Molecular Modelling of Saccharides, 9!! On the Hydrophobic Characteristics of Cyclodextrins: Computer‐Aided Visualization of Molecular Lipophilicity Patterns

Abstract

Abstract Statistical analysis of the solid‐state structures available for the cyclodextrins and their inclusion compounds – 42 for α‐CD ( 1 ), 48 for β‐CD ( 2 ), and 8 for γ‐CD ( 3 ) – revealed their mean molecular geometry parameters to be within normal ranges, such as the intersaccharidic bond angle (φ) and torsion angles Φ and Ψ, or the tilt angle (τ) signifying the inclination of the pyranoid 4 C 1 chairs toward the macroring perimeter. The mean 2–0…0–3' distances between adjacent glucose portions decrease in the order α‐CD > β‐CD > γ‐CD from 3.05 to 2.84 Å, allowing more intense 2–0…H0–3' hydrogen bonding interactions. This reduces the overall flexibility of the macrocycles correspondingly. The intersaccharidic oxygens that without exception point toward the inside of the macrocycles, essentially lie in one plane, deviations from planarity being in the range of only 0.02–0.12 Å. The global molecular shape of 1–3 in their various hydrates and inclusion complexes is thus uniformly characterized by essentially unstrained, torus‐shaped cones with a nearly unpuckered mean plane. These results justify considering the solid‐state structures of α‐, β‐ and γ‐CD hydrates, crystallizing with 8–14 water molecules, as relevant “frozen molecular images” of their solution conformations. The solid‐state data were used to compute the contact surfaces, cavity dimensions, and molecular lipophilicity patterns (MLPs) of 1–3 . The MLPs, presented in color‐coded form, provide a lucid picture of how these cyclodextrins are balanced with respect to their hydrophilic (blue) and hydrophobic (yellow) areas: the larger opening of the cone‐shaped macrocycles carrying the 2‐OH and 3‐OH groups is intensely hydrophilic; the opposite, narrower opening, ringed by the CH 2 OH groups, is considerably less hydrophilic, and is partially permeated by hydrophobic areas, whereas the bulk of the intensely hydrophobic regions is concentrated on the inner region of the cavities. Thus, the complexation of suitable guest molecules by α, β‐, and γ‐cyclodextrin ( 1–3 ), which is governed by a variety of factors, can be rationalized with respect to the hydrophobic interactions on the basis of their MLP profiles. Application of these molecular modelling techniques to the one solid‐state structure available for the nine‐glucose unit δ‐CD tetradecahydrate ( 4 ) suggests a less pronounced separation of hydrophilic and hydrophobic surface regions, obviously due to a bowl‐shaped torus with irregular tilting of four of the nine glucopyranoses which gives rise to substantial puckering of the macrocycle.