Nitrous acid, protonated

There is no doubt that the carbinol equilibrium (Scheme 3-15) is comparable to the nitrous acid protonation-dehydration equilibrium (Scheme 3-8) if one disregards the nitrosoacidium ion intermediate. 

FIGURE 22 5 The diazo mum ion generated by treatment of a primary al kylamine with nitrous acid loses nitrogen to give a car bocation The isolated prod ucts are derived from the carbocation and include in this example alkenes (by loss of a proton) and an al cohol (nucleophilic capture by water)... 

Nitrosation of amines is best illustrated by examining what happens when a secondary fflnine reacts with nitrous acid. The anine acts as a nucleophile, attacking the nitrogen of nitrosyl cation. The intennediate that is fonned in the first step loses a proton to give an N-nitroso anine as the isolated product. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

When a cyclic /3-amino alcohol—e.g. 1—is treated with nitrous acid, a deamination reaction can take place, to give a carbenium ion species 2, which in turn can undergo a rearrangement and subsequent loss of a proton to yield a ring-enlarged cyclic ketone 3. This reaction is called the Tiffeneau-Demjanov reactionit is of wider scope than the original Demjanov reaction ... 

The reaction of nitrous acid with the amino group of the /3-amino alcohol—e.g. 1-aminomethyl-cyclopentanol 1—leads to formation of the nitrosamine 4, from which, through protonation and subsequent loss of water, a diazonium ion species 5 is formed " —similar to a diazotization reaction ... 

A solution of nitrous acid in sulfuric acid exists as the equilibrium indicated in Scheme 2-15, as was shown by Seel and Winkler (1960), and by Bayliss et al. (1963). These authors determined the equilibrium concentration of [HN02] and [NO+] in various acid concentrations spectrophotometrically. They found that in aqueous sulfuric acid containing more than about 57% w/w H2S04 the equilibrium of Scheme 2-15 is predominantly on the right-hand side. This equilibrium and the problem of the potential intermediate nitrosoacidium ion (H20-N0), which is the proton addition product of HN02, will be discussed in Section 3.2. 

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. 

Fig. 3-2. Molecular electrostatic potential with 6-31G //3-21G basis set in the molecular plane of (ii)-nitrous acid. Black dots refer to four different protonation sites in potential minima. For values of isopotential contours see Nguyen and Hegarty, 1984.

No accurate rate measurements have yet been carried out, but qualitative experiments showed that the exchange was acid-catalysed so that it is likely that the protonated form of the nitrosamine (LIII) acts itself as a nitrosating agent. This would account for all the earlier cross-nitrosations that have been observed without necessitating the prior formation of nitrous acid, nitrosyl chloride or any other carrier of NO+. 

These reactions involve a diazonium ion (see 12-47) and are much faster than ordinary hydrolysis for benzamide the nitrous acid reaction took place 2.5 x lo times faster than ordinary hydrolysis. Another procedure for difficult cases involves treatment with aqueous sodium peroxide. In still another method, the amide is treated with water and f-BuOK at room temperature. " The strong base removes the proton from 107, thus preventing the reaction marked k j. A kinetic study has been done on the alkaline hydrolyses of A-trifluoroacetyl aniline derivatives. Amide hydrolysis can also be catalyzed by nucleophiles (see p. 427). 

An acid that forms from a polyatomic anion whose name ends in -ite has a name ending in -ous. For example, HNO2 forms by adding a proton to the nitrite polyatomic anion, so HNO2 is nitrous acid. Likewise, HCIO is hypochlorous acid from the h T)ochlorite anion. 

Nitrite concentration The kinetics of N-nitrosamine formation in vitro has been studied at length (, ) and, in moderately acidic media, the reaction rate is directly proportional to the concentration of the free amine (non-protonated) and to the square of the concentration of the undissociated nitrous acid. Therefore, it is not surprising that the amount of nitrite permitted in bacon has received considerable attention. Although, there have been suggestions that it is the initial and not the residual nitrite that influences N-nitrosamine formation in bacon (41), recent evidence seems to indicate that the lowest residual nitrite gives the least probability of N-nitrosamines... 

This means that the ionization and rearrangement need not be concerted and that symmetrical protonated ethylene can not be a major intermediate in the reaction. A similar experiment with isobutylamine and nitrous acid in heavy water gave products that contained no carbon-deuterium bonds. Since it is known that the -complex formed from isobutylene and acid is in rapid equilibrium with protons from the solvent, none of this can be formed in the nitrous acid induced deamination. This in turn makes it probable that the transition state for the hydrogen migration is of the sigma rather than the -bonded type.261... 

The principal in vitro route to the formation of RSNOs is through the reaction of nitrous acid or protonated nitrite (HN02) with thiols (Eq. (1)). Since the pKa of HN02 is 3.37, this reaction is unlikely to occur in cells and tissues where the pH is maintained at 7.4. 

The carbinol equilibrium (equation 19) is comparable to the nitrous acid equilibrium (equation 18), but this correlation does not exclude the nitrosacidium intermediate because the corresponding protonated carbinol was not positively excluded in equation 19. 

It is remarkable that the only compound isolated from this reaction results from attack by solvent on the carbonium ion atC-2. By analogy with the deamination of the 2-aminocyclohexanols by nitrous acid, it might have been expected that a 3-oxo derivative would have been formed as a result of hydride migration, because the C-3 proton is antiparallel to the leaving group. 

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