Nitrosation reactions

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). 

As already mentioned, Bunton and Halevi (Ref 38) found that ca 60% nitric acid requires the presence of nitrous acid for it to be a nitrating agent. Ingold et al (Ref 36c) postulated the action of nitrous acid to proceed via reactions 9, 10 11. Now in competition with reaction 11, there may be a nitrosation reaction ... 

Scheme 5-14 may be called a two-dimensional system of reactions, in contrast to Scheme 5-1 which consists of a one-dimensional sequence of two acid-base equilibria. In Scheme 5-14 the (Z/E) configurational isomerism is added to the acid-base reactions as a second dimension . The real situation, however, is yet more complex, as the TV-nitrosoamines may be involved as constitutional isomers of the diazohydroxide. In order not to make Scheme 5-14 too complex the nitrosoamines are not included, but are shown instead in Scheme 5-15. The latter also includes the addition reactions of the (Z)- and ( )-diazoates (5.4 and 5.5) to the diazonium ion to form the (Z,Z)-, (Z,E)- and (2 2i)-diazoanhydrides (5.6, 5.7 and 5.8) as well as proto-de-nitrosation reactions (steps 10, 11 and 12). This pathway corresponds to the reverse reaction of diazotization, as amine and nitrosating reagent (nitrosyl ion) are formed in this reaction sequence.

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). 

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-... 

The formation of nitrosamines in aprotic solvents has applicability to many practical lipophilic systems including foods (particularly bacon), cigarette smoke, cosmetics, and some drugs. The very rapid kinetics of nitrosation reactions in lipid solution indicates that the lipid phase of emulsions or analogous multiphase systems can act as "catalyst" to facilitate nitrosation reactions that may be far slower in purely aqueous media (41, 53, 54). This is apparently true in some cosmetic emulsion systems and may have important applicability to nitrosation reactions in vivo, particularly in the GI tract. In these multiphase systems, the pH of the aqueous phase may be poor for nitrosation in aqueous media (e.g., neutral or alkaline pH) because of the very small concentration of HONO or that can exist at these pH ranges. 

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 ... 

The fact that nitrite reacts with the iron of the heme compound was described earlier. Because such a large number of metal ions are present in meat, and because some occur in relatively high concentration, there has been considerable interest in them. For the most part, studies have dealt with how metal ions influence reactions of nitrite. The role of sodium chloride (which is used extensively in meat processing) must also be recognized both in terms of its functional role in making reactants in the meat more or less available, and in terms of reports that it directly influences nitrosation reactions (50). Ando (51) studied the effect of several metal ions on decomposition of nitrite, and in the absence of ascorbate, only Fe++ caused a loss of nitrite but in its presence, the effect of Fe " was more pronounced and Fe+++, Mg++, Ca++ and Zn++ showed similar effects. Lee e al. 

Vitamin E can also inhibit nitrosation reactions but the mechanisms may be somewhat different than those for vitamin C (55,56). Of course, vitamin C is water soluble while vitamin E... 

Based on the above data and on other available experimental work showing that nitroso compounds can induce gastric cancer in animals (O and that nitrosation reactions leading to synthesis of carcinogens can take place in the gastric cavity environment (27, 28, 29), we have formulated an etiologic hypothesis for gastric cancer (S) ... 

Determination of Hydroxy-Nitrosamines. The column extraction procedure has proven flexible and convenient for isolating NDELA and BHP from a variety of matrices. No artifactual formation of these nitrosamines has been observed when sulfamic acid was incorporated with the sample. Addition of excess acid prevents elution of amines from the Celite column, minimizing nitrosation reactions at later stages. The triisopro-panolamine sample examined contained approximately 250 mg/kg BHP (Table IV). 

Prevent the nitrosating reaction with amine precursors. 

Aromatic nitrosation with nitrosonium (NO + ) cation - unlike electrophilic nitration with nitronium (NO ) cation - is restricted to very reactive (electron-rich) substrates such as phenols and anilines.241 Electrophilic nitrosation with NO+ is estimated to be about 14 orders of magnitude less effective than nitration with N02+. 242 Such an unusually low reactivity of NO+ toward aromatic donors (as compared to that of NO ) is not a result of the different electron-acceptor strengths of these cationic acceptors since their (reversible) electrochemical reduction potentials are comparable. In order to pinpoint the origin of such a reactivity difference, let us examine the nitrosation reaction in the light of the donor-acceptor association and the electron-transfer paradigm as follows. 

