THERMODYNAMIC AND NUCLEAR-MAGNETIC-RESONANCE STUDY OF THE INTERACTIONS OF ALPHA-CYCLODEXTRIN AND BETA-CYCLODEXTRIN WITH MODEL SUBSTANCES - PHENETHYLAMINE, EPHEDRINES, AND RELATED SUBSTANCES

Titration calorimetry was used to measure equilibrium constants and st andard molar enthalpies for the reactions of phenethylamine, ephedrine s, and related substances with alpha- and beta-cyclodextrin. Changes i n the chemical shifts Delta delta of both the ligand and cyclodextrin protons were measured with NMR. The thermodynamic results have been ex amined in terms of structural features of the ligand that affect these interactions such as the separation of the charge at an amino group a nd the aromatic ring, steric effects, the presence of additional funct ional groups (amino, hydroxy, methoxy, and methyl) attached to the aro matic ring, the presence and location of hydroxy group(s) on the ligan d, changes in the chirality of the ligand, and the flexibility of the organic molecules attached to the aromatic ring. It was found that the values of thermodynamic quantities for these reactions in phosphate a nd acetate buffers were different. This difference is attributable to the presence of a hydrophobic alkyl group in the neutral acetic acid m olecule and its interaction with the cyclodextrins. Also, there are si gnificant differences in the thermodynamic quantities for the reaction s of the chiral isomers of ephedrine and pseudoephedrine in their reac tions with beta-cyclodextrin. A plot of the standard molar enthalpy vs the standard molar entropy for the reactions of these chiral isomers with alpha- and beta-cyclodextrin is linear; the relative order of the ephedrines and pseudoephedrines in the enthalpy-entropy plot is the s ame for the reactions of these substances with both alpha- and beta-cy clodextrin. NMR studies demonstrated that the magnitude of the upfield shifts of the cyclodextrin's H3 and H5 protons, Delta delta(H3) and D elta delta(H5), and their relative ratio, Delta delta(H5)/Delta delta( H3), can be used, respectively, as a measure of the complex stability and the depth of inclusion of the ligand into the cavity. The equilibr ium constants determined by titration calorimetry correlate well with the changes in chemical shifts Delta delta determined by NMR.