CONFORMATIONAL, CALORIMETRIC AND NMR SPECTROSCOPIC STUDIES ON INCLUSION COMPLEXES OF CYCLODEXTRINS WITH SUBSTITUTED PHENYL AND ADAMANTANE DERIVATIVES

Inclusion modes in complexes with alpha- and beta-cyclodextrins in wat er have been investigated by NMR spectroscopy at 400 or 500 MHz, and c ompared with structures obtained by computer-aided molecular modelling and with calorimetric data. The NOEs observed on o- and m-aryl proton s upon irradiation of either H3 or H5 inside the CD cavity indicate fo r all phenols an inclusion mode with the hydroxy group at the wide cav ity end, and an increasingly deep immersion for phenol or phenolate wi th iodine compared with this nitro group, as para-substituent. This is found to be in line with the complexation-induced NMR shifts. Adamant ane-1-carboxylate is indicated by distinct NOEs to be fully immersed i nto the beta-CD cavity; the corresponding complex with alpha-CD shows contact only at the wider rim and a tilted conformation which allows f ormation of a hydrogen bond between the guest COO- and the 2-OH group of the CD. The same conformation is found by CHARMm calculations, incl uding simulations in a water box. The results, together with some Delt a G degrees values derived from NMR titrations, are in line with data from calorimetric studies. These show for complexes with tight fit (in alpha-CD) large enthalpies of up to 43 kJ mol(-1) as the predominatin g driving force against sizeable entropy disadvantages (T Delta S degr ees less than or equal to -24 kJ mol(-1)), particularly for guest mole cules of higher electron density and/or polarizibility. These observat ions point to predominating dispersive interactions In contrast, inclu sion in the wider beta-CD cavity suffers less from entropy disadvantag e (T Delta S degrees less than or equal to -11 kJ mol(-1)); the bindin g, however, is still dominated by Delta H degrees, pointing to predomi nant cohesive and not entropic hydrophobic forces.