4 -Substituted 1,3-azoles, tautomerism

Table 37 Tautomerism of 3-Substituted Azoles with Heteroatoms-1,2 ...

Table 39 Tautomerism of 2-Substituted Azoles with Heteroatoms-l,3 ...

Table 44 Tautomerism of 5-Substituted Azoles with Heteroatoms-1,2"...

Table 43 Tautomerism of 3-substituted azoles with heteroatoms-1,2...

Table 45 Tautomerism of 2-substituted azoles with heteroatoms-1,3...

Imidazoles and benzimidazoles unsubstituted on nitrogen exhibit fast prototropic tautomerism which leads to equilibrium mixtures of unsymmetrically substituted compounds, for example, 4(5)-substituted imidazoles, 4(7)- or 5(6)-substituted benzimidazoles. The proton exchange is an intermolecular process (which may involve a protic solvent), and is so fast on the NMR time scale that only one species is usually apparent in the spectrum. iV-Substituted azoles cannot exhibit such tautomerism, and strongly acidic media also inhibit proton exchange. Much work since the mid-1980s has focussed on determination of the proportions of isomers in tautomeric mixtures, with theoretical studies applied to the gas phase (and solution), and solid state studies are also receiving considerable attention. Extrapolation of the results of gas phase and solid state studies to solution, though, can only be less than perfect. 

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

Complex tautomerism for azoles with heteroatoms in the 1,2-positions occurs for pyrazoles which are not substituted on nitrogen. Scheme 10 shows the four important tautomeric structures (148)-(151) for 3-methylpyrazolin-5-one, and (152) and (153) as examples of other possible structures. A detailed investigation of this system disclosed that in aqueous solution (polar medium) the importance of the tautomers is (149) > (151) (150) or (148), whereas in cyclohexane solution (non-polar medium) (151) > (148) (149) or (150). 

The tautomerism of 2-substituted 1,3-azoles (154 155) is summarized in Table 39. Whereas amino compounds occur Invariably as such, all the potential hydroxy derivatives exist in the 0x0 form, and in this series the sulfur compounds resemble their oxygen analogs. There is a close analogy between the tautomerism for all these derivatives with the corresponding 2-substltuted pyrldines. 

Substituted 1,3-azoles exist in two non-charged tautomeric forms (156) and (157) together with the zwitterlonic form (158). 5-Substltuted 1,3-azoles also exist in forms (159) and (160) together with the zwitterlonic forms (161). Some results are summarized in Table... 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

Annular tautomerism of azoles and benzazoles [the nonaromatic tautomers of imidazole 17, 2H and 4(5)H have been calculated at the MP2/6-31G level to be about 15 kcal mol less stable than the IH tautomer (95JOC2865)]. We present here the case of 4(5)-substituted imidazoles, different from the histamine, histidine, and derivatives already discussed. By analogy with these histamines, 4-methylimidazole 17a is often named distal [N(t)H] and 5-methylimidazole 17b, proximal [N(7t)H] (Scheme 9). 

The conclusions about the influence of azole ring substituents on the tautomeric equilibria are summarized in Table VIII. Although sufficient data are available for pyrazoles and imidazoles, it is difficult to correlate them within any well-defined scheme. The energy differences between pairs of tautomers are generally quite small and attempts to analyze these using, for example, the Taft-Topson model failed [95JCR(S)172]. In the case of mono-substituted compounds, Hammet-type equations... 

This section covers ligands containing the 1,2,3-triazole ring system. These include, in addition to the parent triazole, various N- and/or C-substituted triazoles, benzotri azole, and a number of 8-azapurines. The coordination chemistry of 5-thio-l,2,3,4-thiatriazole is selectively reviewed. All of these molecules, with the exception of the N-substituted triazoles, are capable of coordinating in anionic as well as neutral form. 1,2,3-Triazole, first prepared by von Pechmann in 1888 (215), is a weak acid (p/ a = 9.26) (88) and exists as a mixture of the tautomeric forms (structures la and lb). Benzotriazole (2), first correctly formulated... 

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