Host-Directed Discovery of Dynamic-Covalent Guests From Dynamic Combinatorial Libraries.

Abstract

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 1H NMR readout is well suited to smaller libraries, 19F 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) × 103 M-1. These findings establish host-directed selection as a practical strategy for coupling molecular recognition with constitutional dynamics in adaptive systems and materials.