Chasing nature’s anion binders

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.