4 Reaction Mechanisms Part (ii) Polar Reactions By D. G. MORRIS Department of Chemistry University of Glasgow Glasgow G12 8QQ 1 Introduction Monographs in this area have dealt with the anomeric effect' and electrophilic additions to unsaturated systems.2 Pertinent reviews have been concerned with the reactivity of tetrahedral intermediate^,^ a qualitative valence-bond approach to organic rea~tivity,~ the thermodynamics of metastable intermediates in s~lution,~ electron-deficient carbocations,6 homoenolate anions,' aromatic substitution reac- tions,* and chemical models of enzymic transimination.' 2 Substitution Reactions Attempted aldol condensation of (1) with paraformaldehyde and ButOK gave the intermediate (2) from which a high yield of (3) was formed almost certainly uia SiMe2Bu' 0 OR (1) R = SiMe,Bu' (2) R = SiMe2Bu' Bu'Me,Si I 0 (3) R = SiMezBu' ' A.J. Kirby 'The Anomeric Effect and Related Stereoelectronic Effects at Oxygen' Springer-Verlag Heidelberg 1983. P. B. D. de la Mare and R. Bolton 'Electrophilic Additions to Unsaturated Systems' Elsevier Amsterdam 1982. R. A. McClelland and L. J. Santry Acc. Chem. Res. 1983 16 394. A. Pross and S. S. Shaik Acc. Chem. Rex 1983 16,363. J. P. Guthrie Acc. Chem. Res. 1983 16 122. 'P. G. Gassman and T. T. Tidwell Acc. Chem. Res. 1983 16 279. ' N. H. Werstiuk Tetrahedron 1983 39 205. J. G. Traynham 1.Chem. Educ. 1983,60 937. M. J. Makela and T. K. Korpela Chem. SOC. Rev. 1983 12 309. 0' 67 D. G. Morris an endocyclic nucleophilic substitution reaction whose transition state contained eight atoms one of which was silicon." Me-S 8 MeO-+ +MeOMe + Sd Scheme 1 The 13C isotope effect of 7-8% observed in the reaction outlined in Scheme 1 is close to the maximum expected for complete loss of the stretching vibration of the C-S bond in the transition state.The miniscule a-deuterium secondary isotope effect indicates that softening of the vibrational potential brought about by departure of sulphur and flattening of the methyl group is compensated by approach of nucleophilic oxygen. The solvent isotope effect kCD3,,/ kCH30Hca. 2 is large enough to suggest that desolvation of MeO- is largely complete in the transition state though this is short of the value 2.47 estimated for complete desolvation." Aspects of the sN2 reaction have been consideredI2 in terms of the correlation diagram developed by the author and co-workers which uses the energy gap (I -ARX) (IN is the ionization potential of the nucleophile N A, is the electron affinity of the substrate RX) as a parameter.A fraction of (I -ARX)enters the activation barrier and is a function of the degree of delocalization of the three- electron bonds (Re-.X)-. The fraction is larger the more delocalized the three-electron bond; in turn greater localization is shown by a-halogeno substitution of R associated with which is a small improvement in the acceptor stability of the modified substrate. The largest delocalization and the largest rate reduction is shown when the halogen introduced into R corresponds to the leaving group; and it has long been known that CH,CI is much less reactive toward nucleophiles than is CH3Cl.a-Substituents which are .rr-acceptors e.g. CN significantly increase the acceptor ability exemplified by CH3CI -30.0 but NCCH2Cl -5.5 kcal mol-' respectively. This has the effect of enhancing reactivity the more so when the nucleophile is powerful. A frequently used method for deprotection of synthetic peptides employs HF with the inevitable consequence that carbocations can intrude. A modified protocol has been developed and involves the use of a weak base typically Me,S (pK = -6.8) in conjuction with HF in order to lower its acidity f~ncti0n.l~ The nucleophilic sulphide which gives inert products is a weaker base than the protecting groups and these alone become protonated (Scheme 2).At an operational level a mixture ") V. H. Rawal and M. P. Cava Tetrahedron Lett. 1983 50 5581. 