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

Fingerprint

Cephalexin
Cephalosporins
Hydrolysis
Lactams
Kinetics
Sulfur
Amines
Rate constants
Oxygen
Derivatives

Cite this

Tsang, Wing Y. ; Dhanda, Anupna ; Schofield, Christopher J. ; Page, Michael I. / Kinetics and Mechanisms of Hydrolysis and Aminolysis of Thioxocephalosporins. In: Journal of Organic Chemistry. 2004 ; Vol. 69, No. 2. pp. 339-344.
@article{7b56f822541c490a8ba106866ed45fd1,
title = "Kinetics and Mechanisms of Hydrolysis and Aminolysis of Thioxocephalosporins",
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.",
author = "Tsang, {Wing Y.} and Anupna Dhanda and Schofield, {Christopher J.} and Page, {Michael I.}",
year = "2004",
month = "1",
day = "23",
doi = "10.1021/jo035471t",
language = "English",
volume = "69",
pages = "339--344",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "2",

}

Kinetics and Mechanisms of Hydrolysis and Aminolysis of Thioxocephalosporins. / Tsang, Wing Y.; Dhanda, Anupna; Schofield, Christopher J.; Page, Michael I.

In: Journal of Organic Chemistry, Vol. 69, No. 2, 23.01.2004, p. 339-344.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Kinetics and Mechanisms of Hydrolysis and Aminolysis of Thioxocephalosporins

AU - Tsang, Wing Y.

AU - Dhanda, Anupna

AU - Schofield, Christopher J.

AU - Page, Michael I.

PY - 2004/1/23

Y1 - 2004/1/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0347763352&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1021/jo049844h

U2 - 10.1021/jo035471t

DO - 10.1021/jo035471t

M3 - Article

VL - 69

SP - 339

EP - 344

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 2

ER -