3 Reaction Mechanisms Part (i) By J. G. TILLETT Chemistry Department University of Essex Colchester NEWbooks published this year include the second editions of two classic works in organic chemistry Hammett’s ‘Physical Organic Chemistry” and Ingold’s ‘Structure and Mechanism in Organic Chemistry’.2 1 Acidity Functions and Molecular Basicity New acidity-function data reported this year include values of Ho for aqueous H2S04 over the temperature range 15-55 OC3 and Do for D2S0,4 (values of pK,,+ for a set of Hammett bases are also recorded). A further study of the effect of added micelles and electrolytes on the Ho” and H,”‘ acidity functions5 and a different approach to the study of electrolyte effects on the activity coefficients of aromatic amines6 have also been reported.Values of H-have been obtained for 40-95 mol ”/ dimethyl sulphoxide in water containing tetramethylammonium hydroxide using a set of substituted fluorenes as indicators.’ Arnett and his co-workers have discussed some of the problems associated with the determination of the pK values of weak organic acids by acidity function methods and in an attempt to avoid some of the difficulties have suggested that heats of ionization be used as an alternative criterion of base strength.’ A good linear correlation was found between the enthalpies of protonation of some 35 aromatic and aliphatic amines and the pK values of the corresponding conjugate acids in water. A wide range of other compounds were found to fit the AH-pK correlation and the pK,’s of alcohols ethers and water could be esti- mated.A study of the temperature variation of the thermodynamic acidity constants of some substituted aminesg and phenols” has been carried out to determine the standard enthalpies and entropies of protonation. Substituent L. P. Hammett ‘Physical Organic Chemistry’ 2nd edn. McGraw Hill Book Co. New York 1970. C. K. Ingold ‘Structure and Mechanism in Organic Chemistry’ 2nd edn. Cornell Univ. Press Ithaca New York 1969. P. Tickle A. G. Biggs and J. M. Wilson J. Chem. SOC.(B) 1970 65. J. Sierra M. Ojeda and P.A. H. Wyatt J. Chem. SOC.(B) 1970 1570. C. A. Bunton and L. Robinson J. Phys. Chem. 1970,74 1062. M. Lucas and J. Steigman J. Phys. Chem. 1970 74 2699. ’ K. Bowden and A. F. Cockerill J.Chem. SOC.(B) 1970 173. E. M. Arnett R. P. Quirk and J. J. Burke J. Amer. Chem. SOC.,1970,92 1260. P. D. Bolton and F. M. Hall J. Chem. SOC.(B) 1970 1247. ’* P. D. Bolton J. Ellis and F. M. Hall J. Chem. SOC.(B) 1970 1252. J. G. Tillett effects on both these properties were found to be strictly additive. A similar linear free-energy-enthalpy correlation was observed for both weakly basic and strongly basic members of the series thus providing further confirmation that the extension of proton ionization studies to weak bases by the indicator overlap method does give meaningful pK data.' The acidity of carbonyl compounds continues to attract interest. An n.m.r. chemical shift method has been used to determine the pK,'s of some very weak ketone bases in superacid media.I2 The use of a series of ketones to determine acidity over a wide range (Ho = 0 to -17.5)in both superacid and conventional acid systems is described.The same method has been used to determine the pK values for 3-pentanone 2-butanone and 3-methyl-2-b~tanone.'~ Arnett and his co-workers have devised a basicity scale for carbonyl compounds based on the relative heats of protonation in fluorosulphuric acidI4 for those compounds which protonate cleanly in this solvent. The data for aromatic ketones correlate well with those for aromatic amines determined by this method (loc. it).^ The protonation of ap-unsaturated ketosteroids was found to correlate with HA and the effect of substituents on pK,,+ to be similar to those previously found for simple ap-unsaturated ket~nes.'~ Both the rate of protonation of dimethylacetamide and dimethylbenzamide,16 and the protonation of several ring-subs titu ted N-(2,2,2- trifluoroe th yl)benzamides' follow the HA acidity function the latter observation suggesting that no separate acidity function based on secondary amides seems to be needed.The effect of substituents on the pK values of 4-substituted 4'-aminobenzanilides and 4'-hydroxybenzanilides shows that there is no conjugative transmission between the phenyl groups of (1) (1) + (Y= NH, OH ;X = MeO Me H C1 NO,) through the amide group.' The effect of substituents on the protonation of azo- compounds' and on the dissociation constants of 4-(substituted styry1)tropo- lones2' have also been investigated.The correlation of acidities of weak carbon acids in the fluorene series with molecular orbital and linear free-energy relation- '' P. D. Bolton C. D. Johnson A. R. Katritzky and s.A. Shapiro J. Amer. Chem. SOC. 1970,92 1567. G. C. Levy J. D. Cargiol and W. Raccla J. Amer. Chem. Soc. 1970 92 6238; G. C. Levy and D. Campioli Tetrahedron Letters 1970 919. I3 D. G. Lee Canad. J. Chem. 1970,48 1919. l4 E. M. Arnett R. P. Quirk and J. W. Larsen J. Amer. Chem. SOC.,1970,92 3978. R. I. Zalewski and G. E. Dunn Canad. J. Chem. 1970,48,2540. l6 B. G. Cox J. Chem. SOC.(B),1970 1780. '' D. W. Farlow and R. B. Moodie J. Chem. SOC.(B) 1970 334. l8 J. A. Donohue R. M. Scott and F. M. Menger J. Org. Chem. 1970,352035. l9 G.A. Eian and C.A. Kingsbury Bull. Chem. SOC.Japan 1970,43 739. *O K. Imafuku. S. Nakama and H. Matsumura Tetrahedron 1970 26 1821. Reaction Mechanisms-Part (i) ships,21 and of trisubstituted methanes22 with oR-have been reported. An extended Hiickel M.O. treatment has been used to correlate the protonation behaviour of meta-and para-substituted aryl~arbinols.~~ Apparent dissociation constants have been measured for meta- and para-substituted benzoic acids with substituents of the -M and +I -M type in either aqueous dioxan ethanol or methyl cello~olve,~~*~~ and a number of new values of Hammett constants 6 and cg,calculated. A linear correlation has been observed between the rate constant for neutralisa- tion by hydroxide ion (log k2) of substituted 1-phenyl-1-nitroethane and the ionisation constants (pK,) with a Brsnsted coefficient p of 1-17-1-20.26 The Brsnsted coefficient of greater than unity is considered to arise from differential substituent effects ; as the electron-withdrawing effect of the substituent is increased the rate constants for neutralisation are affected to a greater extent than the ionisation constants.A similar explanation of the anomalous Brsnsted coefficients obtained in substituted nitroalkanes has also been given by Kre~ge.~’ Using an n.m.r. method Delpuech et al. have studied the rates of deprotonation of mono- di- and tri-methylammonium ions.28 They suggested that the relative (2) + + + order of reactivity MeNH >> Me2NH2 > Me,NH for a reaction with a rate i expression of the form :rate = k,[MeNH,] [HC02 -1 results from a symmetrical transition state (2) which could arise from attack by a HC02H molecule of an internally hydrogen-bonded ion pair in a push-pull mechanism.On the basis of an extensive n.m.r. study of methyl-substituted alcohols and ketones Jackman and Kelly have proposed that the methyl group should be regarded as an electron-attracting group rather than its normally accepted r61e observed in e.g. strengths of acids and bases.29 Such a suggestion has been rejected by Robinson and Lewis who have drawn attention to some of the problems associated with the interpretation of n.m.r. data in terms of the electronic proper- ties of groups.30 Indeed Robinson has suggested that the symbol C +Me should ” K.Bowden A. F. Cockerill and J. R. Gilbert J. Chem. SOC. (B) 1970 179. 22 L. A. Kaplan N. E. Burlinson W. M. Moniz and C. F. Poranski Chem. Comm. 1970 440. 23 A. C. Hopkinson I(.Yates and I. G. Csizmadia Tetrahedron 1970 26 1845. ’* K. Kalfus M. Vecera and 0.Exner Coll. Czech. Chem. Comm. 1970 35 1195. 2s 0. Exner and J. Latomy Coll. Czech. Chem. Comm. 1970,35 1371. ” M. Fukuyama P. W. K. Flanagan F. T. Williams L. Franier S. A. Miller and H. Shechter J. Amer. Chem. SOC. 1970 92 4689. 27 A. J. Kresge J. Amer. Chem. Soc. 1970 92 3210. 28 J. J. Delpuech J. Ducois and V. Michon Chem. Comm. 1970 1187. ’’ L. M. Jackman and D. P. Kelly J. Chem. SOC.(B) 1970 102. .’’ P. M. E. Lewis and R. Robinson Tetrahedron Letters 1970 2783. 66 J.G.Tillett 6-b+ b+ b-not be interpreted as a dipole C-Me implying a reversal of the dipole C-H if H 6+ 6-is replaced by Me but rather as a reduction of the C-H charge ~eparation.~’ Similarly the fact that simple MO theory predicts that a methyl group is electron- attracting (relative to hydrogen) in amines alcohols and ethers suggests that energies of proton transfer reactions do not necessarily correlate with charge densities on the atom to which the proton is atta~hed.~’ Olah and his co-workers have given a comprehensive review of the evidence for the site of protonation of a large number of organic conjugate acids.33 Much of the evidence stems from their own n.m.r. studies in superacid solutions. A recent study in their laboratory has been of the protonation of the meso-ionic 3-phenylsydnone (3).This has now been shown to protonate on the exocyclic oxygen atom rather than on the nitrogen-2 atom as previously supposed.34 Ph-N-C-H P 4\ NkC 2\ 0/5** 1 (3) 2 Acid-Base Catalysis Carboxylic Esters Ethers Acetals and Related Compounds.-The dienone-phenol rearrangement is an example of an A1 reaction. The acid-catalysed iso- merisation of 4,4-dimethylcyclohexadienoneto 3,4-dimethylphenol is a three- step process35 (Scheme 1). Use of kinetic isotope effects shows that the rate- determining step (k’)is the isomerisation of (4)to (5). The dependence on acidity 0 OH Me Me Me. Me (4) lk’ ?H ?H Me Me Scheme 1 (5) 31 R. Robinson Tetrahedron 1970 26 2067. 