Computational Exploration of Stereoelectronic Relationships in Manganese‐Catalyzed Hydrogenation Reactions

Stereoelectronic effects governing Mn-catalyzed hydrogenation reactions have been deconvoluted through the analysis of a series of in silico catalyst modifications using DFT (PBE0-D3_PCM(EtOH)/def2-TZVP//RI-BP86_PCM(EtOH)/def2-SVP level of theory). Computations were performed on the Mn-catalyzed reduction of indanone based on a catalyst from the Clarke group, consisting of a tridentate ligand with pyridine, amine, and phosphine donors and a ferrocenyl linker in the backbone. Enantioselectivity enhancements were found through two pathways; first, with the stabilization of aromatic substrates by means of an extended π-system, enhancing π-stacking noncovalent interactions; second, by the introduction of steric bulk around the active site to destabilize one of the diastereomeric hydride transfer transition states. Electronic effects were differentiated from sterics by modification of the phenyl groups at the phosphine, trans- to the metal-hydride bond. While electron-withdrawing groups increased the thermodynamic driving force, the highest activity is predicted with electron-donating groups due to the improved basicity of the nitrogen lone pair, required for the initiation of hydrogen activation. Based on these observations, promising routes for synthetic catalyst design may involve donating groups which improve activity, coupled with enantiodiscrimination via steric bulk as a more general strategy than being limited to π-containing substrates.