4 Reaction Mechanisms Part (ii) Polar Reactions By J.M. PERCY School of Chemistry University of Birmingham Edgbaston Birmingham 815 2T UK 1 Introduction The mechanisms or reactions mediated by catalytic antibodies' and mechanistic aspects of p-lactam and penicillin hydrolysis2 were reviewed while Menger provided an organic perspective on enzyme rea~tivity.~ Deslongchamps summarized his seminal studies of stereoelectronic effects on the reactions of acetals and ketal~,~ while kinetic techniques for the diagnosis of concerted reaction mechanisms were reviewed. Laser flash photoloysis and pulse radiolysis have made an invaluable contribution to the subject allowing the generation of reactive intermediates such as carbocations and carbanions; the scope of these methods has been summarized.6 Theory and experiment combined in a valuable interplay in the determination of transition state structure,' while the key principles of the curve crossing model were elucidated in a primer article.' The unique chemical properties of perfluorinated resinsulfonic acids were sum- marized,' and A,E mechanism for electrophilic addition was appraised.'' The SET description of the mechanism of aromatic nitration has gained considerable popularity but detailed studies support the polar mechanism proposed originally by Ingold.' ' Mandolini reviewed the mechanisms of metal-catalysed reactions of crown ether substrates," and aspects of the chemistry of bases were reviewed including the solution structures of lithium dialkylamides' and the properties of proton sponges.14 2 Solvolysis and Carbocations It seems appropriate to start this section by reporting recent results from the Olah group.Under superacid conditions (DF/SbF,/SO,CIF/ -78"C) the 2-propyl cation ' J. D. Stewart I. J. Liotta and S. J. Benkovic Acc. Chem. Res. 1993 26 370. F.M. Menger Acc. Chem. Res. 1993 26 206. S. Wolfe Can. J. Chem. 1994 72 1014. P. Deslongchamps Y. L. Dory and S. Li Can. J. Chem. 1994 72 2021. A. Williams Chem. SOC. Rev. 1994 23 93. P.K. Das Chem. Rev. 1993 93 119. ' I. H. Williams Chem. Soc. Rev. 1993 22 277. S. Shaik J. Mol. Liq. 1994 61 49. G. A. Olah in 'Acidity and Basicity of Solids' NATO AS1 Ser. Ser. C No. 444 1994 p. 305. lo W.A. Smit R. Caple and I.P. Smoliakova Chem. Rev. 1994 94 2359. l1 L. Eberson M. P. Hartshorn and F. Radner Acta Chem. Scand. 1994 48 937. l2 R. Cacciapaglia and L. Mandolini Chem. Soc. Rev. 1993 22 221. l3 D.B. Collum Acc. Chem. Res. 1993 26 206. l4 A. L. Llamas-Saiz C. Foces-Foces and J. Elguero J. Mol. Struct. 1994 328 297. 79 J. M. Percy underwent isotopic (H/D) exchange via a gitonic intermediate in which adjacent carbon atoms bore substantial positive charge. Possible structures for the intermediate were investigated by ab initio methods.' Gitonic intermediates may also be important in the superacid chemistry of organic nitriles and possible structures for diazonium dications were investigated.16 In superacid media orthoester (1) ionized to a dioxolanium cation (2) (Scheme 1).l7 On warming to -70 "C,attack of the sidechain methoxy group occurred at C-2 establishing the equilibrium which favoured (3) by a factor of 4 1. An acidity function study of the cyclization of substituted aryl propiophenones (4)to indenes (Scheme 2) supported a mechanism involving a dication intermediate.I8 Monoprotonation of the ketone carbonyl group afforded a monocation (5) which displayed negligible reactivity towards benzene and would therefore be incompetent in the cyclization. The formation of dication (6) triggered rate-limiting attack by the aromatic nucleophile. The result may have general implications for Friedel-Crafts and related reactions. A number of groups reported the results of solvolysis studies. Della and co-workers argued that the solvolysis of (7a) in 80% aqueous ethanol occurred via C1.1.11 bicyclopentyl cation (8).19 A large (1.30-1.37 X = D) y-deuterium isotope effect was measured consistent with a large transannular interaction between the C-D bond and the cationic centre.A Hammett correlation with a revealed the largest reaction constant (p = -2.30) measured to date using these substituent constants. The result contrasts with the fate of iodide (7b) in the presence of azide anion. Bicyclo[1.1.0]- butane derivative (9) was formed via a transition state believed to resemble (8).20 Bentley and co-workers have compiled a comprehensive listing of relative nucleo- fugacities in solvolytic S,1 reactions.21 The scale spans 17 orders of magnitude from acetate to triflate.Huang and Bennet reported homoallylic participation in the solvolysis of bisadamantylidene derivative ( The substrate underwent solvolysis 4 x lo5times more slowly than 2-adamantyl tosylate under the same conditions with l5 G.A. Olah N. Hartz G. Rasul G.K.S. Prakash M. Burkhart and K. L:ammertsma J. Am. Chem. SOC. 1994 116 3187. l6 G. Rasul G. K. S. Prakash and G. A. Olah J. Am. Chem. SOC. 1994 116 8985. l7 R.F. Childs G.J. Kang T.A. Wark and C.S. Frampton Can. J. Chem. 1994 72 2084. l8 S. Saito Y. Sato T. Ohwada and K. Shudo J. Am. Chem. SOC. 1994 116 2312. l9 E. W. Della C.A. Grob and D.K. Taylor J. Am. Chem. SOC.,1994 116 6159. 2o K.B. Wiberg and S. McMurdie J. Org. Chem. 1993 58 5603. 21 T. W. Bentley M. Christl R. Kemmer G. Llewellyn and J.E. Oakley J. Chem.SOC.,Perkin Trans. 2 1994 253 1. 22 X. Huang and A. J. Bennet J. Chem. SOC.,Perkin Trans 2 1994 1279. Reaction Mechanisms -Part (ii) Polar Reactions D Scheme 2 xA Y (7a) Y = Br (8) (9) (7b) Y = I a low Grunwald-Winstein m value (0.66).Steric crowding in (10) further ruled out the possibility of nucleophilic participation by the solvent. Titrimetric methods are used typically to follow the course of solvolysis reactions. Creary and Jiang reported a convenient NMR titration method suitable for following the departure of leaving groups more acidic than 4-nitrobenzoic acid.23 The method used 2,6-lutidine as a basic probe and avoided the use of deuteriated solvents. The powerful LFP technique was used to generate cations (1 la)-( 1 l~).