Chemistry glows green with photoredox catalysis

Can organic chemistry mimic nature in efficiency and sustainability? Not yet, but recent developments in photoredox catalysis animated the synthetic chemistry field, providing greener opportunities for industry and academia.

crucial for drug discovery and development 6 . One example is protocols for the direct and selective functionalisation of drug-like scaffolds (e.g. alkylation, amination, halogenation, perfluoroalkylation). Photoredox methods have been used to install such small functionalities to directly influence the ADME-tox (absorption, distribution, metabolism, excretion, and toxicology) features of a lead candidate 7 , using non-toxic and readily available materials 8 . Within this context, the Britton group and Merck collaborated to develop a photocatalytic C-H fluorination method for the preparative provision of γ-fluoroleucine derivative 2, a key intermediate in the synthesis of Odanacatib, a promising lead structure for osteoporosis treatment (Fig. 1a) 9 . Previous routes for 2 involved multistep synthesis (at least 2-3 steps) and hazardous reagents (e.g. hydrofluoric acid). Here, 2 was obtained directly from the unprotected amino acid derivative 1, using a more user-friendly fluorine source (N-fluorobenzenesulfonimide, NFSI) and with high productivity, thanks to the use of flow settings (90% yield, 45 g after 2 h of residence time). The desired reactivity depends on irradiating, under ultraviolet light, a tungsten-based photocatalyst (tetra-nbutylammonium decatungstenate, TBADT), which can perform the selective hydrogen-atom abstraction at the iso-propyl moiety within 1.
Drug development requires step-economical routes to construct larger libraries of lead analogues. Appealing transformation are those that enables the direct and rapid derivatisation of advanced drug candidate intermediates. Such strategies, referred to as latestage functionalisation, could be successfully implemented by applying photoredox procedures, due to their selectivity and extraordinary functional group tolerance 10 . Drug discovery has also benefited from recent developments in metallaphotoredox catalysis (i.e. the combination of transition metal and photoredox catalysis) 11 , which has expanded the synthetic potential of crosscoupling reactions. This strategy allows unprecedented disconnections and the use of novel coupling partners, creating opportunities to improve the sustainability of carbon-carbon bond-forming coupling processes. Relevant benefits in terms of Green Chemistry are the circumvention of superstoichiometric amounts of reductants in reductive cross-coupling methods, the development of highly available and easily disposable functionalities (e.g. alcohols, carboxylic acid derivatives, and native C-H bonds) as precursors in C(sp 3 )-C(sp 2 ) and C(sp 3 )-C(sp 3 ) couplings, in place of less stable halogenated compounds, and the use of earth-abundant transition metal sources. For example, nickelcatalysed 11 and copper-catalysed 12 photochemical cross-coupling methodologies have been successfully implemented, although a natural direction for this research area would be to achieve more sustainable iron and cobalt catalysis.

Sustainable catalysis for valorisation of renewable sources
The above examples highlight the benefits offered by photoredox catalysis in terms of mass-based metrics (improved E factor and atom economy for shorter synthetic routes). Photoredox chemistry also positively influences industrial production in terms of improved energy efficiency (milder conditions), environmental impact (reduced waste), and use of renewable resources 5 . This aspect is highlighted by the implementation of photochemical methods for the revalorisation of bulk biomass and feedstock materials. For example, Knowles and co-workers have recently obtained valueadded aromatic feedstock chemicals, such as 3 (Fig. 1b,   in the presence of catalytic amounts of an iridium-based photocatalyst, a base, and a hydrogen atom transfer (HAT) thiol catalyst 13 . Along the same line, Zuo and co-workers developed a catalytic system, which combined simple organic alcohols 7 (e.g. trichloroethanol or methanol) and inexpensive cerium sources, enabling the direct functionalisation of hydrocarbon feedstocks, such as methane 6 14 . As depicted in Fig. 1b (bottom), the transient Ce (IV)-alkoxide intermediate I is formed upon the interaction of 7 and the cerium precatalyst. Under violet light irradiation, I undergoes homolysis, generating alkoxy radical II. Then, II triggers the HAT event, generating open-shell radical III from 6. This method converts widely available natural gases into effective alkylating agents for nitrogen compounds and heterocycles. Both strategies depicted in Fig. 1b convert feedstock mass into useful synthetic building blocks, using only simple catalytic agents and light radiation, demonstrating the potential of photoredox methods for circular chemistry 15 .
Looking at a brighter future Despite these achievements, several challenges must be addressed to secure further progress in photochemistry and to facilitate the use of photoredox strategies in industrial settings. In particular, photoredox protocols have generally long reaction times (in the range of hours instead of minutes) and limited scalability (due to the need for an efficiently illuminated surface-to-volume ratio), thwarting their application in high-volume industrial production. Flow techniques have provided promising solutions 16 , although more efficient process-scale photoreactors are still required. A second issue is the extensive use of precious metal complexes as photocatalysts.
They are available in only limited amounts within the Earth's crust. Some engineered organic dyes have achieved comparable efficiency to iridium-or ruthenium-based catalysts 17 , intensifying their use in photoredox protocols 8,18 . For example, the Nicewicz group designed an acridinium-based organic photocatalyst (Mes-Acr + , in Fig. 1c) able to oxidise electron-rich aromatics under irradiation from a blue-emitting laser, thus making them prone to nucleophilic attack by a mild fluorine source, such as tetra-n-butylammonium fluoride (FNBu 4 ) 19 . In a collaboration with the Li group, this metalfree strategy was used for the selective 18 F-fluorination of nonsteroidal anti-inflammatory drugs (NSAID) such as the Fenopren derivative 4. Using a radio-labelled fluoride source, 18 F-compound 5 was obtained in consistent radiochemical yield. The reaction time of 30 min is within the timeframe of the isotopic decay of 18 F. As such, 5 can be converted by simple hydrolysis into [ 18 F]Fenopren and used as a tracer for positron emission tomography (PET), with potential applications in biomedicine and oncology. Nevertheless, the main barrier to the widespread use of organic photocatalysts is their accessibility, which often requires long and elaborate syntheses. The recent development of methods exploiting the photochemical activity of readily available molecules, such as solvents or simple additives, is providing viable solutions in this regard 20 .
In conclusion, photoredox catalysis can provide efficient greener opportunities for industrial and academic research. Ideally, for greater energy efficiency and atom economy, photoredox catalysis would use both solar 21 and direct photochemistry 22 , which can provide for faster processes while avoiding the need for artificial light sources and exogenous catalytic entities. We have not yet fully emulated the leaves of a plant, the most primitive yet most efficient photoreactors, but recent developments in photochemistry suggest that the future will be bright and green.