Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins.
The effect of replacing the beta-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 beta-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 beta(nuc) 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.
Tsang
Wing Y
WY
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, UK.
Dhanda
Anupma
A
Schofield
Christopher J
CJ
Page
Michael I
MI
Dhanda
Anupna
A
D000588:Amines / Q000737:chemistry*; D002511:Cephalosporins / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics
D000588:Amines; D002511:Cephalosporins