Continuous Flow Photochemistry Research Articles

Photosensitizer-Free Benzo[1,4]oxazin-2-one Synthesis by Continuous-Flow Photochemistry.

We report a photosynthetic method for producing 2H-benzo[b][1,4]oxazin-2-ones from aryl azides and α-ketoacids. This method is highly sustainable, requiring only visible light irradiation of the substrates and no external additives. Furthermore, we implemented a continuous-flow system to achieve efficient light irradiation and rapid mixing, significantly improving reaction efficiency and reducing reaction time compared to the batch process. The flow system enabled gram-scale synthesis. We also demonstrated the utility of the products, by employing the benzo[1,4]oxazin-2-one moiety as a directing group for C-H activation on the 3-aryl substituent. This green approach highlights the potential for developing environmentally friendly synthetic processes.

Telescoped Flow Synthesis of Azacyclic Scaffolds Exploiting the Chromoselective Photolysis of Vinyl Azides and Azirines.

An efficient chromoselective photochemical process is presented for the synthesis of 2H-azirines and 1,3-diazabicylo[3.1.0]hex-3-enes from readily available vinyl azides. The method exploits continuous flow photochemistry to enable the safe consumption of the hazardous azide group and provides uniform irradiation using high-power LEDs at 365-450 nm. Additionally, a scaled telescoped process has been developed providing access to drug-like 1,6-dihydropyrimidines and pyrimidines via integrated ring-expansion and oxidation reactions. Given the prevalence of various azacyclic targets in pharmaceutical, agrochemical and materials applications it is anticipated that this methodology will enable further exploitations of these important scaffolds.

Spinning Reactors for Process Intensification of Flow Photochemistry.

The design of new and more sustainable synthetic protocols to access new materials or valuable compounds will have a high impact on the broader chemistry community. In this sense, continuous-flow photochemistry has emerged as a powerful technique which has been employed successfully in various areas such as biopharma, organic chemistry, as well as materials science. However, it is important to note that chemical processes must not only advance towards new or improved chemical transformations, but also implement new technologies that enable new process opportunities. For this reason, the design of novel photoreactors is key to advancing photochemical strategies. In this sense, the use of equipment and techniques embracing processes intensification is important in developing more sustainable protocols. Among the most recent applications, spinning continuous flow reactors, such as rotor reactors or vortex reactors, have shown promising performance as new synthetic tools. Nevertheless, there is currently no review in the literature that effectively summarizes and showcases the most recent applications of such type of photoreactors. Herein, we highlight fundamental aspects and applications of two categories of spinning reactors, the Spinning Disc Reactors (SDRs) and Thin Film Vortex reactors, critiquing the scope and limitations of these advanced processing technologies. Further, we take a view on the future of spinning reactors in flow as a synthetic toolbox to explore new photochemical transformations.

Continuous-flow photochemistry as an automated platform integrated with closed-loop AI/ML approaches

In this Activity article, Brenda Pijper (Horizon 2020 PhotoReAct early-stage researcher in the Chemical Technologies group at Janssen, the Pharmaceutical Companies of Johnson & Johnson) and Jesus Alcázar (head of the Chemical Technologies group at Janssen) and Gabriela Oksdath-Mansilla and Fabricio R. Bisogno (both professors at the Universidad Nacional de Córdoba and researchers at the National Scientific and Technical Research Council of Argentina [CONICET]) discuss the current state of continuous-flow photochemistry in drug discovery and its future as an automated platform integrated with closed-loop artificial intelligence and machine learning (AI/ML) approaches.

Challenge and opportunity: The two edges of continuous-flow photochemistry

In this Activity article, Gabriela Oksdath-Mansilla and Fabricio R. Bisogno (both professors at the Universidad Nacional de Córdoba and researchers at the National Scientific and Technical Research Council of Argentina [CONICET]) and Brenda Pijper (Horizon 2020 PhotoReAct early-stage researcher in the Chemical Technologies group at Janssen, the Pharmaceutical Companies of Johnson & Johnson) and Jesus Alcázar (head of the Chemical Technologies group at Janssen) discuss the importance of implementing continuous-flow photochemistry as a tool in drug-discovery programs as they wonder about the next challenges in the field.

