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Molecular Modeling of Saccharides, Part IX.

On the Hydrophobic Characteristics of Cyclodextrins: Computer-Aided Visualization of Molecular Lipophilicity Patterns

Frieder W. Lichtenthaler and Stefan Immel

Liebigs Ann. 1996, 27-37.

Statistical analysis of the solid-state structures available for the cyclodextrins and their inclusion compounds - 42 for α-CD, 48 for β-CD, and 8 for γ-CD - revealed their mean molecular geometry parameters within normal ranges, such as the intersaccharidic bond angle r and torsion angles F and Y, or the tilt angle t signifying the inclination of the pyranoid chairs toward the macroring perimeter. The mean 2-O ... O-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-O ... HO-3'-hydrogen bonding interactions and, hence, reducing the overall flexibility of the macrocycles in that order. The intersaccharidic oxygens that invariably point toward the inside of the macrocycles essentially lie in one plane, as deviations therefrom are in the 0.02 - 0.12 Å range only. 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 data provide justification for 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. Accordingly, the solid-state data were used to compute their contact surfaces, their cavity dimensions, and their molecular lipophilicity patterns (MLP's). The MLP's 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 side holding the CH2OH groups is considerably less hydrophilic, partially permeated by hydrophobic areas, whereas the bulk of the intensely hydrophobic regions is concentrated in the inner 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 modeling techniques to the one solid-state structure available for the nine-glucose-unit d-CD tetradecahydrate (4) suffices to infer 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, giving rise to substantial puckering of the macrocycle.

Additional Graphics: Cyclodextrins

© Copyright PD Dr. S. Immel