substituent of the ally1 alcohol (Scheme 33).160 Kinetic studies of the photochemical 4 2-cycloaddition of 2,4-dimethylhexa-2,4diene to 9,lO-dichloroanthracene support a singlet mechanism for adduct formation.16’ The cyclohexa-1,3-diene hexacyclo[ 10.2.1.02’”.04’9.09”3]pentadeca-5,7-diene-3, 10dione (83) undergoes Diels-Alder reaction with polyhalocyclopentadienes to produce exclusively the endo, anti adduct (84) (Scheme 34).162,’63Face selectivity in the inverse-electron-demand Diels-Alder reactions of 1,2,3,4,5-pentachloro-5-methoxycyclopenta-1,3-diene was constantly to the face syn to the methoxy Laser Aash photolysis and steady-state photolysis have been used to study 4 2cycloaddition of singlet oxygen with 1,4-dimethylnaphthalene.165 The reaction of imidazole tautomers with ethylene and singlet oxygen have been investigated by ab

+

+

420


Me0 R = Me, CF3 X = 0, O(CH2)30 SCHEME 33

_____t

xylene, reflux

+

initio MO calculations. The diastereoselectivity in the singlet oxygen 4 2cycloaddition to chiral naphthyl alcohol derivatives has been investigated in debi1.167,168 The photochemical addition of singlet oxygen to bisdialine (85) yields predominantly the anti adduct (87) rather than the expected syn adduct (88). A stepwise mechanism involving the perepoxide (86) as intermediate is proposed (Scheme 35).169 AM1 calculations have been carried out on the reactants of the Diels-Alder addition of N-phenylmaleimide and N-methyltriazolinedione with dispiro[4.0.4.4]tetradeca11,13-dienes in order to study their steric, electronic, and electrostatic proper tie^.'^' Intramolecular Diels-Alder cycloadditions of internally sulfonyl-substituted tienes (89) yields bicyclic cycloadducts (90) and (91) with complete cis selectivity (Scheme 36).”’ The thermal intramolecular Diels-Alder reactions of N-substituted sulfoximi-


42 1

(87)

SCHEME 35

(89)

R = TBDMS

(90) 3 SCHEME 36

(91) 1


422

doylnona-1,6,8-trienes and -deca-1,7,9-trienes produce diastereomeric mixtures of bicyclo-[4.3.0]nonanes and -[4.4.O]decane~.'~*The influence of alkyl substituents on the acid-catalysed intramolecular ionic Diels-Alder reaction of methylated analogues of (3E,8E)-undeca-l,3,8,10-tetraene has been rep01ted.I~~The intermediacy of ally1 cations and of 1,3-diene cation radicals in the 2 4-cycloadditions of undeca-l,3,8,10tetraene has been in~estigated.'~~ The intramolecular Diels-Alder reaction of decal ,7,9-trienylboranes (92) provides a highly stereoselective two-step decalin synthesis via the trans-cycloadduct (93) (Scheme 37).175

+

A modified MM2 force field method has been developed to reproduce the selectivities of Lewis acid-catalysed Diels-Alder reactions of chiral acrylates to 1,3dienes. 176 The Diels-Alder reaction of (3R,5S)-3-benzoyloxy-2,2,6,6-tetramethyl-5heptyl acrylate (94) with cyclopentadiene in the presence of TiCl4.(ArnHg),-comp1exed Lewis acids produce the R-isomer (95), whereas in the presence of TiC14 the S-isomer (96) predominates (Scheme 38).177The structure of the complex (97) proposed to be the intermediate in the Ti-TADDOLate-catalysed Diels-Alder reactions with cyclopentadiene has been determined by X-ray diffraction. 78 The reactivity and stereoselectivities of hetero-Diels-Alder additions to furan have been investigated by ab initio calculation^.'^^ The Diels-Alder reaction of furan with methyl acrylate is strongly dependent on pressure.'8o An ab initio study of the DielsAlder addition of furan with cyclopropenone indicates a stabilizing interaction between the ether oxygen and the carbonyl carbon makes the ex0 product the thermodynamic and the kinetic product.18' The furan analogue of o-quinodimethane (98) undergoes Diels-Alder addition with unsymmetrical quinones (99) to yield cycloadducts (100)

423

14 Addition Reactions: Cycloaddition 0

JO

hPO '

Ph2Hg.2TiC14

(94)

t

(97)

SCHEME38

(Scheme 39).1823-Substituted 5-methylene-2(5H)-furanones react with butadiene to produce 1,2- and 1,cadducts through a common biradical inte~mediate.'~~ The intramolecular Diels-Alder reaction of chiral N-substituted Mr y la m in e s with maleic anhydnde produces tricyclic adducts with five chiral centres.'84 The furan derivatives, (E,Z)- and (Z,E)-fulgides (101) and (103), in toluene at room temperature undergo photochemical isomerization to the (E,E)-fulgide (102) followed by intramolecular 2 4-cycloaddition to give the adduct (104) (Scheme 4O).Is5 A PM3 semiempirical MO method has been used to study the competition between Michael addition reactions and Diels-Alder reactions of 1-methyl-2-( 1-substituted-

+


425

viny1)pyrroles with DMAD.'86 However, the PM3 method has been shown to be unreliable for predicting the reactivities and selectivities of cyanoethylenes in DielsAlder reactions with pyrr01e.'~~3,3-Dihydro-lH-thien0[3,4-c]pyrrole 2,2-dioxides (105) react with DMAD to yield the cycloadduct (106), which reacts further with DMAD to produce a number of polycyclic cycloadducts (107) and (108) as outlined in Scheme 41.'88

,

E

E = CO2Me

ww

SCHEME 4I

Kinetic studies on the influence of substituents on the reactivity and stereoselectivity in the Diels-Alder cycloadditions of para-substituted 6-phenyl-6-methylfulveneshas been reported. 89 5-(Alkylaminomethylene)-6-methyleneperhydropyrimidine-2,5diones (109) with tropone yield 4 2-cycloadducts (110), which rearrange firther to the final adducts, 2,5-ethanopyridoquinazoline(1 1l), cycloheptaquinazoline (1 12), and azocine (113) (Scheme 42). 190 The Diels-Alder reactions between pyranobenzoquinones (114) and 1-azadienes produces the unstable cycloadduct (115), which is readily oxidized to the pyranoquinolinequinone (1 16) which dehydrates to the quinone (1 17) (Scheme 43).19' A review of the diastereofacial selectivity in Diels-Alder reactions has been p r e ~ e n t e d . 'Ab ~ ~ initio calculations on the Diels-Alder addition of ethylene to 5-

'

+


426

YHR

?

tropone

t

RNH2, 1,4-dioxane A I

Me

(109) I

R

0

I Me

I Me

0

I Me

0

NMe2 0

@

*0

p-TSA

0

(117)

SCHEME 43

OH

0

427


substituted cyclopenta-1,3-dienes preclude many of the reported rationalizations of the origin of n-facial se1e~tivity.l~~ In the particular case of 5-phenylthiocyclopentadiene with electron-withdrawing dienophiles, the n-face selectivities are shown to be enhanced by the reactivity of the dien0phi1es.l~~ Also, a semiempirical AM1 method successfully reproduces the facial selectivities and relative reactivities for the DielsAlder reactions of maleic anhydride with C(5)-substituted cyclopentadiene~.'~~~'~~ The n-facial selectivity in the Diels-Alder reactions of [3.3]orthoanthracenophanes with electron-deficient dienophiles is controlled by the adjacent aromatic ring system.'" 1@Substituted buta-l,3-dienes undergo uncatalysed Diels-Alder addition with sugarderived nitroalkenes having D-galacto configurations with complete regioselectivity and diastereofacial specificity.'98 In the presence of TiC13, the asymmetric Diels-Alder reaction between (E)-2cyanocinnamates and butadiene proceeds with high diastereoselectivity.'99 exoSelective Diels-Alder reactions between cyclopentadiene and a,P-unsaturated ketones have been achieved by using the complex aluminium tris(2,6-diphenylpheno~ide).~~~ Transition metal-catalysed intramolecular Diels-Alder reactions of tethered dieneallenes (1 18) provide a high-yield stereospecific synthesis of angularly substituted bicyclic adducts (119) (Scheme 44).201The Diels-Alder cycloaddition of 4-vinyl- 1,2isothiazoline-3-one-1-oxides shows high diastereoselectivity via an unusual exo,syn transition state.202A diastereoselective Diels-Alder reaction between cc,j-unsaturated ketones (120) and isoprene has been developed to prepare substituted cyclohexenes via a five-membered cyclic oxocarbenium ion (121) (Scheme 45).203 Unstable phosphaalkene-Mo(CO)s (122) complexes undergo Diels-Alder reactions with electron-rich 1,3-dienes to yield cycloadducts (123) with high stereo- and regioselectivity (Scheme 46).204 The Diels-Alder reactions of trichlorophosphaethene proceed with normal electron demand.205 Miscellaneous Cycloadditions Ab initio MO theory has been used to investigate the transition structures for the trimerization of acetylene and the addition of ethylene and acetylene to formylketene.206The cyclotrimerization of peduoroalkyl- and peduorooxaalkyl-acetylenes has been studied.207Cobalt-mediated 2 2 2-cycloadditions of alkynes to furans and thiophenes (124; X = 0 and X = S) yield the propellenes (126) rather than the expected cycloadducts (125) via an en01 ether migration (Scheme 47).208 The scope and stereoselectivity of nickel-catalysed homo-Diels-Alder reactions between norborna-

+ +

(119) SCHEME 44

98%

428


(120) R = Pr‘, Bur, Me, Ph

JAMe

4

01

-

TsOH

Me

.M e

SCHEME 45

SCHEME 46

429

14 Addition Reactions: Cycloaddition SiMe3

q : zx ...'

CpCoLz, BTSMA

O

L=CO(hv)

*

\

0

m

S

i

M

'

e

3

cocp SiMe3

(125)

(124)

x=o,s

SCHEME 41

R1

"iNL0 I

\

SCHEME 48

+ +

diene and various dienophiles has been studied.209An extended 3 3 2-cycloaddition between a carbonyl oxide, a nitrone, and an aldehyde produces the novel 3,4-dihydro-l,2,5,7,4-tetraoxazocine(127) as outlined in Scheme 48.'" The regiochemical and stereochemical outcomes of intramolecular 4 3-cycloaddition reactions of alkoxyallylic sulfones with TiC14 have been shown to be dependent on the allylic cation stereochemistry.21 The N-substituted oxyallyl cation (128) formed from a,a-phthalimidoyl dibromide readily undergoes 3 + 4-cycloaddition with furan and cyclopentadiene to form cycloadducts (129) and (130) (Scheme 49).212

+


430 0

NPhth

(129) SCHEME 49

The rates of 4 + 4- and 4 + 2-dimerization of furan-based o-quinodimethanes are retarded by a-methyl substitution. This result supports a two-step mechanism involving rate-determining formation of a diradical intermediate followed by rapid cyclization of the diradicaL213 The fulgides, 3,4-bis(9-anthrylmethylene)tetrahydrofuran-2,5-dione (131; X = 0) and the related 5-dicyanomethylene derivative [132; X = C(CN),] undergo intramolecular 4 4-photo-cycloaddition to the adducts (133; X = 0) and [133; X = C(CN)?], respectively, on exposure to white light (Scheme Transition metal-catalysed intramolecular 5 2-cycloadditions between vinylcyclopropanes and alkynes provide a facile synthesis of cycloheptadienes (134) (Scheme 51).’15 The highly strained bicyclo-annelated benzene trisbicyclo[2.1.llhexabenzene (136) was synthesized by base treatment of 2-chlorobicyclo[2.1.l]hex-2-ene(135) (Scheme 52); ab initio calculations disfavour the intermediacy of bicyclo[2.1.l l h e ~ y n e . ~ ’ ~ The Rh,(OA~)~-catalysedcycloaddition of ethyl diazoacetate with 1,2-methylenedioxybenzene gives the corresponding cycloheptatnenes (137) and (139), while the reaction with 1,2-dimethoxybenzene produces a stable norcaradiene (138) (Scheme 53).’17 3-Benzyl(dimethylsila)prop- 1-enes undergo intramolecular meta-photo-cycloaddition where the heteroatom in the linking tether controls the cyclopropane ring formation.218 The meta-photo-cycloaddition of monosubstituted 4-substituted 5-phenylpent-1-ems always prefers 2,6-addition whereas 1,3-addition is preferred with disubstituted compounds.2193220 A nitrile substituent forces the anisole bichromophore (140) to undergo an intramolecular ortho arene-alkene photo-cycloaddition to the cycloadduct (141) which undergoes thermal electrocyclic ring opening to the bicyclo[6.3.0]undecatriene (142) followed by photochemical disrotatory ring closure to the tricyclic adduct (143) (Scheme 54).’”

+

+


X = 0, (13') C(CN)2

/white

43 1

light

J X

(133) SCHEME 50

Me AgOTf [RhCI(PC13)3] (0.5 rnol%), (0.5 mol%) PhMe* 100 T, 20 111

&

Me02C

---

Me02C'

(134) SCHEME 51

43 2


Bu'OK, Bu'Li

*

THF, pentane 10 mol% Ni(Cp)z -78 to 35 "C

SCHEME 52

'n

(137)

M e O D Me0

(138)

N2CHC02E

+

Rhz(OAc)4, r.t.

