An Aziridinium Ion Intermediate in the Nitrosation of a Hexetidine Model

Abstract

The nitrosation chemistry of 1,3,5-trimethyl-5-aminohexahydropyrimidine (2) has been investigated as a model for the behavior of the antimicrobial agent hexetidine (1) under similar conditions. The reaction of 2 with sodium nitrite in glacial acetic acid gives 4-methyl-4-[(methylnitrosamino)methyl]-3-nitroso-1,3-oxazolidine (4) as the major nitrosamine. This compound arises from a molecular rearrangement which proceeds through the diazotization of the primary amino group followed by intramolecular displacement of nitrogen to generate an aziridinium ion. The N-nitrosooxazolidine 4 forms from the nitrosation of an imidazolidine produced from the aziridinium ring hydrolytic opening. The N-nitrosooxazolidine 4, an isomer, 5-methyl-5-[(methylnitrosamino)methyl]-3-nitroso-1,3-oxazolidine (14), which is not formed in the nitrosation of 2, and an analog 4-methyl-4-[[(2-ethylhexyl)nitrosamino]methyl]-3-nitroso-1,3-oxazolidine (22) have been independently synthesized. The N-nitrosooxazolidine 22 which would be formed from hexetidine is not present in its nitrosation mixture, suggesting the absence of reactive aziridinium ions in that case. The dissimilar nitrosation chemistry of 2 and 1 are discussed.

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

“…The nitrosation of hexetidine and related model compounds was undertaken to test the hypothesis that geminal diamines would be susceptible to rapid nitrosation with ensuing generation of nitrosamines. This publication and the accompanying paper (4), which reports the results of a related model study, clearly support this hypothesis. In a preliminary account Loeppky et al reported that the nitrosation of hexetidine resulted in the rapid pro-duction of at least eight different nitrosamines (3).…”

“…It is remarkable that there does not appear to be significant nitrosation and deamination of the primary amine in hexetidine. This pathway was found to be the major pathway for the nitrosation of a hexetidine model compound where the 2-ethylhexyl groups were replaced with methyl groups (4). While the reasons for the differences in reactivity are still under active investigation, a simple rationalization for the reactivity is related to the probable differences in basicity of the primary and tertiary amines in hexetidine, as discussed above.…”

“…A series of three closely spaced peaks between 67.89 and 68.09 arising from a CH2 are the most downfield peaks in the 13C spectrum of HEXNO. To facilitate the structural assignment of HEXNO, the N,N-dimethyl analog of hexetidine was nitrosated (4) and found to give an IV-nitrosooxazolidine as its major product. The 13C NMR spectrum of this N-nitrosooxazolidine exhibits its most downfield peak at <5 80.3 (-OCH2NNO-) (4).…”

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.…”