4 Reaction Mechanisms Part (ii) Polar Reactions By T. W. BENTLEY Department of Chemistry University College of Swansea Swansea SA2 8PP 1 Introduction There is a tendency to become increasingly confident about reaction mechanisms as time elapses after their publication. It is implicitly assumed that any reinterpreta- tions or criticisms would be published without delay. Unfortunately some mechan- isms may become ‘established’ without further experimental verification. In these circumstances critical periodic reassessments of accepted views are necessary. For the classical sN2 and E2 mechanisms ‘revolutionary’ reassessments have already been reported [Ann.Reports (B),1974,71,112], and counter-revolutionary reviews are discussed later (Sections 2 and 5).The ‘revolutionary’ views centre on the role of reactive intermediates in processes previously considered to be concerted. If the reactive intermediate decomposes to the starting material more rapidly than it proceeds to products there are important consequences in correlations of structure and reactivity. Relevant examples are discussed in Sections 2,5 and 7. Two related themes are the effect of increased pressure on reaction rates and products and the nature of mechanistic borderlines. Recent evidence that there is a merging between sN2and SNlmechanisms and between E2 and ElcB mechanisms is presented in Sections 2 and 5. Aspects of carbocations carbanions tetrahedral intermediates and catalysis are also reported but comprehensive annual coverage of the literature of organic reaction mechanisms is presented elsewhere.’ 2 Nucleophilic Substitution at Saturated Carbon The response to Sneen’s criticisms of the classical sN2 mechanism have been overwhelmingly unfavourable [Ann.Reports (B) 1974 71 1141 but preliminary reports of other unfavourable responses continue to be published. A detailed case for the concerted SN2mechanism includes the interesting historical perspective that in the 1930’sthere was considerable opposition to the postulation of ionic inter- mediates whereas now the existence of carbocations and ion pairs is well established. The conclusion was drawn that no currently available evidence demands the formation of intermediates for solvolyses of simple primary and secondary substrates (i.e.these reactions are classical SN2). Also there is no reason why intermediates should intervene in non-solvolytic reactions with stronger nucleophiles.* ‘Organic Reaction Mechanisms 1976’ ed. A. R. Butler and M. J. Perkins Wiley London 1977. D. J. McLennan Accounts Chem. Res. 1976,9 281. 54 Reaction Mechanisms-Part (ii) Polar Reactions The solvolysis of secondary substrates has been a controversial topic for many years partly because it is difficult to fit into the sN2-sN1 framework without ignor- ing evidence that other workers regard as vitally important. The above comments have neglected the evidence (e.g. from ‘80-scrambling in sulphonates and compari- sons of rates of racemization with rates of solvolysis) that ion pairs are formed during solvolytic reactions-but it could be argued that there is no direct evidence that the ion pairs undergoing racemization or 180-scrambling are also undergoing solvolysis.There is independent evidence from comparisons of solvolyses of 2-adamantyl tosylate (1) with other secondary tosylates that secondary solvolyses have varying degrees of sN2 character [Ann. Reports (B) 1974,71 1181. These two interpreta- tions can be reconciled if it is assumed that ion-pair intermediates are nucleophili- cally solvated [(2) where SOH = solvent and X =leaving group]. Furthermore it appears that there is a gradation or merging of mechanism and reactivity from 2-adamantyl to methyl tosylates because the dependence of the reaction rate on solvent ionizing power decreases proportionately as the dependence on solvent nucleophilicity increases.These and other results suggest that there is no clear borderline between sN1 and sN2 reactions and that rear-side nucleophilic assistance by solvent to heterolysis of the R-X bond depends on R X and the solvent. If as in (l) the rear-side is hindered the reaction is sN1 in all solvents examined. Other simple secondary solvolyses (2-propyl cyclohexyl etc.)appear to be SN1 in weakly nucleophilic media (trifluoroacetic acid hexafluoroisopropanol) but sN2 character increases as solvent nucleophilicity increases and/or as the stability of the incipient cation increase^.^ Consistent with this interpretation many secondary solvolyses are now known to proceed with essentially complete inversion of configuration.An alternative SN2 mechanism (Scheme l) in which the solvent attacks the non-nucleophilically solvated ion pair in a slow step requires that k2[SOH]<< k,; i.e. there is ‘hidden’ internal return from an ion-pair intermediate to covalent starting material. Evidence against appreciable hidden return has already been discussed k2~o~’~ ROS +HX SOH = solvent Scheme 1 [Ann.Reports (B),1974,71,116] and additional evidence has now been p~blished.