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The oxygen evolution reaction (OER), characterized by a four‐electron transfer kinetic process, represents a significant bottleneck in improving the efficiency of hydrogen production from water electrolysis. Consequently, extensive research efforts have been directed towards identifying single‐atom electrocatalysts with exceptional OER performance. Despite the comprehensive understanding of the OER mechanism, its application to other valuable synthetic reactions has been limited. Herein, we leverage the MOOH intermediate, a key species in the Mn−N−C single‐atom catalyst (Mn‐SA@NC), which can be cyclically delivered in the OER. We exploit this intermediate' s capability to facilitate electrophilic transfer with silane, enabling efficient silane oxidation under electrochemical conditions. The SAC electrocatalytic system exhibits remarkable performance with catalyst loadings as low as 600 ppm and an exceptional turnover number of 9132. Furthermore, the catalytic method demonstrates stability under a 10 mmol flow chemistry setup. By serving as an OER electrocatalyst, the Mn‐SA@NC drives the entire reaction, establishing a practical Mn SAC‐catalyzed organic electrosynthesis system. This synthesis approach not only presents a promising avenue for the utilization of electrocatalytic OER but also highlights the potential of SACs as an attractive platform for organic electrosynthesis investigations. [ABSTRACT FROM AUTHOR]

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Nickel(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum–hydride reductants, pyrophoric reagents that are not atom‐economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5‐cyclooctadiene)nickel(0) [Ni(COD)2]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be transitioned to large scale through an electrochemical recirculating flow process and extended to an in situ reduction protocol to generate catalytic amounts of Ni(0) for organic transformations. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low‐valent organometallic complexes in academia and industry. [ABSTRACT FROM AUTHOR]

We introduce a methodology for the photocatalytic generation of β‐ketoalkyl radicals from tertiary cyclopropanols, utilizing tetrabutylammonium decatungstate (TBADT) as a photoredox catalyst. The application is demonstrated by the synthesis of distantly functionalized ketones via the redox‐neutral addition of the cyclopropanol‐derived β‐ketoalkyl radicals to the double bond of electrophilic olefins. The transformation occurs under ambient temperature conditions and is suitable for coupling a wide range of cyclopropanol and alkene substrates. This was demonstrated by the preparation of 33 ketone products with 35–92% yield. The method's preparative robustness has been validated through upscaled preparations conducted under continuous flow conditions. Mechanistic investigations support the role of TBADT as a photoredox catalyst, which facilitates the single electron oxidation of cyclopropanols, followed by the electron transfer from the reduced form of decatungstate to the electrophilic double bond of alkene. Moreover, we found that electron‐rich aromatic cyclopropanols and electron‐deficient olefins form photoactive electron donor‐acceptor (EDA) complexes. This property allows the reaction to proceed under UV light irradiation via the photoinduced charge transfer in the absence of the photocatalyst. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Since their structural elucidation in 1935, the introduction and substitution of functional groups and the modification of the steroidal scaffolds have been a fertile ground of research for synthetic and medicinal chemists. The discovery of steroids with hormonal and pharmacological activity has stimulated tremendous efforts to the development of highly selective and efficient synthetic procedures. Despite the progress made, steroid chemistry remains challenging and the preparation of steroidal compounds of pharmaceutical interests and in clinical practice, often requires long and elaborated synthesis. In recent years, a new impetus in the field came with the advent of enabling chemical technologies, such as continuous flow chemistry, which are exploited to overcome problems that arise from batch synthesis. Although it is still a niche sector, the use of flow technology in steroid synthesis and functionalization holds the premise to empower methodology development and to provide innovative tactics also for many hitherto uncharted chemistries. In this review, scientific contributions are reported and discussed in terms of flow set‐up and advantages offered concerning process efficiency, optimization, waste minimization, safety improvement, easy scale‐up and costs. We also highlight the main challenges, key improvements and the future trajectory in the application of continuous flow chemistry and its implementation to different disciplines such as photochemistry and biocatalysis with the ultimate goal of streamlining steroid synthesis. [ABSTRACT FROM AUTHOR]

