Mechanistic studies on the oxidation reaction of antitubercular drug isoniazid and its analogy hydrazides by chlorine dioxide over a wide pH range

Oxidations of the antitubercular drug isoniazid (INH) and its analogy hydrazides, nicotinic hydrazide (NH), picolinoyl hydrazide (PH), and benzohydrazide (BH), by ClO 2 were investigated with a focus on the kinetics and reaction mechanisms. In buffered solutions of a wide pH range (from 0.51 to 10.35), the oxidation reactions strictly followed the second-order kinetics, and the apparent second-order rate constant k app versus pH profiles were established at 25.0 °C and 1.0 M ionic strength. Excess ClO 2 could rapidly oxidize the hydrazides to their corresponding aryl acids which were identified by mass spectrometry. For each of the hydrazides, the proposed reaction mechanism involves parallel rate-determining reactions between ClO 2 and various protolysis species of the hydrazide, rendering two types of hydrazyl free radicals; the free radicals are quickly oxidized by 3 more equivalents of ClO 2 to aryl acids. The derived rate constants for the rate-determining reactions revealed that for each hydrazide a huge reactivity difference existed among the protolysis species (>10 8 times) and that the enolate form (or its resonant structures) was extremely reactive. Two possible modes of electron transfer in the rate-determining reactions are discussed based on the observed reaction characters. In buffered solution of pH 7.0 and 25.0 °C, the measured values of k app are 6.20×10 4 , 7.8×10 3 , 2.57×10 3 , and 1.83×10 3 M −1 s −1 for INH, NH, PH, and BH, respectively, imparting an important data set as a reference to the water treatment. This work may open a new door for resolving water pollution caused by INH and its derivatives.