Structure and Binding for Cyclophane-Arene Complexes in Water From Monte Carlo Simulations

Monte Carlo statistical mechanics simulations have been used to study the complexation of disubstituted benzenes by Diederich's octamethoxy tetraoxaparacyclophane host, 1. The calculations were carried out in the NPT ensemble at 25 °C and 1 atm in the presence of 768 water molecules. Relative free energies of binding were obtained for p-xylene, benzene, p-cresol, and hydroquinone from statistical perturbation theory. The computed preference of 2.8 ± 0.3 kcal/mol in DGb for binding p-xylene over hydroqinone compares well with the experimental result of 2.5 ± 0.3 kcal/mol. The computed results for benzene (2.0 ± 0.2 kcal/mol) and p-cresol (2.4 ± 0.2 kcal/mol) relative to p-xylene were predictions; however, the experimental data are now available and are lower by 1–2 kcal/mol. The computed structures for the complexes reveal interesting details. For example, hydroquinone protrudes somewhat from one side of the complex and participates in hydrogen bonds between one hydroxyl group and 1–2 water molecules and in an intracomplex hydrogen bond between the other hydroxyl group and ether oxygens. Benzene is predicted to be bound even more off-center, while p-cresol is centered and has an intracomplex hydrogen bond as in the case of hydroquinone.