Nitrosation of amines

Amines react with nitrous acid, through nucleophilic attack on the nitrosyl cation, NO. The product depends very much on whether the reactant is an alkanamine or a benzenamine (aniline) and on whether it is primary, secondary, or tertiary. This section deals with alkanamines aromatic amines will be considered in the next chapter. 

To generate NO, we must first prepare the unstable nitrous acid by the treatment of sodium nitrite with aqueous HCl. In such an acid solution, an equilibrium is established with the nitrosyl cation. (Compare this sequence with the preparation of the nitronium cation from nitric acid Section 15-10.) 

The nitrosyl cation is electrophilic and is attacked by amines to form an A-nitrosammonium salt. 

The course of the reaction now depends on whether the amine nitrogen bears zero, one, or two hydrogens. Tertiary A-nitrosammonium salts are stable only at low temperatures and decompose upon heating to give a mixture of compounds. Secondary A-nitrosammonium salts are simply deprotonated to furnish the relatively stable A-nitrosamines as the major products. 

REAL LIFE MEDICINE 21-2 Sodium Nitrite as a Food Additive, N-Nitrosodialkanamines, 

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Nitrosation of amines is best illustrated by examining what happens when a sec ondary amine reacts with nitrous acid The amine acts as a nucleophile attacking the nitrogen of nitrosyl cation The intermediate that is formed m the first step loses a pro ton to give an N nitroso amine as the isolated product... 

Nitrosation (Section 22 15) Nitrosation of amines occurs when sodium nitrite is added to a solution containing an amine and an acid Primary amines y e d alkyl diazonium salts Alkyl diazonium salts are very unstable and yield carbo cation derived products Aryl diazonium salts are exceedingly useful synthetic in termediates Their reactions are de scribed in Table 22 7... 

Efficient nitrosations of amines with inorganic nitrosyl compounds also have been reported (60). 

Nitrosation of amines by soil nitrite is by no means a recent concept. The Van Slykel reaction, summarized as... 

Thiocyanate, an anion normally secreted in human saliva, also catalyzes the nitrosation of amines by nitrite (22). The mechanism of the reaction is thought to proceed through the formation of nitrosylthiocyanate and subsequent reaction with amine to form the nitrosamine. This reaction, originally investigated to assess the... 

In view of the various possible pathways for nitrosation of amines as well as of amine derivatives (amides, ureas, carbamates, etc. ), it is not unexpected then for N-nitroso compounds to be found in many different areas of the human environment (11). It is possible that N-nitroso compounds may represent a carcinogenic exposure which most people experience on a daily basis. The list of items that have now been demonstrated to have measurable levels of various N-nitroso compounds present within them has grown considerably over the past decade (, 11, 12). A portion of this list would include air, water, soil, cheese, meats, fish, eggs. 

In a preliminary study we have recently reported (1) that the air in three rubber and tire industry plants was contaminated with several N-nitroso compounds. The compounds included N-nitrosomorpholine (NMOR), N-nitrosodimethylaminne (NDMA), and N-nitrosodiphenylamine (NDPhA). The latter compound is used as a vulcanization retarder, so its presence near processes employing it was not surprising. Bismorpholine-carbamylsulfonamide, a cross-linking accelerator used in rubber tires was found in tire factories and may be contaminated with NMOR. The source of the NDMA was not identified, but it could arise from nitrosation of amines which may be decomposition products of diamine based accelerators, as pointed out by Yeager, et al (2). 

A second source of nitrosamine formation could be nitrosation of amines by NOx, which has been clearly... 

Challis, B.C. and Kyrtopoulos, S.A.,"Nitrosation of Amines by Two-Phase Interaction of Amines in Solution with Gaseous Oxides of Nitrogen" J.C.S. Perkin I, 1979, 299. 

