# The “Missing Link”, Allostery and SynergismHosting of Metal Cations by Regular and Partial Cone Calix[4]arene Isomers

## TL;DR

This study explores how the structure of calix[4]arene affects its ability to bind metal cations and include solvents, revealing important insights into supramolecular recognition.

## Contribution

The work provides a detailed analysis of conformational effects on cation binding and solvent inclusion in calix[4]arene isomers.

## Key findings

- Partial cone isomer L_p showed reduced cation-binding ability due to incomplete cation desolvation.
- Solvent inclusion was favored in regular cone isomer L_c but not in L_p, affecting complex stability.
- Acetonitrile inclusion was preferred over methanol in complexes, with solvent orientation confirmed by X-ray diffraction.

## Abstract

The influence of the tetra-O-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 cone ligand (L

p
) led to incomplete cation desolvation and
significantly reduced its cation-binding ability compared to the regular cone isomer (L

c
). Aromatic
ring inversion also precluded solvent inclusion in the calixarene basket of both free and complexed L

p
(in contrast to L

c
), 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 L

p
, as well as sodium,
calcium, and barium complexes of L

c
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.