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o-Phthalaldehyde, as well as the α,α′-dideuterio isomer, has been shown to undergo a Cannizzaro reaction in water containing base, while partially hydrated and ionised. The reaction of the monoanion of the hydrate is intramolecular and of the first order in the monoanion of the hydrate, and either first or zero order in the base. The rate coefficients have been measured at several temperatures and activation parameters evaluated. The kinetic isotope effect, kH/kD, for the first and second order processes were found to be ca. 1.9 and 1.8, respectively. The alkaline hydrolysis of the corresponding lactone, phthalide, has also been studied under the same conditions. The evidence for the intramolecular Cannizzaro reaction indicates a mechanistic pathway involving rate-determining hydride transfer from the chain tautomers of both monoanion and dianion of the hydrate.

Rate coefficients for the base-catalysed detritiation of 4,4′,4″-trinitro-,4,4′-dinitro- and 4-nitrotriphenyl-methanes in dimethyl sulphoxide have been measured at 25.0 °C. The bases are a series of secondary aliphatic amines and tetramethylguanidine and of benzoate anions. For 4,4′-dinitrophenylmethane and piperidine, the rate coefficients for detritiation at 55.0 °C and, for α-[2H1]-4,4′-dinitrotriphenylmethane and piperidine, dedeuteriation at 25.0 °C were also measured. The kinetic isotope effect and activation parameters indicate the rate-determining step to be the ionisation process. Bronsted coefficients, β, have been calculated using the known or previously measured pKa values of the conjugate acids of the bases in dimethyl sulphoxide. The β values for both carbon acids are significantly greater for the benzoate anion than for the nitrogen base catalysis, and those for the dinitro-carbon acid are less than those for the trinitro-acid. No reactivity-selectivity relationship exists. This behaviour is discussed in relation to Marcus and related theories.

The rate-coefficients for the alkaline hydrolysis of 3-methyl-5-methylidene- and 3,5-dimethyl-thiazolidine-2,4-diones in water at 25.0 °C have been measured. The reaction of the 5-methylidene substrate is first order in both substrate and hydroxide ion. The reaction of the 5-methyl substrate is two-phase. The first and more rapid reaction of this substrate is 1.4 times faster than the only observed reaction of the former substrate. The second reaction is the hydrolysis of an intermediate, which is first order in substrate and has two components, one first and the other second order in hydroxide ion. The rate coefficients for the addition of a series of thiols to the 5-methylidene substrate in water at pH 7.40 have been measured. A Bronsted coefficient of ca. 0.37 has been found. The detailed reaction pathway and relation to Marcus and related theories are discussed.

The rate coefficients for the alkaline hydrolysis of a series of N-methyl, N-phenyl and bicyclo lactams, penicillins and N-alkyl-N-methylacetamides in water or in aqueous dimethyl sulphoxide have been measured at several temperatures. The reactions were first order in both substrates and base. The reactivities are related to the structures of the substrates, especially N-substitution, ring size and fused ring effects. The reactivities, as well as the activation parameters, kinetic solvent and solvent isotope effects, are used to suggest the detailed mechanisms. All the β-lactams appear to react with rate-determining addition of hydroxide anion; while the N-alkyl γ- and δ-lactams and N-alkyl-N-methylacetamides have rate-determining ring fission of the tetrahedral adduct, assisted by water-catalysis. The reactivity of penicillin in alkaline hydrolysis has been analysed by the studies of model compounds. These show that the increased reactivity of the penicillin β-lactam ring arises from the direct action of the fused ring structure and the acylamino side-chain.

Phenanthrene-4,5-dicarbaldehyde has been shown to form a bridged (cyclic) hydrate in aqueous solution, as a cis–trans mixture. The rate coefficients for the uncatalysed hydration has been measured at two temperatures and the activation parameters evaluated. The dialdehyde, as well as the α,α′-dideuterio isomer, has been shown to undergo a Cannizzaro reaction in 70%(v/v) dioxane-water. The reaction has been shown to be intramolecular and of the second order, i.e. first order in the monoanion of the hydrate and in base. The rate coefficients have been measured at several temperatures and activation parameters evaluated. The kinetic isotope effect, kH/kD, was found to be ca. 1.7 and the kinetic solvent isotope effect, kH2O/kD2O, ca. 0.59. The alkaline hydrolysis of the corresponding lactone of 5-(hydroxymethyl)phenanthrene-4-carboxylic acid was studied under the same conditions. As an intermediate in the intramolecular Cannizzaro reaction, the lactone can be excluded as it cannot be detected directly under conditions where it is relatively long-lived. The evidence for the Cannizzaro reaction indicates a mechanistic pathway involving rate-determining hydride transfer from the chain tautomer of the dianion of the hydrate.

The alkaline hydrolyses of aseriesof substituted (E)-5,5′-diphenylbifuranylidenediones and 3,7-diphenylpyranq[4,3-c]pyran-1,5-diones have been shown to proceed by biphasic pathways. In both cases, a very rapid primary reaction gives hydrolysis of one lactone ring. This is followed by a less rapid secondary reaction giving hydrolysis of the second ring and identical products from both systems. Rate coefficients for the secondary reactions have been measured in 70%(v/v) dioxane–water at 30.0 °C and, for the parent substrates, at 49.0 °C. The enthalpies and entropies of activation have been evaluated. The effects of substitution have been assessed by means of the Hammett equation. Reaction pathways are suggested and the reactivity is related to the ring size.

