A charge-neutral organic cage selectively binds strongly hydrated sulfate anions in water

Abstract

Binding hydrophilic anions such as sulfate in water is a significant academic challenge, in particular for neutral receptors. To achieve this, typically a large molecular receptor is designed that wraps around a bound anion in a hydrophobic microenvironment. Such receptors require multi-step synthesis and often display selectivity towards hydrophobic anions such as iodide. We here report the one-pot synthesis of a [2.2.2]urea cryptand (cage) and its ability to bind sulfate in water with sub-millimolar affinity achievable by incorporation into micelles. Unlike existing neutral receptors, the cage has >10-fold selectivity for sulfate against hydrophobic anions even in pure water. The cage displays rare slow-exchange NMR responses to divalent anions in DMSOwater allowing for simultaneous analysis of multiple divalent anions in water analogous to an ion chromatography instrument. Our results demonstrate the pre-organization of strong directional NH hydrogen bond donors in a cage scaffold as a synthetically less-demanding, yet effective approach to achieving selective binding of hydrophilic anions in water.

Applying a Tripodal Hexaurea Receptor for Binding to an Antitumor Drug, Combretastatin-A4 Phosphate

“…Notably, the binding constants of L 1 to the studied anions in pure DMSO- d 6 were either numerically similar to or smaller than those of L 1 to CA4P in DMSO- d 6 /H 2 O (90%/10%, v / v ) mixed solvents. Considering the substantial decrease in binding constants observed upon water addition, as documented previously [ 40 ], we inferred that the binding affinities of L 1 to common anions are notably lower than those of CA4P. This hypothesis was reinforced by the competitive titration in DMSO- d 6 .…”

A molecular-design approach for selective sulfate separation from competitive acidic and alkaline aqueous media

“…The molecular design approach for developing sulfate selective receptors in water is dictated by a few crucial parameters, as identified in the literature on sulfate recognition. 31–42 Firstly, the larger size, tetrahedral shape, and charge density of sulfate dianion allow it to accept a maximum of twelve hydrogen bonds, which has been exemplified in several crystal structures of receptor–sulfate complexes and by theoretical calculations. 23–25 Thus, an ideal sulfate receptor should possess multiple convergent HBD groups for effective sulfate binding in the solution and solid states.…”

“…Recently, Deplazes and Wu et al reported the synthesis of a [2.2.2]urea cryptand ( L 6 , Scheme 1) that selectively encapsulates sulfate in water with much higher affinities (SO 4 2− : log K ≈ 1.8) than that of selenate (SeO 4 2− : log K ≈ 0.93), hydrogenphosphate (HPO 4 2− : log K ≈ 0.72) and halides (Cl − /Br − : log K ≈ 0.59). 36 The charge-neutral cryptand was water soluble up to 15 mM and the sulfate binding affinity of the receptor could be enhanced to sub-millimolar levels by using micelles. The intrinsic sulfate binding constant of the cryptand in cetyltrimethylammonium bromide (CTAB) micelles was estimated >10 4 M −1 (log K ≈ 4).…”

Biomimetic Charge‐Neutral Anion Receptors for Reversible Binding and Release of Highly Hydrated Phosphate in Water

“…[5] Although a few neutral receptors have been reported to bind anions in 100 % water, only weakly hydrating anions are involved, such as Cl À , [6] I À , [7] H 2 PO 4 À [8] and SO 4 2À . [9] To the best of our knowledge, no charge-neutral anion receptor has been reported to bind the highly hydrated PO 4 3À in 100 % water up to now.…”

“…We attributed the upfield shift to the breaking of intramolecular hydrogen bonds after phosphate binding, a phenomenon commonly seen in the literature. [9] The absence of downfield shifts in H7-H10 of morpholine suggests there are no electrostatic interactions between the phosphate anion and L 1 . These results, including pKa values and 1 H NMR shifts at different pH levels, collectively demonstrate that the charge-neutral L 1 , rather than the positively charged L 1 , exerted the binding ability to PO 4 3À at pH 13.…”