~ The ion-pair SN2 mechanism (Scheme 1) does account for the behaviour of the tertiary allylic systems (3),4 and is not inconsistent with recent studies of other allylic T. W. Bentley and P. von R. Schleyer J. Amer. Chem. SOC.,1976,98,7658; F.L.Schadt T. W. Bentley and P.von R. Schleyer ibid.,p. 7667 and references there cited. * F. G. Bordwell and T. G.Mecca J. Amer. Chem. SOC.,1975,97,123,127;F.G.Bordwell P. F. Wiley and T. G. Mecca ibid.,p. 132. T.W.Bentley ArS02 H Me Me I I /\C=C/ \c/ Me c CH2 C H / \cH/ \ / NC/ H Me CH2 I\ Me Br (31 systems (4).5 Consequently it appears that Scheme 1 should be considered for substrates in which the incipient positive charge is stabilized (e.g. tertiary allylic benzylic) and/or the attack by the nucleophile is hindered sterically. Volumes of activation (A V,') can be determined from the pressure dependence of rate constants [equations (1) and (2)] a positive value of AV,' referring to an In (k,/k,) = a +bp +cp2 AV = -bRT increased 'volume' of the transition state; high-precision data are required to obtain values of A V,' within k0.3 cm3 mol-'.For sN1 reactions A V,' is -20 cm3 mol-' because the positive contributions to A V,' from bond cleavage is outweighed by the negative contribution from solvation of ionic charges. For the fragmentation of y-amino-alcohol derivatives (5) A V' is less negative by 5-10 cm3 mol-' than for the corresponding sN1 reaction of the carbon analogue (5; with CH replacing N). This I/ I/ X- / I I \ C-I\ / \ / \ C-I' (5) suggests that fragmentation may be concerted with heterolysis of the C-X bond which would explain the rate enhancements (up to lo4) observed in some rigid systems (cf the change in the inductive effect when CH is replaced by N should reduce the rate).6 Reaction of triphenylethyl tosylate (6)with sodium ethoxide in ethanol to give (7) is suppressed at high pressures (5500 atm) when the major product is the rearranged ether (8).Interestingly the yield of the rearranged alkene (9) does not increase at OEt EtO-EtOH I Ph3C-CH20Ts Ph3C-CHZOEt + PhZC-CHzPh + PhZC=CHPh (6) (7) (8) (9) high pressure^.^ For the thermal decomposition of optically active N-nitroso- amides the yield of ester of retained configuration increases slightly (59-62%) at high pressures possibly because racemization is hindered by the increased viscosity of the solvent.!-? Since solvation effects appear to dominate A V,'for polar reactions in solution predictions of the effect of pressure are difficult but for some reactions K.B. Astin and M. C. Whiting J.C.S. Perkin ZZ 1976 1160. 6 W. J. le Noble H. Guggisberg T. Asano L. Cho and C. A. Grob J. Amer. Chem. Soc. 1976,98,920. K. K. Lee and Y. Okamoto J. Org. Chem. 1976,41 1552. W. J. le Noble E. H. White and P. M. Dzadzic J. Amer. Chem. Soc. 1976,9%,4020. Reaction Mechanisms-Part (ii) Polar Reactions pressure variation may be a useful empirical way to aid in optimizing yields of desired products. 3 Vinyl Cations Vinyl cations or ion pairs can be produced during substitution reactions of vinyl substrates or by additions to alkynes. Substitution.-The low reactivity of vinylic substrates is often attributed to conjuga- tion between the leaving group X and the double bond (lo),but there is no satisfactory evidence to support this proposal.’ Rather than a stabilized ground state (lo) the low reactivity may be due to a destabilized transition state reflecting the lower stability of vinyl cations and the hindrance to solvation of the developing cationic centre (this also accounts for the tendency towards SN1rather than sN2 reactions).R RR R (10) The electronic effects of p-substituents can be transmitted by the double bond the developing charge may be delocalized and the rates of SNl vinyl solvolyses are less sensitive to solvent ionizing power than expected by comparison with SN1reactions of saturated systems. Also competing reactions such as elimination and substitution by addition-elimination pathways may occur. A sensitive test for competing path- ways is the solvent isotope ef’fect (kRCO2H/kRCo2D); for many vinylic sN1 reactions values are in the range 0.85-1.2 whereas electrophilic addition-elimination path- ways show much higher values; e.g.solvolysis of the tosylate (11) shows kAcOH/kAaD = 0.93 whereas the less reactive substrates (12) show higher values (X = Br 1.45; X = C1 1.94; X = OAc 3.45) due to increasing proportions of the addition-elimination mechanism.’ Ph Ph An H \/ \c=c / TsO/c=c\ph X’ ‘H (11) (12)An = p-MeOC6H4 Much of the classical research on ion pairs investigated acetolysis reactions using the non-nucleophilic perchlorate ion to study the importance of external ion pair return. A rate increase attributed to the ‘special salt effect’ is observed if perchlorate exchanges with the nucleophilic anion [X-; equation (3)] and return to starting RX S R+X-$ R+I(X-$ RfllC104-+ product (3) material is prevented.There is considerable evidence (e.g. from common-ion rate depression) that free vinyl cations are often the product-forming intermediates during acetolysis of a-anisylvinyl halide^'.'