High-speed circulation microflow synthesis facilitating practical large-scale heterogeneous photocatalysis

Abstract

Abstract Although continuous-flow synthesis using microtubing reactors has provided a wealth of opportunities for photochemical synthesis and has proven particularly beneficial in scaling up processes, handling solids and slow reactions remains major hurdles that have hampered its broad application. Here, we present a solution to these issues by changing the continuous-flow mode to a high-speed circulation-flow mode. The high flow rate set in a circulation microflow reactor overcomes solid sedimentation to prevent clogging and improve mixing efficiency. We successfully conducted 100 g-scale C-N and C-S cross-couplings using a heterogeneous photocatalyst and a nickel catalyst in the microflow reactor that significantly outperformed conventional batch reactors. The photocatalyst was recycled and reused 10 times to achieve kg-scale synthesis without obvious deactivation. Even though the reaction occurred in batch mode, semi-continuous production was achieved via automated feeding and collection, and a photo-promoted gas/liquid/solid three-phase trifluoromethylation reaction was employed to produce the drug trifluridine on a kg scale. Our study suggests that a circulation flow reactor with high flow speed will become a crucial tool in the synthetic chemist’s toolbox, owing to its simple infrastructure, ease of operation and automation, significant efficiency improvement compared to conventional batch reactors, scalability, improved safety and tolerance of solids.