0.S. L. Wong and R. L. Schowen J. Am. Chem. Soc. 1983 105 1951. l2 S. S. Shaik J. Am. Chem. SOC.,1983 105 4359. l3 J. P. Tam W. F. Heath and R. B. Merrifield J. Am. Chem. Soc. 1983 105 6442. Reaction Mechanisms -Part (ii) Polar Reactions H Ph + PhCH,SMez Scheme 2 HF-Me,S-p-cresol (25 :65 10 v/v) is employed. The procedure has also found application in solid-phase peptide synthesis. Many reactions are considered to obey rate-equilibrium relationships of the type A(AG') = aA(AG") with a in the range 0-1 ; implicit in this relationship is the belief that influences on equilibria are only partially reflected in reaction rates.No such correlation is shown for the reaction family in Scheme 3 in which K = 1 whereas a change in CH,Cl ClCH Q-0 c1-+ + cf-Y Y Scheme 3 Y does influence the reaction rate. The authorI4 points out that a plot of log kus. log K is linear with a = 00 'the highest value yet observed and substantially larger than previously reported values of ca. 1.5-1.8'. It is proposed that reaction families in which the substituent is adjacent to a site at which charge is neither generated nor destroyed will not exhibit a rate-equilibrium relationship though one is likely for example in the methylation of pyridines. A combination of water and the polar aprotic solvents hexamethylphosphoramide or N-methyl-2-pyrrolidone alone provides a potent and selective source of nucleophilic oxygen; buffering can be provided by NaHCO3.I5 Thus alkyl halides and sulphonates may be converted into alcohols; increased nucleophilicity of alcohols leads to ethers.Terminal epoxides can also be converted into 1,2-diols. Vinyl halides react with sodium alkanethiolates e.g. NaSMe in hexamethylphos- phoramide to give substitution products in high yield and with retention of configur- ation (Scheme 4);I6 little further mechanistic information is available for what appears to be a general reaction. NaSMe Ph Scheme 4 l4 A. Pross Tetrahedron Lett. 1983 24 835. l5 R. 0. Hutchins and I. M. Taffer J. Org. Chem. 1983 48 1360. l6 M. Tiecco L.Testaferri. M. Tingoli D. Chianelli and M. Montanucci J. Org. Chew. 1983 48 4795. D. G. Morris Stohrer17 has commented that the syn-preference generally exhibited by SN2' reactions is favoured on account of stereoelectronic stabilization which may be offset by steric and electrostatic repulsions. An additional factor has been considered ; thus in the anti transition-state (4) the central carbon is planar whereas this is not the case for the syn counterpart where the larger lobe remains on the same side of the molecule along the reaction co-ordinate (5). It is also proposed that a difficult to cleave nucleophile should favour the syn reaction. Nu *-(41 Clean cyclization of the (R)-trans-ester (6) in refluxing trifluoroethanol in the presence of 2.2 equiv.KOBu' gave (7) which was almost entirely racemized though a small amount of chirality was transferred with an anti relationship between entering and leaving groups.'* However in the presence of a catalytic quantity of tetrakis(tripheny1phosphine)palladiumand Et,N (6) reacted to give (7) with essen- tially complete transfer of chirality in the syn sense. The acrylate (8) was reduced by LiBEt,H (Super Hydride) to (9) in a reaction that is both regio- and trans-selective only the E-isomer being detected ('H n.m.r.). This reaction is noteworthy in that it is an SN2' reaction which occurs readily at low temperature (-50 "C) notwithstanding the fact that acetate is generally regarded as a poor leaving group." The reaction of the dieneyl ether with the dianion of methanol as in (10) shows a pronounced endo stereoselectivity which may be rationalized in terms of a " W.-D.Stohrer Angew. Chem. Znf. Ed Engl 1983 22 613. G. Stork and J. M. Poirer J. Am. Chem. Soc. 1983 105 1073. l9 J. Rabe and H. M. R. Hoffmann Angew. Chem. lnt. Ed. Engl. 1983 22 796. Reaction Mechanisms -Part ( ii) Polar Reactions ,--OH six-membered transition-state leading via an SN2'reaction to (1 1).20 The key feature is the chelation of the organolithium reagent to the ether oxygen. Addition of the dichloride (12) to two moles of lithium diphenylphosphide at -70 "C gave (13) via two successive Sy2' reactions.21 3 Carbocations The first carbocation with an a-carbonyl group (14) has been prepared; it has a finite though limited life under normal laboratory conditions.22 Arnett's has so chosen a carbocation and a carbanion that they can co-exist in the same solvent (Scheme 5).The crystal structure of (15) reveals an unusually long C -C bond 1.588(4) A. The orange colour of the carbanion is apparent in acetone and more polar solvents. In MeCN the value AH:, = +5.5 f0.5 kcal mol-' was determined. (B No Scheme 5 20 D. G. Farnum and T. Monego Tetrahedron Lett. 1983 24 1361. '' D. G. Gillespie and B. J. Walker J. Chem. SOC.,Perkin Trans. 1 1983 1689. 22 K. Takeuchi T. Kitagawa and K. Okamoto J. Chem. SOC.,Chem. Commun. 1983 7. 23 E. M. Amett E. B. Troughton A.T. McPhail and K. E. Molter J. Am. Chem. SOC.,1983 105 6172. 72 D. G. Morris The "0-labelled exo-2-norbornyl brosylate ( 16) (and the sulphonyl oxygen- labelled counterpart) have been prepared and the ethanolysis monitored by "0 n.m.r.spectro~copy.