Acidity constants of cefetamet, cefotaxime and ceftriaxone; the effect of the substituent at C3 position

Abstract

Ionization constants of three cephalosporin antibiotics, cefetamet (CEF), cefotaxime (CFX) and ceftriaxone (CFTR) are determined using pH-potentiometric titrations at I = 0.1 M (NaCl) and t = 25°C. Cefetamet and cefotaxime have three ionization groups: carboxylic, amide and aminothiazole. Besides those three, ceftriaxone possesses an hydroxytriazinone group as new and additional ionization center. In acid medium two overlapping acid-base processes are occuring with acidity constants being: pK 1 2.93 (COOH) and pK 2 3.07 (aminothiazole) for cefetamet, and pK 1 2.21 (COOH) and pK 2 3.15 (aminothiazole) for cefotaxime. In the case of ceftriaxone the situation is even more complicated, three overlapping processes coexist with pK 1 2.37 (COOH), pK 2 3.03 (aminothiazole) and pK 3 4.21 (hydroxytriazinone). Protolysis of amide group is happening in the alkaline medium as completely separated process from those in acid medium. The acidity constants which correspond to amide group are pK 3 10.65 (CEF), pK 3 10.87 (CFX) and pK 4 10.74 (CFTR). The influence of the C3 substituent on the dissociation process of the neighboring ionization group, particularly carboxylic group, was considered. The differences in acidity of CEF, CFX and CFTR (pK 1 : 2.93, 2.21 and 2.37, respectively) are likely to be caused by the stereoelectronic properties of substituents in the β-position to the carboxylic group due to the combined inductive, hyperconjugative and resonance effects. © 2005 Elsevier B.V. All rights reserved.