The synthesis of trisubstituted isoxazoles generally requires multiple individual chemical steps, making them amenable to improvements in efficiency by telescoping as a multistep flow process. Three steps (oximation, chlorination and cycloaddition) were developed in continuous flow mode, aiming to function as an high-yielding and efficient sequence. We demonstrate this sequence using two aldehyde starting materials of interest: one carbocyclic and one heterocyclic. Between these two substrates, significant differences in solubility and reactivity necessitated modifications to the route. Most notably, the chlorination step could be carried out using either an organic N-Cl source (applicable for the carbocyclic aldehyde) or Cl2 generated on-demand in a flow setup (applicable for the heterocyclic aldehyde). By selecting the most effective method for each substrate, good yields could be achieved over the telescoped sequence. [ABSTRACT FROM AUTHOR]

Recent developments in automated flow chemistry for pharmaceutical compound synthesis have garnered significant attention. Automation in synthesis represents a cutting-edge frontier in the field of chemistry, offering highly efficient, rapid, and reproducible synthetic methods that significantly shorten reaction time and reduce costs. In the realm of pharmaceutical compound synthesis, automated flow chemistry demonstrates unique importance. By utilizing flow chemistry, reactions can be performed under continuous flow conditions, enabling precise reaction control, higher yields, and increased product purity. Additionally, automated flow synthesis overcomes several challenges encountered in traditional batch synthesis, such as decreased generation of chemical waste, optimization of reaction conditions, and enhanced operational safety. This review highlights the recent developments in automated flow synthesis of various pharmaceutical compounds, including large biopharmaceutical molecules, small organic drug molecules, and carbohydrates. It covers automated iterative synthesis and the use of machine learning to enhance synthesis efficiency. Furthermore, it explores the practical application of high-throughput synthesis and screening technologies. Finally, the review offers concise perspectives on potential future developments in the field. The development of automated flow synthesis kept breaking through new challenges for chemical reactions. Especially with the increasing demand for fast and efficient synthesis of therapeutic compounds, automated systems built a solid foundation for pharmaceutical innovation. Solid-phase flow synthesis has been well-developed in the synthesis of large biopharmaceutical molecules; the immobilized support helps replace tedious separation and purification with a simple solvent wash. Additionally, flow-based pathways could provide convenience for automation. High-throughput synthesis with in-line analysis offers both high-efficiency production and accurate monitoring. Therefore, this combination could be easily applied to rapid screening processes for building a large library, enhancing the performance of machine learning in reaction, and product prediction. Artificial intelligence can be applied to self-optimized synthesis processes. Algorithm-based software could rapidly calculate and optimize insufficient reactions with a learning model built on past reactions posted in the literature. The connected robotic arm can then be automatically set to perform the optimized reaction. [ABSTRACT FROM AUTHOR]

An automated flow chemistry platform for DNA-encoded library (DEL) technologies requires the integration of a purification process for DNA-tagged substrates. It facilitates the development of further DEL reactions, building block rehearsal, and library synthesis. Therefore, a recently developed, manual affinity-based batch purification process for DNA-tagged substrates based on dispersive solid-phase extraction (DSPE) was transferred to automated flow chemistry using tailored 3D-printed microfluidic devices and open-source lab automation equipment. The immobilization and purification steps use Watson–Crick base pairing for a compound-encoding single-stranded DNA, which allows for the thorough removal of impurities and contaminations by washing steps and operationally simple recovery of the purified DNA-encoded compounds. This work optimized the annealing step for flow incubation and DNA purification was accomplished by flow DSPE washing/elution steps. The manually performed batch affinity-based purification process was compared with the microfluidic process by determining qualitative and quantitative DNA recovery parameters. It aimed at comparing batch and flow purification processes with regard to DNA recovery and purity to benefit from the high potential for automation, precise process control, and higher information density of the microfluidic purification process for DNA-tagged substrates. Manual operations were minimized by applying an automation strategy to demonstrate the potential for integrating the microfluidic affinity-based purification process for DNA-tagged substrates into an automated DNA-encoded flow chemistry platform. [ABSTRACT FROM AUTHOR]

