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 . •
References
1 : D . Cambié et al ., Chem . Rev . 2016 , 116 ( 17 ), 10276 – 10341
2 : J . H . Rigby et al ., J . Am . Chem . Soc . 2000 , 122 ( 28 ), 6624 – 6628
3 : C . Sambiagio et al ., Trends Chem . 2020 , 2 ( 2 ), 92 – 106
4 : M . B . Plutschack et al ., Chem . Rev . 2017 , 117 ( 18 ), 11796 – 11893
5 : B . König , Chemical Photocatalysis ( De Gruyter , Berlin , 2013 ), 111 – 138
6 : M . Waterford et al ., Aust . J . Chem ., 2021 : https :// doi . org / 10.1071 / CH20372
7 : N . J . W . Straathof et al ., J . Flow Chem . 2014 , 4 ( 1 ), 12 – 17
8 : N . J . W . Straathof et al ., ChemSusChem 2014 , 7 ( 6 ), 1612 – 1617
9 : A . R . Aguillón et al ., Org . Process Res . Dev . 2020 , 4 ( 10 ), 2017 – 2024
10 : I . Abdiaj et al ., J . Org . Chem . 2019 , 84 ( 8 ), 4748 – 4753
11 : D . A . DiRocco et al ., Angew . Chem . Int . Ed . 2014 , 53 ( 19 ), 4802 – 4806
12 : D . Chandrasekhar et al ., Org . Lett . 2016 18 ( 12 ), 2974 – 2977
Andrew Mansfield
FLOW CHEMISTRY LEADER
SYRRIS
k + 44 1763 242555 J andrew . mansfield @ agi-uk . com j www . syrris . com
56 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981