~~ The most stable cation (1 la) was less reactive towards nucleophilic attack by methanol than the 4-methoxybenzyl cation consistent with the view that increased electron demand triggers enhanced 51-participation from the 4-methoxy group.When the para-substituent was a less effective donor such as a methyl group the more usual reactivity order was observed and (1 1 b) reacted more rapidly than the 4-methylbenzyl cation. Richard and co-workers discussed the nature of nucleophilic solvation of substituted ” X. Creary and Z. Jiang J. Org. Chem. 1994 59 5106. 24 N. P. Schepp and J. Wirz J. Am. Chem. SOC. 1994 116 11 749. J. M. Percy @='@ 4 X/0""H3 (10) X = OTS (lla)X= OCHa (11b) X = CH3 (llc) X = H cumyl cations (12) by alcohol solvents.25 As the cation became more stable the specific interaction depicted in (13) was detected by a good linear correlation between gas-phase and solution-phase Gibbs Free Energies of cation formation with non-unit slope.Solvent effects upon selectivity of nucleophilic attack upon carbocations were measured by the Bentley group.26 An earlier chapter in this series reported preliminary findings concerning the hydrolysis of tetraaryl orthocarbonates. Full publications concerning these highly oxygenated species that the low reactivity of orthocarbonates (14) is due to a significant imbalance between the degree of charge build up on the inductively destabilized cationic centre and charge delocalization via the oxygen atom lone pairs.The high degree of imbalance arises because of high steric constraint in (14) and the extensive reorganization required to progress to a planar cation. Attempts to analyse changes in transition state positions using conventional (two dimensional) Jencks-More O'Ferrall diagrams were unsuccessful. However three dimensional reaction cubes were used to some effect. A surprising result was reported by Lambert and co-workers.28 The diethoxyphos- phoryl group appeared to participate in the solvolysis of (15) and a hyperconjugative mechanism was proposed to provide stabilization of the incipient fi-cation. Stabiliz- ation of carbenium ions by the carbon-silicon bond (p-effect) is of course well known and an attempt to observe a p-silyl cation directly in trifluoroethanol was reported.29 The UV spectrum of a transient generated in the LFP experiment was consistent with the formation of a cation (16) displaying considerable methylenefluorenylidene character.High level ab initio calculations suggested that the presence of a silicon atom would perturb dramatically the balance between benzyl and tropylium cation ta~tomers.~' In the parent hydrocarbon system tropylium cation (17a) is 29 kJ mol- 25 J. P. Richard V. Jagannadhan T.L. Amyes M. Mishima and Y. Tsuno J. Am. Chem. SOC.,1994,116,6706. 26 T.W. Bentley and Z. H. Ryu J. Chem. SOC.,Perkin Trans. 2 1994 1279. '' P. Kandanarachchi and M. L. Sinnott J. Am. Chem. SOC. 1994 116 5601. '' J. B. Lambert R. W. Emblidge and Y. Zhao J. Org. Chem. 1994 59 5397.29 C. S. Lew R. A. McClelland L. J. Johnston and N. P. Schepp J. Chem. SOC.,Perkin Trans. 2 1994 395. 'O A. Nicolaides and L. Radom J. Am. Chem. SOC.,1994 116 9769. Reaction Mechanisms -Part (ii) Polar Reactions 83 A (17a) X = C (I&) x= c (17b)X=Si (18b) X= Si more stable than (18a) whereas the silabenzyl cation (18b) was predicted to be 29 kJ mol- more stable than (17b). 3 Other Nucleophilic Substitutions Kirby and co-workers described the hydrolysis of a glucose tetraphosphate derivative (19) a reaction that features nucleophilic ~atalysis.~' At high pH (19) occupies inverted chair conformation (20) and displacement of the 4-nitrophenolate leaving group occurs with nucleophilic participation by the C-2 phosphate dianion.Participa- tion was not detected in the hydrolysis of the a-anomer. King characterized an interesting ring-opening reaction of lactones to o-alkoxyes- Scheme 3 shows an example which occurred with almost complete inversion of configuration oia attack by methanol at the asymmetric carbon of intermediate (21 ). 0 OxMe HC(OMe)3 e0 + OMe H2S04 MeOH -Meo2CToMe L b. R 98% 8.8. S > 95% 8.8. Scheme 3 An interesting theoretical paper discussed the possibility of the direct inline displacement mechanism with inversion [via transition state (22)] for substitution at 31 P. Cammileri R.F.D. Jones A. J. Kirby and R.Stromberg J. Chem. SOC.,Perkin Trans. 2 1994 2085. 32 S.A. King. J. Org. Chem. 1994 59 2253. J. M. Percy vinylic carbon.33 The authors concluded that the barrier for the concerted mechanism may not be prohibitively high in the gas phase or in solution and cited experimental studies from the synthetic literature to support their hypothesis.Vinyl triflates and vinyl iodonium salts (both species containing excellent leaving groups) undergo substitution reactions with almost or complete inversion of alkene configuration consistent with the concerted displacement mechanism. CI Ph Ph NaN, - / DMF -10 "C (23) Scheme 4 A range of formal S,2' displacement reactions were reported from cyclobutenone (23).34Scheme 4 shows an example. When the acetoxy adduct (24) was dissolved in methanolic sodium methoxide butenolide (25) was obtained following an interesting series of reactions.Ring opening reactions of optically pure @)-styrene oxide were examined in a careful stereochemical In water at pH 11 ring opening occurred with 93% inversion of configuration uia water attack at the benzylic (a) carbon. At higher pH hydroxide ion attacked both CI and fi-carbon atoms at comparable rates leading to complete racemization. The 7% of retained product in the reaction performed at pH 11 arose via the latter route. In acid an enatiomerically enriched mixture of diols was obtained (67% inversion 33% retention) and a range of mechanistic explanations for its formation were discussed. The trifluoroethanolysis of silyl ether (26) was subject to general acid general base and bifunctional catalysis; (27)depicts a possible transition state.36 Brarnsted constants for general acid (aA= 0.65) and general base (fiB = 0.72) fell within experimental error 33 M.N.Glukhovtsev A. Pross and L. Radom J. Am. Chem. Soc. 1994 116 5961. 