3 (Part i) REACTION MECHANISMS By J. G. TiUett (Chemistrv Department Universitv of Essex Colchester) This year an extensive coverage of acid-base catalysis is included since this has not been fully reported recently. Similarly since deuterium isotope effects were dealt with comprehensively last year this topic is covered only briefly on this occasion. Acidity Functions and Molecular Basicity.-New acidity-function data reported this year includes values of H for HClO in aqueous 2-butoxyethanol,' H for aqueous H2S0,,2 and HR for constant ionic-strength solutions of HC104 in aqueous di~xan.~ Good agreement between calculated and experi- mental values of H for iodic acid have been obtained4 by using Wyatt's proton hydration model.' H-Scales for aqueous alkali hydroxides have come under criticism.6 The observed trend in basicity for solutions of equal concentration H-(LiOH) < H-(NaOH) < H-(KOH)is thought to be only apparent when due allowance is made for ion-pair formation,6 attention being drawn to the danger of correlating reaction rates with uncorrected H-values.The protonation in acetonitrile of water alcohols and diethyl ether has been ~tudied.~ The protonation of a number of aromatic and a,P-unsaturated aldehydes ketones and carboxylic acids in sulphuric acid has been shown to follow the HA acidity function rather than H,.8 The basicity of some sulphoxides in aqueous sulphuric acid has been determined by measurements of chemical shifts.' An n.m.r. study of the protonation equilibria of carbamic acid esters reveals similar protonation behaviour to that of amides and in- dicates pK values intermediate between structurally similar amides and esters.lo A detailed study of the protonation of azulene-1-carboxylic acid over a wide pH range has eliminated some of the previous inconsistencies." At low pH it decarboxylates slowly.Above 5.0-~acid however the conjugate acid (I) is formed ' J. G. Tillett and R. C. Young J. Chem. SOC. (B) 1968,209. ' P. Vetesinki J. Bielavsky and M. Vecera Coll. Czech. Chem. Comm. 1968,33 1687. H. Nicholson and P. A. Wyatt J. Chem. SOC. (B) 1968 198. 'J. G. Dawber J. Chem. SOC.(A),1968,1532. ' M. Oyeda and P. A. H. Wyatt J. Phys. Chem. 1964,68,1857. J. R. Jones Chem. Comm. 1968,513. ' I. M. Kolthoff and M.K. Chantooni J. Amer. Chem. SOC. 1968,90 3320. * R. I. Zalewski and G. E. Dunn Canad. J. Chem. 1968,46,2469. P. Haake and R. D. Cook Tetrahedron Letters 1968 427. lo V. C. Armstrong and R. B. Moodie J. Chem. SOC. (B) 1968,275. 'I J. L. Langridge and F. A. Long. J Anier. Cheni. Snc.. 1968.90. 3088. J. G. Tillett HH The slope of the indicator plot (1.1) is similar to that expected for a Hammett base rather than a carbon acid. This is attributed to extensive solvation of (I) compared to the conjugate acid of azulene itself. A study of several acid-base equilibria involving hydrocarbons in Me,SO shows that rates of proton exchange are greater in Me,SO than in methanol for reactions with the same equilibrium constant in both solvents.'2 Acid-Base Catalysis.-Carboxylic Esters Ethers Acetals and Related Compounds.The realisation that the Zucker-Hammett hypothesis can no longer be regarded as a reliable criterion of mechanism has led to a search for other criteria. Bunton and his co-workers have suggested13 that the effect of added electrolytes can be used for this purpose and have pointed out that for A-1 reactions the catalytic effects of added acids decreases in the sequence HC104 > HCl -H,SO, whereas for typical A-2 reactions the relative order is H,S04 > HCl -HBr > HClO,. Thus the hydrolyses of methyl 2,4,6-trimethylbenzoate t-butyl acetate and t-butyl benzoate show the former sequence whilst the hydrolyses of methyl benzoate and ethyl acetate show the latter order.Anions with low charge-density seem to preferentially stabilise transition-states with carbonium-ion character whereas the opposite is true for A-2 reactions where there is considerable hydrogen bonding between the solvent and transition state. Studies of the acid-catalysed hydrolyses of methyl pseudo-2-benzoyl- ben~oate,'~ a-methylallyl acetate,I5 1-arylcyclopropyl acetates,I6 t-butyl acetate," vinyl esters,18 nitroalkanes," amides,,' carbamates,,' and ureas2' have all been reported. The mechanism of hydrolysis of ethyl carbamate changes from A-2 to A-1 with increasing acidity.,' Further kinetic studies of the hydrolyses of ethyl vinyl ether have been reported.21,22 The effect of substituents on the rate of the acid-catalysed C. D. Ritchie and R.E. Unchold J. Amer. Chem. SOC. 1968,90 3415. l3 C. A. Bunton J. H. Crabtree and L. Robinson J. Amer. Chem. SOC. 1968,90 1258. l4 D.P.Weeks A. Grodski and R. Fanucci J. Amer. Chem. SOC. 1968,90,4958. l5 R.A.Fredlen and I. Lauder Austral. J. Chem. 1968,21,1727. l6 J. A. Landgrebe and W. L. Bosche J. Org. Chem. 1968,33 1460. l7 H.Sadek and F. Y. Khalil Z. phys. Chem. (Frankfurt),1968,57 306. L.F. Kulish and 0.I. Kovol Ukrain.khim. Zhur. 1968,34,495. l9 R.B. Cundall and A. W. Locke J. Chem. SOC.(B),1968,98. 'O V.C. Armstrong D. W. Farlow and R. B. Moodie J. Chem. SOC.(B),1968 1099. M. M. Kreevoy and R. Elliason J. Phys. Chem. 1968,72,1313. '' A. J. Kresge and Y. Chiang J. Amer. Chem. SOC..1968.90.5309. Reaction Mechanisms 69 hydrolysis of phenyl vinyl ether is compatible with rate-determining protona- tion at the P-carbon atom.23 (Scheme 1).Hi0 + CH,=CH*OAr CH,-CH*OAr H20 CH,*CHO + HOAr SCHEME 1 The acid-catalysed hydrolysis of ethyl vinyl ether in dimethyl sulphoxide is also controlled by a rate-determining proton transfer to carbon.24 The rate has been divided into components arising from the dimethyl sulphoxide-solvated proton and the monohydrated proton the former being about twice as large as the latter. This shows that direct proton transfer from strong acid to a carbon atom is possible without an intervening water molecule. It is suggested that this mechanism predominates even when water is the solvent. Thus n = 0 in the generalised scheme for proton transfer from an aqueous acid to an organic substrate (S) (Scheme 2).I p-8 . 0- I SCHEME 2 A similar inference has been drawn for the protonation of nitro-alkane anions.” Kinetic studies of the acid-catalysed hydration of phenylacetylene,26 phenylbenzoylacetylene’’~ and 1-phenylpropyne2’ have been reported. The rate of hydration correlates with H, is very sensitive to substituents in the ring and exhibits an inverse kinetic deuterium-isotope effect [k(H,O)/ k(D,O) -21. This is attributed to rate-determining proton transfer which leads to the formation of a vinylic carbonium ion. The acid-catalysed isomerisa- tion of stilbene is also thought to proceed by way of a rate-determining proton transfer.30 The acid-catalysed dehydration of 1,2-diarlyethanols3 32 involves ‘9 reversible formation of a 1,2diarylethyl cation followed by rate-determining proton loss to give trans-stilbene.23 T. Fueno I. Matsumura J. 0.Kuyama and J. Furukawa Bull. Chem. Soc. Japan 1968,41,818. 24 M. M. Kreevoy and J. M. Williams J. Amer. Chem. SOC. 1968,90 6809. 25 D. M. Goodall and F. A. Long J. Amer. Chem. SOC. 1968,90,238. 26 D. S. Noyce and M. D. Schiavilli J. Amer. Chem. SOC.,1968,90,1023. 27 D. S. Noyce and M. D. Schiavilli J. Amer. Chem. SOC. 1968,90 1020. 28 D. S. Noyce and K. E. De Bruin J. Arner. Chern. SOC.,1968,90,372. 29 D. S. Noyce and M. D. Schiavilli J. Org. Chem. 1968,33 845. ’O D. S. Noyce D. R. Hartter and F. B. Miles J. Amer. Chem. SOC.,1968,90,4633. D. S. Noyce D. R. Hartter and R. M. Pollack J. Amer. Chem.SOC.,1968,90 3791. 32 D. S. Noyce. D. R.Hartter. and F. B. Miles. J. Amer. Chem. SOC..1968.90.3794. 70 J. G. Tillett The hydrolyses of l-cyano-2,2-dimethoxyethylene(2) and 2-dichloro-methylene-1,3-dioxalan (3) are both subject to general acid catalysis. 33 CH2-Y NC\ PMe I C=Cl* HF=YOMe CH,-d (2) (3) HlO Has a lower catalytic-constant than predicted from the Brsnsted plot for weaker acids. At high concentrations of carboxylic acid buffers there is a fall-off in the rate of hydrolysis which was attributed to dimerisation of the undissociated acids or association between carboxylic acid and carboxylate anion. For compound (3) the hydrogen atom added in the formation of 2- hydroxyethyl dichloroacetate does not exchange with the solvent so that the product isotope effect could be determined.Taken in conjunction with the isotopic-rate ratio this permitted an evaluation of the transfer contribution to the solvent isotope effect. A systematic study of the effect of leaving group on the mechanism of acetal hydrolysis have been reported.34 The p-value for a series of 2-(para-substituted phen0xy)tetrahydropyrans is -0.92.The deuterium solvent effect decreases with increasing electron-withdrawal in the leaving group. The value of k(D,O)/ k(H,O) = 2-82 found for 2ethoxytetrahydropyran is in the range usually associated with an A-1 mechanism and is in agreement with values for other simple acetals. The solvent isotope effect however For 2+-nitrophenoxy)- tetrahydropyran of 1.33 indicates some solvent participation in the rate- determining step.A mechanism involving partial rate-determining protonation of oxygen (4) is consistent with this view. (4) The values of ASS (+7.9 e.u and -7-6 e.u respectively) provide further confirmation of this change. The extent of proton transfer decreases along the series as electron-withdrawal increases. As might be expected general acid catalysis by formate buffers was observed for the hydrolysis of 2+-nitro- phenoxy)- and 2-(p-~hlorophenoxy)-tetrahydropyran. The hydrolyses of tetramethylene glycol acetals proceed much more slowly 33 V. Gold and D. C. A. Waterman J. Chem. SOC. (B),1968,839,849 34 T. H. Fife and L. K. Jao J. Amer. Chem. Soc. 1968.90.4081. Reaction Mechanisms 71 in comparison with other types of acetals.”’ The AS value for the hydrolysis of 4,4,5,5,-tetramethyl-2-(p-nitrophenyl)-l,3dioxolanein aqueous HCl is -15.8 e.u.This suggests that the presence of methyl substituents in the 1,3- dioxolane ring inhibits the normal A-1 reaction and that attack by a solvent molecule (5)is the ratedetermining step. The AS$ value however of 2,4,4,5,5,-pentamethyl-2-phenyl-1,3-dioxalaneis similar to that observed for ethylene glycol acetals and ketals and it is likely that the transition state for hydrolysis of ths compound may have considerably more unimolecular character than the tetramethylene glycol acetals unsubstituted at the acetal carbon. The kinetics of hydrolysis of 2-alkoxytetrahydrofurans and pyrans have also been reported by other workers.36 The hydrolysis of 3,4-O-benzylidenelincomycin acetal is thought to proceed through the usual A-1 pathway in spite of an atypical ASf value (-13.6 e.u.) which is attributed to the unusual structure of this particular a~etal.~~ Con-formational effects in the hydrolysis of other cyclic acetals have also been in~estigated.~~ A kinetic study of the hydrolysis of the tetramethyl acetal of p-benzoquinone showed surprisingly that the diacetal (6) is about an order of magnitude less reactive than 2,2-dimethoxypropane. 39 Me0 OMe 0 A kinetic study of the acid-catalysed hydrolysis of some indolyl-P-D-gluco- pyranosides has been rep~rted.~’ The kinetic deuterium isotope effect indicates a rapid pre-equilibrium protonation and application of the Zucker-Hammett and Bunnett criteria suggests an A-1 mechanism for hydrolysis.Values of AS* in the range 0.4to 2.2 were obtained. The possibility of an ‘open-chain’ mechanism still cannot be definitely excluded. Studies of the acid-catalysed hydrolyses of a variety of other glycosides have also been reported.4145 The pH-rate profiles for the hydrolyses of both o-carboxyphenyl-P-D- glucopyranoside and o-carboxyphenyl-2-acetamido-2-deoxy-~-~-glucopyrano-35 T. H. Fife and L. H. Brod J. Org. Cheni. 1968,33 4136. 36 A. Kankaanpera and K. Mukki Suomen Kem. 1968,41 B 42. 37 M. J. Taraszka and W. Morozowich J. Org. Chem. 1968,33,2349. 38 P. Watts J. Chem. SOC.(B),1968 543. 39 R. K. Chatwoerdi J. Adams and E. H. Cordes J. Org. Chem. 1968,33 1652.40 J. P. Horwitz C. V. Easwaren and L. S. Kowaleszyk J. Org. Chem. 1968,33 3174. 41 J. Szeytli Acta. Chim. Acad. Sci.Hung. 1968,56 175. 42 M. D. Saunders and T. E. Timell Carbohydrate Res. 1968,6 12 121. 43 C. K. De Bruyne and F. Van Vitnendaele Carbohydrate Res. 1968,6 367. 44 N. Roy and T. E. Timell. Carhohrdrate Res.. 1968. 6.475 7. 17. ‘’ D. Piszkiawicz and T. C. Bruice. J. Anier. Chem. Soc.. 1968. 90.2156. J G. Tillett side show a plateau rate followed by a decreasing slope of ca. -10 above pH 4.46 The plateau and descending rate are ascribed to intramolecular carboxy-group participation rather than specific hydrogen-ion catalysis of the glycoside carboxylate anion. The additional rate enhancement found for the acetamido-deoxypyranoside is attributed to concerted intramolecular carboxy-group general acid catalysis and intramolecular acetamido-group nucleophilic catalysis (Scheme 3).I Me products I Me SCHEME3 Intramolecular nucleophilic attack by the neutral acetamido-group was considered to be more likely than intramolecular nucleophilic attack of the ionized acetamide group on the protonated glycoside site. By analogy it was suggested that spontaneous hydrolysis of o-carboxyphenyl-P-D-gluco-pyranoside involves intramolecular carboxy-group general acid catalysis (7). 0 There was no evidence of intramolecular acetamido-participation in the specific hydrogen-ion-catalysed hydrolysis of 2-acetamido-2-deoxy-~-~-g~uco-pyranosides. Specific hydrogen-ion catalysis has also been observed in the hydrolyses of methyl and pyranosyl glycosides of glucose and N-acetyl- glucosamine.46 When log k,+ values for P-D-glycosides of N-acetylghcosamine are plotted against the k + values for the corresponding P-D-glucopuranosides a linear relationship is obtained.The point corresponding to the methyl glycosides however deviates significantly from the line and corresponds to a 50-fold rate enhancement over that expected. This is attributed to intra- 46 D. Piszkiewicz and T. C. Bruice J. Amer. Chem. SOC.,1968,W.5844. Reaction Mechanisms 73 molecular nucleophilic displacement by the 2-acetamido-group at the proto- nated glycoside bond (Scheme 4). bJOMe HN OHMe I c =o c EO I I Me Me 1 H2O fast b HN / o + *C C=O I I Me Me SCHEME 4 Intramolecular acetamido-participation in the specific acid-catalysed hydrolyses of methyl-P-N-acetylglucosamineis considered to compete favourably with the normal path through an oxocarbonium ion intermediate because the small methyl aglycone does not inhibit the formation of the trans-diaxial conformation most favourable to acetamido-participation.Several other investigations of neighbouring carboxyl-group participation have been reported. The reactions of acetylsalicylic acid and some related phenyl esters with the weak bases nicotinamide semicarbazide and methoxy- amine occur predominantly with the acidic uncharged species of acetyl- salicylic acid and show rate accelerations which are ascribed to intramolecular general acid catalysis (8).47 Rate enhancement of similar magnitude for the reaction of the acetylsalicylate anion with e.g.semicarbazide are attributed to general-base catalysis by the o-carboxylate anion (9). The formation of an anhydride intermediate by intramolecular nucleophilic attack of the carboxylate group on the ester function was discounted. RNH "\ /Me oo-c*3 ' c11-u OIH 0 (8) (9) 47 T. St. Pierre and W. P. Jencks J. Amer. Chem. SOC. 1968,90 3817. 74 J. G. Tillett Bruice and Bradb~ry~~ have studied the related hydrolysis of the p-bromo- phenyl esters of glutaric acid. The rate acceleration caused by 3,3disubstitution in this reaction which is thought to proceed by way of intramolecular nucleo- philic catalysis (Scheme 5)with the formation of a cyclic anhydride intermediate is due almost entirely to a more favourable AS term.R' CH,-CO,H R' CH2-CO; \/ \/ R1 CH,.CO,H \/ c-k 'CH,. C02H SCHEME 5 By comparison with the previous example this suggests the possibility of a change in mechanism from intramolecular nucleophilic attack for those substrates where a cyclic anhydride can be formed to intramolecular general- base assisted attack of water when a cyclic anhydride cannot be formed. Gold and his co-worker~,~~ were able to distinguish between these two mechanisms in the acetate-catalysed hydrolyses of aryl acetates by trapping the acetic anhydride intermediate by reaction with added aniline. The choice between general-base catalysis and intramolecular nucleophilic displacement depends significantly on the relative basicities of the nucleophile and the leaving group.Thus acetate does not catalyse the hydrolysis of substituted phenyl acetates if the leaving group is more than 3-4 pK units more basic than the catalyst5' In the case of acetylsalicylic acid the leaving group is at least 6-7 pK units more basic than the carboxylate group. Incorporation of two nitro-groups ortho and para to the phenolic oxygen should reduce its basicity markedl~.~' Oxygen-18 is incorporated into the 3,5-dinitrosalicylic acid formed on hydrolysis of acetyl-3,5-dinitrosalicylate in an enriched solvent This evidence and the kinetic data is consistent with a mechanism (Scheme 6)involving intramolecular displacement by carboxylate ion with the formation of a mixed salicylic acetic anhydride intermediate.T. C. Bruice and W. C. Bradbury J. Amer. Chem. SOC.,1968,90 3808. 49 V. Gold D. G. Oakenfull and T. Riley J. Chem. SOC.(B) 1968,515. 50 D.G. Oakenfull T. Riley and V. Gold Chem. Comm. 1966,385. 51 A. R.Fersht and A. J. Kirby J. Amer. Chem. SOC. 1968.90. 5818. Reuction Mechanisms 16 J. G. Tillett The slow step is the decomposition of the anhydride intermediate although this is itself subject to intramolecular general-base catalysis. Intermolecular reactions with oxyanion nucleophiles however involve uncatalysed nucleophilic attack on the ester. The hydrolysis of acetyl-3,5-dinitrosalicylicacid is faster than its anion.52 Solvolysis in 50 ”/ aqueous methanol produces significant quantities of methyl 3,5-dinitrosalicylate indicating that intramolecular catalysis and anhydride formation is involved in this case also.Nucleophilic catalysis seems to be favoured for the hydrolysis of acetylsalicylic acids because of a more favourable equilibrium-constant for the formation of the protonated form rather than the anion of the mixed anhydride intermediate. A further striking example of this principle is found when a second carboxy- group is introduced into the 6-position of acetylsalicylic acid.’ This accelerates the rate of hydrolysis by a factor of ca. 6000. This acceleration is attributed to ‘series’ nucleophilic catalysis in which the acetyl group is first transferred to the adjacent carboxy-group and then displaced from it by the second carboxy- group (Scheme 7).CO-H O=y’ -\-,!J OH v ‘OH SCHEME 7 The acetate ion-catalysed methanolysis of p-nitrophenyl acetate also involves an acetic anhydride intermediate.54 The hydrolysis of 4-(2-acetoxyphenyl)imidazolealso proceeds by way of a general-base mechanism (10)rather than by nucleophilic catalysis. This is in accord with the fact that th.