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54 Pharmaceutical Technology APIs, EXCIPIENTS, AND MANUFACTURING eBOOK 2021 P h a r mTe c h . c o m Development vation. Unlike batch procedures, flow does not need a toxic radical initiator, such as azobisisobutyronitrile (AIBN), and presents a much higher yield and selec- tivity for mono- over di-brominated products on both small and large scales in a shorter time (6). The importance of f luorine atoms in molecules has sparked an interest for many research groups in academia, especially those working on building flow reactors. Photocatalytic trifluoromethylation and perfluoroalkylation of a range of heteroarenes, using inexpensive gases and reagents, has been ap- plied successfully in the presence of low loading of a transition metal photoredox catalyst and blue LEDs (7). This has also been performed using the organocatalyst, Eosin Y, as a more cost-efficient al- ternative to metal-based photocatalytic processes, in a white LED microreactor (8). High conversion and isolated yields are obtained in a very short time in continuous flow compared to in batch. Photooxygenations. Photooxygenations use oxygen to produce singlet oxygen ( 1 O 2 ) from triplet ( 3 O 2 )— or ground state—oxygen by light irradiation in the presence of a suitable photosensitizer. Flow pho- tochemistry has the ability to perform multiphase chemistry and provides easier access to 1 O 2 in a much safer process than in batch due to the inher- ent ease of pressurizing flow reactors and, therefore, to control and scale reactions using reactive gases. These reactions also meet some principles of green chemistry, such as atom economy. For example, the continuous flow approach with blue LEDs has been used to obtain a key cannabidiol intermediate, giv- ing 44% conversion and 55% selectivity from (R)- limonene in five minutes, at a productivity value of 580.8 µmol/min after increasing radiant f lux, temperature, and f low (Figure 1) (9). This would otherwise have required a more challenging syn- thetic route employing large amounts of explosive oxidants under high temperatures, with long reac- tion times, low atom efficiency and yields of less than 20%, as well as low stereo- and regioselectivity. Light-induced cross coupling reactions. Another huge benefit of flow chemistry is the ability to generate un- stable intermediates or reagents in situ and use them on demand. Cross-coupling reactions are common in organic chemistry and are particularly important in the formation of carbon–carbon bonds. The irra- diation of light has, in some cases, proven beneficial Figure 1. Photooxgenation set-up in flow to make a key cannabidiol intermediate from (R)-limonene. TPP is tetraphenylporphyrin. BPR is back pressure regulator. GPR is gas pressure regulator. LED is light-emitting diode.