Basicity of imidazole

Among these 1,3-azoles, imidazole is the most basic compound. The increased basicity of imidazole can be accounted for from the greater electron-releasing ability of two nitrogen atoms relative to a nitrogen atom and a hetero-atom of higher electronegativity. Some of the physical properties of these compounds are presented below. 

Another way to look at the basicity of imidazole would be to say that both nitrogen atoms can act at once on tire proton being attacked. It has to be the pyridine-like nitrogen that actually captures the proton but the pyrrole nitrogen can help by using its delocalized electrons like this. 

The effects of substituents on the acidic and basic strengths of imidazoles have been discussed by Hofmann1 and Pozharskii et al.3 in previous reviews. Precise data have been determined175 for the basicity of imidazole in D20-H20 mixtures. Perrin176 has developed methods based on the Hammett equation for predicting the pKa values in water of substituted imidazoles (and other heterocycles), while applications of the Hammett equation have also been made to 2-substituted imidazoles.177 Calculations of j>K values for 2-amino-imidazolium ions suggest that 2-aminoimidazoles are better regarded... 

Proton acids at neutral azoles basicity of imidazoles and benzimidazoles Proton acids at imidazole anions acidity of imidazoles Metal ions... 

One major consequence of the basicity of imidazole is that at physiological pH (—7.4) substantial quantities of both the free base and protonated imidazole species are present in the histidine units of a protein. This allows histidine to act as either a proton acceptor or a proton donor according to the demands of its immediate environment. It seems likely that histidine units in a number of enzymes such as ribonuclease, aldolase and some proteases may have this role. The buffering action of histidine in the hemoglobin-oxyhemoglobin... 

The fused benzene ring of benzimidazole decreases the basicity of imidazole by about the same amount as a 1-phenyl or a 5-chloro or -bromo substituent, and the groups attached to that benzene ring (e.g. Cl, NO2) can enhance this base-weakening effect. The marked difference in basicity between 1- and 2-methylbenzimidazoles may be a consequence of the more symmetrical cation (54) formed by the latter (Scheme 15). 

The basicity of imidazole was thoroughly covered in CHEC(1984) and CHEC-II(1996). The ambivalent acid-base properties of imidazole play an important role in the biochemical activity of the histidine unit. 

In the past, considerable significance was attached to the syn-carboxylate interaction. Candour (1981) suggested that the syn electron pair may be more basic than the anti pair by a factor 10 -10. This seemed to explain the enhanced basicity of imidazole. However, studies of databases (Allen and Kirby, 1991) and model compounds (Zimmerman et ai, 1991) indicate that the difference in the relative basicities between syn- and anti-carboxylates is marginal (0.4—0.6 units). The hPL triad and the Asp-His couple in the active center of phospholipase A2 appear to support this view. Thus, the preference toward syn-type bonds observed in most serine proteinases may be due to packing effects in the active centers rather than to stereoelectronic effects. 

In solution, resonance stabilization (R) is commonly the predominant structural driving force of a reaction. Gas-phase proton-transfer equilibria offer a striking contrast, in which the R effects are frequently found to be secondary to a predominant combination of I and P effects. However, it is recognized that for aromatic compounds, such as, for instance, imidazole, resonance stabilization of the protonated form is the predominant contribution determining the relatively high basicity of imidazole and its congeners in the class of five-membered heteroaromatic compounds. 

The relative gas-phase basicities of imidazole (4), benzimidazole (5), pyrazole (6), indazole (7), 1-methylindazole (8), and 2-methylindazole (9) have been estimated by mass spectrometric methods (Fig. 23) (840MS627). Although the measurement of — log K is affected by some uncertainty, the correlation of Fig. 23 suggests that the experimental and the calculated... 

Proton acids at neutral azoles basicity of imidazoles and benzimidazoles... 

The high basicity of imidazole in comparison with other azoles has been attributed to the stability of the symmetrical imidazolium cation. That pyrazole is less basic can be ascribed to extra destabilization of the 7r-system on protonation <8iJHCl 189). Imidazole s pATj value of close to seven has ramifications for the biological activity of the histidine unit, for example, the two imidazole rings of His 12 and Hisl 19 in Ribonuclease A act as both acid and basic catalysts in the hydrolytic cleavage of RNA <91ACR317>. Some pK. values for substituted imidazoles are tabulated in Table... 

Since the basicity of imidazole is higher than that of pyridine, it is likely that IPs should first be protonated at the imidazole N-atom. But this is not always true. 

With imidazoles 101 as catalysts, the MBH reaction of cyclic enones was greatly accelerated in basic water solution and bicarbonate solution has been shown to be the optimal reaction medium. The reaction runs much faster in sodium bicarbonate solution than in distilled water, and showed an obvious pH dependence. Notably, these conditions have been applied successfully to various aldehydes and cyclic enones, especially to unreactive and hindered aldehydes (Scheme 2.46). The apparent enhanced basicity of imidazoles accounted for the rate increase in alkaline solution. 

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