Step-by-step DFT analysis of the cooperativity in the binding of cations and anions to a tetratopic ion-pairing host

Computational techniques allow insights into chemical processes that are normally experimentally difficult to access (e.g. transition states). Here, we report on the computational modelling of a recently reported supramolecular system that experimentally displays a complex mixture of cooperative, allosteric, homotropic and heterotropic binding behaviour in the interactions of two calcium cations and two chloride anions with a tetratopic ion-pairing host (bis-isophthalamide-crown-6) H. Using DFT, we are able to predict the structural conformations and binding energies of the multi-step thermodynamic binding cycle in both directions for the formation of the quinary 2Ca²⁺·H·2Cl⁻ complex in both vacuum and solvent environments with several key steps validated against experimental X-ray and binding study data. This study revealed unexpected conformational changes in the free host upon binding two Cl⁻ anions, with a tetra-coordinated (four hydrogen-bonds) 1:1 H·Cl⁻ complex forming before the expected bis(isopthhalimide-Cl⁻) 1:2 H·2Cl⁻ complex with two hydrogen bonds is formed. The results here show that given the appropriate method (basis set, solvent environment) DFT calculations can both predict and give unique insight into multi-ion host supramolecular interactions like those encountered in ion-pair host–guest studies.