Absolute configuration of bromochlorofluoromethane from molecular dynamics simulation of its enantioselective complexation by cryptophane-C

Earlier NMR experiments (Canceill et. al. J. Am. Chem. Soc. 1985, 107, 6993) have shown that the inclusion of bromochlorofluoromethane (CHFClBr) 1 within the cavity of (-)-cryptophane-C 2 in chloroform solution is enantioselective and that (-)-1 is more strongly bound than (+)-1 with a free energy difference (Delta Delta G degrees)(exp) of 1.1 kJ mol(-1). In order to gain information on the relative configuration of the diastereomeric complexes and hence on the absolute configuration of !, we have tried to reproduce these experiments by computational methods, and we have calculated the free energy difference for the binding of (R) and (S)-1 to (-)-2. For this purpose, the OPLS parameters for CHFClBr were optimized by Monte Carlo (MC) simulations of the pure liquid. Then molecular dynamics (MD) simulations were performed on the host-guest system in a. solvent hox of chloroform using multiconfiguration thermodynamic integration (MCTl) and free energy perturbation (FEP) methods to calculate the free energy difference between the diastereomeric complexes. The [(R)1-@(-)-2] complex was thus calculated to be more stable than the [(S)-1@(-)-2] one by (Delta Delta G degrees)(calc) 0-2.6 kJ mol(-1), which is of the lame order of magnitude as the experimental result. Since the [(-)-1@(-)-2] complex is more stable than the [(+)-1@(-)-2] one, and since the absolute configuration of 2 is known, it was concluded that the absolute configuration of CHFClBr must be (R)-(-) (or (S)-(+)); this conclusion is in agreement with - recent independent assignment based on Raman Optical Activity studies.