32 W. J.Hehre and J. A. Pople Tetrahedron Letters 1970 2559. J3 G. A. Olah A. M. White and D. H. O’Brian Chem. Reo. 1970,70 561. 34 G. A. Olah D. P. Kelly and N. Sucin J. Amer. Chem. Soc. 1970,92,3133. 35 V. P. Vitullo and N. Grossman Tetrahedron Letters 1970 1559. Reaction Mechanisms-Part (i) 67 of the activity coefficient ratio fsH+/f+ for this step suggests that the transition state is less solvated than the ground state by one water 2,6-Di-t-butyl-4-methyl-4-(1-phenylethy1)cyclohexadien-1-one does not undergo a typical dienonephenol rearrangement in acid solution but hydrolyses by a unimolecular solvol ysis to form 2,6-di-t-bu tyl-4-methylphenol. The hydrolysis of vinyl acetate can proceed either by attack of water on the protonated carbonyl carbon atom as for saturated esters or by an A-S,2 mechan-ism involving protonation of the double bond (Scheme 2).In 6% H2S04 the 0 0 II + It CH,=CH.OC.Me + H+'2CH,CH.O-C.Me 0 0 + II II CH,-CH.OC.Me+ H,O -* CH,$H.O.C.Me 1 +OH* + I1 CH,.CHO + CH3-C02H+ H+ +-CH,CH.O-C.Me II OH H Scheme 2 A-S,2 mechanism accounts for less than 0.5% of the rate for vinyl acetate and about 20% of the rate for isopropenyl acetate.38 At higher acidities however this mechanism becomes increasingly more important. The studies of substituent effects on the hydrolysis of ring-substituted a-acetoxystyrenes reported earlier39 have been extended to an investigation of steric effects in the hydrolysis df both cis-and trans-acet~xystilbene.~' Studies of the acid-catalysed hydrolysis of cyclic vinyl esters"' and the alcoholysis of isobutylene oxide4' have also been reported.The rate-determining step in the decarboxylation of 2,4-dihydroxybenzoic acid changes with increase in acidity over the range 0.1-8 N aqueous HCl from a slow proton transfer to a rate-limiting cleavage of the carbonxarbon bond.43 The kinetics of the decarboxylation in dioxan-water of some substituted benzoyl- acetic acids have also been in~estigated.~~ A study of the decarboxylation of the 2-cyano-2-phenylacetate ion in water aqueous ethanol and aqueous dioxan has been made so as to elucidate the mode of action of cycloamyloses as model cata- lyst systems in decarb~xylation.~~ The results suggest that the rate acceleration observed is due solely to a change in polarity of the local environment when the substrate complexes with the amylose and that catalysis is not due to interaction 36 V.P. Vitullo Chem. Comm. 1970 688. 37 K. Okarnoto I. Nitta and H. Shinga Bull. Chem. SOC.Japan 1970,43 1768. " D. S. Noyce and R. M. Pollack J. Amer. Chem. SOC.,1969 91 7158. '' D. S. Noyce and R. M. Pollack J. Amer. Chem. SOC.,1969,91 119. D. S. Noyce and A. M. Myers J. Org. Chem. 1970,35,2460. " L. H. Branningen and D. S. Tarbell J. Org. Chern. 1970,35 639. S. Sekiguchi K. Matsui and Y. Yasuraoka Bull. Chem. SOC.Japan 1970,43,2523. " A. V. Willi M. H. Cho and C. M. Won Helv. Chim. Arta 1970 53 663. '* R. W. Hay and K. R. Tate Ausrral. J. Chem. 1970 23 140. 45 A. Thomson J. Chem. SOC.(B) 1970 1198.J. G. Tillett with the hydroxy-groups on the outside of the cycloamylose. The spontaneous decarboxylation of the benzisoxazole-3-carboxylateion (Scheme 3) increases markedly as the solvent is changed from water to less polar and especially aprotic solvents because of the different solvation requirements for the initial state (6) with its localised charge and the transition state (7) with its more delocalised Scheme 3 charge.46 The effect of cetyltrimethylammonium bromide micelles on this reac- tion is consistent with the concept that micelles catalyse reactions by changing the microscopic en~ironment.~’ A comprehensive review of micellar catalysis in organic reactions has recently been published.48 A careful study of carbon and oxygen isotope effects on the decarbonylation of benzoylformic acid combined with a detailed kinetic analysis of the steps involved shows that the rate-limiting step in >99 % H,S04 is carbon4xygen bond fission49 and confirms the mechan- ism originally proposed by Hammett.” The rates of the acid-catalysed hydrolysis of a series of benzylidene diacetates were found to correlate with Ho,and to give Bunnett w values consistent with an A1 mechani~m.’~ Furthermore the correlation of rate with c’ and the low 0 II ,o.Co.Me -Hi /o-c.Me APCH -ArCH \ \ OCO.Me 0-C-Me II ‘OH I OH Y J \ArCHO + 2MeC0,H Scheme 4 46 D.S. Kemp and K. Paul J. Amer. Chem. SOC.,1970,92,2553. 47 C. A. Bunton and M. J. Muich. Tetrahedron Letters 1970.3881. *‘ E. J. Fendler and J. H. Fendler Ado. Phys. Org. Chem. ed. Gold 1970 8 271. 49 Z. Margoliu and D. Samuel Chem. Comm. 1970 802. 50 L. P. Hammett ‘Physical Organic Chemistry’ McGraw Hill New York 1940 283. M. J. Gregory J. Chem. Soc. (B) 1970 1201. React ion M echanisms-Part (i) 69 values of AS‘ obtained led to the formulation of this reaction in terms of a cyclic AA,t mechanism (Scheme 4). N.m.r. data for the acid-catalysed [2H,]ethanolysis of alkyl orthoacetates is consistent with the formation of a keten dialkylacetal from the intermediate carboxonium ion by elimination of a proton.52 Lahti and KanKaanpera have reported further studies of the hydrolysis of ethyl orthoformate in aqueous dioxan which confirm their earlier assignment of an A1 mechanism to this rea~tion.’~ The Finnish workers have also discussed the use of solvent effects to distinguish between the A-S,2 and A2 mechanisms of orthoester hydrolysi~.’~ Concurrent but not concerted catalysis by acidic and basic buffers has been found for the lactonisation of a series of /?/?-dimethyl(2-hydroxy-5-substituted)-hydrocinnamic acids.” Although the kinetic effects isotope effects and ASf values do not distinguish between rate-determining formation or breakdown of the tetrahedral intermediate the p values are considered to support the later mechanism which can be catalysed by general acid and water (8) or general base and water (9).The lactonisation of some substituted o-hydroxymethylbenzoic (3 P H-A H rH-OH -& 1 H-X X (8) (9) acids and 8-hydroxymethyl-1-naphthoic and electrostatic participation by carboxylate groups in the formation of lactone?’ have also been investigated.Topping and Burrows have now published a full account of their investigation of base-catalysed intramolecular nucleophilic catalysis by a keto-group in 2-acetylphenyl mesitoate.’8 The Sussex workers have also been reported on neighbouring carboxy-group catalysis in 2-carboxyphenyl me~itoate.’~ The results obtained illustrate the importance of steric effects in determining which of the kinetically indistinguishable mechanisms -general-base catalysis or nucleo- philic catalysis -actually occurs. The products resulting from treatment of the ester with tris(hydroxymethy1)aminomethane in anhydrous methanol were mesitoic acid and methyl salicylate in quantitative yield.These must arise from 52 L. R. Schroeder J. Chem. SOC.(B). 1970 1789. 53 M. Lahti and A. KanKaanpera Acta Chem. Scand. 1970,24 706. 54 M. Lahti and A. KanKaanpera Acta Chem. Scand. 1970 24 360. 55 S. Milstein and L. A. Cohen J. Amer. Chem. SOC.,1970 92 4377. 56 D. P. Weeks and X. Creary J. Amer. Chem. SOC.,1970 92 3418. 5’ F. G. Bordwell and A. C. Knipe J. Org. Chem. 1970 35 2956 2959. H. D. Burrows and R. M. Topping J. Chem. Sac. (B) 1970 1323. ’’ H. D. Burrows and R. M. Topping Chem. Comm. 1970 1389. J. G.Tillett intramolecular nucleophilic attack of the carboxylate anion to form an anhydride intermediate (Scheme 5). Methyl mesitoate and salicylic acid which could arise -0 (Mes = 2,4,6-trirnethylphenyl) Scheme 5 only from the carboxy-group acting as either an intramolecular general-base or acid (Scheme 6),or from intermolecular attack of alkoxide ion on the ester could not be detected Thus the general-base mechanism which is now considered to /p H L-0-c \0-c $0 NO 1 J Q0I-I + MesC0,R C0,- Scheme 6 occur exclusively in the solvolysis of aspirin is entirely suppressed when the carboxy-group is sterically hindered and it is replaced by a nucleophilic catalysis mechanism.The hydrolysis of para-substituted phenyl hydrogen succinates in the pH range below 2 proceeds by an A,,2 me~hanism.~'The constant value of the rate of hydrolysis over the range pH 5.8-7 is attributed to nucleophilic attack by the carboxy-group leading to succinic anhydride formation.In an 6o F. G. Baddow S. A. Wahhab B. M. Awad N. M. Guindy M. Wahba and B. A. Malek J. Chem. SOC.(B) 1970 739. Reaction Mechanisms-Part (i) 71 attempt to investigate further the importance of proximity effects in enzymic catalysis Bruice and Turner have studied the rates of bimolecular attack of acetate ion on substituted phenyl acetates and of intramolecular attack by carboxyl anion on some phenyl succinates phthalates and 3,6-endoxo-A4-tetrahydrophth-alate.6 It was concluded that carboxy-group solvation cannot contribute significantly to the large values of kintra/kinter often obtained when covalently rigid intramolecular models are considered. Another illustration of the influence of steric effects on neighbouring-group participation is shown in the alkaline Intramolecular hydrolysis of methyl 8-acyl- and 8-ar0yl-l-naphthoates.~~ catalysis by the neighbouring carbonyl group occurs for the 8-formyl and 8-(3’-and 4’-substituted benzoyl) esters (Scheme 7) whereas the 8-acetyl 8-propionyl OH I R-C-0-C02Me + OH-1 fast + MeOH t + MeO-(R = H or XC,H,.) Scheme 7 and 8-isobutyryl esters undergo catalysis by the strongly nucleophilic carbon acid anion (Scheme 8).Aniline trapping experiments have confirmed the forma- tion of N-acetylimidazole in the imidazole-catalysed hydrolysis of aryl acetates with both good and poor leaving groups.63 Kinetic studies of naphthylimidazole- catalysed hydrolysis of phenyl esters have also been Menger has reported detailed studies of the imidazole-catalysed hydrolysis of p-nitrophenyl laurate at a heptane-water boundary.65 A determination of the Arrhenius parameters for the alkaline hydrolysis of some aromatic cyclic and open-chain carbonates shows that the kinetic accelera- tion observed is due to a combination of both enthalpy strain and entropy b’ T.C. Bruice and A. Turner J. Amer. Chem. SOC.,1970,92 3422. 