= imidazoyl nitrogen atom is a poorer nucleophile (pK,, 5-5)in this compound than in imidazole (pK,, 7.0). Solvolysis under alkaline conditions of 4(5)-(2-amino-3-bromopropyl)-imidazole forms the aziridine (1 1) 52 A. R. Fersht and A. J. Kirby J. Amer. Chem. SOC. 1968,90 5826. 53 A. R. Fersht and A. J. Kirby J. Amer.Chem. SOC.,1968,90 5833. 54 R. L. Schowen and C. G. Bohm J. Amer. Chem. SOC.,1968,90,5835. 55 S. M. Felton and T. C. Bruice Chem. Comm. 1968 907. 5h D. A. Usher. J. Amer. Chem. SOC..1968.90. 363. Reaction Mechanisms Me H II Simple displacement of bromide can however be effected by external nucleo- philes after chelation with copper (11) ions (12).57A complex pH-rate dependence involving three imidazole-dependent terms is obtained for the hydrolysis of y-methyl- 1,-chloro- and p-nitro-benzoylimidazole in H,O -imidazole buffer solutions. The imidazole-catalysed hydrolysis of N-acetylserinamide is only moderately affected by steric effects in the catalysing base.59 This is consistent with classical base catalysis (13) since nucleophilic catalysis would be strongly retarded by large groups in the 2-position.Oh-NHAc I! I Me C-O.CH,CH.C .NH 1 I I II 0 /Ox*. HH Aminolysis and Related Reactions. Evidence continues to accumulate for the existence of tetrahedral intermediates in the hydrolysis of both cyclic and acylic irnidates6’ The hydrolysis of ethyl N-phenylacetimidate and methyl (+)-N-(a-methylphenylethy1)acetimidate yields amines and esters in acid solution and amides at alkaline pH. At constant pH bifunctional catalysis diverts the breakdown of tetrahedral intermediates from the formation of amides to the explusion of amines.61 The kinetics of hydrolysis of 2,2,2-5’ D. A. Usher J. Amer. Chem. Soc. 1968,90,367. ’13 J. P. Klinman and E. R. Thornton J. Amer.Chem. SOC.,1968,90,4390. 59 J. B.Milstien and T. H. Fife J. Amer. Chem. SOC.,1968,90,2164. 6o G.L. Schmir J. Amer. Chem. SOC. 1968,90,3478. R.K. Chaturvedi and G. L. Schmir. J. Amer. Chem. Soc.. 1968.90.4413. 78 J. G. Tillett trifluoroethyl- 2-methoxyethyl- and ethyl N-methylacetimidate are also consistent with the formation of a tetrahedral intermediate.62 The aminolysis of methyl formate by amines in aqueous solution proceeds predominantly by general base catalysed attack of free amine at high pH.63 The rate-determining step for the reaction of morpholine with methyl formate changes from being the formation of the addition intermediate at high pH to its decomposition at low pH. A comprehensive investigation of the sensitivity of aminolysis reactions to the basicity of amines for a series of acetate esters has been reported.64 The kinetics of the reactions of trifluoroacetanilide with hydroxylamine and hydrazine have been studied.65 The first direct observation of a tetrahedral intermediate in amidine hydrolysis has recently been reported.66 Spectroscopic and kinetic evidence were obtained for the existence of both forms (14 and 15) of the intermediate in the hydrolysis of diphenylimidazolium chloride. n PhNONPh PhN NPh v HXOH U CHO Diazo-compounds. Zwanenburg and his co-workers have reported a further study of the acid-catalysed hydrolysis of aryl- and alkyl-sulphonyldiazo- rnethane~.~~ The reactions shows specific hydrogen-ion catalysis as indicated by the kinetic solvent-isotope effect.Fast H-D exchange of the methine proton observed by n.m.r. spectroscopy shows that carbon protonation occurs as the first step. The effectiveness of added acids is in the order HBr > HC1 > HC104. This different catalytic efficiency is attributed to specific anion or nucleophilic catalysis by the anion of the acid in which anions possessing nucleophilic properties compete with the solvent for the conjugate acid thereby providing an alternative route to that followed in the absence of such nucleophiles (Scheme 8). In perchloric acid containing added chloride ions the rate enhancement as compared with solutions containing the same concentration of added perchlorate could be directly correlated to the amount of chloro-product formed.Such a correlation implies that the water reaction also proceeds by an A-2 mechanism since in an A-1 process with water and 62 T. C. Pletcher S. Kochler and E. H. Cordes J. Amer. Chem. SOC. 1968,90 7072. 63 G. M. Blackburn and W. P. Jencks J. Amer. Chem. SOC. 1968,90,2638. 64 W. P. Jencks and M. Gilchrist J. Amer. Chem. Soc. 1968,90,2622. 65 S. 0.Eriksson Acta Chem. Scad. 1968,22,892. 66 D. R. Robinson Tetrahedron Letters 1968 5007. 67 J. B. F. N. Engbeits and B. Zwanenburg Tetrahedron 1968.24. 1737. Reaction Mechanisms 79 halide ions competing for a carbonium ion additional chloro-product would be formed. + + Ar,SO,CHN + H,O + ArS0,*CH2N2+ H20 + +H,O ArSO,*CH,N ArSO,CH,OH sly' Ar SO,CH,X (X = Br or C1) SCHEME 8 The hydrolysis of ethyl diazoacetate also shows specifichalide-ion catalysis.6 The rate enhancement by halide ions correlates with the amount of halo-genoacetate produced suggesting a similar mechanism of hydrolysis to that postulated for the diazosulphones halide ions again competing with water for the conjugate acid of the substrate in the rate-determining step.A re-investigation of the acid-catalysed hydrolysis of dia~o-ketones~~ suggests that the earlier assignment7' of an A-1 mechanism to this reaction is incorrect. The earlier conclusion was based mainly on an analysis of the kinetic data in terms of the Zucker-Hammett criterion and on entropy of activation data. It has been shown recently,67however that the acidity criterion is not valid for the analogous diazo-sulphone system and this must throw doubt on its use in this case.Evidence has now been presented which shows that for the acid-catalysed hydrolyses of diazo-ketones both the water and halide-ion reactions proceed by an A-2 mechanism.69 The diazo-ketones -sulphones and -esters all hydrolyse therefore by the same mechanism. Several other kinetic studies of diazo-compounds have also been reported. 71-74 Other reactions reported to exhibit nucleophilic catalysis are the acid-catalysed hydrolyses of ethylene sulphoxide7 and 3-phenylsydnone.76 Other Reactions. Kice and his co-workers have published further details of their studies on the reactions of the sulphur-sulphur bond.77Both electro-philic and nucleophilic catalysis either individually or concomitantly can be observed in these systems.Thus the kinetic equation of the halide-and acetate-ion catalysed hydrolysis of sulphinyl sulphones is of the f~rm,~~,~' kobs - kxo[X-] + k,,[X-] [H']. The first term represents solely nucleophilic '' W. J. Albery J. C. E. Hutchins. R. M. Hyde. and R. H. Johnson J. Chenz. Soc. (B),1968 219. 69 S. Aziz and J. G. Tillett Tetrahedron Letters 1968 2321 ;J. Chem. Soc. (B) 1968 1302. 70 H. Dahn and H. Gold Helu. Chim. Actn. 1963,46 983. W. Jugelt and D. Schmidt Tetrahedron 1968,24,59. 72 A. J. Harget K. I). Warren and J. R. Yandle J. Chem. Soc. (B),1968,214. l3 W. Jugelt and L. Berseck Tetrahedron Letters 1968 2659 2665. 74 D. Bethel1 and R. D. Howard J. Chem. Soc. (B),1968,430. 75 G. E. Manser.A. D. Mesure and J. G. Tillett Tetrahedron Letters 1968 3153. 76 S. Aziz A. F. Cockerill and J. G. Tillett Tetrahedron Letters 1968,5479. 7' J. L. Kice Accounts Chem. Res. 1968 1 58. '' J. L. Kice and G. Guaraldi J. Org. Chem. 1968,33 793. 79 J. L. Kice and G. Guaraldi. J. Amer. Cheni. Snc.. 1968.90.4076. 80 J. G.TiIlett catalysis (Scheme 9) whereas the second term involves both electrophilic and nucleophilic assistance (Scheme 10). 0 II X-+ Ar-S-S-Ar ArS-X + Ar*SO II II 00 products (X = C1 Ar = p-MeC,H,) SCHEME 9 0 II kxl X-+ ArS-SAr + H,O ArS-X + ArS0,H + H,O II II "I1 I 00 1 H,O fast products SCHEME 10 The kinetics of the acid-catalysed thiolsulphinate-sulphide reaction have also been investigated.8o The mechanisms of the halide-ion and acid-catalysed racemisation of phenyl benzylthiosulphinate,81 rn-chlorophenyl methyl sul- phoxide,82 and 3-benzylsulphinylbutyricacid83 have also been investigated. The hydrolysis of ethyl thioacetate is catalysed by cyanide ion and by hydrogen cyanide whereas the hydrolysis of ethyl benzoate and ethyl p-nitrobenzoate are not. 84 The kinetic form of the rate equation for the hydrolysis of ethyl thiolacetate in cyanide buffers is k, = ko,-[OH-] 4-kCN-[CN-] + k,m[HCN] The second term represents nucleophilic catalysis by cyanide ion (Scheme 1l) the deuterium solvent effect (k -)Hzo/(k -)D20 -1.25precluding general-base catalysis. slow CN-+ MeCOOSEt -MeCO-CN + EtS-fast MeCO-CN + H20 -MeC0,H + HCN SCHEME 11 8o J.L. Kice and G. B. Large J. Org.Chem. 1968,33 1940. 81 J. L. Kice and G. B. Large J. Amer. Chem. Soc. 1968,90,4069. " D. Landini F. Montanari G. Modena and G. Scorrano Chem. Comm. 1968 86. 83 S. Allenmark and C-E. Hayberg Acta Chem. Scund. 1968,22,1694. 84 F. Hibbert and D. P. N. Satchell. J. Chem. Soc. (B). 1968. 565. 568. Reaction Mechanisms The hydrogen cyanide catalysis represents an unusual acid-catalysed nucleo- philic catalysis of ester hydrolysis for which a number of possible mechanisms may be envisaged. The kinetics of the addition of carboxylic acids to dimethyl- keten in ether and to diphenyl- -and mesitylphenyl-keten in o-dichlorobenzene are consistent with two alternative rnechanism~.