^ [see also Ann. Reports (B) 1975,72 Z. Rappoport Accounts Chem. Res. 1976,9 265. lo Z. Rappoport I. Schnabel and P. Greenzaid J. Amer. Chem. SOC.,1976,98,7726. T. W.Bentley 741. By changing to pivalic acid Me3CC02H a solvent of even lower dielectric constant than acetic acid it was possible to study reactions of less dissociated intermediates. Pivalolysis of (13) is accompanied by a much faster isomerization (>lOO-fold) to the trans-isomer (14) and gives a 1:1 mixture of cis-and trans- (13) (14) pivalates.Addition of 0.01M-LiC10 caused only a 1.5-fold increase in the isomeri- zation rate but there was a much higher increase in the solvolysis rate. As rate depression by added bromide ion was not observed the results are consistent with isomerization (13)+ (14) uiu the contact ion pair (R'X-) and solvolysis products formed uia the solvent-separated ion pair (R+l\X-).lo Other mechanistic evidence has been obtained from 1,2-aryl rearrangements. The degenerate anisyl rearrangement of cations (16) and (17) studied by deuteriation of An* An An* An \/ \+ +/ An'c=c -b C=C-An An*-C=C / \Br An 'An (15) (16) (17) one methoxy-group depends on the solvent 100% in CF3CH,0H 35% in AcOH 11.5% in 60% aqueous ethanol and 0% in pivalic acid.As the process appears to be favoured most in the solvent of highest dissociating power and lowest nucleophilicity rearrangement may occur in free dissociated vinyl cations." Similar results were obtained by generating the cations from trianisylvinyl[ 2-14C]phenyltriazene in acetic acid and rearrangement was reduced by the addition of sodium acetate; presumably the lifetime of the cation is reduced when acetate ions are present.12 Addition.-The n.m.r. spectra of some stabilized vinyl cations have been reported.13 but simpler vinyl cations continue to be elusive. Treatment of several alkynes with FS03H-SbF5 at -78 "C led to complex mixtures of unidentified products and at higher temperatures allyl cations are produced in high yields.As reaction of the alkyne (18) with FS03D-SbF5 produced equal amounts of the allyl cations (20)and (21) the intermediate vinyl cation (19) is probably inv01ved.l~ Addition of but-2-H H &.A /" + Me-C C I I I I Me H Me D 11 Y. Houminer E. Noy and Z. Rappoport J. Amer. Chem. SOC. 1976,98,5632; see also Z. Rappoport E. Noy and Y. Houminer ibid. p. 2238. 12 C. C. Lee and E. C. F. KO,Canad. J. Chem. 1976,54 3041; C. C. Lee and M. Oka ibid. p. 604. 13 Ann. Reports (B),1975.12 73; for a review see M. Hanack Accounts Chem. Res. 1976,9 364. 14 G. A. Olah and H. Mayr J. Amer. Chem. SOC. 1976,98,7333. Reaction Mechanisms-Part (ii) Polar Reactions yne to a solution of [2H,]-t-butyl chloride and SbF in SO2at -78 “C produced the ally1 cation (24) presumably via the vinyl cations (22) and (23).” Even in the much Me Me MeCZCMe +(CD&C’ \ + + C=C -Me + (CD&C-C=C/ + (CD3)3C / \Me (22) (23) I CD (24) less polar solvent methylene chloride addition of [2H2]benzyl chloride to 1,3-diphenylpropyne (25) yields equal amounts of the isomers (27) and (28),16 but it was still proposed that the dissociated vinyl cation (26)was the reactive intermediate [cf.Ann. Reports (B),1974 71,1281. PhCD2Cl \+ C=C-Ph +C1- CH2C12 [PhD2C 1 PhCHZCr CPh % PhH2C/ PhD2C C1 PhDzC Ph \c=c’ + \c=c / PhH2C/ ‘Ph PhH2C/ \c1 4 Other Carbocations &I.-From the gas-phase heats of reaction for cation formation (R-Cl+ R’+ Cl-) it appears that formation of the phenyl cation C6H5+is almost as difficult as formaticn of the methyl cation and significantly more difficult than formation of vinyl or ethyl cations.Consistent with these calculations solvolysis of aryl trifluoromethanesulphonates under extremely vigorous conditions leads to nuc- leophilic attack on sulphur rather than heterolysis of the C-0 bond.” Phenyl cations appear to be intermediates in the reactions of benzenediazonium salts. Thermal decomposition of p -‘SN-labelled benzenediazonium tetrafluorobo- 15 G. Capoui V. Lucchini F. Marcuzzi and G. Melloni Tetrahedron Letters 1976 717. 16 F. Marcuzzi and G. Melloni J. Amer. Chem. SOC.,1976,98 3295; see also F. Marcuzzi and G. Melloni J.C.S. Perkin IZ,1976 1517. 17 A.Streitwieser jun. and A. Dafforn Tetrahedron Letters 1976 1435;see also L. R. Subramanian M. Hanack L. W. K. Chang M.A. Imhoff P. von R. Schleyer and F. Effenberger W. Kurz P. J. Stang and T. E. Dueber J. Org. Chem. 1976,41,4099. T. W.Bentley rate in CF3CH20H proceeds with -8% isotopic rearrangement to a-"N-labelled material. When the reaction was carried out under 300 atm of unlabelled nitrogen the 'external' nitrogen was incorporated into the benzenediazonium ion. These results suggest that the phenyl cation can react reversibly with molecular nitrogen [equation (4)];evidence against alternative mechanisms not requiring a phenyl cation intermediate was summarized. l8 C~HSN~+BF~-$ C6H5++N2 +BF4-(4) Aliphatic.