62 K. Bowden and A. M. Last Chem. Comm. 1970 1315. 63 D. G. Oakenfull J. Chem. SOC.(B) 1970 197. 64 T. Kunitake S. Shinkai and C. Aso Bull. Chem. SOC.Japan 1970,43 1109; T. Kuni-take and S. Shinkai ibid. p. 2581. b5 F. M. Menger J. Amer. Chem. SOC.,1970,92 5965. J. G.Tillett H I R1-C-CO C02Me Rl-E-CO COzMe I + OH-* + H2O '2w 1 R2 /R' /c\ o=c c=o 1 H I R'-C-CO CO2-I R2M + MeOH +H20 + MeOH strain.66 The imidazole-catalysed hydrolysis of bis(4-nitrophenyl) carbonate proceeds by a nucleophilic catalysis mechanism whilst the corresponding hydroly- sis of 0-(4-nitrophenylene) carbonate is general-base-catalysed ( Studies of (10) the alkaline hydrolysis of dihydrouracils,68 some xanthine complexes of acetoxy-cinnamic acids6' and of polynuclear methyl /3-arylacrylate~,'~ and of the mer- cury(I1)-catalysed hydrolysis of isopropenyl acetate7 and some thiol esters and related compounds72 have been reported. " J. G. Tillett and D. E. Wiggins J. Chem. SOC.(B) 1970 1359. 67 T. H.Fife and D. M. McMahon J. Org. Chem. 1970,35 3699. 68 I. Blagoeva B. J. Kurtev and I. G. Pojarlieff J. Chem. SOC.(B) 1970 232. 69 H. Stelmach and K. A. Connors J. Amer. Chem. SOC.,1970,92,863. '' M. K. Hoffman and E. Berliner J. Org. Chem. 1970 35 745. '' J. E. Byrd and J. Halpern Chem. Comm. 1970 1332. D. P. N. Satchel1 and I. I. Secemski J. Chenz. SOC.(B) 1970 1306. Reaction Mechanisms-Part (i) 73 The effects of substituents on the reaction of ortho-substituted phenylacetic acids with diazodiphenylmethane in various alcohols have been correlated in terms of polar and steric effects.73 Substituent effects on the alkaline hydrolysis of substituted benzoylcholine esters74 and of substituted pyridine carboxy- lates75-77 and the solvolysis of 1-arylethyl acetates78 have been analysed by the use of linear free-energy relationships.Shorter has given a concise review of the use of such relationships in the separation of polar steric and resonance effects in organic reaction^.^' General-acid catalysis of the hydrolysis of tropone diethyl ketal has been observed and a mechanism involving partial rate-determining protonation has been suggested (11).80 Thus if the intermediate carbonium ion is of sufficient A6-H (11) stability general-acid catalysis can be observed even with ketals of aliphatic alcohols where the leaving group is poor. The pH-independent mechanism of hydrolysis of 2-(pnitrophenoxy)tetrahydropyran is strongly accelerated by increase in solvent polarity has a deuterium kinetic solvent isotope effect of about unity and AS' is +2.2 e.u.and is therefore considered to involve uni- molecular decomposition to p-nitrophenoxide ion and the resonance stabilised carbonium ion (12).81 Solvent effect studies on the A1 hydrolyses of 2,2-dimethyl- and 2-isopropyl-2-methyl- 1,3-dioxolones and 2,2-dimethyl-4-hydroxymethyl-l,3-dioxolone have shown that activation parameters are affected by solvation of 7J N. B. Chapman J. R. Lee and J. Shorter J. Chem. SOC. (B) 1970,755. 74 J. J. Zimmerman and J. E. Goyan J. Medicin. Chem. 1970 13 492. 75 A. D. Campbell S. Y. Chooi L. W. Deady and R. A. Shanks J. Chem. SOC.(B),1970 1063. 76 A. D. Campbell E. Chan S. Y. Chooi L. W. Deady and R. A. Shanks J. Chem. SOC. (B),1970 1065. 77 A. D.Campbell E Chan S. Y.Chooi L. W. Deady and R. A. Shanks J. Chem. SOC. (B),1970 1068. '' E. A. Hill M. L. Gross M. Stasiewicz and M. Manion J. Amer. Chem.SOC.,1969,91 738 1. 79 J. Shorter Quart. Rev. 1970 24 433. E. Anderson and T. H. Fife J. Amer. Chem. SOC.,1969,91 7163. T. H. Fife and L. H. Brod J. Amer. Chem. Soc. 1970,92 1681. 74 J. G. Tillett both ground state and transition state.” Neighbouring carboxy-group catalysis has been observed in the general-acid-catalysed hydrolysis of methyl phenyl acetals of f~rmaldehyde.~~.~~ An electrostatically assisted mechanism is pre- ferred over the mechanistically indistinguishable general acid catalysis involv- ing essentially complete proton transfer in the transition state. The additional rate enhancement caused by a second ortho-carboxy-group has been investigated and the implications of the results on the mode of action of lysozyme are discussed.Bruice and his group have also shown by studies of the hydrolysis 1 HO OMe (13) of methyl-2,6-anhydro-a-~-altropyranoside (13) and related pyranosides that fixing the ground state of the C-2 C-1 0 C-5 region of the glycoside in a planar configuration does not change the mechanism from A1 to an A-S,2 pro~ess.~’ The hydrolyses of the isomeric 2,3-0O-benzylidene-norbornane-exo-2 exo-3-diols are thought to proceed through bimolecular attack of water on the conjugate acid of the cyclic acetal.86 The hydrolysis of 8-hydroxy- quinoline-/l-D-glucoside by Cu” ions has also been studied.” Secondary deuterium isotope effects show that whereas the transition states for the hydroly- sis of orthoesters resemble the substrate those for acetal hydrolysis resemble more the carbonium ion intermediate.88 It is of interest to note that the extent of proton transfer to the substrate in the transition state for orthoester hydrolysis as indicated by the Bronsted or-value does not parallel the extent of C-0 bond cleavage as indicated by the deuterium isotope effects.The acid-catalysed hydrolysis of a series of benzaldehyde methyl S-(substituted phenyl) thioacetals proceeds via the normal A1 mechanism of acetal hydr~lysis.~~ No general-acid catalysis could be detected. Further details of studies on the formation and breakdown of hemithioacetals for which a diffusion-controlled step becomes rate-determining have been described.” The products of the reaction of a series of para-substituted methyl orthobenzo- ates with substituted amines arise from partitioning of the carbonium ion derived from the orthoester between the amine and water.” (Scheme 9).The aminolysis 82 L. L. Schaleger and C. N.Richards J. Amer. Chem. SOC.,1970,92 5565. ’’ B. M. Dunn and T. C. Bruice J. Amer. Chem. SOC.,1970,92,2410. M4 B. M. Dunn and T. C. Bruice J. Amer. Chem. SOC.,1970,92,6589. 85 T. A. Gindici and T. C. Bruice Chem. Comm. 1970 690. 86 B. Capon and M. I. Page Chem. Comm. 1970 1443. ’’ C. R. Clark and R. W. Hay Chem. Comm. 1970,794. 88 H. Bull T. C. Pletcher and E. H. Cordes Chem. Comm. 1970 527. T. H. Fife and E.Anderson J. Amer. Chem. SOC.,1970 92 5464. 90 R. E. Barnett and W. P. Jencks J. Amer. Chem. SOC.,1969,91 6758. ” K. Koehler and E. H. Cordes J. Amer. Chem. SOC.,1970,92 1576. Reaction Mechanisms-Part (i) Adduct acid Scheme 9 of acetylimidazole by ethylenediamine shows a rate enhancement of more than lo3relative to glycine which is attributed to intramolecular general-base catalysis by the second amino-gr~up~~ (Scheme 10). There appears to be no significant rate enhancement however in the reaction of ethylenediamine with the acetylimida- zolium ion which has a better leaving group. Further studies of the base-catalysed Scheme 10 hydrolysis and aminolysis of some substituted phenyl acetates and propionates have been rep~rted.’~ The self-catalysed reaction of decylamine with p-nitro- phenyl acetate provides an example of an amine-catalysed aminolysis of an ester with an excellent leaving The nature of the transition state for aminolysis in aprotic solvents has also been disc~ssed.~~*~~ Jencks and his co-workers have examined the site at which proton transfer occurs in the general-acid-catalysed aminolyses of acetylimidazole by replacing the proton of the acetylimidazolium ion (AcImH) by a methyl group.97 No methylimidazole catalysis of the aminolysis of l-acetyl-3-methylimidazolium chloride (AcIm+Me) or of its aminolysis by ethylamine could be detected.This is consistent with a mechanism involving proton donation to the leaving group (Scheme 11)rather than proton removal from the attacking amine by general-base R’NHAc + ImH + Hh Scheme 11 ” W.P. Jencks and K. Salvesen Chem. Comm. 1970 548. y3 T. C. Bruice A. F. Hegarty S. M. Felton A. Donzel and N. G. Kundu J. Amer. Chem. SOC.,1970 92 1370. “ D. G. Oakenfull Chem. Comm. 1970 1655. ” F. M. Menger and J. H. Smith Tetrahedron Letters 1970 4163. 96 D. P. N. Satchel1 and I. I. Secemski J. Chem. SOC.(B) 1970 1013. ’’ W. P. Jencks D. G. Oakenfull and K. Salvesen J. Amer. Chem. SOC.,1970 92 3201. J. G. Tillett catalysis (Scheme 12). When the attacking amine is a weaker base than the leaving group however e.g. as in the imidazole-catalysed aminolysis of AcIm'Me by trifluoroethylamine proton transfer occurs at the other end of the system and the + B + R'NH,! + AcImR2 + BH' + R'NHAc + ImR2 Scheme 12 mechanism shown in Scheme 12operates.In such reactions therefore the proton transfer involves the less basic of the attacking or leaving groups. The general- acid- and -base-catalysed methoxylaminolysis of methyl thioformate proceeds via four different transition states one of which involves a diffusion-controlled proton tran~fer.'