34 J. L. Dillon and Q. Gao J. Org. Chem. 1994 59 6868. 35 B. Lin and D.L. Whalen J. Org. Chem. 1994 59 1638. 36 P.E. Dietze C. Foerster and Y. Xu J. Org. Chem. 1994 59 2523. Reaction Mechanisms -Part (ii) Polar Reactions of each other consistent with a constant for bifunctional catalysis of zero (PAB). Exploded transition-state representations of phosphate monoester dianion hydroly- sis were confirmed by a detailed kinetic isotope effect The hydrolysis of 4-nitrophenyl phosphate in water catalysed by phosphatases and the solvolysis in t-butanol were examined.Catalysis of phosphate diester hydrolysis by La3+ was reported by two groups. Breslow and Zhang described the hydrolysis of bis(4-nitropheny1)phosphate in the presence of hydrogen peroxide and a cyclodextrin host,38 while the catalytic hydrolysis of (28) involved two La3 + cations.39 The metal cations acted cooperatively the first as a source of coordinated hydroxide ion and the second as a Lewis acid resulting in a reported rate acceleration of 1013. Methyl transfer reactions between (29) and a large family of amine nucleophiles were studied.40 Unusually a close linear relationship (equation 1) was discovered between the Swain-Scott n constant and the Ritchie N parameter. N+ = 2.ln -4.3 (1) Also light-atom electrophiles (amines water hydroxide azide and cyanide anion) were considerably more reactive than thiosulfate thiocyanate iodide and bromide ions all usually reactive nucleophiles towards methyl derivatives.A broken pH-rate profile encountered in a study of the hydrolysis of sulfinamide (30) suggested the existence of a sulfurane intermediate. An l8Olabelling study confirmed the presence of the hypervalent intermediate and indicated that it underwent pseud~rotation.~' 4 Elimination Reactions Mechanisms of solvolytic elimination reactions were reviewed by Thibblin.42 An ab initio study of the E2 elimination at the MP2/6-31+ G* level calculated transition state structures for the reactions of chloroethane with 11 bases.43 The calculations 37 A.C. Hengge W.A. Edeus and H. Elsing J.Am. Chem. SOC. 1994 116 5045. R. Breslow and B. Zhang J. Am. Chem. SOC. 1994 116 7893. j9 A. Tsubouchi and T.C. Bruice J. Am. Chem. Soc. 1994 116 11 614. 40 J. W. Bunting J. M. Mason and C.K. M. Heo J. Chem. SOC.,Perkin Trans. 2 1994 2085. 41 T. Okuyama J. P. Lee and K. Ohnishi J. Am. Chem. SOC. 1994 116 11 614. 42 A. Thibblin Chem. SOC. Rev. 1993 22 427. 43 S. Glad and F. Jensen J. Am. Chem. SOC.,1994 116 9302. J. M. Percy reproduced movements on the three dimensional energy surface predicted by Jencks-More O’Ferrall diagrams from a central E2 transition state devoid of E1,B character. However the study revealed that there was no simple correlation between transition state geometry symmetry and the size of the primary kinetic isotope effect.Treatment of (31) with sodium ethoxide in ethanol/DMSO solvent led to the exclusive formation of phenyl vinyl sulfide.44 Though substitution products could be formed by direct attack or episulfonium ion pathways none was observed. Failure to observe isotopic exchange of the methylene protons attached to the sulfur bearing carbon was taken as evidence against an E1,B pathway and to be in favour of a E2 process. Eliminations from cis-and trans-1,2-dichlorocycloalkanesto form the same 1 -chlorocycloalkene were performed competitively using a sodium amide/sodium t-butoxide base mixture in THF.45 In the trans isomer dehydrochlorination occurred to an unusual extent via a syn elimination. Changing to a less complex base (such as a t-butoxide salt alone) lowered the rate of the syn elimination.Two studies of antibody-catalysed elimination were reported. Catalytic antibody 43D4-3D12 accelerated the dehydrofluorination of (32) by a factor of lo5. An anti elimination occurred via an E2 or E1,B mechanism and apparently without acid catalysis of fluoride ion depart~re.~~ The Scripps group raised a catalytic antibody using (33) a mimic for an eclipsed E2 transition state in the ha~ten.~~ The antibody catalysed a syn elimination (Scheme 5). 0 P h v Ph Scheme 5 A Grob-type fragmentation (D,D mechanism) was reported for the conversion of N-haloamino acids to aldehydes.48 Hammett correlations were obtained varying the alkyl substituent at the a-carbon (p* = -3.9) and on the nitrogen atom (p* = -2.1) 44 H.-Q.Xie N. Truomg E. Buncel and J.G. Purdon Can. J. Chem. 1994,72 448. 45 A. P. Croft and R. A. Bartsch J. Org. Chem. 1994 59 1930. 46 K. Shohat T. Uno and P.G. Schultz J. Am. Chem. SOC. 1994 116 2261. 47 B. F. Cravatt J. A. Ashley K. D. Janda D. L. Boger and R. A. Lerner J. Am. Chem. SOC.,1994,116,6013. 48 X. L. Armesto M. Canle M. Losada and J.A. Santaballa J. Org. Chern. 1994 59 4659. Reaction Mechanisms -Part (ii) Polar Reactions indicating that C-C bond separation is extensive and leads nitrogen-halogen bond cleavage (Scheme 6). Scheme 6 Nucleophilic displacements from N-bromoacetophenone oxime occurred by para- llel direct and elimination-addition pathways.49 The inversion of oxime configuration from the syn to the less thermodynamically stable anti diastereoisomer led to the detection of a nitrosostyrene intermediate in which rotamer (34) is more reactive.Scheme 7 outlines the overall conversion. MeoH anti 0 Scheme 7 In non-polar solvents the reaction with weakly basic nucleophiles afforded syn products uia an S,2 displacement of bromide. In the Schmidt reaction of gem-diazide (35) in acidic acetonitrile and elimination across the carbon-nitrogen double bond of the kinetically competent iminodiazonium cation (36) leads to the formation of aryl nitrile product^.