Development of a modular photoreactor for the upscaling of continuous flow photochemistry.

The upscaling of biphasic photochemical reactions is challenging because of the inherent constraints of liquid-gas mixing and light penetration. Using semi-permeable coaxial flow chemistry within a modular photoreactor, the photooxidation of the platform chemical furfural was scaled up to produce routinely 29 gram per day of biobased building block hydroxybutenolide, a precursor to acrylate alternatives.

Tuning the gas-liquid-solid segmented flow for enhanced heterogeneous photosynthesis of Azo- compounds

Difficult handling the solid catalysts remains one of the pain points in the continuous flow photochemistry. In this work, the gas–liquid-solid segmented flow was employed in the photocatalytic production of azo- compounds (azoxybenzene and azobenzene) from nitrobenzene using graphitic carbon nitride (g-C3N4) as solid catalyst. Compared with the batch reactor, the photocatalytic reaction rate was greatly improved in the microreactor, and the reaction time was shortened from 180 min of the batch to 7.5 min for near-full conversion of nitrobenzene. The effects of various reaction parameters (temperature, light source power, catalyst content) in the continuous system were examined, and the reaction kinetic was found in first order. The photocatalytic reaction performance was very sensitive to the gas–liquid-solid segmented flow conditions, which needed to be carefully tuned. With the help of high-speed camera and micro particle image velocimetry (µ-PIV) techniques, it was identified that the increasing inert gas fraction resulted in more stable segmented flow with shorter liquid segments, favoring the reaction rate. With a high gas fraction, the intensity of recirculation in the liquid segments was strengthened by the increasing total flow rate, enhancing the local mass transfer, thereby benefiting the photocatalytic reaction. Overall, the continuous microreactor reached 5.6 times higher productivity per volume (26.1 mmol/h*L) of azo- compounds than the batch reactor under the same conditions. The successful photosynthesis of azo- compounds demonstrated the great potential of the presented gas–liquid-solid segmented flow, and the findings of this work provide useful guidance on its future application in other heterogeneously catalyzed reactions.

Decagram Synthesis of Dimethyl 1,4-Cubanedicarboxylate Using Continuous-Flow Photochemistry

AbstractThe highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. A straightforward approach is reported for the scale-up of a [2+2] photocycloaddition step using convenient home-made flow photoreactors to access dimethyl 1,4-cubanedicarboxylate on decagram-scale in 33–40% yield over 8 steps. The process is demonstrated on 3.4 g·h–1 input with 30 minutes residence time, enabling to reduce the process time and to avoid the use of batch photoreactors. Completion of the characterisation of the photocycloadduct and its hydrates is reported.

Continuous-flow photochemistry: An expanding horizon of sustainable technology

Understanding the unique characteristics of continuous-flow photochemistry will lead to a paradigm shift in the way we enhance sustainability and wellbeing. In this mini-review, we first provide a succinct overview of working principles of this technique and discuss several recent synthetic protocols. Then, emphasis is given to those representative examples which address environmental issues such as indoor air pollutants and water contamination. Finally, recent progress made using this technique to deal with rising CO2 emission, solar energy utilization and biomedical equipment is described. It is believed that this mini-review could inspire more chemists to utilize this technique in their research, either in the academic or industrial field.

Continuous Flow Photochemistry for the Preparation of Bioactive Molecules.

The last decade has witnessed a remarkable development towards improved and new photochemical transformations in response to greener and more sustainable chemical synthesis needs. Additionally, the availability of modern continuous flow reactors has enabled widespread applications in view of more streamlined and custom designed flow processes. In this focused review article, we wish to evaluate the standing of the field of continuous flow photochemistry with a specific emphasis on the generation of bioactive entities, including natural products, drugs and their precursors. To this end we highlight key developments in this field that have contributed to the progress achieved to date. Dedicated sections present the variety of suitable reactor designs and set-ups available; a short discussion on the relevance of greener and more sustainable approaches; and selected key applications in the area of bioactive structures. A final section outlines remaining challenges and areas that will benefit from further developments in this fast-moving area. It is hoped that this report provides a valuable update on this important field of synthetic chemistry which may fuel developments in the future.

