Theoretical Calculations of the pKa Values of 1-Aryl-4-propylpiperazine Drugs in Aqueous Solution

Theoretical calculations were carried out to predict the aqueous-phase acidities of a series of drug 1-phenyl-4-propylpiperazine and its derivatives. The performances of the density functional theory(DFT) methods B3LYP and B3P86, solvation models[the polarized continuum model(PCM) and the conductor-like polarized continuum model(CPCM)], and the basis set effect were tested. A comparison between the theoretical and experimental pK(a) values forpara-substituted 1-phenyl-4-propylpiperazines reveals that the accuracy of B3LYP is better than that of B3P86, and the basis set 6-31++G(d,p) and the CPCM model are suitable for calculating pK(a) values of the substituted 1-phenyl-4-propylpiperazine. For the investigated compounds, a reasonable agreement between the experimental and calculated pK(a) values was also observed.