-A solution of the s-butyl cation has been prepared quantitatively by the slow addition of a mixture of SbF and S0,ClF to s-butyl chloride in S0,ClF below -100 "C.An exothermic rearrangement to the t-butyl cation occurred above -60 "C and the enthalpy of rearrangement (14.5f0.5 kcal mol-' determined by dynamic calorimetry) is remarkably similar to values obtained in the gas phase (15-17 kcal mol-'). This suggests that the degree of electrostatic solvation varies little between similar carbocations in contrast to the behaviour of ammonium and alkoxide ions which are capable of strong hydrogen-bonding or ion-pairing interac- tions." Other detailed descriptions of procedures for obtaining concentrated (1 moll-') solutions of cations in SbF,-S02CIF should reduce the difficulties of beginning independent research in this area." In many reactions catalysed by aluminium chloride it is assumed that cations are produced.Earlier research indicated that weak donor-acceptor complexes were formed between alkyl chlorides and A1Cl3 but it has now been shown that t-butyl chloride reacts with excess of A1Cl3 in anhydrous liquid hydrogen chloride at 25 "C to produce the t-butyl cation quantitatively [equation (5)]; the anion [A1,C17]- was characterized by its Raman spectrum. Removal of the solvent at -1 12 "C gave a solid which decomposed at ca. -50 "C.'l Me3CCI+A12C16 G= [Me&'] [A12Cl,]-(5 1 The cyclobutenes (29) readily react with SbF in SO2at -78 to -10 "C to produce an equilibrating pair of cyclobutenyl cations (30) and (31); the barrier to rotation of the methoxy-group is 16 kcal mol-' for R = F C1 or MeO.Evaporation of the solvent in an inert atmosphere produces crystalline solid salts stable at room temperature and useful in syntheses as alkylating agents in electrophilic substitution reactions.22 F A (29) (30) (31) 18 R. G. Bergstrom R. G. M. Landells G. H. Wahl jun. and H. Zollinger J. Amer. Chem. SOC. 1976,98 3301; see also C. G. Swain J. E. Sheats and K. G. Harbison ibid. 1975,97 783. 19 E. W. Bittner E. M. Arnett and M. Saunders J. Amer. Chem. SOC.,1976 98 3734; see also T. S. Sorensen Accounts Chem. Res. 1976,9 257. 20 D. P. Kelly and H. C. Brown Austral. J. Chem. 1976,29,957; see also H. Hart and M. Kuzuya J. Amer. Chem. SOC. 1974,% 6436. 21 F. Kalchschmid and E.Mayer Angew. Chem. Internat. Edn. 1976 15 773. 22 B. E. Smart and G. S. Reddy J. Amer. Chem. SOC. 1976,98 5593. Reaction Mechanisms-Part (ii) Polar Reactions Further studies of the remarkable rearrangements of the cation (32) have appeared [see also Ann. Reports (B) 1973,70,219]. Above -60 "C (32)rearranges to (33) possibly via cyclopropylcarbinyl-like intermediates. On standing in deuteriotrifluoroacetic acid all nine methyl groups of the cation (33) become labelled but at different 8.4 & b5 1-2 (33) 5 Elimination Some of the possible mechanisms for E2 eliminations are shown in Scheme 2. In step (a) a carbanion the conjugate base (cB) of the starting material is produced irreversibly (I) in an (ElcB) process which would be first-order in base (B) and first-order in starting material.The classical concerted E2 process is shown in step IS la BH++-c-c-x IS la (c) \/ B+H-C-C-X -B BH++ C=C +X-II /\ B I 01 B +H-C-C+X-II Scheme 2 (c) and the ion-pair E2 mechanism is shown in steps (d) and (e). Included in the classical E2 mechanism are processes in which significant positive charge develops on the a-carbon and/or significant negative charge develops on the P-carbon. Thus a key mechanistic question is whether E2 reactions are concerted and if not whether the reactive intermediate is a carbanion or a carbocation. In the classical E2 mechanism the P-H is removed as a proton and electron release for the C-H bond can provide nucleophilic assistance to ionization of the C-X bond.Also SN2 and E2 processes often occur concurrently. Thus the earlier discussion (Section 2) of the importance of nucleophilic assistance to ion-pair formation is relevant and the ion-pair E2 mechanism seems unlikely except in substrates where the ion-pair sN2 mechanism cannot be excluded e.g. if the positive charge is stabilized (benzylic allylic or tertiary substrates) or if the base/nucleophile 23 H.Hart and M.Kuzuya J. Amer. Chem. Soc. 1976,98 1545. T. W.Bentley B is weak as in the solvolysis of t-butyl halides in 97% trifluoroethanol-water.24 Even then it is not clear whether the base attacks at the a-carbon the 6-hydrogen or both. In a defence of the classical E2 mechanism it was concluded that there was no unequivocal case of the ion-pair E2 mechanism but that the two mechanisms were very difficult to disting~ish.~~ Evidence for the (ElcB) mechanism is becoming more ~ubstantial~~ [see also Ann.Reports (B) 1975,72,78] particularly in activated systems similar to those in which a carbanion intermediate is known from isotopic exchange experiments to be formed reversibly i.e.