A low-cost 3D printed standardized flow-photochemistry setup has been designed and developed for use with a pressure-driven flow system using photochemistry lamps available in most laboratories. In this research, photochemical reactors were 3D printed from polypropylene which facilitated rapid optimization of both reactor geometry and experimental setup of the lamp housing system. To exemplify the rapidity of this approach to optimization, a Kessil LED lamp was used in the bromination of a range of toluenes in the 3D printed reactors in good yields with residence times as low as 27 s. The reaction compared favorably with the batch photochemical procedure and was able to be scaled up to a productivity of 75 mmol h−1. Highlights: • We demonstrate the rapid optimization of 3D printed polypropylene reactors for flow photochemistry. • We show that the reactors can be used with a standardized 3D printed Kessil lamp set up. • We show how the system can be used in an exemplary photochemistry reaction for the bromination of a range of toluenes and that it can be easily scaled. [ABSTRACT FROM AUTHOR]

BACKGROUND: Flow chemistry is becoming an essential technique in organic synthesis. This trend is expected to continue and broaden in scope and complexity. This miniaturized protocol that includes microreactors enables excellent heat transfer, low solvent wastage, shorter reaction times, higher productivity and higher space–time yields. RESULTS: In this study, we synthesized four ionic liquids and applied them as catalysts for the selective preparation of 5‐hydroxymethylfurfural (5‐HMF) from fructose using the continuous flow system. The effects of reaction time and temperature, catalyst loading, solvent and substrates for carbohydrate conversion to 5‐HMF have been carefully investigated, and 5‐HMF yields were determined by high‐performance liquid chromatography. CONCLUSION: As a result, 1‐(4‐sulfobutyl)pyridinium iron(III) chloride gave 71% yield of 5‐HMF for 30 min. The results of this research demonstrate that this approach is not only straightforward in design but also rapid and convenient in operation, and it has the potential to be carried out on a massive scale. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Enzymes are natural catalysts which are gaining momentum in chemical synthesis due to their exquisiteselectivity and their biodegradability. However, the cost-efficiency and the sustainability of the overall biocatalytic process must be enhanced to unlock completely the potential of enzymes for industrial applications. To reach this goal, enzyme immobilization and the integration into continuous flow reactors have been the cornerstone of our research. We showed key examples of the advantages of those tools for the biosynthesis of antivirals, anticancer drugs, and valuable fragrance molecules. By combining new strategies to immobilize biocatalysts, innovative bioengineering approaches, and process development, the performance of the reactions could be boosted up to 100-fold.

Abstract Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low‐volume optimization experiments are reported. A Buchwald–Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self‐optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using

Mixed‐metal nanoparticles present a challenging task for synthesis with high precision and reproducibility due to the complex interplay of compositional and reaction condition factors. The present study demonstrates a highly precise and automated flow chemistry technique for synthesizing AgAu alloy nanoboxes with tailored optical properties. The synthesis process involves a proportional–integral (PI) feedback control mechanism that enables accurate regulation of reaction parameters, such as the flow rate, to achieve the target AgAu nanoboxes having a desired UV–vis absorbance wavelength. The PI control algorithm is built on the first‐order plus dead‐time model, which correlates the flow rate of the precursors with the maximum absorbance peaks of the resultant nanoalloy products. Based on the difference between the real‐time measured UV–vis absorbance wavelength and the target wavelength, the flow rate of the precursor (i.e., reagent concentration) is tuned via an iterative process until the real‐time absorbance wavelength of the AgAu alloy nanoboxes is matched with the target setpoint. The implementation of a PI feedback control mechanism in a flow chemistry system can offer a highly versatile and universal strategy for generating on‐demand complex nanomaterials with significantly enhanced consistency and reliability by mitigating concentration variations and minimizing the need for human intervention.