~~ In ether solution the addition of weak carboxylic acids involves a cyclic transition-state (16) with nucleophilic attack by the acid on the carboxy-carbon of the keten R’,CX=O R’ 25=C 7 -R’,CH .C02.COR2 + R’CO~H -H\a&? \R2 The preferred mechanism for stronger carboxylic acids is thought to involve carbon protonation (Scheme 12). R;C==C=O + R2*C02H-[RiCH-CH=O]+ [R2C02]-I R~H-co 00 COR~ SCHEME12 The kinetics of the addition of water and alcohols to dimethylketen have also been measured.86 Both the spontaneous and acid-catalysed addition of nucleophiles proceed by way of cyclic transition states analogous to that discussed above. The addition of hydrogen chloride to dimethylketene involves carbonyl addition followed by a prototropic rearrangement.”Further studies of bifunctional catalysis on the mutarotation of glucoseg8* 89 and in esterolytic reaction^,'^ have been reported. The catalytic effect of micelles on the hydrolyses of ester.^^'-^^ and on the addition of cyanide ion to N-substituted 3-carbonyl- pyridinium ions9’ have also been reported. Esters of Inorganic Oxy-acids.-( a) Phosphorus ucids. Bun ton has reviewed ‘’ J. M. Broidy P. J. Lillford and D. P. N. Satchell J. Chem. SOC.(B),1968 885. 86 P. J. Lillford and D. P. N. Satchell J. Chem. SOC.(B) 1968 889. 87 P. J. Lillford and D. P. N. Satchell J. Chem. SOC.(B) 1968 897. 88 A. Kerzomard and M. Renard Tetrahedron Letters 1968 769. 89 P. R. Rony J. Amer. Chem. SOC. 1968,90,2824. R. F. Pratt and J. M. Lawler Chem. Comm.1968,522. L. R. Romstead and E. H. Cordes J. Amer. Chem. Soc. 1968,90,4404. 92 T. C. Bruice J. Katzhemtler and L. R. Fedor J. Amer. Chem. SOC. 1968,90 1333. 93 R. B. Dunlop and E. H. Cordes J. Amer. Chem. SOC.,1968,90,4395. 94 C. Gitier and A. Ochoa-Solama J. Amer. Chem. SOC. 1968,90 5004. 9s R. N. Lindquist and E. H. Cordes. J. .4nirv. Chem. Soc.. 1968.90. 1269. 82 J. G.Tillett the mechanisms of hydrolysis of mono-alkyl and aryl derivatives of ortho- phosphoric acid,96 and Westheimer has discussed the significance of pseudo- rotation in the hydrolysis of phosphate esters and related corn pound^.^^ The rate of the acid-catalysed hydrolysis of p-nitrophenyl diphenyl phosphate in aqueous dioxan goes through a maximum as a function of acid concen- trati~n.~~ This is not due to complete protonation of the substrate but is another example of a reaction for which negative salt-effects outweigh positive catalysis by protons.The rates of hydrolysis of a series of acyl phosphates with varying steric bulk in the acyl group have been studied as a function of acid and temperat~re.'~ The hydrolysis proceeds by an A-2 mechanism involving attack of solvent on the protonated acyl phosphate. The effect of variation of both nucleophile and leaving group on the reactivity of phosphate monoesters has been examined. loo The reactivity of the dianions depend strongly on the nature of the leaving group but only weakly on the bacicity of the nucleophile. For a sufficiently good leaving-group the Brsnsted co- efficient is zero and pyridines differing in basicity by several powers of ten attack the dianion of 2,4-dinitrophenyl phosphate at the same rate.The reactions of monoanions are very sensitive to nucleophile basicity and to the leaving- group as is consistent with an S,2 (P) mechanism. A reaction between an amine and a simple phosphate monoanion was demonstrated for the first time. Nucleophilic attack by fluoride ion on the monoanion of 2,4dinitro- phenyl phosphate was also observed. Both steric and polar substituent effects influence the rates of hydrolysis of 2,4-dichlorophenyl methyl N-alkylphosphoramidates.lo' The initial rapid pre-equilibrium protonation may occur at both oxygen and nitrogen. A variety of tentative mechanisms of hydrolysis are proposed.The hydrolysis of isopropyl methylphosphonofluoridate is catalysed by magnesium ions.'02 The active species is a magnesium hydroxo-complex which is slightly more active than the equivalent concentration of HO-. The catalytic effect could be due to either a 'super-acid' effect (17) or to hydrogen bonding (18). \ /.%PH2 Y N-o-H-~ II -Lo R-C -CH,-O-P< I 0-H Me y6 C. A. Bunton J. Chem. Educ. 1968,45,21. y7 F. H. Westheimer Accounts Chem. Res. 1968,1 70. C. A. Bunton S. J. Farber and E. J. Fendler J. Org.Chem. 1968,33 29. 99 D. R. Phillips and T. H. Fife J. Amer. Chem. SOC.,1968,90 6803. loo A. J. Kirby and A. G. Vargolis J. Chem. SOC.(B) 1968 135. lo' A. W. Garrison and C. E. Boozer J. Amer. Chem. SOC.,1968,90 3486. '02 J.Epstein and W. A. Mosler. J. Phvs. Chem. 1968. 72. 622. Reaction Mechanisms Neighbouring oxime-group participation has been reported" for the hydrolysis of p-nitrophenyl phenacyl methyl phosphonate oxime the rate- determining transition state (19) involving an oximate anion-catalysed water- mediated reaction. Whereas the hydrolysis of methyl N-cyclohexylphosphor- amidothioc chloride proceeds stereospecifically under neutral condition^,'^^ alkaline solvolysis gives a racemic product suggesting the existence of the planar intermediate (20). Me0 S Me0 'P' +HO-+ RNH/\C1 RN' 'Cl1 slow Me0 \ (racemic) product -!??-% /p=s RN (20) The concept of pseudorotation has been used to rationalise the observation of kinetic acceleration in cyclic phosphates and related compounds not only for ring-opening saponification but also for reactions not involving ring fission such as oxygen exchange and hydrolysis of groups external to the ring.97 Such reactions are considered to proceed through bipyramidal intermediates which can undergo pseudorotation.Thus ring strain in a five-membered cyclic phosphate is reduced without ring-opening in a transition state that has a naturally small 0-P-0 bond angle. Such a hypothesis explains the lack of kinetic acceleration in simple five-membered cyclic phosphinates which would require a trigonal-bipyramidal intermediate with an alkyl group in an energetically unfavourable apical position. '"9 Highly strained cyclic phosphinates for which an exceptionally large diminution in ring-strain accompanies the formation of the transition state do show the expected large rate-differences.lo Under alkaline conditions 1,2,2,3,4,4,-hexamethyl-l-phenylphosphetanium iodide"' (21; R' = R2= Me) and bromidelO'~''O undergo ring expansion to the five-membered phosphorus heterocycle (22).C. N. Lieske J. W. Hovance G. M. Steinberg and P. Blumberg Chem. Comm. 1968. 13. lo4 A. F. Gerrard and N. K. Hamer J. Chem. SOC.(B),1968 539. lo' G. A. Aksnes and K. Bergeson Acta. Chem. Scand. 1966,20,2508. E. A. Dennis and F. H. Westheimer J. Amer. Chem. SOC. 1966,88,3431. lo7 R. Kluger F. Kerst D. G. Lee E. A. Dennis and F. H. Westheimer J. Amer. Chem. SOC.,1967 89,3918. lo* S. E. Fishwick J. A. Flint W. Hawes and S. Trippett Chem.Comm. 1967 1113. log S. E. Cremer and R. J. Chorvat Tetrahedron Letters 1968,418. 'lo S. E. Cremer. Cheni. Comm.. 1968. 1132. J. G. Tillett H RZ MeUR' Me& Me D Me HH The alkaline hydrolysis of however 1,2,2,3-tetramethylphosphetaniurniodide (21 ; R' = Me RZ = H) forms the open-chain phosphme oxide (23).'" 0 Me Me I1 I I Ph-P-C-C-H I l l Me Me Me The formation of the acylic phosphine oxide is attributed to opening of the four-membered ring by fission of the P-CH bond in the trigonal-bipyramidal intermediate (24) rather than the P-CMe bond in (25) It is suggested that the CH carbanion from (24) can separate and add a proton but the less-stable CMe carbanion which is the only possible carbanion in the pentamethyl case attacks the phenyl group to give the rearranged product.The alkaline hydrolysis of 1-benzylphosphetanium bromide (21 ; R' = CH,Ph R2 = Me) proceeds with retention of configuration at phosphorus. ''' This is consistent with the view adopted above that the four-membered ring occupies an equatorial-apical position in the hydrolysis of phosphetanium salts. Usually the apical group opposed to 0-is expelled as the anion leading to inversion at phosphorus (26). 'I' S. E. Fishwick and J. A. Flint Chem. Comm. 1968 182. 'I2 W. Hawes and S. Trippett. Chem. Comm.. 1968. 295. Reaction Mechanisms H H H Me Me H In the benzyl case however the ring blocks loss of the benzyl anion from an apical position opposite to 0-.Loss of the benzyl anion must then occur either from an equatorial position of (27) or after pseudorotation to a new trigonal- bipyramidal intermediate (28) from an apical position.Both of these alternatives will lead to the observed retention of configuration at phosphorus. The four-membered cyclic phosphinate ester (29) hydrolyses in alkaline solution at about the same rate as triethyl phosphite,l13 whereas the relief of steric strain in a trigonal-bipyramidal intermediate in which the four- membered ring occupied an apical equatorial position would be expected to lead to rapid hydrolysis. Such a 'normal' rate of hydrolysis could arise from a combination of steric strain and retardation due to steric hindrance. One t-butyl group attached to phosphorus produces little steric hindrance to attack of OH-.However in the series of phosphinate esters RP(:O)*OEt there is a sharp fall-off in the rate of hydrolysis between R = Pr' and R = But 114 With two t-butyl groups attached to phosphorus one must occupy an equatorial position in the initial trigonal bipyramid (30). Bu* Me x \OMe Bu' But I 0;P-Y x x 'I3 K. Bergeson Acta. Chem. Sand.. 1967,21 1587. 'I4 W. Hawes and S. Trippett. C'heni. Comm.. 1968. 