Comparative computational and thermodynamic study of cation complexation by tetra-O-2-oxopropyl-substituted...

The binding of alkali and alkaline earth metal cations by 1,2-alternate (L12) and 1,3-alternate (L13) conformational isomers of a lower-rim calix[4]arene ketone derivative was investigated in vacuo and in explicit acetonitrile and methanol solvents by means of classical molecular dynamics simulations and quantum chemical calculations. The resulting thermodynamic and structural features were compared among these isomers and with those of the previously computationally and experimentally studied cone (Lc) and partial cone (Lp) conformers. In most cases the L12 and L13 complexes were found to be thermodynamically less stable than those of Lc and Lpin vacuo, primarily due to a lower number of available coordinating ether and carbonyl oxygen atoms in the cation-binding site and hence less favourable reaction enthalpies, as well as more unfavourable entropic contributions to the corresponding reaction Gibbs energies. MD simulations with an explicit solvent model revealed that the formation of diverse complex structures, particularly endo- and exo-complexes, and the associated cation-binding energetics were governed by the outcome of an interesting interplay between solvation effects (including that of specific solvent-solute interactions) and the cation coordination with the atoms comprising the ligand binding site. These findings emphasise the decisive role of solvation processes in determining both the complex structures and thermodynamics of cation binding and underscore that reliable computational predictions of binding properties require their thorough consideration.