4 Reaction Mechanisms Part (ii) Polar Reactions By D.G. MORRIS Department of Chemistry University of Glasgow Glasgow GI2 8QQ 1 Introduction The present Report is concerned with nucleophilic substitution carbo-cations carbanions the reactivity of carbonyl groups and of esters and elimination and addition reactions together with miscellaneous topics. A review on pyramidal carbo-cations’ and one on long-lived cations2 have appeared. Several constructive papers have been published in this challenging area which may be witnessing a period of enhanced interest following a period of ennui probably brought about by norbornyl cation overkill. Gas-phase reactions of anions have been the subject of two reviews devoted to bimolecular aspects3 and to the use of the flowing afterglow technique as a m~nitor.~ A review with emphasis on the number of stages involved in nucleophilic vinylic substitution has also been publi~hed.~ 2 Nucleophilic Substitution A number of papers have been concerned with the position of the transition state during SN2reactions at saturated carbon.From entropies of activation and standard entropies of the dissociated ions in the Menschutkin reaction of Me3N with EtI in a variety of solvents it has been concluded6 that in contrast to a recently expressed and cited estimation the transition state is early. Based on the response of the rate to substitution by methyl at the a carbon it has been concluded’ that bond-making and -breaking at the central carbon are synchronous. In the hydrolysis of methyl perchlorate standard Gibbs energies of transfer after correction for cavity and non-electrostatic effects indicate that the C-0 bond is longer than expected in the transition state which is indicated to be ‘looser’ than its counterpart for MeI.8 By means of Grunwald-Winstein plots regions of decreasing rate with increasing ionizing power of the solvent are observed in the hydrolysis of MeOClO in aqueous ’ H.Schwarz Angew. Chem. Znt. Ed. Engl. 1981 20 991. G. A. Olah Chem. Scr. 1981,18,97. ’N. M. M. Nibbering Recl. Trav. Chim. Pays-Bas 1981,100 297. C. H. De Puy and V. M. Bierbaum Acc. Chem. Res. 1981,14,146. ’ Z. Rappoport Acc. Chem. Res. 1981,14,7. M. H. Abraham and A. Nasehzadeh J. Chem. SOC. Chem. Commun. 1981,905. ’D. N. Kevill J.Chem. SOC. Chem. Commun. 1981,421. M. H. Abraham and A. Nazehzadeh Tetrahedron Lett. 1981.22 1929. 65 D. G.Morris DMSO mixtures;' the leaving group is better solvated in dipolar aprotic solvents than in water. In the regions of decreasing rate with increasing ionizing power of the solvent the authors claim the first reported solvolysis by nucleophilic substitu- tion of an initially neutral substrate. It has been concluded" that in a vinylogous SN2'reaction bond formation to C-1 and bond cleavage from C-5 are mutually trans as in (l),in a concerted but non-synchronous process whereas syn stereochemistry is predicted for a fully concerted reaction." (1) Solvolyses (in CF3C02H CH3C02H and 80% aq. EtOH) have been effected on 2-adamantyl benzenesulphonate that is labelled with l80, and they were so monitored that the "0 content of the alkoxyl and sulphonyl moieties of the original ester could be determined the latter by a novel (and outlined) technique." Accord- ingly it was shown that the minimum fraction of internal return lay in the range 0.69-0.84 in the above solvents; this is in contrast to cited reports in which it is proposed that ion-pair return is not appreciable.The rate of bonding between the cation and the solvent is probably controlled by separation of the intimate ion-pair. However in a slightly later paper it is stated,12 with respect to the solvolysis of 2-adamantyl tosylate that 'internal return of substantial magnitude (>5-fold effect on k,)is absent'. The formation of a bridged carbo-cation from the tetracyclic ester (2) is postulated to occur with appreciable strain increase whereas a classical counterpart would cause minimal deformation at C-2.For the tertiary substrate (2) and its epimer the ratio of rate constants ke,,/kendo is 164 in 60% aqueous acetone (broadly similar to values in related tertiary systems) whereas the corresponding ratio for (3) is much lower i.e. 7.4 in 80% aqueous acetone with the main contributory reason being the diminished reactivity of the exo-e~ter.'