Alkali cation extraction by 18-crown-6 and its derivatives: A free energy perturbation study

Alkali cation extraction by 18-crown-6 derivatives (Li, G.; Still, W. C. J. Am. Chem. Sec. 1993, 115, 3804-3805) has been studied by means of free energy perturbation (FEP) methods. The FEP simulations of the cation extraction in homogeneous solutions such as in aqueous solution or in chloroform did not yield consistent results with the corresponding experimental data. Thus, a mixed solvent system is proposed to play an important role in determining the extraction properties of the ionophores in the study. The FEP simulations in such a model system suggest that the cation extraction process occurs in organic solvent mixed with water molecules. The involvement of water in the process is determined by two factors: (1) the ability of an ionophore to form a hydrogen bond with water near its binding pocket and (2) the conformational rigidity of the host. Our calculations suggest that remote substitution can enhance the extraction property of a conformational rigid ionophore by attracting water near its binding core via a hydrogen bond network.