PER-O-METHYLATED ALPHA-CD AND BETA-CD - CYCLODEXTRINS WITH INVERSE HYDROPHOBICITY

The investigation focuses on the computer-aided generation of the mole cular geometries, contact surfaces, and lipophilicity patterns of per- O-methylated alpha-CD (1) and its beta-CD homolog 2, and compares them with their parent non-substituted cyclodextrins. The molecular geomet ries, compared via statistical analysis of crystal structure data avai lable, reveal 1 and 2 to be considerably more flexible than alpha- and beta-CD, allowing wide variations in the tilting of the glucose units relative to the macrocyclic ring axes. The comparative evaluation of their contact surfaces not only discloses a substantial increase of th e torus heights upon per-O-methylation (from approximate to 8.0 Angstr om, in alpha- and beta-CD, to approximate to 11.1 Angstrom in 1 and 2) , but also an enlargement of their cavity areas by 40% (+35 Angstrom(2 ) for alpha-CD --> 1) and 70% (+75 Angstrom(2) for beta-CD --> 2), res pectively. The hydrophobic characteristics of 1 and 2, emerging from t he molecular lipophilicity patterns (MLPs) generated and projected ont o the contact surfaces in color-coded form, are inverse to those for a lpha- and beta-CD: the most hydrophobic surface regions of 1 and 2 are located at the torus rims made up by the 2-OMe and 3-OMe groups at on e side, and the 6-CH(2)OMe moieties at the other, with a hydrophobic ' 'band'' wrapping around the outside of the macrocycles; these ''exo-li pophilic'' topographies are opposed by pronouncedly hydrophilic centra l cavities. A variety of experimental findings can be rationalized on the basis of the opposite lipophilicity profiles of the CDs and their permethylated analogs, such as for example the opposite orientation of benzaldehyde, p-nitrophenol, and 3-iodopropionic acid in the cavities of alpha-CD and of 1. Thus, the notion is substantiated that the oper ation of dispersive interactions between guest and CD-host cavities pl ay a more dominant role in inclusion complex formation than hitherto a ppreciated.