~ From buffered acetolysis of (4) 2% of endo-acetate was produced this being ca. 90 times more than that formed in the corresponding reaction of exo-norbornyl tosylate. Thus acetolysis of (2) is R' (2) R' = R2 = Me,X = pNB (3) R' = R2 = H,X = Bs (4)R' = H,R2 = Me,X = Ts D.N. Kevill and A. Wang J. Chem. SOC.,Chem. Commun. 1981,83. lo W. S. Murphy and B. O'Mahony Tetrahedron Lett. 1981 22 585. It C. Paradisi and J. F. Bunnett J. Am. Chem. SOC.,1981,103,946. *'T. W. Bentley C. T. Bowen D. H. Morten and P. von R. Schleyer J.Am. Chem. SOC.,1981,103,5466. l3 J. E. Nordlander J. R. Neff W. B. Moore Y. Apeloig D. Arad S. A. Godleski and P. von R. Schleyer Tetrahedron Lett. 1981 22 4921. Reaction Mechanisms -Part (ii) Polar Reactions considered to involve a localized ion-pair in contrast to the delocalized species from exo-norbornyl tosylate. The role of ion-pairs in biological systems has been detailed in two investigations. Thus farnesylpyrophosphate synthetase catalyses the condensation between isopen- tenyl pyrophosphate and geranyl pyrophosphate (5) wherein cleavage of the C-0 bond in (5) is a discrete step yielding a geranyl cation-pyrophosphate ion-pair which then (see Scheme 1) alkylates isopentenyl pyr~phosphate.'~" By means of C,HI PP-J J I Scheme 1 (5) that was labelled with C-'80-P it was shown that ion-pair return does not occur with randomization of the "0 It is contended that ion-pair return does take place but is not detected on account of topological constraints which impede relative motion of the two ions io the enzymic reaction.Farnesyl pyrophosphate (6) is converted into nerolidyl pyrophosphate (7) by cell-free enzymes from Gibberella fujikuroi ; the transformation is a net suprafacial process1s involving an ion-pair in which the three non-bridge oxygens of the pyrophosphate are able to scramble.The reaction sequence is then completed by transformation of (7) into cyclonerodiol (8) by means of all-trans addition of water across the vinyl and the central double-bonds. The E-isomer (9) in trifluoroethanol (TFE) or ethanol gave the appropriate aromatic ether (10) or (11)in 26 or 6% yield respectively uia an intermediate T OPP**HOH +-PH OH (7) (a) C. D. Poulter P. L. Wiggins and A. T. Le J. Am. Chem. Soc. 1981 103 3926; (6) E. A. Mash G. M. Gurria and C. D. Poulter J. Am. Chern. Suc. 1981 103 3927. D. E. Cane R. Iyengar and M.-S. Shiao J. Am. Chern. Suc. 1981,103,914. D.G.Morris phenonium ion (13)whose intermediacy has been confirmed16 by interception with excess bromide ion in TFE-H20dioxan to give the bromide (12). R Mel$ Me Me Meo (10) R = OCH2CF3 (11) R = OCHZCH3 (12) R = Br A gas-phase investigation of nucleophilic displacements has been made by means of a y-radiolytic technique which permits isolation and structure determination of the neutral end-products following the generation of the halonium ions (14).”The gaseous ions are produced in the presence of an external nucleophile e.g. H,O or H2S which gives rise to products. In the gas phase the stability of the chloronium ion (14) is less than that of its bromonium counterpart (15). X --c/_r_\c-.-/\ (14) X = CI (15) X = Br The mechanism of the a-chymotrypsin-catalysed hydrolysis of amides and esters is believed to involve nucleophilic attack by the OH group of serine-195.However N-nitroso-amides from alanine and phenylalanine release carbo-cations at or near to the active site.18 These are then capable of alkylating nucleophilic groups such that the a-chymotrypsin activity is reduced by 100% and <9% for D-and ~-(16) 0 N=O II I Ph CH2-CH -C-N-CHzPh I NHCOCHMe2 (16) respectively at ratios of substrate to a-chymotrypsin of 40:1; the inhibition may be irreversible. 3 Carbo-cations Addition of (17) to SbF,-S02CIF-S02F at -130 “C gave rise to the first example of a bisected primary cyclopropylcarbinyl cation (18),formed by a mechanism given in Scheme 2.19 The 1,S-dimethylcyclo-octyl cation has been assigned a p-hydrido bridging structure (19) on the basis of a signal at very high field (8 -6.3) for the bridging l6 M.Hanack and W. Holwager J. Chem. SOC., Chem. Commun. 