The catalytic activity of artificial chymotrypsin in the hydrolysis of m-tert-butylphenyl acetate (k = 2.8xl02 s 1, KM = 13xl05M) was found to be close to the activity of chymotrypsin in the hydrolysis of p-nitrophenyl acetate (k,.at = l.lxlO2 s 1, KM = 4x105M). Another example of mimicking enzyme catalysis by P-cyclodextrin is general acid-base-catalyzed hydrolysis and nitrosation of amines by alkyl nitrites (Iglesias, 1998). 

C. A. Reynolds and C. Thomson, Int. ]. Quantum Chem., Quantum Biol. Symp., 11, 167 (1984). Ab Initio Calculations Relevant to the Mechanism of Chemical Carcinogenesis by N-Nitrosamines. 1. The Nitrosation of Amines. 

The foimation of aromatic diazonium salts from aromatic primary amines is one of the oldest synthetic procedures in organic chemistry. Methods based on nitrosation of amine with nitrous acid in aqueous solution are die best known, but diere are variants which are of particular use widi weakly basic amines and for the isolation of diazonium salts fiom nonaqueous media. General reviews include a book by Saunders and AUen and a survey of preparative methods by Schank. There ate also reviews on the diazotization of heteroaromatic primary amines and on the diazotization of weakly basic amines in strongly acidic media. The diazotization process (Scheme 11) goes by way of a primary nitrosamine. 

Since alcohols and carbohydrates readily form equilibrium concentrations of alkyl nitrites which are themselves inactive as direct nitrosating agents (see below), it is to be expected that the addition of alcohols and carbohydrates will inhibit N-nitrosation of amines. This has been shown to be the case for aniline derivatives, and the reduction in the measured first order rate constants can be accounted for quantitatively by such equilibria (Aldred and Williams, 1982). But since alkyl nitrite formation is a rapid equilibrium process, it is not possible, at least for the aniline derivatives studied, to suppress N-nitrosation completely this way. This is in contrast to the effect of thiols discussed in Section 9. In another study (Kurechi et al., 1980), the same effect was observed at pH 3 for the nitrosation of dialkylamines, whereas at pH 5 there was claimed to be a rate enhancement on addition of alcohols, an effect which was not explained. 

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. 

In summary, the general concept, that ascorbic acid can inhibit or prevent the nitrosation of amines, is essentially true. The specific eflFects, however, which can be expected in a given system, depend on a complex set of interactions among pH, the nature of the amine, the amount of... 

Uses of the reagent listed below do not include diazotization, nitrosation of phenols and tertiary aromatic amines, and simple N-nitrosation of amines. 

Bioavailability from Environmental Media. No studies were located regarding the bioavailability of NDMA from environmental media. Since NDMA has been detected in ambient air, water and soil (ppb levels), it is important to determine if NDMA can be absorbed by humans from environmental samples. It must be noted that NDMA has been found in trace amounts in some foods and beverages and that endogenous formation of NDMA has been found to occur from the nitrosation of amines in the gastrointestinal tract. An... 

Lastly, but importantly, in a chapter titled Chemical Carcinogenesis, the following cited authors note that vitamin C inhibits carcinogenesis in the stomach by blocking the formation of nitrosamines from the nitrosation of amines (Williams and Weisberger, in Amdur et al.,1991, p. 146). This is aside from the usual view of medical orthodoxy that vitamin C has no special therapeutic effects other than the alleviation of scurvy (e.g., Marcus and Coulston, in Pharmacological Basis of Therapeutics, pp. 1568-1571). 

Dinitrogen trioxide reacts with the unshared pair of electrons on unprotonated secondary amine by a nucleophilic substitution reaction to form nitrosamines. The rate of nitrosation of secondary amines in a weakly acidic aqueous solution is proportional to the concentration of the amines and to the square of the nitrite concentration. The concentrations of these two precursors depend on the pH of the medium. While the concentration of unprotonated amines increases when pH increases, the concentration of nitrous acid increases when the pH decreases. Hence, the pH rate profile for the nitrosation of amines shows a maximum resulting from the interaction between these two opposite... 

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