Thiourea reaction with nitrous acid

As long ago as 1912 it was shown that thiourea reacted with nitrous acid by two routes which can readily be interpreted as involving N- and S-nitrosation respectively (Werner, 1912). It appeared that the S-nitrosation route was favoured at higher acidities and N-nitrosation (which leads to the formation of nitrogen and thiocyanate ion) at lower acidities. More recently the reaction has been studied in detail mechanistically (Al-Mallah et al., 1974). At high acidities the initial product is the S-nitroso ion formed according to (45). The... 

Oxidation of (266 Ar = Ph) with nitrous acid produces the thiadiazole (86) which can be isolated when R is alkyl. Treatment of (86) with acid produces Hugerschoff bases (87 Scheme 93). When R of (266) is aryl, isomerization is rapid and only (87) is obtained when acidic peroxide is used as the oxidant (65AHC(5)119>. Recently the reaction has been studied using mixtures of thiourea and jV.JV -disubstituted thioureas. Products of type (267) and (268) were isolated from N-aryl-TV -alkylthioureas but only (268) was obtained from the yV-aryl-W-aryl and JV-alkyl-AT-alkyl derivatives (Scheme 94) (80IJC(B)667,75IJC(B)24l). 

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... 

In the absence of added nucleophiles, nitrosation occurs virtually irreversibly by an acid-catalysed pathway, presumably by attack by HjNO or NO". The third order rate constant from the rate equation equivalent to (46) has a value of 840 dm moF s- at 31°C (c/. 456 and 6960 dm mol- s for cysteine and thiourea respectively at 25°C) which suggests that for this neutral substrate the reaction rate is somewhat less than that expected for an encounter-controlled process. There is a major difference between the nitrosation of alcohols and that of thiols in that, whilst the former reactions are reversible (with equilibrium constants around 1), the reactions of thiols are virtually irreversible. It is possible to effect denitrosation of thionitrites but only at high acidity and in the presence of a nitrous acid trap to ensure reversibility (Al-Kaabi et al., 1982). Direct comparisons are not possible, but it is likely that nitrosation at sulphur is much more favoured than reaction at oxygen (by comparison of the reactions of N-acetylpenicillamine and t-butyl alcohol). This is in line with the greater nucleophilicity expected of the sulphur atom in the thiol. For the reverse reaction of denitrosation [(52) and (53)], the acid catalysis observed suggests the intermediacy of the protonated forms... 

Moderate yields of thiadiazoles (255) also have been obtained by the thermolysis of mixtures of thioamides (253) and N -sulfinylsulfonamides (259 Scheme 91) (62AG135). The manner in which the proposed intermediate (260) is converted into (255) has not been discussed and the mechanism of this reaction deserves further study. (V-Aryl thioureas (261) form 1,2,4-thiadiazole derivatives (73) ( Hector s bases ) in good yields when oxidized with acidic hydrogen peroxide or other oxidizing agents (nitrous acid, iron(III) chloride) as indicated in Scheme 92 (65AHC(5)119). Evidence for the intermediate formation of dithio-... 

The denitrosation reaction was also examined, using hydrazine as a trap for free nitrous acid. A range of denitrosation reactions have been studied together with the reactivity of thiourea, alkylthioureas, cysteine, glutathione, 5-methyl-cysteine and methionine toward A -methyl-A -nitrosoaniline. The results are consistent with an initial rate-determining 5-nitrosation of the thiourea by the protonated nitrosamine. Alicyclic nitrosamines and nitrosoamino acids have also been considered as transnitrosating agents. 

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