Molecular Basis of Cyclodextrin Inclusion Complexation

Cyclodextrins are cyclic macromolecules built up from glucose units. Due to their capability to include organic molecules (guests) into their hydrophobic cavity, they are widely used in different branches of technical, environmental and analytical chemistry as well as in pharmaceutical technology. In the present project the molecular basis of cyclodextrin-guest association will be investigated. In previous research projects on quantitative structure activity relationships regression models have been developed for the prediction of the free energy of the complexation between various cyclodextrins and a large series of guest molecules. The analysis of the scaled regression coefficients of the models suggests that the driving forces in the complexation process is different for beta- and gamma-cyclodextrin. Therefore, one aim of the project is to perform experiments to explain the complexation mechanisms for various cyclodextrins. The refinement of the obtained prediction models by experiments on specific inclusion complexes and the application of new molecular descriptors should lead to an improvement of the model and to a better understanding of the nature of the host- guest interaction. A second point will be the investigation of the host-guest complexation mechanism with intramolecular proton transfer probes. Molecules with proton transfer equilibria, which are highly dependent on the environment will be used to characterize the interior of various cyclodextrins. A systematic analysis of the stability constants, the proton transfer constants and the corresponding thermodynamic parameters (enthalpy, entropy) using various solvent compositions, different cyclodextrins and different protic and aprotic solvents, will give a more precise image of the solvent reorganization accompanying complexation. The typical phenomenon of host-guest complexation, namely enthalpy-entropy compensation, will be analyzed by a computational approach, in which the total free energy of the inclusion reaction is calculated by a continuum approximation from the solvent accessible surface, while the conformational entropy is calculated from populations of substructures. In this way conclusions on enthalpic and entropic contributions to complex stabilization will be possible. Finally, calculations on the structure of cyclodextrins will be performed, using convenient semiempirical and to some extent ab initio quantum-chemical methods, to estimate the molecular geometries and the related molecular properties, which can be applied as molecular descriptors.