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

Antonio Llinás, Bartolomé Vilanovaa, Michael I. Page

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

LanguageEnglish
Pages521-528
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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expulsion
Cephalosporins
Sulfhydryl Compounds
thiols
Amines
Anions
hydrolysis
Hydrolysis
amines
Cephaloridine
anions
Protonation
High performance liquid chromatography
beta-Lactams
Alkalinity
breakdown
Isotopes
Nuclear magnetic resonance spectroscopy
Nitrogen
liquid chromatography

Cite this

Llinás, Antonio ; Vilanovaa, Bartolomé ; Page, Michael I. / Thiol-catalysed hydrolysis of cephalosporins and possible rate-limiting amine anion expulsion. In: Journal of Physical Organic Chemistry. 2004 ; Vol. 17, No. 6-7 SPEC.ISS. pp. 521-528.
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Llinás, A, Vilanovaa, B & Page, MI 2004, 'Thiol-catalysed hydrolysis of cephalosporins and possible rate-limiting amine anion expulsion', Journal of Physical Organic Chemistry, vol. 17, no. 6-7 SPEC.ISS., pp. 521-528.

Thiol-catalysed hydrolysis of cephalosporins and possible rate-limiting amine anion expulsion. / Llinás, Antonio; Vilanovaa, Bartolomé; Page, Michael I.

In: Journal of Physical Organic Chemistry, Vol. 17, No. 6-7 SPEC.ISS., 06.2004, p. 521-528.

Research output: Contribution to journalArticle

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AB - 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.

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