1981 713. ” G. Angelini and M. Speranza J. Am. Chem. Soc. 1981 103 3792. ’* E. H. White L. W. Jelinski I. R. Politzer B. R. Branchini and D. F. Roswell J. Am. Chem. SOC. 1981,103,4231. l9 L. R. Schmitz and T. S. Sorensen Tetrahedron Lett. 1981 22 1191. Reaction Mechanisms -Part (ii) Polar Reactions Scheme 2 proton a rather small coupling constant (lH-l3C)of 40 Hz and a S separation of ca. 2Hz on isotopic perturbation by substitution of a CD group.2o Analogous behaviour was noted for the cyclononyl homologue but not for the 1,4-dimethyl- cyclo-octyl cation.The same criteria indicate p bridging in 1,5- and 1,6-dimethylcyclododecyl cations.21 Molecular orbital calculations on acyclic prototypes e.g. CH3--H--CH3+ indicate a preferred CHC bonding angle of ca 180" the hybridisation of these carbons being intermediate between sp2 and sp3. The p-hydrogen is indicated to have a slight negative charge and to be located in a loose potential such that it is capable of movement (up down or sideways) at very little energetic cost. The bridging hydrogen is not electrophilic and cannot be removed as a proton.21 By means of both 'H and *Hn.m.r. spectroscopy a rapidly established equilibrium was determined22 such that K{ = [(21)]/[(20)]} is 4.5 at -130°C. This value is similar to primary isotope effects in rate studies; however in (20) and (21) the C-H(D) bonds are considerably elongated and they simulate a purported transi- tion state in a hydride-transfer reaction.The barrier to interchange of HTand p-H in (20) and (21) and in their alkylated analogues is independent of the nature of R. (20) (21) (22) (23) The positive charge lies preferentially on 13C in (22) rather than in (23) with which it is connected by hydride The equilibrium constant varies between 1.0014 and 1.0197 in the temperature range -135 to -62 "C as determined by a 13 C shift-difference method that is limited to molecules (or ions) that are undergoing 20 R. P. Kirchen K. Ranganayakulu B. P. Singh and T. S. Sorensen Can. J. Chem. 1981,59,2t73. 21 R.P.Kirchen K. Ranganayakulu A. Rauk B. P. Singh and T. S. Sorensen J. Am. Chem. SOC.,1981 103 588. 22 R. P. Kirchen N. Okazawa K. Ranganayakulu A. Rauk and T. S. Sorensen 1 Am. Chem. SOC. 1981,103,597. 23 M.Saunders M. R. Kates and G. E. Walker J. Am. Chem. SOC.,1981,103,4623. D. G.Morris degenerate rearrangement. The solution was referenced with the corresponding ion which was labelled with 13C at both potential positive carbon sites and which absorbed at higher field. A previous and surprising report claiming observation of the n.m.r. spectrum of the 2-methylbicyclo[3.2.2]nonatrienyl cation has been amended.24 Thus 2- methylenebicyclo[3.2.2]nona-3,6,8-trienein FS03H-S02CIF-S02F2 at -136 "C gave in two separate experiments only the 9-methyl-9-barbaryl cation (24); at -1 16 "C this rearranged in turn to the more stable cation (25).Scheme 3 Aryl-substituted Coates' ions (26; R = Ar) show symmetry in their 13C n.m.r. spectra i.e. C-2 -3; C-6 -7; and C-4 -5show single peaks attributed to a rapid bridge 'flipping' which interconverts (26a) and (26b) as shown in Scheme 3 and which contrary to the behaviour if R = H or Me is not frozen out at -110 "C. It is considered25 that the ions may become classical if they are substituted by a strongly electron-demanding aryl substituent. The 'H n.m.r. spectrum of the dication (27) with both CD3 groups in basal positions gave two singlets in the ratio ca. 1:3 at -50 0C.26 Between -60 and -10 "C the 90.52 MHz I3C n.m.r. spectrum of (27) showed a small (0.44 p.p,m.) deuterium-induced perturbation of the low-field absorption in accord with the attribution of a non-classical symmetrical bridged structure for (27) although the ion is formally outside the terms of reference of Saunders' original proposal.12+ (27) (28) (29) The same method involving isotopic perturbation of chemical shifts has been applied to the 9-barbaryl cation prepared from the precursor (28) that is labelled as shown.*' The 13C n.m.r. spectra are in accord with a series of structures for the barbaryl cation as exemplified by (29) which undergoes a rapid degenerate 24 M. J. Goldstein J. P. Dinnocenzo P. Ahlberg C. Engdahl L. A. Paquette and G. A. Olah J. Org. Chem. 1981,46,3751. 