R

C02Et

Me0 M e O u o 2 E t

SCHEME 53

CN

o,^c"" OMe

I

M e Me

hv MeCN

M&

Me I

Me

I

A

r

CN

hv

Me0

Me

H

L

(142)

(143) SCHEME 54


r

(144)

433

SCHEME 55

(145)

A novel homo-Cope rearrangement reaction has been reported for the thermolysis of the endo,endo-cycloadduct (144) leading to compound (145) (Scheme 55).222 References 1

2 3 4

5 6

7 8 9

10

11 12

13 14

15 16

17

'

18

'

19

2o

21

'* 23

Mattay, J. and Griesbeck, A. (Eds), Photochemical Key Steps in Organic Synthesis. A Practical Guide to Photochemical Cycloadditions, VCH, Weinheim, 1994. Patalakha, A. E., Vasil'ev, N. V, and Buzaev, A. V, Khim. Fiz., 13, 65 (1994); Chem. Abs., 122, 80553 (1 995). Hu, X., Daxue Huaxue, 8, 29 (1993); Chem. Abs., 122, 9265 (1995). Chen, L., Chen, G., and Fu, X., Wuli Huaxue Xuebao, 10,680 (1994); Chem. Abs., 121,280033 (1994). Marcus, R. A., 1 Am. Chem. SOC.,117,4683 (1995). Kim, T., Sarker, H., and Bauld, N. L., 1 Chem. SOC.,Perkin Trans. 2, 1995, 577. Graziano, M. L., Iesce, M. R., Cermola, F., Ialongo, G., and Giordano, F., 1 Chem. Res. (S), 1995, 176. Takahashi, Y., Ando, M., and Miyashi, T., 1 Chem. SOC.,Chem. Commun., 1995, 521. Smart, R. F! and Wagner, F! J., Tetrahedmn Lett., 36, 5131 (1995). Bradford, C. L., Fleming, S. A., and Ward, S. C., Tetrahedron Lett., 36, 4189 (1995). Broeker, J. L., Eksterowicz, J. E., Belk, A. J., and Houk, K. N., 1 Am. Chem. SOC.,117, 1847 (1995). Andrew, D., Hastings, D. J., and Weedon, A. C., 1 Am. Chem. SOC.,116, 10870 (1994). Adamson, G., Beckwith, A. L. J., Kaufmann, M., and Willis, A. C., 1 Chem. SOC.,Chem. Commun., 1995, 1783.

Chung, W . 3 , Liu, Y. D., and Wang, N.-J., 1 Chem. Soc., Perkin Trans. 2, 1995, 581. Chung, W.-S., Wang, N.-J., Liu, Y.-D., Leu, Y.-J., and Chiang, M. Y., 1 Chem. SOC.,Perkin Trans. 2,1995, 307.

Hyatt, J. A. and Raynolds, €? W., Org.React., 45, 159 (1994). Ali, Sk. A., Muqtar, M., and Al-Huiini, A. H., 1 Chem. SOC.,Perkin Trans. 2, 1995, 1001. Hosoya, T., Hasegawa, T., Kuriyama, Y., and Suzuki, K., Tetrahedmn Lett., 36, 3377 (1995). Zemribo, R. and Romo, D., Tetrahedron Lett., 36, 4159 (1995). Concepcion, A. B., Maruoka, K., and Yamamoto, H., Tetmhedmn, 51, 401 1 (1995). Lopez, R., Suirez, D., Ruiz-Lopez, M. F., Gonzalez, J., Sordo, J. A,, and Sordo, T. L., 1 Chem. Soc., Chem. Commun., 1995, 1677. Croce, I? D., Femccioli, R., and La Rosa, C., Tetrahedron, 51, 9385 (1995). Dehmlow, E. V, Bollmann, C., Neumann, B., and Stammler, H.-G., Liebigs Ann. Chem., 1995, 1915.

26

Schmittel, M. and von Seggem, H., Liebigs Ann. Chem., 1995, 1815. Matsuoka, T., Oiso, S., Eto, M., and Harano, K., Tetrahedmn Lett., 36, 8031 (1995). Padwa, A,, Meske, M., Murphree, S. S., Watterson, S. H., and Ni, Z., 1 Am. Chem. SOC.,117, 7071

27

Yamazaki, S., Tanaka, M., Inoue, T., Morimoto, N., Kumagai, H., and Yamamoto, K., 1 Org. Chem., 60,

28

Bravo-Zhivotovskii, D., Zharov, I., Kapon, M., and Apeloig, - Y., 1 Chem. SOC.,Chem. Commun., 1995,

24

25

(1995).

6546 (1995). 1625.

29 30 31

32 33 34

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67 68 69

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Zhulin, Y M., Koreshkov, Y.D., Kel'tseva, M. Y, and Bogdanov, Y S., Dokl. Akud. Nauk, 338, 344 (1994); Chem. Abs., 122, 213333 (1995). Bachrach, S. M., 1 Org Chem., 60, 4395 (1995). A1 Hariri, M., Pautet, F., Fillion, H., Domard, M., and Fenet, B., Tetrahedron, 51, 9595 (1995). de Echagiien, C. 0. and Ortufio, R. M., Tetrahedron Lett., 36, 749 (1995). 184 Zylber, J., Tubul, A., and Brun, P., Tetrahedron: Asymmehy, 6, 377 (1995). Heller, H. G., Hughes, D. S., Hursthouse, M. B., Levell, J. R., and Ottaway, M. J., 1 Chem. SOC.,Chem. Commun., 1995, 837. Domingo, L. R., Jones, R. A,, Picher, M. T., and Sepulveda-Arques, J., Tetrahedron, 51, 8739 (1995). Jursic, B. S. and Zdravkovski, Z., 1 Heterocycl. Chem., 31, 1429 (1994). 188 Ando, K., Kankake, M., Suzuki, T.,and Takayama, H., Tetrahedron, 51, 129 (1995). Gugelchuk, M. M., Chan, I? C.-M., and Sprules, T. J., 1 (3%. Chem., 59, 7723 (1994). 190 Kobayashi, T., Ikuno, K., Noguchi, M., and Kakehi, A,, 1 Chem. Soc., Perkin Trans. 1, 1995, 1453. 19' Zuloaga, F., Tapia, R., and Quintanat, C., 1 Chem. Soc., Perkin Trans. 2, 1995, 939. I 92 Coxon, J. M. and McDonald, D. Q., Adv. Detailed React. Mech., 3,131 (1994); Chem. Abs., 121,280022 (1994). Iy3 Poirier, R. A., Pye, C. C., Xidos, J. D., and Bumell, D. J., 1 Urg. Chem., 60, 2328 (1995). 194 Ishida, M., Kakita, S., and Inagaki, S., Chem. Lett., 1995, 469. 195 Werstiuk, N. H. and Ma, J., Can. 1 Chem., 72, 2493 (1994). 196 Adam, W., Jacob, U., and Prein, M., 1 Chem. Soc.. Chem. Commun., 1995, 839. 197 Mataka, S., Ma, J., Thiemann, T., Rudzinski, J. M., Sawada, T., and Tashiro, M., Tetrahedron Lett., 36, 6105 (1995). Iq8 Serrano, J. A,, Caceres, L. E., and Romh, E., 1 Chem. Soc.. Perkin Trans. I , 1995, 1863. 19' Cativiela, C., Avenoza, A,, Paris, M., and Peregrina, J., 1 O x , Chem., 59, 7774 (1994). Maruoka, K., Imoto, H., and Yamamoto, H., 1 Am. Chem. Soc., 116, 12115 (1994). Wender, P. A,, Jenkins, T. E., and Suzuki, S., 1 Am. Chem. SOC., 117, 1843 (1995). 202 Bell, A. S., Fishwick, C. W. G., and Reed, J. E., Tetmhedron Left., 36, 7713 (1995). 203 Sammakia, T.and Berliner, M. A., 1 Org. Chem., 60, 6652 (1995). Trauner, H., de la Cuesta, E., Marinetti, A., and Mathey, E, BUM SOC. Chim. Fr., 132, 384 (1995). ' 0 5 Teunissen, H. T., Hollebeek, J., Nieuwenhuizen, F! J., van Baar, B. L., de Kanter, F. J. J., and Bickelhaupt, F., 1 Urg. Chem., 60, 7439 (1995). '06 Wagenseller, F! E., Bimey, D. M., and Roy, D., 1 Org. Chem., 60, 2853 (1995). '07 Batizat, D. V, Glazkov, A. A,, Ignatenko, A. V, Yarosh, A. A,, and Ponornarenko, V. A,, Izv. Akad. Nauk, Ser Khim., 1994, 1789; Chem. Abs., 123, 55188 (1995). 208 Boese, R., Harvey, D. F., Malaska, M. J., and Vollhardt, K. P. C., 1 Am. Chem. SOC.,116, 11153 (1994). 2oy Lautens, M., Edwards, L. G., Tam, W., and Lough, A. J., 1 Am. Chem. Soc., 117, 10276 (1995). 210 Satake, S., Ushigoe, Y., Nojima, M., and McCullough, K. L., 1 Chem. SOC., Chem. Commun., 1995, 1469. Harmata, M., Gamlath, C. B., Barnes, C. L., and Jones, D. E., 1 Urg. Chem., 60, 5077 (1995). 212 Walters, M. A., Arcand, H. R., and Lawrie, D. J., Tetrahedron Lett., 36, 23 (1995). 213 Leung, M. and Trahanovsky, W. S., J. Am. Chem. Soc., 117, 841 (1995). 214 Heller, H. G. and Ottaway, M. J., J. Chem. Sac., Chem. Commun., 1995, 479. 215 Wender, P. A., Takahashi, H., and Witulski, B., 1 Am. Chem. Soc., 117,4720 (1995). Frank, N. L., Baldridge, K. K., and Siegel, J. S., 1 Am. Chem. Soc., 117, 2100 (1995). 2'7 Matsumoto, M., Shiono, T., Mutoh, H., Amano, M., and Arimitsu, S., J. Chem. SOC., Chem. Commun., 1995, 101. Blakemore, D. C. and Gilbert, A., Tetrahedron Left., 36, 2307 (1995). 219 Barentsen, H. M., Sieval, A. B., and Cornelisse, J., Tetrahedron, 51, 7495 (1995). Barentsen, H. M., Talman, E. G., Piet, D. F!, and Cornelisse, J., Tetmhedron, 51, 7469 (1995). 221 Nuss, J. M., Chinn, J. P., and Murphy, M. M., 1 Am. Chem. SOC.,117, 6801 (1995). 222 Hochstrate, D. and Klirner, F.-G., Liebigs Ann. Chem., 1995, 745.

CHAPTER 15

Molecular Rearrangements A . W. MURRAY Department of Chemistry. University of Dundee Aromatic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzene Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heterocyclic Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sigmatropic Rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [3.3 ].Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Claisen and related rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . Cope and related rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . [2,3 ]-Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 1,3 ]-Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . [ 1.5 ].Migrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrocyclic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anionic Rearrangements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cationic and Related Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . Rearrangements in Natural-product Systems . . . . . . . . . . . . . . . . . . . . . . . Rearrangements Involving Electron-deficientHeteroatoms . . . . . . . . . . . . . . Rearrangements Involving Organometallic Compounds . . . . . . . . . . . . . . . . Rearrangements Involving Ring Opening . . . . . . . . . . . . . . . . . . . . . . . . . Isomerizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tautomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

439 439 450 462 462 462 471 476 483 486 487 490 498 505 519 523 527 530 539 540 542

Aromatic Rearrangements

Benzene Derivatives The kinetics of the Fischer-Hepp rearrangement of N-nitrosodiphenylamine in anhydrous hydrochloric acid have been studied’ in methanol.toluene . 1,2.Diphenylhy . drazine has been reported’ to rearrange exclusively to o-semidine in the presence of square-planar rhodium(1) complexes. The authors have proposed that the rearrangement involves the initial coordination of 1 Zdiphenylhydrazine as a bidentate ligand to rhodium(1) when steric constraints place the phenyl rings of coordinated substrate into the perfect position to allow the exclusive formination of o-semidine via a mechanism similar to the acid-catalysed benzidine rearrangement. Treatment of N-aryl-Nmethoxyacetamides bearing strong electron-donating groups on the aryl ring. with A1C13-Me2S. has been shown3 to result in heterolytic cleavage of the N - 0 bond and

.

