Theoretical Calculations of the pKa Values of 1-Aryl-4-0rooylpiperazine 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 conti- nuum model（CPCM）], and the basis set effect were tested. A comparison between the theoretical and experimental pKa values for para-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 pKa values of the substituted 1-phenyl-4-propylpiperazine. For the investigated compounds, a reasonable agreement between the experimental and calculated oKo values was also observed.