Mechanism for binding to the flexible cavity of permethylated alpha-cyclodextrin

The cavity of alpha-cyclodextrin (alpha-CDx) is too small to include o-toluic acid (o-TA) while it is filled by p-toluic acid (p-TA) to form a relatively stable inclusion complex. Such strict selectivity is ascribed to a rigid structure of the alpha-CDx cavity which is stabilized by intramolecular hydrogen bonds between the O(2) hydroxyl groups and the O(3) hydroxyl groups of adjacent glucopyranose units. Meanwhile, the substrate selectivity of hexakis(2,3,6-tri-O-methyl)-alpha-CDx (TMe-alpha-CDx) remains somewhat obscure because of the flexible nature of its cavity. The absence of the intramolecular hydrogen bonds seems to cause the flexible nature of the TMe-alpha-CDx cavity leading to an induced-fit type inclusion. The structures of the inclusion complexes have been presented on the basis of the H-1 NMR data. The thermodynamic parameters indicate that the complexation of TMe-alpha-CDx with o-TA or p-TA is the entropically favorable process. The entropically favorable complexation of TA with TMe-alpha-CDx seems to occur through dehydration from the CO2H group of TA which is situated at the hydrophobic CDx cavity. The dipole-dipole interaction has been regarded as the force which dominates the orientation of the polar guest molecule in the CDx cavity.