Organic Reaction Mechanisms 1995 . Edited by A . C . Knipe and W. E. Watts 0 1997 John Wiley & Sons Ltd

439


440

introduction of a methylsulfanyl group at the ortho orpara position of the aryl ring. The photochemical rearrangement of o-phenylhydroxylamine has been studied4 and 0aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamineshave been rearranged5 in acetwhich, in onitrile to 1,5-dimethyl-5-aryloxy-6-N-acetyliminocyclohexa-l,3-dienes, aqueous solution, produce m-aroyloxy- and m-hydroxy-2,6-dimethylacetanilidesin an H+-catalysed reaction, and the corresponding para products in a non-catalysed reaction. Trapping results have determined6 the nature of the nitrenium-carboxylate ion-pair intermediates in the hydrolysis of these hydroxylamines. A novel type of rearrangement has been reported’ to occur when aromatic bis(imides), which are usually chemically inert, are treated with alkali metal hydroxides in alcohols. A likely mechanism for this rearrangement is shown in Scheme 1, where the first step of the reaction is similar to the benzilic rearrangement to which it is vinylogous. The Smiles rearrangement of a-aminodiphenyl ethers has been reviewed8 and the cyclization of 4-chloro-2,3,5,6-tetrafluoro-2’-amino-substituted diphenyl ethers to phenoxazines has been studied.’ A Smiles rearrangement has been utilized” in a novel approach to 1-awl- 1H-4,l ,2-benzoxadiazinesYand chromium tricarbonylpromoted @so-Smilesrearrangements of 0-phenyl to N-phenyl derivatives of ephedrine and pseudoephedrine have been reported” (Scheme 2). Mechanistically informative Brsnsted plots for two examples of Smiles photo-rearrangements that are regiospecific for the ring position meta to a nitro group have been presented.” The reaction of thioquinanthrene (1) with alkali metal alkanethiolates has been found13 to proceed via the Smiles rearrangement of 3’-quinolinethiolate (2) to 4’-quinolinethiolate (3) to give 4,4’-dialkylthio-3,3’-diquinolinylsulfides (4) as the final products, and the reaction of 4-nitro-8-hydroxyquinolinewith (diacetoxyiodo)benzene has been shown to afford aryliodonioquinoline-8-olates(5). Subsequent thermal migration of the aryl group from

RSNa

SR

SR’

(4)

(3)

441

15 Molecular Rearrangements

N-u

-

\ /

‘0

w

0

\O

SCHEME 1

Me

I

BuLi

I

-

-Cr(C0)3

1 SCHEME 2

iodine to oxygen and photochemical migration from oxygen to nitrogen have been postulatedI4 to account for the formation of the intensely coloured arylquinolinium8-olates (6) (Scheme 3), the ultimate products of this reaction. New heterocyclic ring-annulated azepines have been prepared15 in good yields by capturing didehydroazepines intramolecularly with an amino group, during the photolysis of 2-(w-aminoalkyl)phenyl azides. The Fries rearrangement of phenyl acetate, p-tolyl acetate, and phenyl benzoate has been investigated16 using the H-form of various zeolites as catalysts, and the Fries rearrangement of acyloxynaphthalene to the corresponding hydroxynaphthyl ketones

442


rt+

-

0-

0 I

SCHEME 3

has been shown" to proceed smoothly using a catalytic amount of scandium trifluoromethanesulfonate. The photo-Fries rearrangement of naphthyl acetate in supercritical carbon dioxide has been used" to probe the existence of supercritical solvent-solute clusters. The photo-Fries rearrangement of 2,2,2-trichloroethyl-3,5bis(benzoy1oxy)benzoate has been investigated,19 and the rate constants for the [ 1,3]and [ 1,5]-sigmatropic hydrogen shifts in the ground state of the photo-Fries rearranged intermediates of phenyl acetate, produced by laser flash photolysis, have been measured directly.20 It has been shown21 that, in a homogeneous solution, the photo-Fries rearrangement of 2,5-disubstituted phenyl acetates yields o-hydroxyacetophenones as major products, and a new approach to the synthesis of 7,8-dioxygenated tetrahydroisoquinoline alkaloids, based on the photo-Fries rearrangement of esters derived from 3-hydroxy-4-methoxyphenylacetonitrile, has been reported.22Pinacolone photolysis in the presence of phenols has led to phenyl acetates and hydroxyacetophenones. The process has been explained23by Nomsh type I cleavage and subsequent hydrogen abstraction from the phenol by the t-butyl radical to give rise to acyl-aryloxy radical pairs which recombine, thus constituting an intermolecular photo-Fries rearrangement. It has been shown24that the solid P-cyclodextrin complex of benzyl

443


phenyl sulfone, upon irradiation, undergoes a unique intramolecular rearrangement yielding exclusively o-methyldiphenyl sulfone. A kinetic study of the acid-catalysed cleavage of phenylthioacetic acid by sodium perborate has been undertaken.25A mechanism involving an intramolecular Pummerertype rearrangement, followed by cleavage, has been suggested to account for the formation of thiophenol in the process. A facile two-step preparation of oaryloxyphenols has been described26 in which the key step is the intramolecular trapping of an a-keto sulfonium salt prepared by Pummerer rearrangement of a symmetrical 0-hydroxyaryl sulfoxide to give an orthoquinone mono(monothioaceta1). Treatment of p-sulfinylphenol derivatives (7; R = H) with trifluoroacetic anhydride has initiated2’ a Pummerer-type rearrangement on aromatic rings and concomitant desulfurization to give 1 : 1 mixtures of the corresponding p-quinones (8) and p dihydroquinones, while similar treatment of p-(phenylsulfiny1)phenyl ethers (7; R = alkyl) has yielded protected dihydroquinone derivatives (9), presumably via the direct @so substitution of the sulfinyl group by a trifluoroacetoxy group.28The recently reported29 Pummerer-induced rearrangement of aryl amido sulfoxides with trifluoroacetic anhydnde represents a highly efficient method for the synthesis of oxindole and tetrahydroisoquinoline ring systems. The details of this new rearrangement are summarized in Scheme 4.A novel preparation of 1,3-oxathiane derivatives through the Pummerer rearrangement of y,b-unsaturated sulfinyl compounds has been described3* and a plausible mechanism for the process has been outlined (see Scheme 5). The presence of an o-hydroxymethyl group in aryl methyl sulfoxides has been found3lS3’ to ensure the exclusive formation of chloromethyl sulfides, mediated via an intramolecular

6 4 -

0

0 0

II II

CF3COCCF3 R=H

s-0 I

+

0

s-o-

CF3CO

IW

R

R’

(7)

1

\

R = alkyl

I

OCOCF3

0

OCOCF3

444

Organic Reaction Mechanisms 1995 Ar

Ar

I

-CF,CO*H

I

R

.-' I R

I R

SCHEME 4 H

J SCHEME 5

f


445

attack, to yield an alkoxysulfonium salt (see Scheme 6), thus preventing the formation of siloxymethyl sulfides via a sila-Pummerer rearrangement. The 1,a-migration of the phenyl group in the acid-catalysed rearrangement of 4hydroxy-4-phenylcyclohexa-2,5-dienonehas been compared with that of the migration of the ethyl (or vinyl) group in 4-hydroxy-4-ethyl(or vinyl)cyclohexa-2,5-diene.The slower phenyl group migration is considered to be due to the electronic cloud overlap between the phenyl group and protonated dienone in the transition state.33 Azaspirodienones (1l), synthesized via intramolecular cyclization of p-hydroxybenzylacetoximes (lo), have been t r an ~ f o r m edinto ~ ~ quinolines (12) via a dienone-phenol rearrangement, while thermal cyclization of p-benzoquinone imine derivatives (13) has yielded spirodienone diazacarbocycles, such as (14), which have been converted35into diazepine (15) via a dienonephenol rearrangement. The photochemical behaviour of 5,5-diphenylcyclohexa-1,3-diene has been inve~tigated~~ and the significant role played by spin-orbit coupling and symmetry in controlling the mode of phenyl migration and ring contraction has been delineated. One of the major products 4,6,7-trimethyl-l(2’,2’,2’-trinitroethylnaphthalene(18), obtained on photolysis of 1,4,6,7-tetramethyl-r1-nitro-t-4-trinitromethyl-1,4-dihydronaphthalene(16), has been postulated37 to arise via 1,4,6,7-tetramethyl-t-2-nitro-r1-trinitromethyl-1,2-dihydronaphthalene (17), as shown in Scheme 7. AM1 calculations with full geometry optimization have been carried out3* for polyfluorobenzenes and their protonated forms. A mechanism (part of which is outlined in Scheme 8), involving ips0 protonation of biphenyl followed by 1,2-migration of a phenyl group via the novel phenonium ion (19) and rearomatization, has been postulated39to explain the results of a labelling study of the acid-catalysed degenerate isomerization of biphenyl. A comprehensive study has been undertaken4’ of the structure and reactivity of free arylium ions, while two stable isomers of the benzenium ion, the most stable of which appears to be the face-centred n-complex, have been identified41 by CIDMS. Cram’s phenonium ion (20) has been obtained by the independent route of protonation of benzocyclobutene under superacidic stable-ion conditions, and shown42to be de fact0 a spirocyclopropylbenzeniumion and not a nonclassical carbocation. A novel rearrangement has been observed43 during the synthesis of poly(phtha1idylidenearylenes) by the Friedel-Crafts self-condensation of 3-aryl-3-chlorophthalides. Thus monomers containing substituents at the 4- and 6-position of the phthalide ring were found to rearrange in the course of the polymer synthesis. Trifluoroacetic acidcatalysed rearrangement of 1,Cdihydro- 1,5,8-trimethoxy-1,Cethenonaphthalene has been shown to produce precedented products of bicyclic rearrangement along with 2,4’,5-trimethoxybiphenyl,the product of a remarkable retro-Friedel-Crafts protodealkoxyalkylative fragmentation of the bicyclic system44 (Scheme 9), while a 14C tracer study has e ~ t ab l i s h e dthe ~ ~ likely pathways that operate in the acid-catalysed rearrangement of 1,4-dihydro-1-methoxy-1,Cethenonaphthalene and its 5,6,7,8-tetrahalogeno derivative into the corresponding 3,4-dihydro-l,4-ethenonaphthalen-2( 1H)ones. Exposure of u-tocopherol (21) to nitric oxide in air-saturated cyclohexane has been reported to lead to a complex mixture of products, one of which has been identified46 as the novel 2,3-dimethyl-4-acetyl-4-hydroxy-5-nitrosocyclopent-2-enone


446

1

M€!o*c&uMe HO

OH

/

derivative (22). It has been demon~trated~~ that 2,6-dimethoxycinnamic acid ethyl ester undergoes an interesting rearrangement to afford the same calix[4]resorcinarenes as those obtained from the 2,4-dimethoxy isomer. Cyclo-condensation of 2-alkylresorcin01s with 1,3,5-trioxane has produced4*both calix[4]resorcinarene and calix[6]resorcin-

I5 Molecular Rearrangements

he (18)

447

8

he

SCHEME 7

/

arene, the latter being isomerized to the former on prolonged heating in acid. An intermolecular migration of sulfonyl groups in 1,3-bis(triflate) and 1,3-bis(rnesylate) derivatives of p-t-butylcalix[4]arene has been found to take place49 in the presence of both a palladium catalyst and chloride. A report has appeared'' on the synthesis of


448

@

H+

___)

+OMe

OMe

M e 0 - - -H

qoMe

Me0

-H+

OMe

Me ~.

OMe

OMe SCHEME 9

topologically chiral catenanes bearing sulfonamide units. Flash vacuum pyrolysis of 1,2-dialkoxybemenes (23) has been shown to yield 0-hydroxy carbonyl compounds whose formation can be rationalized5’ by the radical pathways outlined in Scheme 10, while 1-alkyl-4-hydroxyoxindoleshave been obtained” by a 1,3-migration of the hydroxyl group on irradiation of 1-alkyl-3-hydroxyindoles in degassed solutions. A free-radical mechanism has been suggested53to account for the products observed on thermolysis of ketoxime arenesulfonates, and 1,2-radical rearrangements of aryl, k a n y l , and thiophenyl groups from carbon to nitrogen, using azido groups as radical precursors, have been observed for the first time.s4 The 1,2-aryl rearrangement has been applied to the synthesis of phenanthridine derivatives from 6-fluorenyl aides. 1A5,3AsBenzodiphospholes (24), on heating, have been reported” to undergo a phosphoranephosphane rearrangement, (24) -+(25), which results from the migration of a phenyl ring and formation of a biphenyl moiety at the ylidic phosphorus atom. An interesting rearrangement involving a novel 1,Chydrogen shift from a carbon of an aromatic nucleus to an sp2 silicon atom of a silicon-carbon double bond has been postulateds6


449

1

-R2cn, R‘

SCHEME 10

heat

1.4-H

for the conversion of 1-naphthyl-1-methylsilane (26) into 1-methyl-1-sila-acenaphthene (27). A mechanistic study of the thermal cyclo-isomerization of 1,4-diphenylbut-l-en-3yne has been ~ndertaken,~’ and a double-labelling experiment has demon~trated~~ that a 1,%-sty1371 migration is involved in the process. Ab initio quantum mechanical methods have been employed59to study [4]paracyclophane and its Dewar benzene isomer. This study indicated that the boat-shaped benzene, with the same geometry as [4]paracyclophane, has the same magnetic susceptibility as the hypothetical cyclohexatriene.