~ Robinson has published full details of his observation of a tetrahedral inter- mediate in amidine hydrolysisg9 and Jencks and Fersht on the formation and 0 0 II NH-C NH*C \ NHR CNHR 0 0 0 I H NR 0 0 H Scheme 13 (14) y8 G. M. Blackburn Chem. Comm. 1970,249. y9 D. R. Robinson J. Amer. Chem. Sor. 1970,92 3138. Reuction Mechanisms-Part (i) hydrolysis of the acetylpyridinium ion intermediate in the pyridine-catalysed hydrolysis of acetic anhydride.'" Structure-reactivity correlations have also been investigated for the reactions of a series of nucleophiles with substituted N- acetylpyridinium ions.As a model system for biotin action Hegarty and Bruice have studied the hydrolysis and aminolysis of 2-amino-4,5-dibenzo-6-oxo-l,3-oxazine." '*lO2 The mechanism of intramolecular nucleophilic attack by the ureido-group at the carbonyl carbon of esters and amides of o-ureidobenzoic acids have been investigated. O3 For o-(H,NCONH)C,H,COX three different reaction pathways could be delineated (Scheme 13); when X-is a strong base (0-,NH, NMe, OMe and OCH,CF,) reaction occurs through the ureido nitrogen anion to give the quinazoline (14),path (c); as the basicity decreases (e.g.with SMe,) reaction occurs increasingly through the oxygen anion to give the benzoxazine (15) path (b);for good leaving groups participation by the oxygen of the undissociated ureido-group again gives the benzoxazine (15) path (a). An oxygen- 18 tracer study of the hydrolysis of N-phenylmaleisoimide has confirmed that hydrolysis in acid solution involves attack at imino-nitrogen whereas in basic solution attack occurs at the carbonyl group'04 (Scheme 14). coo" 0 y C'*ONHPh CO + Hz"O N.Ph Scheme 14 The effects of substituents on the alcoholyses of some N-aroyl-N'-phenyldi- imides and N-benz~yl-N'-aryldi-imides'~~ and on the hydrolyses of substituted salicylideneanilines'06 have been examined.The rate of hydrolysis of N-iso- butylidenemethylamine varies in a complex manner with pH."' The rate constant increases at pH -= 0 where decomposition of the zwitterion Pr'-CH(0-)NH,Me is rate-controlling up to cu. pH 4.5,where it begins to level off as the attack of water on the iminium ion becomes rate-controlling. The rate then falls to a constant value about pH 8 where hydroxide ion attack predominates. The mechanism of formation of N-isobutylidenemethylamine from isobutyralde- hyde and methylamine was also studied."* looA. R. Fersht and W. P. Jencks J. Amer. Chem. SOC. 1970,92 5432 5442. lo' A. F. Hegarty and T. C. Bruice J. Amer. Chem. SOC.,1970 92 6568. lo* A. F. Hegarty and T. C. Bruice J. Amrr.Chrm. Soc. 1970 92 6561. lo' A. F. Hegarty and T. C. Bruice J. Amer. Chem. SOC.,1970,92 6575 lo4 C. K. Sauers Tetrahedron Letters 1970 1149. lo' T. Carty and J. M. Nicolson Tetrahedron Letters 1970 4158. Io6 J. Hoffmann J. Klienar V. Sterba and M. Vecera Coll. Czech. Chem. Comm. 1970 35 1387. J. Hine J. C. Craig J. G. Underwood and F. I. Via J. Amer. Chem. Soc. 1970,92 5194. 'On J. Hine F. A. Via J. K. Gotkis and J. C. Craig J. Amer. Chem. SOC. 1970 92 5186. J.G. Tillett The rate-determining step for the hydrolysis of acetophenone oxime in acidic solution is thought to be the general-base-catalysed loss of hydroxylamine from a tetrahedral intermediate"' (Scheme 15). A study of the rearrangement of ortho-substituted acetophenone oximes has established that an N-arylnitrilium ion (17) is an intermediate in the Beckman rearrangement in sulphuric acid' ( =-90 %) (Scheme 16).For those oximes which will rearrange in <70% H2SO4 or in Me -C -NHGy Me-C=NaY OH 'OH2 II I Scheme 16 HC104 the reactive species will be the 0-protonated oxime (16) and not the oxime-0-sulphonic acid. Enhanced reactivity of nucleophiles with lone pairs of electrons adjacent to the nucleophilic centre (the so-called 'a-effect') has been attributed to either (a) electron repulsion due to p,-p interaction or to (b)intramolecular catalysis.' For the reactions of p-nitrophenyl acetate with oximate anions in which a lone pair on oxygen is conjugated the former effect is ruled out and the observed rate enhancement must be due to intramolecular catalysis.The rate enhancements observed for the acylation of hydroxamic acids are also attributable to such 'OD B. J. Gregory and R. B. Moodie J. Chem. SOC.(B) 1970 862. 'lo B. J. Gregory R.B. Moodie and K. Schofield J. Chem. SOC.(B) 1970,338. '" J. D. Aubort and R. F. Hudson Chem. Comm. 1970 937. Reaction Mechanisms-Part (i) catalysis (Scheme 17).' The rate enhancement however for N-substituted hydroxamic acids which cannot tautomerise in this way can arise either from 0-I 0 R' H Scheme 17 intramolecular catalysis or from steric hindrance which removes the nitrogen from conjugation with the carbonyl group. An alternative explanation of the a-effect in terms of the theory of charge and frontier controlled reactions has been suggested.lI3 Studies of the acid-catalysed hydrolysis of acetamide l4 the Cu"-catalysed hydrolysis (and methanolysis) of NN-di-(2-pyridylmethyl)amides,' and the Co"'-catalysed hydrolysis of chelated glycine amides and esters' l6 have been reported.The 2-imino-A3- 1,3,4-oxadiazolines ( 18) hydrolyse readily in dilute acid to form azocarboxylic acid lactones (19) (Scheme 18).' '' The ring-opening (18) (19) (R' = R2 = Me; R' = Me R2= Et) Scheme 18 reactions of some model thiazolium ions have also been described."* The acid- catalysed ring-opening of 3-phenylsydnone and 3-m-nitrophenylsydnone are thought to proceed via a rapid protonation followed by nucleophilic attack by the anions of the acids involved.' l9 The acid-catalysed Wallach rearrangement of azoxybenzene (20) in sulphuric acid is considered to involve a rate-determining proton transfer concurrent with N-0 bond-fission (Scheme 19) rather than the formation of a dication."' Leverson and Thomas have shown that the entropies of activation for the acid-catalysed hydrolysis of o-diazoacetophenones in aqueous dioxan vary considerably with solvent composition and provide a 'I2 J.D. Aubort and R. F. Hudson Chem. Comm. 1970,938. I' G. Klopman K. Tsuda J. B. Louis and R. E. Davis Tetrahedron 1970 26 4549. M. M. Mhala and M. H. Jagdale Indian J. Chem. 1970 8 147. 'I5 R. P. Houghton and R. R. Puttner Chem. Comm. 1970 1270. 'I6 D. A. Buckingham C. E. Davis D. M. Foster and A. M. Sargeson J. Amer. Chem. SOC.,1970,92 5571.'I7 S. L. Lee G. B. Gubelt A. M. Cameron and J. Warkentin Chem. Comm. 1970 1074. P. Haake and J. M. Duebo Tetrahedron Letters 1970 461. 'I9 S.Aziz and J. G. Tillett J. Chem. Soc. (B) 1970 416. IZo E. Buncel and W. M. J. Strachan Canad. J. Chem. 1970,48 378. J. G. Tillett doubtful criterion of mechanism in this case.'" N.m.r. studies on primary diazoketones in superacid solutions show that 0-protonation occurs,122 rather 0-+ OH I +H,O I + Ph-N=N-Ph Ph-N=N-Ph -+ Ph-N-N-Ph + + I; OH.-H--A (20) 1 ++ products +-Ph-NrN-Ph Scheme 19 than as previously assumed at the a-carbon atom. The mechanism of the acid- catalysed rearrangement of N-chl~roacetanilide'~~ and of the nitramine re-arrangement'24 have been further investigated.Esters of Inorganic Oxy-Acids.-The mechanisms of hydrolysis of orthophos-phate esters have been reviewed by B~nt0n.l~~ The rates of the acid-catalysed hydrolysis of N-(p-nitropheny1)diphenylphosphinamide(21) correlate with H but with a low slope ( -O-5-0.6).'26 The correlation of log k for (21)with the pK,'s of anilinium ions and the observed deuterium solvent isotope effect suggests pro- tonation on nitrogen and an A1 mechanism (Scheme 20). That protonation occurs predominantly on nitrogen has been established for some phosphinamides by n.m.r. studies.'27 The hydrolysis of (21) has also drawn attention to a possible 0 0 II II + Ph-P-NHAr + H,O+ Ph-P-NH,Ar I Ph (21) -0 II 6+ 6+ products + Ph-P--NH,Ar I -Ph Scheme 20 anomaly in the use of the entropy of activation as a criterion of mechanism when protonation occurs on nitrogen.The observed value of AS' is -22 e.u. At first sight this is hardly consistent with an A1 mechanism. The observed entropy of activation is the sum of both the entropy change for the protonation step and of 12' C. W. Thomas and L. L. Leverson J. Chem. SOC.(B) 1970 1061. lz2 C. Wentrup and H. Dahn Helv. Chim. Acta 1970 53 1637. lZ3 A. H. El Nadi W. J. Hickinbottom and S. Wasif J. Chem. SOC.(B) 1970 I131 lz4 W. N. White C. Hathaway and D. Huston J. Org. Chem. 1970,35,737. lZ5 C. A. Bunton Accounts Chem. Res. 1970 3 257. lz6 P. Haake and D. A. Tyssee Tetrahedron Letters 1970 3513. P. Haake and T. Koizumi Tetrahedron Letters 1970 4849.Reaction M echanisms-Part (i) 81 the rate-determining step. Whereas the first term is likely to be small for oxygen bases which have only one acidic hydrogen to be solvated in the conjugate acid a value of -22e.u. was estimated for formation of (22) which has two acidic protons. Taking this into account the entropy change is now consistent with that expected for a unimolecular mechanism. The reactivity towards hydrolysis of the normally unreactive phosphate diester anion depends critically on the basicity of the leaving group and is much more sensitive to this than are the reactions of the corresponding monoanions of phosphate monoesters.'28 Thus the differences in reactivity between the two series of esters should disappear with a good leaving group having pK -2.The solvent isotope effect and entropy of activation are consistent with a simple bimolecular mechanism (Scheme 2 1) involving a pentaoxyphosphorane inter- mediate (cf:also ref. 129) although a concerted S,2(P) reaction is not ruled out. ArO 0 OAr +I HlO + \ P/*#< -H,O-P-OAr / \'.0 / \o-ArO -0 11 ArO 0 OAr \ /; 1 P;'-HO-P-OAr / \;.. + ArO-HO 0 HO/ '0-Scheme 21 The effect of varying both the nucleophile and leaving group on the reactivity of a series of aryl methyl phosphates in SN2(P)reactions has been compared with displacement of the same anion from a triester and from the dianion of a mono-ester.'30 The rate retardation observed (ca. 100 times) for the attack of anionic nucleophiles on phosphate diester monoanions is attributed to electrostatic repulsion between the anion and nucleophile.The attack of neutral nucleophiles is slower than the corresponding reactions of either of the other phosphate esters. This is considered to arise from the S,l(P)-like or borderline character of the transition state for displacements at the phosphorus centre of phosphate dianions XP0,2-with good leaving groups (e.g. X = p-NO,.C,H,.). The transition states are dominated by the bond-breaking process with only a small amount of bond-formation. Evidence for an S,l(P) mechanism has also been found in the formation of six-membered cyclic phosphonates.' Neighbouring carboxy-group catalysis has been observed in the hydrolysis of the 2-carboxyphenyl anion (23).'32 The rate enhancement of 107-108 is 12' A.J. Kirbyand M. Yournas J. Chem. SOC.