Kinetics and Mechanisms of Hydrolysis and Aminolysis of Thioxocephalosporins

Wing Y. Tsang, Anupna Dhanda, Christopher J. Schofield, Michael I. Page

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The effect of replacing the β-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 β-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 βnuc 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.

Original languageEnglish
Pages (from-to)339-344
Number of pages6
JournalJournal of Organic Chemistry
Volume69
Issue number2
Early online date17 Dec 2003
DOIs
Publication statusPublished - 23 Jan 2004

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