Nitrosamines formation from secondary amines

Microorganisms have been shown to catalyze the formation of nitrosamines from secondary amines in the presence of nitrite (26). The amount of nitrosamine formed, however, increased as the basicity of the parent amine decreased, presumably due to the increase in the amount of unprotonated amine present (27). This reaction is especially important with respect to metalworking fluids since water-based fluids are inevitably contaminated by microbes and fungi. Microbes are thought to catalyze nitrosamine formation by lowering the pH of the medium or catalysis by one or more unidentified metabolic products. 

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... 

The reactions for the formation of nitrosamines from secondary amines is as follows ... 

Kunisaki, N. and M. Hayashi. 1979. Formation of N-nitrosamines from secondary amines and nitrite by resting cells of Escherichi coli B. Appl. Environ. Microbiol. 37 279-282. 

A154. Sen, N.P, D.C. Smith, and L. Schwinghamer Formation 26A171. of A-nitrosamines from secondary amines and nitrite in human and animal gastric juice Food Cosmet. Toxicol. 

Methods of formation of IV-nitrosamines from secondary amines have been reviewed. The most widely used reagent is sodium nitrite in an aqueous acidic medium others include nitrosyl chloride, nitrogen oxides and nitrite esters. Fremy s stdt (S03")2N0-] reacts with hydroxylamine in the presence of secondary amines to give A -nitrosamines, or, in the presence of an excess of hydroxylamine, tetrazenes RaNN sNNR . The nitrosating agent derived from hydroxylamine and Fremy s salt is suggested to be the anion (S03")2N0N0. ... 

Formation of Af-Nitrosamines from Secondary Amines (Section 23.8C) Reaction... 

Figure 1, Nitrosamine Formation from a Secondary Amine and Nitrate in an Acid Environment.

The issue of nitrosamine formation from the decomposition of accelerators based on secondary amines during vulcanisation at elevated temperatures is... 

In classical organic chemistry, nltrosamlnes were considered only as the reaction products of secondary amines with an acidified solution of a nitrite salt or ester. Today, it is recognized that nitrosamines can be produced from primary, secondary, and tertiary amines, and nltrosamides from secondary amides. Douglass et al. (34) have published a good review of nitrosamine formation. For the purposes of this presentation, it will suffice to say that amine and amide precursors for nitrosation reactions to form N-nitroso compounds are indeed ubiquitous in our food supply, environment, and par-... 

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]. 

Methylenediamines are readily synthesized from the reaction of secondary amines with formaldehyde. Many aliphatic amines are too basic for direct nitration without a chloride catalyst, and even then, nitrosamine formation can be a problem. Their conversion into intermediate methylenediamines before nitration is therefore a useful route to secondary nitramines. The success of these nitrolysis reactions is attributed to the inherent low basicity of the methylene-diamine nitrogens. 

In view of the highly carcinogenic nature of many nitrosamines any experiments involving their isolation must be discouraged, and for this reason, this section has only been written for completeness. This high toxicity is unfortunate because the preparation of nitrosamines from the parent amines is often facile and they provide a route to highly pure nitramines. Other equally useful methods for the synthesis of nitramines, such as the chloride-catalyzed nitration of secondary amines, also suffer from the formation of nitrosamines in appreciable amounts and must also be viewed with caution. 

Since nicotine is the major precursor to NNN in tobacco and tobacco smoke, the reaction of nicotine with sodium nitrite was studied to provide information on formation of other tobacco specific nitrosamines, especially NNK and NNA, which could arise by oxidative cleavage of the l -2 bonds or l -5 bond of nicotine followed by nitrosation (26). The reaction was investigated under a variety of conditions as summarized in Table I. All three nitrosamines were formed when the reaction was done under relatively mild conditions (17 hrs, 20 ). The yields are typical of the formation of nitrosamines from tertiary amines (27). At 90 , with a five fold excess of nitrite, only NNN and NNK were detected. Under these conditions, both NNK and NNA gave secondary products. NNK was nitrosated a to the carbonyl to yield 4-(N-methyl-N-nitrosamino)-2-oximino-l-(3-pyridyl)-1-butanone while NNA underwent cyclization followed by oxidation, decarboxylation and dehydration to give l-methyl-5-(3-pyridyl)pyrazole, as shown in Figure 4. Extensive fragmentation and oxidation of the pyrrolidine ring was also observed under these conditions. The products of the reaction of nicotine and nitrite at 90 are summarized in Table II. 

Although many of the details remain to be clarified, transfer of nitrosyl groups onto preformed iron-sulfur frameworks of the natural type is well established (107,108). The transfer of nitrosyl groups from iron-sulfur-nitrosyl complexes to atoms other than iron is more problematical, as reported work on the ability of these complexes to nitrosate secondary amines RR NH, with formation of secondary nitrosamines RR NNO, has provided conflicting conclusions. 

The formation of Af-nitrosamines which usually separate as orange-yellow oils or low melting solids indicates the presence of a secondary amine. Confirm the formation of the nitrosamine by the Liebermann nitroso reaction. This consists in warming the nitrosamine with phenol and concentrated sulphuric acid. The sulphuric acid liberates nitrous acid from the nitrosamine, and the nitrous acid reacts with the phenol to form p-nitrosophenol, which then combines with another molecule of phenol to give red indophenol. In alkaline solution the red indophenol yields a blue indophenol anion. 

Challis, B. C. Yousaf, T. I. Facile formation of N-nitrosamines from bromonitromethane and secondary amines./. Chem. Soc. Chem. Commun. 1990, 1598-1599. 

Since Amadori compounds are secondary amines, the question of the formation and reactivity of /V-nitroso derivatives arises. Accordingly, Pool el al 22 tested those derived from glucose with Ala, Asp, Phe, Gly, Ser, and Try in five strains of S. typhimurium with and without S9. The first three compounds were not mutagenic, the next two showed low but reproducible increases in the number of his+ revertants in TA1535 (without S9), but the last, containing indolyl-nitrosamine-D-fructose-L-tryptophan, was mutagenic in all five strains, with and without S9. When separated, the Try compound was mutagenic in three strains, without S9. 

When oxides of nitrogen come in contact with water, both nitrous and nitric acids are formed (18) (Table IV). Toxic reactions may result from pH decrease. Other toxic reactions may be a consequence of deamination reactions with amino acids and nucleic acid bases. Another consideration is the reactions of oxides of nitrogen with double bonds (Table IV). The cis-trans isomerization of oleic acid exposed to nitrous acid has been reported (19). Furthermore, the reaction of nitrogen dioxide with unsaturated compounds has resulted in the formation of both transient and stable free radical products (20, 21) (Table V). A further possibility has been raised in that nitrite can react with secondary amines to form nitrosamines which have carcinogenic properties (22). Thus, the possible modes of toxicity for oxides of nitrogen are numerous and are not exhausted by this short list. 

---