Ion pair stabilization effects on a series of procaine structural analogs

In this work, a series of 10 structural procaine analogs have been synthesized in order to investigate the structural features affecting the stability of ion pair formation and its influence on the lipophilicity of ionizable compounds. The structural variation within this series was focused on the terminal nitrogen substituents and on the intermediate chain linkage nature. The hydrophobic parameters log Pn and log Pi (partition coefficient of the neutral and ionic species, respectively), as well as the ionization constants pKa and pKaoct, were obtained from log D–pH profiles measured at pH values ranging from 2 to 12. The difference between log Pi and log Pn values (i.e. difflog P) of each prepared compound was considered a measure of the stability of ion pair formation. In this set, the difflog P values varied nearly over one log unit, ranging from −2.40 to −3.37. It has been observed that the presence of hydrogen bonding groups (especially donor) and low steric hindrance around the terminal amine ionizable group increases the relative lipophilicity of the ionic species as compared to the corresponding neutral species. These results were interpreted as due to the increased stability of ion pairs of the compounds bearing these structural features.