The ligand screening process, in which an optimal ligand for a reaction of interest is identified from an enormous and diverse set of candidate molecules, is of particular importance in the development of transition metal catalysis. Conventionally, this process has been performed by experimental trial-and-error cycles, which require significant time and resources. Herein, we report a novel strategy called “virtual-ligand-assisted (VLA) screening” that enables practical in silico ligand screening based on the transition state theory. We developed a virtual ligand, PCl*3, which parameterizes both the electronic and steric effects of monodentate phosphorus(III) ligands in quantum chemical calculations, and used it to assess how these effects perturb the energy profile of a reaction. This parameter-based ligand screening approach allowed us to identify the optimal electronic and steric effects for a reaction of interest, thereby affording guiding principles for rational ligand design. The VLA screening strategy was demonstrated for the selectivity-determining step of the rhodium-catalyzed hydroformylation of a terminal olefin, and phosphorus(III) ligands with potentially high linear or branched selectivities were designed. These findings indicate that VLA screening is a promising approach for streamlining the ligand screening process.
Table of Contents: 1. Computational details 2. List of calculated ligands 3. Approximation of electronic effects with various virtual ligands 4. Determination of the correction constant (b) for ligand–ligand repulsion 5. Tolman’s maps with all ligands assigned 6. Discussion about the selectivity-determining step of Rh-catalyzed hydroformylation 7. Discussion about alternative reaction paths for Rh-catalyzed hydroformylation 8. Optimized geometries of transition states for insertion of olefin 9. Supplemental references 10. Cartesian coordinates of optimized structures