Shining Light on the Coiled-Flow Inverter—Continuous-Flow Photochemistry in a Static Mixer

We present the use of a coiled-flow inverter (CFI) for continuous-flow photochemistry at competitive photon efficiencies. The static mixer is placed inside a reaction chamber, whereas a dark adjace...

Timothy Noël

Timothy Noël

Synthesis of N-Heterocycles with Continuous Flow Photochemistry

Key words iridium catalysis - continuous flow - photochemistry - saturated N-heterocycles

Iridium-catalyzed Synthesis of Saturated N-Heterocycles from Aldehydes and SnAP Reagents with Continuous Flow Photochemistry.

Commercially available tin amine protocol (SnAP) reagents provide a simple approach to the synthesis of a wide variety of saturated N-heterocycles from aldehydes. In this report, we disclose that the copper(II) promoter and hexafluoroisopropanol can be replaced by photocatalytic conditions using Ir[dF(CF3)ppy]2(dtbbpy)PF6 in CH3CN. Continuous flow photochemical conditions provide a clean, scalable approach to valuable products including morpholines, piperazines, thiomorpholines, diazepanes, and oxazepanes from aldehyde starting materials.

Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment.

Continuous-flow photochemistry in microreactors receives a lot of attention from researchers in academia and industry as this technology provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochemical transformations in continuous-flow reactors, including applications in organic synthesis, material science, and water treatment. In addition, the advantages of continuous-flow photochemistry are pointed out and a thorough comparison with batch processing is presented.

Continuous-flow photochemistry: A need for chemical engineering

The present paper aims to illustrate that chemical engineering enables to address some of the current challenges and issues in continuous-flow photochemistry. For that, some common limitations encountered in industrial photochemistry are firstly highlighted and a general overview on flow photochemistry equipment is presented. The main challenges linked to photochemical (micro)reactor engineering are subsequently stated. By considering only the case of a purely direct photochemical reactions A→Bhυ in homogenous medium, the key factors to consider when implementing such photochemical reactions in microstructured technologies are outlined. Their influence on the outputs (conversion, productivity, photonic efficiency) of this simple type of photochemical reaction is then discussed. The significance of chemical engineering frameworks is finally demonstrated using several examples concerning the understanding of the coupling between the different phenomena involved, the predictions of the performances obtained, the acquisition of kinetics data and the elaboration of strategies for photochemical process intensification and smart scale-up. In the future, the challenge will be to integrate the complexity of photochemistry (e.g. heterogeneous phase reactions) into the present modelling tools so as to enlarge the spectrum of strategies devoted to photochemical process intensification.

Rapid and Scalable Access into Strained Scaffolds through Continuous Flow Photochemistry

Two conformationally restricted three-dimensional aminoketone scaffolds have been synthesized in only three steps, using a continuous flow photochemistry approach, which is also amenable to scale-up. In addition, several approaches to further derivatize these scaffolds for the synthesis of low molecular weight compound libraries have been detailed.

Correction: Continuous flow photochemistry as an enabling synthetic technology: synthesis of substituted-6(5H)-phenanthridinones for use as poly(ADP-ribose) polymerase inhibitors

Correction: Continuous flow photochemistry as an enabling synthetic technology: synthesis of substituted-6(5H)-phenanthridinones for use as poly(ADP-ribose) polymerase inhibitors

Continuous flow photochemistry as an enabling synthetic technology: synthesis of substituted-6(5H)-phenanthridinones for use as poly(ADP-ribose) polymerase inhibitors

Methods utilizing continuous flow photochemistry have been developed for the synthesis of phenanthridinones via an intramolecular photochemical cyclization reaction in yields up to 99%, as a means to generate poly(ADP-ribose) polymerase inhibitors.

Application of photo degradation for remediation of cyclic nitramine and nitroaromatic explosives

Photo degradation is a rapid and safe remediation process and advances in continuous-flow photochemistry can scale-up yields of photo degradation.