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.