2s D. G. Farnum and T. P. Clausen Tetrahedron Lett.1981 22 549. 26 H. Hogeveen and E. M. G. A. van Kruchten J. Org. Chem. 1981,46,1350. 27 P. Ahlberg C. Engdahl and G. Jonsall J. Am. Chem. Soc. 1981,103 1583. Reaction Mechanisms -Part (ii) Polar Reactions rearrangement with a barrier of <4 kcal mol-'. Alternative cited structures are precluded. The I3C n.m.r. spectrum of the s-butyl cation (from the chloride and SbF,) has been recorded in the solid state by means of an apparatus shown diagrammatically.28 At temperatures <-85"C a sample that was enriched with I3C at C-3 showed scrambling over the four-carbon unit although too slowly to effect coalescence of the 13C signals at -60°C. The scrambling occurs via a protonated cyclopropane but takes place much more slowly than in solution.A break in the Hammett plot for the rate constants for ethanolysis of aryl- substituted mesylates (30) (as their logarithms) us u+has been construed in terms of stabilization of the a-keto carbo-cation by a resonance form such as (31);29 in these aberrant cases the rate constants are greater than expected on the basis of (++. (30) (31) The reaction of 3-phenylpropyne with liquid HCl gave (34) the proposed mechanism of whose formation (Scheme 4) involves the first reported 1,2-phenyl shift towards the double-bond of the first-formed vinyl cation (32); this leads to the allylic cation (33) which then gives (34) in unexceptional Ph Ph I + PhCH,-C=CH (32) (33) J (34) Scheme 4 A partially reversible initial slow protonation has been proposed3' in the acid- catalysed hydrolysis of methyl vinyl selenides which is associated with a kinetic solvent isotope effect kH30+/kD30+in the range 1.4-1.8.Reversibility is favoured by stabilization of the carbo-cation centre by a methylseleno-group and by the build-up of hemiselenoacetal during the hydrolysis (Scheme 5).To the better known ability of an a-SeR group to stabilize a carbanion is thus added the ability of a-SeR to render a carbo-cation more stable. In an enticingIy entitled paper Bunnett's group3' describe the generation of the 2-pyridyl cation (33 one of whose resonance forms (36) indicates that interception 28 P. C. Myhre and C. S. Yannoni J. Am. Chem. SOC.,1981,103,230. 29 X.Creary J. Am. Chem. SOC., 1981,103 2463.30 K.Vittinghoff and K. Griesbaum Tetrahedron Lett. 1981,22 1889. 31 L. Hevesi J.-L. Piquard and H. Wautier J. Am. Chem. Soc. 1981 103 870. 32 J. F.Bunnett and P. Singh J. Org. Chem. 1981 46,4567. D.G. Morris (slow) HY 0 cI lH23 3 Me Scheme 5 by means of anthracene may be feasible. In the event no evidence for aryne character could be detected; rather the products obtained were those of elec- trophilic aromatic substitution. 4 Carbanions By means of semi-empirical MNDO and ab initio-calculations the structures of a number of anions have been calc~lated.~~ For HCO the C=O bond length was calculated to be 1.254W,owhich is longer than in HCHO; the calculations indicate a long C-H bond (1.66 A) which is hence weak.The species has been calculated to be only slightly stable with respect to loss of CO. Greater stability has been ascribed to alkylated derivatives. In acetaldehyde however loss of a proton from the methyl group is estimated to be 28 kcal mol-’ more favourable than from the carbonyl-bonded proton. Ab initio calculations indicate that there is no necessary relationship between the electron-withdrawing or -releasing character of a substituent that contains a first- or second-row heteroatom and its ability to stabilize positive or negative charges via a u-effe~t.~~ A second-row heteroatom is calculated to stabilize both anionic and cationic substrates; the converse is true when the charge is delocalized. A number of cases offering experimental support are It has been calculated3’ that the interactions between occupied and unoccupied orbitals that produce homoaromaticity can only be realized when an empty p-orbital is juxtaposed geometrically and energetically with a filled T-or 0-orbital; such is the case in carbo-cations.In neutral molecules or anions which have been exten- sively investigated and to which extensive references are given the interactions induce overwhelming losses of bonding or increased four-electron repulsions. A similar conclusion that no homoaromatic stabilization exists for the bicyclo[3.2.l]octa-3,6-dien-2-yl anion has been proposed by Schleyer’s group,36 33 J. Chandresakar J. G. Andrade and P. von R. Schleyer J. Am. Chem. SOC.,1981,103,5612. J. R.Larson and N. D. Epiotis J. Am.Chem. SOC.,1981,103 410. 