Although a detailed kinetic analysis of the nitrosation reaction with NO+BFJ is not available, the time/conversions with various aromatic donors suggest that the reactivity does not follow the variation of the ionization potentials of the... 

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

D. L. H. Williams Nitrosation Reactions and the Chemistry of Nitric Oxide , Elsevier, Amsterdam, 2004. 

Nitric oxide is a physiological substrate for mammalian peroxidases [myeloperoxide (MPO), eosinophil peroxide, and lactoperoxide), which catalytically consume NO in the presence of hydrogen peroxide [60], On the other hand, NO does not affect the activity of xanthine oxidase while peroxynitrite inhibits it [61]. Nitric oxide suppresses the inactivation of CuZnSOD and NO synthase supposedly via the reaction with hydroxyl radicals [62,63]. On the other hand, SOD is able to modulate the nitrosation reactions of nitric oxide [64]. 

N02 probably plays a more important role in nitrosating reactions in biological systems than proposed earlier. Thus Espey et al. [94] suggested that the oxidation of NO into N203 with the intermediate formation of N02 could be more important in cells compared to aqueous solution. Furthermore, N02 is a likely candidate in oxidative processes due to its ability to penetrate cells [95],... 

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. 

There appears to be little reported work on S-nitrosation reactions of simple thioke-tones. Thiocamphor when treated with /50-amyl nitrite in fact gives the oxime58 (formerly called a isonitroso compounds), presumably via the tautomeric form of the thione, i.e. the enethiol. In this respect the reaction is very similar to the reactions of ketones59 which give oximes or C-nitroso compounds via the enol intermediates60. 

At higher acidities the S-nitrosation reaction of thiourea leads to the formation of urea64 (equation 28) via, it is believed, the intermediate formation of the S-nitroso species. The reaction can also be brought about by nitrosamines or alkyl nitrites as the carriers of NO+. Reaction is thought to involve nucleophilic attack of the intermediate by water or the elimination of HSNO giving a carbodiimide, which is then hydrated. 

The N-nitrosation reaction is usually very slow at neutral or alkaline pH due to the low equilibrium concentration of anhydrous nitrous acid. However, in the presence of formaldehyde or chloral as a catalyst (21), appreciable nitrosation occurs, even at pH 6 to 11. Similarly, Keefer (22) showed that some metal ions could catalyze the reaction under basic conditions. 

Amino acids undergo similar nitrosation reactions to yield hydroxy acids or lactones. Diamino acids tend to yield cyclic imino acids, so that ornithine and lysine give rise to proline and pipecolic acid, respectively. 

Stich, H. F., M. P. Rosin and L. Bryson. Inhibition of the mutagenicity of a model nitrosation reaction by natu-... 

An apparent order in nitrite of 3 or more would also be consistent with a-amino nitrite fragmentation mechanisms if one assumes that nitrite is preferentially consumed in redox or nitrosation reactions elsewhere in the molecule which compete with nitrosation of the dimethylamino group. One such possibility was suggested by Dr. R.N. Loeppky (private communication), as shown in Fig. 6. This mechanism, which postulates the intermediacy of two different o-amino nitrites, le and If, should obey third order kinetics, since dimethylnitrosamine is produced only after aminopyrine reacts with the third mole of nitrite. Moreover, this pathway offers a mechanistic explanation for the direct production of nitrosohydrazide V, which has also been reported to be a product of aminopyrine nitrosation (12.17). 

Roller, P. P. Keefer, L. K. Catalysis of nitrosation reactions by electrophilic species. In Bogovski, P. ... 

Some effects of phenol- and thiol-nitrosation reactions on N-nitrosamine formation. In Walker, E. A. Castegnaro, M. Griciute, L. Lyle, R. E., Eds. "Environmental Aspects of N-Nitroso Compounds" lARC Scientific Publication No. 19 International Agency for Research on Cancer Lyon, France, 1978 pp. 183-197. 

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