Chasing nature’s anion binders

Abstract

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  Development of uncharged molecular cages with highly pre-organized urea sites
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  Neutral hydrogen bonds achieve micromolar affinities for hydrophilic anions
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  A cage-integrated ionic liquid selectively captures chromate and sulfate from water

Sulfate-binding proteins from bacteria capture strongly hydrated sulfate anions from the environment as an initial step of nutrient uptake. Surprisingly, their interaction with sulfate is purely hydrogen bonding, without the formation of salt links, yet achieves remarkable sub-micromolar affinities. Supramolecular chemists have faced significant challenges in using hydrogen bonds to attain comparable host-guest binding strengths in water. In this work, the authors demonstrate that highly pre-organized, charge-neutral urea cages can bind hydrophilic chloride, sulfate, and chromate anions with micromolar affinities in water, even though the urea sites are exposed to water such that significant energetic penalties from host dehydration have reduced the overall binding strength. In addition, an ionic liquid material integrating a thiourea cage is shown to remove chromate and sulfate anions selectively in complex water samples, highlighting its real-world applicability. In the future, the design principles used in this work open opportunities to create larger hydrogen-bonding host architectures to recognize more complex biological targets, such as peptides and proteins, toward applications in targeted delivery, biological sensing, and therapeutic intervention.

In water, hydrogen bonds between solute molecules are disfavored because they must compete with the overwhelming abundance of water forming hydrogen bonds with solutes. Thus, molecular recognition by hydrogen bonds in water has long been considered challenging, often requiring auxiliary interactions such as ion pairing and hydrophobic contacts. Yet through evolved structural sophistication, certain biological receptors such as sulfate-binding proteins use hydrogen bonds alone to bind hydrophilic anions with remarkable (sub)micromolar affinities. Here, we report highly pre-organized, uncharged hydrogen-bonding molecular cages that match the micromolar affinities of nature’s anion receptors in water. Contrasting large biological receptors that bury polar binding sites within hydrophobic cores, these synthetic hosts have just 52 heavy atoms with polar binding sites exposed to water. These results establish the capabilities of unshielded polar hydrogen bonds in aqueous supramolecular chemistry, providing new opportunities for biological interventions and molecular separations.

In water, hydrogen bonds between solute molecules are disfavored because they must compete with the overwhelming abundance of water forming hydrogen bonds with solutes. Thus, molecular recognition by hydrogen bonds in water has long been considered challenging, often requiring auxiliary interactions such as ion pairing and hydrophobic contacts. Yet through evolved structural sophistication, certain biological receptors such as sulfate-binding proteins use hydrogen bonds alone to bind hydrophilic anions with remarkable (sub)micromolar affinities. Here, we report highly pre-organized, uncharged hydrogen-bonding molecular cages that match the micromolar affinities of nature’s anion receptors in water. Contrasting large biological receptors that bury polar binding sites within hydrophobic cores, these synthetic hosts have just 52 heavy atoms with polar binding sites exposed to water. These results establish the capabilities of unshielded polar hydrogen bonds in aqueous supramolecular chemistry, providing new opportunities for biological interventions and molecular separations.

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