450 Heterocyclic Derivatives

5,5-Dimethy1-3-phenyl-1-pyrroline-1-oxide (28) has been found6’ to undergo an unprecedented acid-catalysed 1,3-0xygen migration to give the 1-pyrroline (29), and a base-catalysed 1,2-0xygen migration to give the pyrroldin-2-one (30). When heated in an alcoholic solvent, 4-substituted 3-aroyl-1-alkylpyrrolidines (31) have been found61 to afford 4-substituted 1-alkyl-2-aryl-3-methylpyrrolederivatives (32) by a thermally induced retro-Michael addition (Scheme 1l), and the thermal rearrangement of 2,5diaryl-3,3,4,4-tetracyanopyrrolidineshas been studied.62 The tosyl group of 3,4disubstituted 2-tosylpyrroles has been easily transferred from the 2- to the 5-position by treatment of these compounds with trifluoroacetic acid.63A possible mechanism for this rearrangement is shown in Scheme 12. The rearrangement of some N-substituted pyrrolo[3,4-c]pyrroles to the corresponding pyrrolo[3,4-c]pyridines has been reported.64 The mechanism outlined in Scheme 13 has been postulated6’ for the acidcatalysed rearrangement of 1-arylindoles to SH-dibenz[b,flazepines, and the formation of 1,2,3,4-tetrahydro-j-carbolinein the Pictet-Spengler reaction has been studied66 using an MNDO approach. Ph

Ph base

Me M

eH a o

SCHEME 11

OH

45 1


J

H

SCHEME 12

I

Ph

I

Ph

I

ox

Ph

i

-xo-

SCHEME 13

A convenient synthesis of the coffee and caramel flavour component 2-methylfuran3(2H)-one has been developed6’ by acid-catalysed rearrangement of 2-methoxy-2methyltetrahydrof-3-one (Scheme 14). Semiempirical MO calculations have been used6*to explain the formation of (37)as the product obtained from the reaction of 4acylfuran-2,3-diones (33) with ketenimines (34). The rearrangement of the primary


452

H+

OMe

Me

H

SCHEME 14

cycloadduct (35) via intermediate (36) appears to be the most feasible pathway. Condensation of amidines with 2-amino-3-cyanofUrans (38) has been reported69 to yield 2-substituted 4-aminopyrrolo[2,3-4pyrimidines by a ring opening-ring recyclization sequence of reactions (see Scheme 15) by which the starting furan 2-amino nitrogen becomes the pyrrole nitrogen of the final product, and one of the amidine nitrogens becomes N(l) of the fused pyrimidine ring. During the photo-reaction of thiobenzamide with substituted furans (39), transformation of the furans to pyrroles (Scheme 16) was found to in preference to p-benzoylation, while photoirradiation of 3-alkoxy-6-chloro-2-(2'-furyl)-4-oxo-4H-1-benzopyrans(40) has led to the formation of methyl 8-chloro-1O-oxo-2-phenyl-2,3,4,1O-tetrahydropyrano-

453


SCHEME 15

SCHEME 16

[3,2-b][ llbenzopyran-3-yl acetate (45). It was p ~ s t u l a t e d that ~ ~ the reaction proceeds through the formation of 8-chlor0-4-phenyl-3a,4,6,11 b-tetrahydrofuro[2’,3’ : 4,5]pyrano[3,2-b]benzopyran-6-one(41), which subsequently undergoes a ring contraction-ring expansion mechanism to give the cyclopropanecarbaldehyde (42) followed by its rearrangement to ketene (44) via the carbene (43) to furnish ester (45). In addition to the expected substitution product (47), the unexpected product (48) was also obtained from the reaction of 3-bromo-2-nitro-benzo[b]thiophene with various mines. The formation of (48) represents a novel aromatic nucleophilic substitution reaction and a number of alternative intermediates, e.g. (46), have been proposed7’ to account for the observation.

454


Ph

OCHzPh 0

0

H

t

R=H

1

3-Acetyl-2-pyrazolines have been to 3-methyl-4(1H)-pyridazinones. The mechanism of the themolytic ring opening of 5-azido-4-formyl-3-methyl1phenylpyrazole to yield (4-cyanopyrazol-3-ylmethy1)pyrazoleshas been in~estigated,~~


455

and lH-pyraz0[3,4-dlthiazole-5-carbonitriles(51) have been obtained75by treating 4unsubstituted 5-aminopyrazoles (49) with Appel's salt (50) at room temperature in the presence of 2,6-dimethylpyridine. The mechanism of the thermal rearrangement of 1,4dinitroimidazole to 2,4-dinitroimidazole has been interpreted76as a [ 1,5]-sigmatropic type shift, and the rearrangement of 1-(dimethylsulfmoyl)-5-imidazolecarboxaldehyde to the corresponding 4-carboxaldehyde has been considered to proceed by the pathway outlined in Scheme C1

R'

1

(49)

\

OHC

-4) CI

-

R2

OHC

-4-$

- 4.-

S02NMe2

Nu-

R'

2

OHC -

/

OHC

SCHEME 17

A frequency descriptor-aided study78has been made of the rearrangement of l-oxa2-moles. 5-Azidoisoxazoles containing an unsaturated group in the 4-position have been found to rearrange by two discrete processes to yield, either bicyclic isoxazoles which result from direct attack of the a i d e (or nitrene) on the unsaturated group, or

456


0

SCHEME 18

monocyclic pyrroles and pyrazoles which result from ring opening followed by bond reorganization and subsequent ring closure.79Naphth12,l -dJisoxazoles, 1llbenzofuro[6,7-dJisoxazoles, -[5,4-d]diisoxazoles, and 1,2-benzisoxazoles have been prepared8' by the thermal decomposition of dimethyl 2-[5-aryl(or fury1 or alkenyl)]-3methylisoxazol-4-yl)-2-oxo-1-diazoethylphosphonatesthrough a tandem Wolff rearrangement-benzannulation sequence. It has been demonstrated*' that the thermal rearrangement of spirocyclopropaneisoxazolidinescan be utilized in an intramolecular fashion to lead to interesting bicyclic tetrahydropyridones with high selectivity. NBenzoylamino acids have been found to react with excess oxalyl chloride followed by addition of alcohols to afford 4-substituted 2-phenyloxazole-5-carboxylates82 (Scheme 18). A novel rearrangement of the oxazolidin-2-thione (52) to 1,3-oxazin-4-one (53), which involves attack of the side-chain hydroxyl on the thiocarbonyl group, has been

457


reported.83 and an interesting oxazoline to thiazoline conversion, which involves thiolysis of oxazolines with H2S in methanol-triethylamine and subsequent cyclodehydration of the corresponding thioamide (Scheme 19), has been achieved.84 A straightforward two-step sequence capable of converting simple thiazoles into different sets of ring-expanded N,S-heterocycles of various ring sizes has been developed85(Scheme 20), and a novel rearrangement has been discovered86during an investigation of the lithium-bromine exchange reaction of bromothiazole derivatives and their subsequent reactions with various electrophiles. The 1,4-dipolar cycloaddition of 3-phenyl-7[~-phenyl(carbamoyl)]-5,6-dihydroimidazo[2,1-b]thiazolium betaine (54) with a series of aliphatic alkylating agents have been found to yield a variety of new ring-expanded cycloadducts such as (55).87

SCHEME 20

4-Alkyl-substituted 4H-1,2,4-triazoles have been found to undergo thermal rearrangement to the corresponding 1-alkyl-substituted triazoles in the crystalline in the presence of dimethyl state,88while pyrolysis of 4-aryl-5-amino-l,2,3-triazolines acetylenedicarboxylate has produced" 1-aza-l,3-dienes and 2-pyrrolines via the intermediacy of 2-aminoaziridines. Phosphonium bromides (56) on treatment with base have been found to afford the stable phosphorylides (57), which upon refluxing in xylene give good yields of pyrazolo[4,3-dJ(2,3)-benzodiazepines(58) via a Dimroth-


458

like rearrangement." 2-(Benzotriazol-1-yl)enamines (59), readily available from lithiated 1-(arylmethyl)benzotazole and nitriles, have been found to undergo facile rearrangement to 2,4-diarylquinazolines. A plausible mechanism for this novel rearrangement" is shown in Scheme 21.

R R4 R'

3 \

m

R

2

1

NH

R' SCHEME 21

-

R3m R4

\

R'

NH2


459

-

-

hv

-PhCN

+ZH

SCHEME 22

Desilylation of N-trimethylsilylmethyl-1,2,5-oxadiazolium salts and deprotonation of the N-methyl analogues have been shown to initiate ring expansion to 6H-1,2,5oxadiazine~.~'The photochemical behaviour of 1,2,4- and 1,2,5-0xa&azoles has been reviewed,93 and the irradiation of 3-(acetylamino)-4-phenyl-1,2,5-oxadiazolehas been developed94as a new methodology for the synthesis of 3-substituted 1,2,4-oxadiazoles (Scheme 22). A study has been made95 of the mechanism of formation of 1,3,4thiadiazol-2(3H)-ones during the reaction of hydrazonoyl halides with 1,3,4oxadiazole-2(3H)-thiones. The Boulton-Katritzky rearrangement of 5-(cyanoimin0)1,2,4-thiadiazolines has been reported,96 and the rearrangement of 5-amino-l,2,3thiadiazole-4-carbothioamides(60) to (61) via ring cleavage has been studied9' by NMR.

The thermal rearrangement of 1-alkoxy-5-aryltetrazolesto 3-alkyl-5-aryltetrazole1oxides has been i n ~ e s t i g a t ed . ~ ~ The hydrolysis of 2-chloro-3,5-dinitropyndine (62) to the 2-pyridone (64) has been shown to proceed through the remarkable intermediate (63), whose formation and disappearance have been followed separately in a number of mixed solvents.992,4,4,6Tetraaryl-4H-thiopyrms (65) have been found to react smoothly with chlorine to yield the corresponding 3,5-dichloro derivatives. However, with longer reaction times and higher temperatures, trichloro derivatives (66) were found to be the major products and their formation was explainedIoOby the mechanism outlined in Scheme 23. A mechanism involving a 'benzva1ene'-type intermediate has been proposed"' to explain the first reported thermal rearrangement reaction of a phthalazine to a quinazoline, while a plausible explanation for the formation of products (68) from the pyrolysis of N-( 1-phthalazinyl)-N-cycloalkylidenehydrazines (67) has been proposed"' (Scheme 24). Photochemical transformations of pyrazolopyridazine (69) have been rep~rted,"~a novel thermal rearrangement in the pyrido[ 1,2-a]pyrirnidine series has been ob~erved,''~and 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidinesupon heating in

460


HO-

J

Ar Ar

Ar

SCHEME 23

water or ethanol have been found to undergo ring opening followed by decarboxylation to yield phenylpyrimidylmethanol and phenylpyrimidyl methyl ethers."' Unprecedented transformations of 1,3-dialkyl-5-formyluracilsto 1,3-dialky1-7hydroxyquinazolines have been observedIo6during the treatment of the former with a series of carbanion precursors such as ethyl acetoacetate and the like, while a new type of rearrangement has been added to those already known for the glycol half-ethers


46 1

mCN

H7 I?

of uric acid.'07 Fervenulone (70) has been shown to undergo an unprecedented and facile ring contraction'08 (Scheme 25) upon attempted N-alkylation with I-butyl bromoacetate. Alper et al.'09 have established that a variety of suitably substituted 1,3thiazanes are able to undergo a unique iridium-catalysed disproportionation reaction to give thiazines in moderate to good yields. As illustrated by the simplified scheme (71) 3 (72) -+ (73), chromium(0)-promoted 6 2-cycloaddition-thallium(III)-mediated oxidative rearrangement of N-substituted azepines has afforded'" a novel and efficient entry into tropane alkaloid building blocks. It has been postulated" that flash vacuum pyrolysis of 2,3-dihydro-l,4diazepines involves interaction of the saturated portion of the molecule with the vinamidine system and causes [1,5]-hydrogen shifts, while at higher temperatures ring contraction to yield pyrazines has been established as the main pathway. Microwave heating of pyrrolo- and pyrido-[2,l-c][ 1,4]benzodiazepinediones in boiling phosphorus oxychloride has produced a new rearrangement' l2 leading to cyclopenta[b][1,4]benzodiazepines and tetrahydrodibenzo[b,fl[1,4]diazepines. A mechanism based on tightly bound ion pairs and transfer of the CH2CH2C(0)C (Me)=CH2 moiety to the nitrogen centre has been p r o p ~ s e d ' ' ~ for the thermal rearrangement of (2-oxyethylmethacryl)pentachlorocyclotriphosphazene (74) to (75).

+

'

462


Br/’C02Buf

CO~BU‘

SCHEME 25

(74)

(75)

Sigmatropic Rearrangements [3,3]-Migrations Ciaisen and related rearrangements An account which details the insights, arguments, and events which have shaped our current vision of the nature of the transition states of pencyclic reactions has appeared.’14 A quantum chemical study’” has been made of the Claisen rearrangement, and the Claisen rearrangement of chorismate to prephenate, and models for the catalysis of this reaction by the enzyme chorismate mutase, have been studied’I6 using


463

Hartree-Fock and density functional theories. A simple and generalized method which gives more detailed information than that from the Woodward-Hofiann rule and the usual molecular theories has been developed’ l 7 for investigating non-adiabatic transitions in photochemical [i,/l-sigmatropic rearrangements. A new treatment of solvation effects on the Claisen rearrangement has been reported,*18a factor analysis of solvent effects on reactions has been applied”’ to the Claisen rearrangement, and a hybrid, explicit solvent and continuum model has been described and used’” to study the acceleration of the Claisen rearrangement of allyl vinyl ether in aqueous medium. Sehgal et a1.’” have carried out a combined quantum mechanical and statistical mechanical investigation and provided computational evidence of substitution patterns that can amplify the solvent effect on Claisen rearrangements in water. A new chiral Lewis acid for the asymmetric Claisen rearrangement has been designed. The Claisen rearrangement of 6-methoxyallyl vinyl ether has been catalysed by a soluble diarylurea. Evidence has been presentediz3to show that the urea stabilizes a dipolar transition state by hydrogen bonding. A metal-mediated one-pot synthesis of cyclopentanones from allyl vinyl ethers via a tandem Claisen rearrangement and hydroacylation has been reported,’24 an improved procedure for the Pd(I1)-catalysed Claisen rearrangement via in situ enol ether exchange has been described, while the Pd(I1)-catalysed Claisen rearrangements of the geometrical isomers of crotyl en01 ether have been shown to exhibit identical anti diastereoselection,lZ6 in marked contrast to the high stereospecificity observed in the thermal rearrangements. Several cases of significant enhancement in the diastereoselectivity of the acyclic Claisen rearrangement of cyclohexenyl allyl ethers, governed principally by remote asymmetric centres, have been observed when Lewis acid catalysts are empl~yed”~ rather than the usual thermal rearrangement conditions. A convenient synthetic route to 8,E-unsaturated P,j-difluoro-a-keto esters has been developedIz8by utilizing the Claisen rearrangement of allyl-substituted difluoroenol pyruvyl ethers, while difluoroallylic alcohols have been found to undergo a range of Claisen and related [3,3]-sigmatropic rearrangements to yield 0-fluorocarbonyl and P,P-difluorocarbonyl deri~atives.’’~ The enantioselective synthesis of an oxataxane derivative via a tandem intramolecular 2 2-cycloadd~tionand [3,3]-sigmatropic rearrangement of an allenyl ether has been des~ribed’~’ (Scheme 26), and a new synthesis of retinal and various poly-unsaturated carbonyls has been pr~posed’~’ which involves a Pd(0)-catalysed vinylogous acetylenic Claisen rearrangement.