(B) 1970 510. 129 C. A Bunton and S. J. Farber J. Org. Chem. 1970 34 769. 130 A. J. Kirby and M. Yournas J. Chem. SOC.(B) 1970 1165. j3' W. Wadsworth and H. Horton J. Amer. Chem. SOC.,1970,92 3785. 132 S. A. Khan A. J. Kirby M. Wakselsman D. P. Homing and J. M. Lawlor J. Chem. SOC.(B),1970 1182. J. G. Tillett attributed to intramolecular nucleophilic catalysis (Scheme 22) in which both the appearance and disappearance of the salicyclic acid cyclic phosphate intermediate (24) have been observed spectroscopically. The specific displacement of phen- oxide ion at the expense of salicylate ion despite their similar leaving-group qp 0 0,II r0At 0,II 0-0opo:-0 qi’+ I co-0-\ \ \ co2-0 0 (23) (24) Scheme 22 properties is explained in terms of the pseudorotation of quinquevalent phos- phorus intermediates.Thus. the intermediate involved (25) will have the two negatively charged oxygen atoms equatorial and the phenoxy-group apical correctly aligned as a leaving group. Pseudorotation of (25)to allow the salicylate OPh 0 (25) anion to leave from an apical position would also bring a negatively charged oxygen into an apical position giving an energetically unfavourable intermediate and only phenoxide ion is displaced. Phenyl cis-4-hydroxytetrahydrofuran 3-phosphate (26) has been studied as a model system for ribonuclease action.133 In morpholine or acetate buffers it reacts initially to give only the cyclic phosphate (27) and phenol.In the amine buffer specific-base catalysis amounts for 60 of the observed rate and general acid-base catalysis the remainder. Further confirmation has been obtained + PhO-0 00 00 OH 1; \/ -0’ \ RP\ OPh 0 0-(26) (27) Scheme 23 ”’ D. A. Usher D. I. Richardson and D. G. Oakenfull J. Amer. Chem. SOC.,1970 92 4699. Reaction Mechanisms-Part (i) that hydroxide ion catalysis involves a pre-equilibrium followed by an in-line' S,2(P) displacement of phenoxide ion by the neighbouring alkoxide group (Scheme 23). Neighbouring hydroxy-group catalysis in the hydrolysis of 3-hydroxy-2-pyridylmethyl phosphate has also been observed.' 34 The reactivi- ties of a wide range of nucleophiles towards phosphorus in a series of dialkyl substituted-phenyl phosphite esters have been examined.' 35 General-base catalysis of hydrolysis is the narmal mechanism for catalysis when the catalysing 0 .-H,O H-0 I-OAr I /\ H RO.'OR (28) base is much less basic than the leaving group (28). With strongly basic nucleo- philes however the mechanism changes to nucleophilic catalysis (Scheme 24). RO 0-\p//o -I Y-+ -YIP-OAr '\ RO' 'OAr RON OR * (RO),P(O)Y + ArO-Scheme 24 Structure-activity correlations for the cholinesterase inhibition of diethyl substituted-phenyl phosphates' 36 and studies of the hydrolysis of trimethyl phosphate in DMSO-H,O and ethylene glycol-H,O mixtures'37 have been reported. The hydrolysis of ethyl P-hydroxy-trans-cinnamic acid cyclic phosphate (29) is catalysed by hydroxide ion hydrogen ions and by general bases.'38 The most likely mechanism for the latter mechanism involves the formation of a tetrahedral intermediate (30) (Scheme 25).It is interesting to note that nucleo- philic attack does not occur at the phosphorus atom of (301 in contrast to the reported reactions of the corresponding five-membered cyclic ester. Further studies of the effects of micellar catalysis on the hydrolysis of phosphate esters by Bunton and his and a detailed re-investigation of the hydrolysis of acetyl phosphate catalysed by various uni-and bi-valent have also been reported. The reactions of phenyl methylphosphonic acid and p-nitrophenyl methylphosphonic acid and their anions with nucleophiles have been '34 Y.Murakami J. Sunamoto and H. Ishiza Chem. Comm. 1970 1665. S. A. Khan and A. J. Kirby J. Chern. SOC.(B) 1970 1172. S. Hausch J. Org. Chem. 1970 35 620. 13' P. T. McTigue and P. V. Renowden Austral. J. Chem. 1970 23 297. 13' J. F. Merecek and D. L. Griffith J. Amer. Chem. Sac. 1970,92,917. 139 G. J. Buist C. A. Bunton L. Robinson L. Sepuiveda and M. Stam J. Amer. Chem. Sac. 1970 92 4072. I4O C. A. Bunton L. Robinson and L. Sepulveda J. Org. Chem. 1970,35 1081. I" P. J. Briggs D. P. N. Satchell and G. F. White J. Chem. SOC.(B) 1970 1008. J. G. Tillett H H (30) Ph-C+ C-COZH I Scheme 25 H ~tudied.'~~,'~~ Peroxide and hydroxamate ions show a large a-effect for this reaction with p-nitrophenyl methylphosphonate anion.'43 The reaction of this anion with most amines proceeds via an SN2(P)mechanism with attack at phos- phor~~.~~~ With piperidine however approximately 35 "/ of the total reaction 0 A 0 0-= occurs at aromatic carbon (Scheme 26) with the formation of 1-(p-nitropheny1)-piperidine.Neighbouring oxime group participation facilitates the acid-catalysed hydrolysis of alkyl a-hydroxyimino-p-nitrobenzylalkylpho~phonates'~~ (Scheme 27). R' I 0% /0!- 0 P --H R( I 1-\\/OH + R'.OH O\ /Od-R2' 'O-C=NOH C=N I I Ar Ar (Ar = p-N02C,H,. R' = Bu'CHMe R2 = Me) Scheme 27 '42 E. J. Behoman M.J. Biallis H. J. Brass J. 0.Edwards and M. Isaks J. Org. Chem. 1970 35 3063. 14' E. J. Behoman M. J. Biallis H. J. Brass J.0.Edwards and M. Isaks J. Org. Chem. 1970,35 3069. 144 H. J. Brass J. 0. Edwards and M. J. Biallis J. Org. Chem. 1970,35 4675. 14' J. I. G. Cadogan and D. T. Eastlick Chem. Comm. 1970 1546. Reaction Mechanisms-Part (i) 85 Mislow has given a general review of the r61e of pseudorotation in the stereo- chemistry of nucleophilic displacement rea~ti0ns.I~~ Haake and his group have recently shown that both the chloride (31 ;X = C1) and the amide (3 1 ;X = NMe,) are hydrolysed much more slowly than the corresponding acyclic compounds (32 ; X = C1 NMe,) whereas for the corresponding esters (31 32; X = OEt) the reverse is the case.I4' It was suggested that this rate inhibition could be used as a Me H Me Me Me*Me Me4 )-Me Me p Me P \ \ X X mechanistic probe to determine the mechanism of reaction at phosphorus.Thus the more rapid hydrolysis of the phosphetan ester was ascribed to relief of ring strain on forming an intermediate in which the four-membered ring spans an apical-equatorial position. On the other hand the slower rate of reaction of the four-membered ring indicates increased strain in the transition state which requires entering and leaving groups co-linear with phosphorus and suggests an SN2(P)mechanism. Trippett and his co-workers however have criticised this criterion and have proposed that all displacements at phosphorus in a four- membered ring proceed via a trigonal-bipyramidal intermediate in which the ring spans apical-equatorial positions and that the rate of reaction depends critically on the electroneghivity of the leaving Substitution at the phosphetanium ring is accelerated by relief of strain in (33) but is retarded because only one electro-negative group occupies an apical position compared with two groups occupying such a position in the corresponding intermediate for an acyclic compound.The more electronegative groups are usually better leaving 14' 'JI Scheme 28 K. Mislow Accounts. Chem. Res. 1970 3 321. 14' P. Haake R. D. Cook T. Koizumi P. S. Ossip W. Schwarz and D. A. Tyssee J. Amer. Chem. SOC.,1970,92 3828. '" J. R. Corfield N. J. De'ath. and S. Trippett Chem. Comm. 1970 1502. J. G.Tillett groups and the greater will be this retardation for X = C1 or &Me,. Such a theory also explains the observed stereochemical changes.When X is highly electronegative the preferred pseudorotation will be (33) *(34) resulting in retention of configuration whilst if X and R have comparable electronegativities (33) -P (35) is energetically favourable and inversion of configuration occurs (Scheme 28). Retention of configuration at a phosphoryl centre in the reaction of methoxide ion with the trans-cyclic phosphinate ester (36) is attributed to attack of MeO- along an apical co-ordinate to give the intermediate (37) which pseudorotates about 0-as a pivot group to give (38).14’ Displacement of CD,O-from an apical position in (38) which is required by the principle of microscopic reversibility leads to the trans product (Scheme 29). The alkaline (37) Scheme 29 hydrolysis of cis-and trans-1,4-dibenzyl- 1,4-diphenyl- 1,4-diphosphoniacyclo- hexane dibromide,’ of some tris-(2-thienyl)phosphonium salts,’’’ and of cis-and trans- l-benzyl-4-methyl- l-phenylphosphorinanium bromide’ 52 have been studied.The nucleophilic ring-opening of cyclic OS-ethylene phosphorothioate derivatives (39) proceeds with P-0 bond-fission* 53 whereas the reactions of the corresponding acyclic 0sesters and of OS-ethylene O-methyl phosphorothioate (39) (40) (40)involve P-S bond-fission.154 Initial attack is considered to involve the for- mation of (41 ;R = OMe) where the more electronegative oxygen atom occupies 149 S. E. Cremer and B. C. Trivedi J. Amer. Chem. SOC.,1969 91 7200. G. E. Driver and M. J. Gallagher Chem.Comm. 1970 150. 15’ D. W. Allen J. Chem. SOC.(B) 1970 1490. ls2 K. L. Marsi and R. T. Clark J. Amer. Chem. SOC.,1970,92 3791. 153 D. C. Gay and N. K. Hamer J. Chem. SOC.(E) 1970 1123. Is4 D. C. Gay and N. K. Hamer J. Chenr. SOC.