Novel prediction for the driving force and guest orientation in the complexation of α- and β-cyclodextrin with benzene derivatives

Taking the possibility of different inclusion orientations into consideration, a nonlinear free energy relationship model has been established by means of a genetic algorithm for the molecular recognition of alpha- and beta-CD with mono- and 1,4-disubstituted benzenes. The association constants (K-a) for the inclusion complexation of alpha- and beta-cyclodextrin with a number of benzene derivatives were evaluated by the model from the substituent molar refraction R-m hydrophobic constant pi, and Hammett constant sigma, which respectively reflect the volume, hydrophobicity, and electronic property of the substituents in the guest compounds. The K-a values calculated by the model are quite close to those determined experimentally. It suggested that the van der Waals force, hydrophobic interactions, and electronic effects comprise the main driving forces for CD molecular recognition. Furthermore, van der Waals force plays a dominant role in alpha-CD complexation; on the other hand, van der Waals force and hydrophobic interactions play the major roles in beta-CD complexation. The model is capable of quantitatively estimating the orientation of guest compounds in CD cavities. The predictions in both driving force and the orientation are in good agreement with the experimental studies.