Host‐Directed Discovery of Dynamic‐Covalent Guests From Dynamic Combinatorial Libraries

Dynamic covalent chemistry and host–guest recognition are complementary tools for constructing adaptive molecular systems and functional materials, yet their integration has been hindered by the lack of general strategies for efficiently discovering host‐compatible dynamic‐covalent guests. Here we report a host‐directed screening strategy that directly identifies optimal imine guests from dynamic combinatorial libraries. Upon addition of the macrocyclic host, selective host–guest binding drives thermodynamically controlled library redistribution, leading to significant constitutional amplification of the preferred guests. A one‐pot workflow involving activation, complexation, deactivation, displacement, and readout enables precise quantification of this redistribution by simple one‐dimensional NMR spectroscopy. While 1 H NMR readout is well suited to smaller libraries, 19 F NMR offers clear advantages for more complex libraries, as demonstrated with a [5× 5] library. [2×n] library architecture further improves screening robustness by directing the major antagonistic response toward a channel excluded from candidate ranking. Although pillararene‐imine complexes have rarely been reported because of their weak binding, stepwise screening of three library sets identified imine guests for ethyl pillar[5]arene with association constants of up to (2.2 ± 0.1) × 10 3 M −1 . These findings establish host‐directed selection as a practical strategy for coupling molecular recognition with constitutional dynamics in adaptive systems and materials.