N nitrosation

Some recent general reviews deal with the mechanism of N-nitrosation in aqueous solution (345), the nitrosation of secondary amines (346). the effect of solvent acidity On diazotization (347) and the reactivity of diazonium salts (1691). Therefore, a complete rationalization of the reactivity of amino azaaromatics would be timelv. 

It has already been pointed out that nitrosation is probably the first step in diazotization. Ingold (1952) describes the reaction as N-nitrosation and classifies it as an electrophilic substitution, together with related processes such as the formation of 4-nitrosophenol, an example of a C-nitrosation. It was probably Adamson and Kenner (1934) who first applied these ideas to diazotization and realized that in aniline itself the electron density at the nitrogen atom is greater than in the anilinium ion, so that the base is more reactive. On the other hand, the nitrosoacidium ion (3.1), the addition product of nitrous acid and a proton, is a more powerful electrophilic reagent than the HN02 molecule. They therefore represented the first step of diazotization as in Scheme 3-5. 

Clearly, the previously observed acidity dependencies cannot be satisfactorily diagnostic of the nitrousacidium ion being the electrophile, and, significantly perhaps, the rate of N-nitrosation of benzamide follows the hR acidity function, which indicates that the nitrosonium ion is the electrophile122. 

Rate measurements were also carried out81 in the presence of added urea in an attempt to remove the free nitrite species formed and so prevent N-nitrosation (the reverse of de-nitrosation). The observed rate coefficient was now found to be the sum of the rate coefficients for rearrangement (kr) and de-nitrosation (ka)... 

When secondary amines are treated with nitrous acid, N-nitroso compounds (also called nitrosamines) are formed. The reaction can be accomplished with dialkyl-, diaryl-, or alkylarylamines, and even with mono-N-substituted amides RCONHR -I-HONO RCON(NO)R. Tertiary amines have also been N-nitrosated, but in these cases one group cleaves, so that the product is the nitroso derivative of a secondary amine.The group that cleaves appears as an aldehyde or... 

Other studies on the involvement of microorganisms with N-nitrosation have either been insufficiently controlled or have been only incompletely reported. Radomski ( ) found NDMA... 

How proline is converted to NPYR has not yet been fully elucidated and could conceivably occur by either of two pathways (29, ). One pathway involves the initial N-nitrosation of proline, followed by decarboxylation, while in the other, proline is first decarboxylated to pyrrolidine followed by N-nitrosation to NPYR. Since the conversion of N-nitrosoproline (NPRO) to NPYR occurs at a much lower temperature than the transformation of proline to pyrrolidine, the pathway involving intermediacy of NPRO is thus the more likely route ( ). It has been reported that preformed NPRO in raw bacon is not the primary precursor of NPYR in cooked bacon (29,33-5), as shown by the fact that ascorbyl paImitate, when added to bacon, inhibits the formation of NPYR (33). However, this by no means rules out the intermediacy of NPRO which could be formed at the higher temperatures attained during the frying process (29,36). 

N-Nitrosamine inhibitors Ascorbic acid and its derivatives, andDC-tocopherol have been widely studied as inhibitors of the N-nitrosation reactions in bacon (33,48-51). The effect of sodium ascorbate on NPYR formation is variable, complete inhibition is not achieved, and although results indicate lower levels of NPYR in ascorbate-containing bacon, there are examples of increases (52). Recently, it has been concluded (29) that the essential but probably not the only requirement for a potential anti-N-nitrosamine agent in bacon are its (a) ability to trap NO radicals, (b) lipophilicity, (c) non-steam volatility and (d) heat stability up to 174 C (maximum frying temperature). These appear important requirements since the precursors of NPYR have been associated with bacon adipose tissue (15). Consequently, ascorbyl paImitate has been found to be more effective than sodium ascorbate in reducing N-nitrosamine formation (33), while long chain acetals of ascorbic acid, when used at the 500 and lOOO mg/kg levels have been reported to be capable of reducing the formation of N-nitrosamines in the cooked-out fat by 92 and 97%, respectively (49). 

The N-nitrosation of these amides was subsequently studied as a function of pH and temperature (78). There was no apparent pH maximum for the reaction, N-nitrosamide formation increasing with increasing hydrogen ion concentration. The rates of N-nitrosation decreased rapidly as the pH increased and little reaction occurred above pH 3. A unit drop in pH from 2 to I increased the rate of N-nitrosation by a factor of 5-8 times. 

