Amines nitrosation of secondary

C-Nitroso derivatives of secondary aromatic amines can be prepared by the so-called Fischer-Hepp rearrangement,303 which involves the action of a hydrogen halide on the corresponding A-nitroso amine. In this process the A-nitroso group is split off as nitrosyl halide which then nitrosates the ring 

Not only simple iV-alkyl-iV-nitr osoanilines 303,308 undergo this reaction, but also ring-substituted aniline derivatives with a free / ara-position, such as iV-ethyl-jV-nitroso-n-toluidine,303 m-chloro- and m-bromo-iV-methyl-jV-nitro-soaniline,310 and iV-methyl-JV-nitrosoanthranilic acid 301,311 the C-nitroso derivative obtained from the last-mentioned compound can be hydrolysed to nitrosalicylic acid.312 Rearrangements of the derivatives of 1- and 2-naph-thylamine have been reported by several authors.305,308,309,313 

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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. 

W-Nitroso amine (Section 22.15) A compound of the type R,N—N=0. R may be alkyl or aryl groups, which may be the same or different. A-Nitroso amines are formed by nitrosation of secondary amines. 

Research into the mechanism of diazotization was based on Bamberger s supposition (1894 b) that the reaction corresponds to the formation of A-nitroso-A-alkyl-arylamines. The TV-nitrosation of secondary amines finishes at the nitrosoamine stage (because protolysis is not possible), but primary nitrosoamines are quickly transformed into diazo compounds in a moderately to strongly acidic medium. The process probably takes place by a prototropic rearrangement to the diazohydroxide, which is then attacked by a hydroxonium ion to yield the diazonium salt (Scheme 3-1 see also Sec. 3.4). 

It is appropriate to add here some comments on diazotization in anhydrous carboxylic acids. They may be relevant for the diazotization of heteroaromatic amines carried out in acetic acid/propionic acid mixtures (Sec. 2.2). Extensive studies by Casado et al. (1983, 1984) showed that in nitrosation of secondary amines the nitrosyl ion, nitrosyl acetate, and dinitrogen trioxide are formed, and all three may act as nitrosating agents. The results do not, however, account for the considerable improvement that is claimed in the patent literature (Weaver and Shuttleworth, 1982) to result from the addition of carboxylic acids in the diazotization of heteroaromatic amines. 

This relationship, studies less than that of nitrosamines and microorganisms, offers similar possibilities. Plants could presumably affect nitrosation of secondary amines under certain... 

Scheme 8.4 Nitrosation of secondary amines from NONOates.

Many different pathways, mechanisms, and enzymes are associated with activation. These include dehalogenation, AT-nitrosation of secondary amines, epoxidation, conversion of phosphothionates to phosphate, metabolism of phen-oxyalkanoic acids, oxidation of thioethers, hydrolysis of esters and peroxides. The following is a summary. 

The nitrosation of secondary amines with sodium nitrite in the presence of acids is by far still the most widely used method for the preparation of N-nitrosamines. Several variations of this... 

Nitrosylhaems are readily formed from nitric oxide and haems and appear again to be carriers of NO which can effect nitrosation of secondary amines (Bonnett et a .. 1975). The structure of the nitrosylhaems was confirmed by their esr spectra, including those obtained by direct examination of a variety of cured meats (Bonnett et al., 1980). 

The nitrosation of secondary amines is reversible in acid solution, so A-nitrosamines may be hydrolized at low pH. Such hydrolysis is especially important for diaryl nitrosamines but also significant for aryl akyl nitrosamines. The NO liberated in the hydrolysis may react with the reduction product from the A-nitrosamine, the unsymmetrical hydrazine, with formation of amine and N2O [213,214] ... 

Ascorbic acid is known to inhibit the nitrosation of secondary amines. A computer model has been developed to predict the amount of nitrosamine formed under conditions that are experimentally inaccessible. The computer-calculated rates for N-nitrosomorpholine formation using rate and equilibrium constants from the literature agree well with experimental values in the absence of and presence of ascorbic acid under anaerobic conditions. In the aerobic system the inhibitory efficiency of ascorbic acid is lower, and the nature of the interactions among the various components of the mixtures is less well understood. The use of ascorbic acid for inhibition of N-nitroso compound formation both in vitro and in vivo is briefly reviewed. 

Mono-A-nitrosation of 1,2-dialkylhydrazines can be effected in the same way as nitrosation of secondary amines. For instance, 1,2-diisopropyl-1-nitrosohydrazine is obtained by using sodium nitrite in either glacial acetic or hydrochloric acid.222... 

Nitrosation. Nitrosation of secondary amines and thiols under heterogeneous conditions uses NaN02-oxalic acid in dichloromethane and r-butanol, respectively. 

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... 

Secondary aliphatic amines form stable N-nitrosoamines, however, and therefore, their investigation will be discussed briefly in this section, although N-nitroso derivatives of secondary aliphatic amines do not fall within the scope of this book. We will see that kinetics and mechanisms of nitrosation of secondary amines display many similarities with the diazotization of primary aromatic amines. 

Because of Oxone s acidic nature, (V-nitrosation of secondary amines is possible with the use of sodium nitrite in the presence of wet Si02 (eq 55). Nitrophenols can be obtained via nitrosation-oxidation of phenols under similar conditions (eq 56). Although acidic, the use of Oxone for these reactions eliminates the need for strong acids to generate NO+ unlike traditional methods. Nitrosoarenes can also be prepared by oxidation of anilines with Oxone (eq 57). ... 

N-Nitrosamines deserve special attention owing to their toxic and carcinogenic properties. They can be formed by nitrosation of secondary amines such as diethanolamine present in triethanolamine and coconut diethanolamide. Their analysis methods are diverse colorimetric, polarographic, and chromatographic (GC, GC-MS, and LC). 

Karami et al. (2005a) reported the first application of TSA/NaN02 as a novel heterogeneous system for the N-nitrosation of secondary amines under mild conditions (Scheme 3.3). 

The first application of MSA was in nitrosation of secondary amines nnder mild conditions (Scheme 3.19) (Montazerozohori and Karami, 2006). 

The general mechanism of nitrosation of secondary amines is shown in Figure 12.26. Nitrosation reagents are formed in acidic solutions from nitrous acid and nitrites, respectively, by a sequence of reactions indicated in Figure 12.27. Nitrites are present in foods as additives or contaminants. In foods and beverages obtained by fermentation, nitrites may arise by reduction of nitrates by microbial reductases. In beer, for example, wild yeasts partly assimilate nitrates to give ammonia, and the activity of nitrate reductase... 

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