Nitrosamines chemistry

Hoffmann D, Brunnemann KD, Prokopczyk B, Djordjevic MV. (1994). Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines chemistry, biochemistry, carcinogenicity, and relevance to humans. J Toxicol Environ Healdi. 41(1) 1-52. 

Hoffmann, D., K.D. Brunnemann, B. Prokopczyk, and M.V. Djordjevic Tobacco-specific A-nitrosamines and Areca-derived A-nitrosamines Chemistry, biochemistry, carcinogenicity, and relevance to humans J. Toxicol. 

Reactions. The chemistry of the /V-nitrosamines is extensive and will be only summarized here (8,35,42). Most of the reactions of the nitrosamines, with respect to thek biological or environmental behavior, involve one of two main reactive centers, either the nitroso group itself or the C—H bonds adjacent (a) to the amine nitrogen. The nitroso group can be removed readily by a reaction which is essentially the reverse of the nitrosation reaction, or by oxidation or reduction (68,69). 

The symposium upon which this volume is based was organized at a turning point in nitrosamine research. Almost all types of commercial products have been tested for volatile nitrosamines, and there have been a number of outstanding accomplishments of combined university-gov-emment-private industry actions to lower or eliminate volatile nitrosamines in those products found to be contaminated. However, there is still a major gap of knowledge with regard to compounds that are not amenable to analysis by gas chromatography, and this is clearly a frontier of current research. There are also many important questions regarding chemistry, mechanism of action, and relation to human disease whose answers lie in the future of research in this field. 

The purpose of the discussion of alternative pathways of nitrosamine activation (alternative to the a-hydroxylation hypothesis) is to demonstrate how fundamental organic chemistry may help classical metabolism studies to provide clues... 

Our approach is to examine small, closely-related series of nitrosamines and to develop structure-activity models based on molecular descriptors which are explicitly meaningful with respect to the organic chemistry and biochemistry of the compounds. The forms of these models can then often be interpreted in terms of the mechanisms through which these compounds exert their carcinogenic effects. 

A research program in progress at Raltech Scientific Services is designed to find inhibitors which will prevent nitrosamine formation in cosmetic products, A review of the literature (4) indicated that the oil phase of emulsions may play an important role in nitrosation chemistry. Thus, results from studies in water alone could be misleading when reduced to practice. 

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-... 

Several aspects of the problem of herbicides being contaminated with nitrosamines, and the resulting inadvertent introduction of nitrosamines into the environment, will be discussed in other papers in this symposium. Unrecognized until less than five years ago, the situation has inspired intense debate and prompted several of the environmental chemistry studies mentioned in this paper. Like the presumed threat from the in vivo nitros-ation of pesticide residues, discussions sometimes lack the type of anticipated dose and effect calculations just mentioned. Unlike the active ingredients, whose benefits can justify residue tolerances and acceptable daily intakes, nitrosamine contaminents afford no known benefits, and the desirability of minimizing their levels is undisputed. 

The chemistry and toxicology of nitrosamines have been adequately reviewed by Magee et al (1976), Mirvish (1975), Douglas et al (1978) and Fridman et al (1971). The problem of eliminating nitrosamines occurring as trace contaminants in pesticide formulations is markedly different than that of dealing with neat reactions of a given nitrosamine. 

Although N-nitrosamines (l) have been known since the nineteenth century, it was not until quite recently that they became the subject of intensive investigations. This renewed interest was spurred in large part by the report of Magee and Barnes ( ) on the carcinogenicity of these compounds. Since then, research into the chemistry and biological properties of N-nitrosamines has accelerated. This brief survey is intended to serve both as a summary of some of the frontiers in this area and as an introduction to the chemistry of N-nitrosamines discussed in the remaining chapters of this Volume. 

Reactions of the Nitroso Group. Up until recently, the chemistry of N-nitrosamines was restricted to the reaction involving the nitroso group. It was not until the usefulness of N-nitros-amines in synthesis [concept of "Umpolung (3.)] was demonstrated, that the long-known denitrosation of N-nitrosamines became impor-... 

Reactions Caused by the Nitroso Group, A major consequence of the strongly dipolar nature of N-nitrosamines - a fact now firmly established by the work of Phillips (lO) and of Karabatsos (11) - has been a better understanding of the chemistry of N-ni-... 

In the short span of twenty-five years, the hitherto rather prosaic N-nitrosamines have revealed themselves to possess a rich and varied chemistry as subsequent chapters of this volume will further demonstrate. 

Concurrent with our investigation on nitrosamine photochemistry (11), we also initiated an investigation of the ground and excited state chemistry of nitrosamides because of a wide discrepancy in the chemical behavior of these two classes of nitroso compounds. For nitrosamines, the presence of extensive delocalization of the unshared electron pair and the tt electrons of the N=0 group as in VI and VII has been well supported by i) n.m.r. evidence of the restricted rotation about the N-N bond (12), ii) electron diffraction analysis revealing the rather short N-N bond... 

We have just begun to explore the chemistry of these vinyl nitrosamines (which are really N-nitroso enamines) which are extremely interesting synthetic intermediates. One very exciting development has been their conversion to the corresponding epoxides. 

Both the nitrosoenamine II and the nitrosamino acetate III demonstrated some unusual chemistry which led us to the study of nitrosamine fragmentation reactions which will be discussed below. Treatment of the nitrosoenamine II with dilute sulfuric acid led to the formation of benzyl phenyl ketone as anticipated, but the major product from this reaction was benzoin, as is illustrated in equation 2 (3). While this transformation and the proper-... 

Roller, P.P., Shimp, D.R. and Keefer, L.K., "Synthesis and Solvolysis of Methyl (acetoxymethy 1) nitrosamine. Solution Chemistry of the Presumed Carcinogenic Metabolite of Dimethylnitros-amine". Tetrahedron Letters, 1975, 2065-2068. 

Structure-Activity Relationships. More interesting, and -scientifically, at least - more significant, is the question of why one nitrosamine should be more or less carcinogenic than another. In a general sense, the answer is obvious differences in reactivity within a series are, almost by definition, the result of differences in structure. This concept is one of the cornerstones of physical organic chemistry and, more recently, has been applied extensively to drug systems in a systematic and quantitative way following the initial and continued successes of Corwin Hansch and his coworkers (18-25). 

Grosjean, D Atmospheric Chemistry of Toxic Contaminants. 6. Nitrosamines Dialkyl Nitrosamines and Nitrosomorpholine, J. Air Waste Manage. Assoc., 41, 306-311 (1991d). 

Marzulli, F.N., Anjo, D.M. Maibach, H.l. (1981) In vivo skin penetration studies of 2,4-toluenediamine, 2,4-diaminoanisole, 2-nitro-/>-phenylenediamine, />-dioxane and N-nitrosodiethanolamine in cosmetics. Food Cosmet Toxicol., 19, 743-747 Michejda, C.J., Koepke, S.R., Kroeger-Koepke, M.B. Hernandez, L. (1994) Activation of (1-hydroxyalkylnitrosamines. Evidence for involvement of a sulfotransferase. In Pignatelli, M., Loeppky, R.N. Michejda, C.J., eds, Nitrosamines and Related N-Nitroso Compounds. Chemistry and Biochemistry (ACS Symposium Series 553), Washington DC, American Chemical Society, pp. 195-210... 

Challis, B. C., and Outram, J. R. (1979). The chemistry of nitroso-compounds. Part 15. Formation of N-nitrosamines in solution from gaseous nitric oxides in the presence of iodine. J. Chem. Soc. Perkin Trans. 1, 2768-2775. 

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