35 J. B.Grutmer and W. L. Jorgensen J. Am. Chem. SOC.,1981.103 1373. 36 E.Kaufmann H. Mayr J. Chandrasekhar and P. von R. Schleyer,J. Am. Chem. SOC.,1981,103,1375. Reaction Mechanisms -Part (ii) Polar Reactions who concluded that the observed stabilizing effect of the C-6-C-7 double-bond is brought about by an inductive effect. A very large primary kinetic isotope effect has been reported for the ionization of (4-nitrophenyl)[ l-3Hl]nitromethane. Internal return was found to be absent and the observed kH/kT is 45.8 at 25 "C; this translates to a value of 14 for the corresponding kH/kD,which is ca 3 times smaller than previously determined although still of such a magnitude as to indicate some proton t~nnelling.~~ N-Pivalylphenylalanine dimethylamide (37) underwent exchange with an excess of retention with Bu'OK in BU'OD such that the ratio of the bimolecular rate constants kJk (k for exchange; k for loss of optical activity) is 2.4 at 30°C.38 A prerequisite of the observed behaviour is a large group R since k = k for (38); this equality is also observed when a crown ether is added thereby indicating an important role for K' in determining the rate of stereochemical change.The pivaloyl oxygen in (37) is considered to complex with K' and it thereby lowers the transition state for protonation sufficiently for it to compete with conformational change. With still bulkier groups k = k, probably because steric retardation of protonation increases the lifetime of the enolate such that conformational equilibration occurs with attendant loss of any stereochemical preference for protonation.The anionic moiety in (39) experiences negligible bonding interaction with the counter-ion and accordingly is highly nu~leophilic.~~ Thus if (40) Me,CHCHO PhCH2-CH-CONMe2 0-I NHR (37) R = COCMe3 (38) R = H (39) and a catalytic amount of (39) are allowed to react at -78"C with excess of Me,SiF a good yield of the p-trimethylsiloxy-ketone (41) is obtained which consists entirely of the erythro-isomer under kinetic control. Less diastereoselection is prj-OSiMe,0 &!:::HMe R2 R' R3 (40) (41) (42) observed at higher temperatures and with other substrates. The origin of diastereoselectivity is different from that with conventional Lewis-acid-co-ordinated enolates in that an enolate that is derived from (39) shows a high negative charge in the now extended transition state (42) arising from (39) and RCHO.This has the effect of minimizing electrostatic interactions between oxygen atoms. An interesting set of results has been obtained from the reaction of m-ClC,H,CHCNM' with aromatic aldehydes in THF in the presence of H' and 37 A. J. Kresge and M. F. Powell J. Am. Chem. Soc. 1981 103 201. 38 R.D.Guthrie and E. C. Nicolas J. Am. Chem. SOC.,1981,103,4637. 39 R.Noyori T. Nishida and J. Sakata J. Am. Chem. SOC.,1981 103 2107. D. G.Morris added HMPA.40 When M is Li the reaction is faster in the absence of [2.1.1] cryptand since complexation of the carbonyl oxygen with lithium ion prevails over association of the cation with the substituted acetonitrile anion; the converse is observed when M is K40 The aldehyde p-NCC6H4CH0 reacts more slowly in the presence of Li' again on account of association of the Li' with the acetonitrile anion.The authors4' suggest that complexation with lithium ion brings the energy levels of the LUMO of the aldehyde very close. In a tight ion-pair the HOMO level of the nucleophile is lower in energy than in a loose ion-pair. The differences in frontier orbital between the HOMO of a tight ion-pair and the LUMO of the complexed aldehyde are greater than those of the HOMO of a loose ion-pair and the LUMO of a free aldehyde for p-NCC6H4CH0 whereas the opposite holds for p-MeOC6H4CH0.5 Reactivity of Carbonyl Groups Reactions of a series of carbanions with esters have been studied41 in the gas-phase via ion cyclotron resonance and products have been detected with