EXPERIMENTAL AND THEORETICAL APPROACH TO HYDROGEN-BONDED DIASTEREOMERIC INTERACTIONS IN A MODEL COMPLEX

Binding affinities of (R,R)-1,2-cyclohexanediamine (R) to (R,R)-1,2-cy clopentanediol (R-5) and (S,S)-1,2-cyclopentanediol (S-5) and to the c orresponding cyclohexanediols (R-6 and S-6) have been measured in benz ene and in CCl4 at 298 K by microcalorimetry, and unexpected differenc es between the diastereomeric complexes are observed. Long time scale (0.1 mu s) molecular-dynamics simulations of the two smaller diastereo meric complexes, R/R-5 and R/S-5, in a simplified solvent model are re ported. A direct free energy calculation gives results in good agreeme nt with the experimental values measured in benzene for the first pair , but nearly identical results for the second pair, which is at varian ce with experiment. A systematic analysis of the dependence of simulat ion results on model parameters is performed, and no possibility is fo und to improve the enantioselectivity by parameter tuning. Other possi ble causes for discrepancies are specific solute-solvent or solvent-so lvent interactions, electronic charge redistribution effects, or forma tion of clusters of more than two molecules. Owing to the long time sc ales reached, a well-converged picture of the dynamics is obtained, an d the species present at equilibrium can be studied in detail. The ave rage lifetime of the complex is found to be about 200 ps, whereas that of a hydrogen bond is only about 5 ps. Besides the unbound state, the dominant species observed in the simulations for both diastereomeric pairs are singly hydrogen-bonded complexes, with a clear preference fo r a O to N over the N to O hydrogen bond. Many other hydrogen-bonding patterns (bridged, double) are also observed in minor amounts.