MOLECULAR MODELING OF SACCHARIDES .9. ON THE HYDROPHOBIC CHARACTERISTICS OF CYCLODEXTRINS - COMPUTER-AIDED VISUALIZATION OF MOLECULAR LIPOPHILICITY PATTERNS

Statistical analysis of the solid-state structures available for the c yclodextrins and their inclusion compounds - 42 for alpha-CD (1), 48 f or beta-CD (2), and 8 for gamma-CD (3) - revealed their mean molecular geometry parameters to be within normal ranges, such as the intersacc haridic bond angle (phi) and torsion angles Phi and Psi, or the tilt a ngle (tau) signifying the inclination of the pyranoid C-4(1) chairs to ward the macroring perimeter. The mean 2-O ... O-3' distances between adjacent glucose portions decrease in the order alpha-CD > beta-CD > g amma-CD from 3.05 to 2.84 Angstrom, allowing more intense 2-O ... O-3' hydrogen bonding interactions. This reduces the overall flexibility o f the macrocycles correspondingly. The intersaccharidic oxygens that w ithout exception point toward the inside of the macrocycles, essential ly lie in one plane, deviations from planarity being in the range of o nly 0.02-0.12 Angstrom. The global molecular shape of 1-3 in their var ious 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 structu res of alpha-, beta- and gamma-CD hydrates, crystallizing with 8-14 wa ter molecules, as relevant ''frozen molecular images'' of their soluti on conformations. The solid-state data were used to compute the contac t surfaces, cavity dimensions, and molecular lipophilicity patterns (M LPs) 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 in tensely hydrophilic; the opposite, narrower opening, ringed by the CH2 OH groups, is considerably less hydrophilic, and is partially permeate d 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 alpha-, beta-, and gamma- 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 techn iques to the one solid-state structure available for the nine-glucose unit delta-CD tetradecahydrate (4) suggests a less pronounced separati on of hydrophilic and hydrophobic surface regions, obviously due to a bowl-shaped torus with irregular tilting of four of the nine glucopyra noses which gives rise to substantial pukkering of the macrocycle.