Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins

Tsang, Wing Y., Dhanda, Anupma, Schofield, Christopher J. and Page, Michael I. (2004) Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins. The Journal of Organic Chemistry, 69 (2). pp. 339-344. ISSN 00223263

Abstract

The effect of replacing the -lactam carbonyl oxygen in cephalosporins by sulfur on their reactivity has been investigated. The second-order rate constant for alkaline hydrolysis of the sulfur analogue is 2-fold less than that for the natural cephalosporin. The thioxo derivative of cephalexin, with an amino group in the C7 side chain, undergoes -lactam ring opening with intramolecular aminolysis by a reaction similar to that for cephalexin itself. However, the rate of intramolecular aminolysis for the S-analogue is 3 orders of magnitude greater than that for cephalexin. Furthermore, unlike cephalexin, intramolecular aminolysis in the S-analogue occurs up to pH 14 with no competitive hydrolysis. The rate of intermolecular aminolysis of natural cephalosporins is dominated by a second-order dependence on amine concentration, whereas that for thioxocephalosporins shows only a first-order term in amine. The Bronsted nuc for the aminolysis of thioxo-cephalosporin is +0.39, indicative of rate-limiting formation of the tetrahedral intermediate with an early transition state with relatively little C-N bond formation

Item control for Repository Staff only: