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.