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The results of ab initio (HF, MP2) and density functional (B3LYP) calculations on a series of γ-oxocarboxylic acids [(Z)-3-acetyl or benzoylacrylic and 2-acetyl or benzoylbenzoic acids] A and their cyclic tautomers B are presented. For the open-chain tautomers, different rotamers were considered. Bulk solvent effects were considered by using the polarised continuum model (PCM) and were found to be essential for a proper description of the ring-chain tautomeric equilibrium. Acetyl derivatives generally prefer the cyclic form, whereas for benzoyl derivatives the preference depends on the nature of the link. Introduction of substituents (methyl, phenyl) at C2 and/or C3 for acrylic acid derivatives substantially shifts the equilibrium towards the cyclic form B.

Ab initio (HF and MP2) and density functional (B3LYP) calculations with different basis sets (6-31G∗, 6-311+G∗∗, 6-311+G(2df,p)) on the various conformers of (Z)-3-formyl-acrylic acid and the corresponding ring-closed tautomer 5-hydroxy-furan-2(5H)-one are performed. At all levels of theory the ring tautomer is predicted to be the most stable one. Inclusion of bulk solvent effects (H2O) by the self-consistent isodensity surface polarized continuum model (SCIPCM) further shifts the ring-chain tautomeric equilibria towards the furanone form. Among the open chain tautomers, the s-cis–s-trans conformation is the most stable.

The rate coefficients for the esterification of a series of oxocarboxylic acids with diazodiphenylmethane have been determined in ethanol or 2-methoxyethanol at 30.0 °C. These and the rates of reaction with model compounds have been used to estimate the equilibrium constants for ring-chain tautomerism for the oxocarboxylic acids.

Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-trichloro- and tribromoacetylbenzoate, as well as the alkaline hydrolysis of the corresponding 2-trichloro- and tribromobenzoate anions, in 30% (v/v) dioxane–water at several temperatures. The relative rates of hydrolysis and activation parameters demonstrate relatively rapid hydrolysis via neighbouring group participation by the acyl-carbonyl group in the ester hydrolysis and slower hydrolysis via intramolecular fission of the adducts in the benzoate anion hydrolysis. The pKa values of the corresponding benzoic acids have been measured in water and their ring–chain tautomeric equilibrium constants determined.

Rate coefficients were measured for the base-catalysed hydrolysis of a series of substituted 3-(phenoxy- or thiophenoxymethylene)-(Z)-1(3H)-isobenzfuranones (3-phenoxy- or thiophenoxymethylenephthalides) in 70% (v/v) aqueous dioxane at 30.0 °C, in addition to the carbonyl stretching frequencies in chloroform and tetrachloromethane following deconvolution and band separation, when required. The Hammett reaction constants for the alkaline hydrolysis of the 3-/4-substituted phenoxy and thiophenoxy series are ca 0.75 and 1.10, respectively. These results are related to electrostatic field and resonance effects. Successful correlations between the carbonyl stretching frequencies and substituent constants and the rates of alkaline hydrolysis were found. Computational studies using the semi-empirical AM1 method correctly model both the details of the mechanistic pathway and the substituent effects. © 1998 John Wiley & Sons, Ltd.

The infrared and 13C NMR spectra and the kinetics of alkaline hydrolysis of chromium, tricarbonyl[3-[(η6-aryl)methylene]-Z-1(3H)-isobenzofuranones] have been studied in comparison with those of 3-arylmethylene-Z-1(3H)-isobenzofuranones. The 13C NMR spectroscopy has been found to be the most suitable tool for recognition of the site of complexation in the 3-arylmethylene-Z-1(3H)-isobenzofuranone system. A statistically significant correlation has been found between the arithmetic means of the wave numbers of symmetric and asymmetric stretching vibrations of Cr(CO)3 group and σp constants of the substituents. The large slope of this linear dependence suggests an important role of the mesomeric mechanism in the transmission of electronic effects to the Cr(CO)3 moiety. The strong electron-withdrawing effect of the Cr(CO)3 group causes a significant decrease of the polarity of the phthalide CO bond. The reaction rates of the alkaline hydrolytic ring-opening reaction dramatically increase due to the effect of Cr(CO)3 group. The absorption bands of the carbonyl stretching vibrations are markedly split due to Fermi resonance effect. After mathematical correction for Fermi resonance the wave numbers of the unperturbed fundamental CO stretching vibration and the log k values of alkaline hydrolysis exhibit significant linear correlations mutually, as well as with Hammett σ substituent constants. Charton's transmissive factors γ(PhCr(CO)3) have been determined for tricarbonylchromiumphenyl system using the parameters of the linear correlations. The efficiency of the substituent effect transmission is high in CCl4, because a back-donation effect of the carbonyl ligands and decreases in CHCl3 due to the hydrogen bonding between carbonyl groups and solvent molecules. The preparation of some novel chromium, tricarbonyl[3-[(η6-aryl)methylene]-Z-1(3H)- isobenzofuranones] is described.

