Alkali metal cation selectivity of [1₇]ketonand in methanol: Free energy perturbation and molecular dynamics simulation studies

Free energy perturbation and molecular dynamics simulations were carried out to investigate the relative binding affinities of [1₇]ketonand (1) toward alkali metal cations in methanol. The binding affinities of 1 toward the alkali metal cations were calculated to be in the order Li⁺ > Na⁺ > K⁺ > Rb⁺ > Cs⁺, whereas our recent theoretically predicted and experimentally observed binding affinities for [1₈]starand (2) were in the order K⁺ > Rb⁺ > Cs⁺ > Na⁺ > Li⁺. 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 1 can reorganize to form a cavity with the optimal M⁺-O distance, even for the smallest Li⁺, without imposing serious strain on 1. The highest affinity of 1 for Li⁺ was predominantly due to the highest Coulombic attraction between the smallest Li⁺ and the carbonyl oxygens of 1.