(B) 1970 1564. Reaction Mechanisms-Part (i) 87 an apical position even though the thiolate is a better leaving group (Scheme 30). The pseudorotation (41)-+(42) is more favourable for R = OMe than for 0-and leads to P-S bond-fission. Kinetic solvent isotope effects in the alkaline hydrolysis of phosphonium salts suggest that in the transition state very little P-C bond-breaking has occurred and only a small degree of proton transfer to the incipient carbanion. The considerable energy barrier to pseudorotation if 0-is not the pivot atom is used to explain that the lack of oxyen-18 exchange in the hydrolysis of phosphine oxides with a benzyl leaving group does not neces- sarily exclude the formation of a quinquecovalent intermediate.' 56 Reviews have been published of the acid-base-catalysed hydrolysis of organic sulphites'" and of the enzymatic and non-enzymatic reactions of cyclic sulphate and sulphonate esters.' 58 Neighbouring imidazoyl group catalysis in the hydroly- sis of 2-[4(5)-imidazoyllphenyl sulphate (43) is considered to involve mainly intramolecular general-acid catalysis (Scheme 31).' 59 Micellar effects on the " " I H I H IH (43) Scheme 31 hydrolysis of 2,4-dinitrophenyl sulphate have also been reported.160 The entropy of activation and kinetic solvent isotope effect for the hydrolysis of the phenyl phosphosulphate monoanion are consistent with an A 1 mechanism involving uni- molecular elimination of sulphur trioxide.' The reaction of p-nitrophenyl sulphate with thiophenol in aqueous DMF is also considered to follow a similar mechanism (Scheme 32).16' 0-Sulphobenzoic anhydride hydrolyses more rapidly (X = H Br Me or MeO) Scheme 32 155 J.R. Corfield and S. Trippett Chetm Comm. 1970 1267. 56 P. Haake and G. W. Allen Tetrahedron Letters 1970 31 13. 15' J. G. Tillett Mech. React. Sulfur Compounds 1969 4 129. IS' E. T. Kaiser Accounts Chem. Res. 1968 3 145. '59 S. J. Benkovic and L. K. Dunikoski Biochemistry 1970,9 1390. 16* E. J. Fendler R. R. Liechte and J. H. Fendler J.Org. Chem. 1970 35 1658. "' S. J. Benkovic and R. C. Hevey J. Amer. Chem. Soc. 1970 92,4971. 16' T. Kuroso W. Tagaki and S. Oae Bull. Chem. SOC.Japan 1970,43 1553. 88 J. G. Tillett under neutral conditions than either the corresponding carboxylic anhydrides or sulphonyl halides.' Unlike the hydrolysis of carboxylic anhydrides no evidence of acid catalysis could be found. Further details of the reactions of anhydrosul-phites (mixed carboxylic-sulphurous anhydrides) have been published by Tighe and his group. 16&' 66 Sulphonyl fluorides are usually unreactive towards hydrolysis under acidic or neutral conditions. The relatively rapid hydrolysis of o-acetamidobenzenesulphonyl fluoride suggests neighbouring-group catalysis by the acetamido-group (Scheme 33).16' The reactions of benzenesulphonyl chloride Me Me I I Scheme 33 with aniline azide imidazole and fluoride lead to stable product^.'^^^^^^ The hydrolysis reaction is catalysed by other nucleophiles such as pyridine and acetate and is considered to proceed via a similar nucleophilic catalysis mechanism although no evidence of intermediates was obtained.A comparison of Brransted slopes for nucleophilic attack by amines at saturated carbon sulphonyl sulphur and carbonyl carbon indicates that sulphonyl sulphur is midway in hardness (in the sense of hard and soft acids and bases) between the other two centres. The hydrolysis of aryl or-disulphones in aqueous dioxan is catalysed by added nucleophiles such as F-or AcO- via a nucleophilic catalysis mechanism (Scheme HzoP' ArS0,H + H++ Nu-Scheme 34 16' R.M. Laird and M. J. Spence J. Chem. SOC.(B) 1970 388. 164 M. D. Thomas and B. J. Tighe J. Chem. SOC.(B) 1970 1039. 165 D. J. Fenn M. D. Thomas and B. J. Tighe J. Chem. SOC.(B) 1970 1044. 166 B. W. Evans D. J. Fenn and B. J. Tighe J. Chem. SOC.(B) 1970 1049. 167 M. E. Aberlin and C. A. Bunton J. Org. Chem. 1970 35 1825. 168 0.Rogne J. Chem. SOC.(B) 1970 727. 169 0. Rogne J. Chem. SOC.(B) 1970 1056. Reaction Mechanisms-Part (i) 89 34). 70 With primary and secondary amines the intermediate (44)formed does not react further and can be isolated. Kice and Kasperek have now shown that the major effect of added tertiary amines on the hydrolysis of disulphones arises from general-base catalysis (Scheme 35) -nucleophilic catalysis being reduced to a minimum because of steric hindran~e.'~' The effect of the basicity of entering 00 0 I1 II Et3N + H-0 + Ar-S-S-ArII -+Et3NH+ + Ar.S-OH + ArS02-II II II HI 00 0 Scheme 35 and leaving groups on nucleophilic substitution at bivalent sulphur in p-substi- tuted phenyl sulphenate esters favours a loose S,2 transition state in which bond- breaking is far more advanced than bond-formation.' 72 The base-catalysed hydrolysis of some 2-nitrobenzenesulphenate esters has also been studied.'73 + Ph-S-S-Ph + H+ Ph-S-S-Ph II I l80 180H + k* 18 NU-+ Ph-S-S-Ph GPh.S*Nu+ Ph.S.OH 1 k-2 "OH Ph?3.1sOH + H+ + Nu-kSPhSNu + H2180 Ph.S.Nu + Ph-SOH kif Nu-+ Ph-S-6-Ph I 11 OH NU-+ Ph-S-S-Ph + H+ II 0 (NU= Bu",S) Scheme 36 The mechanisms of oxygen exchange reactions of sulphoxides have been reviewed.'74 The acid- and nucleophile-catalysed oxygen-exchange of phenyl benzenethiolsulphinate proceeds in a multi-stage process (Scheme 36).The fact that benzenesulphenic acid is more than lo5times more reactive as a nucleo- + phile towards Ph-S-S-Bun than is water (i.e. k-,/k- > 10') provides an explanation of why thiolsulphinates are usually the first isolable products of the hydrolysis of reactive sulphenyl derivatives in water."' As soon as any benzene- 170 J. L. Kice G. J. Kasparet and D. Patterson J. Amer. Chem. SOC.,1969,91 5516. 17' J. L. Kice and G. J. Kasparet J. Amer. Chem. SOC.,1970 92 3393.L. Senatore E. Ciuffarin and A. Fava J. Amer. Chem. SOC.,1970,92 3035. D. R. Hogg and P. W. Vipond J. Chem. SOC.(B) 1970 1242. 174 S. Oae Quart. Reports Sulfur Chem. 1970,5 53. J. L. Kice and J. P. Cleveland J. Amer. Chem. SOC.,1970 92 4757. 90 J. G.Tillett sulphenic acid is formed by hydrolysis of PhSNu it reacts with some of the remaining PhSNu faster than the latter hydrolyses. The nucleophile-catalysed racemisation of 2-methylsulphinyl benzoic acid has also been examined.' 76 The hydrolysis reactions of nitrate esters have also been covered in a recent review.'77 3 Electrophilic Aromatic Substitution Several MO studies of substitution effects on aromatic substitution have been reported.' 78-1 81 Reviews of the r81e of n-complexes as reaction intermediatesand of the effect of substituents on n-electron systems have been published by Ban- thorpe' 82 and by Katritzky and Topsom,' 83 respectively.Whereas the nitrations of many aromatic compounds by anhydrous nitric acid in carbon tetrachloride are zeroth-order in aromatic substrate the nitration reactions of mesitylene and p-xylene are sixth-order in nitric acid and the reaction rate has a negative temperature ~0efficient.l~~ The high order in nitric acid is attributed to the r81e of nitric acid as a solvating agent in non-polar media. The rates of nitration in sulphuric acid and perchloric acid of polyhalogenobenzenes deviate considerably from the additivity principle and have been discussed in terms of MO theory and a simple electrostatic t~eatment.'~' The distribution of products in the nitration of substituted benzo[b]thiophen derivatives has been st~died.'~~,'~' The high percentage of dinitrobibenzyl found in the nitronium tetrafluoroborate nitration of bibenzyl in sulpholan has been shown to arise from reaction occurring during the mixing procedure.'88 Ridd and his group have also shown that one of the consequences of such behaviour is that competi- tive nitration of similar aromatic substrates under these conditions should give apparent relative reactivities near unity and does not therefore provide a proper measure of the selectivity of the nitronium ion towards different substrates.3-Hydroxy- and 3-methoxy-pyridine undergo nitration through their conjugate acids at the 2-position whereas nitration of reactive pyridones proceeds through the free base form.'89 Furthermore the latter substrates react at or near the encounter rate under the conditions used.S. Allenmark and C. E. Hagberg Acra Chrm. Scund. 1970 24 2225. N. W. Connon Eastman Org. Chem. Bull. (Eastman Kodak Co.) 1970,42 No. 2. A. Streitwieser P. C. Mowery R. G. Jesaitis and A. Lewis J. Amer. Chem. SOC., 1970 92 6529. 179 G. R.Howe Chem. Comm. 1970 868. 0. Chalvet R. Daudel and T. F. McKelIop Tetrahedron 1970 26 349. W. T. Dixon J. Chem. SOC.(B) 1970 612. IR2D.V. Banthorpe Chem. Rev. 1970 70 295. A. R. Katritzky and R. D. Topsom Angew. Chem. Internrij. Edn. 1970. 9 87. IB4 T. G. Bonner R. A. Jancock F. R. Rolle and G. Yousif J.Chem. SOC.(B) 1970,314. lE5R. G. Coombes D. H. G. Grant J. G. Hoggett R. B. Moodie and K. Schofield J. Chem. SOC.(B) 1970 347. J. Cooper D. F. Ewing R. M. Scrowston and R. Westwood J. Chem. SOC.(0,1970 1949. 187 G. C. Brophy S. Sternhall N. M. Brown I. Brown K. I. Armstrong. and M. Marten- Smith J. Chem. SOC.(C),1970,933. P. F. Christy J. H. Ridd and N. D. Stears J. Chem. SOC.(B) 1970 797. A. R. Katritzky H. 0.Tarhan and S. Tarhan J. Chem. SOC.(B) 1970 114. Reaction Mechanisms-Part (i) Primary deuterium isotope effects for the nitrosation of a number of aromatic and hetero-aromatic compounds confirm that the rate-determining step involves decomposition of the Wheland intermediate (45) (Scheme 37).I9O N-Nitrosation H A NO NO Scheme 37 is known to be the rate-determining step at low acidities in the diazotisation of aromatic amines (Scheme 38).Further studies of the chloride-ion-catalysed ArNH -+Ar.NH.NO -+ ArN=N.OH 1 Ar'N Scheme 38 diazotisation of toluidines suggest that the initial step approaches closely to a diffusion-controlled proce~s.'