Interaction of lipid oxidation products and amino compounds. Amino acids and primary amines may be involved in other reactions which could lead to the formation of compounds having the potential to undergo N-nitrosation. Malonaldehyde, produced as a result of oxidation of lipids, particularly polyunsaturated fatty acids, has been shown to react with amino acids to produce... 

The nitrosation of N-methyltyramine represents an interesting case of N-nitrosation and C-nitrosation in the same molecule. In relatively strong acid (below pH 5), C-nitrosation is predicted to be more rapid (36) but in dilute acid where there is a considerable amount of unprotonated amine available, it is not yet clear which type of nitrosation is favored. N-methyltyramine would serve as a useful model to study the competitive kinetics of N-nitrosation and C-nitrosation in dilute acid. Details of the synthesis and nitrosation of N-methyltyramine will be published elsewhere. 

Precursors and Formation. Tobaccos used for commercial products in the U.S.A, contain between 0,5 and 2,7% alkaloids. Nicotine constitutes 85-95% of the total alkaloids (14,26,27). Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine and N -formylnornicotine (Figure 6), Several of these alkaloids are secondary and tertiary amines and, as such, amenable to N-nitrosation. The N-nitrosated alkaloids identified to date in tobacco and tobacco smoke include N -nitrosonornico-tine (NNN), 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) and N -nitrosoanatabine (NAT Figure 7). In model experiments, nitrosation of nicotine also yielded 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA 28). 

We thus assume, that the biochemical processes during tobacco curing may be different from the ui vitro N-nitrosation of secondary and tertiary amines (30). 

It has been shown that N-nitrosation was enhanced by the increase in organic matter content of the soil (13). It was postulated that a simple constituent of soil organic matter may be involved as a catalyst. For example, thiocyanate has been... 

Whether the N-nitrosation of glyphosate in soil to form N-nitrosoglyphosate will occur under natural conditions is still a matter of conjecture. However, based on our studies (12), the formation of detectable amounts of N-nitrosoglyphosate in soil under normal field conditions is not expected. It was observed that high concentrations of the herbicide glyphosate and nitrite were essential to get measureable amounts of N-nitrosoglyphosate in soil. Thus, to produce 5 ppm N-nitrosoglyphosate in the soil used in our study, one requires about 185 ppm of the herbicide... 

Under appropriate conditions, they are readily N-nitrosated. The authors tentatively concluded that the major contribution of N-substituted amides, if they were present in foods, could be as precursors of N-nitroso compounds formed by vivo N-nitrosation reactions ... 

An N-nitrose compound that is unstable is obtained by the effect of dinitrogen trioxide on caproiactam at a low temperature. The compound detonates when the medium is not cooled enough. 

Chemical complexes of various transition metals have been shown to promote N-nitrosation (28). These metal complexes include ferrocyanide, ferricyanide, cupric ion, molybate ion, cobalt species, and mercuric acetate. All of the reactions are thought to proceed by oxidation-reduction mechanisms. However, such promotion may not be characteristic of transition metal complexes in general, since ferricyanide ion has been shown to promote nitrosation in metalworking fluids, whereas ferric EDTA does not (2 0). Since the metalworking operation generates metal chips and fines which build up in the fluids, this reaction could be of significance in the promotion of nitrosamine formation in water-based metalworking fluids. 

Keefer, L. K. "Promotion of N-nitrosation reactions by metal complexes." In Environmental N-Nltroso Compounds. Analysis and Formation. E.A. Walker, P. Bogovski, and L. Griciute (Eds.). IARC Scientific Publication No. 14. Lyon, France. 1976, pp. 153-159. 

Many activations involve compounds which are used as pesticides. In the case of N-nitrosation, the precursors are secondary amines and nitrate. The former are common synthetic compounds and the latter is an anion found in nearly all solid and aqueous phases. The N-nitrosation of a secondary amine [R-NH-R ] occurs in the presence of nitrite formed microbiologically from nitrate. The product is an N-nitroso compound (i.e., a nitrosamine [RR -N-N=0]). The reason for concern with nitrosamines is their potency, at low concentrations, as carcinogens, teratogens, and mutagens. 

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