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Alkali Metal Cation Selectivities of Novel Ionophores, [18 ]Starand and [17 ]Ketonand in Methanol:
Free Energy Perturbation and Molecular Dynamics Simulation Studies

Free energy perturbation (FEP) and molecular dynamics simulations were carried out to investigate the relative binding affinities of novel ionophores, [18 ]starand (1) and [17 ]ketonand (2), toward alkali metal cations in methanol. Theoretically predicted and experimentally observed binding affinities of 1 were in the order K+ > Rb+ > Cs+ > Na+ >> Li+ , whereas the binding affinities of 2 were calculated to be in the order Li+ > Na+ > K+ > Rb+ > Cs+ . The FEP simulation results were able to predict the relative binding free energies with errors less than 0.13 kcal/mol, except for the case between Li+ and Na+ . Ionophore 1 showed better association constants toward alkali metal cations except Li+ and Na+ when compared with 12-crown-4 having the same number of oxygen atoms participating in binding as that of 1. The cation selectivities were rationalized by analyzing the radial distribution functions of M+ -O and M+ -C distances of free metal cations in methanol and those of metal-ionophore complexes in methanol. The extremely different affinities of 1 and 2 toward smaller cations, Li+ and Na+ , were explained in terms of the differences in their ability to change the conformation to accommodate cations of different sizes. The carbonyl groups constituting the central cavity of 2 can reorganize to form a cavity with the optimal M+ -O distance, even for the smallest Li+ , without imposing serious strain on 2. The highest affinity of 2 for Li+ was predominantly due to the highest Coulombic attraction between the smallest Li+ and the carbonyl oxygens of 2.