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.

Rate coefficients were measured for the base-catalysed hydrolysis of a series of γ-lactones, i.e. 39 substituted 3-(aryl- and alkylmethylene)-(Z)-1(3H)-isobenzofuranones (3-aryl- and alkylmethylenephthalides) in 70% (v/v) aqueous dioxane at 30·0 °C. A Hammett reaction constant for the 3- or 4-substituted phenyl series is ca 1·5, whereas those for the 2-substituted phenyl and 4-substituted 1-naphthyl series, using para-σ values, are ca 1·0 and 1·9. These results are related to an electrostatic field effect model. A very successful correlation between the rates of alkaline hydrolysis of all 39 phthalides and the carbonyl stretching frequencies in chloroform was found. Substituent effects in widely different environments give linearly related effects on both reactivity and physical properties. Computational studies using the semi-empirical AM1 method correctly modelled both the details of the mechanistic pathway and the substituent effects. © 1997 John Wiley & Sons, Ltd.

The rate coefficients for the rearrangement of substituted (E)-5,5′-diphenylbifuranylidenediones to form the corresponding 3,7-diphenylpyrano[4,3-c]pyran-1,5-diones in ethane-1,2-diol at 30.0 °C, catalysed by sodium acetate, were determined. For the unsubstituted dione, the rate coefficients for there arrangement in various alcohols at 30.0 °C, and for three at 59.8 °C, were measured. The reactions were first order in both substrate and acetate anion. Rate coefficients were also measured for the catalysis of the rearrangement of the unsubstituted dione in ethanol and ethane-1,2-diol at 30.0 °C by a series of sodium meta/para-substituted benzoates. Bronsted-type correlations for the latter give α≈1.2. Substrate substitutent effects on the rates of rearrangement of the diones were not marked. A good correlation was found between the rates of rearrangement of the unsubstituted dione and the solvent effect parameter ET(30). This and other evidence indicated a probable mechanism involving a rapid pre-equilibrium between the substrate diones and the carboxylate anion, followed by the formation of an s-trans-enolate anion. The latter rotates to the s-cis isomer, which then intramolecularly attacks the second lactone ring. The process is then repeated with the product dione resulting from loss of the carboxylate anion. © 1997 John Wiley & Sons, Ltd.

The absorption bands of the C=O Stretching vibrations of a series of thirty-nine substitutedZ-3-methylene phthalides (1a-s, 2a-h, 3a-f, 4a-c, and5a-c) were measured in CHCl3 and CCl4. The two-levelFermi resonance effect on the infrared spectra of the above compounds was investigated after deconvolution and band separation. The wave numbers of the unperturbed fundamental C=O stretching vibrations exhibit excellent linear correlations withHammet's constants of substituents and13C NMR chemical shifts of the C=O group.

Rate coefficients have been measured for the base-catalysed cyclisation of 1,2-diacetylbenzene 1, 1,8-diacetylnaphthalene 2, 4,5-diacetylphenanthrene 3 and 2,2′-diacetylbiphenyl 4 in a range of aqueous dimethyl sulfoxide (DMSO) compositions at 30.0 °C, as well as at 45.0 and 60.0 °C at certain concentrations, containing tetramethylammonium hydroxide. For three of the substrates, 1, 2 and 4, the di-[2H3]acetyl compounds were also studied. Studies of the relative rates, activation parameters, kinetic isotope and solvent isotope effects and correlation of the rates with an acidity function were made to give detailed mechanistic pathways. Thus, 2, 3 and 4 react with rate-determining base-catalysed ionisation to give the enolate anion, followed by relatively rapid intramolecular nucleophilic attack and dehydration to give the corresponding cyclic enones; whereas, 1 reacts by the same pathway but with rate-determining intramolecular nucleophilic attack. An intermolecular base-catalysed aldol reaction was also detected for the product of the intramolecular reaction of 2 at high DMSO contents.

