Scientific Publications

Continuous Flow Processing of Bismuth-Photocatalyzed Atom Transfer Radical Addition Reactions Using an Oscillatory Flow Reactor - Kappe, C. O. et al. Green Chem. 2021. DOI: 10.1039/D0GC03070H

ABSTRACT: Metal oxides represent an abundant and non-toxic class of photocatalysts for organic transformations. However, their use in larger scale processes is complicated by incompatibilities with continuous flow processing – a proven scale-up route for photochemistry. We detail the development of an efficient atom transfer radical addition protocol using a sustainable solvent system (acetone : PEG 400) and a low loading (2 mol%) of Bi2O3, which can be handled in an oscillatory flow reactor. Optimization of the reaction and oscillatory parameters led to high throughput (36 g in 4 h, 89% yield, 599 g L−1 h−1), with a process mass intensity (PMI) of just 8.5. The process also facilitates high recyclability (3 cycles with no loss of yield), and was demonstrated to be applicable to a range of other substrates on multigram scale, in moderate to excellent yields.

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Optimization of a Decatungstate-Catalyzed C(Sp 3 )–H Alkylation Using a Continuous Oscillatory Millistructured Photoreactor. - Noël, T. et al. Org. Process Res. Dev.  2020, 24 (10), 2356–2361

ABSTRACT: Tetrabutylammonium decatungstate (TBADT) has emerged as an efficient and versatile photocatalyst for hydrogen atom transfer (HAT) processes that enables the cleavage of both activated and unactivated aliphatic C–H bonds. Using a recently developed oscillatory millistructured continuous-flow photoreactor, investigations of a decatungstate-catalyzed C(sp3)–H alkylation protocol were carried out, and the results are presented here. The performance of the reactor was evaluated in correlation to several chemical and process parameters, including residence time, light intensity, catalyst loading, and substrate/reagent concentration. In comparison with previously reported batch and flow protocols, conditions were found that led to considerably higher productivity, achieving a throughput up to 36.7 mmol/h with a residence time of only 7.5 min.

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Ir/Ni Photoredox Dual Catalysis with Heterogeneous Base Enabled by an Oscillatory Plug Flow Photoreactor. - van Aken, K. et al. Org. Process Res. Dev. 2020, 24 (10), 2319–2325.

ABSTRACT: Continuous flow reactor technology has a proven track record in enabling photochemical transformations. However, transfer of a photochemical batch process to a flow protocol often remains elusive, especially when solid reagents or catalysts are employed. In this work, application of an oscillatory plug flow photoreactor enabled a heterogeneous MacMillan-type C(sp2)–C(sp3) cross-electrophile coupling. Combination of an oscillatory flow regime with static mixing elements imparts exquisite control over the mixing intensity and residence time distribution, pinpointing a mindset shift concerning slurry handling in continuous flow reactors. The C(sp2)–C(sp3) cross-electrophile coupling was successfully transferred from batch to flow, resulting in an intensified slurry process with significantly reduced reaction time and increased productivity (0.87 g/h).

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An Oscillatory Plug Flow Photoreactor Facilitates Semi-Heterogeneous Dual Nickel/Carbon Nitride Photocatalytic C–N Couplings. - Kappe, C. O. et al. React. Chem. Eng. 2020, 5 (3), 597–604.

ABSTRACT: Carbon nitride materials have emerged as an efficient and sustainable class of heterogeneous photocatalysts, particularly when paired with nickel in dual catalytic cross-coupling reactions. Performing these transformations on larger scales using a continuous process is difficult due to the problems associated with handling solids in flow. By combining an oscillatory pump with a microstructured plug flow photoreactor, a stable suspension of the photocatalyst can be maintained, circumventing clogging of the reactor channels. Through careful tuning of the oscillator properties, the residence time distribution (RTD) was optimized, whilst maintaining a stable catalyst suspension. Short residence times (20 min) were achieved using optimized conditions and the recyclability of the photocatalyst was demonstrated over 10 cycles with no loss of activity. During a stable 4.5 hour scale-out demonstration, the model substrate could be isolated on 12 g scale (90% yield, 2.67 g h−1). Moreover, the method was applied for the gram scale synthesis of an intermediate of the active pharmaceutical ingredient tetracaine.

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