mass/charge ratios that are consistent with there having occurred an addition-elimination- deprotonation sequence as indicated in Scheme 6. Reaction co-ordinate diagrams have been constructed in a number of specific cases and in contrast to solution reactions have the feature that the tetrahedral ion (43) is lower in energy than the reactants. (43) Scheme 6 The reaction of the benzoquinone imine (44)with excess phenol gives good yields of (46)in an acid-catalysed reaction that is mediated by the N-protonated derivative of (44),one resonance form of which is (45).42Polarization of a carbonyl group in the sense that is observed occurs in only a few examples and is made possible by aromatization of the protonated species (45).62Me 6 50" 0(44) (45) O+ .-QOH (46) 40 A. Loupy M. C. Roux-Schmitt and J. Seyden-Penne Tetrahedron Lett. 1981 22 1685. 41 J. E. Bartmess R. L. Hays and G. Caldwell J. Am. Chem. Soc. 1981 103,1339. 42 K. Shudo Y. Orihara T. Ohta and T. Okarnoto J. Am. Chem. SOC., 1981,103 943. Reaction Mechanisms -Part (ii) Polar Reactions 75 Ph Ph + \ c=o-Po~~-/ Me (47) (48) The long-sought monomeric metaphosphate ion PO3- has been generated; it reacts with the oxygen of acetophenone to give (47) which reacts with base to yield (48).43 Attack of aniline on (47) produces PhC(Me)=NPh in a reaction that is parallel with the enzyme-catalysed reactions of ATP which may be a source of Po,2-.The acid-catalysed bromination of 2,4,6-trimethylacetophenonein 50% aqueous acetic acid shows a first-order dependence of the rate on the concentration of this is in marked contrast to the behaviour of e.g. acetophenone. An inexplicably rapid rate of formation of an enol has been proposed for 2,4,6-trimethylacetophenone the slow step being the reaction of bromine with the enol to give (49); subsequent steps leading to the isolated mono-bromo-ketone are + Br-(49) rapid. In the condensation of 4-methylindan-1 -one (50)with 2-lithio-NN-diethyl-l- naphthamide a 30% yield of (51) is produced; repetition of the experiment with both hydrogens a to the ketone replaced with deuterium results in an essentially doubled4' yield of (51) since side-reactions of (50) which are mediated by enoliz- ation are now suppressed on account of an adverse isotope effect..(50) (51) On the basis that the rate of H,O'-catalysed ketonization of vinyl alcohol should be comparable with that of the known rate of hydrolysis of methyl vinyl ether a premise subsequently found to be inaccurate the generation of vinyl alcohol was achieved by methods which produce it at a faster rate than that of its ket~nization.~~ Several related precursors were employed exemplified by (52) from which an intermediate divinyl hemiorthoformate (53)was detected by 'H n.m.r. spectroscopy. An interesting method of inducing selectivity of reduction of carbonyl groups has been developed.47 Thus (EtO),SiH activated with KF reduces aldehydes 43 A.C. Satterthwait and F. H. Westheimer J. Am. Chem. Soc. 1981 103 1177. 44 A. G. Pinkus and R. Gopalan J. Chem. SOC.,Chem. Commun. 1981 1016. 45 S. A. Jacobs C. Cortez and R. G. Harvey J. Chem. SOC.,Chem. Commun. 1981 1215. 46 B. Capon D. S. Rycroft T. W. Watson and C. Zucco J. Am. Chem. SOC.,1981,103 1761. 47 J. Boyer R. J. P. Corriu R. Perz and C. Rei J. Chem. Soc. Chem. Commun. 1981 121. 76 D. G.Morris quantitatively and with 100% selectivity in the presence of ketones; in like vein (EtO),SiH or Me(EtO),SiH when activated with CsF reduces ketones selectively in the presence of esters. A wide variety of other functionality is tolerated.OSiMe I fiCHPh (53) R = M(D) Benzaldehyde does not react with (54) if held at 100 “C for 3 days. In the presence of a catalytic amount of KOBu‘ however an unusual substitution takes place even at low temperature to give (59,in high yield by means of a mechanism that is as yet ~ncertain.~~ 6 Reactivity of Esters Hydrolysis of (56) proceeds with expulsion of an ethoxy-group followed by hydra- tion to give (57) thereby providing the tetrahedral intermediate in the lactonization of (58) to (59);(57) may also revert to (58).The intermediate (57)has its maximum lifetime (ca 0.1 s) at pH 3.5. A very rapid breakdown of (57),at a rate probably close to the diffusion limit takes place in base. At pH C3.5,the breakdown of (57) is merely rapid in a hydronium-ion-catalysed rea~tion.