Structures of Azoles

3- and 1,2-azoles, five-membered rings with two heteroatoms, present a fascinating combination of heteroatom types - in all cases, one heteroatom must be of the five-membered heterocycle (pyrrole, thiophene, furan) type and one of the imine type, as in pyridine imidazole with two nitrogen atoms illustrates this best. Contributor 39 is a particularly favourable one. 

Structure of imidazole resonance contributors (mesomeric structures) 

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Experimental values are collected in the McClellan book (B-63MI40400) and in a review on dipole moments and structure of azoles (71KGS867). Some selected values are reported in Table 3. The old controversy about the dipole moment of pyrazole in solution has been settled by studying its permittivity over a large range of concentrations (75BSF1675). These measurements show that pyrazole forms non-polar cyclic dimers (39) when concentration increases and, in consequence, the permittivity value decreases. 

Figure 16.30 Chemical structures of azole thiophenes and azine-thiophenes...

The same reaction performed in ether at 0°C (336) gives the same major adduct, but the structure proposed by Acheson et al. corresponds to 86, although such a structure is hardly compatible with the presence of an isolated low-field proton. Very recently, in a reinvestigation of these cyclo-additions of DMA to azoles (338, 339), Acheson et al. were able to establish the correct structure of the adducts on the base of CNMR spectra and X-ray diffraction studies. The adduct of thiazole is represented by formula 87, and it results from the rearrangement of the... 

Orientation in azole rings containing three or four heteroatoms Effect of azole ring structure and of substituents Proton acids on neutral azoles basicity of azoles Proton acids on azole anions acidity of azoles Metal ions... 

Oxidation of azole anions can give neutral azole radicals which could, in principle, be tt (139) or a- (140) in nature. ESR spectra indicate structure (141 hyperfine splittings in G) for imidazolyl radicals, but both tt- and cr-character have been observed for pyrazolyl radicals. Tetrazolyl radicals (142 4 143) are also well known (79AHC(25)205). Oxidation of 2,4,5-triarylimidazole anions with bromine gives l,l -diimidazolyls (144) which are in equilibrium with the dissociated free radical (145) (70AHQ 12)103). 

The imbalance between and NMR studies in the solid state (Section VI,F) partly reflects the fact that it is easier to introduce N than into heterocyclic compounds, particularly azoles (DNMR in the solid state usually requires isotopic enrichment). Compared to solution studies, solid-state intermolecular proton transfer between tautomers has the enormous advantage that the structure of the species involved is precisely defined. 

Whereas vicinal hydroxy, mercapto, and hydroselenoaldimines of azoles strongly prefer the aminomethylene tautomeric form (Section II,E,2), their metal chelates 380 are characterized by.pronounced equalization of bond lengths within the chelate ring, which makes their structures similar to those expected for the aldimine tautomeric type. 

The cyclization of l-alkoxybut-l-en-3-ynes with hydrazine was first achieved by Franke and Kraft (55AG395). By heating 1-methoxybut- l-en-3-yne with hydrazine sulfate in an aqueous alcohol medium they obtained 3(5)-methylpyrazole (13) in high yield. Winter (63HCA1754) used the cyclization of 1-methoxybut-l-en-3-yne with hydrazine hydrate and phenylhydrazine to establish the structure of the initial enyne ether [in this case a mixture of l-phenyl-3(5)-propylpyrazoles was obtained]. The reaction with hydrazine sulfate gives only one product, 3(5)-propyl-pyr azole. 

The structure of the intermediate obtained from 3-phenyl-5-amino-l,2,4-thiadi-azole (Goerdeler and Deselaers, 1958) was elucidated by UV- and IR-spectroscopy. The results are consistent with the nitrosoamine structure 3.18. Its UV spectrum (Fig. 3.4) is very similar to that of the A-methyl-TV-nitroso compound 3.19, but different from that of the isomeric compound 3.20 with a methyl group in the 4-position (Goerdeler and Deselaers, 1958). The spectrum of this 4-methyl derivative is expected to be similar to that of the nitrosoamine structure 3.21, which is obviously not present, at least not in detectable tautomeric equilibrium concentration. 

Table 7 shows the structures of representative azole compounds and several structurally related compounds such as benzimidazoles, thiazoles and imidazolines. 

Neutral complexes with azolate ligands of the type [AuL(PPh3)], with L representing differently substituted pyrazolates,2251,2366 imidazolates,365,2 69 2370 benzidimidazolates, 71 2372 triazolate,2373 tetraazolate (403),536 or 2,2 -bibenzimidazolates (404),2374,2375 have been prepared. The structure of the [Au(l,2,4-triaz)(PPh3)] is a dimer with Au-,Au interactions (405).23 3 The antimicrobial... 

Model systems for Type I copper proteins structures of copper coordination compounds with thioether and azole-containing ligands.17... 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

All the studies on the elucidation of the structure of diazoazoles lead unequivocally to a mesoionic structure in which the negative charge is localized in the azole ring. Of primary importance were C-NMR and IR spectra, as well as X-Ray crystal diffraction data. With regard to the stability in the solid state of diazoazoles and in solution in the pH range where they are not protonated, the presence of ortho ring nitrogens destabilizes the diazo compounds. 

Podust, L. M., Poulos, T. L., and Waterman, M. R. (2001) Crystal structure of cytochrome P450 14alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc. Natl. Acad. Sci. USA 98, 3068-3073. 

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