Rate coefficients have been measured for the alkaline hydrolysis of a series of chain (normal) esters, the methyl cis-3-(substituted benzoyl)-2,3-diphenylacrylates, and the corresponding ring (pseudo) esters, the 5-methoxy-5-(substituted phenyl)-3,4-diphenylfuran-2(5H)-ones, in 70% (v/v) dioxane–water at 30 °C. Those for the two parent esters were also measured at 45.0 and 60.0 °C and the enthalpies and entropies of activation have been evaluated. A consideration of relative rates, activation parameters and substituent effects indicates hydrolysis of the chain esters with neighbouring group participation by the keto-carbonyl group. The ring esters demonstrate the high reactivity of the five-membered lactone-like system. The steric effects of the phenyl groups does not switch mechanisms, but only modifies reactivity. The equilibrium constants for ring-chain tautomerism in a series of cis-3-(substituted benzoyl)-2,3-diphenylacrylic acids have been determined by using the observed pKa values in 80% (m/m) 2-methoxyethanol–water together with estimated true pKa (pKTa) values. The equilibrium constants for these acids have been correlated using the Hammett equation to give ρ as ca. 1.3. The results are discussed in terms of steric ‘bulk’ and resonance effects.

The rate coefficients for the base-catalysed ring fission of a series of substituted 3,4-diphenylcyclobut-3-ene-1,2-diones to give the corresponding (Z)-2-oxo-3,4-diphenylbut-3-enoic acids have been determined in 50% (v/v) aqueous dimethyl sulfoxide (DMSO) at 25.0 and 45.0 °C, as well as for a limited series in 70% (v/v) aqueous DMSO. The activation parameters have been calculated. The effect of both mono- and di-substitution of the phenyl groups has been studied and gives a Hammett ρ value of ca. 1.3 in 50% aqueous DMSO at 25.0 °C. The kinetic solvent isotope and solvent effect and enrichment in 18O-enriched water have been studied. The product composition of the reaction of the monosubstituted compounds gave a ρ value of ca. 0.9. All the evidence indicates a mechanistic pathway which proceeds by a rapid, reversible addition of hydroxide anion to the dione, followed by a benzilic acid-type rearrangement to form a 1-hydroxycyclopropene-1-carboxylic acid. The latter then suffers ring fission to give the final product.

Rate coefficients have been measured for the alkaline hydrolysis of 2-formylbenzonitrile 1, N-(2-formyl and -acetylphenyl)acetamides 2, N-(2-formylphenyl)-3-substituted benzamides 3,4-(2-formylbenzoyl)morpholine 4, 3-(4-morpholino)- and -(N-methylanilino)-phthalides 5 and -naphthalides 6 in 70% (v/v) dioxane–water at various temperatures. The enthalpies and entropies of activation have been evaluated. The hydrolysis of the nitrile is second order in base and that of the amides is first order in base. The relative rates of hydrolysis, activation parameters and substituent effects have been used to suggest the mechanisms of the reactions. Intramolecular catalysis by the neighbouring carbonyl group occurs in the alkaline hydrolysis of 1–4. The alkaline hydrolysis of 5 and 6 is rapid due to their lactone structures.

The rate coefficients for the hydrolysis of p-nitrophenyl acetate catalysed by a series of imidazoles, 4,5-diphenylimidazoles, benzimidazoles and perimidines in 30 mol% aqueous dimethyl sulfoxide at 30.0 °C have been measured, as have the pKa values of the catalysts in the same medium. The effect of a 2-(2-carboxyphenyl) substituent in each system has been studied. The pKa values of the imidazolium and related ions show that the 2-carboxylate group increases their acidity by 1.03 to 1.32 pKa units. The same effect on the nucleophilicity of the corresponding imidazole and related compounds gives rise to rate increases of a factor of 1.4 to 3.2. These effects are related to the structure of the imidazoles, indicating the importance of the environment of carboxylate groups.

