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 apr otic, 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 calculati ons using molecular dynamics (MD) simulations in the liquid phase. The purpose of this work was to test the reproducibility of the experimen tal results with computer simulation techniques and obtain more detail s at the molecular level on the origin of these strong solvent effects . Gibbs free energy calculations of cyclophane-pyrene complex 2 in wat er 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 scal ing of the nonbonded potential energy functions was performed using a soft-core interaction function. The result confirmed the experimentall y measured trend of a stronger complexation in water than in chlorofor m (Delta(Delta G)(exp) = 7.1 kcal mol(-1), T = 303 K). Although the ab solute value was overestimated (Delta(Delta G)(calc) = 10.2 kcal mol(- 1)), the result confirms the efficiency of the soft-core scaling techn ique for the deletion of large molecules. Moreover, it could be shown that in this case the strong solvent dependence of the cyclophane-pyre ne complexation is mainly due to the different free energies of cavita tion in water and chloroform. The stronger cohesive interactions of wa ter make the disappearance of pyrene from the solution into the cyclop hane cavity more favorable than in chloroform.