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

Antonio Llinás, Bartolomé Vilanovaa, Michael I. Page

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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 βnuc 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 ρ of ca 12, which is compatible with C-N bond fission occurring without protonation of the β-lactam nitrogen. Solvent kinetic isotope effects kH2O/k D2O 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.

Original languageEnglish
Pages (from-to)521-528
Number of pages8
JournalJournal of Physical Organic Chemistry
Volume17
Issue number6-7 SPEC.ISS.
Early online date25 May 2004
Publication statusPublished - Jun 2004

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