Amine nitrosation

The largest known htiman exposures to exogenous nltrosamines have been shown to occur in the work place, particularly in the rubber and leather tanning industries. Recent data for amines, nitrosating potential and nitrosamines will be presented in the framework of assessing the extent of the various exposures. 

Ascorbic acid has been found to be the most effective and useful inhibitor of amine nitrosation [23]. Ascorbic acid inhibits the formation of DMN from oxytetracycline and nitrite, and also from aminophenazone (aminopyrine) and nitrite. Tannins are present in a variety of foods, competing with secondary amines for nitrite and thus leading to a reduction in the amount of nitrosamine formed [24]. 

The first clues that compounds of structure I might be involved in nitrosamine-forming reactions came during the study of tertiary amine nitrosations. Smith and Loeppky had proposed ( ) in their detailed, classical investigation of the mechanism of this reaction that the first steps involve nitrosammonium ion formation followed by elimination of nitroxyl (HNO). The resulting immonium ion was postulated to hydrolyze to the secondary amine, which reacted with nitrosating agent to form the observed product. These mechanistic proposals are summarized in Fig. 2a. 

The Smith-Loeppky mechanism [2) convincingly rationalized much of what was known about tertiary amine nitrosations. However, there was some evidence in the literature that there might be more to the mechanistic story. For one thing, it was not clear why the nitrosation of tertiary amines should have a higher pH optimum than that of secondary amines (2). Even more troubling was the somewhat controversial later report by Mai ins (15) that dimethylnitrosamine formed at pH 6 more readily from trimethyl amine than from dimethyl amine. If that report is correct, then free dimethylamine and the corresponding ammonium ion could not be the only kinetically significant intermediates in the trimethyl amine nitrosation. 

Assuming that the above rationale for tertiary amine nitrosation was valid, we predicted 3) that the reaction of secondary amines with nitrite at milder pH s should be catalyzed by electrophilic carbonyl compounds, since secondary amines are known to form immonium ions on admixture with appropriate aldehydes and ketones. The prediction turned out to be true. Formaldehyde was shown to promote nitrosamine formation from a... 

Figure 7. Proposed mechanism for methylene chloride promotion of secondary amine nitrosations by solid sodium nitrite (13)...

Figure 8. Alternate mechanistic possibility for catalysis of secondary amine nitrosation by aryl nitroso compounds...

As a result of our previous work on the scope and mechanism of tertiary amine nitrosation (X), we became interested in the behavior of N-alkylaziridines toward nitrous acid. Possible modes of reaction are illustrated in Scheme 1. The operation of either path A or C would be consistent with our previous studies of oxidative dealkylation of tertiary amines (1 ), while pathway B would be akin to the observed cheleotropic transformation of N-nitroso-aziridines (2). 

A kinetic study has been reported recently for the nitrosation of many symmetrical tertiary amines in aqueous acid-acetate buffers (Gowenlock et al., 1979). One experimental difficulty in tertiary amine nitrosations generally is that the reactions are much slower than for the analogous secondary amines, and are more conveniently studied at a higher temperature, typically 75°C, where the decomposition of nitrous acid is quite rapid. In this study, rate constants were obtained from the less accurate method of initial rate measurements. Nevertheless, for acidities less than pH 3.1, rate eqn (16) was established. The acid dependence is complicated by the protonation of the... 

Reagents for amination, nitrosation and nitration of tertiary alkylamines are discussed in the appropriate reviews listed in Sections 6.1.3.1.4 and 6.I.3.I.5. Tertiary amines can be nitrosated with dealkylation by dinitrogen tetroxide for example, 1-methylpiperidine gave 1-nitrosopiperidine (80%). lliis reaction probably starts by one-electron oxidation of the amine, the aminium ion then undergoing dealkylation. Other oxidative d ylations and dealkylations include the formation of iV-nitrosodibenzylamine in high yield from the acid chloride (PhCH2)2NCOCl and sodium nitrite and the conversion of the amine (43) into the nitramine (44) with nitric acid. ... 

In anaerobic systems, ascorbic acid/ascorbate reacts with all of the nitrosating agents shown in Scheme 1. These reactions are generally faster than the reactions between amines or amides and the respective nitrosating agents, and ascorbic acid has been shown to be an effective in vitro inhibitor of amine nitrosation via competition for these agents (17,24). These results have been extended to more practical areas such as the prevention of nitrosamine formation in foods and in vivo (20, 21,22). 

In addition to these aspects of the amine nitrosation reaction, the reactions of ascorbic acid with various components of the nitrite equilibria involve transformations that are also aflFected by the presence or absence of oxygen (1,23), Some of these are shown schematically in Scheme 3. If attention is then focussed on the reactions of ascorbic acid/ascorbate rather than on the nitrosation of amines, it can be seen that the amount of ascorbic acid or ascorbate available for inhibition of nitrosation can be diminished by the presence of oxygen. 

The serious problem of disentangling diazonium ion reactions from carbocation reactions makes diazonium ion rearrangements difficult to study. It seems likely that products of primary aliphatic amine nitrosation are derived from the diazonium ion rather than a primary aliphatic carbocation formed by spontaneous loss of nitrogen, since primary carbocations are unknown in solution. Products from secondary aliphatic amine nitrosation are formed from either the diazonium ion or the carbocation. 

The study of amine nitrosation has made progress as analytical methods have increased in sophistication, since complex mixtures of products in various stages of racemization are often obtained. 

Whiting s results differ from those of the groups of White , who studied the decomposition of butyl A-nitrocarbonates in ethanol, and found that the primary alkyl intermediate was more likely to trap the counterion than the secondary or tertiary. However, Whiting pointed out that the intermediate in this case is the species R—N=N=0. Certainly, a comparison of the products of this reaction with amine nitrosation showed overall similarities, but considerable differences in detaiP. ... 

The importance of ion pairing in amine nitrosation has been further demonstrated by Kirmse and Siegfried . They studied the nitrosation of the optically active 2-norbomamines, andconfirmed that the endo isomer 183 yields a mixture of 90% racemic exo alcohol 184 and 10% racemic endo alcohol 185. Formation of 184 is easily explained by formation of the... 

F1qur 12.26 General mechanism of secondary amine nitrosation. 

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