Modulation of pKa by cyclodextrins; subtle structural changes induce spectacularly different behaviors

Abstract

Tuning of acidity-related properties by host–guest complexation is one of the most promising concepts in current supramolecular chemistry. However, still little is known about structural effects which determine direction and magnitude of supramolecular pK_a shifts. Here we present the first systematic comparison of cyclodextrin-induced pK_a shifts with a focus on minor structural differences between guests – phenolic drug warfarin and its six isomeric derivatives, and hosts – various structurally similar cyclodextrins. Warfarin and five hydroxywarfarins exert upward pK_a shifts upon complexation with β-cyclodextrin and its neutral derivatives. However, the magnitude of these shifts depends on the cyclodextrin substituent, and even, on the average substitution degree. The strongest shifts are observed for methyl-β-cyclodextrin, they are among the greatest cyclodextrin-induced pK_a shifts noted so far. By contrast, 10-hydroxywarfarin exhibits only minor shifts whose direction is, surprisingly, dependent on temperature. Furthermore, the temperature variations of pK_a show that endothermic dissociation is observed for 2-hydroxypropyl-β-cyclodextrin, similarly as in the host-free state, while it becomes exothermic for methyl-β-cyclodextrin. In other words, acid dissociation of two structurally similar host–guest complexes is characterized by dramatically different enthalpic contributions. Finally, some enantioselective effects are also observed. We infer that intramolecular hydrogen bonds and enantioselective interactions with portal cyclodextrin groups are likely crucial for these phenomena. Our work may open up new horizons in understanding of structural effects in the supramolecular pK_a tuning.