~~ In the presence of praseodymium( 111) nitrate as a shift reagent it is possible to monitor the rates of scrambling of the label and the ethanolysis separately. The authors state that return occurs without the oxygen atoms having fully equilibrated. Further 170-enriched acid and natural-abundance ester gave no hint of ( 16) (or the sulphonyl oxygen-labelled counterpart) thereby excluding external return. A proposition that the volume of activation of a solvolysis reaction to produce Coates' non-classical ion from (17) should show an activation volume significantly different from one in which a classical ion is unequivocally involved was tested using t-butyl chloride as a ~ubstrate.,~ In 80% aqueous ethanol at 30 "C the respective values were -19 cm3 mol-' and -40 cm3 mol-I.Charge dispersal within an ion leads to a smaller interaction with the medium; however the difference found here is larger than expected. pg In HOS0,F-S0,ClF at -120 "C diazomethane is protonated to give the methyl diazonium ion which absorbed at 4.75 6 (singlet).26 In the more strongly acidic solvent HOS02F-SbFS the methylenediazenium ion (18) is also formed in a kineti- cally controlled process; (18) can however be converted into the more thermody- namically stable C-protonated isomer. Asymmetric introduction of deuterium into a molecule and subsequent analysis of the n.m.r.spectrum can serve to distinguish between carbocations which equili- brate rapidly over a low barrier and one which possesses a single minimum energy surface. The 'H n.m.r. spectrum of the monodeuteriated norbornyl cation (prepared from 2-[2H,]norbornan-2-01) showed a peak to highfield of the averaged H- I H-2 24 S. Chang and W. J. le Noble J. Am. Chem. SOC.,1983 105 3708. 25 G. Jenner S. Srivastava and W. J. le Noble TetrJhedron Lett. 1983 24 2429. 26 J. F. McCarrity and D. P. Cox J. Am. Chem. Snc. 1983 105 3961. Reaction Mechanisms -Part (ii) Polar Reactions 73 H-6 signal between -105 and -43 "C. This arises from perturbation of the average shift of the three remaining protons by an equilibrium isotope effect in that fraction of molecules which possess deuterium on C-1 C-2 or C-6.27 The observed isotope induced shift is 0.146 p.p.m.upfield whereas a classical ion is predicted to show a downfield shift of 0.059 p.p.m. at -43 "C; a non-classical ion structure is thus preferred. Exposure of the acid (19) to trifluoroacetic acid gives rise to the virtually racemic lactone (20) (one enantiomer shown) and it is proposed that a novel and racemizing 6,2-endo methyl migration in the ion (21) accounts for the loss of optical activity.28 (19) (20) (21) A residual possibility that (20) simply has a low specific rotation slightly mars this elegant experiment. The novel bishomoaromatic allylic dication (23) has been generated from (22) at -1 20 "C in FS03H-SbF5 (Scheme 6).29 The twelve absorptions in the I3C nmr.Scheme 6 spectrum of (23) relate closely to those of the corresponding monoanions. At -40 "C a new dication is formed from (23) and is assigned structure (24) on the basis of only six absorptions in the I3C n.m.r. spectrum (Scheme 7); here the rearranging part of (23) is shown as a classical ion for clarity. Me Me Me Me (24) (23) Scheme 7 77 -' M. Saunders and M. R. Kates J. Am. Chem. SOC.,1983 105 3571. 20 W. R. Vaughan B. A. Gross S.E. Butkle M. A. Langell R.Caple and D. B. Oakes J. Org. Chem. 1983 48 4792. 29 G. A. Olah M.Arvanaghi and G. K.Surya Prakash Angew. Chem. Int. Ed. Engl. 1983 22 712. D. G. Morris The triflates (25) and (26) undergo trifluoroacetolysis via the corresponding vinyl cations without participation ; some internal return is found however.30 The much more rapid trifluoroacetolysis of (27) occurs with w-participation involving ion (28) ; the major product from this compound is the triflate (26) and the corresponding trifluoroethyl ether.OTf (27) The same group has shown that trifluoroethanolysis of (29) gives rise to the cyclobutanones (30) and (31) (Scheme 8).31 The distribution of label in the product is nicely rationalized by postulating the intermediacy of (32) and subsequent conver- sion of this ion into product via the non-classical ions shown. +Cc=C-Me I '** j + *\y-(: C-%D2 D Me I c CH2 + -I Ill C=C-Me C CD,' (30) Scheme 8 A phenyl carbocation whose collisional activation (CA) mass spectrum was identical to that of C6H5+ obtained from the molecular ion of bromobenzene has been obtained from (33) which does not cyclize concomitantly with formation of molecular ions but rather after rupture of the C-Br bond.32 This is supported by 30 M.Hanack K.-A. Fuchs and C. J. Collins J. Am. Chem. SOC.,1983 105 4008. 