No abstract

A computational study was undertaken to discern where and how chiral alkanes, alcohols, and acetates enantioselectively bind to permethyated -cyclodextrin, the most commonly used chiral stationary phase in gas chromatography. We found that enantioselective binding data could be reproduced with standard molecular dynamics techniques if averages are taken over multiple trajectories of nanosecond simulation times each, while Metropolis Monte Carlo simulations using rigid body molecules are unable to reproduce chromatographic retention orders. Data extracted from the molecular simulations revealed the preferred binding site for small analytes to be the interior of the macrocycle, with rapid shuttling between the primary and secondary rims and low-energy excursions into and out of the host cavity. The dominant forces holding the host-guest complexes together are the short range dispersion forces. The enantiodiscriminating forces responsible for chiral recognition are also the short range van der Waals forces and these enantiodifferentiating forces are typically 1-2 orders of magnitude smaller than the binding forces. An assessment of the number of hydrogen bonds for the diastereomeric complexes is presented along with the locations of dominant hydrogen-bonding sites on the macrocycle. A comparison is made between analytes capable of intramolecular hydrogen bonding with those that can not. It is pointed out that the 3-point binding description of chiral discrimination can be used, but it loses its appeal at such high temperatures due to ill-defined structures.

The concept of maintaining spatial congruence between substrate binding site and regions of greatest enantiodifferentiation to ensure efficient chiral recognition in host-guest chemistry is described in this paper. Regions of maximum chiral recognition were located by determining Boltzmann-weighted intermolecular energies of chiral probe molecules placed at well-defined grid points around a molecule and then evaluating the magnitude of (dis)similarity of interaction at each grid point. Sites having little or no energy differences between enantiomeric probes are nondiscriminatory while those of greatest energy difference correspond to regions of maximum chiral discrimination. Seven analyte molecules containing a diverse set of organic functional groups were evaluated when binding to permethylated β-cyclodextrin, a popular chiral stationary phase used in chromatography. The preferred binding site for host-guest association is the interior of the cyclodextrin, and the region of maximum discrimination is found to coincide with this location for all analytes studied. Forcing the guests to bind to the exterior of the macrocycle by blocking the interior of the cyclodextrin is predicted to reduce or eliminate resolution. A literature report confirming this prediction is cited.

Five guest molecules, isomenthone, pulegone, 1-fluoro-1-phenylethane, 1-phenylethanol, and 2-methylbutanoic acid, binding to permethyl-beta-cyclodextrin, a chiral host molecule, have been simulated by molecular dynamics techniques. From the simulations we find the preferred binding site to be the interior of the macrocyclic cavity. A new technique was used for locating the host's most enantiodiscriminating domain, which was also found to be inside the macrocyclic cavity. It is concluded that this particular host molecule displays its enhanced chiral discriminating capacity because of this spatial coincidence. Also evaluated in this paper are the types and magnitudes of intermolecular forces responsible for diastereomeric complexation and chiral discrimination; in both cases the short-range dispersion forces dominate. This study illustrates the "principle of maximum chiral recognition", the idea that maximum chiral recognition can be achieved by maintaining a spatial congruence between the host's domain of greatest enantiodifferentiation with the guest's preferred binding site.

The concept of molecular kurtosis as a dynamic molecular shape descriptor is introduced and used to compare the relative flexibilities of benzene and cyclohexane. For small torsional deformations (<15°) the potential energy surfaces are similar, indicating both molecules are flexible. Using molecular kurtosis, the stiffness of benzene and cyclohexane are compared from gas‐phase stochastic dynamics simulations and validated by distributions found in the Cambridge Structural Database. © 1993 John Wiley & Sons, Inc.