577 0' J. G. Tillett Due to the 'equatorial' t-butyl group there is substantial steric hindrance in the transition state leading to the formation of this intermediate to the approach of the nucleophile. With only one t-butyl on phosphorus ths can occupy an apical position as in (32).Pseudorotation to (33) then occurs before expulsion of the group Y from an apical position. Final confirmation of the view that the rates of alkaline hydrolysis of cyclic phosphinates are effected by competing steric acceleration and retardation comes from the observation of kinetic acceleration in (31) where the relief of steric strain is not accompanied by steric hindrance. (b) Sulphur Acids. The pH-rate profiles for the hydrolysis of nitrophenyl and dinitrophenyl sulphates are characterised by a plateau in the pH 4-12 region,' ''which is associated with a 'neutral' rate (k,). A linear free-energy plot of log ko against the pK of the corresponding phenol gave a slope of -1.2. A similar correlation for the acid-catalysed rate of hydrolysis (k& gave slopes in the range 0-22-0.26 indicating the relative insensitivity of the reaction to the electron-withdrawing power of the leaving group.The catalytic efficiency of the acids studied was in the order H,SO >HCIO >HCl. This differential behaviour was attributed to specific electrolyte effects. Plots of log k +H against aN were curved but a good linear correlation was obtained for the sulphates studied by plot.ting log k +H against H +C,+. The 4 values so obtained corresponded to little or no water participation in the rate- determining step. The solvolyses of 0-and p-carboxyphenyl sulphates in aqueous methanol have also been examined. 'The data suggests transition states of considerable sulphur trioxide character for catalysis by hydroxonium ions and the o-carboxy-group.The possibility of Lewis acid-base interactions influencing the product composition is also considered. As part of a study of kinetic acceleration in cyclic esters of sulphur-containing acids Kaiser and his group have shown"7 by oxygen-18 studies that the hydrolyses of the SS-dioxides of benzo[d][ 1,3,2]-dioxathiole (34) benzo[d- [1,2]oxathiole (35) and benzo[e][ 1,2]oxathiin (36) in alkaline solution proceed entirely with S-0 bond fission. mso* \ There was no evidence of reversible incorporation of l80 in the unchanged starting material. It has been suggested .that the 5-nitro-derivative of (34) is a convenient reagent for the 'titration' of a-chymotrypsin in the pH range 'I5 E. J. Fendler and J. H. Fendler J.Org. Chem. 1968,33 3852. S. J. Benkovic and P. A. Benkovic J. Amer Chem. SOC.,1968,90 2646. 'I7 E. T. Kaiser and 0.R. Zaborsky. J. Amer. Chem. SOC. 19hS. 90. 4626. Reaction Mechanisms 7-8. * The effect of structure variation on the hydrolysis of sultones has also been investigated. l9 Kaiser and his co-workers12' have recently reported on the extraordinary reactivity of vinylene sulphate compared to ethylene and dimethyl sulphate. It is of considerable interest to note that crystallographic determinations show that whilst the 0-SO bond angle in ethylene sulphate is 98.4" the corresponding angle in vinylene sulphate has the extremely 'low' value of 93.6" and so is therefore very close indeed to the 90"required to achieve a trigonal-bipyramidal transition state for alkaline hydrolysis.Analysis of the kinetic data for the alkaline hydrolysis of aliphatic and aromatic organic sulphites shows that kinetic acceleration in cyclic sulphites is due almost entirely to the differences in the entropies of activation of the cyclic esters and their open-chain analogues. 21 The acid-catalysed hydrolyses of cholesteryl methyl menthyl methyl dibornyl and 2-dinorbornyl sulphites all proceed by the well documented A-2 mechanism as indicated by kinetic acidity dependence and entropy of activation data.lz2 The order of effectiveness of mineral acids is HClO < H,SO < HCl which is attributed to concomitant acid and specific anion catalysis. Substituent Effects and Linear Free-energy Relationships.-Several attempts have been made to determine the relative importance of the direct and field effect components of the inductive effect.It has proved difficult however to provide an unambiguous answer to this important question because the two effects often act in the same direction. Wilson and Le~ng'~~ have attempted to obviate some of the difficulties by comparing the pK values of 4-substituted bicyclo[2.2.2]octane (37) and bicyclo[2.2.l]heptane-l-carboxylic acids (38) in which the direct effects would be expected to be very similar and the inductive effects different but calculable. (37) ''*J. H. Heidema and E. T. Kaiser Chem. Comm. 1968 300. '' E. M. Philbin. Chem. and Ind. 1968 688. F. P.Boer J. J. Flynn E. T. Kaiser 0.R. Zaborsky D.A. Tomalin A. E. Young and Y. C. Tong J. Amer. Chern. SOC.,1968,90 2970. 12' P. A. Bristow J. G. Tillett and D. E. Wiggins J. Chem. SOC.(B),1968 1360. 122 G. E. Manser A. D. Mesure J. G. Tillett and R. C. Young J. Chem. SOC.(B),1968,267. 123 C. F. Wilson and C. Leung J. Amer. Chem. SOC.,1968,90,336. J. G.Tillett The inductive model with a constant fall-off factorf with account of all three chains yields a substituent effect ratio p given by P = (2/f3) + (l/f2)/3/f3= (2 +f)/3 For a range offvalues of 2.0-3.0 the corresponding p-values are 1-33-1.67. The most realistic value forfwas assumed to be 2.7 to give a p-value of 1.57 which is independent of substituent. Use of the cavity model gives a predicted value of p = 1.20. The experimentally determined value of 1.175 suggests that transmission by the inductive effect occurs predominantly by the field effect and only to a small extent by inductive transmission.There is a growing interest in reversed dipolar substituent effects. From the following pK values of a series of 8-substituted 1-naphthoic acids124 in 80 % 2-methoxyethanol it can be seen that normally acid-strengthening substituents here have decreasing acidity H 6.40 C1 6-04 Br 6.16 NO2 6.00 and Me 5.99. Similar substituent effects were observed on the pK values of some cis-ortho-substituted a-phenylcinnamic acids. This decrease in acidity was attributed to decrease in the stability of the corresponding carboxylate anions (39) and (40) by a reversed dipolar effect. H/\ Ph The relative rates of reaction of these acids with diazodiphenylmethane support this interpretation.&war has critici~ed'~' Bowden and Parkin's work on the grounds that it is inconclusive since hydrogen-bonding in both 8-substituted 1-naphthoic acids and in o-substituted a-phenyl-cis-cinnamic acids could account for the observed effects. This could stabilise the acids relative to their conjugate bases and hence lower acidity. Clearly further experimental data is needed on this point. Another group of workers however have also produced independent evidence for a reversed dipolar effect in ths system.126 A plot of the pK values of a series of 8-substituted-1-naphthoic acids against (T has a p-value of -0.06. The corresponding values for substituents in the 5- 6- and 7-positions are 0.76,0.67 and 0.63 respectively.This abnormally low slope for substituents in the 8-position indicating an apparent absence of electronic effects on acidity is attributed to the almost exact cancellation of the normal polar effects of substituents by the reverse polar substituent effect. K. Bowden and D. C. Parkin Chem. Comm. 1968 75. M. J. S. Dewar Ckem. Comm. 1968 547. M. Hojo. K. Katsurakawa. and Z. Yoshida. Tetrahedron Letters 1968 1497. Reaction Mechanisms 89 A kinetic study of the alkaline ring-fission of substituted coumarins (Scheme 13) shows that electronic transmission to the reaction site occurs by way of both the cis-ethylenic and oxygen links.'27 + OH -pco; R R OH SCHEME 13 Substituent effects on fluorine-19 chemical-shifts in saturated systems have been analysed in terms of a n-inductive effect."* The relatively minor role of this latter effect has also been pointed out.129 The transmission of polar effects through the piperidine' 30 and quinoline' 31 rings has been investigated.Substituent effects on the ionization of rneta-substituted phenols,' 32 picric acids' 33 and monoalkylhydrazines' 34 have also been studied. The effect of ortho-substituents on the entropy of activation for the esterifica- tion of substituted benzoic acids by methanol has been analysed in terms of a 'bulk effect' which tends to decrease AS and steric inhibition of solvation of the transition state which tends to increase AS:. 35 Decrease of the enthalpy of activation by substituents was attributed to both a secondary steric effect of ortho-substituents and a steric inhibition of 'ring solvation' of the initial state which may be brought about by substituents in any position in the ring.The retarding effect of ortho-alkyl substituents is less marked in the analogous reaction of substituted phenyl acetic acids.136 This is attributed to a smaller primary steric effect in this system. The influence of solvents on the reaction of substituted benzoic acids with diazodiphenylmethane has been in~estigated.'~~ For a variety of solvents the rate correlation with dielectric constant has the form log k = 0.98 -(2.60)/(0.9 16 + 0.084~). The Hammett p-value correlated with dielectric constant in a similar manner p = 0.60 + 2.40/(0*75 + 0.2%).Specific inter- actions were observed for both correlations particularly in aprotic solvents. Liotta' 38 has reported an attempt to determine a,-parameters which are free from steric and solvation effects. A plot of log KOagainst log K from earlier data' ''for the extent of ion-pair formation of a series of substituted benzoic "-K. Bowden M. J. Hanson and G. R. Taylor. J. Chrnt. SOC.