3' C. J. Collins M. Hanack H. Stutz G. Auchter and W. Schoberth. J. Org. Chem. 1983 48 5260. 32 G. Depke M. Hanack W. Hummer and H. Schwarz. Angew. Chem. Int. Ed. Engb 1983 22 786. Reaction Mechanisms -Part (ii) Polar Reactions 75 the finding that the CA mass spectra of the molecular ions of (33) and bromobenzene are different and also since the kinetic energy released on decomposition of (33)'.to C6HSt differs from that of the corresponding reaction of C6H,+'. 4 Elimination Reactions Interest in elimination reactions has been bullish. Tritylpotassium brings about rapid dehydrohalogenation of secondary alkyl halides at 0 "C within 5 min to produce olefin presumably via an E2 mechanism; the reaction does not work well with primary alkyl halides.33 Large I4C kinetic isotope effects k/k = 1.061 (1.044) and k/ kp = 1.036 (1.040) are shown for the syn elimination of the parent (X = H) members of a series of para-substituted (2-phenylethy1)dimethylamine oxides (Scheme 9).34 Values in + 65"c CpH2-C,H2-NMe 10% aq. Me,SO XOCH=CH2 + Me,NOH I 0-Scheme 9 parentheses refer to the values for base-promoted anti elimination of the correspond- ing trimethylammonium bromides.These data are construed to indicate a greater bonding change at C in the amine oxide pyrolysis for which a Hammett p value of 2.1 1 was found. Accordingly the reaction is characterized by extensive rupture of both the C,-N and C,-H bonds with relatively little C,-C double-bond character. In the presence of the complex base NaNH,-NaOR in tetrahydrofuran trans- 1 -bromo-2-chlorocyclohexane underwent syn elimination with dehydrochlorination preferred (54-65°/i).35 Preferred loss of the normally poorer leaving group is accounted for by an interaction between the metal (e.g. Na) and the leaving group (34). In the presence of the strong complexing agent for Na+ 15-crown-5 loss of Br takes precedence and dehydrochlorination is reduced to 3% for the NaNH,- NaOBu' system.Koch and McLennan and their co-workers have measured the chlorine isotope effects in a series of alkoxide-ion promoted dehydro- and dedeuterio- chlorination^.^^ For eliminations by ethanolic sodium ethoxide the chlorine isotope effect k3J k3 values were 1.00590 * 0.00013 and 1.00507 * 0.00036 for (35) and (36) respectively. R / Ph-C-CH,Cl / Me B--M (35) R = H (34) (36) R = D 33 D. R. Anton and R. H. Crabtree Tetrahedron Lett. 1983 24 2449. 34 D. R. Wright L. B. Sims and A. Fry J. Am. Chem. SOC.,1983 105 3714. 35 A. P. Croft and R. A. Bartsch J. Org. Chem 1983,48 876. 3h H. F. Koch D. J. McLennan J. G. Koch W. Tumas B. Dobson and N. H. Koch J. Am. Cbem.Soc. 1983 105 1930. D. G. Morris These values were taken as indicative of an E2 reaction for dehydrochlorination. Calculations indicated that the latter figure would be 1.00090 in the case of an E lcb reaction when the substrate was (36). The rates of eliminations of 1-arylethyl chlorides at 45 "C to give the corresponding styrene are significantly increased by both electron-releasing and electron-with- drawing substituents upon reaction with the conjugate base from the solvent system bis(2-hydroxyethyl) ether-lO% v/v DMS0.37 The change in substituent character in the above sequences causes a change from an El-like E2 mechanism to one which is E lcb-like. This is supported by the P-14Ckinetic isotope effects such that kl+/k14~ratios are 1.038 1.058 and 1.068 for (37) (38) and (39) respectively.(37) X = Me x7 (38) X = H \-CI (39) x = c1 In acyclic systems the propensity for syn elimination increases with the steric requirements of the p-substituents in protic solvents.38 The anti transition-state (40) contains non-bonded interactions between the P-substituents and the bulky leaving group; relief of any interaction by torsion around the C,-C bond only induces other interactions. Thus whereas EtOH-EtO- at 60 "C reacts via anti elimination (40) to the extent of > 95% the syn pathway (41) is followed to the extent of 62% H when R' = C6H5,R2 = p-MeOC& in 50% Me2SO-H20 in the presence of -OH. A corresponding figure of 68S0/0 for syn elimination via (41) when R' = C6H5 R2 = Me2CH suggests that electronic effects are not important.After analysis of deuterium isotope effect data the authors propose that the principal difference is that the syn transition state has less carbon-nitrogen cleavage than the anti counterpart. Full details have appeared39 of the mechanistic study of the eliminations of (42) (NR3 = trimethylamine or quinuclidine) with -OH and buffer bases. These indicate a change in mechanism from (E Icb) to (E Icb) ;indeed the E Icb mechanism was proposed for (42; R = Me) fifty years ago. (42) 37 T. Hasan L. B. Sims and A. Fry J. Am. Chem. SOC.,1983 105 3967. 