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 t o be the protonated clonidine (pK, 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.

Rate limiting electrophilic attack in nitrosation of aminoguanidine

“…The slopes of the plot display a familiar catalytic sequence, Cl À < Br À < SCN À , found in nitrosation reactions. This behaviour indicates that, unlike other guanidines, [18][19][20] nitrosation of AG is subject to nucleophile catalysis, Figure 1. Influence of aminoguanidine concentration upon k obs , (*) and seems to confirm a mechanism for AG nitrosation that is similar to that for amines, i.e.…”

“…Previous studies on nitrosation of guanidines of different basicity [18][19][20] showed that their kinetic behaviour differs from that of most amines. In order to explore the apparent differences between amines and guanidines, we studied the influence of the usual catalysts of the nitrosation process on the rate of the reaction.…”

“…2) and the observed rate equation indicates, therefore, that the protonated AG is the reactive species. This situation becomes possible for AG because protonation of guanidines occurs mostly on the iminic nitrogen [20] (as shown in Chart 2). The reaction via neutral AG cannot be detected because its concentration is so low that the reaction rate of this process is much lower than that resulting from the less basic and less reactive, but more abundant protonated AG.…”

“…However, their peculiar structure makes them the compounds of great basicity, and in this sense, more similar to amines than amides. Previous studies on nitrosation of guanidines of different basicity carried in our group [18,19] and by others [20] showed that their kinetic behaviour differs from that of most amines, whose basicity causes them to be mostly protonated and react with nitrosating agents through the free base, which is more nucleophilic than the neutral guanidines. When the guanidines are in solution in the protonated form the experimental behaviour indicates that protonated guanidine, of very low basicity, is the reactive species.…”

Kinetic study of nitrosation of guanidines

“…This situation makes the kinetic study of the nitrosation of Gs, molecules that combine characteristics of both functional groups, very interesting and provides a bridge between amines and ureas. In fact a study of the nitrosation of clonidine [15] (a guanidine with hypotensive properties) has shown than in acid medium, the mechanism shows parallels with that found for ureas. However, in basic medium, the kinetic behaviour is similar to that exhibited by amines.…”