An Integrated Approach (Thermodynamic, Structural, and Computational) to the Study of Complexation of Alkali-Metal Cations by a Lower-Rim Calix[4]arene Amide Derivative in Acetonitrile

The calix[4]­arene secondary-amide derivative L was
synthesized, and its complexation with alkali-metal cations in acetonitrile
(MeCN) was studied by means of spectrophotometric, NMR, conductometric,
and microcalorimetric titrations at 25 °C. The stability constants
of the 1:1 (metal/ligand) complexes determined by different methods
were in excellent agreement. For the complexation of M+ (M = Li, Na, K) with L, both enthalpic and entropic
contributions were favorable, with their values and mutual relations
being quite strongly dependent on the cation. The enthalpic and overall
stability was the largest in the case of the sodium complex. Molecular
and crystal structures of free L, its methanol and MeCN
solvates, the sodium complex, and its MeCN solvate were determined
by single-crystal X-ray diffraction. The inclusion of a MeCN molecule
in the calixarene hydrophobic cavity was observed both in solution
and in the solid state. This specific interaction was found to be
stronger in the case of metal complexes compared to the free ligand
because of the better preorganization of the hydrophobic cone to accept the solvent molecule. Density functional theory calculations
showed that the flattened cone conformation (C2 point group) of L was generally
more favorable than the square cone conformation
(C4 point group). In the complex with
Na+, L was in square cone conformation, whereas
in its adduct with MeCN, the conformation was slightly distorted from
the full symmetry. These conformations were in agreement with those
observed in the solid state. The classical molecular dynamics simulations
indicated that the MeCN molecule enters the L hydrophobic
cavity of both the free ligand and its alkali-metal complexes. The
inclusion of MeCN in the cone of free L was accompanied by the conformational change from C2 to C4 symmetry. As in solution
studies, in the case of ML+ complexes,
an allosteric effect was observed: the ligand was already in the appropriate
square cone conformation to bind the solvent molecule,
allowing it to more easily and faster enter the calixarene cavity.