Acidities of azoles in the gas phase and in DMSO: an ab initio and DFT study§

Abstract

Acidity of azoles, a very important family of biological molecules with useful pharmacological applications, is examined in the gas phase and in DMSO. The gas phase proton affinities of the corresponding conjugate bases are calculated by the G3 computational scheme and used as a measure of acidity. A good accordance with available experimental data is obtained. It is confirmed that acidity increases with the number of nitrogen atoms in the five-membered ring. The calculated deprotonation energies are interpreted by the triadic formula. It turns out that acidity of azoles is a result of the final state effect and the relaxation energy contribution. It is shown, by using NICS(1) values, that azoles are aromatic compounds and that their aromatic character increases with the number of N atoms. It is also found that aromaticity slightly increases upon deprotonation. Acidity of azoles in DMSO is considered using the isodensity polarized continuum model (IPCM) at the DFT-B3LYP level. A good agreement with accessible experimental results is obtained again. In other cases pKa values are theoretically predicted and it was found that pentaazole is the most acidic compound with pKa = 2. A very good linear relation between theoretical pKa values and calculated proton affinities of conjugate bases is obtained implying that the trend of changes in the gas phase and in the DMSO solutions is the same.