The anatomy of the energetics of molecular recognition by calorimetry: Chiral discrimination of camphor by α-cyclodextrin

The molecular recognition of both camphor enantiomers 2 with the chiral α-cyclodextrin (α-CD) 1 in water and D₂O was examined by calorimetry. On the basis of statistically supported determinations the thermodynamics of 2:1 host-guest binding and chiral discrimination was evaluated. The energetic signature strongly supports hydrophobic interaction as the dominant driving force for camphor encapsulation by α-CD in water. The solvent isotope effect on the binding equilibrium served to dissect the experimental enthalpy ΔH_ass into direct interaction (ΔH_intr) and solvent reorganization (ΔH_solv) terms. From this analysis the mutual interaction of two cyclodextrin and one camphor molecules contributes only 25% to the observed enthalpy of binding ΔH_ass all the test is attributed to solvent restructuring. Furthermore, the dramatic change in the pattern of thermodynamic state functions on solvent transfer from water to D₂O is taken as compeling evidence for the involvement of water as a structural tectone in the supramolecular architecture of the 2:1 complex. As a corollary, bilateral host-guest interactions as conveyed by the lock-and-key metaphor of molecular recognition provide an inadequate description of this seemingly simple artificial host-guest system.