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.

Rapid and scalable photocatalytic C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling of aryl bromides with alkyl boranes.

In recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp3-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a powerful approach for the light-mediated B-alkyl Suzuki-Miyaura cross-coupling between alkyl boranes and aryl bromides. Alkyl boranes were easily generated via hydroboration from readily available alkenes, exhibiting excellent regioselectivity and enabling the selective transfer of a diverse range of primary alkyl fragments onto the arene ring under photocatalytic conditions. This methodology eliminates the need for expensive catalytic systems and sensitive organometallic compounds, operating efficiently at room temperature within just 30 min. We further demonstrate the translation of the present protocol to continuous-flow conditions, enhancing scalability, safety, and overall efficiency of the method. This versatile approach offers significant potential for accelerating drug discovery efforts by enabling the introduction of complex aliphatic fragments in a straightforward and reliable manner.

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.

Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes.

In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)-C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic ß-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.

Modular synthesis of congested ß2,2-amino acids via the merger of photocatalysis and oxidative functionalisations.

A two-step protocol for the modular synthesis of ß2- and α-quaternary ß2,2-amino acid derivatives is reported. The key steps are a photocatalytic hydroalkylation reaction, followed by an oxidative functionalisation to access N-protected ß-amino acids, esters, and amides. This strategy can be effectively scaled up via continuous-flow technology.

Automated self-optimization, intensification, and scale-up of photocatalysis in flow.

The optimization, intensification, and scale-up of photochemical processes constitute a particular challenge in a manufacturing environment geared primarily toward thermal chemistry. In this work, we present a versatile flow-based robotic platform to address these challenges through the integration of readily available hardware and custom software. Our open-source platform combines a liquid handler, syringe pumps, a tunable continuous-flow photoreactor, inexpensive Internet of Things devices, and an in-line benchtop nuclear magnetic resonance spectrometer to enable automated, data-rich optimization with a closed-loop Bayesian optimization strategy. A user-friendly graphical interface allows chemists without programming or machine learning expertise to easily monitor, analyze, and improve photocatalytic reactions with respect to both continuous and discrete variables. The system's effectiveness was demonstrated by increasing overall reaction yields and improving space-time yields compared with those of previously reported processes.

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.

Solar-Driven Continuous CO2 Reduction to CO and CH4 using Heterogeneous Photothermal Catalysts: Recent Progress and Remaining Challenges.

The urgent need to reduce the carbon dioxide level in the atmosphere and keep the effects of climate change manageable has brought the concept of carbon capture and utilization to the forefront of scientific research. Amongst the promising pathways for this conversion, sunlight-powered photothermal processes, synergistically using both thermal and non-thermal effects of light, have gained significant attention. Research in this field focuses both on the development of catalysts and continuous-flow photoreactors, which offer significant advantages over batch reactors, particularly for scale-up. Here, we focus on sunlight-driven photothermal conversion of CO2 to chemical feedstock CO and CH4 as synthetic fuel. This review provides an overview of the recent progress in the development of photothermal catalysts and continuous-flow photoreactors and outlines the remaining challenges in these areas. Furthermore, it provides insight in additional components required to complete photothermal reaction systems for continuous production (e. g., solar concentrators, sensors and artificial light sources). In addition, our review emphasizes the necessity of integrated collaboration between different research areas, like chemistry, material science, chemical engineering, and optics, to establish optimized systems and reach the full potential of this technology.

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.

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.

A field guide to flow chemistry for synthetic organic chemists.

Flow chemistry has unlocked a world of possibilities for the synthetic community, but the idea that it is a mysterious "black box" needs to go. In this review, we show that several of the benefits of microreactor technology can be exploited to push the boundaries in organic synthesis and to unleash unique reactivity and selectivity. By "lifting the veil" on some of the governing principles behind the observed trends, we hope that this review will serve as a useful field guide for those interested in diving into flow chemistry.

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.

Scale-Up of Photochemical Reactions: Transitioning from Lab Scale to Industrial Production.

In the past two decades, we have witnessed a rapid emergence of new and powerful photochemical and photocatalytic synthetic methods. Although these methods have been used mostly on a small scale, there is a growing need for efficient scale-up of photochemistry in the chemical industry. This review summarizes and contextualizes the advancements made in the past decade regarding the scale-up of photo-mediated synthetic transformations. Simple scale-up concepts and important fundamental photochemical laws have been provided along with a discussion concerning suitable reactor designs that should facilitate scale-up of this challenging class of organic reactions.

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.

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.

Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow.

The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselectivity, safety and/or scalability. Herein, we describe a fast, safe and scalable flow process which allows preparation of said C-4 alkylated pyridines. The process involves a photochemical hydrogen atom transfer (HAT) event to generate the carbon-centered radicals needed to alkylate the C-2 blocked pyridine. In a two-step streamlined flow process, this light-mediated alkylation step is combined with a nearly instantaneous inline removal of the blocking group. Notably, cheap benzophenone plays a dual role in the pyridine alkylation mechanism by activating the hydrocarbon feedstock reagents via a HAT mechanism, and by acting as a benign, terminal oxidant. The key role of benzophenone in the operative reaction mechanism has also been revealed through a combination of experimental and computational studies.

Membrane-based TBADT recovery as a strategy to increase the sustainability of continuous-flow photocatalytic HAT transformations.

Photocatalytic hydrogen atom transfer (HAT) processes have been the object of numerous studies showcasing the potential of the homogeneous photocatalyst tetrabutylammonium decatungstate (TBADT) for the functionalization of C(sp3)-H bonds. However, to translate these studies into large-scale industrial processes, careful considerations of catalyst loading, cost, and removal are required. This work presents organic solvent nanofiltration (OSN) as an answer to reduce TBADT consumption, increase its turnover number and lower its concentration in the product solution, thus enabling large-scale photocatalytic HAT-based transformations. The operating parameters for a suitable membrane for TBADT recovery in acetonitrile were optimized. Continuous photocatalytic C(sp3)-H alkylation and amination reactions were carried out with in-line TBADT recovery via two OSN steps. Promisingly, the observed product yields for the reactions with in-line catalyst recycling are comparable to those of reactions performed with pristine TBADT, therefore highlighting that not only catalyst recovery (>99%, TON > 8400) is a possibility, but also that it does not happen at the expense of reaction performance.

The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

Rapid and Replaceable Luminescent Coating for Silicon-Based Microreactors Enabling Energy-Efficient Solar Photochemistry.

The sun is the most sustainable source of photons on the earth but is rarely used in photochemical transformations due its relatively low and variable intensity, broad wavelength range, and lack of focus. Luminescent solar concentrator-based photomicroreactors (LSC-PMs) can be an answer to all these issues, but widespread adoption is plagued by challenges associated with their complicated manufacturing. Herein, we developed a new strategy to accelerate and ease the production of LSC-PMs by depositing a thin luminescent film on commercially and widely available silicon-based microreactors. The protocol is fast and operationally simple, and the luminescent coating can be easily removed and replaced. This enables rapid tuning of the luminescent coating to fit the requirements of the photocatalytic system and to increase the photon flux inside the microreactor channels.