A tetrahedral intermediate in the aminolysis of benzylpenicillin

There is a non-linear dependent of the rate of aminolysis of benzylpenicillin upon hydroxide ion concentration which is interpreted in terms of formation of a tetrahedral intermediate; the rate of breakdown of the intermediate into reactants is ca. 109 s–

The effect of increasing the hydrophobicity of penicillin on its micelle-catalysed hydrolysis

Micelles of cetyltrimethylammonium bromide catalyse the alkaline hydrolysis of alkylpenicillins and benzylpenicillin methyl ester, The equilibrium constant for binding the alkylpenicillin to the micelle and the rate constants have been obtained. Binding increases with increasing alkyl chain length but shows a non-linear dependence upon the Hansch -value and the rate reaches a maximum value with heptylpenicillin. The free energy of transfer of a methylene group from water to the micelle shows a maximum value of 0.71 kcal mol–1. The negative charge of the carboxytate group of penicillin is not necessary tor catalysi

The aminolysis of penicillin derivatives. Rate constants for the formation and breakdown of the tetrahedral addition intermediate

There is a non-linear dependence of the rate of aminolysis of benzylpenicillin and 6--aminopenicillanic acid upon hydroxide ion concentration which is interpreted in terms of formation of a tetrahedral addition intermediate. At high concentrations of hydroxide ion the rate-limiting step is formation of the tetrahedral intermediate but at low concentrations it is the diffusion-controlled encounter of the intermediate and hydroxide ion. Rate constants for the formation of the intermediate and its breakdown to reactants are reported for a variety of amines. The dependence of these rate constants upon the pKa of the conjugate acid of the amine yield Brønsted values of ca. 0.3 and –0.6 for the formation and breakdown of the intermediate, respectively. There is thus quite a large dependence of the rate of expulsion of the amine from the intermediate upon the basicity of the amine despite the rate constants for this step being ca. 109–1010 s–1. Possible stereoelectronic control in the breakdown of the tetrahedral intermediate is discussed. There is no evidence for intramolecular general base catalysis in the formation of the tetrahedral intermediate from 6--aminopenicillanic aci

The micelle-catalysed hydrolysis of benzylpenicillin

Micelles of cetyltrimethylammonium bromide catalyse the alkaline hydrolysis of benzylpenicillin with a rate enhancement of ca. 50-fold. However, the rate of reaction is inhibited by increasing concentrations of hydroxide ion and penicillin anion. A saturation phenomenon is observed with increased concentration of surfactant. Attempts are made to determine the binding- and rate-constants using existing kinetic models. These are not completely satisfactory and a model is proposed which assumes that both hydroxide ion and penicillin have to be bound to the micelle for reaction to occur. Bromide, chloride, acetate, fluoride, and benzylpenicilloate ions all inhibit the micellar catalysis

Metal-ion catalysed hydrolysis of some ?-lactam antibiotics

The metal(II)-ion catalysed hydrolysis of some pencillin and cephalosporin derivatives in water at 30° shows saturation kinetics. A 1 : 1 complex is formed between the metal ion and penicillin which is attacked by hydroxide ion up to 108 fold faster than the unco-ordinated compound. The site of co-ordination of the penicillins and copper(II) ions is the -lactam nitrogen and the carboxylate group. The association constants for the cephalosporins and metal ions are greater than those for the penicillins but the transition states for the cephalosporin reaction with hydroxide ion bind less tightly to metal ions. The order of rate enhancement brought about by the metal ion is CuII > ZnII > NiII CoII. The metal ions are thought to stabilise the tetrahedral intermediate formed by hydroxide ion attack on the -lactam. Some comments are made about metal ions as electrophilic catalysts in enzymes

Metal ion catalysis in the aminolysis of penicillin

The copper(II) ion catalysed hydrolysis and aminolysis of benzylpenicillin in water at 30° shows saturation kinetics. A 1 : 1 complex is formed between the metal ion and benzylpenicillin which is attacked by hydroxide ion and amine ca. 107-fold faster than unco-ordinated benzylpenicilin. The Brønsted value for nucleophilic attack by amines is 0.87. The copper(II)ion catalysed reactions of the methyl ester of benzylpenicillin show much smaller rate enhancements indicating that the site of co-ordination for the antibiotic involves the ionised carboxy-group. The mechanism of the catalysed reactions does not involve the intermediate formation of benzylpenicillenic acid or a keten. The reactions are inhibited by buffers which co-ordinate to copper(II)ions. Trifluoroethylamine forms a 1 : 1 complex with copper(II) ion with an equilibrium constant of 15.6 l mol–

The chemical reactivity of penicillins and other b-lactam antibiotics

The rates of the acid catalysed hydrolysis of penicillins and cephalosporins are linear in Ho and, unlike other amides, show no rate maximum with increasing acidity. Electron-withdrawing substituents at C-6 in penicillins decrease the rate of hydrolysis with a I of ca.4 and they decrease the rate when attached to the amine leaving group. The acylamido-group at C-6 in penicillins, but not at C-7 in cephalosporins, exhibits neighbouring group participation with a rate enhancement of ca. 103. The absence of penicillenic acid formation from benzylpenicillin in acidic solution is not due to the ionisation of the carboxy-group. These observations are rationalised by a scheme, involving N-protonation and formation of an acylium ion intermediate. The alkaline hydrolysis of penicillins proceeds 102 faster than a -lactam after correction for substituent effects. There is no evidence for substantial inhibition of amide resonance in the bicyclic -lactam antibiotics, little evidence to indicate extra strain in these systems and no evidence that expulsion of the leaving group at C-3 in cephalosporins occurs in the transition stat