~’ (56) R = Et (57) R = H The greater basicity of HO-in 80% Me,SO-H20 led to an investigation” of the hydrolysis of phenyl esters of p-nitrophenylacetic acid for which the rate constants for loss of a carbanion correlate quite well with u-with p = 4.4.For esters such as (60) and (61) a departure from linearity is noted and in such cases unusually free-radical intermediates were detected. MeSO2CHzSO20Ar (60) X = Me (62) (61) X = OMe 2-MeS02-C -S020Ar MeS02C=S02 MeS02CH=S02 F. Effenberger and W. Spiegler Angew. Chem. Znt. Ed. Engl. 1981 20,265. 49 R. A. McClelland and M. Alibahi Can. J. Chem. 1981 59 1169. T. J. Broxton and N. W. Duddy J. Org. Chem.1981 46 1187. Reaction Mechanisms -Part (ii) Polar Reactions 77 Base -cat a1 ysed hydrolysis of met hylsulp hon ylme t hanesulp hona t e ester (62) occurs via an Elcb mechanism involving the sulphene (63)as the product-forming intermediate that is produced by loss of OAr- from the conjugate base of (62).51 In more strongly basic media a second proton is lost to give the dianion (64) from which the expulsion of OAr- now leads to the sulphene anion (65) as the precursor of a sulphonic acid. The authors claim that (64) represents the first example of a 1,l-dicarbanion that exists in aqueous solution. 'Water-catalysed' hydrolysis of p-nitrophenyl dichloroacetate occurs in 10-'M- HC1 solution and in Bu'OH-H20 (containing 0.i mole fraction Bu'OH) in which solvents the solvent isotope effect kHzO/kDzO has values of 3 and 3.40 re~pectively.~~ The hydrolysis reaction is estimated to have an order of ca 5.7 with respect to water and the authors implicate between four and seven water molecules in the transition state for hydrolysis; however they note that in other cited work changes in the order for water do not always reflect the structure of the transition state.A transition state (66) is envisaged and extrapolation to catalytic sites in hydrophobic pockets of enzymes has been considered. '0-H H (66) (67) The 'H n.m.r. spectrum of the carbamate (67) in fluorosulphuric acid at -74 "C indicates protonation on The variation in 'H chemical shift as a function of concentration indicates that in dilute solution there is substantial 0-protonation.Values of pK(0) and pK(N) are -2.8 and -4.9 respectively. 7 Elimination and Addition Reactions An alternative method to the Hofmann elimination has been developed; this centres on the formation of an acridinium salt (68) from amine and pyrylium salt. After thermolysis of (68) at 150°C with triphenylpyridine olefin was isolated in high yield; small amounts of non-terminal olefin were also formed.54 Ph q-p ,c=o 51 S. Thea G. Guanti and A. Williams J. Chem. SOC.,Chem. Commun. 1981 535. 52 W. P. Huskey C. T. Warren and J. L. Hogg J. Org. Chem. 1981,46 59. 53 P. J. Battye J. F. Cassidy and R. B. Moodie J. Chem. SOC.,Chem. Commun. 1981 68. 54 A. R. Katritzky and A. M. El-Mowafy J. Chem. SOC., Chem.Commun. 1981 96. D. G.Morris Activated 0-aryl esters undergo base-catalysed hydrolysis via rate-determining loss of OAr from the conjugate base of the ester e.g. (69); hydrolysis of the corresponding S-aryl ester follows an analogous mechani~rn.~~ With the aid of isobasic plots it was shown that for identical values of pKa RO-is a better nucleofuge than RS-from an ester such as (65) by a factor of 80; this figure is enhanced to 5 x lo3 when these groups leave from the appropriate acetoacetate by the same Elcb mechanism. In a related there is shown to be no correlation between the leaving-group ability of a carbon nucleofuge and the pKa of its conjugate acid. The inverse solvent isotope effect on initial rates increases with increasing buffer concentration at constant buffer ratio in the base-induced (e.g.AcNHO-) elimina- tion of (70) and it attains a maximum value of 7.7.57This together with curvature (70) in a plot of log kobsdvs[AcNLO-] (L = H or D) has been postulated to establish an Elcb mechanism when transfer of H' is not entirely rate-controlling and in particular to distinguish it from an E2 mechanism occurring with concurrent isotope exchange; a freely solvated