Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry.

Photoinduced chemical transformations have received in recent years a tremendous amount of attention, providing a plethora of opportunities to synthetic organic chemists. However, performing a photochemical transformation can be quite a challenge because of various issues related to the delivery of photons. These challenges have barred the widespread adoption of photochemical steps in the chemical industry. However, in the past decade, several technological innovations have led to more reproducible, selective, and scalable photoinduced reactions. Herein, we provide a comprehensive overview of these exciting technological advances, including flow chemistry, high-throughput experimentation, reactor design and scale-up, and the combination of photo- and electro-chemistry.

Multiphasic Continuous-Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes.

The use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous-flow reactors has resulted in rapid development of gas-handling technology because of several advantages such as increased interfacial area, improved mass- and heat transfer, and seamless scale-up. This technology enables shorter and more atom-economic synthesis routes for the production of pharmaceutical compounds. Herein, we provide an overview of literature from 2016 onwards in the development of gas-handling continuous-flow technology as well as the use of gases in functionalization of APIs.

Photocatalytic Functionalization of Dehydroalanine-Derived Peptides in Batch and Flow.

Unnatural amino acids, and their synthesis by the late-stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. Herein, we present a photocatalytic hydroarylation process targeting the electrophilic residue dehydroalanine (Dha). This residue possesses an α,ß-unsaturated moiety and can be combined with various arylthianthrenium salts, both in batch and flow reactors. Notably, the flow setup proved instrumental for efficient scale-up, paving the way for the synthesis of unnatural amino acids and peptides in substantial quantities. Our photocatalytic approach, being inherently mild, permits the diversification of peptides even when they contain sensitive functional groups. The readily available arylthianthrenium salts facilitate the seamless integration of Dha-containing peptides with a wide range of arenes, drug blueprints, and natural products, culminating in the creation of unconventional phenylalanine derivatives. The synergistic effect of the high functional group tolerance and the modular characteristic of the aryl electrophile enables efficient peptide conjugation and ligation in both batch and flow conditions.

Graphitic Carbon Nitride as a Photocatalyst for Decarboxylative C(sp2)-C(sp3) Couplings via Nickel Catalysis.

The development of robust and reliable methods for the construction of C(sp2)-C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocatalysts based on precious-metals due to their efficient redox processes and tuneable properties. However, due to the cost, scarcity, and toxicity of these metals, the search for suitable replacements should be a priority. Here, we show the use of commercially available heterogeneous semiconductor graphitic carbon nitride (gCN) as a photocatalyst, combined with nickel catalysis, for the cross-coupling between aryl halide and carboxylic acid coupling partners. gCN has been shown to engage in single-electron-transfer (SET) and energy-transfer (EnT) processes for the formation of C-X bonds, and in this manuscript we overcome previous limitations to furnish C-C over C-O bonds using carboxylic acids. A broad scope of both aryl halides and carboxylic acids is presented, and recycling of the photocatalyst demonstrated. The mechanism of the reaction is also investigated.

Photoinduced Halogen-Atom Transfer by N-Heterocyclic Carbene-Ligated Boryl Radicals for C(sp3)-C(sp3) Bond Formation.

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)-C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes via single-electron transfer (SET) and deprotonation. These boryl radicals subsequently engage with alkyl halides in an XAT step, delivering the desired nucleophilic alkyl radicals. The present XAT strategy is very mild and accommodates a broad scope of alkyl halides, including medicinally relevant compounds and biologically active molecules. The key role of NHC-ligated boryl radicals in the operative reaction mechanism has been elucidated through a combination of experimental, spectroscopic, and computational studies. This methodology stands as a significant advancement in the chemistry of NHC-ligated boryl radicals, which had long been restricted to radical reductions, enabling C-C bond formation under visible-light photoredox conditions.

Ni-Catalyzed Electro-Reductive Cross-Electrophile Couplings of Alkyl Amine-Derived Radical Precursors with Aryl Iodides.

In recent years, the "Escape-from-Flatland" trend has prompted the synthetic community to develop a set of cross-coupling strategies to introduce sp3-carbon-based fragments in organic compounds. This study presents a novel nickel-catalyzed electrochemical methodology for reductive cross-electrophile coupling. The method enables C(sp2)-C(sp3) linkages using inexpensive amine-derived radical precursors and aryl iodides. The use of electrochemistry as a power source reduces waste and avoids chemical reductants, making this approach a more sustainable alternative to traditional cross-coupling methods.

