Complexation of adamantyl compounds by beta-cyclodextrin and monoaminoderivatives

Area of Science:

• Supramolecular Chemistry
• Host-Guest Chemistry
• Physical Organic Chemistry

Background:

• Beta-cyclodextrin (beta-CD) is a cyclic oligosaccharide with a hydrophobic cavity capable of forming inclusion complexes.
• The geometry of the beta-CD cavity is not a simple cone, featuring constrictions that may influence guest inclusion.
• Understanding guest inclusion mechanisms is crucial for applications in drug delivery and molecular recognition.

Purpose of the Study:

• To investigate the formation of isomeric inclusion complexes (c(p) and c(s)) by bulky hydrophobic guests with beta-cyclodextrin and its amino derivatives.
• To determine the influence of guest entry side (primary vs. secondary) on complex formation and stability.
• To elucidate the thermodynamic parameters governing these inclusion processes.

Main Methods:

• Rotating-frame Overhauser enhancement spectroscopy (ROESY) to determine complex stoichiometry and orientation.
• Isothermal titration calorimetry (ITC) to measure thermodynamic parameters (free energy, enthalpy, entropy).
• Synthesis and use of beta-cyclodextrin, 6-amino-beta-cyclodextrin (6-NH2beta-CD), and 3-amino-beta-cyclodextrin (3-NH2beta-CD) as hosts.

Main Results:

• Rimantidine and adamantylmethanol formed c(s) complexes with beta-CD and 6-NH2beta-CD, but c(p) complexes with 3-NH2beta-CD.
• The hydrophilic group of the guest consistently protruded from the cyclodextrin cavity.
• A significant free energy difference (11.5 +/- 0.8 kJ mol(-1)) was observed between c(s) and c(p) complexes, explaining the preferential formation of one isomer.

Conclusions:

• The constrictions in the beta-cyclodextrin cavity play a critical role in determining the preferred orientation of bulky guests.
• The observed isomeric preference is driven by substantial thermodynamic differences between the two possible inclusion modes.
• A hyperboloid model may better represent the beta-cyclodextrin cavity shape than traditional cone or trapezium models.