Imidazole, delocalisation

Thus, delocalisation of the nitrogen lone pair completes the sextet of electrons required for aromaticity. These two examples illustrate the point that certain heterocycles (closely analogous to benzene and naphthalene) such as pyridine 5.1, pyrimidine 10.1, and quinoline 6.1 are aromatic by right whereas other heterocycles such as pyrrole 2.1, imidazole 3.2, and triazole 8.7 have to earn aromaticity by delocalisation of a lone pair of electrons from the heteroatom. 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

Every additional nitrogen atom must be of the pyridine sort and this has the curious effect of increasing both the acidity and the basicity. There is another difference. Protonation now occurs on the pyridine-like nitrogen atom but both nitrogen atoms cooperate to deliver electrons in both pyrazole 111 and imidazole 112. In this process the pyridine-like nitrogen atom becomes pyrrole-like and vice versa but this is merely formal as the cations 110 and 113 are symmetrically delocalised and the two nitrogen atoms are equivalent. 

The pA a for loss of the A -hydrogen of imidazole is 14.2 it is thus an appreciably stronger acid than pyrrole (pATa 17.5) because of the enhanced delocalisation of charge, involving both nitrogens in the imidazolyl anion. Salts of imidazoles can be alkylated or acylated on nitrogen. One convenient method is to use the dry sodium/potassium salt obtained by evaporation of an aqueous alkaline solution sodium hydride in dimethylformamide also serves very well for this purpose. 

Purine, with a pA a of 8.9, is slightly more acidic than phenol and much more acidic than imidazole or benzimidazole (pA aS 14.2 and 12.3, respectively). This relatively high acidity is probably a consequence of extensive delocalisation of the negative charge over four nitrogens, however alkylation of the anion takes place in the live-membered ring, since attack at N-1 or N-3 would generate less aromatic products. 

Fig. 23. Delocalisation of unpaired electron in haem (A) and the effect of the proximal histidine imidazole orientation on the haem electronic structure (B).

The for loss of the N-hydrogen of imidazole is 14.2 it is thus an appreciably stronger acid than pyrrole pK 17.5) because of the enhanced delocalisation of charge, especially onto the second nitrogen, in the imidazolyl anion. 

Cyclic peptide antibiotic. The imidazole ring shows charge delocalisation. Isol. from the sponge Theonella swinhoei. Antifungal agent. Powder, [aj +19 (c, 0.4 in MeCN aq.). Similar to Theonellamide F, T-10084. 

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