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.

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.

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.

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.

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.

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 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.

Rate coefficients have been measured for the Smiles rearrangement of a series of 4- and 5-substituted 2-hydroxy-2′-nitrodiphenyl sulphones in 70%(v/v) dioxane–water at 60.0 °C, and for three substrates at several temperatures. The activation parameters for these substrates have been evaluated, as has the dependence on solvent composition [aqueous dioxane and dimethyl sulphoxide (DMSO)] of the rates for these substrates. The effects of substitution have been assessed by means of the Hammett equation using meta- and para-σ values for the 4- and 5-substituents, respectively, to give ρca.–2.0. All the evidence indicates reaction via a spiro Meisenheimer intermediate with the formation of the intermediate being rate determining. Rate coefficients have been also measured for the Smiles rearrangement of a series of 5-substituted 2-hydroxy-2′,4′-dinitrodiphenyl sulphones in 70%(v/v) dioxane–water at 24.8 °C and for three typical substrates at several temperatures. The activation parameters for these substrates have been evaluated, as has the dependence of rate on aqueous dioxane and aqueous DMSO solvent composition. In aqueous DMSO spiro Meisenheimer complexes are observed as the DMSO content increases. Above 50 mol% DMSO these intermediates are very rapidly and completely formed. The effects of substitution in 70%(v/v) dioxane–water have been assessed by means of the Hammett equation using meta-σ values to give ρca. 1.7. The evidence indicates that, in aqueous dioxane, reaction occurs via the spiro intermediate, with rate-determining decomposition of the Meisenheimer intermediate, and, in aqueous DMSO, the spiro intermediate becomes effectively the ‘initial’ state. The rate coefficients for the formation of the symmetrical spiro complex from 2-hydroxy-2′,4′-dinitrodiphenyl ether in DMSO–water and DMSO-tert-butyl alcohol containing base have been measured. The rate coefficients for the rearrangements of 2-amino-2′,4′-dinitrodiphenyl sulphide and 2-[(2-aminophenyl)thio]-3-nitropyridine have been measured in the same systems. Under these conditions, the ‘initial’ state is the spiro complex and the rate-determining step is the decomposition of the intermediate to form the product.

Biphenyl-2,2′-dicarbaldehyde, along with its α,α′-[2H2] isomer, and a series of 4,4′-, 5,5′- and 6,6′-disubstituted biphenyl-2,2′-dicarbaldehydes have been shown to undergo Cannizzaro reactions in 30%(v/v) dioxane-water containing base. The reaction has been shown to be intramolecular and of the third order; first order in substrate and second order in base. The rate coefficients have been measured at several temperatures and activation parameters evaluated. Studies of solvent isotope, solvent and salt effects have been made. The kinetic isotope effect, kH/kD, was found to be ca. 1.8. The effect of 4,4′- and 5,5′-disubstitution was assessed by use of the Hammett equation to give ρ at 30 °C to be ca. 4.6. Severe steric effects were noted for 6,6′-dimethyl substitution. The alkaline hydrolysis of the corresponding Iµ-lactones of 2′-hydroxymethylbiphenyl-2-carboxylic acids was studied under the same conditions. The intermediacy of the lactones in the intramolecular Cannizzaro reaction can be excluded. The evidence for the Cannizzaro reaction indicates a mechanistic pathway involving rate-determining hydride transfer from the dianion of a hydrated formyl group to the second formyl group. An estimate is made of effective concentration of the intramolecular hydride transfer.