(B),1968 174. M. J. S. Dewar and T. G. Squires J. Amer. Chern. SOC.,1968,90,210. lZ9 C. W. L. Bevan T. A. Eucokpae and J. Hirst J. Chem. SOC. (B),1968,238. '30 T. D. Sotolova S. V. Bogatkov Yu. F. Malina B. V. Unkovski and E. M. Cherkasova Reakts. spos. org. Soedinenii 1968 5 160. 13' C. W. Donaldson and M. M. Joullic J. Org. Chem.1968,33 1504. 13' P. D. Bolton F. M. Hall and J. Kudryuski Austral. J. Chem. 1968 21 1541. 133 P. J. Pearce and R. J. J. Simkins Canud. J.Chem. 1968,46,241. 134 R. Pollet and H. vanden Eynde Bull. SOC. chim. belge. 1968,77,341. 135 N. B. Chapman M. G. Rodgers and J. Shorter J. Chem. SOC.(B),1968 157. N. B. Chapman M. G. Rodgers and J. Shorter J. Chem. SOC. (B) 1968 164. 131 A. Buckley N. B. Chapman M. R. J. Dack J. Shorter and H. M. Wall J. Chem. Soc. (B) 1968 631. C. L. Liotta Chem. Comm. 1968 338. 139 M. M. Davis and H. B. Hetzer. J. Rey. Nut. Bur. Siontl. 1958. 60.569. 90 J. G.Tillett acids towards 1,3-dihexylguanidine gave excellent correlation even for sub- stituents of widely differing steric bulk. This suggests that both primary and secondary steric effects are absent and that only polar effects are operative.Values of the parameter 0,"given by the correlation log (KX/K& = 1.41 log (K,/H& =o:,are as follows :H (OW) F (0-51), C1(0.82) Br (0.91) I (0-96) Me (-0.32) NO (2.18). Taft's o,*parameters are not a linear function of the values listed here which is a further indication that a values are not com- pletely free from steric effects. The rates of alkaline hydrolysis of a series of phenyl benzoates substituted in both the acyl and aryl moities have been measured.I4' A good o-p plot was obtained when the aryl group was kept constant. A poorer correlation obtained when the aryl group was varied could be improved if the p-nitrophenyl group was allocated a o-value of 0.89.Swain and Lupton14' have suggested that any set of substituent constants may be expressed in terms of a simple two-parameter equation of the form o =fF +rR where F and R are the field and resonance constants different for each substituent and f and r are empirical weighting factors independent of substituent but different for each set of substituent constants (om,op,a; o' etc.). It is assumed that r = 0 for 0'(from ionization of 4-substituted bicyclo- [2,2,2]octanecarboxylic acids) and R = 0 for the Me,N substituent. The assumption that the field effects of a particular substituent in both rneta-and para-positions are equal is shown to be incorrect. Weighting factors have been calculated for various reaction sets by computer analysis the average correlation coefficient being 0.96'7.It is interesting to note that this correlation is not significantly increased by the use of an additional variable. The correla- tion is exceptionally high for both the ionization of 4-substituted bicyclo- [2,2,2]octane-l-carboxylic acids (0.990) and the alkaline hydrolysis of ethyl arylacetates (0.992). A further example of the way in which linear free-energy relationships sometimes disperse into separate lines characteristic of different types of substituent is illustrated by the reaction of trivalent phosphorus compounds with phenyl azide.142 The log k versus a* points lie on two parallel straight lines. The introduction of an oxygen atom changing from Ar,P to Ar,POR causes a sharp discontinuity whereas second and third oxygens [on going to ArP(OR) and P(OR),] do not.Hammett o' -values have been calc~lated'~~ by an extension of the localised- orbital model for the determination of substituent electronic effects on 7c-electron systems. An inductive parameter model of substituent effects has been adopted for HMO theory for monosubstituted anthraquinones. 144 An approach to linear free-energy relationships by non-equilibrium thermodynamics has also been re~0rted.l~~ I4O J. F. Krisch W. Clewell and A. Simon J. Org. Chem. 1968,33 127. 14' C.G. Swain and E. C. Lupton J. Amer. Chem. SOC.,1968,90,4328. 14' R.D.Temple and J. E. Leffler Tetrahedron Letters 1968 1893. 143 M.Godfrey J. Chem. SOC. (B) 1968,75. 144 W.Kemula and M. T. Krygowski. Bull. Acad. polon.Sci. Ser. Sci. chim.. 1967.15.479. Reaction Mechanisms 91 Further correlations of mass-spectral ion intensities with o-values have been reported. 146-149 The earlier assumption that a precise o-correlation implied that decomposition of e.g. substituted benzophenones (PhCO C6H4Y+*+PhCO+ + C6H4Y0) produces C7H50+ ions that are identical in average internal energies has been shown to be incorrect.”’ The Hammett relationship has also been applied to enzyme kinetics’” and in heterogeneous catalysis.’ 52 Electrophilic Substitution.-Another monograph on aromatic substitution reactions” and a review of electrophilic substitution in heteroaromatic compounds154 were published during 1968. Ridd and his co-workers have published further details of their work on the substituent effect of positive + poles.The rates of meta-nitration of ions Ph[CH,],NMe (n = 0 1 2 or 3) in aqueous sulphuric acid are consistent with the transmission of polar effects mainly by a direct-field effect rather than by the classical inductive mechanism. The variation of the enthalpy and entropy of activation with the number of + methylene groups is also consistent with this view. The reactivity of PhXMe, where X = N P As or Sb towards nitration in sulphuric acid increases steadily with atomic weight of the atom bearing the positive charge.ls6 The amount of para-substitution is greater for the AMe group than for SbMei and passes through a minimum with phosphorus and arsenic poles. In contrast the amount of ortho-substitution is much greater for the antimony pole than for nitrogen.These differences are attributed to the effect of p- and d-orbital interactions on the mesomeric effect. A kinetic study of the silver ion-catalysed chlorination and bromination of dimethyl-sulphonium and -selenonium ions157 shows that whilst the meta :para ratio for chlorination bromination and nitration are very similar the ortho :para ratios for chlorination and bromination are much higher than for nitration Even in highly electron-demanding situations such as the nitration in 98 :< H2S04 of the 4-alkylphenyltrimethylammoniumions alkyl groups influence nitration by electron release in the inductive order. The rates of nitration by nitronium ion of benzene and other reactive species reach a limiting value in both sulphuric and perchloric acids.lS9 This limiting 14’ T.Suzuki M. Seno and T. Yamabe J. Chem. SOC. Japan 1968,89 136. 146 R. A. W. Johnstone and D. W. Payling Chem. Comm. 1968 601. 147 M. M. Bursey J. Org. Mass. Spec. 1968 1,31. 148 F. W. McLafferty and M. M. Bursey J. Org. Chem. 1968,33 124. 149 M. M. Bursey and E. S. Wolfe J. Org. Mass Spec. 1968,-1 543. 150 M. L. Cross and F. W. McLafferty Chem. Comm. 1968 254. E. A. Zeller P. F. Palmberg and B. H. Babu Biochem. J. 1967 105,41. T. Hishida T. Uchijuma and Y. Yoneda J. Catalysis. 1968 11 71. L. M. Stock ‘Aromatic Substitution Reactions,’ Prentice-Hall New Jersey 1968. J. H. Ridd 2.Chem. 1968 (I 201. T. A. Modro and J. H. Ridd J. Chem. SOC. (B) 1968,528. A.Grastraminza T. A. Modro J. H. Ridd and J. H. P. Utley J. Chem. SOC.(E) 1968 534. 157 H. M. Gilow R. B. Camp and E. C. Clifton J. Org. Chem. 1968,33 230. J. H. P. Utley and T. A. Vaughan J. Chem. SOC. (B),1968 196. 159 R. G. Coombes. R. B. Moodie. and K. Schofield. J. Chem. SOC.(B).1968. 800. D J. G. Tillett rate is ascribed to the rate of encounter of nitronium ions and aromatic sub- strate (k3in Scheme 14) HNO + H+ k NO; + H20 k2 k3 NO; + Ar ====(encounter pair) k k5 (e.p.) -products SCHEME 14 If the encounter pair is treated as a transient intermediate steady-state treat- ment leads to the expression For highly reactive substrates k5 is large and k2(obs) is determined only by the concentration ratio and by the encounter rate k,.In sulphuric acid up to 68% the rate of nitration of benzene is less than a fortieth of the theoretical limit set by the encounter rate whilst in 80% sulphuric acid the observed rate approaches to within a sixth of the encounter rate. This suggests that meaningful comparisons of the reactivity of deactivated substrates can be made in sulphuric acid up to 68% but above this such comparisons may well be open to question. The rates of nitration with anhydrous nitric acid in carbon tetrachloride of benzene toluene p-xylene and mesitylene are all very similar.16* The reaction is zero order in aromatic substrate and of order 6 in nitric acid. This latter feature suggests that the rate-determining step involves desolvation of a solvated ionic or polar species and is the same for all the substrates studied.Consistent with this view is the observation that the rate of nitration of mesity- lene shows a substantial increase in going from 40"to O" since solvation phenomena are known to be very sensitive to temperature. Both 2-phenylpyridine and 2-phenylpyridine-N-oxideundergo nitration as their conjugate acids (41) and (42).16' I I H OH lh0 T. G. Bonner R. A. Hancock and F. R. Rolle Tetrahedron Letters 1968 1665. 16' A. R. Katritzky and M. Kingsland. J. Chem. Soc. (B). 1968. 