Preorganized PSP Ligands Yield Monomeric Cu(I) Complexes with Subzeptomolar Cu(I) Dissociation Constants.

Unraveling the function of biological copper (Cu) requires tools that can selectively recognize and manipulate this trace nutrient within the complex chemical environment of biological systems. Increasing evidence suggests that cells maintain an exchangeable pool of Cu(I) that is buffered in the high zeptomolar to low attomolar range. While mixed amine-thioether donors have been commonly employed for the design of Cu(I)-selective ligands and probes, their dissociation constants are limited to the pico- to femtomolar range. To address this challenge, we combined our previously devised phosphine sulfide-stabilized phosphine donor motifs with a rigid 1,2-phenylene or 1,8-naphthylene ligand backbone. The resulting ligands, phenPS and naphPS, bind Cu(I) with a 1:1 complex stoichiometry and offer dissociation constants of 0.6 and 0.8 zM, respectively. Concluding from the crystal structures of the free and Cu(I)-bound ligands, the 1,2-phenylene-bridged ligand phenPS provides a high degree of structural preorganization to accommodate the Cu(I) center without large conformational changes, while the 1,8-naphthylene-bridged ligand revealed significant out-of-plane distortions in both the free and Cu(I)-bound states. Both ligands were accessed by palladium-catalyzed cross-coupling reactions from the corresponding arylhalides under mild conditions, an approach that could be readily expanded toward the design of other ligands and probes.