Speciality Chemicals Magazine NOV / DEC 2021 | Page 56

PHOTOCHEMISTRY

‣ over short residence times . An organocatalyst , Eosin Y , has been demonstrated as a cost-efficient alternative to a traditional transition metal photoredox catalyst . ^{7 , 8} Flow photochemistry can safely perform multi-phase chemistry such as photooxygenation , which uses oxygen for easy access to singlet oxygen ( ¹ O ₂

) from triplet ( ³ O ₂

) oxygen by light irradiation in the presence of a suitable photosensitiser . ¹ O ₂ shows higher electrophilicity than ³ O ₂

, allowing substrates that are otherwise unreactive to oxygen to be oxidised . Compared to batch , pressurisation of flow reactors makes it easier to control and scale reactions using reactive gases . For example , the continuous flow approach with blue LEDs has been used to obtain a key cannabidiol intermediate , giving better conversion selectivity from ( R ) -limonene in a much shorter time compared to using a traditional reaction set-up ( Figure 1 ). ⁹ Another huge benefit of flow chemistry is the ability to generate unstable intermediates or reagents in situ and use them on demand , such as lightinduced cross-coupling reactions for the formation of carbon-carbon bonds . While these reagents may be commercially available , they can be dangerous to handle and are often air- and moisturesensitive , leading to degradation and batch-to-batch variation . The irradiation of light has , in some cases , proven beneficial for increasing yields and selectivity in these types of reactions . The work of Alcázar et al . demonstrates this well , combining continuous flow synthesis over two steps , and innovative analytical tools for process control . The photoinduced Negishi coupling starts with the formation of the organozinc reagent

Figure 3 - Building complex molecules using flow photochemistry

in flow , followed by coupling with the aryl-halide halide in the presence of blue LEDs , a nickel catalyst and ligand ( Figure 2 ). ¹⁰ The direct C – H functionalisation of heterocycles has become an increasingly valuable tool in modern drug discovery . More recently , difficult late-stage alkylation of biologically active heterocycles – such as the potent vasodilator , Fasudil – has been achieved using stable organic peroxides activated by visible light photoredox catalysis ( 450 nm blue LEDs and an iridium or ruthenium photocatalyst ). ¹¹ The direct C – H functionalisation of heterocycles has become an increasingly valuable tool in modern drug discovery . More recently , difficult late-stage alkylation of biologically active heterocycles – such as the potent vasodilator , Fasudil – has been achieved using stable organic peroxides activated by visible light photoredox catalysis ( 450 nm blue LEDs and an iridium or ruthenium photocatalyst ). ¹¹ Researchers have also used flow photochemistry to synthesise complex molecules in a single step , while also allowing for shorter reaction times , higher product yields and improved safety profiles compared to batch synthesis . For example , 1,2,3,4-tetrahydroβ-carbolines were coupled with α-keto vinyl azides through a visible light Ru ( bpy ) ₃

( PF ₆

) ₂

/ TBHP-mediated photocascade strategy that involves photosensitisation , photoredox catalysis and [ 3 + 2 ] cycloaddition reaction increasing complexity in a single step ( Figure 3 ). ¹² The protocol was applied to obtain 18 products with 62-81 % isolated yields , in residence times of 43 minutes each .

A bright future

The increased interest in photochemistry flow systems revolves around its ability to deliver efficiency , control and scalability unmatched by batch chemistry , as well as ongoing innovation in reactor technology . The vision of continuous flow photoreactors is to seamlessly implement a broader selection of reactions , while meeting the demands of the pharmaceutical , agrochemical and fine chemical industries . •

56 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981