Rapid Assembly of a Covalently Locked Organic Cage Revealing Symmetry‐Matched Guest Recognition

ABSTRACT Robust organic cages featuring convergent hydrogen‐bonding cavities constitute attractive platforms for confined molecular recognition. Here, we report a rapid four‐step synthesis of a well‐defined pyridyl hexa‐amide cage based on a readily accessible benzylic tris‐aniline platform. Microwave‐assisted imine condensation enables fast cage assembly, while subsequent Pinnick oxidation converts the dynamic architecture into a permanently locked C 3 ‐symmetric host. Single‐crystal x‐ray diffraction reveals a rigid cavity lined with six inward‐oriented N–H donors, generating a confined hydrogen‐bonding environment suitable for anion recognition. In DMSO, mono‐ and dicarboxylate guests bind in a fast‐exchange regime with comparable apparent affinities. In contrast, a symmetry‐matched tricarboxylate (nitrilotripropionate, NTP) induces the formation of a discrete 1:1 host–guest complex displaying distinct titration behavior and confirmed crystallographically. Control experiments with a more rigid tricarboxylate (aluminon) revealed no detectable binding under comparable conditions, suggesting that guest conformational adaptability also contributes to complex formation. These observations highlight how rigidification and geometric complementarity within a confined cavity can influence host‐guest recognition behavior in solution.