’’

’”

+

SCHEME 26


464

The suitability of the Claisen ring-expansion protocol for the construction of crenulide diterpenes has been established,' 32 and the sesquiterpene ceratopicanol has been s y n t h e s i ~ e d' ~ by~ a route based on a Claisen rearrangement and radical cyclization. Convenient two-step syntheses of seselin and angelicin derivatives have been achieved'34 using a tandem Claisen rearrangement and Wittig reaction. The thermal rearrangement of ally1 aryl ethers (76) generated in situ from hydroquinone and conjugated polyenols has afforded 2 , 3 - d i h y d r o b e n z o f o l ~ 'such ~ ~ as (77), while 1-enes (78) have successive Claisen rearrangements of 2-aryloxymethyl-3-aryloxypropled'36 to the corresponding 2-(o-hydroxyaryl)methyhyl-3-(o-hydroxyaryl)-prop-l-enes (79).The effect of substituents on the phenyl ring on the caesium fluoride-mediated Claisen rearrangement of phenyl propargyl ethers has been studied.137Polyheterocycles such as 7a-methyl-2-phenyl-l3,13a-dihydro-7aH-furo[3,2-a : 5,4-h']bis[ llbenzopyran4-ones have been ~ y n t h e s i z e d ' by ~ ~ a series of sequential [3,3]-sigmatropic rearrangements of 7-(4-aryloxybut-2-yn-1-yloxy)[l]benzopyran-4-ones, while hitherto ' ~ ~the unreported 3H-pyrano[2,3-c]quinolin-5(6H)-ones(81) have been sy n th e ~ iz e dby thermal [3,3]-sigmatropic rearrangement of 3-propargyloxyquinolin-2-ones (SO) and subsequent acid-catalysed cyclization (Scheme 27). A study has been made'40 of the solvent dependence of ips0 versus ortho selectivity in the reductive iodonio-Claisen rearrangement of allenyl(p-methoxypheny1)iodane.

-

Me

Me

Me

t

(77)

Me

The chelation-controlled ester enolate Claisen rearrangement has been shown to yield trisubstituted(2)alkenes with high selectivity as a result of heteroatom-enforced control over the conformation of the transition state. In this way y,b-(Z)-unsaturated carboxylic


i

465

-

Me

.Me

L

I

Me (80)

0

-

___)

I

Me

R

S

'N

R

2

I

Me (81)

SCHEME 27

acids, with outstanding stereocontrol at the a$-stereogenic centre as well as in the alkene double bond, have been ~repared.'~' The ester enolate Claisen rearrangement of chelated N-protected amino acid allylic esters has resulted in the formation of aalkylated y,b-unsaturated amino acids in good yields and in a highly diastereoselective fashion.142,143 A simple stereoselective synthesis of ethy1(42)-4-cyanoalk-4-enoates via the Johnson-Claisen rearrangement of 3-hydroxy-2-methylenealkanenitriieshas been described,'44while a Johnson-Claisen rearrangement of the chiral intermediate (82) has been used145as a key step in a synthesis of both the (3R)-( -)- and (3S)-(+)-A factors. The Johnson variation of the Claisen rearrangement has also been used'46 to introduce the C(8) side-chain of the pyran nucleus of pseudomonic acid A regio- and stereoselectively. The use of a tandem Ireland-Claisen rearrangement followed by an in situ silicon-mediated epoxide fragmentation has provided an efficient entry to 1,3-dienes containing an E double bond and an exo-methylene group.'47 An enantioselective total synthesis of p-elemene and fuscol based on an enantio-controlled Ireland-Claisen rearrangement has been described,148 and the p-lactone enzyme inhibitors (-)ebelactone A and (-)-ebelactone B have been prepared'49 using a series of three boron enolate aldol reactions coupled with a remarkable Ireland ester enolate Claisen rearrangement, A novel stereo-controlled route to 5-oxaprostaglandin intermediates has used'50 a sequence of 1,2-0-0-silyl migration, Claisen rearrangement, and SN2'displacement. Acetoacetates, easily prepared from substituted p-quinols, have been found to undergo a Carroll rearrangement under mild conditions to afford substituted arylacetones and related derivatives."' Enders et ~ 1 . have ' ~ ~ reported on a highly diastereo- and enantio-selective synthesis of sterically demanding functionalized

466


ketones (85) with adjacent quaternary and tertiary centres, starting from P-hydrazono esters (83). The key step is the stereoselective [3,3]-sigmatropic Carroll rearrangement of the hydrazono ester dienolate (84). The chiral auxiliary used in this rearrangement is (5)-1-amino-2-methoxymethylpyrrolidine,and the ketones (85) are obtained after reductive work-up and oxidative cleavage of the auxiliary. A Claisen orthoester rearrangement has been used'53 to prepare (2,)-isositsirikine and (2,)-geissoschizine derivatives possessing the right oxidation state at C( 17). A mild, regioselective ketal Claisen rearrangement promoted by triisobutylaluminium has been reported,154 and a new ketal Claisen rearrangement for C(S)-unit elongation has been established and A new sequence for the applied to the synthesis of a sarcophytol A inte~mediate.'~~ highly stereoselective synthesis of trisubstituted y,d-unsaturated acids has been d e ~ c r i b e d . It ' ~ consists ~ of a ketal Claisen rearrangement of a terpene allylic alcohol with 2,2-dimethoxy-3-methylbutan-3-ol,and subsequent oxidative cleavage of the resulting a-ketol.

coy

Me

0

SCHEME 28

The aromatic amino-Claisen rearrangement of N-alkenyl-2,5-dimethoxyanilineshas been studied,'57 an amino-Claisen rearrangement has been observed'58 in substituted N-(2-propynyl)anilines on electron impact, and new tetrahydroazocinoquinones and

467


N x SePh o SCHEME 29

dihydroazepinoquinones have been prepared’59by the amino-Claisen rearrangement of 4-(2-vinyl-azetidino or -aziridino)-5-methoxy-1,2-benzoquinones (Scheme 28). The utility of [3,3]-sigmatropic rearrangements of hydroxylamine derivatives has been exemplified’6o by the rearrangement of N-phenyl-0-acylhydroxylamines,N,Odiacylhydroxylamines, and N-acylhydroxylamine-0-carbamates.Evans et al.16’ have reported the use of a novel Claisen rearrangement to prepare the highly strained Nbenzyloxycarbonyl-substitutedlactam (88). It involves the Claisen rearrangement of the ketene aminal(87) which was generated by in situ elimination of the selenoxide derived from (86) (Scheme 29). A zwitterionic Claisen rearrangement has been developed for optically active N-allylpyrrolidines using a two-phase system (Scheme 30), and the inherent 1,Zasymmetic induction has been investigated’62for the generation of a new carbon-carbon bond adjacent to a chiral carbon-oxygen function. The y-lactam portion of the non-protein neurotrophic factor (+)-lactacystin has been constructed stereoselectively from D-glucose using the allylic tichloroacetimidate rearrangement as the key reaction,’63 and (2-cyclopropylideneethyl)acetimidates (89) have been found’64to undergo a thermally induced, or palladium(I1)-catalysed, aza-Claisen rearrangement to 1-ethenylcyclopropyl acetamides (90), thus providing convenient precursors to 1aminocyclopropanecarboxylic acids (91). Inverse regioselectivity in the cycloaddition of diazomethane and diphenyldiazomethane to methyl acetyloxyimino(cyano)acetate

C02H

I\/

R (89)


468

Ph

R=

2

’ 0 -

J

c,-

base -HC1

SCHEME 30

(92) has led165to the specific evolution of the transient triazoline (93), which by an eventual [3,3]-sigmatropic transposition yields imines (94) (Scheme 3 1). An unusually

facile thermal aza-Claisen rearrangement’66has been used in a stereospecific synthesis of novel 2’,3’-dideoxynucleoside precursors, and the asymmetric synthesis of an allylic azide combined with the facility of its [3,3]-sigmatropic rearrangement has provided’67 a simple strategy for the synthesis of conduramine E. Generated in situ,the parent ally1 vinyl sulfonium ion (95) has been found to undergo a rapid thio-Claisen rearrangement16*(Scheme 32), while 1,8-bis(allylthio)naphthaIene

-

NckdocoMe R’R2CN2 Me02C

(92)

(93)

SCHEME 31

-I

n


469

-

I

OMe SCHEME 32

qs P s-0

(97)

L

SCHEME 33

monoxides (96) have been o b ~ e r v e d ' ~to~undergo ~ ' ~ ~ consecutive [2,3]-sulfur-sulfur and thio-Claisen rearrangements to afford 2-allylnaphtho[1J3-cdI-1 ,a-dithioles (97) (see Scheme 33). A diastereoselective thio-Claisen rearrangement of S-allylic a-silyloxyketene dithioacetals has been r e ~ 0 r t e d . l ~ An ~ ab initio study17* of the thermal fragmentation of N-(acyloxy)pyndine-2-thiones has indicated that a [3,3]-sigmatropic process initiates the radical fragmentation, and S-allyl-, S-propargyl-, and S-methallylthioiminium salts derived from methyl 1-benzyl-5-thioxoprolinatehave been found to undergo a facile thio-Claisen rearrangement which has provided easy access to 4substituted thioxoprolinate~.'~~ A one-pot synthesis of allyl dithioesters has been achieved by employing a tandem condensation-alkylation-sigmatropic rearrangement sequence,174,175 and it has been that 0-substituted allyl N-acylmonothiocarbamates (98) spontaneously undergo [3,3]-sigmatropic rearrangement to Ssubstituted allyl N-acylmonothiocarbonates (99) which, on further heating, undergo a [1,3]-sigmatropic shift to yield (100). A highly stereoselective synthesis of Z or E


470

double bonds in 10-membered thiolcarbonates has been achieved by the [3,3]sigmatropic ring expansion of eight-membered thionocarbonates which proceeds through a chair-like transition state.'77 The methodology has been used to provide a unique stereoselective synthesis of ( -)-yellow scale pheromone. A similar [3,3]sigmatropic ring expansion of alkynyl cyclic thionocarbonates (101) has been used'78 to prepare medium-sized heterocyclic allenes (102) (Scheme 34), and further applied to the synthesis of the antifungal constituent of Sapium japonicum. FurfUryl sulfides (104) have been prepared readily via extrusion of COS from the corresponding xanthates (103). Cross-over experiments have indicated that the reaction probably proceeds intermolecularly via ion pairs than via an energetically unfavourable [3,3]-sigmatropic route. 179 ,R'

R' C'

R : H

SCHEME 34

A selenoaldehyde, a selenoketone, and telluroaldehydes have all been generated18' by the [3,3]-sigmatropic rearrangement of ally1 alkenyl selenides and tellurides, respectively.


