Nitrosation of primary amines

Blangey314 obtained direct C-nitration of some primary amines when he added the amine to an ice-cold solution of sodium nitrite in concentrated sulfuric acid with exclusion of moisture. After complete consumption of the nitrous acid the products were precipitated by ice-water and proved in each case to be the / -nitroso amine. Thus were obtained the 4-nitroso derivatives of 1-naphthylamine and its 2-, 6-, 7-, and 8-monosulfonic acids, and in the benzene series those of m-anisidine, m-toluidine (NH2 = 1), etc. The sulfo group was split off from naphthionic acid, which gave a good yield of the product obtained from 1-naphthylamine. For the preparation of C-nitroso derivatives of primary amines from nitrosophenols see page 529. 

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The nitrosation of primary amines, RNH2, with, for example, sodium nitrite and dilute acid (cf. p. 107) leads to the formation of diazonium... 

Primary amines. The nitrosation of primary amine type compounds yields small amounts of secondary amine type N-nitroso compound (14, 15, 16). The reaction mechanism is not well understood. 

The formation of the anhydride (N2O3) from equation (3) can lead to both direct and indirect DNA damage. Direct action results from nitrosation of primary amines on DNA bases which leads to deamination and at physiological pH, N2O3 has been demonstrated to be the most important species [130]. Indirect actions are due to mutations that can arise from the deamination of bases where guanine deaminates to xanthine, mispairing of which can cause a G C to A T transition which will ultimately lead to single strand breaks [131]. 

One of the best leaving groups is molecular nitrogen attached to alkyl groups in alkyl diazonium ions. Diazonium ions are generated by nitrosation of primary amines. The diazonium ions generated from alkyl amines are very unstable and immediately decompose with loss of nitrogen. 

The nitrosation of primary aromatic amines 1 with nitrous acid 2 and a subsequent dehydration step lead to the formation of diazonium ions 3. The unstable nitrous acid can for example be prepared by reaction of sodium nitrite with aqueous hydrochloric acid. 

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). 

This type of scheme for the nitrosation of primary aromatic amines was first used by Ridd in 1959. The comparison of the present scheme with that from 1959 demonstrates how much more diversified the knowledge on diazotization mechanisms has become in three decades. 

NDE1A is not the only nitrosamine reported to have been identified in metalworking fluids. A fluid in the Netherlands was found to be contaminated with 5-methyl-N-nitrosooxazolidine (17). The two most likely explanations by which nitrosooxazolidines may be formed in metalworking fluids are (1) simple nitrosation of oxazolidine antimicrobials and (2) nitrosation of primary beta-hydroxy amines (18). The latter reaction is an example of the conversion of a primary amine into a nitrosamine. 

Tertiary aromatic amines may be nitrosated directly with nitrous acid, whereas primary aromatic amines normally are diazotized under these conditions. Some phenols may also be nitrosated under conditions similar to those used for the nitrosation of tertiary amines. 

The nitrosation of primary aromatic amines with nitrous acid (generated in situ from sodium nitrite and a strong acid, such as hydrochloric acid, sulfuric acid, or HBF4) leads to diazonium salts, which can be isolated if the counterion is non-nucleophilic. 

Rearrangement of N-nitrosoamides. N-Nitrosamides (1), prepared by acetylation of primary amines followed by nitrosation, are known to decompose in nonpolar solvents at 80-100° to form alkyl acetates with elimination of nitrogen.9 The presumed diazoalkane intermediate (a) can be trapped as a rhodium carbene (b), which undergoes rearrangement to an alkene (equation I). The overall result is a mild, nonbasic version of the classical Hofmann degradation of amines. 

Until recently most of the mechanistic studies on nitrosation have been concerned with N-nitrosation reactions of amines, including the diazotisation reactions of primary amines. Now, work has been extended to include both O- and S-nitrosation, so that comparisons can be made. Mechanistic studies have also been extended in recent years to include reactions of nitrogen oxides, nitrosamines, alkyl nitrites, thionitrites and transition metal nitrosyl complexes. Many of these reactions have been used preparatively for a long time, but little has been known about their detailed reaction mechanisms. 

The fonnation of aromatic diazonium salts from aromatic primary amines is one of the oldest synthetic procedures in organic chemistry. Methods based on nitrosation of die amine with nitrous acid in aqueous solution are the best known, but there are variants which are of particular use with weakly basic amines and for the isolation of diazonium salts from nonaqueous media. General reviews include a book by Saunders and Allen and a survey of preparative methods by Schank. There are 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. 

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. 

On the basis of mechanism (4-10), it is likely that nitrosation products of primary amines are also carcinogenic. This is, however, not easy to observe, since nitroso-amines of primary amines very rapidly decompose solvolytically, whereas N-nitroso derivatives of secondary amines may accumulate and degrade over a longer period. Indeed, alkylation products of DNA in vitro have been found in the presence of N-nitroso-alkyl-ureas (summary Wiessler, 1986). With AT-nitroso-butylurea, even rearranged butyl-1- and butyl-2- guanine and thymine adducts were found, i. e., products which are typical for the well-known rearrangement of the 1-butyl into the 2-butyl cation. 

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... 

Dyes. Sodium nitrite is a convenient source of nitrous acid in the nitrosation and diatozation of aromatic amines. When primary aromatic amines react with nitrous acid, the intermediate diamine salts are produced which, on coupling to amines, phenols, naphthols, and other compounds, form the important azo dyes (qv). The color center of the dye or pigment is the -N=N- group and attached groups modify the color. Many dyes and pigments (qv) have been manufactured with shades of the entire color spectmm. 

Nitrosation (Section 22.15) The reaction of a substance, usually an amine, with nitrous acid. Primary amines yield dia-zonium ions secondary amines yield A-nitroso amines. Tertiary aromatic amines undergo nitrosation of their aromatic ring. 

Ring nitrosation with nitrous acid is normally carried out only with active substrates such as amines and phenols. However, primary aromatic amines give diazonium ions (12-47) when treated with nitrous acid, " and secondary amines tend to give N-nitroso rather than C-nitroso compounds (12-49) hence this reaction is normally limited to phenols and tertiary aromatic amines. Nevertheless secondary aromatic amines can be C-nitrosated in two ways. The N-nitroso compound first obtained can be isomerized to a C-nitroso compound (11-32), or it can be treated with another mole of nitrous acid to give an N,C-dinitroso compound. Also, a successful nitrosation of anisole has been reported, where the solvent was CF3COOH—CH2CI2. " ... 

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