intermediate rather even than an ion-pair is required. Both enantiomers of (71) bind with approximately equal effectiveness to the active site of carboxypeptidase A (CPA) though only ( + )-(71) (of uncertain absolute configuration) is a substrate for enzyme-catalysed elimination to (72).58 The authors consider that the p-nitrophenyl group would be placed in a hydrophobic pocket and the carboxylate anion of (71) would interact with the positively charged side-chain of Arg-145 with the carbonyl oxygen of (71) co-ordinated to the zinc ion in the reactive site and to a hydrogen of the a-methylene group that is reasonably close to the y-carboxylate group of Glu-270.In tetrahydrofuran t-butyl alcohol or benzene the rate of elimination of (73) to form (75) was 35 times faster than that of (74).59In t-butyl alcohol with potassium H R' \c=c=c=c/ ~~ Me3C/ 'R2 Me3C-C~C-C=C-CMe3 (73) R' = C1,R2 = CMe3 (74) R' = CMe3,R2 = C1 (75) 55 K. T. Douglas and M. Alborz J. Chem. SOC.,Chem. Commun. 1981,551. 56 M. Varma and C. J. M. Stirling J. Chem.SOC.,Chem. Commun. 1981 553. '' J. R. Keeffe and W. P. Jencks J. Am. Chem. SOC.,1981,103,2457. N. T. Nashed and E. T. Kaiser J. Am. Chem. SOC.,1981,103,3611. 59 M. Schlosser C. Tarchini Tran Dinh An R. Ruzziconi and P. J. Bauer Angew. Chem. Znt. Ed. Engl. 1981,20,1041. Reaction Mechanisms -Part (ii) Polar Reactions 79 t-butoxide the formal concentration of base enters the rate equation with an exponent 0.8. This has been rationalized in terms of a trimeric entity as in (76) effecting elimination with the faster reacting isomer. Gas-phase eliminations of dialkyl ethers with p-hydrogens occur readily in preference to substitution with NH2- and OH- and have been investigated by means of a flowing afterglow technique.60 The most acidic &proton is abstracted with NH2- as expected for an Elcb mechanism; the direction of elimination is less predictable when the reagent is OH- with the stability of the resulting alkoxyl anion being important.With for example s-C4H90C2H5 two products are formed i.e. EtO-(84%)and S-C,H,O- (11'/0). Electrophilic additions to olefins e.g. bromination and oxymercuriation exhibit different patterns of reactivity with a common set of olefins. However when account is taken of steric effects in the transition state calculated from the charge-transfer spectra of electron donor-acceptor complexes a common mechanism of elec- trophilic addition is indicated for both reactions.61 8 Miscellaneous An experimental determination of the difference in enthalpy between the chair conformations of e.g.4-chloro-1,1-bis(trifluoromethyl)cyclohexanehas shown62 that the values obtained are not accounted for on the basis of the alternation of induced charge in saturated systems which derives from CND0/2 calculations. In a detailed analysis of linear free-energy relationships Sjostrom and Wold63 emphasize the local validity of linear free-energy relationships and caution against the combination of scales derived from different data sets. +/T%.. Me2N NMe2 I MeomoMe (77) Loss of tritium from (77) to an aqueous solvent has been studied in the presence of a basic catalyst.64 An oxygen-containing base gives a rate profile against pH which consists of two phases whereas much more gradual curvature is shown in 'O C. H. De Puy and V.M. Bierbaurn J. Am. Chem. Sac. 1981,103,5034. 61 S.Fukuzumi and J. K. Kochi J. Am. Chem. Sac. 1981,103,2783. '* R.D.Stolow P. W. Samal and T. W. Giants J. Am. Chem. Sac. 1981,103 197. 63 M.Sjostrorn and S. Wold Acta Chem. Scand. Ser. B 1981 35 537. 64 A.J. Kresge and M. F. Powell J. Am. Chem. Sac. 1981,103 973. D. G.Morris the slower transfer to nitrogen-containing bases on account of the lower elec- tronegativity and the poorer hydrogen-bond acceptor character of nitrogen. The authors thus suggest that N-DN transfers of protons are intrinsically slower than their N-+O counterparts. It has been shown that both the carbanion Ph3C- and the carbo-cation Ph3C+ can be converted into the radical of intermediate oxidation state (Ph3C*) when either isfllowed to react with di-t-butyl nitroxide; this is converted into Bu$NO- and Bu:N=O respectively.6s 65 H.Singh and J. M. Tedder J. Chem. SOC.,Chem. Commun. 1981,70.