Naphthalene-1,8-dicarbaldehyde monohydrate has been shown to have a bridged (cyclic) structure in solution, as a cis–trans mixture. The hydrated dialdehyde, as well as the α,α′-dideuterio isomer, has been shown to undergo a Cannizzaro reaction in 70%(v/v) dioxane–water. The reaction has been found to be intramolecular and of the second order, i.e. first order in the monoanion of the hydrate and in base. The kinetic isotope effect, kH/kD, was found to be ca. 1.7 and the kinetic solvent isotope effect, kH2O/kD2O, ca. 0.60. The alkaline hydrolysis of the corresponding lactone of 8-(hydroxymethyl)-1-naphthoic acid (naphthalide) was studied under the same conditions. The lactone can be excluded as an intermediate in the intramolecular Cannizzaro reaction as it cannot be detected directly under conditions where it would be sufficiently long-lived. The evidence for the Cannizzaro reaction indicates a mechanistic pathway involving rate-determining hydride transfer in the chain tautomer of the dianion of the hydrate.

The equilibrium constants. Ke, for ring–chain tautomerism in a series of substituted benzil-2-carboxylic and 2-phenylacetylbenzoic acids, as well as for the methyl esters of the latter series, have been determined by IR and NMR spectroscopic methods. The observed pKa values, which have been measured for solutions in 80%(w/w) 2-methoxyethanol–water, have been corrected for the tautomeric equilibria to give the true pKa(pKaT). The effects of substitution on both log Ke and pKa, values have been assessed by means of the Hammett equation. The results are discussed.

Semi-empirical molecular orbital (AM1 and PM3) calculations including solvent effects by the SCRF model on the mechanism of the addition of nucleophiles to unsaturated five- and six-membered bislactones of the Pechmann dye type indicate a similar mechanism for both systems. The rate-determining step appears to be the addition of a second nucleophile to the enol of the ring-opened monolactone. The five-membered lactones are found to be more reactive than their six-membered analogues. Electron donor substituents (p-Me, p-MeO) increase and acceptor substituents (p-Cl, m-NO2) decrease the activation energy.

Summary The synthesis and study of a novel series of potential prodrugs of aspirin is reported. 2-, 3- and 4-formylphenyl aspirins, as well as a series of 4-substituted 2-formylphenyl aspirins, have been prepared. A study of their alkaline hydrolysis indicates that these compounds act as true prodrugs of aspirin which hydrolyse to aspirin and the formylphenol. The rates of hydrolysis and activation parameters indicate that hydrolysis of the 2-formylphenyl esters employs an intramolecular catalytic route.

The design and synthesis of a series of multifunctional metronidazole derivatives are described. The main series are multi-esters having two or more metronidazole groups linked together by aryl or alkyl systems. A second system is two nitro-2-methylimidazole groups joined by a dimethylene link. The third is polymeric 2-(2-methyl-5-nitroimidazol-1-yl)ethyl acrylate. The triester, metronidazole trimesate, is exceptionally active as an antibacterial compound, which appears to be associated with a rigid, three-point attachment.

The pKa values of a series of 2′- and 4′-substituted-biphenyl-2-carboxylic acids have been determined in 80%(w/w) 2-methoxyethanol-water at 25 °C. The rate coefficients for the esterification of these acids with diazodiphenylmethane have been measured in 2-methoxyethanol at 30 °C. The transmission of polar effects from the 4′-position is normal and the transmission coefficient is ca. 0.4. However, for the normally electron-withdrawing substituents at the 2′-position, reversed dipolar substituent effects are observed in both reactions. The reactivity studies indicate that the conformation of the 2,2′-disubstituted-biphenyl system appears to be close to that having orthogonal aryl groups.

The detailed mechanism of the Baker–Venkataraman rearrangement has been studied. The kinetics of the rearrangement of a series of 2-acetylphenyl 3- or 4-substituted benzoates and acetylnaphthyl benzoates catalysed by a basic ‘non-nucleophilic’ buffer in dimethyl sulphoxide have been measured. Studies of substituent effects, kinetic isotope effects, and acidity function correlations indicate a pathway involving pre-equilibrium formation of the carbanion, followed by rate-determining intramolecular nucleophilic attack. The methanolysis of the 2-acetylphenyl benzoates catalysed by methoxide in methanolic dimethyl sulphoxide has been similarly investigated. In this case the pathway appears to involve neighbouring group participation by the ketonic carbonyl group.

The detailed mechanism of the methoxide-catalysed rearrangement of both normal and pseudo methyl o-acylbenzoates and 8-acyl-1-naphthoates to form indane-1,3-diones and phenalene-1,3-diones, respectively, has been studied. Rate–acidity function correlations for the reactions in methanolic dimethyl sulphoxide give linear relations. The kinetic isotope effects have been observed with kH/kD equal to 0.7–0.9 and 5–7 for methyl o-acetylbenzoate and normal methyl 8-acetyl-1-naphthoate, respectively. The effect of substituents and ring–chain tautomerism on the rates has been considered. For the o-acylbenzoates the initial state is the ring-chain tautomeric equilibrium mixture and the rate-determining step is the intramolecular attack of the anion of the normal ester. For normal 8-acyl-1-naphthoates the rate-determining step is the ionisation of the normal esters; for the corresponding pseudo esters, the rate-determining step is the isomerisation of the psuedo to the normal ester.