Sharing the salt bowl : counterion identity drives N-alkyl resorcinarene affinity for pyrophosphate in water

Abstract

N-Alkyl ammonium resorcinarene chloride receptors, NARX4, have been shown to act as high-sensitivity detectors of pyrophosphate (PPi), a biomarker of disease, in aqueous media through the chloride-to-PPi exchange [NAR(Cl)4 to NARPPi]. The nature of the anion of the macrocyclic NARX4 (X = Cl−, Br−, triflate OTf−) receptor greatly influences the PPi-affinity in aqueous media. The binding affinity for [NAR (Cl)4] is 3.61 × 105 M−1, while the NAR (Br)4 and NAR (OTf)4 show stronger binding of 5.30 × 105 M−1, and 6.10 × 105 M−1, respectively. The effects of upper rim ammonium cation, –N+H2R substituents (R = 3-hydroxypropyl, cyclohexyl, benzyl, or napththalen-1-ylmethyl), of the macrocyclic resorcinarene hosts have also been evaluated. The highest affinity was obtained using 3-hydroxypropyl groups due to the additional hydrogen bonds and the naphthyl upper-rim group that provides a larger hydrophobic surface area and favorable stacking interaction (i.e., π–π and CH–π). We note that two PPi molecules can bind to the more selective receptors through an additional interaction with the lower rim hydroxyls, making the resorcinarene a divalent binder. Comparing PPi with other phosphate anions (PO43−, AMP, ADP, and ATP) shows that the receptors are more selective for PPi due to the size and charge complementarity. Experimental (1H, 31P NMR, and isothermal titration calorimetry), and computational analyses support the reported trends for PPi selectivity even in highly competing aqueous media.