The Nitrosation of Hexetidine and Hexedine: Characterization of the Major Nitrosamine from Common Antimicrobial Agents

Abstract

The acidic nitrosation of hexetidine and hexedine, common antimicrobial agents and drug constituents, leads to a mixture of nitrosamines. The major nitrosamine product, "HEXNO", forms rapidly in yields as high as 60% over the pH range 1-4.8 at incubation times of 1 h at 37 degrees C with 40 mM NO2- and 10 mM hexetidine. On the basis of extensive spectroscopic characterization and independent synthesis HEXNO has been assigned the structure of 1-(2-ethylhexyl)-3-nitroso-4-methyl-4-[[N-(2-ethylhexyl)-N- nitrosoamino]methyl]imidazolidine (7). The synthesis of HEXNO involves the novel interception by potassium nitrite in ether/18-crown-6 of an imminium ion produced from the reaction of hexedine with benzyl chloroformate. Collapse of the alpha-amino nitrous ester produced by this reaction yields the nitrosamine containing carbamate 8, which yields HEXNO after removal of the carbamate with trimethylsilyl iodide and subsequent nitrosation. The rapid formation of HEXNO from hexetidine and hexedine supports the hypothesis that tertiary geminal diamines will produce nitrosamines rapidly by a mechanism which involves the cleavage of a nitrosammonium ion with the assistance of the neighboring nitrogen atom. This process is deemed to be of possible importance in the endogenous production of potentially carcinogenic nitrosamines because of its low nitrite requirement and high nitrosation rate. The available data suggest the probable formation of HEXNO and other nitrosamines from hexetidine under conditions of its use.

Analytical Aspects of Amino, Quaternary Ammonium, Nitro, Nitroso and Related Functional Groups

“…The major nitrosamine product, 'HEXNO' (295), can be characterized and analyzed using common spectroscopic methods. Rapid formation of 295 from 293 and 294 supports the hypothesis that tertiary geminal diamines produce nitrosamines rapidly, by a mechanism involving cleavage of a nitrosammonium ion with the assistance of the neighboring nitrogen atom 600 .…”

Evidence for Radical Cations in Linked Mechanisms of N,N-Dialkyl Aromatic Amine Nitration and Nitrosative Dealkylation

“…The mechanism and kinetics of nitrosative dealkylation of trialkyl tertiary amines have been investigated. , A key marker of this mechanistic pathway, shown as path A ( 1 → 4 → 8 → 2 ) in Scheme , is the formation of 0.5 mol of N 2 O for every mole of nitrosamine formed. We have identified other structural features of tertiary amines which render them highly reactive toward nitrosative dealkylation and demonstrated that they occur by different mechanisms than that shown in path A of Scheme , but none of these would appear to be applicable to the reactions of N,N -dialkyl anilines. − Our preliminary investigations of the nitrosation of 1 (X = CO 2 Et) showed that the relative yields of nitrosamine and nitro compound vary significantly with relatively minor changes in reaction conditions. These data suggested the operation of facile mechanistic switching and led us to consider a possible role for radical cation intermediates in the nitrosation chemistry of these aromatic amines.…”

Blocking Nitrosamine Formation

“…We have shown in Scheme 3 that electron rich aromatic compounds can undergo nitrosamine formation through attack at the aromatic ring. Our work on the nitrosation of 2-dimethylaminomethylpyrrole (Equation 2) indicated that the pyrrole ring was being extensively degraded by nitrosating agents (27). These results suggested that pyrrole and its derivatives might act as effective inhibitors of N-nitrosation.…”

“…The major nitrosamine formed from the reaction of even limited nitrous acid and hexetidine is shown in Equation 8. The identity of this material is based on spectroscopic data (27). As indicated, numerous products result from the nitrosation of hexetidine.…”

“…They showed that gramine rapidly generated dimethylnitrosamine when treated with nitrous acid (Equation 2). Our interest in the mechanism of this process led to nitrosation studies on 2-dimethylaminomethylpyrrole (27), a structurally related compound, which also nitrosates very rapidly at 25° C to produce dimethylnitrosamine (Equation 3). Our work has revealed that the latter two compounds nitrosate by two new and distinct mechanistic pathways.…”