Theoretical aspects of the enhancement of metal binding affinity by intramolecular hydrogen bonding and modulating pKa values

Abstract

Polyols were used as model ligands for Mg²⁺, Ca²⁺, and Zn²⁺ complexes to study the role of the hydrogen bond network on the metal binding affinity and modulation of successive pK_a values using density functional theory. The results confirm that the acidity of polyols dramatically increases upon metal complexation in the order Zn²⁺ > Mg²⁺ > Ca²⁺. For example, the three H-site positions in the hydroxyl groups of the heptaol, bound to Zn²⁺, are 11.2, 29.9, and 30.9 pK_a units (in methanol) more acidic than those of pure heptaol. This acidity enhancement leads to making polyols as good ligands toward complexation. For instance, the formation constants of the heptaol in the presence of Zn²⁺, Mg²⁺, and Ca²⁺ in methanol were 5.67 × 10⁷¹, 6.46 × 10⁶⁶, and 1.26 × 10⁵³ times lower than those in its third deprotonation state, respectively. The natural bond orbital (NBO), quantum theory of atoms in molecules (QTAIM), and reduced density gradient (RDG) analyses show that the intramolecular hydrogen bond network and increment of carbon chain length lead to the enhancement of metal binding affinity. These findings can be used for the manipulation of ligands and metal cations in designing metalloproteins.