Ya-Mei Tan, Huoqing Chen, Zhe Zhang, Pingshan Wang, Qi Zhang
Achieving high thermodynamic selectivity in supramolecular assembly is highly desirable, as it simplifies synthesis and yields assemblies of enhanced stability. Heteroleptic assemblies─which can integrate diverse functionalities from different building blocks─have attracted growing interest, yet their selective construction under thermodynamic control remains challenging when using structurally similar ligands, due to the minimal energy differences among numerous possible species. We report a strategy that leverages intracavity noncovalent interactions to reshape the energy landscape and selectively stabilize a single thermodynamic product. Using Pd(II)-pyridine coordination, ligands featuring internal amide or carboxyl groups are designed to incorporate both steric and hydrogen-bonding functionalities. This enables high-fidelity assembly of a trans -Pd 2 A 2 B 2 cage from a system that would otherwise yield a statistical mixture of nearly isoenergetic isomers. Two complementary interaction modes are identified: hydrogen bonding between opposing B ligands (B–B mode) or between adjacent A and B ligands (A–B mode). The target cage, characterized by NMR, mass spectrometry, and X-ray crystallography, is selectively driven to the global energy minimum. This work establishes a robust design paradigm for achieving precise thermodynamic control in complex multicomponent systems, opening new avenues for the construction of functional supramolecular architectures.