Solvent and counterion effects on Na+/Cs+ complexation selectivity by conformationally locked calix[4]-bis-crown ligands: Molecular dynamics and free energy perturbation studies in water and methanol, acetonitrile and chloroform solutions

Calix[4]arene-bis-crown ligands (L), conformationally locked in the 1,3-alternate conformation, display remarkable ionophoric properties with respect to alkali cations (M(+)). Of particular interest is the large Cs+/Na+ binding selectivity displayed by calix[4]-bis-crown-6, in separating radioactive Cs+ from nuclear waste. Based on Molecular Dynamics and Free Energy Perturbation simulations, we report a consistent comparison of Na+, K+, Rb+ and Cs+ complexes in four different solvents (water, methanol, acetonitrile and chloroform) and in the gas phase, in order to elucidate solvent effects on structures and stabilities of these complexes. We predict that Cs+ is complexed by calix[4]-bis-crown-6 better than Na+ in water and methanol and acetonitrile solutions, whereas in chloroform and in the gas phase, Na+ is preferred. Also, calix[4]-bis-crown-5 hosts are predicted to bind selectively Na+ in chloroform, but K+ or Rb+ in methanol. Additionally, our studies on calix[4]-bis-crown-6 involve: (i) the effect of a picrate counterion on structures and selectivities; (ii) the role played by the hydrophobic p-t-butyl substituents; (iii) modelling of ditopic bis-cation 2M(+) complexes.