862. React ion Mechanisms 93 The partial rate factors show overall similarity to those of the benzyltrimethyl- ammonium cation suggesting that the inductive effect is again more important than the mesomeric effect.Comparison of the rates of nitration of cinnoline and 2-methylcinnolinium perchlorate suggest that the former compound also undergoes nitration as the 2-cinnolinium cation. 162 The nitration of cinnoline 2-oxide occurs through both neutral and conjugate acid species. 163 Reaction through the cation leads mainly to 5-and 8-nitrocinnoline whilst nitration of the neutral species leads mainly to the 6-nitro-derivative. The kinetics of the two processes involved in the nitration of quinoline 1-oxide leading to the formation of the 5-and 8-nitro-compounds at lower temperature and to the 4-nitro-compound at higher temperature have been separated and have been shown to be due to involve the 1-hydroxyquinolinium cation and the free base respectively.Studies of the nitration of substituted pyri- dines164,165 have also been reported. The nitration of acetanilides with mixed acids results in attack para to the acetamido-group whereas the use of acetyl nitrate or nitronium fluoroborate produces predominantly the ortho-substituted product. 166 It is suggested that ortho-substitution results from S,2 displacement by an electron pair (on nitrogen or on carbonyl oxygen) on the species N02X (X = BF or OAc) leading to formation of the most readily accessible o-complex (Scheme 15) while the para-substituent favoured in mixed acids results from attack on the conjugated acid of acetanilide. No clear distinction between the two S,2 mechanisms can be made at present. Part of the driving force for ortho-nitration is thought to be the strong hydrogen- bonding interaction between the nitro-group and the acetamide hydrogen atom.This is supported by the observation that the major product in the acetyl nitrate nitration of N-methylacetamide-where such hydrogen bonding is absent-is 4-nitro-N-methylacetanilide. A variety of N-nitropyridinium tetrafluoroborates have been used to effect nitration of aromatic substrates under mild conditions in homogeneous solution.167 Thus a-picolinium tetrafluoroborate nitrates toluene readily and quantitatively at room temperature. The 2,6-lutidine salt is even more reactive. These salts show considerable substrate selectivity k(toluene)/ k(benzene) being 36.5 and 39-0for the picolinium and lutidine salts respectively.The kinetic isotope effect for the nitro-deprotonation of a series of 1-sub- stituted-2,4,6-tri-t-butylbenzenesvaries' 68 with the substituent as follows H(k,/k 1.0). F (2-3) NO (3.0) and CH (3-7). This suggests that there can be R. B. Moodie E. A. Qureshi K. Schofield and J. T. Cleghorn J. Chem. Soc. (B) 1968 312. 163 R. B. Moodie E. A. Qureshi and K. Schofield J. Chem. SOC.(B),1968 316. 164 R. C. de Selms J. Org. Chem. 1968,33,478. L. D. Smirnov V. P. Lezina B. E. Zaitsev and K. M. Dyumaev Zzoest. Akad. Nauk. SSSR Ser. khim. 1968 1652. B. M. Lynch C. M. Chen and Yak-Yung Wigfield Canad. J. Chem. 1968,46 1141. C. A. Cupas and R. L. Pearson J. Amer. Chem. SOC.,1968,90,4742. 16' P. C. Myhre. M. Beng. and L. L. James. J. Amer. Chem. SOC.. 1968.90.2105.J. G. Tillett / Me I SCHEME 15 a change-over from the rapid proton transfer envisaged in the usual two-stage mechanisms of nitration to a slow rate-determining proton transfer 702 k2 ArH + NO; kl Ar’ -ArNO + H+ k-1 \ slow H The observed isotope effect is attributed to differential increase of k compared to k- by steric repulsion effects at C-1. The electron-releasing effect of the 5-acetamido-group is insufficient to overcome the deactivating influence of the 2-phenyl group of the pyrimidine ring169 and the only product of nitration is the rn-nitro-derivative (43). The nitration of various polycylic compounds has been rep~rted.”~-’~~ (43) M. P. L. Caton and J. F. W. McOmie J. Chem. SOC.(C),1968 836. A. Davies and K.D. Warren J. Chem. SOC.(B),1968 1337. 17’ V. V. Zverev G. P. Shronin and I. D. Morocova Zhur. org. Khim. 1968,4 148 1236. 17’ C. C. Cook and F. K. Sutcliffe J. Chem. SOC.(C),1968,957. H. F. Andrew N. Campbell J. T. Craig and K. J. Nichol J. Chem. SOC.(C),1968 1761. 174 I. L. Klundt and W. K. Hoya J. Org. Chem. 1968,33 3327. Reaction Mechanisms OH 9 6+ HNO 0 - - 6 Qo NOH The nitration of alkyl substituted 2,3-dihydro-1,4-diazepiniumsalts is the unusual example of a cation reacting with another positive species.'75 The radiation-induced nitration of benzene with anhydrous potassium nitrate under heterogeneous conditions gives a 95 % yield of nitrobenzene. 176 The primary isotope effect (k,/k ca. 3.8) observed for the nitrosation of phenol and the acidity dependence for this reaction are consistent with the formation of a dienone intermediate (44) which can undergo decomposition spontaneously or by an acid-catalysed pathway.177 A further example of transannular directive influences has been reported. l7* The bromination of a 4-bromo [2,2]paracyclophane results in seven times more pseudo-ortho and pseudo-para than pseudo-meta compound and the ortho-and para-positions of the starting material carry more negative charge than the rneta-positions C(45) and (46)l. The resonance form (47) is clearly unimportant. The observed products suggest that the product-determining step is proton transfer to an acceptor site on the originally substituted ring. On the approach of the electrophile a proton is transferred from ring to ring and a proton then departs from the face of the unsubstituted ring.The reaction sequence leading to the formation of the pseudo-para-product is shown in Scheme 16. De la Mare and his co-workers have recently shown that chlorination of naphthalene leads to products of both substitution and addition. 179 Similarly the chlorination of 2,4dichloro-l-naphthol leads to the formation of (48) and (49). 175 A. M. Gorringe D. Lloyd D. R. Marshall and L. A. Mulligan Chem. and Ind. 1968 130. 17' W. W. Epstein R. N. Kurt and D. MacGregor Chem. Comm. 1968 1190. 177 B. C. Challis and A. J. Lawson Chem. Comm. 1968 818. 178 H. T. Reich and D. J. Cram J. Amer. Chem. Soc. 1968,90 1365. 179 P. B. D. de la Mare M.D. Johnson J. S. Lomas and V. Sanchez del Olmo J. Chem. SOC.(B) 1966,827. 180 P. B. D. de la Mare and H. Suzuki. J. Chem. SOC.(C),1968.648. J. G Tillett E+ fast Br@ H SCHEME 16 The side-chain chlorination of 2,3-dirnethylbenzothiopher1~'~has been considered to involve the formation of either the ion-pair (50) or the adduct (51)where chlorine adds across a double-bond. A tetrachloride adduct is also formed in the chlorination of 1-iodo-2-naph- thol. 82 The products of the bromination of trihydroxynaphthalene are thought to arise from initial addition across the carbon-carbon double-bond. The bromination of 2-phenanthrol has also been investigated. The rates of chlorination of some substituted rn-dimethoxybenzenes correlate with o+-values.185 The high p-value confirms the heterolytic nature of the rate-determining step.The reactive chlorinating species in the sulphenyl chloride chlorination of a number of alkylbenzenes is shown to be molecular E. Baciocchi and L. Mandolini J. Chem. SOC. (B),1968,397. H. Suzuki Bull. Chem. SOC. Japan 1968,41 1265. lE3 B. S. Balgir and R. H. Prager Austral. J. Chem. 1968,21 2327. E. Ota and K. Iwamoto J. Synthetic Org. Chem. Japan 1968,26 161. lS5 R. Bo1ton.J. Chem. SOC.(B).1968. 712. Reaction Mechanisms 97 sulphuryl chloride. 186 Molecular chlorine formed by dissociation of the reagent however provides a second minor chlorination pathway. The kinetics of bromination of alkybenzenes,' 87 1,5-dimethylnaphthalene,' 88 and some aromatic amine~'~~.have also been recorded. The acid-catalysed bromination of some aromatic compounds has also been studied. 19'* 192 The rates of iodination of nitrobenzene and benzoic acid with the tri-iodide cation have been investigated. l9 A two-stage mechanism is proposed to explain the observation of a kinetic isotope effect (k,/k ca. 3.2). Katritzky and his co-workers have reported studies of the acid-catalysed hydrogen exchange of 4-substituted anilines,lg4 3,5-dimethylphen01,'~~ and some pyridazine derivatives. lY6 The rates of detritiation of some substituted tritionaphthalenes' 97 and thiophens198 have also been reported. Kinetic studies of aprotic diazotisation of arylamine~'~~~~~~ and a further study of the mechanism of aromatic sulphonation201 have also been carried out.Nucleophilic Aromatic Substitution.-Several investigations reported this year provide further evidence for the existence of Meisenheimer complexes as intermediates in nucleophilic aromatic displacement reactions. The complex (52) obtained by the attack of methoxide ion on l-methoxy-2,4-dinitronaph-thalene is more stable than that formed with 3.4-dinitroanisole but less stable than the corresponding picryl complex.202. 203 CN (53) The crystalline salt isolatedZVs after the addition of methoxide ion to 4-CyanO- 2,4-dinitroanisole was shown to have the structure (53). The stability of Meisenheimer complexes clearly depends significantly on the ability of the 186 R. Bolton J. Chem. SOC.(B),1968 714. J.E. Dubois P. Alcais and F. Rottenberg J. Org. Chern. 1968,33 439. E. Berliner J. B. Kim and M. Link J. Org. Chem. 1968,33 1160. 189 J. E. Dubois. P. Alcais. and G. Barbeis. Bull. Soc. chinr. Frrrnce. 1968. 605. 61 1. I9O J. E. Dubois R. Uzan and P. Alcais Bull. Soc. chim. France 1968 617. 19' Y. Furaya A. Morita and I. Urasaki Bull. Chem. SOC.Japan 1968,41,957. 