~' The kinetics of the diazo-coupling reactions of substituted benzenediazonium chlorides with a~etoacetanilide'~~ and of p- methoxyphenol with sulphanilic acid and p-nitroaniline' 93 have also been investigated. The rates of formation and decomposition of the a-complex intermediate in the diazo-coupling reactions of sulphanilic acid with some 8- substituted-2-naphthols have been determined.Ig4 The Hammett correlation between log k and a,fet,suggests that 8-substituents influence the rate offormation N.Ar N =N-Ar Scheme 39 I9O B.C. Challis R. J. Higgins and A. J. Lawson Chem. Comm. 1970 1223. 19' A. Aboul-Seoud and M. Ahmad Bull. SOC. chim. belges. 1970 79 53. 19* V. Machacek J. Panchartek V. Sterba and M. Vecera Coll. Czech. Chem. Comm. 1970 35 844. lg3 I. Dobis J. Panchartek V. Sterba and M. Vecera Coll. Czech. Chem. Comm. 1970,35 1288. F. Snyckers and H. Zollinger Helv. Chim. Acta 1970 53 1294. J. G. Tillett of the intermediate only by their electronic properties and not by their size and it also excludes steric destabilisation of the intermediate (i.e. k- insensitive to steric bulk) (Scheme 39). The steric effect operates mainly on k and the depend- ence of kJk on a newly defined steric parameter suggests an asymmetrically shaped intermediate (47) with the sp3-hydrogen in a pseudo-equatorial position and the electrophile pseudo-axial.In this position steric interactions between the electrophile and the peri-substituent would be minimised. The diazo-coupling of 8-(2’-pyridyl)-2-naphthol provides an interesting example in which intermolec- ular base catalysis is excluded on steric grounds whilst the bulky group itself has a basic nitrogen site conveniently situated for intramolecular base catalysis [see (48)].1g5 It was also concluded that attack of the basic site on the leaving proton (47) (48) occurs before the electrophile swings into the plane of the naphthalene nucleus and that a linear a-complex-hydrogen-base transition state is not a necessary requirement for base catalysis.The additivity principle has been tested for the rates of bromination of mono-and di-methyl naphthalene^."^ The observed partial rate factors correlated better with approximate molecular orbital parameters derived from a transition- state model than from an isolated-molecule approach. The additivity principle has also been used to obtain indirect estimates of the partial rate factor meta to chlorine (fk’)for molecular chlorination in acetic acid by comparison of rates of chlorination of 2-chloroacetanilide with that of acetanilide. 97 Me 1 CH,Br Scheme 40 (49) ly5 F. Snyckers and H. Zollinger Tetrahedron Letters 1970 2759. L96 J. B. Kim C. Chen J.K. Krieger K. R. Judd C. C. Simpson and E. Berliner J. Amer. Chem. SOC.,I970,92,910. 19’ 0.M. H. el Dusouqui M. Hassan and 9. Ibrahim J. Chem. SOC.(B) 1970 2926. Reaction Mechanisms-Park (i) 93 The formation of 9-bromomethyl-2-methylanthracene (49) by bromination of 2,9-dimethylanthracene with bromine in carbon tetrachloride is considered to proceed uia a free-radical mechanism (Scheme 40)."* With rigorous exclusion of both light and oxygen however normal electrophilic substitution occurs and l0-bromo-2,9-dimethylanthracene (50) was formed exclusively (Scheme 41). mMe @Me H Br 1 Me Scheme 41 Bromodeacylation accompanying substitution previously only clearly established in the naphthalene series has now been observed in benzene derivative^.'^^ In the bromination of some 2,6-dialkylphenyl acetates in nitromethane a number of products are obtained (Scheme 42).The chlorination of adamantane by ferric 02CR2 02CR2 OH Br, ~10~1~ 1 0 + ~~11 0 ~ 1 MeNO \ \ \ 0,CR2 OH (R' = Me,Pr'; R2 = Me) Scheme 42 chloride and antimony pentachloride is thought to proceed uia a radical path- way.2oo Earlier reports that electrophilic substitution of 4-hydroxy-3,5,2',6'-tetramethyldiphenyl ether (51) occurs mainly in the 4'-position have been shown to be in Detailed spectroscopic identification of the product shows 19' J. Flood A. D. Mosnaim and D. C. Nonhebel Chem. Comm. 1970 761. 199 P. B. D. de la Mare and B. N. B. Harman Chem. Comm. 1970 156. P. Kovacic and J. H. Chen Chang Chem.Comm. 1970 1460. S. B. Hamilton and H. S. Blanchard J. Org. Chem. 1970,35 3341. 202 S. B. Hamilton and H. S. Blanchard J. Org. Chem. 1970,35 3348. J. G. Tillett it to be (52) (Scheme 43). The absence of the 4-product is attributed to the steric effect of the two methyl groups ortho to the aryl-ether linkage which push the MegMe MeQMe OH OH Br MeoMe I Br2 I 0 + 0 MeOMe ..bMe ring almost perpendicular to the non-bonding orbitals of oxygen and so prevent any conjugative activation of the 4'-position. The reversible bromination of p-bromophenols has also been in~estigated."~Another example of steric hindrance of conjugation of an aromatic ring with oxygen is found in the sulphuryl chloride chlorination of 2,6-disubstituted phenols for which the additivity principle breaks down.204 A study of the bromination and Friedel-Crafts acetylation of thioanisole has also been reported.205 A study of salt effects activation para-meters and isotope effects on electrophilic attack on the thiophen ring confirms that this follows the usual two-stage substitution mechanism.'06 The application of linear free-energy treatments to electrophilic substitution on the thiophen ring207*20' have been reported.and to the bromination of 2-aminopyridine~~~~ The iodination of acenaphthene and fluorene with iodine-paracetic acid gives 5-iodoacenaphthene and 2-iodofluorene. respectively.' lo Although the 2,7-di-iodofluorene could be obtained with excess of the reagents attempts to di-iodinate acenaphthene were unsuccessful.A solution of iodine in 20% oleum can be conveniently used to iodinate aromatic nitro-compounds although it will not replace a hydrogen atom ortho to a nitro-group.'ll The protonation of 9-ethyl-10-methylanthracene (53) in HF or CF3C02H-H,0-BF3 gives a mixture of the ions (54) and (55).212 The small difference in energy between these ions (0.9-1.0kcal mol-') suggests that contrary to conclusions based on calorimetric data there is no large Baker-Nathan effect in alkylarenium-ion formation. The rates of protodetritiation of a large number of polycyclic aromatic hydrocarbons in '03 E. J. O'Bara R. B. Balsley and I. Starer J. Org. Chem. 1970 35 16. '04 R. Bottom J. Chem. SOC.(B) 1970 1770. '"'S. Clementi and P. Linda Tetrahedron 1970 26 2869.206 A. R. Butler and J. B. Hendry J. Chem. SOC.(B) 1970 170. '07 A. R. Butler and J. B. Hendry J. Chem. SOC.(B) 1970 848. '08 S. Clementi P. Linda and G. Marino J. Chem. SOC.(B) 1970 1153. 'OY P. J. Brignell P. E. Jones and A. R. Katritzky J. Chem. SOC.(B) 1970 117. ''" Y.Ogata and I. Uraseki J. Chem. SOC.(C) 1970 1689. '" J. Arotsky R. Butler and A. C. Darby,J. Chem. Sac. (0,1970 1480. '" D. M. Brouwer and J. A. Van Doorn Rec. Trau. chim.,1970 89 88. Reaction Mechanisms-Part (i) CF,CO,H-HCIO and in CF,CO,H-CCl have been determined. ’ The rela- tive order of reactivity towards detritiation of the five non-equivalent positions in fluoranthene has been determined (3 > 8 > 1 > 7 > 2) and the results have been correlated with various theoretical reactivity parameter^.^'^ The acid- catalysed hydrogen exchange of phenalone is initiated by nucleophilic attack on its conjugate acid by a water molecule (Scheme 44).’15 A re-investigation of the D Scheme 44 acid-catalysed detritiation of 1,3,5-trirnethoxyben~ene[2-~H] confirms the earlier value of a(0-56 & 0.03).,’‘ Correlations based on subsets of data however give rise to values ranging from 0-56-0.71 and suggest that the extent of proton trans- fer in the transition state may be a function of the type of catalyst (see also refer- ence 27).Protodetritiation studies of 2-and 3-tritiothiophen confirm that the mechanism of hydrogen-exchange in thiophen is similar to that in benzene com- pounds.” ’ Substituent effects on the para-substituted benzoylation of benzene in non- polar solvents such as ethylene chloride or tetrachloroethane correlate with the ’I3 A.Streitwieser,A. Lewis I. Schwager R. W. Fish and S. Labonn J. Amer. Chem. SOC. 1970,92,6525. ’I4 K. C. C. Bancroft and G. R. Howe J. Chem. SUC.(B),1970 1541. 2L5 A. A. El-Anani C. C. Greig and C. D. Johnson Chem. Cornm. 1970 1024. A. J. Kresge S. Slae and D. W. Taylor J. Amer. Chem. SOC.,1970,92,6309. *I7 A. R. Butler and J. B. Hendry J. Chem. SOC.(B) 1970 852. 96 J. G. Tillett Hammett equation whereas in nitrobenzene the correlation breaks down prob- ably as a result of complex formation between aluminium chloride and nitro- benzene.218 The relative reactivities of a variety of acylating agents towards benzene and mesitylene2 l9 and the reaction of acetic anhydride with 2-benzyl- pyridine and 2- and 4-picoline N-oxides have been studied.22o The Kostanecki- Robinson acylation reaction involves the formation of trans-enol esters as inter- mediates which subsequently cyclise to 4-~yrones.