Modeling the complexation of substituted benzenes by a cyclophane host in water.

Abstract

Monte Carlo statistical mechanics simulations have been used to study the complexation of disubstituted benzenes by Diederich's octamethoxy tetraoxaparacyclophane host. Relative free energies of binding were obtained in water at 250C for benzene, p-xylene, p-cresol, p-dicyanobenzene, and hydroquinone from statistical perturbation theory. The computed results agree well with experimental data, including the binding affinity of benzene, which was determined after the calculations were completed. The computed structures for the complexes reveal details that are important for understanding the order of binding affinities. It is found that hydroquinone protrudes from one side of the complex and participates in hydrogen bonds between one hydroxyl group and two water molecules and in an intracomplex hydrogen bond between the other hydroxyl group and ether oxygens. The calculations also show a clear preference for binding p-cresol with the hydroxyl group hydrated rather than inside the host's cavity.The central role of intermolecular binding events in biochemistry and the potential for developing synthetic catalysts and novel materials have helped foster great experimental (1-5) and computational (6-19) interest in host-guest chemistry. The interplay between theory and experiment has been aided by the development of methodology that allows computation ofrelative and absolute free energies ofbinding (6,15,16) and by the ability of fluid simulations to provide exquisite structural details. Much computational effort has been directed at enzyme-ligand binding and the complexation of atomic ions by organic hosts (6-14), though complexes of neutral guests with organic hosts are now receiving increased attention (17-19). Water-soluble hosts that bind neutral guests are of particular interest as models of biological systems and as starting points for the design of nonenzymatic catalysts. Important contributions have been made in this area by many researchers, as reviewed by Diederich (4). The most common examples feature cyclodextrins and cyclophanes, which have relatively hydrophobic binding cylinders or slots. We have chosen to direct computational efforts at the cyclophanes in view oftheir potential structural diversity and the availability of experimental binding data for many systems. They also provide a rich venue for investigating the factors that control binding in water and the opportunity to complement the experimental studies by helping characterize the structures of the complexes, including specific interactions between host, guest, and water.Our first effort has been aimed at Diederich's octamethoxy tetraoxaparacyclophane, 1, which binds substituted benzenes in its slot-like cavity (20)(21)(22)

Exciplex Formation in Complexes between Cyclophane Hosts and Aromatic Guests: Evidence That the Ground-State Complexes Exist in More Than One Distinct Geometry

“…Furthermore, freedom of rotation about these bonds (which can readily occur while the guest remains in the cavity) would be favorable in terms of the entropy of the complex. Finally, as noted above, computational studies have suggested that interactions between the methoxy methyl groups of the host and the π-systems of certain guests are stabilizing . Similar stabilizing interactions can also be envisaged between bound guests and the inward-directed OCH 2 groups of B and C.…”

“…In molecular dynamics studies with cyclophane 3 , it was found that benzene preferred an orientation in which it was not deeply buried in the host cavity . Rather, the benzene ring is “clasped by the four methoxy methyl groups on one side of the host”, an interaction that is energetically favorable due to the partial positive charges on the methyl group hydrogens and the partial negative charges on the aromatic carbons . A similar kind of arrangement can be envisaged for 6 and 7 , wherein the unsubstituted ring of the guest interacts preferentially with the methoxy methyl groups on one side of the host, while the ring bearing the methyl group is inserted in the host cavity, interacting favorably with the host aromatic rings.…”

“…In molecular dynamics studies with cyclophane 3 , it was found that benzene preferred an orientation in which it was not deeply buried in the host cavity . Rather, the benzene ring is “clasped by the four methoxy methyl groups on one side of the host”, an interaction that is energetically favorable due to the partial positive charges on the methyl group hydrogens and the partial negative charges on the aromatic carbons .…”

“…The CH 2 groups attached to the oxygen atoms with exo lone pairs are pointed inward, whereas those attached to the oxygen atoms with endo lone pairs are directed outward. An extensive conformational search using Monte Carlo statistical mechanics methods has suggested that the orientations described above are maintained in the complex with p -xylene and other benzene derivatives …”

Selective Anion Complexation by a Calix[4]pyrrole Investigated by Monte Carlo Simulations

“…Computer simulations have been successfully applied to investigate host−guest recognition processes in solution . By carefully sampling the interactions among host, guest, and solvent, structural arrangements and energetic components which determine experimental binding affinities have been elucidated . The binding of anions by calix[4]pyrrole 1 is explored here in a similar manner and complements a recent study of anion binding by a bis(phenylurea) calix[4]arene derivative .…”