Interfacing single-atom catalysis with continuous-flow organic electrosynthesis.

The global warming crisis has sparked a series of environmentally cautious trends in chemistry, allowing us to rethink the way we conduct our synthesis, and to incorporate more earth-abundant materials in our catalyst design. "Single-atom catalysis" has recently appeared on the catalytic spectrum, and has truly merged the benefits that homogeneous and heterogeneous analogues have to offer. Further still, the possibility to activate these catalysts by means of a suitable electric potential could pave the way for a true integration of diverse synthetic methodologies and renewable electricity. Despite their esteemed benefits, single-atom electrocatalysts are still limited to the energy sector (hydrogen evolution reaction, oxygen reduction, etc.) and numerous examples in the literature still invoke the use of precious metals (Pd, Pt, Ir, etc.). Additionally, batch electroreactors are employed, which limit the intensification of such processes. It is of paramount importance that the field continues to grow in a more sustainable direction, seeking new ventures into the space of organic electrosynthesis and flow electroreactor technologies. In this piece, we discuss some of the progress being made with earth abundant homogeneous and heterogeneous electrocatalysts and flow electrochemistry, within the context of organic electrosynthesis, and highlight the prospects of alternatively utilizing single-atom catalysts for such applications.

Efficient C(sp3 )-H Carbonylation of Light and Heavy Hydrocarbons with Carbon Monoxide via Hydrogen Atom Transfer Photocatalysis in Flow.

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C-H functionalization at sp3 -hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C-H bonds known in Nature, requiring extreme activation conditions that are not tolerant to most organic molecules. To bypass these issues, synthetic chemists rely on prefunctionalized alkyl halides or organometallic coupling partners. However, new synthetic methods that target regioselectively C-H bonds in a variety of different organic scaffolds would be of great added value, not only for the late-stage functionalization of biologically active molecules but also for the catalytic upgrading of cheap and abundant hydrocarbon feedstocks. Here, we describe a general, mild and scalable protocol which enables the direct C(sp3 )-H carbonylation of saturated hydrocarbons, including natural products and light alkanes, using photocatalytic hydrogen atom transfer (HAT) and gaseous carbon monoxide (CO). Flow technology was deemed crucial to enable high gas-liquid mass transfer rates and fast reaction kinetics, needed to outpace deleterious reaction pathways, but also to leverage a scalable and safe process.

Photocatalytic Alkylation of C(sp3 )-H Bonds Using Sulfonylhydrazones.

The ability to construct C(sp3 )-C(sp3 ) bonds from easily accessible reagents is a crucial, yet challenging endeavor for synthetic organic chemists. Herein, we report the realization of such a cross-coupling reaction, which combines N-sulfonyl hydrazones and C(sp3 )-H donors through a diarylketone-enabled photocatalytic hydrogen atom transfer and a subsequent fragmentation of the obtained alkylated hydrazide. This mild and metal-free protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products and is tolerant of a variety of functional groups. The application of this chemistry further provides a preparatively useful route to various medicinally-relevant compounds, such as homobenzylic ethers, aryl ethyl amines, ß-amino acids and other moieties which are commonly encountered in approved pharmaceuticals, agrochemicals and natural products.

Accelerated Electrophotocatalytic C(sp3 )-H Heteroarylation Enabled by an Efficient Continuous-Flow Reactor.

Electrophotocatalytic transformations are garnering attention in organic synthesis, particularly for accessing reactive intermediates under mild conditions. Moving these methodologies to continuous-flow systems, or flow ElectroPhotoCatalysis (f-EPC), showcases potential for scalable processes due to enhanced irradiation, increased electrode surface, and improved mixing of the reaction mixture. Traditional methods sequentially link photochemical and electrochemical reactions, using flow reactors connected in series, yet struggle to accommodate reactive transient species. In this study, we introduce a new flow reactor concept for electrophotocatalysis (EPC) that simultaneously utilizes photons and electrons. The reactor is designed with a transparent electrode and employs cost-effective materials. We used this technology to develop an efficient process for electrophotocatalytic heteroarylation of C(sp3 )-H bonds. Importantly, the same setup can also facilitate purely electrochemical and photochemical transformations. This reactor represents a significant advancement in electrophotocatalysis, providing a framework for its application in flow for complex synthetic transformations.

