Recognition of bio-relevant dicarboxylate anions by an azacalix[2]arene[2]triazine derivative decorated with urea moieties

Abstract

A new dichloroazacalix[2]arene[2]triazine receptor (1) with two chiral urea binding moieties is reported. The binding affinity of this macrocycle was evaluated by ¹H NMR titrations in CDCl₃ for the dicarboxylate anions oxalate (ox²⁻), malonate (mal²⁻), succinate (suc²⁻), glutarate (glu²⁻), diglycolate (dg²⁻), fumarate (fum²⁻), maleate (male²⁻), and (R,R)- and (S,S)-tartarate (tart²⁻) enantiomers. Among the first five linear anions, the higher association constants were calculated for the larger anions glu²⁻ and dg²⁻ and for the smallest anion ox²⁻, with K_ass values following the sequence dg²⁻ > glu²⁻ > ox²⁻ > suc²⁻ > mal²⁻. Despite the high binding affinity of 1 for both tart²⁻ enantiomers, no enantioselectivity was observed. By contrast, K_ass for fum²⁻ is ca. 8.9 times greater than that for male²⁻, showing the selectivity of 1 for the trans isomer. These binding preferences were further elucidated by theoretical methods. Molecular dynamics simulations showed that the linear anions are lodged between both pendant arms and that each anion can assume two distinct binding poses, with one or two carboxylate groups establishing intermittent hydrogen bonds with both urea binding units. On the other hand, the recognition of male²⁻ ensues in an alternative scenario, characterised by the interaction between a carboxylate group and a single urea binding unit, mirroring the lower experimental binding affinity relatively to fum²⁻. A linear increase of the receptor's N_urea⋯N_urea and the anions’ ⁻O₂C⋯CO₂⁻ distances versus experimental K_ass was established for mal²⁻, suc²⁻, glu²⁻ and dg²⁻ associations, indicating that the match between these two distances determines the anion binding strength. The affinity for ox²⁻ was associated with the most negative values of electrostatic potential positioned near carboxylate groups.