Towards understanding formation and stability of cyclodextrin inclusion complexes: Computation and visualization of their molecular lipophilicity patterns

Five cyclodextrin inclusion complexes - typical examples for their solid state as well as exemplary ''frozen molecular images'' of their status in solution - were subjected to a molecular modelling study comprising the computer-assisted generation of the molecular lipophilicity patterns (MLP's), i.e. the p-iodoaniline inclusion into alpha-CD, the complexes of beta-CD with 1,4-butanediol, adamantane-1-carboxylic acid, and adamantane-1-methanol, and the unique 12-crown-4 ether inclusion compound of gamma-CD. Based on their solid state structures, the ''solvent-accessible'' contact surfaces were generated by the MOLCAD program. Calculation and color-coded projection of the MLP's onto these surfaces easily allows to locate the hydrophobic and hydrophilic surface regions of CD-host and guest alike. Their detailed analysis revealed a far-reaching, mostly complete conformity between the hydrophobic surface areas of the guest and the hydrophobic domains in the CD cavity. This striking tendency to optimize the reciprocal concurrence of lipophilic as well as hydrophilic domains at the guest-host-interface may accordingly be concluded to be an important, if not the decisive element in orienting the guest into the cavity and in determining the stability of the complex, particularly in cases where the guest is devoid of polar groups; if these are present, dipole-dipole alignments and the need for their solvation may diminish the importance of hydrophobic attractions for orienting and stabilizing the guest in the CD cavity.