47 1

Cope and related rearrangements

IGLO computations have revealed'" the aromatic character of the transition structures for the Cope rearrangement of hexa-1,5-diene and, in addition, high-level ab initio calculations have favoured a synchronous, concerted mechanism via intermediates not having significant diradicaloid character for the rearrangement. Moreover, a reinvestigation' 82 of the Cope rearrangement using multi-reference perturbation theory has shown that the Dewar-type diradicaloid stable intermediate does not occur as a minimum in the potential surface and that the aromatic transition state moves to shorter bond lengths. Evidence for competitive and diradical processes has been obtained'83 during the rearrangement of the Diels-Alder adducts of cyclic 1,3-dienes to norbornadienes [see (105) -+ (106)l. An ab initio study of the use of kinetic isotope effects as a guide to transition state geometries for the Cope rearrangement has been ~ n d e r t a k e n , 'and ~ ~ Hine's D values (the double-bond-stabilizing abilities of diverse groups) have been shown to have a semi-quantitative predictive value in determining the position of equilibrium in Cope rearrangement^.'^^ An ab initio MO study'86 has been made on the thermal rearrangements of bicyclo[5.1.O]octa-2,4-dieneand its 8-oxa, 6-oxa and 6,8-dioxa derivatives and an oxa-Cope rearrangement route has been reported' 87 as a competitive alternative to previously published sphingosine syntheses. Semiempirical AM1 SCF MO calculations have shown188that the activation energy for the degenerate Cope rearrangement of hypostrophene is greater than that for comparable rearrangements of bullvalene, barbaralane, and semibullvalene, while a systematic search has been made for substituted semibullvalenes that can provide suitable substrates for a laser pulse-mediated Cope r e a ~ ~ a n g e m e n t. ' ~ ~

The application of [3,3]-sigmatropy to the enantioselective synthesis of natural products containing bridgehead unsaturation has been re~iewed.'~'The [3,3]-Cope rearrangement of the pheromone (107) of the marine brown alga Ectocurpus siliculosus to cyclophepta-1,4-diene (108) has been established'" as the fastest known reaction for the spontaneous inactivation of a pheromone, and it has been shown that cyclohexa-2,4dienones behave as the 4n component during their pericyclic reaction with cyclohexa-

472


1,3-diene and cycloheptatriene. The adducts of these additions have been isolated and their Cope rearrangements studied.192 Treatment of 2-allyl-1,2-dihydroindo1-3-ones (109) with phosphorus ylides has afforded 3-indole acetates (110) in good yields by a tandem Wittig reaction and an aromatization-induced Cope rearrangement.'93 The first oxy-Cope rearrangement involving the endocyclic double bond in a 7oxanorbomenic system has been d e ~ c r i b e d . An ' ~ ~anionic oxy-Cope rearrangement of (111) has been developed'95 (Scheme 35) to produce enantiomerically pure keto ester (112), which has been structurally modified to yield a 1 : 1 mixture of (-)-vulgarolide and its anomer, while the anionic oxy-Cope rearrangement of bicyclo[2.2.2]octadienols has served'96 as a key step for the construction of substituted bicyclo[5.3.1]undecenones, thus providing a novel entry to the AB ring system of the taxane diterpenes (Scheme 36). A tandem oxy-Cope-transannular ring-closure route to polyquinanes (Scheme 37) has been described,197and the diastereoselective synthesis of cis-l,2dialkenylcyclopropanols (1 13), and their subsequent oxy-Cope rearrangement, has provided'98 stereoselective syntheses of fused bicyclic compounds, such as bicyc10[5.4.0]undecanes,which have several sites for further structural elaboration (Scheme 38). Ab initio calculations have indicated199that the anionic aza-Cope rearrangement of the l-azahexa-l,5-dienyl anion (114) to the 3-azahexa-l,5-dienyl anion (115) probably proceeds by an exothermic, stepwise process with a relatively low activation energy. The 3-aza-Cope rearrangement has been identified*'' as a convenient route to higher branched aliphatic aldehydes from telomers of isoprene with secondary amines. A tandem imine-enamine equilibrium-3-aza-Cope-Mannich reaction (Scheme 39) has been explored2" to assemble chiral 4-hydroxy-4-alkylcyclopentenones,and a novel

473


L

OSEM

L

(111)

OSEM

0-

J

SEM = trimethylsilyl enol ether

SEMO

w\

Me

Me

-

Me

‘0-

R Me

OH

W = H, OR, SR SCHEME 36

synthetic approach to carbapenems utilizing an aza-Cope-Mannich cyclization has been described202(Scheme 40). The zinc chloride-promoted 3-aza-Cope rearrangement of benzoyl-substituted heterocyclic ketene aminals has been reported203(Scheme 4 l), and a new synthesis of desoxyeseroline, which involves the [3,3]-sigmatropic rearrangement of bis(enamine) (116) into the suitable precursor (117), has been

474


-

TM so

I7

0-

TMSO

c--

H

OH

SCHEME 37

Me

475


1

aza-Copc

SCHEME 39

+ BuTvle2SiO

Bu'MeISiO

M % e7

-C1-

___)

OSiMezBu'

OSiMezBu'

C02Me

Bu'MezSiO CHO

C02Me

-

C02Me

me^ ~7

Bu'Me2SiO

OSiMe2Bu'

C02Me

SCHEME 40

presented.204Variable-temperatureNMR spectroscopy and X-ray crystallography have been employed205to study the stereochemistry of 2-cyano-3,3-dimethyl-l-phenylpyrazolidin-5-one (118) which thermally rearranges to 2,3-dihydro-2,2-dimethylpyrimido[] ,2-a]benzimidazol-4(lH)-one (1 19). An ab initio investigation of the phospha-Cope rearrangement converting 1,6diphosphahexa-1,S-diene into 3,4-diphosphahexa-1,S-diene, has been undertaken,2°6 and the use of the [3,3]-sigmatropic selenocyanate to isoselenocyanate rearrangement has led to the first synthesis of vinyl isoselen~cyanates~~~ [see (120) + (121)l.


476

ZnCll

-ZnC12

SCHEME 41

NCSe\

-

[2,3]-Migrations

A method for determining Huckel-Hubbard parameters has been extended to analyse the stereochemistry of [2,3]-sigmatropic rearrangements,208 and a review which outlines the synthetic scope, stereochemistry, and mechanistic aspects of the [2,3]Wittig rearrangements has appeared.209A [2,3]-Wittig rearrangement using glucose as a chiral auxiliary has been reported,210 an asymmetric [2,3]-Wittig approach to the formal synthesis of (+)-brefeldin-A has been published,21 and the [2,3]-Wittig rearrangement of the propargylic ether of B-( 1-alkoxymethyl)allyl alcohol has been found to proceed with a high degree of either 1,4-syn or 1,4-anti selection, depending on the choice of alkoxy group and solvent.212 The [2,3]-Wittig rearrangement of

’


477

trimethylsilylpropargyl ethers of k a n o i d glycals derived from D-mannose and Lgulonic y-lactone has been used213to afford cis-2,5-disubstituted dihydrofurans with predominant etythro selectivity, while the Wittig rearrangement of 3-furylmethyl ethers (122) has been found to proceed efficiently to yield either 3-methyl-2-furylmethanols (123) or 3-furylethanols (124), depending on the basicity of the butyllithium used.’I4 Ally1 alcohols (126), prepared by addition of lithium vinylcuprates to (R)-2,3-0isopropylideneglyceraldehyde (125) have been converted into 3,4,5-trimethoxybenzyl ethers (127) by a one-pot desilylation-alkylation. After deprotonation, these benzyl ethers have been observed215to undergo a [2,3]-sigmatropic Wittig rearrangement with complete 1,3-chirality transfer and good diastereoselectivity to afford homoallyl alcohols (128). The diastereoselective [2,3]-Wittig rearrangement of the oxazoline ether of a bis(ally1ic) tertiary alcohol has been described,216and the strategy successfully and other used2I7 to synthesize (2E,4E)-4,6,10,12-tetramethyltrideca-2,4-dien-7-one closely related analogues which serve as sex pheromone components of female Matsucoccus pine scales. Compounds containing a CF2 group in mid-chain have been obtained’l8 from the [2,3]-sigmatropic rearrangement of 3,3-difluoro-2-alkylalken-lols, and a-hydroxy-y-amino acids having y-turn conformational features have been produced2I9by a stereoselective [2,3]-Wittig rearrangement of enantiomerically pure 4aminoallyloxyacetates. The diastereoselective and enantioselective synthesis of Bsubstituted y,h-unsaturated a-hydroxy ketones has been accomplished via the [2,3]Wittig rearrangement of a-allyloxy ketone hydrazones:20 and this methodology has been extended2” to the synthesis of ( - )-oudemansin starting from crotyloxyacetaldehyde hydrazone. The reaction of singlet carbene with 2-methylbut-3-en-2-01 has been found to lead to several products, including 4-methylpent-3-en-1-01, whose formation has been explained”’ as the result of the [2,3]-sigmatropic rearrangement of an ylide intermediate (Scheme 42). A variety of substituted benzocyclopentenones have been synthesized by the rhodium(I1)-catalysed reaction of a-diazo ketones bearing tethered alkyne units. The results obtained in all cases have pointed to a mechanism which involves addition of the rhodium-stabilized keto-carbenoid to the acetylenic n-bond to give a new rearranged vinyl-carbenoid. In the case223where an ether oxygen is present on the backbone of the vinyl-carbenoid, the resulting oxonium ylide (129) undergoes a [2,3]-shift to give the rearranged product (130) (Scheme 43).

Sigmatropic rearrangements of sulfur and nitrogen allylic ylides have been studied by ab initio method^."^ The first example of an acyclic aza-[2,3]-Wittig rearrangement has been presented, and its application to the synthesis of unnatural amino acids has been described225(Scheme 44). N-Alkylation of a series of 2-ketoaziridines, followed


478 0

4

OH

H

R

+

MeA Me -0

Me

?Me

OMe

a

Me

Me

d 0 ’

MeAMe -0

SCHEME 42

0

(129) SCHEME 43

R

479


by Wittig olefination, has generated intermediate vinylaziridines which have been found to rearrange by an aza-[2,3]-Wittig process to create a new carbon-carbon bond with concomitant ring opening of the aziridine, thus affording unsaturated p i p e r i d i n e ~ , ~ ~ ~ ' ~ ~ ' of indolizidines and indeed, the key step in the recently r e p ~ r t e d ~total ~ ' , ~syntheses ~~ 209B and 209D has involved just such as aza-[2,3]-Wittig rearrangement of vinylaziridines to tetrahydropyridines (Scheme 45). Gawley et al.230have established that both [2,3]-anionic and ylide rearrangements of unstabilized a-lithio-mines occur with inversion of configuration at the metal-bearing carbon and that [1,2]- and [2,3]mechanisms compete in the aza-Wittig rearrangement. Ammonium benzylides generated from salts (131; R = H, Cl), have been shown23' to undergo, in addition to the expected [2,3]-reamgement, a new [1,4]-rearrangement (Scheme 46), while trans2-methyl-3-(substituted-phenyl)-1,2,3,4-tetrahydroisoquinolinium2-methylides have been to undergo predominantly a [2,3]-sigmatropic rearrangement. With the cis-ylides, an intramolecular Hofinann degradation was the single pathway. An efficient enantioselective synthesis of the azabicyclo[6.3.O]undecane (133) from (9prolinol has been described.233The key step in the route to (133) was the intramolecular generation and rearrangement of the spiro-fused bicyclic ylide (132) from a copper carbenoid.

4"Ph

Ph

I

BbC

BbC

SCHEME 44

\/Me SCHEME 45

480


1

CN I

CN I

SCHEME 46

The effectiveness of ab initio calculations in the elucidation of reaction paths and solvent effects on the [2,3]-sigmatropicrearrangement of allylic sulfoxides to sulfenates has been determined,234and this study has been extended235to investigate the origin of the observed control of olefin geometry by analysing the constituent interactions in the alternative transition structures for the rearrangement. (4-y-Hydroxy sulfoxides (136) have been prepared236 in good yield from simple aldehydes (134) and chiral bis(su1foxide) (135) in a one-pot procedure based on a Knoevenagel condensation, subsequent prototropic shift and [2,3]-sigmatropic sulfoxide-sulfenate rearrangement (Scheme 47). Sulfenic acid (138), obtained on thermolysis of thiosulfinic S-ester (137), has been found to afford 1,3-oxathiolane S-oxide (139) by a process which can be regarded as a 'reverse' [2,3]-sigmatropic rearrangement.237Pyne and co-workers238~23y have shown that allylic sulfoximines (140) undergo a novel and efficient Pd(0)catalysed allylic sulfoxide to allylic sulfinamide rearrangement, (140) +.(141), but ab initio calculations on the [2,3]-sigmatropic shift of allylic sulfoximines and sulfilimines have indicated240that a substantial kinetic barrier exists for the former relative to the

(-"-

Tol.,

R1

+

)-CHO

R2

2-O

R1

R2 J - k O T O l

To1

(134)

(135)

0

(136)

SOTol

0

SCHEME 47

48 1


R+ TsN-s, I/

0

Ph

-

R-

SOPh NTs I

latter. It has been shown that the chiral rhenium Lewis acid [$-CpRe(NO)(PPh,)]+ can serve as a readily recycled auxiliary for the conversion of achiral symmetrical diallyl and dipropargyl sulfides into chiral rearranged sulfides of high enantiomeric purity. In particular, alkoxide bases have been used to deprotonate the cationic adducts to sulfur ylides which undergo rapid [2,3]-sigmatropic bond shifts at - 80 0C241(Scheme 48). Rhodium(I1) acetate-catalysed cyclization of methyl 2-diazo-5-[2-methoxy-5(2-phenylsulfanylethylidene)tetrahydro-2Hpyran-4-yl]-3-oxopentanoatehas been shown242to proceed through the [2,3]-sigmatropic rearrangement of a nine-membered cyclic ally1 sulfonium ylide, to afford a cis-2-oxa-9-vinyldecalin derivative, the basic AB ring skeleton of vernolepin, and highly substituted cyclohexanones such as (142) have been prepared in a similar m a r ~ n e ?as ~ ~shown in Scheme 49. Sommelet-Hauser products have been established244as the sole products obtained from the rearrangement of S-methylbenzylsulfonium S-alkylides in non-basic media, while Sommelet-Hauser and Stevens products were obtained from the rearrangement of 1-phenyl-3,4-dihydro1H-2-benzothiopyranium2 - m e t h ~ l i d e sNovel . ~ ~ ~ chiral ferrocenyl selenides have been prepared and shown to be good reagents for the asymmetric synthesis of c h i d allylic alcohols by [2,3]-sigmatropic rearrangement of the corresponding ~ e l e n o x i d e s ~ ~ ~ (Scheme 50), and an asymmetric [2,3]-sigmatropic rearrangement of the chiral cinnamyl(ferroceny1)selenimide (143) to produce the corresponding optically active allylic amine (144) with high enantioselectivity has been accomplished.247Similarly, when the chiral ferrocenyl telluride (145) was treated with an imination agent under various conditions, the chiral amine was isolated with even higher enantio~electivity.~~~ This observation was in sharp contrast to the result of [2,3]-sigmatropic rearrangement of chiral allylic ferrocenyl telluroxides where the formation of allylic alcohols of only low enantioselectivities was observed.249The first reported example of enantioselective carbenoid addition to chalcogen atoms of prochiral organic chalcogenides, and the

