KINETICS AND MECHANISM OF OXIDATION OF SOME SULPHA DRUGS BY PERIODATE

Abstract

Suloha drugs are the chief medical weapon against many common gram positive bacterial diseases. It is supposed that the bacteriostatic action of sulpha drugs is mainly due to their oxidation products. As little information is available on the kinetic studies of oxidation of sulpha drugs, a systematic study on the kinetics of oxidation of sulphanilamide, sulphacetamide (s), sulphadiazine, sulphaguanidine and sulphamethizole by periodate has been carried out. The kinetics of oxidation of sulpha drugs by periodate has been followed spectrophotometrically by recording the absorbance of products, initially formed, at different intervals of time. All the reactions followed second order kinetics, being first order in sulpha drug and first order in periodate. Under pseudo first order conditions, reciprocal rates vs reciprocal concentration plots were found to be linear and passing through the oriain, thereby confirming the second order kinetic behaviour and indicating the absence of the formation of a stable complex between the substrate and the oxidant in the rate determinino step. The reactions of sulphanilamide and sulphacetamide with periodate exhioited a primary salt effect suggesting that the reaction might take place between two ionic species in case of sulphacetamide (s) and between an ion and a neutral molecule in case o^ sulphanilamide. pH had a marked effect on the rate of these reactions. The pH effect has been interpreted in terms of a reac tion between unprotonated sulpha drug ana periodate in the slow ii step. The rate was found to decrease with decrease in the diele ctric constant of the medium. Mn++ ions were found to be effective catalyst for these reactions. All these reactions are characterised by a high negative value of entropy of activation and low values of energy of activat ion. The large negative values of entropy of activation suggested that the activated species is strongly solvated and thus supports the formation of the charged intermediate. Moreover, it also sugg ested the dissociation of this charged intermediate into more than one component. The validity of isokinetic relation for these reac tions suggested the operation of a single interaction mechanism. Comparable values of the rates for the oxidation of different sulpha drugs indicated that -NH2 grouo, at p- to amido group, is the site of attack in the oxidation process. The products of oxidation characterized by separating them by TLC were the corresponding azo and azoxy derivatives of the sulpha drugs in case of sulphacetamide(s) and sulphanilamide. These results are correlated in terms of an ionic mechanism in which the first step is the electrophilic attack by the periodate iodine on the loan pair of the nucleophilic amino group of the sulpha drug, in the rate determining step, forming a bimolecular SN2 transition state. This charged intermediate then breaks down into more than two species. On the basis of proposed mechanism the following rate law resulted. -•L-j-i = k2 [Periodate] [Sulpha drug] Ill which is in accordance with the second order kinetic behaviour observed for these reactions. In addition to the above kinetic studies, a scheme for the separation of sulpha drugs on thin layer chromatographic plates, impregnated with pyridinium tung^stoarsenate, has been worked out using the oxidation of suloha drugs by periodate for locating the drugs on TLC plates.