^' In water gem-diazide hydrolysis led to the isolation of 4-methoxybenzaldehyde as the major reaction product. 49 K. Wirnalasema and D. C. Haines J. Org. Chem. 1994 59 6472. 50 J. P. Richard T.L. Amyes Y.-G.Lee and V. Jagannadhan J. Am. Chem. SOC. 1994 116 10833. J. M. Percy 5 Addition Reactions Various aspects of the Michael addition reaction have attracted the attention of investigators. Hoz has used the reaction as a case study of the relationship between transition state structure location and the nature of reactant and product states.” Addition reactions to N-methyl vinylpyridinium cations (37) were studied using a wide range of amine nu~leophiles.~~ The addition rates correlated well with the Ritchie N parameter establishing the utility of the scale for probing reactions at tetravalent sp2 hybridized electrophiles. A study of the reactions of synthetically important Gilman and heterocuprate reagents to cyclic enones concluded that the addition reactions occurred via a polar mechanism leading directly to the formation of metal en~lates.’~ Mechanisms involving SET processes have achieved some popularity for the description of these important reactions but in the recent study the formation of kinetically important 7t complexes could not be excluded.The cytotoxic compound CC-1065 contains a rich array of functional groups. A key feature is the y-cyclopropyl enone a Michael acceptor identified as a site for attack by biological nucleophiles. Scheme 8 shows parallel mechanisms for the specific-acid- catalysed reaction of analogue (38) with hydroxide ethoxide and chloride anions.54 I 1 Nu-Nu-Nu )-jjR H OH H OH Scheme 8 Direct attack yielding (39) competed with opening of the distal bond of the cyclopropane ring to afford a carbenium ion (stabilized presumably by homoallylic or phenonium participation).Nucleophilic trapping led to the formation of [indolo] piperidine products. 51 S. Hoz Acc. Chem. Res. 1993 26 69. 52 C. K. M. Heo and J. W. Bunting J. Chem. SOC. Perkin Trans. 2 1994 2279. 53 A. S. Vellekoop and R.A. J. Smith J. Am. Chem. SOC. 1994 116 2902. 54 M.A. Warpekoski and D. E. Harper J. Am. Chem. SOC.,1994 116 7573. Reaction Mechanisms -Part (ii) Polar Reactions Electrophilic additions to enol ethers formed the subject of a number of important papers. Fecapentaene is one example of a remarkable class of polyenic natural products. The key functionality is a highly conjugate enol ether which hydrolyses by an extremely unusual mechanism.Kresge and co-workers examined the hydrolysis of both diastereoisomers of 1-methoxybutadiene to explore the effect of conjugation upon the normal vinyl ether hydrolysis mechanism. Both isomers hydrolysed more slowly than methyl vinyl ether despite the higher degree of stabilization of the intermediate oxacarbenium ions and there was a marked dependence of reactivity upon configuration. The 2 diastereoisomer was 160 times less reactive than methyl vinyl ether while the E diastereoisomer was only eight times less reactive; both reacted exclusively through protonation at the 6-positi0n.’~ A study of intramolecular catalysis of enol ether hydrolysis yielded the highest EM (6 x 104M) for a reaction involving a proton-transfer step to date.The development of a strong intramolecular hydrogen bond between the /?-carbon atom of enol ether (41) and the ammonium proton presumably relieves some peri strain as the system progresses towards the transition state.’ OMe Alkenyl glycosides are important intermediates in oligosaccharide synthesis and a recent study reveals that protonation occurs via protonation at carbon.57 The glycosidicC-0 bond of (42)therefore remains intact during the hydrolysis reaction. At pH 3 (42) was 4.5 times more reactive than the /?-anomer. One of the techniques developed for the generation of high concentrations of enol intermediates found a synthetic application. Vinyl ketene acetal (43) was used to generate a concentrated (0.2 M) solution of acetaldehyde enol which formed a 1 1 copolymer with maleic anhydride upon treatment with tributyltin hydride and a radical initiat~r.~~ Furan when converted into pentaamine osmium(1r) complex (44) behaved like a typical enol ether.For example iminium salt (45)was formed when (44) was dissolved in a solution of acetonitrile containing methyl triflate.’9 High asymmetric induction in enol ether protonation was achieved by a catalytic antibody.60 Enol ether (46)formed S ketone (47) exclusively; however (47)and the R enantiomer bound to the antibody with similar affinities consistent with the antibody exercizing maximal chiral discrimination between the transition states. 55 Y. Chiang R. Eliason G.H.-X. Guo and A.J. Kresge Can. J. Chem. 1994 72 1632. 56 A. J.Kirby and F. O’Carroll J. Chem. SOC.,Perkin Trans. 2 1994 649. 57 H. K. Chenault and L. F. Chafin J. Org. Chem. 1994 59 6167. A.K. Cederstav and B. M. Novak J. Am. Chem. Soc. 1994 116,4073. 59 H. Chen L. M. Hodges R. Liu W. C. Stevens M. Sabat and W. D. Harman J. Am. Chem.SOC. 1994,116 5499. 6o G.K. Jahangiri and J. L. Reymond J. Am. Chem. SOC. 1994 116 11 264. J. M. Percy OMe A0-F5-doR (Ma) R = But (48b) R = H Protiolysis of enol ether (48a) led to the formation of enol (48b) and none of the corresponding ketone.61 In THF or ether solution ketone (49)existed exclusively as enol (50). The combined fluorine atom substituent effects acted to destabilize ketone forms rather than by stabilizing enol tautomers. The mechanism of alkene bromination remains a problem of current interest.In an elegant study Rodebaugh and Fraser-Reid examined the reactions of o-alkenyl glycosides key species in the armed-disarmed glycosylation strategy with N-bromosuccinimide (NBS).62 MeCN -40°C 90% Scheme 9 Exploiting the different hydrolytic reactivities of the o-alkenyl glycosides elec- trophilic bromination was shown to be reversible with bromonium ion transfer 61 R. A. Correa P. E. Lindner and D. M. Lemal J. Am. Chem. SOC.,1994 116 10795. 