Kinetics and Mechanism of Degradation and automerization of Cefotetan in Aqueous Solution

The kinetics of the degradation and tautomerization of cefotetan in aqueous solution was studied at 25°C and ionic strength 0.6 over the pH range of 2.0-12.0. The degradation rates of cefotetan and its tautomer were found to be identical and the rate law reflected the spontaneous hydrolysis of each molecular species and the hydroxide ion-catalyzed hydrolysis of the dianionic species. The tautomerization was remarkable especially in the alkaline region and the equilibrium of the tautomerization shifted toward the tautomer as the hydroxide ion concentration was increased.Divalent metal ions were found to catalyze the tautomerization by chelation. Electron transfer triggered by the attack of hydroxide ion at the amide of the 1, 3-dithiethane moiety and electron withdrawal by hydronium ion from the nitrogen atom on the isothiazole ring of the anion intermediate formed from the tautomer by hydroxide ion were proposed as the mechanisms of the forward and reverse tautomerizations, respectively. The latter reaction is considered to be accompanied with epimerization. The apparent activation energies of the degradation at pH 3.0, 7.0 and 9.0 and those of the forward and reverse tautomerizations at pH 9.0 were 23.3, 22.9, 31.4, 35.5 and 24.4 kcal mol-1, respectively.