(ElcB)R Scheme 2 with the reverse of step (a)faster than step (b). The concerted E2 mechanism can be established if it can be shown that the reaction proceeds faster than expected on the basis of a stepwise mechanism (see below). Other criteria such as the extent of bond cleavage to the leaving group and the extent of proton transfer to the base are more arbitrary. Activation volumes have been proposed as a measure of the E2-ElcB character of a reaction.Processes in which there is more bond-making between an anionic base (B-) and the H-C bond than bond-breaking to the leaving group should have negative volume changes (-10 cm3 mol-I) provided that there is no appreciable change in the volume of electrostricted solvent; this limits the method to negatively charged bases reacting with neutral substrates. The (ElcB)R mechanism is charac- terized by bond-breaking and appears to correspond to positive activation volumes (CQ. + 10 cm3 mol-I). As might be expected considerably negative charge is developed during eliminations from the p -sulphonyl compound (34; Z = Cl) and the activation volume is only -1f1cm3 mol-'; various other examples were also reported.26 The results support the interpretation that there is a merging of mechanism between E2 and (E1cB)R mechanisms but this approach does not enable the (ElcB)I mechanism to be distinguished from a classical E2 mechanism with a carbanion-like transition state.PhS02 \ CH-CH2Z -PhS02CH=CH2+ AcOH + Z-/ ACO-+H' (34) (35) The distinction can be made from experimentally determined ionization rates by extrapolations using linear free-energy relationships [see also Ann. Reports (B) 1975,72,78]. For a series of sulphones (34) (Z = Me H Ph NMe2 CH2S02Ph OH OMe OEt SPh or OPh) the observed rate constants for detritiation were corre- lated with the Taft c7"value for the CH2Z group. Correction of these results for the kinetic isotope effect (kH/kT= 7.1) and extrapolation of the correlation line allowed prediction of the ionization rates for other leaving groups.For Z = F C1 OTs or OAc the predicted ionization rates were close (within a factor of 2.1) to the observed elimination rates consistent with an (ElcB)I mechanism. For Z=Br or I the observed elimination rates were over ten times greater than predicted supporting *4 V. J. Shiner jun. W. Dowd R. D. Fisher S. R. Hartshorn M. A. Kessick L. Milakofsky and M. W. Rapp J. Amer. Chem. Soc. 1969,91,4838;D. J. Raber R. C. Bingharn J. M. Harris J. L. Fry and P. von R. Schleyer ibid.,1970,92 5977. 2s W. H. Saunders jun. Accounts Chem. Res. 1976,9 19. *' K. R. Brower M. Mushin and H. E. Brower J. Amer. Chem. SOC.,1976,98,779. Reaction Mechanisms-Part (ii)Polar Reactions 63 the concerted E2 mechanism.Also the reactions classified as concerted showed higher kinetic isotope effects than the reactions classified as (ElcB)I. The authors concluded that these results ‘contra-indicate a mechanistic discontinuity’ at the E2-ElcB b~rderline.~’ Another elimination close to the E2-ElcB borderline is the NaOMe-MeOH- induced dehydrochlorination of substrates in the series (p-YC,H4),CHCHCl2. When Y =C1 H or OMe the small leaving group kinetic isotope effect is consistent with an E2 process. When Y = NO2 no kinetic isotope effect is observed and the rate constant is as predicted from the pK of the substrate consistent with an ElcB mechanism.28 The temperature dependence of kinetic isotope effects is attracting increasing attention.For hydrogen/deuterium primary kinetic isotope effects the ratio of Arrhenius pre-exponential factors AH/AD,is ‘normally’ close to unity. If proton tunnelling occurs A H/A is less than unity and the difference in activation energies ED-EH,exceeds the ‘normal’ values of -1kcal mol-’ e.g. in the Crvr oxidation of di-t-b~tylcarbinol.~’ Anomalous activation parameters with ratios A H/A up to 4.8 and with ED-EH,have been obtained for substrates related to (36). It was proposed that the system may be finely balanced with internal return (Ll)competing favourably with the forward reaction (k2)in Scheme 3.30 Br Br Br I kl -/ k2 I Arc-CF2Br g Arc-CF2Br 3 ArC=CF2 +Br-I k-1 H AOR +HOR +-OR Scheme 3 6 Carbanions Solutions of many carbanions have been examined by spectrophotometry or by conductance measurements and it is known that various ion pairs or free ions can be formed depending on the counterion (Li+ Na’ K+ etc.),the solvent the concentra- tion of carbanion and the temperature.Also different ion pairs from the same carbanion can react at markedly different rates and sometimes can lead to different products. As many polymerization processes and laboratory syntheses utilize car- banion reactions an improved understanding of the behaviour of carbanions in solution would assist in the prediction of optimum conditions needed to carry out particular reactions. This approach is applicable to other areas of reaction mechan- isms e.g. after too many years of discussion about various fanciful gas-phase transition states for LiAlH4 reduction of ketones some progress has recently been made towards understanding the nature of the species present in solutions of complex metal hydrides in ethereal 27 P.J. Thomas and C. J. M. Stirling J.C.S. Chem. Comm. 1976 829. 