Microreactor technologies have emerged as versatile platforms with the potential to revolutionize chemistry and materials research, offering sustainable solutions to global challenges in environmental and health domains. This survey paper provides an in-depth review of recent advancements in microreactor technologies, focusing on their role in facilitating accelerated discoveries in chemistry and materials. Specifically, we examine the convergence of microfluidics with machine intelligence and automation, enabling the exploitation of the cyber-physical environment as a highly integrated experimentation platform for rapid scientific discovery and process development. We investigate the applicability and limitations of microreactor-enabled discovery accelerators in various chemistry and materials contexts. Despite their tremendous potential, the integration of machine intelligence and automation into microreactor-based experiments presents challenges in establishing fully integrated, automated, and intelligent systems. These challenges can hinder the broader adoption of microreactor technologies within the research community. To address this, we review emerging technologies that can help lower barriers and facilitate the implementation of microreactor-enabled discovery accelerators. Lastly, we provide our perspective on future research directions for democratizing microreactor technologies, with the aim of accelerating scientific discoveries and promoting widespread adoption of these transformative platforms.

In the context of advanced nanomaterials research, nanogels (NGs) have recently gained broad attention for their versatility and promising biomedical applications. To date, a significant number of NGs have been developed to meet the growing demands in various fields of biomedical research. Summarizing preparation methods, physicochemical and biological properties, and recent applications of NGs may be useful to help explore new directions for their development. This article presents a comprehensive overview of the latest NG synthesis methodologies, highlighting advances in formulation with different types of hydrophilic or amphiphilic polymers. It also underlines recent biomedical applications of NGs in drug delivery and imaging, with a short section dedicated to biosafety considerations of these innovative nanomaterials. In conclusion, this article summarizes recent innovations in NG synthesis and their numerous applications, highlighting their considerable potential in the biomedical field.

Sustainable oxidation protocols aim to provide an environmentally friendly and cost-effective method for the production of various chemicals and materials. The development of such protocols can lead to reduced energy consumption, fewer harmful byproducts, and increased efficiency in industrial processes. As such, this field of research is of great importance and interest to both academia and industry. This work showcases a sustainable and catalyst-free oxidation method for heteroatoms (e.g., S, P, and Se) using only air, water and light. An additional reaction pathway is proposed in which the incorporated oxygen on the heteroatoms originates from water. Furthermore, the addition of certain additives enhances productivity by affecting kinetics. The industrial potential is demonstrated by conveniently transferring the batch protocol to continuous flow using the HANU flow reactor, indicating scalability and improving safety.

The advent of flow chemistry and flow microreactor technology in organic synthesis has added a series of options to the toolbox of synthetic chemists by enabling access to chemical reactions, which had hitherto been little explored or impossible in classical batch methods. In this review article, we provide an update on recent reports (published since 2020) showcasing examples of flow technology enabling the genesis and use of highly reactive organometallic intermediates for the synthesis of key building blocks and active pharmaceutical ingredients. In addition to showcasing the known advantages of flow technology (e.g., safety, scalability and productivity) we also highlight its positive impact on the greenness of organic reactions.

Without a doubt, asymmetric catalysis has been significantly enriched by the introduction of cinchona alkaloid derivatives. Moreover, such methods have been further enabled when used in conjunction with continuous flow systems.Besides being used in flow chemistry as organocatalysts, they also have been used as ligands or modifiers of metal catalysts. This has generally been accomplished via their immobilization on heterogeneous supports and incorporation into catalysis-enabling reactors or similar systems. In this minireview we look at the impact that cinchona-based catalysts and analogues have had on the field of continuous flow-chemistry during the last two decades or so.