38 Y.-T. Tao and W. H. Saunders jun. J. Am. Chem. SOC.,1983 105 3183. 39 J. R. Keeffe and W. P. Jencks J. Am. Chem. SOC. 1983 105 265. Reaction Mechanisms -Part (ii) Polar Reactions Menger's group has used elimination and kindred reactions to address the question of the directionality of proton transfer which has relevance to both chemical and biochemical processes.a Thus in the reaction in Scheme 10 (a) the separation 0-H in (43) is 2.9 A and (b) the angle 0-HC is 82" and little torsional freedom is possible.In the event the reaction is completely intermolecular either because the separation in (a) is too great or the angle in (b) is too small. OH (43) Scheme 10 In (44) with the corresponding dimensions as shown the exchange of endo-3-H is 27 times faster at pD = 13.9 than with the endo-5-OMe derivative and a true intramolecular catalysis by endo-5-OH is indicated. These data correspond to an intramolecular catalysis of 1 O5 and one mechanism is initiated by the electron sequence shown in (49 although a molecule of water may intervene as in (46).A rapid intramolecular elimination ( < 1 h) at 53 "C is indicated in Scheme 11 ;40 direct involvement of solvent in the reaction mechanism is considered unlikely. Scheme 11 The authors suspect that the separation -0-a-H is the critical factor in bringing about an intramolecular reaction with the crossover point between 2.2 and 2.9 A. This finding has ramifications in that 'long distance catalysis' appears to be unlikely both in organic molecules and at the active site of enzymes. Further it appears39 that assertions that the three atoms involved in an intermolecular proton transfer must necessarily be collinear are probably suspect.F. M. Menger J. F. Chow H. Kaiserman and P. C. Vasquez J. Am. Chem. Soc. 1983 105 4996. 78 D. G. Morris The variable transition-state theory of bimolecular eliminations proposed several years ago by Bunnett has been subject to intense and sophisticated scrutiny; but it has not yet been tested to destruction and serves as an admirable model. Probably the most contentious aspect of alkene-forming reactions is the E2C mechanism with which two papers have been concerned. The temperature depen- dence of the kinetic deuterium isotope effect has been used as an approach for elucidating transition-state geometry in reactions having a single rate-determining step.41 -+ PhCHDCH,X PhCH=CH + PhCD=CH (47) X = OTs (48) X = Br (49) X = 'SMe (50) X = +NMe Scheme 12 Reactions of F- in MeCN with substrates (47)-(50) Scheme 12 were studied.For (47)-(49) the ratios of frequency factors AH/AD were respectively 3.6 4.6 and 6.6 and in particular were >> 21/2,by which criterion a bent transition state with non-linear H-transfer is indicated ; support was provided by the essentially temperature-invariant deuterium kinetic isotope effects. By way of contrast A,/A is 0.212 for (50) and kH/kDvaries from 6.177 (293 K) to 3.514 (353 K); the authors associate these data with a linear transition-state and hydrogen tunnelling. The authors state that the angle of H transfer is a direct function of A,/AD although values of 110" (47) 125" (48) 160" (49) and 180" (50) are quoted.For the first three substrates an E2C mechanism is proposed. Between 78.5 "C and 128.6 "C the bromide ion promoted elimination of (51) in MeCN gave a mean kinetic isotope effect of 2.606 and an unusually large a-deuterium effect of 1.214 was also measured for (52).42 An angle of ca. 100" was PhCH R1 CR2 BrCO Et (51) R1 = D,R2 = H (52) R' = H,R2 = D calculated for the angle of H transfer rather smaller than that for P-phenylethyl tosylates. From these results the authors conclude that an E2C mechanism is operative. At room temperature in DMSO the sulphonium salts (53) and (54) gave almost exclusively the respective terminal olefins (55) and (56) after reaction with Bu'OK. However under the same conditions (57) gave (58) and the non-terminal olefin (59) in essentially equal amounts whereas (60) again gave predominantly terminal 01efin.4~ 4' H.Kwart K. A. Wilk and D. Chatellier J. Org. Chem. 1983 48 756. 42 H. Kwart and A. Gaffney J Org. Chem. 1983,48 4502. 