Precise functionalization in nano-confinement: a bottom-up approach to the evolution of selective molecular receptors

Precise molecular recognition depends on the delicate interplay between a guest molecule and a host possessing complementary functional groups. The de novo design of selective artificial receptors remains a formidable challenge, given the complexity of predicting these interactions. We present herein a bottom-up approach to the evolution of selective molecular receptors through precise endo-functionalization of a supramolecular cage. Internal functional groups were introduced within the heteroleptic palladium coordination cage in a site-precise fashion. With just five different functional groups, we successfully created a library of 32 isoreticular nano-cages, each featuring a unique micro-environment, by varying the nature, location and combination of endo-functional groups. The nano-cage exhibited adaptive recognition ability towards guest molecules of distinct geometries and hydrogen bonding capabilities. Titration experiments demonstrated that the binding affinity for a specific guest can be finely tuned and optimized by changing the endo-functional groups. As a proof of principle, by strategically screening our nano-cage library, we identified a receptor with high affinity and specificity for the dihydrogen phosphate guest. X-ray analysis and DFT calculation highlighted the pivotal role of the synergistic interactions among distinct endo-functional groups in achieving high-fidelity molecular recognition. This study is expected to provide a versatile solution for the bottom-up construction of tailor-made molecular receptors.