Direct Synthesis of α-Sulfenylated Ketones under Electrochemical Conditions.

We investigated the electrochemical sulfenylation reaction in both batch and continuous flow regimes, involving thiophenols/thiols and enol-acetates to yield α-sulfenylated ketones, without using additional oxidants or catalysts. Studies with different electrolytes were also performed, revealing that quaternary ammonium salts are the best mediators for this reaction. Notably, during the study of the reaction scope, a Boc-cysteine proved to be extremely tolerant to our protocol, thus increasing its relevance. The methodology also proved to be scalable in both batch and continuous flow conditions, opening up possibilities for further studies since these relevant functional groups are important moieties in organic synthesis.

The development of luminescent solar concentrator-based photomicroreactors: a cheap reactor enabling efficient solar-powered photochemistry.

Sunlight strikes our planet every day with more energy than we consume in an entire year. Therefore, many researchers have explored ways to efficiently harvest and use sunlight energy for the activation of organic molecules. However, implementation of this energy source in the large-scale production of fine chemicals has been mostly neglected. The use of solar energy for chemical transformations suffers from potential drawbacks including scattering, reflections, cloud shading and poor matches between the solar emission and absorption characteristics of the photochemical reaction. In this account, we provide an overview of our efforts to overcome these issues through the development of Luminescent Solar Concentrator-based PhotoMicroreactors (LSC-PM). Such reactors can efficiently convert solar energy with a broad spectral distribution to concentrated and wavelength-shifted irradiation which matches the absorption maximum of the photocatalyst. Hence, the use of these conceptually new photomicroreactors provides an increased solar light harvesting capacity, enabling efficient solar-powered photochemistry.

Emerging roles of adhesion G protein-coupled receptors.

Adhesion G protein-coupled receptors (aGPCRs) form a sub-group within the GPCR superfamily. Their distinctive structure contains an abnormally large N-terminal, extracellular region with a GPCR autoproteolysis-inducing (GAIN) domain. In most aGPCRs, the GAIN domain constitutively cleaves the receptor into two fragments. This process is often required for aGPCR signalling. Over the last two decades, much research has focussed on aGPCR-ligand interactions, in an attempt to deorphanize the family. Most ligands have been found to bind to regions N-terminal to the GAIN domain. These receptors may bind a variety of ligands, ranging across membrane-bound proteins and extracellular matrix components. Recent advancements have revealed a conserved method of aGPCR activation involving a tethered ligand within the GAIN domain. Evidence for this comes from increased activity in receptor mutants exposing the tethered ligand. As a result, G protein-coupling partners of aGPCRs have been more extensively characterised, making use of their tethered ligand to create constitutively active mutants. This has led to demonstrations of aGPCR function in, for example, neurodevelopment and tumour growth. However, questions remain around the ligands that may bind many aGPCRs, how this binding is translated into changes in the GAIN domain, and the exact mechanism of aGPCR activation following GAIN domain conformational changes. This review aims to examine the current knowledge around aGPCR activation, including ligand binding sites, the mechanism of GAIN domain-mediated receptor activation and how aGPCR transmembrane domains may relate to activation. Other aspects of aGPCR signalling will be touched upon, such as downstream effectors and physiological roles.

Dehydrogenative Azolation of Arenes in a Microflow Electrochemical Reactor.

The electrochemical synthesis of aryl azoles was performed for the first time in a microflow reactor. The reaction relies on the anodic oxidation of the arene partners making these substrates susceptible for C-H functionalization with azoles, thus requiring no homogeneous transition-metal-based catalysts. The synthetic protocol benefits from the implementation of a microflow setup, leading to shorter residence times (10 min), compared to previously reported batch systems. Various azolated compounds (22 examples) are obtained in good to excellent yields.

Rapid and Direct Photocatalytic C(sp3 )-H Acylation and Arylation in Flow.

