The “Missing Link”, Allostery and Synergism─Hosting of Metal Cations by Regular and Partial <i>Cone</i> Calix[4]arene Isomers

The influence of the tetra-<i>O</i>-2-oxopropyl-substituted calix-[4]-arene conformation on its binding affinity toward first- and second-group metal cations, as well as on the solvent molecule (acetonitrile or methanol) inclusion in the calixarene hydrophobic cavity, was investigated experimentally and computationally. Misorientation of one monomeric subunit in the partial <i>cone</i> ligand (<b>L</b> _<b>p</b> ) led to incomplete cation desolvation and significantly reduced its cation-binding ability compared to the regular <i>cone</i> isomer (<b>L</b> _<b>c</b> ). Aromatic ring inversion also precluded solvent inclusion in the calixarene <i>basket</i> of both free and complexed <b>L</b> _<b>p</b> (in contrast to <b>L</b> _<b>c</b> ), which considerably affected the complex stabilities and highlighted the pronounced cooperative allosteric effect of this process on the cation binding. Comprehensive structural and energetic studies, carried out by classical molecular dynamics simulations and quantum chemical calculations, showed that inclusion of acetonitrile within the complexes was favored over methanol, whereby the nitrile group of the solvent coordinated the second-group cations. Conversely, the methyl group of included acetonitrile or methanol molecule faced the alkali metal cations in the corresponding adducts. Molecular and crystal structures of free <b>L</b> _<b>p</b> , as well as sodium, calcium, and barium complexes of <b>L</b> _<b>c</b> with included acetonitrile, were determined by single-crystal X-ray diffraction. The orientations of solvent molecules within the calixarene cavity in the solid state closely matched computational predictions, further supporting conclusions drawn from the experimental data. Overall, this work presents a particularly detailed account of the thermodynamic and structural aspects of chelate, macrocyclic, and medium effects on the cation-hosting processes, providing valuable insights into the driving forces governing supramolecular recognition in solution.