62 R. Rodebaugh and B. Fraser-Reid J. Am. Chem. SOC. 1994 116 3155. Reaction Mechanisms -Part (ii) Polar Reactions occurring between competing alkene nucleophiles. Rozen and colleagues in Tel-Aviv described the preparation and reactions of methyl hypofluorite MeOF a powerful oxygen electrophile unlike all the other 0-F reagents.63 Regioselective anti-1,2-addition occurred with most alkenes including indene (Scheme 9).Additions to alkynes included an interesting (and remarkably efficient) tetra- fluorination of 1,2-diphenylethyne described by the Olah group (Scheme NOBF, PPHF Ph-Ph CHzClp 0°C Ph? FF Ph 75% Schemm 10 Nitrosation of the alkyne initiated the sequence followed by fluoride ion attack on the vinyl cation intermediate. Alkyne protonation under mild conditions (neat trifluoroacetic acid) initiated the quantitative biscyclization depicted in Scheme 1 1 .65 OR OR CF&OZH -4 RO RO Scheme 11 6 Aromatic Addition and Substitution This section deals mainly with addition reactions.The one exception concerns the transfer of the triazinyl group between substituted pyridines.66 The Brsnsted plot for the reaction of salt (51) with substituted pyridines contained a break where the pK,s of incoming and outgoing species were equal. The result was entirely consistent with the 63 S. Rozen E. Mishami M. Kol and I. Ben-David J. Am. Chem. SOC. 1994 116 4281. 64 C. York G.K.S. Prakash and G.A. Olah J. Am. Chem. SOC.,1994 116 6493. 65 M.B. Goldfinger and T. M. Swager J. Am. Chem. Soc. 1994 116 7895. 66 A. H. M. Redrew J. A. Taylor J. M. J. Whitmore and A. Williams J. Chem. SOC.,Perkin Trans. 2 1994 2383. J. M. Percy formation of a highly stabilized Meisenheimer complex. The Brlernsted constant for the reaction (Peg= 1.O) was significantly smaller than the value obtained for concerted acyl transfer reactions (Peg= 1.6).The regioselectivities of aromatic sulfonation of halobenzenes halonaphthalenes and anthracenes has been described using sulfur trioxide as the ele~trophile.~~ Partial rate factors were calculated for the various aromatic nucleii. Rate constants for aromatic iodination were measured,68 forming a good correlation with the a-basicity of the aromatic substrate. The correlation constitutes a potential test for distinguishing between polar and SET reaction mechanisms. For example mesitylene displays higher a-basicity than durene whereas consideration of their redox potentials predicts that durene should participate more readily in SET reactions.The higher reaction rate of mesitylene with an iodine electrophile is therefore consistent with a polar reaction mechanism. A similar conclusion was reached for bromination acylation mercuri- ation and thalliation reactions while the order of reactivity observed for aromatic nitration suggested an SET pathway. Brosh and Kochi examined the mechanism of aromatic nitrosation6’ in acetonitrile and measured a significant primary isotope effect associated with a rate-determining deprotonation of the Wheland intermediate. The unusual mechanistic feature was attributed to the high Lewis basicity of nitrosoarenes. A mild nitration mixture containing dinitrogen pentaoxide was generated in dich- loromethane solution from ozone and nitrogen dioxide.70 Under these conditions the nitrations of propiophenone and related ketones (Scheme 12) yielded remarkably high proportions of ortho product (ortho:meta 1.1-3.8 :1) via a delivery mechanism involving (52).n 0 Scheme 12 67 H. Cerfontain Y. Zou B. H. Bakker and F. van de Griendt Can. J. Chem. 1994,72 1966. 68 C. Galli and S.D. Giammarino J. Chem. SOC. Perkin Trans. 2 1994 1261. 69 E. Bosch and J.K. Kochi .I.Org. Chem. 1994,59 5573. ’O H. Suzuki and T. Murashima J. Chem. SOC.,Perkin Trans. 2 1994 903. Reaction Mechanisms -Part (ii) Polar Reactions None of the sidechain positions were attacked. A study of sulfinamide hydrolysis revealed an arylthiolation reaction believed to involve an arylsulfenium ion intermedi- ate (Scheme 13).7’ Scheme 13 A sequence of intersecting cyclization and rearrangement reactions was proposed to explain the conversion of 2-nitrobenzyl alcohol into (53)in moderate (66%) yield in trifluoromethanesulfonic acid.’* Under the same conditions a converging mechanism led to the efficient (78%) formation of (54).OSO2CF3 (53)X = COZH (54)X= H ’’ H. Takeuchi H. Oya T. Yanase K. Itou T. Adachi H. Sugiura and N. Hayashi J. Chem. Soc. Perkin Trans. 2 1994 827. ’* R.P. Austin and J.H. Ridd J. Chem. SOC. Perkin Truns.2 1994 1411. J.M. Percy 7 Carbanions and Proton Transfer Taft Koppel and co-workers reported a major compilation of gas phase acidities measured using pulsed ion cyclotron resonance.73 Strong neutral Brernsted acids included aryl malononitriles fluorosulfonylmethanes sulfonimides and other oxygen acids.The compilation which identified (55) as the strongest gas-phase acid to date should form a useful reference scale. Sulfur-stabilized carbanions exhibit a wide range of uses as reagents and carbon nucleophiles in synthetic organic chemistry. A theoretical study explored the acidity trend in the series dimethylsulfide dimethylsul- foxide and dimethyl~ulfone.’