Determination of 1-aryl-4-propylpiperazine pKa values: the substituent on aryl modulates basicity.

In order to design a potential drug, it is important to know its pK(a) because the protonation state of the molecule will be critical for ligand-receptor interaction and for the pharmacokinetic of the molecule. pK(a) values of a series of 1-(substitutedphenyl)-4-propylpiperazines were measured to study how the presence of a substituent on the phenyl ring modulates the basicity of N-4 nitrogen. pK(a) values indicated that the position of the substituent was crucial. In general, the introduction of the substituent in ortho-position of the phenyl ring increased the basicity of the molecule. This effect appeared to be related to steric and conformational effects and not to the electronic properties of the substituent. On the other hand, meta- and para-substituted derivatives showed a slight decrease of pK(a) that was qualitatively consistent with the electronic properties of the substituent.