The thiol catalysed hydrolysis of cephalosporins and possible rate-limiting amine anion expulsion

Llinas, Antonio, Vilanova, Bartholomew and Page, Michael I. (2004) The thiol catalysed hydrolysis of cephalosporins and possible rate-limiting amine anion expulsion. Journal of Physical Organic Chemistry, 17 (6-7). pp. 521-528. ISSN 1099-1395

Abstract

The rates of thiolysis of cephalosporins were investigated by high-performance liquid chromatography and 1H NMR spectroscopy. Thiols catalyse the hydrolysis through the formation of a thioester intermediate and the catalytically reactive form of the thiol is the thiolate anion. Variation of nucleophilic reactivity by changing the basicity of the thiolate anion generates a Brønsted nuc value of 1.22 with cephaloridine, indicating that the breakdown of the tetrahedral intermediate is the rate-limiting step. The effect of C3 substituents on the rate of thiolysis of cephalosporins generates a large Hammett of ca 12, which is compatible with C - N bond fission occurring without protonation of the -lactam nitrogen. Solvent kinetic isotope effects kH2O/kD2O of ca 1.1 also indicate that solvent water probably does not act as a general acid catalyst facilitating breakdown of the tetrahedral intermediate by protonating the departing amine. Copyright © 2004 John Wiley & Sons, Ltd.

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