192 R. M. Kellogg A. P. Schaags E. T. Harper and H. Wynberg J. Org. Chem. 1968 33 2902. 193 J. Arotsky A. C. Darby and J. B. A. Hamilton J. Chem. SOC.(B),1968 739. 194 G. P. Bean and A. R. Katritzky J. Chem. SOC.(B),1968,864. 19' P. Bellingham C. D. Johnson and A. R. Katritzky J. Chem. SOC.,1968 866. 196 A. R. Katritzky and I. Pojarlieff J. Chem. SOC.(B),1968 873. 19' C. Eaborn P. Golborn R.E. Spillett and R. Taylor J. Chem. SOC.(B),1968 1112. 198 A. R. Butler and C. Eaborn J. Chem. SOC.(B),1968,370. 199 L. Friedman and J. F. Chlebowski J. Org. Chem. 1968,33 1633 1636. 2oo 0.Sziman and A. Messmer Tetrahedron Letters 1968 1625. 201 C. W. F. Kort and H. Cerfontain Rec. Trav. chim. 1968,87 24. 202 J. H. Fendler E. H. Fendler W. E. Bryne and C. E. Griffin J. Org. Chem. 1968 33 977. 203 C. F. Bernasconi J. Amer. Chem. SOC.,1968,90,4982. 204 J. E. Dickerson L. K. Dyall. and V. A. Pickles Austral. J. Chem.. 1968,21. 1267. J. G. Tillett ring substituents to accept a negative charge. Servis showed205 that the reaction of methyl picrate with methoxide ion in dimethyl sulphoxide initially yields the 1,3-dimethoxycyclohexadienylide (54).This undergoes a rapid conversion to the thermodynamically more stable complex (55). OMe NO2 OMe Crampton and Gold206 had earlier suggested that the reason for this isomerisa- tion is that whilst (55) is a less strained structure than methyl picrate the transition state leading to its formation is more strained than for (54).It should prove possible to find other examples which illustrate this interplay between kinetic and thermodynamic control. Until this year however no further examples of 1,3complex formation have been reported. Fendler et al.,207followed the course of the reaction of 2-cyano-4,6-dimethoxyanisole with methoxide ion by 'H n.m.r. spectroscopy. The spectrum of the known complex (56) was observed together with that of the 1,3-complex (57) which had a half-life of approximately 1 hr.OMe Similar observations were made in studies of the reactions of methoxide ion with 4-cyano-2,6-dinitroanisoleand 2,4-dicyano-6-nitroanisole. In both cases the 1,3-complexes are again formed initially and then undergo conversion to the isomeric 1,l-complexes. The isolation of the 1,l-complex of the former compound has also been reported by other workers (see above).204 The bright red colour formed on the addition of sodium hydroxide to an acetone solution of l-(~-hydroxyethoxy)-2,4-dinitrobenzene20s was thought to be due to the formation of a spiro-Meisenheimer complex (58). 205 K. L. Servis J. Amer. Chem. SOC. 1967,89 1508. 206 M. R. Crampton and V. Gold J. Chem. SOC.(B),1966 893. 207 E.J. Fendler C. E. Griffin and J. H. Fendler Tetrahedron Letters 1968 5631. 208 F. J. Pollitt and B. C. Saunders J. Chem. Soc. 1964 1132. Reaction Mechanisms Subsequently the analogous trinitro-Meisenheimer complex (59) was isolated from the reaction mixtures of 1-(P-hydroxyethoxy)2,4,6-trinitrobenzeneand sodium gly~ollate.~'~ The rate of decomposition of (59) in aqueous sodium hydroxide was shown to be several orders of magnitude slower than for noncyclic 1,l-dialkoxy-Meisenheimer complexes [e.g. (53)l. Fendler et al.21 have now reported the synthesis and isolation of the crystalline complexes (58),(60),and (61). N (60) (61) (62) The i.r. and 'H n.m.r. spectra substantiate the postulated structures. This provides compelling evidence of sp3-hybridization at C-1 of the cyclohexa- dienyl system of Meisenheimer complexes because the existence of spiro- complexes requires such hybridisation.Several investigators have reported evidence for the formation of Meisen-heimer complexes in nucleophilic displacement reactions of N-heteroaromatic substrates e.g. for the reaction of sodium methoxide with 4-methoxy-3,5- 3,5-dinitro~yridine,~'~ dinitr~pyridine,~~~-~" and 2-dimethylamino-3,5-di-nitropyridine.212 Fyffe2 l2 has also postulated the formation of a spiro Meisen- heimer complex (62) formed from the reaction between sodium methoxide and 2-(2' -hydroxyethoxy)-3,5-dini tropyridine. Kinetic studies of the effects of base catalysts on nucleophilic aromatic displacement have led to the adoption of a two-step mechanism for such reactions involving the formation of an addition intermediate which can decompose either spontaneously (k2)or by a base-catalysed pathway2 l3 (kB).'09 R. Foster C. A. Fyffe and J. W. Morris Rec. Trav. chim. 1965,84,516. *lo E. J. Fendler J. H. Fendler W. E. Bryne and C. E. Griffin J. Org.Chem. 1968,33,4141. '11 G.Illuminati and F. Stegel Tetrahedron Letters 1968,4169. '"C. A. Fyffe Tetrahedron Letters 1968 659. '13 J. F. Bunnett and R. H. Garst J. Amer. Chem. SOC.,1965,87 3875. 100 J. G. Tillett SCHEME 17 Most studies of the effect of steric hindrance on the entering and leaving group have been carried out in aprotic solvents. A recent of the reaction of various amines with halogeno-nitrobenzenes in a protic solvent (methanol) in which the formation step (k,) is thought to be rate-determining indicates that steric effects are much less important than with aliphatic sub- strates.The kinetics of the reversible reaction of piperidine with 2,4-dinitroani- sole have also been studied215 in this solvent. The relative reactivities in dimethyl sulphoxide of a series of substituted amines towards various fluoro- and chloro-nitroaromatics do not vary greatly with change of substrate.2 The ortho:para ratio also changes little with nucleophile. The facts are in- terpreted in terms of a nearly tetrahedral transition-state in which steric inhibition of resonance of the ortho-nitro-group is not pronounced. The kinetic form of the rate equation for the catalysis by added phenol on the reaction between piperidine and 1-fluoro-2,4-dinitrobenzene in benzene as solvent is given by:217 Rate/"ArF] CPi~l,ree = ko + kpip[Pi~lfree+ khOH[ArOHlfree + ksa,tCSaltl (where salt = piperidino-phenoxide).The first term (k,) represents the uncatalysed decomposition of the addition intermediate and the last three terms its decomposition catalysed by base phenol and salt. In contrast the reaction of piperidine with l-chloro-2,4- dinitrobenzene for which the rate-determining step is thought to be formation of the addition intermediate is not catalysed by either phenols or salts. The term which is first-order in amine concentration is attributed to intramolecular catalysis of the reaction by the ortho-nitro-group. Catalysis by free phenol is almost independent of any substituent which suggests that phenols act as a bifunctional catalyd3 for piperidino-defluorination.Powerful catalysis of the rate by tetra-n-butylammonium chloride and the complete absence of any effect with the corresponding perchlorate indicate G. Bartoli L. Di Nunno and P. E. Todesco Tetrahedron Letters 1968 2369. 215 J. F. Bunnett and R. Xi.Garst J. Org. Chem. 1968,33,2320 F. Pietra and F. Del Cima J. Org. Chem. 1968,33 1411. *" F. Pietra and D. Vitali J. Chern. Sac. (B). 1968. 1318. Reaction Mechanisms that the ‘salt’ is involved in catalysing decomposition of the intermediate. The analogous reaction with l-chloro-2,4-dinitrobenzene is not affected by the addition of added chloride.The anion of the salt must be jnvolved in proton abstraction because of the lack of this effect with non-basic anions like per- chlorate. It is interesting to compare the catalytic effect of quaternary ammonium salts on this reaction with that on the mutarotation of glucose in benzene (loc. cit). An alternative mechanism for base catalysis in nucleophilic aromatic displacements has recently been A study of the relative activating + + powers of the NMe,O NMe, and NO groups towards displacement of fluorine by methoxide ion in fluoroaromatics has led to the conclusion that electron displacement through the aromatic ring is indeed partly transmitted by a small 7c-inductive effect.129 The first account of the displacement of a nitro-group from an unactivated nitro-compound has been reported.Triethyl phosphite will displace the nitro-group from p-nitrotoluene. This is not considered however to involve direct displacement of the nitro-group but to be initiated by nucleophilic attack on an oxygen atom of the nitro-group. Photochemically induced nucleophilic displacements continue to be reported. The first example of the displacement of a dianionic species from an aromatic ring is provided by the displacement of the sulphoxylate anion (SO,’-) from sodium toluene-p-sulphinate with methyl lithium.220 Values of the kinetic solvent isotope effect for the reaction of 2,4-dinitro- chlorobenzene with ethoxide ion and pyridine”’ [k(EtOD)/k(EtOH)] = 1-84 and 1.30 for EtO- and pyridine respectively) were in reasonable accord with those predicted by the Bunton-Shiner treatment.222 Molecular orbital calculations have been used in an attempt to interpret the kinetics of aromatic replacement reaction^."^ An attempt has also been made to correlate the reactivity of aromatic and aliphatic substrates towards nucleophiles in dipolar aprotic solvents.224 ’’’ S.D. Ross Tetrahedron Letters 1968,4699. 2’9 J. I. G. Cadogan D. J. Sears and D. M. Smith Chem. Comm. 1968 1107. 220 R. H. Shapiro and K. Tomer Chem. Comm. 1968,460. 221 1. R. Bellobono P. Beltrame M. G. Cattanla and M. Sunonetta Tetrahedron Letters 1968 2673. 222 C. A. Bunton and V. J. Shiner J. Amer. Chem. SOC.,1961,83,42,3207. 223 P. Beltrame P. L. Beltrame and M. Simonetta Tetrahedron 1968,24,3043. 224 G.Bartoli and P. E. Todesco Tetrahedron Letters 1968,4867.