28 A. Grout D. J. McLennan and I. H. Spackman J.C.S. Chem. Comm. 1976,775. 29 H. Kwart and J. H. Nickle J. Amer. Chem. SOC.,1976 98 2881. 30 H. F. Koch D. B. Dahlberg M. F. McEntee and C. J. Klecha J. Amer. Chem. Soc. 1976 98 1060. 31 E. C. Ashby F. R. Dobbs and H. P. Hopkins jun. J. Amer. Chem. SOC.,1975.97 3158. T. W. Bentley For protonation of the ion pairs of the 1,3-diphenylallyl carbanion (37) by fluorene (38;R = H) with lithium as the counterion the loose ion pair in tetrahydrofuran reacts about 100 times faster than the tight (contact) ion pair in 2,5-dimethyltetrahydrofuran.Also reaction of fluorene with the sodium tight ion pair is about 30 000times faster than with the lithium tight ion pair in the same Equilibrium constants for the addition of the 9-methylfluorenyl carbanion (39; R = Me) to l-phenyl-l-(4-pyridyl)ethene (4PPE) are markedly dependent on the PhPh * + ---* Ph-Ph + M' / R R Mt (37) (38) (39) counterion. In tetrahydropyran KLi+[equation (6)] exceeds Kc,+ by a factor of 1.6x 10'. Generally K decreases with increasing cationic radius and increasing cation solvation. The results can be explained at least partially by the stability of tight FPPE-Li' ion pairs and indicate that ion-pairing effects are potentially very large when the newly generated carbanion differs considerably from the reacting carbanion in charge distrib~tion.~~ 9-MeF-M+ +4PPE FPPE- M+ (6) (39; R = Me) Michael additions and autoxidations of sodium salts of 9-substituted fluorenes (39) (R = CN C02Me or S02Ph) in t-butyl alcohol illustrate the differing reactivities of free and associated carbanions which are evaluated from the kinetic effects of dilution and addition of common-ion salts (e.g.sodium perchlorate). For the addition of the carbanion of 9-cyanofluorene (39; R = CN) to methyl methacrylate no common-ion effect was detected suggesting that free and paired ions were equally reactive. In all other cases examined [additions of (39; R = C02Me) and (39; R = S0,Ph) to methyl methacrylate and additions to methyl acrylate and methyl crotonate] the free ion was 10-100 times more reactive than the ion pair.As the rate-determining step in the autoxidation of carbanions of 9-substituted fluorenes is thought to be electron transfer from the carbanion to a ground-state oxygen molecule differences from Michael additions would be expected. For autoxidations in t-butyl alcohol the kinetic effects of added salts are small and difficult to distinguish from a medium effect. Addition of dimethyl sulphoxide changes the solvating properties ofthe medium and increases the proportion of free carbanions. It appears that (39; R = S02Ph) is autoxidized eight times faster as the free ion than as the ion pair but the ion pair of (39; R =CN)is five times more reactive than the free Autoxidation of the phenol (40) using Bu'O-02 in t-butyl alcohol at 75°C produces the cyclopentadienone (43).At lower temperatures intermediates (4 1)and (42) can be isolated and a partial mechanism is outlined in Scheme 4.35 32 G. C. Greenacre and R. N. Young J.C.S. Perkin IZ 1976 1636. 33 C. J. Chang and T. E. Hogen-Esch Tetrahedron Letters 1976 323. 34 D. Bethell C. S. Fairclough R. J. E. Talbot and R. G. Wilkinson J.C.S. Perkin ZZ 1976 55. 35 A. Nishinaga and A. Rieker J. Amer. Chem. SOC.,1976,98,4667. Reaction Mechanisms-Part (ii) Polar Reactions Ar Al- Ar (40) (41) (42) 75 T RU'O-B~'OH1 0 Scheme4 The pKa for production of the t-butyl carbanion from isobutane has been determined from a thermodynamic cycle [equation (7)].Relative to triphenyl- R-H -+ R'+H' 3 R-+H' -+ R-+H' (7) methane (pK, 3 1.5)and using a fast technique (second-harmonic a.c. voltammetry) to determine the reversible potential for reduction of R-to R- a value of 70.7 for the pKa of isobutane was calc~lated.~~ Previous estimates of the pKa's of simple saturated hydrocarbons have ranged from 42 to 85 but none has involved a thermodynamic method. 7 Tetrahedral Intermediates The rate-determining step in the hydrolysis of a-acetoxy-a-methoxytoluene (44; X = H) in acid solution appears to be the decomposition of the hemiacetal(45); the reaction (Scheme 5)is general acid and general base catalysed and the rate constants /OMe -0COCH2X /OMe PhCH PhCH=6Me -+ PhCH -+ PhCHO 'OCOCH2X \OH (44) (45) Scheme 5 for (44;X = H) and (44; X =Cl) are identical within experimental error.37 At the next higher oxidation level the analogous decomposition of acetoxydimethox-ymethane (46) at -35 "C in a mixture of 12H6]acetone and deuterium oxide to the tetrahedral intermediate (47) (Scheme 6) was observed by n.m.r.The build-up of 36 R. Breslow and R. Goodin J. Amer. Chem. SOC.,1976 98 6076; M. R. Wasielewski and R. Breslow ibid. p. 4222. 