Computer Simulations of the Solvent Dependence of Apolar Association Strength:  Gibbs Free Energy Calculations on a Cyclophane−Pyrene Complex in Water and Chloroform

The inclusion complexation of pyrene with the macrobicyclic cyclophane host 1 has been described in previous experimental studies and showed a strong solvent dependence. Upon changing from apolar to dipolar aprotic, to polar protic solvents, and to water, the association strength of complex 2 increases steadily. Following a detailed conformational analysis of this system, we then performed Gibbs free energy calculations using molecular dynamics (MD) simulations in the liquid phase. The purpose of this work was to test the reproducibility of the experimental results with computer simulation techniques and obtain more details at the molecular level on the origin of these strong solvent effects. Gibbs free energy calculations of cyclophane−pyrene complex 2 in water and in chloroform were carried out by performing a deletion of the pyrene molecule in the pure solvent and inside the cyclophane cavity, following the double annihilation technique. The procedure allowed the free energy of complexation in both solvents to be obtained. The scaling of the nonbonded potential energy functions was performed using a soft-core interaction function. The result confirmed the experimentally measured trend of a stronger complexation in water than in chloroform (Δ(ΔG)exp = 7.1 kcal mol-1, T = 303 K). Although the absolute value was overestimated (Δ(ΔG)calc = 10.2 kcal mol-1), the result confirms the efficiency of the soft-core scaling technique for the deletion of large molecules. Moreover, it could be shown that in this case the strong solvent dependence of the cyclophane−pyrene complexation is mainly due to the different free energies of cavitation in water and chloroform. The stronger cohesive interactions of water make the disappearance of pyrene from the solution into the cyclophane cavity more favorable than in chloroform.