Nitroimidazoles, annular tautomerism

While dealing with imidazoles, an important characteristic is their annular tautomerism. A tautomeric equilibrium for many imidazoles is rapidly achieved at room temperature. In some tautomeric pairs, though, one tautomer often predominates over the other. For instance, 4(5)-bromoimidazole favors the 4-bromo-tautomer in a 30 1 ratio, whereas 4(5)-nitroimidazole exists predominantly as the 4-nitro tautomer (700 1) [11]. 4(5)-Methoxyimidazole has a ratio of 2.5 1 for the 4- and 5-methoxy tautomers. 

This special case of prototropy is known as annular tautomerism (see p 111). In solution, equilibria are established so rapidly that the separate tautomers cannot be isolated. However, their presence can be demonstrated by spectroscopic methods. In this case, e.g. R = CH3, the compound is known as 4(5)-methylimidazole. With certain substituents R, the equilibrium lies predominantly to one side, for instance, in the case of the nitro compound (4-nitroimidazole) or with the methoxy compound (5-methoxy-imidazole). Annular tautomerism has also been demonstrated for 4,5-disubstituted imidazoles ... 

When the imidazole ring already has a substituent at C-4 or C-5 then there will be a directional effect imposed on electrophilic attack at annular nitrogen. As outlined earlier (Section 4.02.1.3) this orientation may be related to the tautomeric nature of the substrate. In spite of the inherent pitfalls in equating tautomeric nature with chemical reactivity there are examples which seem only to be explicable in terms of a major tautomer reacting, e.g. methylation of 4-nitroimidazole. Substituents at C-2 can only affect the rate of a reaction at ring nitrogen. 

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