37 B. Capon K. Nimmo and G. L. Reid J.C.S. Chem. Comm. 1976,871. T. W.Bentley OMe OMe OMe / / H-C / 4 H-C + H-C 1 1 \OMe \OMe \O OCOMe OD (46) (47) Scheme 6 (47) reached a maximum after 20 min when it accounted for 75% of the starting material and at the same time (47)slowly decomposed to methyl formate.These results show that at least one simple tetrahedral intermediate can be generated by hydrolysis of its 0-acetate and it may be possible to generate related species by similar processes.38 In continuation of a study of the steric and electronic effects in additions to aldehydes and ketones the rates and equilibria for hydration of and bisulphite addition to 1,3-dimethoxyacetone (48) have been investigated. The equilibrium constant (K)for formation of the bisulphite adduct (49) is high (880 1 mol-') and the pK for the hydroxylic hydrogen atom of (49) is 9.89. Decomposition of (49)at 25 "C over the pH range 4.5-8.5 may involve rate-determining decomposition of the corresponding dianion.The rate-constants for additions of hydroxide and bisulphite to (48) were smaller than analogous rate constants for reactions of aldehydes having K values similar to that of (48). This suggests that for these nucleophilic additions to both aldehydes and ketones steric hindrance is greater in the transition states than in the MeOH2C MeOH2C OH K \C=O +NaHS03 $ \C/ MeOH2C/ MeOH2C' \S03-Na' (48) (49) Base-catalysed hydrolysis of esters of aliphatic carboxylic acids is generally accepted to occur via the tetrahedral intermediate (50) and the observed rate constant (/cobs) for this mechanism (Scheme 7) is given by equation (8). The extent of OH -kl k2 R'C02R2 +OH $ R'-d-OR2 + R'CO,H+ OR2 k-1 I 0-(50) Scheme 7 kobs = kl/k2/&1+ k2) (8) reversibility (k-l/kz) depends on R2; when -OR2 is the very stable p-nitrophenoxide l~-~/k, is essentially zero and kobs= kl.The volumes of activation 38 B. Capon J. H. Gall and D. McL. A. Grieve J.C.S. Chern. Comm. 1976 1034. 39 J. Hine L. R. Green P. C. Meng jun. and V. Thiagarajan J. Org. Chem. 1976,41 3343. Reaction Mechanisms-Part (ii) Polar Reactions 67 for p-nitrophenyl acetate propionate dimethylacetate and trimethylacetate are -3 -4,-4,and -10 cm3 mol-' respectively and these values were thought to reflect the volume change on formation of the transition states leading to the tetrahedral intermediate (50). Comparison of these results with those for esters with k-Jk Z0 shows that the ratio k-Jk2 decreases with increasing pressure possibly because R'C02H is more highly solvated than R'C02R2.40The analogous process for hydrolysis of amides is inefficient because -NR2 is a poorer leaving group than -OH and reversion of the tetrahedral intermediate to starting material is preferred.For the hydrolysis of tertiary amides addition of strong base (Bu'O-) produces a dianion which readily ejects -NR2 in a synthetically useful process.41 Further evidence for an ElcB mechanism for ester hydrolysis has been obtained [see also Ann. Reports (B) 1969 66 701. The hydrolysis of monoesters of malonic acid (51) but not of dialkylmalonic acids with good (nitrophenolate) leaving groups is catalysed by low concentrations of general acids and general bases more efficiently than expected.The catalysis disappears at high concentrations of catalyst. Exchange of deuterium from solvent D20 into the methylene group of monoethyl malonate supports the proposal that hydrolysis occurs via the dianion (52) (Scheme 8). This mechanism is products Scheme 8 not observed with p-nitrophenylacetate so there must be a small but decisive stabilizing effect of the C02-on the adjacent carbanion. The dianion (52) may also be an intermediate in certain Knoevenagel reactions.42 Schiff's bases are intermediates in the catalytic mechanism of several enzymes and the kinetics and mechanism of both their formation and their decomposition have been studied. It appears that hydrolysis to the corresponding aldehyde or ketone is subject to general acid-base catalysis but the reaction rates are lower than those observed for enzymic reactions.The rate-determining step for the hydrolysis of (53) is as shown in Scheme 9. As the transition state for attack by water (54)+ (55) NCH2CF HNCH,CF H20 HNCH,CF ZfJ 35fJf-& -I-CF,CH,NH, (53) (54) (55) Scheme 9 R. C. Neuman jun. G. D. Lockyer jun. and J. Marin J. Amer. Chern. SOC.,1976,98,6975. 41 P. G. Gassman P. K. G. Hodgson and R. J. Balchunis J. Amer. Chem. SOC.,1976.98 1275. 42 A. J. Kirby and G. J. Lloyd J.C.S. Perkin If 1976 1762. T. W.Bentley probably involves delocalization of charge it is not surprising that the reaction rate is accelerated in less polar media e.g.reaction in 90% dioxan-water is 18 times faster than in pure water corresponding to a 180-fold change in the presumed second- order rate constant for attack by water.There is an even greater increase in the rate of the general base-catalysed process in less polar media presumably because the charge in the transition state is partially neutralized as well as delocalized. Thus it was proposed that the enzymic processes may utilize a combination of general base catalysis and an apolar active site to facilitate the hydrolysis of Schiff’s bases.43 The question of concertedness in general