Studies Toward Computer Liquid Phase Simulations of the Solvent-Dependency of Apolar Association Strength: Conformational Analysis of a Cyclophane-Pyrene Complex by Pseudo Monte Carlo and Molecular Dynamics Methods

Abstract

Previous studies showed a strong solvent dependency for the inclusion complexation of pyrene with the macrobicyclic cyclophane host 1. Upon changing from apolar to dipolar aprotic, to polar prouc solvents, and to water, the association strength of the complex (2) increases steadily. Calorimetric investigations of thermodynamic properties showed that, in all the solvents studied, the formation of 2 is enthalpically driven. For a better understanding of these solvent effects on an individual molecular level and in order to complement the experimental data, we decided to carry out computer liquid phase simulations on this system. In the absence of an X-ray crystallographic structure of 2, a detailed conformational analysis was required. In this study, we used Pseudo Monte Carlo (PMC) and Molecular Dynamics (MD) methods for the search of conformational space. Results of both techniques are described and compared. PMC-simulations show a complex with a quite rigid region around the cavity binding site of 1, which is shaped by three diphenylmethane units bridged in a cryptand-type array, and greater flexibility in the external piperidine rings. The obtained conformations prefer an arrangement of the bridges to the ‘cryptand-N-atoms’ with the protons of the aryl ether methylene groups (ArOCH 2 ) inside the cavity, in good agreement with the large upfield complexation-induced changes in the 1H-NMR chemical shifts of these protons. In the MD-simulation the pyrene guest rotates in the cavity; jumping between two favored orientations, which the PMC-simulations found to be isoenergetic. MD-simulations of the empty cyclophane 1 were carried out at 900 K. Even though distorted conformations were generated, the structure calculated by averaging the atom positions presents an open cavity, which clearly demonstrates the preorganization of the host.