Catching the chloride: searching for non-Hofmeister selectivity behavior in systematically varied polyamide macrocyclic receptors

Abstract

The binding selectivity of structurally simple anion receptors is governed by the Hofmeister series (SO > HPO > carboxylates ∼ HPO > HCO > Cl), and exceptions to this rule are rare and require utilization of structurally sophisticated receptors. In this paper we examined a set of 48 structurally diverse anion receptors, barely one fourth of which exhibit selectivity for chloride over more basic dihydrogen phosphate (HPO) or carboxylates (MeCO and PhCO). Searching for regularities in the properties of these mainly macrocyclic-derived receptors across quite systematic changes in structure, combined with analysis of multiple crystal structures, allowed us to identify the crucial structural features that are likely required for the occurrence of the phenomenon of selective chloride binding. Examination of a subset of other 'case study' receptors reported in the literature as being particularly chloride-selective served as a confirmation of our hypotheses. As such, our findings are valid for all artificial receptors with exceptional selectivity for chloride, as well as for natural chloride channel proteins (ClC).

1‐(Methylamino)anthracene – An Accessible Building Block for Photoresponsive Compounds

“…[26] In our case the presence of anthracene groups results in equalization of association constants. Quite interestingly, host 10 exhibits similar affinity for chloride and benzoate.…”

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

“…With receptors 1 – 5 in hand, we commenced a detailed analysis of their structural properties as well as their selectivity and affinity for anion binding. We used the Cl − anion as the model target anion due to its aforementioned significance and its recurrent relatively low affinity and selectivity for neutral receptors . First, we investigated the conformational properties of the free receptors and of their Cl − anion complexes by using X‐ray crystallography.…”

“…Notably, the crystal structure of the chloride complex of receptor 4 suggests that the 20‐membered macro‐ring, previously identified as optimal for macrocyclic tetra‐amide receptors, is slightly too large to accommodate precisely small chloride anions. Studies in solution showed that all the receptors 1 – 5 have high affinities for binding to anions of different sizes and geometries (H 2 PO 4 − , carboxylates, Cl − , Br − ), even in highly competitive polar solvent media (DMSO/25 % MeOH). This confirms the privileged properties of the azulene‐based building blocks and of the macrocyclic topology for the construction of anion receptors. The relative selectivity of the binding of different anions shows that receptors containing azulene‐1,3‐bisamide building blocks display high selectivity, with an unusually high affinity for H 2 PO 4 − , in line with both the Hofmeister trend and previous findings; however, receptors containing the azulene‐5,7‐bisamide building block display a higher affinity for commonly weakly binding Cl − over the carboxylates PhCO 2 − and MeCO 2 − , which are typically strongly interacting anions. This shows that the usual selectivity of anion binding of the Hofmeister series can be overturned by making adjustments to the geometry of the binding site.…”

“…The relative selectivity of the binding of different anions shows that receptors containing azulene‐1,3‐bisamide building blocks display high selectivity, with an unusually high affinity for H 2 PO 4 − , in line with both the Hofmeister trend and previous findings; however, receptors containing the azulene‐5,7‐bisamide building block display a higher affinity for commonly weakly binding Cl − over the carboxylates PhCO 2 − and MeCO 2 − , which are typically strongly interacting anions. This shows that the usual selectivity of anion binding of the Hofmeister series can be overturned by making adjustments to the geometry of the binding site.…”

“…The key characteristics of such anion receptors are their affinity to the target anion, and their selectivity for binding the target anion over other anions potentially present in the analyte. Although immense progress in the field of supramolecular chemistry has provided guidelines for the design of receptors with high anion affinities, the a priori design of such receptors with target anion selectivity remains largely beyond our reach . Therefore, fundamental research providing an insight into structure–selectivity relationships is required to enable the rational design of selective and effective receptors for practical applications…”