The Influence of Binding Site Geometry on Anion‐Binding Selectivity: A Case Study of Macrocyclic Receptors Built on the Azulene Skeleton

• Published in: Chemistry : a European journal 2018-08, Vol.24 (45), p.11683-11692
• Main Authors: Lichosyt, Dawid, Wasiłek, Sylwia, Dydio, Paweł, Jurczak, Janusz
• Format: Article
• Language: English
• Subjects: Anions; Azulene; Binding sites; Bonding strength; Chemistry; Chlorides; Construction; host–guest systems; hydrogen bonds; macrocycles; molecular recognition; Molecular structure; Organic chemistry; Receptors; Selectivity; Topology
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201801460

An understanding of host–guest noncovalent interactions lies at the very heart of supramolecular chemistry. Often a minute change to the structure of a host molecule's binding site can have a dramatic impact on a prospective host–guest binding event, changing the relative selectivity for potential guest molecules. With the overall goal of aiding the rational design of selective and effective receptors for anions, we have studied the influence of small perturbations in binding site geometry for a series of five closely related 20‐membered macrocyclic tetra‐amide receptors, constructed from two building blocks from a pool of azulene‐5,7‐bisamide, azulene‐1,3‐bisamide, and dipicolinic bisamide units. The solid‐state structures revealed that the conformational preferences of the free receptors are driven by the inherent preferences of the building blocks, yet in some cases the macrocyclic topology is able to over‐ride these to promote pre‐organized conformations favorable for anion binding. The solid‐state structures of the chloride complexes of these receptors revealed that although all the receptors can adapt to binding to the challenging small Cl− guest with all the NH groups, only receptors containing azulene‐5,7‐bisamide units form short and linear, and therefore strong, hydrogen‐bonding interactions. These conclusions are further supported by studies in solution. Although all the receptors showed high affinities toward a series of anions (H2PO4−, PhCO2−, Cl−, and Br−), even in a highly competitive polar medium (DMSO/25 % MeOH), only receptors containing azulene‐5,7‐bisamide units exhibited non‐inherent selectivity for Cl− over PhCO2−, breaking the Hofmeister trend of selectivity. The data presented herein highlight the privileged properties of the azulene‐5,7‐bisamide building block for binding to chloride anions and provide guidelines for the construction of selective and efficient anion receptors with prospective practical applications. Two faces of azulene: Which one likes chloride more? With the goal of aiding the rational design of selective anion receptors, the influence of small perturbations in the binding site geometry for a series of tetra‐amide macrocycles built on the azulene moiety has been studied (see figure). These closely related receptors demonstrate strongly varied selectivity, and some of them break the Hofmeister trend of selectivity to bind preferentially chloride anions over carboxylate anions!