~~'-~~~ Olah and his co- workers have published a preliminary report of their studies on the titanium tetrachloride-catalysed benzylation of benzene and toluene with substituted benzyl chlorides which provides evidence that the position of the transition state in electrophilic substitution can be changed from a late one resembling the Wheland intermediate to an early one resembling the reactants by changing the electrophilicity of the reagent (by change of substituent in the reagent A photochemical counterpart of the Friedel-Crafts reaction has also been reported.22 The toluene-p-sulphonylationof halogenobenzenes occurs ex-clusively at para-positions but with toluene 13 % ortho- and 86.6 % para-isomers were obtained.226 The data so far obtained for arylsulphonoxylation of aromatic compounds are consistent with an ionic electrophilic substitution mechan- ism.227,228 This reagent provides an alternative to the Friedel-Crafts route for the synthesis of phenols.Further studies of the oxidation of dimethoxybenzenes with lead tetra-acetate show that whereas plumbylation is a typical electrophilic substitution acetoxylation is abnormal.229 4 Substituent Effects and Linear Free-energy Relationships This year many reports of correlations of substituent effects with linear free-energy relationships are included in other sections and are not repeated here.Substituent constants have been reported for a number of groups including the pentafluoro- ~henyl,~~' b~ta-l,3-diynyl,~~~ 3,5-dichlor0-4-cyanophenyl,~~ difluoroamino-alkyl and gern-bis(difluoroamino)alky1,233and 2-and 3-thien~l~~~ groups. Substituent effects in the trifluoroacetylation of substituted thiophens furans and 218 I. Hashimoto T. Nojiri and Y. Ogata Tetrahedron 1970 26 4603. P. H. Gore J. A. Hoskins and S. Thorburn J. Chem. SOC.(B) 1970 1343. 220 S. Oae S. Tamagaki T. Negoro and S. Kozuka Tetrahedron 1970 26 4051. 221 T. Szell L. Dozsai M. S. Zarandy and K. Mengharth Tetrahedron 1969 25 715.222 T. Szell K. Kalman M. S. Zarandy and A. Erdohelyi Helv. Chim. Acta 1969 52 2636. 223 T. Szell Gy. Schobel and L. Balaspiri Tetrahedron 1969 25 707. 224 G. A. Olah M. Tashiro and S. Kobayashi J. Amer. Chem. SOC.,1970,92 6369. 225 D. Bryce-Smith R. Deshpande A. Gilbert and J. Grzonka Chem. Comm. 1970 561. 12' M. Kobayashi H. Minato and Y. Kohara Buff. Chem. SOC. Japan 1970,43 234. 22' R. L. Dannley and G. E. Corbett J. Org. Chem. 1970,35 153. 228 R. L. Dannley J. E. Gagen and 0.J. Stewart J. Org. Chem. 1970 35 3076. 2zy R. 0.C. Norman and C. B. Thomas J. Chem. SOC.(B) 1970,421. 230 W. A. Sheppard J. Amer. Chem. SOC.,1970,92 5419. 23' P. G. Gassman and A. F. Fentiman Tetrahedron Letters 1970 1021. 232 C. Eaborn A. R. Thompson and D.R. M. Walton J. Chem. SOC.(B) 1970,357. 233 K. Baum J. Org. Chem. 1970 35 1203. 234 F. Fringuelli G. Marino and A. Taticchi J. Chem. SOC.(B) 1970 1595. Reaction Mechanisms-Part (i) 97 pyr~les~~~ and the temperature dependence of the Hammett reaction constant p for the hydrogen-exchange reactions of various substituted NN-dimethylani- lines2 have also been investigated. Linear free-energy relationships have also been used to correlate the bromination of ~tilbenes,~~' the half-wave potentials of substituted N-aroyl-N'-phenyl di-imides and N-benzoyl-N'-aryl di-imide~,~~~ and the ethanolysis of l,l'-thio~arbonyl-bis-pyrazoles.~~~ Bowden and his co-workers have reported further studies on 8-substituted 1-naphthoic acids and cis-and trans-ortho-substituted cinnamic acids which con- firm earlier observation of reversed dipolar substituent effects in these systems.240 A mathematical model for the direct field electrostatic effect has also been re- ported.241 Good linear free-energy correlations observed in the cleavage of X.C,H,.(C-C),GeRt compounds by aqueous mathanolic perchloric acid between the effects of substituents X in these reactions and those involving the compounds with n = 1 and 0 suggest that the balance between inductive and resonance effects of the systems remain constant despite the varying distance between the substituent and the reaction 5 Nucleophilic Aromatic Substitution The nature of intermediates in nucleophilic aromatic substitution reactions continues to attract interest.Strauss has given a comprehensive and up-to-date account of this rapidly moving The reaction of 1,3,5-trinitrobenzene with ethylamine and the corresponding ketone leads to the formation of (56).244 + Et,N + NBS -? ozNoNoz + (n = 3 Of 4) NH + Et,NH.Br-Scheme45 0 +c in the presence of N-bromosuccinimide (NBS) (56) is converted to (57) (Scheme 45)in high yield.245 The 'H n.m.r. spectra observed in solutions containing equal 235 S. Clementi and G. Marino Chem. Comm. 1970 1642. 236 T. E. Biherwolf R. E. Linder and A. C. Ling J. Chem. SOC.(B) 1970 1673. " M. F. Rusasse and J. E. Dubois Tetrahedron Letters 1970 1163. 238 J. T. Larkins H. Evans and J. M. Nicholson Tetrahedron Letters 1970,4159. 239 L. 0. Carlsson and J. Sandstrom Acta Chem.Scand. 1970,24,299. 240 K. Bowden M. J. Price and G. R. Taylor J. Chem. Soc. (B) 1970 1022. 241 K. C. C. Bancroft and G. R. Howe Tetrahedron Letters 1970 2035. 242 C. Eaborn R. Eastmond and D. R. M. Walton J. Chem. SOC.(B) 1970 752. 243 M. J. Strauss Chem. Rev. 1970 70 667. 244 M. I. Foreman R. Foster and M. J. Strauss J. Chem. SOC.(B) 1970 147. 245 A. Regnick and M. J. Strauss Tetrahedron Letters 1970 4439. J. G. Tillett concentrations of 1,2,3,5-tetranitrobenzeneand either sodium ethoxide or sodium hydroxide correspond to structure (58).246 There was no evidence of complex NO2 NO NO (58; R = H or Et) (59) formation between 1,2,4,5-tetranitrobenzeneand hydroxide ion but with ethano- lic ethoxide or dilute aqueous sodium sulphite blue colours probably attributable to (59; Nu = OEt or SO,-) were observed.Substituted picramides (60) on treatment with methanolic potassium methoxide give the complex (61) which on treatment with an equivalent amount of hydrochloric acid forms (62)247(Scheme 46). This provides a further example of a neutral Meisenheimer complex. The (R = CHMeCO.NHMe) (62) Scheme 46 contrasting behaviour of 2-and 4-methoxy-3,5-dinitropyridinein a-complex formation with methoxide ion in DMSO is attributed to differential steric and solvation effects.248 Meisenheimer complexes with alkyl groups co-ordinated to the ring (63)and (64),have now been isolated.249 Other Meisenheimer complexes H Me H Bu a -,. As+Ph . r NMe No NO (63) (64) 246 M.R. Crampton and M. El Ghariani J. Chem. SOC.(B) 1970 391. 247 E. Bergmann N. R. McFarlane and J. J. K. Boulton Chem. Comm. 1970,511. 248 M. E. C. Biffin J. Miller A. G. Moritz and D. P. Paul Austral. J. Chem. 1970,23,957. 249 R. P. Taylor J. Org. Chem. 1970 35 3578. Reaction Mechanisms-Part (i) reported formed from heteroaromatic substrates include the 4-aza-1,l-dimeth- 0xy-2,6-~~’ and 2-aza-l,3-dimethoxy-4,6-dinitrocyclohexadienate2s ’ ions (65) and (66) respectively. Rate and equilibrium constants for the formation and Me0 OMe .I N Me0 N (65) (66) decomposition of 1,l-dimethoxy o-complexes of 2,6-dicyano-4-nitroanisole and 2,4-dicyan0-6-nitroanisole,~and 2,4,5-trinitr~naphthalene~have been re-ported. The formation of the intermediate in the reaction of 2,4-dinitro-l-naph- thy1 ethyl ether with primary aliphatic amines is not base-catalysed but its de- composition involves general-acid catalysis254 (Scheme 47).Three distinct NR-NHR Scheme 47 relaxation times were observed in a temperature-jump study of the reaction of 1,3,5-trinitrobenzene with aliphatic amines in aqueous dio~an.~~ The first of these arises from formation of the conventional Meisenheimer complex ; the second from an oxyhydroxylamine and the third from formation of a Meisen- heimer complex between the substrate and hydroxide ion. The rate-coefficients for complex formation between 1,3,5-trinitrobenzene and hydroxide methoxide and ethoxide ions are in the ratio 1 188 :918.256 As with 2,4,6-trinitroanisole 250 P.Bemporad G. Illurninatti and F. Stegel J. Amer. Chem. SOC.,1969 91 6742. 25’ C. Abbolito C. Iowarone G. Illurninatti. F. Stegel and A. Vazzoler J. Amer. Chem. SOC.,1969 91 6746. 252 E. J. Fendler J. H. Fendler C. E. Griffin and J. W. Larsen J. Org. Chem. 1970 35 3378. 253 E. J. Fendler and J. H. Fendler J. Org. Chem. 1970,35 3378. 254 J. A. Orvik and J. F. Bunnett J. Amer. Chem. SOC.,1970 92 2417. 255 C. F. Bernasconi J. Amer. Chem. SOC.,1970 92 129. 256 C. F. Bernasconi J. Amer. Chem. SOC.,1970,92 4682. 100 J. G.Tillett 1,3-complexesof 1,3,5-trinitrobenzene are formed more rapidly than 1,l-complexes but are thermodynamically less stable. The reaction of anions with 3,5-dinitro- pyridine2” and base catalysis in the reactions of primary and secondary amines with methyl 4-nitrophenyl phosphate,258 and of piperidine with 2,4-dinitrophenyl aryl ethers259 and 4-chloro-3-nitrobenzotrifluoride260 have also been studied.Micellar and electrolyte effects on the reaction of 2,4-dinitrofluorobenzene with amines261.26 2 and on the decomposition of the l,l-dimethoxy-2,4,6-trinitro-cyclohexadienylide and studies of kinetic isotope effect^^^^.'^^ and of primary steric effects266 in nucleophilic aromatic substitution have been re-ported. The reaction of o-and p-fluoronitrobenzenes with sulphite ions involves Ph \CH-CN + oN02 NaNH, -Ph-C 0NO, / R CN Scheme 48 a transition state which closely resembles the reactant^.'^' The direct nucleo- philic replacement of a hydrogen atom in nitrobenzene has also been reportedz68 (Scheme 48).The photoreactions of some methoxynitro- dimethoxynitro- and dinitronaphthalenes in alkaline solution269 and the reaction of o-dinitrobenzene with triethyl phosphite and diethyl methylpho~phonite~’~ have been described. 257 R. Schaal F. Terrier J. C. Halle and A. P. Chatrousse Tetrahedron Letters 1970 1393. 258 A. J. Kirby and M. Yournas J. Chem. SOC. (B) 1970 1187. 259 J. F. Bunnett and C. F. Bernasconi J. Org. Chem. 1970 35 70. 260 F. Pietra and F. D. Cima Tetrahedron Letters 1970 1041. 261 C. A. Bunton and L. Robinson J. Org. Chem. 1970,35,733. 262 C. A. Bunton and L. Robinson J. Amer. Chem. SOC. 1970 92 356. 26’ E. J. Fendler and J. H. Fendler Chem. Comm. 1970 816. 264 P. Beltrame M.G. Cattania G. Massolo and M. Sumonetto J. Chem. SOC.(B) 1970 453. 265 G. Ayrey and W. A. Wylie J. Chem. SOC. (B) 1970 738. 266 F. Pietra D. Vitali F. Del Cima and G. Cardinali J. Chem. SOC. (B),1970 1659. 267 C. W. L. Bevan A. J. Foley J. Hirst and W. 0.Vivamu J. Chem. SOC.(B) 1970 794. 268 M. Makosza and M. Jawdosiuk Chem. Cornm. 1970 648. 269 G. M. Van Henegoniven and E. Havinga Rec. Trau. chim. 1970,89 907. 270 J. I. G. Cadogan and D. T. Eastlick J. Chem. SOC.(B) 1970 1314.