Cyclodextrin-induced acidity modification of substituted cathinones studied by capillary electrophoresis supported by density functional theory calculations

Abstract

This paper shows that the acidity of substituted cathinones can change in a diversified and poorly predictable manner upon supramolecular interaction with cyclodextrins used as buffer additives in capillary electrophoresis. The direction and range of pK_a shifts may be noticeably different for the particular cyclodextrins and cathinones, suggesting a strict correlation with structure. The most interesting results were observed for 2-hydroxyethyl-β-cyclodextrin, which is capable for inducing the large negative and enantioselective apparent pK_a shifts for α-pyrrolidinovalerophenone and methylenedioxypyrovalerone, even much above -1.0 pH unit. A thermodynamic analysis was performed, to identify the role of enthalpy and entropy in the formation and deprotonation of the respective diastereomeric complexes. The former process turned out to be driven by an energetically favorable increase in entropy, related probably to a hydrophobic effect. Deprotonation enthalpy in the complexed state, in turn, occurred to be more favorable than in the free molecule state, entailing the large drop in pK_a after complexation. The DFT calculations allowed us to identify some structural effects that most likely contribute to these phenomena. At last, we have demonstrated that at low cyclodextrin concentration and pH ensuring partial ionization, pK_a shifts contribute to chiral separation of the abovementioned cathinones. This analytically important effect may be helpful in anticipating the most efficient chiral separation mechanism of other systems.

Keywords: Acidity; Capillary electrophoresis; Cathinone; Chiral separation; Cyclodextrin; Thermodynamics.