43 B. Badet M. Julia J. M.Mallett and C. Schmitz Tetrahedron Lett. 1983 24 4331 Reaction Mechanisms -Part (ii) Polar Reactions (53) Z = H (55) Z = H (54) Z = OH (56) Z = OH (57) Z = OPh (58) Z = OPh The mechanism of dehydrohalogenation of the dihalides derived from 1,4-benzoquinone has been studieda in the solvent mixture EtOH :H20:Me2C095 :5 1. Acid catalysis is unimportant and loss of HBr from ClC-CBr is a little faster than loss of HC1 from C1C-CC1 after statistical correction.The geometric requirements for rapid concerted E2 reactions are not present in either of the conformationally isomeric transition-states of which one (61) is shown; accordingly the mechanism is well towards the Elcb end of the spectrum of transition states available for elimination with the dominant feature being proton loss which was essentially ( 99%) irreversible. Cyclization of (62) to (63) occurs readily in ButO-Bu‘OH in the temperature range 20-80°C and has t,,2 ca. 5 min at room temperat~re.~’ The mechanism involves nucleophilic attack of alkoxide ion on an isolated double bond and is formally the reverse of an Elcb reaction. In accord with this proposal a small solvent isotope effect kRo,/kRo = 1.7 together with ASS + 67.4 J K-’ mol-l was observed.0’ % 0 %OH R. C. Atkinson P. B. D. de la Mare and D. S. Larsen J. Chem. SOC.,Perkin Trans. 2 1983 271. A. A. Smeaton W. V. Steele G. M. R. Tombo and C. Ganter Helv. Chim. Acta 1983 66 2449. D. G. Morris 5 Ester Hydrolysis and Reactivity of Carbonyl Derivatives Since the ester (64) is hydrolysed ca. lo7 times faster than (65) in basic solution a dissociative path via (66) is proposed for the phenolic ester; the increased reactivity of the conjugate base of (64) over (67) ca. lo3 is attributed to enhanced nucleophilic- ity of the phenoxy anion in the former case resulting in the more rapid expulsion of the 2,4-dinitrophenoxy R' (64) R' = Me,R2 = H (65) R' = Me,R2 = Me (67) R' = H,R2 = H A comparison of the kinetics of hydrolysis shows that at alkaline pH the cyahester (69) is more reactive than (68) by both E lcb and BAc2 mechanism^.^' In the former reaction the greater reactivity of (69) by a factor of 70 stems from relief of strain in proceeding from the ground state to the transition state.The rate constant kpl for the BAC2 hydrolysis of (69) is ca. 20 times that of (68) when the pH >> pK of the ionizable proton; under the opposite conditions however the more bulky substrate (69) is ca.8-times slower. The increase of k, on t-butylation is ascribed to the increase in the pK of the acid proton by ca. 2 units. CN / (68) R = H R-CH \ (69) R = Me,C C0,Et In 60/40 v/v dioxan-water the initial specific rate of the reaction between hydroxide ion and the cyclic diester (70) to give the rjcyclic half-ester was greatly increased upon addition of low concentrations of NaCl KCl RbCl or C~c1.4~ The complex formed between (70) and the metal ion decreases in reactivity in the 46 S.Thea G. Guanti N. Kasheh-Naini and A. Williams 1.Chem. Soc. Chem. Carnmun. 1983 529. 47 M.lnoue and T. C. Buice J. Org. Chem. 1983,48 3559. 48 D. S. Baker and V. Gold 1.Chem. Soc. Perkin Trans. 2 1983 1129. Reaction Mechanisms -Part (ii) Polar Reactions sequence K+ > Rb+ > Na+ > Cs'; Lif was without effect. It is inferred that the Bjerrum model which relates to the effect of remote charges on ionization equilibria may be relevant to the effects of guest metal-ions on ionic reactions of crown ether molecules with possible ramifications for the chemistry and physiological activity of ionophoric antibiotics and enzymes.The authors propose that the bulk relative permittivity attenuates electrostatic interaction of the charges. With respect to the uncatalysed hydrolysis of the phospholene (7 I) a rate enhance- ment of more than fifty is brought about by a 2.4-fold excess of imidazole in 50% aq. methanol in a reaction which is first order in each component; methanol is also formed.49Two independent and competitive routes were proposed one involving nucleophilic attack on the methoxy carbon by water which is involved in general-base catalysis by imidazole as in (72) leading to (73). A ring-opened intermediate H detectable by n.m.r.spectroscopy which probably results from analogous general- base catalysed attack at phosphorus followed by reclosure is thought to be involved. The effective molarity of -COT which is a powerful nucleophilic catalyst for the hydrolysis of phosphate esters is 6 x 108M; the rate-determining step is loss of the apical phenolate anion (Scheme 13). The pH-rate profile for the hydrolysis of OPh OPh Scheme 13 (74) shows a pronounced maximum at pH ca. 4.5 in which region the concentration of the dianion is expected to be a maximum.50 The rate enhancement brought about through the introduction of one carboxy and one carboxylate group is of the order of lo'' which is taken as evidence for nucleophilic catalysis. The observed rate of hydrolysis of the dianion (75) is ca.four times the maximum value calculated; this small but significant value firmly suggests intramolecular general-acid catalysis by the carboxy group (Scheme 14). Even so this catalysis is relatively inefficient probably on account of an early transition-state for the cleavage of (76) ;accordingly there is little negative charge on the departing oxygen to induce the proton-transfer step readily. Hydrolysis of (77) in which the trans-ring junction locks the leaving group in an equatorial position is appreciably (x105) slower than expected for a 49 R. S. Macomber J. Am. Chem. SOC.,1983 105 4386. 