~ The main effect of the added oxygen atoms was exerted through an inductive channel rather than providing a route for delocalizing the negative charge. The increasing acidity was attributed to destabilization of the carbon acid rather than stabilization of the conjugate base. In DMSO solution (56) ionized spontaneously and completely; pK,s for a number of other highly delocalized carbanions were reported in the same study.75 Fluorohydrocarbons often display relatively low pK,s; for example tris(trifluoromethy1)methane (57) was relatively acidic in DMSO (pK = 12.6) while bicyclic fluorohydrocarbons (58k(59) were all considerably less acidic.(58a)X=H (59) (58b) X= F The difference in acidities was attributed to the non-availability of hyperconjugative interactions between the carbanion and C-F r~* orbitals in the bicyclic carbon acids due to ~rthogonality.~~ Supercritical water (4OO0C 300 bar) has been used as a medium for studying isotopic exchange into di-n-b~tylamine.~~ Deuterioxide-catalysed isotopic exchange occurred most rapidly at C-1 and C-3. The C-4 methyl protons exchanged less rapidly while the C-2 methylene protons were least reactive.The relative acidities of the various chain positions appeared to alternate with the odd positions being more acidic and the even positions less so. Oxygen acids (60)-(62) have very similar pK,s in DMSO (11.2 f0.2) but very different 0-H bond dissociation energies suggesting that resonance stabilization in the -ate form is a more powerful determinant of acidity than the strength of the scissile 0-H bond.78 Fluorenyl esters (63a)-(63c) proved to be relatively strong carbon acids with pK,s of 7.40 10.51 and 11.52 in water re~pectively.~~ Though much of the acid strength lies in the carbanion stabilizing effect of the fluorenyl group and the high 73 I. A. Koppel R.W. Taft F.Anvid S.Z. Zhu L. Q. Hu K. S. Sung D. D. Desrnarteau L. M. Yagupolskii Y. L. Yagupolskii,N. V. Ignatev N. V. Kondratenko,A. Y. Volkonskii V. M. Vlasov R. Notario and P. C. Maria J. Am. Chem. SOC.,1994 116 3047. 74 P. Speers K. E. Laidig and A. Streitweiser J. Am. Chem. SOC. 1994 116 9257. 75 T. Kinoshita H. Kirnura I. Nakajirna S. Tsuji and K. Takeuchi J. Chem.SOC. Perkin Trans.2 1994 165. 76 I. A. Koppel V. Pihl J. Koppel F. Anvia and R. W. Taft J. Am. Chem. SOC. 1994 116 8654. 77 J. Yao and R.F. Evilia J. Am. Chem. SOC. 1994 116 11 229. 78 F.G. Bordwell and A.V. Satish J. Am. Chem. SOC. 1994 116 8885. 79 Y. Chiang J. Jones and A. J. Kresge J. Am. Chem. SOC. 1994 116 8358. Reaction Mechanisms -Part (ii) Polar Reactions (ma)X = S;Y = 0 (63b) X= 0;Y = S (63b) X = 0;Y = 0 fulvenoid character of the enolates the thiono C=S group in (63a) exerts a significant further effect worth three pK units.Rate constants for acid-catalysed protonation of the enolates were also reported. Two groups generated related fulvene diol (64) by LFP.80,81 All the rate and equilibrium constants for (64)were isolated and the authors concluded that the benzocyclopentadienyl (indenyl) and carbonyl groups exerted similar carbanion stabilizing effects. Dienol (65) is a strong acid (pKf = 0.99) and conjugate base (66) is a much stronger carbon acid (pKHK = 15.19) than phenylacetate anion (pKHK = 30.2) demonstrating the powerful carbanion stabilizing effect of a cyano group.82 The phenylalkynyl group also exerts a powerful pK lowering effect (zten pK units) and amine (67) is a strong nitrogen acid (pK = 10.28 & 0.01).83 The enolization of pyrazinyl ketone (68) is initiated by protonation at nitrogen; the enol(69) is stabilized by the formation of an intramolecular hydrogen bond consistent with the low pK and high equilibrium constant recorded for (68).84 The fury1 nucleus in (70) stabilizes the keto form relative to the en01.~~ Though the acidities of ketones ‘O J.-I.K.Almstead B. Urwyler and J. Win J. Am. Chem. SOC. 1994 116 954. J. Andraos A. J. Kresge and V. V. Popik J. Am. Chem. SOC. 1994 116 961. ’’ J. Andraos Y. Chiang A. J. Kresge I. G. Pojarlieff N. P. Schepp and J. Wirz J. Am. Chem.SOC.,1994,116 13. 83 J. Andraos Y. Chiang A. S. Grant H.-X. Guo and A.J. Kresge J. Am. Chem. SOC. 1994 116 741 1. 84 A. R. E. Carey R.A. More O’Ferrall M.G. Murphy and B.A. Murray J. Chem. SOC.,Perkin Trans. 2 1994 247 1. A. Fontana and R.A. More O’Ferrall J. Chem. SOC.,Perkin Trans. 2 1994 2453. J. M. Percy (71a) and analogous (and less acidic) sulfones (71b) differ by x ten pK units the rates of deprotonation are remarkably similar.86 Deprotonation of the sulfones is only two to three orders of magnitude slower than the deprotonation of the ketones. As the carbanion stabilizing effect of the sulfonyl group is primarily inductive minimal solvent reorganization is required upon deprotonation in contrast to the extensive changes required on passage from ketone to enolate. In terms of Marcus theory sulfones are around two orders of magnitude more intrinsically acidic than ketones.(71a) Y = C=O (71b) Y = SOP Exchange of the imidazole C-2 proton occurred rapidly in complex (72); slower exchange at C-4 and C-5 was also detected along with rapid exchange of the C-8 proton in purines. The chromium catalyst was the most effective species reported to date; exchange rates exceeded those obtained for proton-catalysed C-2 H exchange.' The quenching of amide enolates using anilide (73) as the chiral acid occurred in high e.e.88The pK of the acid falls two to three units below those of the amides used in the study; a difference in pK of this magnitude allows the protonation reaction (k,) to occur at a reasonable rate while maintaining a useful energy difference between the diastereoisomeric transition states while ensuring that the back or return reaction is (k1)negligible (k,>>k-,).Kinetic isotope effects were used to identify a non-concerted carbanionic mechanism for the reaction shown in Scheme 14. Treatment of vinylcyclobutanol (74) with potassium hydride forming the alkoxide under ion-pair dissociating conditions resulted in the formation of (76). Instead of the 1,3-shift from (75) the rearrangement probably involves carbanionic intermediate (77).89 86 S. Wodzinski and J. W. Bunting J. Am Chem. SOC.,1994 116 6910. 