Optimized Immobilization Strategy for Dirhodium(II) Carboxylate Catalysts for C−H Functionalization and Their Implementation in a Packed Bed Flow Reactor

Herein we demonstrate a packed bed flow reactor capable of achieving highly regio‐ and stereoselective C−H functionalization reactions using a newly developed Rh2(S‐2‐Cl‐5‐CF3TPCP)4 catalyst. To optimize the immobilized dirhodium catalyst employed in the flow reactor, we systematically study both (i) the effects of ligand immobilization position, demonstrating the critical factor that the catalyst‐support attachment location can have on the catalyst performance, and (ii) silica support mesopore length, demonstrating that decreasing diffusional limitations leads to increased accessibility of the active site and higher catalyst turnover frequency. We employ the immobilized dirhodium catalyst in a simple packed bed flow reactor achieving comparable yields and levels of enantioselectivity to the homogeneous catalyst employed in batch and maintain this performance over ten catalyst recycles. Supported rhodium catalysts anchored to mesoporous silica in three different locations demonstrate optimal tethering location, allowing for deployment in a fixed bed flow reactor for enantio‐ and regioselective C−H functionalization. Tuning silica particle size/shape enhances reactivity and the catalyst immobilization methodology is widely applicable.