50 K. W. Y. Abell and A. J. Kirby J. Chem. SOC.,Perkin Trans. 2 1983 1171. D. G. Morris 0 (74) (75) II O,p/O--+ salicylate 0 (76) Scheme 14 conformationally flexible acetal on account of the stereoselective barrier to cleavage of the acetal C-0 bond denied assistance from .rr-donation from the donor oxygen atom.5' Hydrolysis of (77) is not reversible thereby excluding equilibration with (78).Under most conditions the products consist of a mixture of (78) and (79) itself a mixture of isomers. The spontaneous cleavage of (78) yields a zwitterion and recyclization is antici- pated to be more rapid than addition of water to give (79); support for this contention is provided by the solvent isotope effect kHzo/ kDzo = 1.74 at 100 "C.This reaction is now characterized by a different rate-determining step viz. hydration to form (79) and this accounts for the slow reaction.The cis axial bis-acetal (80) which contains the remote oxygen atom as a .rr-donor in a favourable stereoelectronic environment reacts ca. 200 times faster than the trans isomer (81) in reactions in which the leaving group departs irreversibly and in which there is a relatively early transition-state for spontaneous cleavage.52 In '' A. J. Kirby and R. J. Martin J. Chem. SOC.,Perkin Trans. 2 1983 1627. A. J. Kirby and R. J. Martin J. Chem. Soc. Perkin Trans. 2 1983. 1633. Reaction Mechanisms -Part (ii) Polar Reactions I H the trans isomer the remote oxygen is thought to be functioning solely as a u-acceptor thereby destabilizing the developing oxocarbocation. The depiction of the fragmenta- tion shown in (80) is incomplete in respect of the curly arrow formalism.Lysozyme catalyses the hydrolysis of a polysaccharide constituent of bacterial cell walls and cleaves a P-glycosidic linkage with retention of configuration. As with the conformationally fixed acetal (82) which is hydrolysed only with extreme reluctance the lone pairs on the ring oxygen of P-glycoside (83) cannot overlap significantly with because two ring bonds are anti-periplanar to the C-OR bond.53 The stereoelectronic barrier to C-OR cleavage is ca. 19 kcal mol-’ when the OR group is held equatorial; as an alternative an energetically less costly reaction was proposed via a relatively facile conformational change around the (ring)O-C( OR) bond and lone-pair-&, overlap becomes progressively more efficient as the ring flattens.The energy required to form the reactive conformation of higher energy can be readily recouped providing that the conformational barrrier is appreciably less than the energy of activation for the cleavage reaction. It is conceivable that the reaction of (83) proceeds via (84) (part structure) in which the conformation is akin to that of a half chair.53 The normally very rapid hydrolysis of ketene diethyl acetals is diminished by introduction of chloro or cyano substituents. Reactions catalysed by perchloric acid (in H20 and D20)indicate rate-determining proton transfer to the P-carb01-1.~~ The observed isotope effects were 2.46-2.96 ; the smallest difference between observed and calculated values was observed with the least bulky substrate cyanoketene dimethyl acetal.Bulky substituents at the P-carbon reduce the reactivity more so than for the hydrolysis of vinyl ethers. A solvent isotope effect of 2.19 was found for the water-catalysed hydrolysis of the immonium ion (85).55From proton inventory techniques in H20-D20 a transi- tion state exemplified by (86) and containing an immature hydronium ion is impli- cated. 53 A. J. Briggs C. M. Evans R. Glenn and A. J. Kirby J. Chem. SOC.,Perkin Trans. 2 1983 1637. 54 A. J. Kresge and T. S. Straub J. Am. Chem. SOC.,1983 105,3957. 55 R. L. Erhardt G. Gopalakrishnan and J. L. Hogg J. Org. Chem. 1983 48,1586. D. G. Morris Ph Me \ C=N+/ 6 Aromatic Reactivity The rate of hydrolysis of 3-methyl- 1-picryl-imidazolinium ion (87) is strongly cata- lysed by oxygen bases between pH 1.7 and 9.3 and gives picric acid q~antitatively.