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Hydrogen bonding is prevalent in biological systems, dictating a myriad of life-sustaining functions in aqueous environments. Leveraging hydrogen bonding for molecular recognition in water encounters significant challenges in synthetic receptors on account of the hydration of their functional groups. Herein, we introduce a water-soluble hydrogen bonding cage, synthesized via a dynamic approach, exhibiting remarkable affinities and selectivities for strongly hydrated anions, including sulfate and oxalate, in water. We illustrate the use of charge-assisted hydrogen bonding in amide-type synthetic receptors, offering a general molecular design principle that applies to a wide range of amide receptors for molecular recognition in water. This strategy not only revalidates the functions of hydrogen bonding but also facilitates the effective recognition of hydrophilic anions in water. We further demonstrate an unconventional catalytic mechanism through the encapsulation of the anionic oxalate substrate by the cationic cage, which effectively inverts the charges associated with the substrate and overcomes electrostatic repulsions to facilitate its oxidation by the anionic MnO4–. Technical applications using this receptor are envisioned across various technical applications, including anion sensing, separation, catalysis, medical interventions, and molecular nanotechnology. 

Abstract Achieving selective molecular recognition of hydrophilic anions in water remains a formidable challenge due to the competitive nature of water and the high hydration energies of target anions such as sulfate. Here, we report the design, synthesis, and characterization of a simple dicationic tetralactam macrocycle (BPTL²⁺·2Cl⁻) capable of binding highly hydrated anions in water via charge‐assisted hydrogen bonding. Structural, spectroscopic, thermodynamic, and computational studies reveal that BPTL²⁺ exhibits a strong binding affinity for sulfate (K_a = 2892 M⁻¹), driven primarily by entropic gain from water release and reinforced by electrostatic and hydrogen bonding interactions. Single‐crystal X‐ray diffraction and DFT‐optimized structures confirm the formation of directional [N─H•••O] and [C─H•••O] hydrogen bonds. Comparative studies with a control macrocycle (6Na⁺•HCTL⁶⁻) that has a charge‐neutral binding cavity underscore the essential role of cationic charge in overcoming desolvation enthalpic penalties. The receptor displays anti‐Hofmeister selectivity, preferentially binding more hydrophilic anions. This work provides fundamental insights into the mechanisms of anion recognition in water. It establishes charge‐assisted hydrogen bonding as a powerful strategy for developing next‐generation receptors for sensing, separation, sequestration, transport, and catalysis in aqueous environments.