acid-base catalysis has received more attention [see also Ann. Reports (B) 1975 72 801. Earlier results indicating the possibility of concerted acid- and base-catalysed enolization of oxaloacetic acid (57) with tertiary amine buffers have been checked and extended and an alternative mechanism involving carbinolamines (Scheme 10) has been proposed.Plots of observed rate constants (kobs) versus total amine concentrations (NT including protonated amine) exhibit a break kobs becoming first-order in NT at its higher values. The results suggested that oxaloacetic acid and the tertiary amine form an intermediate (58) which yields the enol(60) on reaction with additional amine and that decomposition of the carbinolamines (58) and (59) is rate-determining at high amine con~entrations.~~ This appears to be the first report of nucleophilic catalysis as a mechanism for enolization. 0 0-OH I1 kl I + H+ I H02CCCHZC02H + N $ -02CCCH2C02-02CCCH2C02-k-1 I -H+ I N+ N+ /I\ /I\ (57) (58) (59) 1 1 8 Neighbouring Group Participation The rates and equilibria of many ring-closure reactions are enhanced by increasing alkyl substitution on the backbone of the ring.Very large rate enhancements for the acid-catalysed lactonization of hydrocoumarinic acids have been reported [e.g. (62) -+ (63) is -lo1’ times faster than (64) -+ (65)] which were attributed to ‘stereopopulation control’ in which restriction of rotational freedom leads to a narrow distribution of conformational populations ideally by removing non-productive conformer^.^^ By comparison with their bimolecular counterparts the 43 R. M. Pollack and M. Brault J.Amer. Chem. SOC.,1976,98,247; see also R.M. Pollack and R. H. Kayser ibid. p. 4174. 44 P. Y. Bruice and T. C. Bruice J.Amer. Chem. SOC.,1976,98 844. 45 S.Milstien and L. A. Cohen J. Amer. Chem. SOC.,1972,94 9158. Reaction Mechanisms-Part (ii) Polar Reactions Me Me (62) (63) (64) (65) rate enhancements correspond to factors of about of similar magnitude to the accelerations observed for some enzyme-catalysed processes. Whereas the possibil- ity that the origin of these rate enhancements is relief of ground-state strain was considered as a minor factor,45 a case has now been made that this is the dominant factor. If the change in ground-state energy in lactonization [(62)+ (63) and (64)+ (65)] can be modelled by [(66)-P (67) and (68)+ (69)] respectively steric Me Me B H&Me M?6Me M P \ \ \ \ H&H accelerations in the range 1012-10’4 can be expected.This ‘rough estimate’ was supported by detailed empirical force-field calculations for (62) (64) and related Comparison with other model compounds led to the suggestion that conformational restrictions may account for a factor of -lo4in rate:’ which is more in line with earlier proposals. There has also been further criticism of the concept of ‘orbital steering’. From molecular orbital calculations of potential energy surfaces for attack of nucleophiles on carbonyl compounds [F- + FCHO HO- + FCHO MeO-+ H,NCHO NH3+ HCHO MeOH + HC02H and MeOH + HC(OH),’] it appears that the potential energy surfaces in the region of the transition states are very flat in those directions corresponding to deformation of the incipient bond. Thus the ‘loose’ transition states are predicted to be relatively insensitive to the orientation of the incoming nucleophile and the carbonyl group.48 Hydrolysis of monoaryl malonate anions is subject to intramolecular general base catalysis by the ionized carboxy-group (71)and appears to be relatively insensitive to structural variations (R).Limiting effective concentrations of 100moll-’ were calculated in contrast to the value of -10’ moll-’ for intramolecular nucleophilic catalysis (70) uncomplicated by strain. It was noted that the efficient intramolecular reactions involve bond formation or cleavage between heavy-atom centres (C 0,N P etc.) and that base catalysis (71) may have a less favourable entr~py.~’ R. E. Winans and C. F. Wilcox jun. J. Amer. Chem. SOC.,1976,98,4281.O7 C. Danforth A. W. Nicholson J. C. James and G. M. Loudon J. Amer. Chem. SOC.,1976,98,4275. O8 S. Scheiner W. N. Lipscomb and D. A. Kleier J. Amer. Chem. SOC.,1976 98 4770. O9 A. J. Kirby and G.J. Lloyd J.C.S. Perkin II,1976,1753;see also T. C. Bruice Ann. Rev. Eiochem. 1976 45. 352. T. W.Bentley The pH-rate profile for cyclization of methyl 2-aminomethylbenzoate (72) to give (74) changes slope at pH 8.6 probably because of protonation of the amine.50 The Brmsted coefficient @ for a series of general base catalysts is 1.O and there is a large solvent isotope effect (kH20/kD20= 2.8) consistent with rate-determining proton transfer [e.g. (72) -+ (73)]. Possible alternative mechanisms were discussed and it was noted that intramolecular aminolysis of (72) is different in several respects from bimolecular aminolysis reactions [see also Ann.Reports (B),1974 71 1311. 50 T. H. Fife and B. R. DeMark J. Amer. Chem. Soc. 1976,98,6978; see also A. J. Kirby and G. J. Lloyd J.C.S. Perkin II 1976 1748.