α-(Acyloxy)dialkylnitrosamines:  Effects of Structure on the Formation of N-Nitrosiminium Ions and a Predicted Change in Mechanism

Abstract

The decay of α-(acyloxy)dialkylnitrosamines in aqueous solutions has been studied with a view toward elucidating mechanistic details and effects of structure on mechanism and reactivity. Rate constants (k 1) for the pH-independent decay of 43 α-(acyloxy)dialkylnitrosamines have been determined. Observations from these and other experiments rule out decomposition via an anchimeric assistance mechanism involving the Z isomer that had previously been suggested. All of the reported data for most of the compounds is consistent with a mechanism involving the formation of N-nitrosiminium ions in or before the rate-limiting step. Structure−reactivity correlations indicate that the stability of α-(acyloxy)dialkylnitrosamines is determined by electronic properties of substituents at RN and RC as well as by the ability of substituents RC to engage in hyperconjugative interactions of C−H bonds with the developing cationic center in the transition state for nitrosiminium ion formation. Attachment of substituents of sufficient electron-withdrawing power at RN and RC results in a predicted change in mechanism to what appears to be an acyl group attack mechanism.

Cyclic α-Acetoxynitrosamines: Mechanisms of Decomposition and Stability of α-Hydroxynitrosamine and Nitrosiminium Ion Reactive Intermediates

“…In the case of α-acetoxynitrosopiperidine, below pH 6, the kinetics of decay were not first order, as typified by the absorbance versus time plot in Figure . Such behavior was reminiscent of our earlier observation that some acyloxydialkylnitrosamines have a reactivity comparable with the product α-hydroxydialkylnitrosamine so that the latter is formed as a non-steady-state intermediate 6b. Treatment of these data is explained in the Discussion section.…”

“…In the case of α-acetoxynitrosopiperidine ( 7 ), below pH 6, the decay of absorbance was distinctly non-first order (Figure ), consistent with the formation of a non-steady-state intermediate. We have encountered examples of this behavior previously and assumed that the non-steady-state intermediate might be the α-hydroxynitrosamine 6b. Indeed the data give a good fit (solid line, Figure ) to the model in eq 4 using the appropriate eq 5 with the assumption that the extinction coefficient of the ester and the α-hydroxy compound are identical.…”

“…α-Hydroxydialkylnitrosamines subsequently give rise to electrophiles that covalently modify DNA. The mechanism by which α-acetoxynitrosamines decompose has been the subject of differing reports, − but it has most recently been claimed that the simplest acyclic members of the family undergo S N 1 solvolysis to give N -nitrosiminium ions that subsequently hydrate, as in eq 2.

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Role of Aldehydes in the Toxic and Mutagenic Effects of Nitrosamines

“…46 AMMN and NNK-4-OAc may also decompose via the intermediary formation of a nitrosiminium ion. 47 Independent of the mechanism of hydrolysis, the net result is the formation of methanediazohydroxide for all three compounds and an aldehyde in the cases of AMMN and NNK-4-OAc. The chemical stability of the intermediates following ester hydrolysis is another factor that will affect the levels of DNA alkylation by these three compounds.…”

“…Cellular thiols have also been implicated in the decomposition of NMUr . AMMN and NNK-4-OAc may also decompose via the intermediary formation of a nitrosiminium ion . Independent of the mechanism of hydrolysis, the net result is the formation of methanediazohydroxide for all three compounds and an aldehyde in the cases of AMMN and NNK-4-OAc.…”