Imidazole hydroxy-, tautomeric forms

As discussed in the General Chapter (Section 4.01.5), imidazoles with potential hydroxy, thiol and amino substituents can exist in a variety of tautomeric forms. In contrast to the hydroxypyrazoles which have been studied in detail, comparatively little is known about the corresponding 1,3-diazoles. Many of the imidazoles are not easily accessible synthetically, and they may not be particularly stable e.g. 4-hydroxyimidazoles). Amino derivatives... 

Among the species produced upon radiolysis of water, hydroxyl radical ( OH) is the most reactive. Indeed, its reaction rate with the four bases and related nucleosides is diffusion-controlled. The main reactive sites of hydroxyl radicals on nucleobases are the double-bonds of the heterocycles. Accordingly, addition of OH at the C8 position of adenine and guanine yields the corresponding reducing 8-hydroxy-7,8-dihydropurin-7-yl radical (Fig. 2). Oxidation of this intermediate leads to the formation of related 8-hydroxypurines that are in dynamic equilibrium with their more stable 8-oxo-7,8-dihydropurine tautomeric form. Competitive reduction of the latter purine radical gives rise to imidazole ring opened compounds the... 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

A strictly dehned region of chemical shifts of C2, C4, and C5 atoms in A-oxides of 4A-imidazoles allows to dehne clearly the position of the A-oxide oxygen atom (102). Chemical shifts of the a-C nitrone group in a-N-, O-, and S-substituted nitrones are located in the region of 137 to 150 ppm (388, 413). On the basis of 13C NMR analysis of 3-imidazoline-3-oxide derivatives, the position of tautomeric equilibria in amino-, hydroxy-, and mercapto- nitrones has been estimated. It is shown that tautomeric equilibria in OH- and SH-derivatives are shifted toward the oxo and thioxo forms (approximately 95%), while amino derivatives remain as amino nitrones (413). In the compounds with an intracyclic amino group, an aminonitrone (A) - A-hydroxyaminoimino (B) tautomeric equilibrium was observed (Scheme 2.76), depending on both, the nature of the solvent and the character of the substituent in position 2 of the heterocycle (414). 

Investigations on the tautomerism of fused heterocyclic moieties favor the lactam form of the imidazole substructure of 16 (65CPB473) and the thiolactam tautomer in thiazoles 192 and 197 [62BCJ1998 64BCJ1526 95PS(101)167], but the hydroxy form in pyrazole 183 [82IJC(B)765]. 

The tautomerism of these compounds has been discussed in detail in the chapters on structure (Sections 4.01.1.1 and 4.06.5.2), and general reactivities have been considered in Chapter 4.02.3.7 wherein the relative reactivities and interconversions of the hydroxy and carbonyl forms are summarized. Some of the reactions have also been covered in the section dealing with non-aromatic derivatives of imidazoles (Section 4.07.2). Discussion here will be limited to reactions which do not lead to ring fission. 

Unlike formamidine, acetamidine and benzamidine react with both aromatic and aliphatic a-hydroxyketones to give imidazoles exclusively. It has been suggested that aryl groups favour the enolic form (2) of the tautomeric mixture, resulting in the formation of oxazoles as major products. Aliphatic groups favour the keto form (1), from which imidazoles are derived. That amidines more complex than formamidine favour imidazole formation may be a consequence of steric hindrance to reaction of the enolic hydroxy groups with the amidine carbon in (2). The general reaction has been used to prepare such compounds as 4,5-dipropyl imidazole (25% yield from tris(formylamino)-methane and 5-hydroxyoctan-4-one), and a variety of 2-imidazolones and 2-aminoimidazoles [8]. The fact that oxazoles can be converted into imidazoles with some ease extends the applicability of this reaction. 

Aminonitrone-A -hydroxyaminoimine tautomerism in 2-substituted l-hydroxy-4,4,5,5-tetramethyl-4,5-dihydro-l//-imidazole 140 is considered to be an acid-base equilibrium with the ratio between the forms dictated by the ratio of their acidity constants. A substituent with a positive mesomeric and/or inductive effect stabilizes the nitrone form 140A more effectively than the A-hydroxyaminoimino form 140B (Scheme 35) <2004JST(697)49>. ... 

Calculation of the heats of combustion for imidazoles suggest that, in substituent-nucleus tautomerism, the tautomer with the mobile proton on nitrogen should be more stable than that with it on carbon, and that the amino forms of amines, and the carbonyl forms of hydroxy compounds, are preferred. ... 

A review has highlighted the roles of zwitterions in hydroxyimidazole tautomerism, for example, an aromaticity index (7 see Section 3.02.4.2.1) of 68 points to a zwitterionic species (39) rather than the hydroxy tautomer (40) which would have an value of around 79 (Equation (4)) <94H(37)249>. Thiols generally resemble the oxy analogues. Solid state IR and Raman spectroscopy point to imidazole-2-thiol existing in the SH form in the solid <89CCC2045>. 

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