482


R2 SCHEME 48

0

R' R'

R402c*R2

SCHEME 49

F

S

e

F

\\0f

- @(==

OSeFc*

--Q6

SCHEME 50

chirality transfer from the resulting chiral chalcogen ylide via [2,3]-sigmatropic rearrangement has provided250a new methodology for carbon-carbon bond formation with chiral induction at both carbon centres (Scheme 51). C02Et

N=N=C,

/

H

ML*

M = Cu, Rh

*LM=C,

CO2Et

/

H

Ph-f+ph P-CO2Et

PhY-(!i!--COzEt I H

I H

SCHEME 51


483

The [2,3]-Wittig sigmatropic rearrangement of distannyl- and silylstannyl-substituted diallyl ethers has been achieved25' using LDA; in certain cases252the rearrangement was found to be followed by a spontaneous anionic oxy-Cope rearrangement. The stereoselective synthesis of y,d-unsaturated a-hydroxyphosphonates via the [2,3]-Wittig sigmatropic rearrangement of a-allyloxyphosphonates has been reported,253and the facile and highly stereoselective [2,3]-Wittig rearrangements of chirally-modified phosphorus-stabilized anions have been An in-depth of the mechanism of the p-(phosphat0xy)alkyl radical migration has shown that phosphoranyl radicals are not intermediates in this rearrangement. The study has shown that the migration is intramolecular and proceeds through competing [ 1,2]- and [2,3]-pathways, and does not involve fragmentation to a cage pair followed by recombination.

CH2CHO (146)

X=0,5

SCHEME 52

[I, 31-Migrations An ab initio study has been made of the allene effect in [ 1,n]-sigmatropic hydrogen

shifts.257Although benzyl and naphthylmethyl vinyl ethers have been found to be inert to lithium perchlorate in diethyl ether, hetero-aromatic methyl vinyl ethers, such as 2fury1 and 2-thienylmethyl vinyl ethers (146), have been found to undergo formal [ 1,3]rearrangement in that medium258(Scheme 52). The electron-transfer photochemistry of vinylcyclopropane systems (147) and (148) has been found to proceed via strainreleasing reactions of their radical cations. These rearrangements have been described259 as sigmatropic shifts with inversion of configuration at the carbon receiving the migrating hydrogen. The energetics of the [ 1,3]-hydrogen shift in formyland diformyl-phosphine have been determined260by ab initio methods, and secondary alkyl(cl-ethoxyethenyl)phosphines, prepared by the palladium-catalysed cross-coupling of alkyl(trimethy1silyl)phosphines with (a-bromoetheny1)ethyl ethers, have presented the first example of compounds which undergo a reversible intramolecular [ 1,3]-shift of hydrogen in a phosphorus-carbon-carbon triad.261

Me

(147)

484


A facile [1,3]-shifl of a methoxy group has been shown261 to interconvert imidoylketene (149) and ketenimine (150), and the first direct evidence for the vinylketene-acylallene rearrangement, ( E l ) $ (152), using alkoxy- and (dialkylamino)vinylketene precursors and the corresponding allenecarboxylic acid derivatives, has been reported.263Direct dynamics calculations have been carried out on the formal [1,3]-sigmatropic migration that interconverts bicyclo[3.2.0]hept-2-ene and norbornene, and these calculations264have shown that the transformation occurs with a preference for inversion of configuration at the migrating carbon. A stereochemical analysis of the fragmentation of 2-oxabicyclo[3.2.O]hepteneto furan and ethene has led to the conclusion265that a sigmatropic [ 1,3]-carbon shiR proceeding with inversion of the migrating carbon, followed by a stereospecific retro Diels-Alder reaction, is the major pathway for this reaction. Direct photolysis of 1-methyl-1-silabicyclo[2.2.llhept2-ene (153) in alcohols has resulted266in the [1,3]-migration of C(7) to produce 3alkoxy-3-methyl-3-silabicyclo[4.1 .O]heptanes (154). The thermal isomerization of cycloocta[dlpyridazine (155) in non-polar solvents to the barreleno[dJpyridazine (156) has been explained267by invoking a formal [1,3]-carbon migration. A kinetic study of the thermal rearrangement of 2-(trifluoromethy1)-1-vinylcyclopropane to 3and 4-(trifluoromethyl)cyclopentenes has been undertaken.268A theoretical study of the photochemical behaviour of vinylcyclopropanes has indicated269that the photorearrangement to cyclopentenes is completely stereospecific and proceeds via a concerted process. On the other hand, a recent ~ a p e ? ~has ' shown that the thermal isomerization of (1S,2R)-l-(E-styryl)-2-phenylcyclopropaneto 3,4-diphenylcyclopentenes can be viewed as processes passing though alternative kinetically competitive diradical transition structures, rather than controlled by orbital-symmetry considerations. The allylidenecyclopropane to methylenecyclopentene thermal isomerization has

485


I

CF3

(155)

phneMe Ph

_._t

Ph/

'Ph

Ph

Ph

SCHEME 53

been subjected to a detailed theoretical e~amination,~~' and it has been concluded272 from a study of the direct photochemistry of 1-anisyl-2-phenyl-3-methyl-3-isobutenylcyclopropene that bond b scission operates to a greater extent in the reaction mechanism than formation of bond a (Scheme 53). The activation barrier for the [1,3]phosphorus migration in 1,3,5-triphosphabicycIo[2.1.O]pent-2-ene has been estimated273as being considerably smaller than the barrier for [ 1,3]-carbon migration of the corresponding hydrocarbon. It has been shown that the intramolecular photochemical reaction of 0-alkenyl thiocarbamates yields photo-products in which the photo-processes are defined by the length of the carbon chain between the oxygen and the alkenyl group attached to the thiocarbamate. Photolysis of 0-allylthiocarbamates which have one carbon between the oxygen and the alkenyl group was found to promote a concerted [ 1,3]-allyl migration leading to S-allylthio~arbamates~~~ (Scheme 54). It has been suggested275that the photochemical [1,3]-stannyl migration of 3-aryl-substituted allyltins, (157)s (158), involves photo-excitation of the cinnamyl 7c system and proceeds intramolecularly via an orbital-symmetry-allowed concerted [ 1,3]-sigmatropic mechanism as has been proposed in germyl migration. A new silene-to-silene thermal rearrangement, which involves the [1,3]-shifts Me3% and Me3Si0 groups that are attached to the siliconcarbon double bond of silenes, has been observed.276

486

Organic Reaction Mechanisms 1995 R'

R2

SCHEME54

[I, 51-Migrations The involvement of a [ 1,5]-sigmatropic shift via [ 1,5,] geometry from a higher excited state has been invoked277to explain the photo-cyclization of an o-alkenylbenzaldehyde (159) to a benzocyclobutenone (160) (Scheme 55). [ 1,5]-Hydrogen shift products (162) and (163) were obtained in addition to the usual fragmentation product when 7-ethyl-7methylbicyclo[3.2.0]hept-2-ene (161) was subjected to gas-phase pyrolysis.278An investigation of substituent effects in the homodienyl[ 1,5]-hydrogen shift in vinylaziridines [see proposed transition state (164)] has shown that the rearrangement is affected by substituents at both the rearrangement origin and terminus.279 A theoretical study of the cyclization of a-iminothioaldehydes to dihydrothiazoles has been undertaken.28oa-Oxy- and a-thio-substitutedradicals, e.g. (165), derived from the [ 1,5]-shift of samarium diiodide-generated vinyl radicals,28' have been hrther rearranged to alcohols and thiols through a Wittig rearrangement (Scheme 56). It has been suggested282that the iron(II1)-mediated rearrangement of 1,2,4-trioxanes (166) to 1,2-diol mono-esters (168) involves reduction of (166) to an oxyl radical (167) followed

487

I 5 Molecular Rearrangements 0

&Ph \

c//o U \

Ph

\P

Phh

\

Ph

(159)

SCHEME 5.5

x=o,s

J XH

SCHEME 56

R Fe3+

Me Me

Me

(165)

Me Me

R

-

___)

Me Me

Me Me

by a [1,5)-hydrogen-transfer sequence similar to that implicated in the molecular mechanism of action of the antimalarial artemsinin. Miscellaneous

It has been that the thermal rearrangement of enantio-enriched a-ally1 and atrimethylsilylpropargyl a-hydroxyimines (169) proceeds with a complete 1,2-transfer of chirality. Moreover, the [1,2]-shift was shown to be suprafacial and to proceed with inversion of configuration. The synthetic value of the rearrangement has been highlighted284by its use in the synthesis of (170), an advanced intermediate in the synthesis of (- )-perhydrohistrionicotoxin. The formation of the hydantoin biotransformation product (172) of alosetron (171) has been shown285to proceed via a [1,2]migration of the tricyclic lactam moiety which occurs with retention of both hydrogens in the C(7’)-methylene group. The thermal rearrangement of endoperoxide (173) to


488

OMe

I

(169) R = CH2CH=CH2, CH2C=CSiMe3

Me

(174) and (175) has provided286an example of a bicyclic endoperoxide leading to the direct formation of an enedione system by consecutive carbon-carbon cleavage and [ 1,2]-hydrogen (or [1,2]-alkyl) migration. An I80-labelling study287 of the 8(nitroxy)alkyl and 0-(trifluoroacetoxy)alkyl radical migrations has shown that these migrations OCCUT to a greater extent through the [1,2]-shift pathway as opposed to a [2,3]-shiR mechanism. The thermal isomerization of olefins to carbenes via a [ 1,2]-silyl shift (Scheme 57) has been examined both by experiment and by theory.288The study

Me&*,'

0-y Ph

-

Me@ Ph

+

Me

.,oT

.,%"

'2

0

Ph'

0


489

- 3

MqSi?I

Me2Si

SCHEME 57 R' H-} 0

b@

R40 R3 (176)

J

SCHEME 58

has shown that, for silyl migration, the transition state was late and was actually the carbene, whereas for carbon migration, the transition state was early and considerably higher in energy than the resulting carbene. Lithioalkynyltriorganoborates(177) derived from propargylic acetals (176) have been found to rearrange in the presence of BC13, to homopropargylic alcohols (180) free of the corresponding allenic isomers. From a mechanistic point of view, these results have been explainedzE9by the intermediate formation of an allenylboron compound (178) as shown in Scheme 58, where the ate complex (177) has rearranged in the presence of BC13 with one R group migrating from boron to the adjacent carbon with concomitant elimination of the complexed acetal moiety. Addition of the carbonyl species (179) to the allenylborane affords, after oxidation via a usual allylboration type reaction, the alcohol (180). Kocienski and cow o r k e r ~have ~ ~ ~demonstrated the value of the Cu(1)-mediated [ 1,2]-metallate rearrangement for the connective and stereoselective synthesis of alkenyl metals from a-heteroalkenyllithiums and alkyllithiums and utilized this methodology for the syntheses of the C( 16)-C(23) fragment of FK-506, ja~pamide,~"and (3R,4R)l~ffariolide.~~~ Ab initio and semiempirical MO theory has been usedz937z94 to explore the ion-pair and lithium-catalysedpathways in the Stevens rearrangement of alkylammoniumylides to amines. In every case studied, the stepwise free-radical pathway was predicted to be the favoured mechanism for the rearrangement. Enantio-pure 1,3,4,6,11,11a-hexahydro[1,4]0xazino[4,3-b]isoquinolines have been prepared295by a cyclization rearrangement of L-serine-derived diazo esters. 2-Phenylhexahydroazeto[1',2', 1,2lpyrido[3,4-b]

490


indoles, on oxidation with MCPA, have been observed to undergo ring expansion by a [1,2]-Meisenheimer rearrangement.296 The spin-orbit coupling components of the effective one-electron Hamiltonian operator, with the inclusion of symmetry, have been used to investigate the photochemical behaviour of the di-x-methane rearrangement in cyclic and acyclic non-conjugated systems.297The cyclopropanolactone (182) has been prepared298by the di-n-methane rearrangement of the 4-benzylfuran-2(5H)-one system (181).

In solution, 9,10-dihydro-9,1O-ethenoanthracene-11,12-bis(diphenylmethanol) (183) has been found to undergo a di-n-methane photo-rearrangement to (1134):~~whereas irradiation of its crystalline complexes led to a novel dehydration reaction to yield (185).

Several novel examples of the oxa-di-x-methane rearrangement in P,y-unsaturated aldehydes have been observed,300and a new photochemical synthesis of cyclopropanecarboxylic acids present in pyrethroids has been achieved3" by utilizing the aza-dix-methane rearrangement.