Herein, we report a photocatalytic procedure that enables the acylation/arylation of unfunctionalized alkyl derivatives in flow. The method exploits the ability of the decatungstate anion to act as a hydrogen atom abstractor and produce nucleophilic carbon-centered radicals that are intercepted by a nickel catalyst to ultimately forge C(sp3 )-C(sp2 ) bonds. Owing to the intensified conditions in flow, the reaction time can be reduced from 12-48 hours to only 5-15 minutes. Finally, kinetic measurements highlight how the intensified conditions do not change the reaction mechanism but reliably speed up the overall process.

Decatungstate-Mediated C(sp3 )-H Heteroarylation via Radical-Polar Crossover in Batch and Flow.

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp3 )-H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical-polar crossover concept to access the direct net-oxidative C(sp3 )-H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology. The developed protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as stanozolol, (-)-ambroxide, podophyllotoxin, and dideoxyribose.

Silyl Radical-Mediated Activation of Sulfamoyl Chlorides Enables Direct Access to Aliphatic Sulfonamides from Alkenes.

Single electron reduction is more challenging for sulfamoyl chlorides than sulfonyl chlorides. However, sulfamoyl and sulfonyl chlorides can be easily activated by Cl-atom abstraction by a silyl radical with similar rates. This latter mode of activation was therefore selected to access aliphatic sulfonamides, applying a single-step hydrosulfamoylation using inexpensive olefins, tris(trimethylsilyl)silane, and photocatalyst Eosin Y. This late-stage functionalization protocol generates molecules as complex as sulfonamide-containing cyclobutyl-spirooxindoles for direct use in medicinal chemistry.

Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery.

Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.

The Fundamentals Behind the Use of Flow Reactors in Electrochemistry.

In the past decade, research into continuous-flow chemistry has gained a lot of traction among researchers in both academia and industry. Especially, microreactors have received a plethora of attention due to the increased mass and heat transfer characteristics, the possibility to increase process safety, and the potential to implement automation protocols and process analytical technology. Taking advantage of these aspects, chemists and chemical engineers have capitalized on expanding the chemical space available to synthetic organic chemists using this technology. Electrochemistry has recently witnessed a renaissance in research interests as it provides chemists unique and tunable synthetic opportunities to carry out redox chemistry using electrons as traceless reagents, thus effectively avoiding the use of hazardous and toxic reductants and oxidants. The popularity of electrochemistry stems also from the potential to harvest sustainable electricity, derived from solar and wind energy. Hence, the electrification of the chemical industry offers an opportunity to locally produce commodity chemicals, effectively reducing inefficiencies with regard to transportation and storage of hazardous chemicals. The combination of flow technology and electrochemistry provides practitioners with great control over the reaction conditions, effectively improving the reproducibility of electrochemistry. However, carrying out electrochemical reactions in flow is more complicated than just pumping the chemicals through a narrow-gap electrolytic cell. Understanding the engineering principles behind the observations can help researchers to exploit the full potential of the technology. Thus, the prime objective of this Account is to provide readers with an overview of the underlying engineering aspects which are associated with continuous-flow electrochemistry. This includes a discussion of relevant mass and heat transport phenomena encountered in electrochemical flow reactors. Next, we discuss the possibility to integrate several reaction steps in a single streamlined process and the potential to carry out challenging multiphase electrochemical transformations in flow. Due to the high control over mass and heat transfer, electrochemical reactions can be carried out with great precision and reproducibility which provide opportunities to enhance and tune the reaction selectivity. Finally, we detail on the scale-up potential of flow electrochemistry and the importance of small interelectrode gaps on pilot and industrial-scale electrochemical processes. Each principle has been illustrated with a relevant organic synthetic example. In general, we have aimed to describe the underlying engineering principles in simple words and with a minimum of equations to attract and engage readers from both a synthetic organic chemistry and a chemical engineering background. Hence, we anticipate that this Account will serve as a useful guide through the fascinating world of flow electrochemistry.

Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts.

A ruthenium-catalyzed photoredox coupling of substituted N-aryltetrahydroisoquinolines (THIQs) and different bench-stable pyridinium salts was successfully developed to give fast access to 1-benzyl-THIQs. Furthermore, secondary alkyl and allyl groups were also successfully introduced via the same method. Additionally, the typically applied N-phenyl group in the THIQ substrate could be replaced by the cleavable p-methoxyphenyl (PMP) group and successful N-deprotection was demonstrated.