~~ A reversibly formed (Ll ca.10's-10'6 s-') and short lived intermediate (88) resulting from concerted addition of water to the aromatic ring is proposed and support is provided by the value AS' -28.6 cal mol-' deg-' at 25 "C when water functions as the base. cj'"' N No (87) In benzene the observed second-order rate constant for the reaction of 2,4-dinitrofluorobenzene with o-anisidine (89) shows a quadratic dependence on ( 89).57 H A dimer nucleophile ArN.-.H-NAr is implicated and reaction to form (91) is H H considered to occur via the cyclic intermediate (90). NHAr 56 R. H. de Rossi and A.Veglia J. Org. Chem. 1983 48 1879. 57 N. S. Nudelman and D. Palleros J. Org. Chem. 1983 38 1613. Reaction Mechanisms -Part (ii) Polar Reactions 7 Micelle-aneous and Other Reactions The anilinium ion precursor of (92) gave vesicles of diameter ca. 9008 after sonication in aq. HBr; these led to (92) diameter ca. 660 A at pH 5.58Azo coupling of vesicular (92) with &naphthol was biphasic consisting of a rapid pseudo first-order reaction (85%) attributed to an exo-vesicular diazonium group and a slower endo counterpart (1 5%). However the endo-vesicular reaction of (92) with (93) is completely suppressed. Thus whereas P-naphthol permeates vesicular (92) at a rate competitive with that of azo coupling such permeation does not occur with (93).(92) (93) The micro-environment of the micelles (94) and (95) has been examined by monitoring the solvent-sensitive chemical shifts of the acetylenic For aqueous solutions in the micellar state these occur at 2.16 and 2.10 S respectively and being downfield from the anticipated region of 1.&I .8 S indicate that the chain termini are wet on a time-averaged basis.59 Water-hydrocarbon contact is considered to occur throughout the micellar region external to the relatively small apolar core. Equimolar amounts of solubilized alcohol shifts the absorption of the terminal carbon to upfield as water is displaced from surface irregularities. H-C rC -C D (C H2),,NMe (94) H-CrC-CD,(CH,),,OSO; (95) Energies for N-to-N proton transfer in H2NCH2hH3 were calculated with the migrating proton confined to the bisecting xz plane (Figure 1).60 The transition state so obtained places the mobile proton in the NCN plane 21 kcal mol-' above the ground state with a partial N-H bond distance of 1.27 8 and an LNHN of 103".Movement of the proton from this transition state can be carried out at comparatively little energetic cost exemplified by a destabilization of 1.1 kcal mol-' for a proton movement of 0.2 8,out of the xy plane. The proton thus appears to have considerable freedom of motion in the transition state. Although the value of the activation energy is high the values achieved in practice may be so modified by solvent as to make rates in the region 106-108s-' possible. Figure 1 58 R. A. Moss and J.-S.Shin J. Chem. SOC.,Chem. Commun. 1983 1027. 59 F. M. Menger and J. F. Chow J. Am. Chem. SOC.,1983 105 5501. 60 F. M. Menger J. Grossman and D.C. Liotta J. Org. Chem. 1983 48,905. D. G. Morris Gas-phase basicity of a number of conformationally stable P-amino-alcohols has been examined by ion cyclotron resonance spectrometry. The dihedral angles (8) between the functional groups of the compounds ranged from 0" for (96) to 180" for (97).61 A continuous increase in basicity is observed as 8 decreases and in the conjugate acid of (96) stabilization brought about by hydrogen bonding is ca. 5 kcal mol-'. In the case of (97) a localized N-protonated species is obtained. Calculations suggest that the most stable form of 2-aminoethanol occurs when 8 = 19.2" and the stabilization amounts to ca.15.5 kcal mol-' with respect to the anti-periplanar conformation. Conversion of (98) into (99) was readily achieved with the aid of electrophilic catalysis of mercuric ions which have the effect of blocking attack at C-6 and also weakening the S-C-6 bond (Scheme 15).62 This mechanism may be compared with one of S~hubert,~~ who uncovered an example of an SN1reaction of an a-amino sulphide without electrophilic catalysis. Scheme 15 A useful paper describes the relative efficiency of the methods for drying alcohols and is addressed principally to methanol ethanol butanols and 1,2-ethanedi01.~ " R. Houriet H. Riifenacht P.-A. Carrupt P. Vogel and M. Tichy J. Am. Chem. Soc, 1983 105 3417. 62 C.Tea-Gokou J. P. Pradere J. Villieras and H. Quiniou Tetrahedron Lett. 1983 24 3713. 63 W. M. Schubert and Y. Motogama J. Am. Chem. SOC.,1965 87 5123 64 D. R. Burfield and R. H. Smithers J. Org. Chem. 48 2420.