87 E. Buncel 0.Clement and I. Onyido J. Am. Chem. SOC. 1994 116 2679. E. Vedejs N. Lee and S.T. Sahata J. Am. Chem. SOC. 1994 116 2175. 89 N. J. Harris and J.J. Gajewski J. Am. Chem. SOC.,1994 116 6121.Reaction Mechanisms -Part (ii) Polar Reactions 0- (74) (75) Scheme 14 8 Carbonyl and Related Reactions Equilibrium constants were reported for the formation of dimethyl acetals from benzophenone pinacolone and methyl formate.” The latter case (an orthoester is formed of course) represents the first example of the determination of an equilibrium constant for this reaction of an acyclic ester. Hammett correlations were constructedg1 for the acid-catalysed breakdown reactions of acetophenone dimethyl acetal (p = -2.28) (the reference compound for Guthrie’s study”) and the hemiacetal (p = -2.29) using a stopped-flow pH-jump technique. Hemiacetal breakdown involved a general-acid-catalysed expulsion of methoxide from the conjugate base.MeC02- +MeC02Ph -(MeC0)20 + PhO-Scheme 15 The equilibrium shown in Scheme 15 was studied from both directions by the Canterbury group.92 Brernsted constants were reported for both reactions in water and chlorobenzene and the transfer reactions were faster in the organic solvent. Non-polar organic solvents such as chlorobenzene or dichloromethane may be the media of choice for the acetylation of more basic phenolates instead of the more polar DMF. Sanders and co-workers described catalytic acyl transfer (Scheme 16) with turnover inside the cavity of a porphyrin 90 J. P. Guthrie and J. Guo Can. J. Chem. 1994 72 2071. 91 R. A. McClelland K. M. Engel1,T. S. Larsen and P. E. Sorensen J.Chem.SOC.,Perkin Trans. 2,1994,2199. 92 S.A. Ba-Saif A.B. Maude and A. Williams J. Chem. SOC. Perkin Trans. 2 1994 2395. 93 L.G. Mackay R. S. Wylie and J.K. M. Sanders J. Am. Chem. SOC. 1994 116 3141. J. M. Percy Scheme 16 Though only a small effective molarity (2M) was calculated for the reaction the non-covalent pre-organization of electrophile and nucleophile is a notable feature. The question of the origin of the Thorpe-Ingold effect and high effective molarities in enzyme-catalysed reactions remain subjects for discussion. Bruice and Lighthouse94 calculated the conformer populations of gem dialkylated a,o-dicarboxylic acid derivatives which cyclized to anhydrides. The paper concluded that the presence of gem dialkyl substituents favoured productive conformations or resulted in a propinquity effect of the type proposed by Menger.Thiol proteases catalyse the hydrolysis of amide bonds and (thiomethy1)imidazole (78) contains a sulfur nucleophile and an acid/base system to assist with tetrahedral intermediate formation and breakd~wn.~’ Catalysis of the hydrolysis of unactivated formyl amides was observed between pH 6.5 and 9. The cyclization of amide (79) to perimidine (80) occurred spontaneously in aqueous DMSO presumably with some relief of peri strain (Scheme 17).96 An interesting proton switch mechanism involving two molecules of water was identified as the rate determining step. 0 (79) Scheme 17 94 F. C. Lighthouse and T.C. Bruice J. Am. Chem. SOC.,1994 116 10 789. 95 J. W. Keillor A.A. Neverov and R. S. Brown J. Am. Chem. SOC.1994 116 4669. 96 A.S. Baynham and F. Hibbert J. Chem. SOC.,Perkin Trans. 2 1994 1435. Reaction Mechanisms -Part (ii) Polar Reactions Less well-known carbonyl derivatives include selenocarboxylic acids.97 In the solid state or in non-polar solution the C=O group was identified while the THF solution at low temperature contained (81) stabilized by hydrogen bonding to the O-H group. Raman spectroscopy was used to study the hydrolysis of cyanate anion. Two parallel reactions led to the formation of urea and carbamate anion which failed to interconvert under the reaction condition^.'^ 9 Other Reactions A number of papers have discussed mechanistic aspects of the chemistry of important oxidants oxidized species or oxidation reactions. The Baeyer-Villiger oxidation of cyclic ketones occurred efficiently when oxygen was bubbled through a solution of the ketone containing benzaldehyde (Scheme 18).0 9 90% Scheme 18 The reaction proceeded in the absence of metal catalysts and involved the formation of perbenzoic acid (detected by I3C NMR) in sitwg9 The Criegee rearrangement has been used to synthesize oxepines from cyclohexenyl hydroperoxide (82) (Scheme 19).loo Trifluoroacetylation in the presence of amine bases led to the formation of F3CC00 OOH tP I Scheme 19 97 H. Kageyama T. Murai T. Kanda and S. Kato J. Am. Chem. SOC. 1994 116 2195. 98 N. Wen and M. H. Brooker Can. J. Chem. 1994 72 1099. 99 K. Kaneda S.Ueno,T. Imanaka E. Shimotsuma Y. Nishiyama,and Y. Ishii J. Org.Chem.1994,59,2915. loo R. M. Goodman and Y. Kishi J. Org. Chem. 1994 59 5125. 100 J. M. Percy cyclohexenone via an elimination. However running the acylation reaction without an amine base but in the presence of a catalytic amount of DMAP led to the formation of the oxepine (83) by a ring expansion reaction. The reviewer has written a two-step mechanism for this conversion. Dimethyldioxirane is an extremely effective oxidant under a range of mild conditions. The oxidation by insertion of (84) was accelerated by solvents capable of hydrogen bonding to the oxidant (Scheme 20)."' Scheme 20 A solvent isotope effect (k,/k = 1.1) was measured in chloroform which appeared to be the solvent of choice. Some remarkably stable ozonides were reported including (85).'02 Less-substituted species decomposed to 1,5-dicarbonyl products when treated with triphenylphosphine but (85) survived several days at reflux in diethyl ether.Ozone proved to be the reagent of choicelo3 for the stereoselective oxidation of 1,3-dithian- (S)-oxide to trans-dioxide (86). The C-2 methylene protons of (86) underwent exchange in neutral D,O (t1,* = 4 hours) and a pK of 24.9 were reported in DMSO. The Dess-Martin periodinane reagent has been used extensively for a range of demanding oxidations. However reproducibility has proved a problem because of the presence of decomposition products in many samples. Schreiber and Meyer'04 have addressed the problem identifying (87) as the reactive species in most oxidations. Oxidation reactions of organic compounds in aqueous solutions of bromine have been reviewed.'05 The Hoffmann rearrangement of aromatic amides to arylamines 'O' R. W. Murray and D. Gu J. Chem. SOC. Perkin Trans. 