Nitrous acid Nitrosation

Synthesis. Almost without exception, azo dyes ate made by diazotization of a primary aromatic amine followed by coupling of the resultant diazonium salt with an electron-rich nucleophile. The diazotization reaction is carried out by treating the primary aromatic amine with nitrous acid, normally generated in situ with hydrochloric acid and sodium nitrite. The nitrous acid nitrosates the amine to generate the N-nitroso compound, which tautomerizes to the diazo hydroxide. 

An important property of the S-nitroso thiourea derivatives is the ability to effect electrophilic nitrosation of any of the conventional nucleophilic centres. This is manifest kinet-ically by the catalysis of nitrous acid nitrosation effected by added thiourea (equation 29). The situation is completely analogous to the catalysis of the same reactions by added halide ion or thiocyanate ion. The catalytic efficiency of thiourea depends on both the equilibrium constant Xxno for the formation of the intermediate and also its rate constant k with typically a secondary amine65. Since Xxno is known (5000 dm6 mol-2), it is easy to obtain... 

We are not concerned here with the mechanism of nitrosation, but with the anticatalytic effect of nitrous acid upon nitration, and with the way in which this is superseded with very reactive compounds by an indirect mechanism for nitration. The term nitrous acid indicates all the species in a solution which, after dilution with water, can be estimated as nitrous acid. 

Nitration at the encounter rate and nitrosation As has been seen ( 3.3), the rate of nitration by solutions of nitric acid in nitromethane or sulpholan reaches a limit for activated compounds which is about 300 times the rate for benzene imder the same conditions. Under the conditions of first-order nitration (7-5 % aqueous sulpholan) mesitylene reacts at this limiting rate, and its nitration is not subject to catalysis by nitrous acid thus, mesitylene is nitrated by nitronium ions at the encounter rate, and under these conditions is not subject to nitration via nitrosation. The significance of nitration at the encounter rate for mechanistic studies has been discussed ( 2.5). 

Under the conditions mentioned, i-methylnaphthalene was nitrated appreciably faster than was mesitylene, and the nitration was strongly catalysed by nitrous acid. The mere fact of reaction at a rate greater than the encounter rate demonstrates the incursion of a new mechanism of nitration, and its characteristics identify it as nitration via nitrosation. 

Under the same conditions the even more reactive compounds 1,6-dimethylnaphthalene, phenol, and wt-cresol were nitrated very rapidly by an autocatalytic process [nitrous acid being generated in the way already discussed ( 4.3.3)]. However, by adding urea to the solutions the autocatalytic reaction could be suppressed, and 1,6-dimethyl-naphthalene and phenol were found to be nitrated about 700 times faster than benzene. Again, the barrier of the encounter rate of reaction with nitronium ions was broken, and the occurrence of nitration by the special mechanism, via nitrosation, demonstrated. 

The evidence outlined strongly suggests that nitration via nitrosation accompanies the general mechanism of nitration in these media in the reactions of very reactive compounds.i Proof that phenol, even in solutions prepared from pure nitric acid, underwent nitration by a special mechanism came from examining rates of reaction of phenol and mesi-tylene under zeroth-order conditions. The variation in the initial rates with the concentration of aromatic (fig. 5.2) shows that mesitylene (o-2-0 4 mol 1 ) reacts at the zeroth-order rate, whereas phenol is nitrated considerably faster by a process which is first order in the concentration of aromatic. It is noteworthy that in these solutions the concentration of nitrous acid was below the level of detection (< c. 5 X mol... 

Butler recently reviewed the diazotization of heterocyclic amines (317). Reactions with nitrous acid yield in most cases N-exocyclic compounds. Since tertiary amines are usually regarded as inen to nitrosation, this... 

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) The reaction of a substance usu ally an amine with nitrous acid Pnmary amines yield dia zonium 10ns secondary amines yield N nitroso amines Tertiary aromatic amines undergo nitrosation of their aro matic ring... 

Synthesis. The classic laboratory synthesis of /V-nitrosamines is the reaction of a secondary amine with acidic nitrite [14797-65-0] at ca pH 3. The primary nitrosating intermediate is N2O2 arising from nitrous acid [7782-77-6] (48). 

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. 

V-Alkylpipera ines and PIP can react with nitrosating agents such as nitrogen oxides, nitrites or nitrous acid to form nitrosamine derivatives (61,62). Piper a2ine dihydrochloride [142-64-3] reacts with aqueous sodium nitrite and HCl to give the dinitrosamine that melts at 156—158°C (61). 

When solutions of sodium nitrite (NaN02) aie acidified, a number of species ar e formed that act as nitrosating agents. That is, they react as sources of nitrosyl cation, N=0 . For simplicity, organic chemists group all these species together and speak of the chemistry of one of them, nitrous acid, as a generalized precursor to nitrosyl cation. 

The most convenient route to S-nitrosothiol formation is the nitrosation of thiols by nitrous acid (Eq. 9.13). 

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. 

The reactive species for the transfer of the nitrosyl cation NO+ is not the nitrous acid 2 but rather N2O3 4 which is formed in weakly acidic solution. Other possible nitrosating agents are NOCl or H2N02 ", or even free NO+ in strong acidic solution. The initially formed N2O3 4 reacts with the free amine 1 ... 

The nitrosation of amides may also be carried out with nitrosyl chloride.2 Related methods of deamination of aliphatic amines are the triazene3 and nitrous acid methods4... 

Dimtrogen tetroxide is the most versatile of the nitrosating reagents and, in addition, it is readily available. The nitro-soamide method of deamination gives far superior yields and much less skeletal isomerization than the nitrous acid method (which is essentially limited to aqueous media), and it leads to a greater retention of optical activity than the triazene method3... 

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 ... 

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. 

Analogies for such a mechanism in diazotization are found in the nitrous acid-catalyzed nitration of A,A-dimethylaniline, mesitylene, 4-nitrophenol, and some related compounds, which were investigated by 15N NMR spectroscopy in Ridd s group (Ridd and Sandall, 1981 Ridd et al., 1992 Clemens et al., 1984a, 1984b, 1985 Johnston et al., 1991 review Ridd, 1991). Ridd and coworkers were able to demonstrate clearly that not only the nitration proper, but also the preceding C-nitrosation, is accompanied by a marked 15N nuclear polarization. This was at-... 

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