Kinetics and mechanism of nitrosation of clonidine: a bridge between nitrosation of amines and ureas

Abstract

Nitrosation of clonidine has been studied kinetically both in acid medium (with nitrous acid) and in basic medium (with 2,2-dichloroethyl nitrite). The reactive form in acid medium was found to be the protonated clonidine (pK_a 8.18). The absence of catalysis by halides or thiocyanate, the existence of general base catalysis, and the measured solvent isotope effect all indicate that the reaction mechanism is different from that for the N-nitrosation of amines. Specifically, kinetic results indicate that the attack of the nitrosating agent on the substrate is not the rate determining step of the process, and suggest a mechanism that shows parallels with that found for ureas. However, in slightly basic medium, the reaction of clonidine with the alkyl nitrite occurs through the free base form of clonidine, as shown by the influence of acidity upon the reaction rate. In this case, the kinetic behaviour is similar to that exhibited by amines.