Electrocyclic Reactions It has been noted that diastereotopic protons have different kinetic isotope effects in a variety of concerted pericyclic reactions. Moreover, these differences follow a pattern that makes it possible to use the IN and OUT protons as probes for the properties of the transition states.302The transition structures for the disrotatory electrocyclizations of a variety of 1-substituted hexa-1,3,5-trienes have been located303using ab initio MO calculations, and appreciable electrostatic acceleration of the electrocyclization of hexa-

1.5 Molecular Rearrangements

49 1

1,3-cis-5-triene to cyclohexa-l,3-diene by Li+ complexation has been predicted at the theoretical level, and shown to occur e~perimentally.~'~ In addition to its described perk and regio-selectively, the electrocyclic ring closure of (8E,13E)-12-t-butyl-l1,7retroretinal has also been found to be torquo-selective, leading exclusively to the (1OE)-alkylidenecyclobutana1.305The experimental results have been explained by an ab initio study of transition structures. A kinetic study306has been made of the ring closure of unstabilized bis(ketenes) to cyclobutenediones, and at 200 "C the diepoxide (186) derived from perfluoro-3,4-dimethyl-2,4-dienehas been found to undergo an unprecedented rearrangement to the corresponding 1,4-dioxine derivative (187). This rearrangement can be described3" either as proceeding in a concerted manner or via radical intermediates (Scheme 59).

F3cHcF3 0

)*'

F

OFF CF3 CF3

SCHEME 59

The observed cyclization of 1-azatrienes,formed in situ by simply mixing the t-butylsubstituted cr,b-cis-dienal with a primary amine, represents a useful method for the preparation of 1,2-dihydropyridines.The reactivity profile and activation parameters for the cyclization have been determined308and the mechanism shown to correlate well with the classical concerted disrotatory mode of electrocyclizations. Deprotonation of 4-azahepta-1,3,6-trienes(188) using LDA has been found to yield 4-azaheptatrienyllithium compounds (189), which on warming to room temperature undergo a 1,7electro-cyclization309to afford 3-azacycloheptadienyllithium compounds (190). Subsequent treatment of (190) with various electrophiles has provided access to several substituted 4,5-dihydroazepines (191). The facility of N-aziridinyliminoureas (192) for the synthesis of 1,2,4-triazole-f%sedheterocycles (193) via electro-cyclizationshas been achieved3" under mild conditions, and an unusual electrocyclic transformation of the azabicyclo[7.3. llenediyne dynemicin core analogue (194) to (195) has been observed3" during treatment of (194) with excess bromine.


492

E I

R

(191) 7

N/N

Me

Ph,P, CC14, Et,N

0

_____)

ANAN/R H

H

(192)

P OMe /

OMe

Br


493

to investigate the Ab initio and force-field calculations have been carried torquo-selectivity of ring openings of cyclobutenes with substituents which sterically influence the selectivity, and a theoretical study has predicted3’ that electron donors have larger outward rotation preferences than electron acceptors in thermal ring openings of cyclobutenes. A number of unusual rearrangements of 4-alkyl-4hydroxycyclobutenones, in which the alkyl group bears a heteroatom at its 2-position, e.g. (196; X = heteroatom), have been reported. The authors3I4have envisaged that thermolysis of such compounds would result in stereospecific electrocyclic ring opening to the cis-vinylketene (197), followed by intramolecular attack of the heteroatom on the ketone moiety to give (198) which would lead directly to the macrocycle (199). A direct one-step conversion of diisopropyl squarate into unsaturated diquinanes has been uncovered315an4 as shown in Scheme 60, the route is thought to utilize two consecutive conrotatory processes, the first being 4n and the second 871. Similar successive electrocyclic rearrangements, initiated by the addition of a lithiated cyclopropenone acetal to a squarate ester, have been r e p ~ r t e dl 6. ~ Pentacyclo[6.5.0.043’2.05~’0.09~13]trideca-2,6-diene (200) has been observed to undergo asymmetry-forbidden thermal 2 2-cycloreversion of its cyclobutane ring to afford a cis,czsoid,cis-[2.2,l]tricyclic tetraene (201), which subsequently undergoes an intramolecular Diels-Alder cycloaddition to (202).3l7 The selectivity observed in rhodium(I1)catalysed rearrangements of cycloprop-2-ene-1- carboxylates has been accounted for3’ by a mechanism in which attack of the electrophilic Rh(I1) species is considered to be concerted with disrotatory ring opening of the incipient cyclopropyl cation. Thermal and silver ion-induced electrocyclic ring opening of cyclohexa-annulated [5.3.llpropellanes have provided3I9 ABC ring analogues of taxol, and 4-(trans-1,2-dicarbo-

+

OH

(199)


494

Me

H3C=C,

Li

0-

SCHEME 60

methoxy-2-iodoviny1)-5 -methyl-6,7-dicarbomethoxy-4,5-dihydrothieno[2,3-c]quinoline has been isolated32oas an unexpected 2 2-cycloaddition product from the reaction of 4-methyldithieno[3,4-b : 3’,2’-d]pyridinium iodide with 2 equiv. of dimethyl acetylenedicarboxylate. The thermal rearrangement of azulenes with dimethyl acetylenedicarboxylate in supercritical carbon dioxide has been studied.321The isomerization of 6(1,l -dimethylethoxy)-2H-pyran-3-oneto 4-( 1,l-dimethylethoxy)-5-hydroxycyclopent2-enone has been as a key step in the preparation of 2-bromo-5-[(1,1dimethylethyl)dimethylsiloxy]-4-hydroxycyclopent-2-enone, a potential intermediate for the synthesis of neocarzinostatin and kedarcidin chromophores. In addition to normal electrocyclic B-ring opening, la-hydroxyprovitaminD (203)has been found to undergo a new photochemical isomerization cascade initiated by I, 10-bond cleavage. This new isomerization, which becomes the major pathway when a methyl group is present in the lp-position, has been proposed323 to involve a 6n photochemical conrotatory electrocyclic reaction, (204) + (205), and a typical intramolecular photochemical n4s xza cycloaddition, (205) -+ (206). A comparative study has been made324on the energetics and mechanism of the ene reaction. The ene reaction of maleimide and 1-alkenes has been studied by both semiempirical and ab initio methods, and the information obtained has aided the

+

+

495

15 Molecular Rearrangements Me..,,,,

R30

X

synthesis of suitable transition-state analogues with the ultimate purpose of generating an antibody against the transition state.325The regioselectivity of the ene dimerization of 8-chlorobicyclo[5.1.O]oct-l(8)-ene has been described.326The singlet oxygen ene reaction of chiral cyclohexadienes has been shown to proceed with high regio- and diastereo-selectivity through control by a combination of electronic and steric interactions.327 On photo-oxygenation, aryl vinyl sulfides (207), with powerful electron-accepting substituents in the para-position, have been found to undergo predominantly:28 the ene reaction to (208). An unusual acid-catalysed rearrangement of cyclodecene-1,4-diones such as (209) to five-membered spiro-y-lactones (210) has been cla~sified~~' as an ene-type process, and the stereoselective formation of six carbon-carbon bonds and four rings in a one-pot cascade ene-type 2 + 2 + 2 then 4 + 2sequence has been achieved330from an acyclic polyunsaturated precursor bearing three uncontrolled centres, using a cobalt(1) catalyst. The discovery of an effective metallo+me-allene reaction from polysubstituted e n y n e ~ ~has ~ ' represented a new and promising way to generate polysubstituted cyclopentylmethylzinc derivatives under mild cyclization conditions, while the


496

synthesis of polysubstituted tetrahydrofurans has been made available by a new zincene-allene reaction.332 Details of inter- and intra-molecular imino ene reactions involving N-alkyl, N-acyl, and N-sulfonyl imines or iminium ions have been presented333with particular emphasis on the regio- and stereo-chemical issues accompanying these processes. The same group334 has developed a synthesis of (-)-papuamine by utilizing a novel but apparently general type imino ene reaction of allenylsilanes (Scheme 6 l), while further studies on novel intramolecular ene reactions of allenylsilanes have been reported.335 A kinetic study336of the thermal isomerization of gaseous cis-cyclooctene has indicated that the formation of octa-1,7-diene in the reaction probably proceeds by a concerted retro-ene pathway. Formation of 5-aryl-4-methylhex-5-en-2-ones(214) by heating 4-aryl-4-methylhex-5-en-2-ones (21 1) in acid has been explained337by the route depicted in Scheme 62, where an intramolecular ene reaction of the enol tautomer H

-

1. PhCHZNH2 2. SnC14

H

NHCHZPh

I

phc SiMezPh

SiMezPh SCHEME 61

497


oMe A Mer

ArMe

G

M

e

Me Me Ar

SCHEME 62

(2 12) provides acetylcyclopropanes (213) which undergo a retro-ene reaction to furnish the rearranged enone. A similar rearrangement has been extended to a formal synthesis of B-cuparenone. The exploitation of a retro-ene reaction of alkynylsulfinic acids (216), generated by aluminium amalgam reduction of alkynyl P-keto sulfones (215), has provided338 a simple, high-yielding, and versatile mode for the synthesis of trisubstituted allenes (217). Labelled allylsulfinic acids have been observed to undergo spontaneous decomposition with y-syn deuterium a fact that is consistent with a concerted retro-ene mechanism for the process (Scheme 63). It has been shown340 that benzothiophenethiol and benzofuranthiol (218; X = S and 0, respectively), react under non-radical conditions with electron-rich alkenes to yield

R’

so

:’3 0-

5

0-

5

H /

0 II

o//s Me

SCHEME 63

498


Me

Ph

I

I

SCHEME 64

products derived from a retro-hetero-ene reaction in which the aromatic thiols behave as the hetero-ene reagent (Scheme 64).

Anionic Rearrangements The various rearrangements of ethyl, ethenyl, and ethynyl anions, as well as the stabilities of these anions towards spontaneous electron loss, has been studied at the Gaussian-2 The isomerization of [(3-t-butyl-l -bicycle[ 1.1.l]pentyl)methyl]lithium (219) to 4-t-butyl-2-methylidene-4-pentenyllithium (221) via [(l-t-butyl-3methylidenecyclobutyl)methyl]lithium (220) has been found to involve a very rapid initial ring opening of (219) to (220) followed by a slow isomerization of (220) to (221).342A study has been made 343 of the solvent dependence of enantioselectivity for the base-catalysed prototropic rearrangement of 1-methylindene to 3-methylindene, and a general method for the catalytic asymmetric synthesis of chiral amines via a 1,3proton transfer reaction of imines has been d e v e l ~ p e dA. ~theoretical ~ study of the rearrangement of ketenimine to acetonitrile has predicted345that the rate-determining step in the rearrangement is the 1,2-hydrogen transfer of the imine hydrogen to the adjacent carbon to produce vinylnitrene. The base-catalysed rearrangement of 0propargyl ketoximes (222) to N-( 1 -alkenyl)acrylamides (225) has been visualized346to proceed as shown in Scheme 65, where the key step is the rearrangement of the intermediate allenyl carbanion (223) to enolate (224), which then predictably transforms into N-( I-alkeny1)acrylamide (225). BF3-complexed N-allyl- and N-

499


R21Nx/ R'

H

(225) SCHEME 65

benzyl-tetrahydroisoquinolines have been found to react with s-BuLi in an anionic rearrangement to afford 1-substituted tetrahydroisoq~inolines,~~~ and a PotierPolonovski rearrangement sequence has been to establish the carbamoyl enamine structure of the naturally occurring sulfonamide ( - )-altemicidin. Intramolecular nucleophilic attack at the ct-carbon of cyclopropanone Favorskii intermediates by enolate anions has provided a novel, flexible entry to hnctionalized tri- and tetra-cyclic systems.349The Favorskii rearrangement of 3-bromo-4-0x0-1-0xyl2,2,6,6-tetramethylpiperidinehas been used3" as a convenient route to esters of 1-0xyl2,2,5,5-tetramethylpyrrolidine-3-carboxylicacid, and a study of the Favorskii radical has been rearrangement of 3-bromo-4-oxo-2,2,6,6-tetramethylpiperidin-l-oxyl described.351The latter reaction has resulted in a viable alternative method for the direct synthesis of saturated pyrrolidine derivatives. A total synthesis of hinesol and agarospirol via a retro-benzilic acid rearrangement has been reported.3523353 Trapping experiments have shown3s4 that anionic ring opening of the C( 1)-C(2) bond in benzylidenebenzocyclobuten-ols and -ones can best be explained as occurring Me

% -Br\

R@-Me

Ye

\

- R&xMe \

SCHEME 66

/ j

500


via carbon-carbon cleavage resulting in vinyl anions, rather than via oxyanionpromoted electrocyclic ring opening to an alkoxy o-quinodimethane. A plausible reaction mechanism has been proposed355for the electrolytic reduction of 2-( 1-bromo1-methylethyl)benzohans to 2,2-dimethylchromenes (Scheme 66), while metallation of cyclic carbamate (226) has been found to lead to a 3-hydroxytetrahydroh (227) via a metallation-ring-opening sequence356(Scheme 67). cr-Ethylidenecycloalkanones have been reported to undergo ring enlargement to P-alkylidenecycloalkanoneswith

-

Cbm-0

n-BuLilTMEDA ClCONPr'2 Et3N

o m co

Organic Reaction Mechanisms: An Annual Survey of Literature, 1995

Organic reaction mechanisms 1998..An annual survey

Organic Reaction Mechanisms , Organic Reaction Mechanisms, 1997

Organic reaction mechanisms 1998 - an annual survey covering the literature dated December 1997 to November 1998

Organic reaction mechanisms 1998 - an annual survey covering the literature dated December 1997 to November 1999

Organic reaction mechanisms 1998 - an annual survey covering the literature dated December 1997 to November 2000