Scale-Up of Continuous\nMetallaphotoredox Catalyzed\nC–O Coupling to a 10 kg-Scale Using Small Footprint Photochemical\nTaylor Vortex Flow Reactors

We report the development and optimization of a scalable\nflow process\nfor metallaphotoredox (Ir/Ni) C–O coupling, a mild and efficient\napproach for forming alkyl-aryl ethers, a common motif in medicinal\nand process chemistry settings. Time-resolved infrared spectroscopy\n(TRIR) highlighted the amine as the major quencher of the photocatalyst\ntriplet excited state, along with the formation of an Ir(II) species\nthat, in the presence of the Ni cocatalyst, has its lifetime shortened,\nsuggesting reductive quenching of Ir(III)*, followed by reoxidation\nfacilitated by the Ni cocatalyst. TRIR and batch reaction screening\nwas used to develop conditions transferrable to flow, and many processing\nbenefits of performing the reaction in flow were then demonstrated\nusing a simple to construct/operate, small-footprint FEP coil flow\nreactor, including short (<10 min) space times and reduced catalyst\nloadings (down to 0.1 mol % Ir, 1 mol % Ni) while retaining good yield/conversion.\nScalability was demonstrated by increasing the length or diameter\nof the FEP coil flow reactor tubing, however, due to suspected mass\ntransfer/mixing limitations, the yield decreased upon scale-up in\nsome cases. Therefore, we applied a modified version of our previously\nreported photochemical Taylor Vortex Flow Reactor (PhotoVortex), where\nTaylor vortices and a short-irradiated path length allow photochemical\nreactions to be performed efficiently via excellent mixing. In a small\nPhotoVortex (8 mL irradiated volume), we have demonstrated projected\nproductivities around 1 kg day<sup>–1</sup> and >10 kg day<sup>–1</sup> in a large PhotoVortex (185 mL irradiated volume)\nwith good product yields (>90%) and low catalyst loadings (0.1\nto\n0.5 mol % of [Ir{dF(CF<sub>3</sub>)ppy}<sub>2</sub>dtbbpy]PF<sub>6</sub>), enabled by excellent mixing ensuring sufficient mass transfer\nbetween short-lived photoexcited and other transient species.