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.

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

Fingerprint

expulsion
Cephalosporins
Sulfhydryl Compounds
thiols
Amines
Anions
hydrolysis
Hydrolysis
amines
Cephaloridine
anions
Lactams
Protonation
High performance liquid chromatography
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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AU - Llinás, Antonio

AU - Vilanovaa, Bartolomé

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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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