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 2′- and 4′-substituted 2-methoxy-carbonyldiphenylacetylenes and (Z)-2-methoxycarbonylstilbenes have been determined in 70%(v/v) dimethyl sulphoxide–water at both 30.0 and 50.0 °C and at 24.0, 30.0, 40.0, and 50.0 °C, respectively. The pKa values of (Z)-2′- and -4′-substituted 2-carboxystilbenes have been measured in 80%(w/w) 2-methoxyethanol-water at 25 °C. The rate coefficients for the esterification of the corresponding acids with diazodiphenylmethane have been measured at 30.0 °C. For the diphenyl-acetylene system, normal substituent effects are observed from both the 2′- and 4′-position. A trans-mission coefficient for polar effects of ca. 0.2 has been calculated for both positions. The evidence, including the carbonyl stretching frequencies of the esters, indicates an s-trans conformer for the 2′-substituted 2-methoxycarbonyldiphenylacetylenes. For the (Z)-stilbene system, normal substituent effects are observed from both the 2′- and 4′-position. Transmission coefficients for polar effects, with regard to both the 2′- or 4′-position and the reaction studied, vary between 0.2 and 0.7. This appears to arise from the conformers available to the (Z)-2′- and -4′-substituted 2-carboxystilbenes.

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.

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 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 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.

A series of 5-substituted 2,4-diaminoquinazolines (3) has been synthesized and evaluated as inhibitors of the enzyme dihydrofolate reductase (DHFR) from both bacterial and mammalian sources. The best compounds (e.g. 53) show good activity against Escherichia coli DHFR, but there is no significant selectivity for the bacterial over the mammalian enzyme. The structure-activity relationships for enzyme inhibition appear to be complex and not amenable to simple analysis; a hypothesis to explain the observed qualitative structure-activity relationships is proposed. The inhibitory activities of the compounds against the growth of intact bacterial cells in vitro closely parallel those for the inhibition of the isolated bacterial enzymes, suggesting that their antifolate action is responsible for their antibacterial effects. Five of the compounds were tested for their ability to cure a systemic E. coli infection in the mouse, but they showed no therapeutic effects at their maximum tolerated doses.

Rate coefficients have been measured for the alkaline hydrolysis of 2,3-ethanoxy- and 2,3-propanamino-2,3-dihydro-1H-benz[de]isoquino lin-1-ones‡ in 70% (v/v) dimethyl sulfoxide–water at several temperatures and of N,N-dimethyl-1-naphthamide in water: the relative rates of hydrolysis, activation parameters and other studies indicate the importance of the torsional distortion of the lactam nitrogen and steric $lsquo;bulk’ factors in controlling reactivity.

Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-methylsulfonyl-, 2-methylsulfinyl- and 2-methylsulfanyl-benzoates and 2-methylsulfonyl-, 2-methylsulfinyl- and 2-methylsulfanyl-phenyl acetates, as well as of the parent esters, in 30% (v/v) 1,4-dioxane–water at several temperatures: the relative rates of hydrolysis and the activation parameters indicate the importance of both polar and steric effects.

A series of 5-mono- and 5,6-di-substituted indane-1,2,3-triones, phenalene-1,2,3-trione and 1,3-diphenylpropane- 1,2,3-trione form 2,2-dihydroxy-1,3-dione hydrates; the rates for the uncatalysed hydrations were measured and the structure of the transition state is elucidated from activation parameters, the kinetic role of water, and solvent isotope and substituent effects.

Rate coefficients are measured for the alkaline hydrolysis of methyl 2-formyl-, 2,6-diformyl- and 2-trifluoroacetyl-benzoates and for the alkaline and neutral hydrolysis of 2-formyl-, 2,6-diformyl-4-methyl- and 2-trifluoroacetyl-phenyl acetates in water at several temperatures: the relative rates of hydrolysis and activation parameters demonstrate neighbouring group participation by the acyl-carbonyl groups in the ester hydrolysis.

Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-[2-oxa-2-(3- or 4-substituted phenyl)ethyl]benzoates, 2-[2-(3- or 4-substituted benzoyl)phenyl]acetates, 2-(2-oxopropyl) and 2-(1,1-dimethyl-2-oxopropyl)benzoates, 2-(2-acetylphenyl)acetate and 2-(2-acetylphenyl)-2,2-dimethylacetates in 70%(v/v) dioxane–water at 30.0 °C. Those for the six parent esters were also measured at 45.0 and 60.0 °C and the enthalpies and entropies of activation have been evaluated. The relative rates of hydrolysis, activation parameters and substituent effects have been used to demonstrate neighbouring participation by the keto-carbonyl groups in the alkaline hydrolysis of the esters under study. For comparable systems, participation by six-membered ring intermediates appears somewhat less advantageous than five-membered.

