Solubility of Hydrophobes into Macrocyclic Hosts

The intrinsic nature of macrocyclic molecules to preferentially absorb a specific solute has been opening up supramolecular chemistry. Nevertheless, the determinant factor with molecular perspectives in promoting host-guest complexations remains inconclusive, due to the lack of rigorous thermodynamic examination on the guest solubility inside the host. Here, we quantify the solute-solvent energetic and entropic contributions between the end states and on the docking route during inclusion of noble gases in cucurbit[5]uril, cucurbit[6]uril, and alpha-cyclodextrin, using molecular dynamics simulations in combination with the potential distribution theorem. Results show that in all of the pairs examined both the solute-solvent energy and entropy favor the inclusion, while the former is rather dominant. The frequency of interior drying, which pertains to the entropic contribution, differs between the hosts and is controlled by the existence of lid water at portal and the flexibility of host framework. Moreover, the hosts exhibit various types of absorption manners, involving non-, single-, and double-free-energy barriers.