2 1994 451. Io2 H. Mayr J. Baran E. Will H. Yamakoshi K. Teshima and M. Nojima J. Org. Chem. 1994,59,5055. V. K. Aggarwal I. W. Davies R. Franklin J. Maddock M. F. Mahon and K. C. Molloy J. Chem. Soc. Perkin Trans. 2 1994 2363. '04 S. D. Meyer and S. L. Schreiber .I.Org. Chem. 1994 59,7549. J. Palou Chem. SOC.Rev. 1994 23 357. Reaction Mechanisms -Part (ii) Polar Reactions relies on an N-bromination reaction usually performed under alkaline conditions. The reactive brominating species formed in alkaline aqueous solutions of N-bromosuc- cinimide has been identified as (88).'06 The formation of (88)is unexpectedly slow and its stability is low above -5°C.Modifying the Hoffmann protocol to exploit this information allowed the reaction yields to be improved dramatically. (87) 10 Probes of Polar Reactions Most of the activity reported in this area dealt with solvation or with kinetic isotope effects. The well-known decarboxylative ring opening of benzisoxazole-2-carboxylate has been used as a probe of solvation effects. A unified scale of solvent parameters for specific and non-specific interactions was used to interpret the results.' O7 The dependence of the E,(30) scale on solvent composition has been investigated using a range of empirical solvent parameters.lo8 Marcus has shown that specific solvation effects are particularly important in non-polar solvents.The finding implies that polarity scales derived using specific solutes may not be transferrable for use with other s~lutes.''~ The SWAG model which quantifies solvation by summing increments from polar and non-polar groups with solvent components has been applied to the enolization of acetylacetone."' The keto and enol forms are of similar polarity while the cis enol is most hydrophobic and the keto form has the highest dipolar character. The 4-methoxybenzyl dimethylsulfonium cation (89) has been proposed as a chemical probe for the determination of the role of solvent nucleophilicity." Buncel lo6 C. H. Senariayake L. E. Fredenburgh R. A. Reamer R. D. Larsen T. R. Verhoeven and P.J. Reider J. Am. Chem. SOC. 1994 116 7947. lo' D.C. Ferris and R. S. Drago J. Am. Chem. Soc. 1994 116 7509. R. D. Swierczynski and K. A. Connors J. Chem. SOC. Perkin Trans. 2 1994 467. lo9 Y. Marcus J. Chem. SOC. Perkin Trans. 2 1994 1015. 'lo W. Blokzijl J. B. F. N. Engberts and M. J. Blandamer J. Chem. SOC. Perkin Trans. 2 1994 455. D.N. Kevill N. H. J. Ismail and M. J. D'Souza J. Org. Chem. 1994 59 6303. 102 J.M. Percy and co-workers' l2 have tuned the nucleophilicity of substituted phenolates in the sulfonyl transfer reaction with (90). Conventional Brarnsted correlations (constant solvent vary phenoxide pK,) yielded different values for pN in a each of the solvents studied suggesting a shift in transition-state structure. However when the pK of the nucleophile was varied by changing the solvent composition each phenolate yielded the same value of BN (0.6).The result implies a single transition state structure with systematic variations in the intrinsic barrier for sulfonyl transfer.Reliable isotopic fractionation factors are required if proton inventory methods are to be used successfully. NMR methods were used to obtain fractionation factors for benzylamine and benzylammonium cation.' ' Unlike in the corresponding oxygen case the development of positive charge at nitrogen does not increase the fractionation factor. Values of = 0.958 _+ 0.07 and $ammonium = 0.80 & 0.13 were obtained. Kinetic isotope (p)effects upon the identity reaction of (91) and (92) with bromide ion were measured.' l4 Br Br PhYCL3 (91) (92) (9%) X = H (93b) X = OSiMe3 (93c)X = C02Me Kinetic isotope effects were also used to probe the [3,3] Claisen rearrangement' of ally1 vinyl ether (93a) and the hetero-Cope rearrangements'16 of (93b) and (93c).The investigation of (93a) concludes strongly that the aqueous acceleration of the Claisen rearrangement is not due to the development of polar or ion-pair character in the transition state. Deuterium (D,)effects at C-4 and C-6 failed to show the anticipated increase in heterolytic bond breaking as the solvent became more polar. The rate of ion pair formation from (93a) was calculated under rearrangement conditions and the value obtained was too small to explain the observed reaction rates. A rigorous isotope effect study of the hydrolysis of both anomers of glucopyranosyl fluoride reached some interesting conclusions.' ' The a-anomer hydrolysed through the familiar exploded S,2 transition state while the p-anomer reacted by an.SN1 mechanism.Both anomers reacted in the 4C1conformation in contradiction of the antiperiplanar lone pair hypothesis. '12 R. M. Tarkka W. K. C. Park P. Liu E. Buncel and S. Hoz J. Chem. SOC.,Perkin Trans. 2 1994,2439. 'I3 C.H. Arrowsmith H.-X. Guo and A.J. Kresge J. Am. Chem. SOC. 1994,116 8890. '14 A. R.Stein Can. J. Chem. 1994 72 1789. J.J. Gajewski and N.L. Brickford J. Am. Chem. SOC. 1994 116 3165. L. Kupczyk-Subotkowska W. H. Saunders H. J. Shine and W.Subotkowski J. Am. Chem. SOC. 1994 ''' Y. 116 7088. Zhang J.Bommuswamy and M.L. Sinnott J. Am. Chem. SOC. 1994 116 7557.