Rate coefficients have been measured for the base-catalysed rearrangement of a series of symmetrically 2,2′-, 3,3′- and 4,4′-disubstituted benzils at 30.0 and 60.0 °C in 70%(v/v) aqueous dimethyl sulfoxide (DMSO), as well as at 40.0 and 50.0 °C for benzil itself. The enthalpies and entropies of activation have been evaluated. For benzil itself, rate coefficients have been measured at 60.0 °C in a series of aqueous DMSO and dioxane mixtures. The effects of meta/para-substitution have been assessed by means of the Hammett equation to give, using σ(and not 2σ), a ρ value of about 5.7. The role of these effects for the migrating and non-migrating phenyl groups have been separated. The steric effects from ortho-substitution have been evaluated. The limiting conditions for the observation of the base-catalysed rearrangement and two types of fission for benzils are delineated. The results are discussed in terms of mechanistic paths for the rearrangement and fission processes and the structures of the transition states.

Rate coefficients have been measured for the alkaline hydrolysis of methyl 3′- and 4′-substituted benzil-2-carboxylates at 21.0 °C and methyl 2-(3- and 4-substituied phenylacetyl)benzoates at 24.0 °C in 70%(V/V) dioxane–water. Those for the two parent esters were also measured at several temperatures and the enthalpies and entropies of activation have been evaluated. The relative rates of hydrolysis, activation parameters and substituent effects have been used to demonstrate neighbouring group participation by keto-carbonyl groups in the alkaline hydrolysis of the esters under study. For the methyl benzil-2-carboxylates, the α-carbonyl group appears to participate by means of an intermediate having a five-membered ring.

Intramolecular catalysis by the neighbouring carbonyl group occurs in the alkaline hydrolysis of methyl benzil-2-carboxylates. The α-carbonyl group participates by giving rise to an intermediate having a five-membered ring.

The pKa-values of a series of 8-(2-substituted phenyl)-1-naphthoic and 2- and 4-(8-substituted 1-naphthyl)benzoic 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. For the reactivity of the 2- and 4-(8-bromo-1 -naphthyl)benzoic acids, reversed dipolar substituent effects were observed in both reactions. The reactivities are quantitatively accounted for by either comparison with the results for the 2- and 4-bromobenzoic acids or Kirkwood–Westheimer calculations. For the reactivity of the 8-(2-substituted phenyl)-1-naphthoic acids, both normal and reversed dipolar substituent effects were observed in the ionisation reaction; whereas, for the esterfication reaction, only normal effects were shown.

Rate coefficients have been measured for the alkaline hydrolysis of 3-(3-substituted phenoxy)phthalides, -3-methylphthalides, -3-phenylphthalides, naphthalides, -3-phenylnaphthalides, and phenanthralides at 30.0 and 50.0 °C and for a series of methyl pseudo-2-acylbenzoates at several temperatures in 70%(v/v) dioxane–water. The enthalpies and entropies of activation have been evaluated. The effects of substitution on the phenoxy esters have been assessed by means of, the Hammett equation. The results for the methyl esters are related to the steric effect of substituents using the Taft equation. All the pseudo-esters are hydrolysed with rate-determining attack by hydroxide anion at the carbonyl group, followed by rapid ring fission to form the carboxylate anion of the corresponding acid as the product. Reactivity–selectivity is not shown over the whole range of the six series of the phenyl pseudo-esters. These results are discussed in terms of the structure of the transition state and the steric, stereochemical and polar factors influencing reactivity.

The pKa values of 3-(1-naphthyl)propiolic acid, together with the 8-bromo- and 8-chloro-substituted derivative, and of (E)-3-(1-naphthyl)acrylic acid, together with the 8-bromo- and 8-chloro-substituted derivatives, 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 rate coefficients for the alkaline hydrolysis of the corresponding methyl propiolates have been determined in 70%(v/v) dioxane–water at both 30.0 and 50.1 °C. In the ionisation and esterification reactions, reversed dipolar substituent effects were observed. The ΔpKa values are quantitatively accounted for either by comparison with the results for simple model compounds or by Kirkwood–Westheimer calculations. The retardations observed for the effect of 8-halo substituents in the alkaline hydrolysis reaction are in agreement with a reversed dipolar effect and no steric ‘bulk’ effects are observed.