Crystalline porous organic salts (CPOS) are a subclass of molecular crystals. The low solubility of CPOS and their building blocks limits the choice of crystallisation solvents to water or polar alcohols, hindering the isolation, scale‐up, and scope of the porous material. In this work, high throughput screening was used to expand the solvent scope, resulting in the identification of a new porous salt, CPOS‐7, formed from tetrakis(4‐sulfophenyl)methane (TSPM) and tetrakis(4‐aminophenyl)methane (TAPM). CPOS‐7 does not form with standard solvents for CPOS, rather a hydrated phase (Hydrate2920) previously reported is isolated. Initial attempts to translate the crystallisation to batch led to challenges with loss of crystallinity and Hydrate2920 forming favorably in the presence of excess water. Using acetic acid as a dehydrating agent hindered formation of Hydrate2920 and furthermore allowed for direct conversion to CPOS‐7. To allow for direct formation of CPOS‐7 in high crystallinity flow chemistry was used for the first time to circumvent the issues found in batch. CPOS‐7 and Hydrate2920 were shown to have promise for water and CO2 capture, with CPOS‐7 having a CO2 uptake of 4.3 mmol/g at 195 K, making it one of the most porous CPOS reported to date. [ABSTRACT FROM AUTHOR]

Oxidation flow reactors (OFRs) have been widely used to investigate the formation of secondary organic aerosol SOA). However, the UV lamps that are commonly used to initiate photochemistry in OFRs can lead to increases in the reactor temperature with consequences that have not been assessed in detail. In this study, we systematically investigated the temperature distribution inside an Aerodyne Potential Aerosol Mass OFR and the associated impacts on flow and chemistry arising from lamp heating. A lamp-induced temperature enhancement was observed, which was a function of lamp driving voltage, number of lamps, lamp types, OFR residence time, and positions inside OFR. Under common OFR operational conditions (e.g., < 5 days of equivalent atmospheric OH exposure under low-NOx conditions), the temperature enhancement was usually within 1-5 °C. Under extreme (but less commonly used) settings, the heating could reach 15 °C. The influence of the increased temperature over ambient conditions on the flow distribution, gas, and condensed phase chemistry inside OFR was evaluated. We found that the increase in temperature changes the flow field, leading to a reduced tail on the residence time distribution and corresponding oxidant exposure due to faster recirculation. According to simulation results from a box model using radical chemistry, the variation of absolute oxidant concentration inside of OFR due to temperature increase was small (<5%). The temperature influences on existing and newly formed OA were also investigated, suggesting that the increase in temperature can impact the yield, size, and oxidation levels of representative biogenic and anthropogenic SOA types. Recommendations for temperature-dependent SOA yield corrections and OFR operating protocols that mitigate lamp-induced temperature enhancement and fluctuations are presented. We recommend blowing air around the outside of the reactor with fans during OFR experiments to minimize the temperature increase inside OFR. Temperature increases are substantially lower for OFRs using less powerful lamps than the Aerodyne version. [ABSTRACT FROM AUTHOR]

The synthesis of [n]cycloparaphenylenes ([n]CPPs) and similar nanohoops is usually based on combining building blocks to a macrocyclic precursor, which is then aromatized in the final step. Access to those building blocks in large amounts will simplify the synthesis and studies of CPPs as novel functional materials for applications. Herein, we report a continuous‐flow synthesis of key CPP building blocks by using versatile synthesis techniques such as electrochemical oxidation, lithiations and Suzuki cross‐couplings in self‐built reactors on up‐to kilogram scale. [ABSTRACT FROM AUTHOR]

Nitrate esters are important organic compounds having wide application in energetic materials, medicines and fuel additives. They are synthesized through nitration of aliphatic polyols. But the process safety challenges associated with nitration reaction makes the production process complicated and economically unviable. Herein, we have developed a continuous flow process wherein polyol and nitric acid are reacted in a microreactor to produce nitrate ester continuously. Our developed process is inherently safer and efficient. The process was optimized for industrially important nitrate esters containing two, three and four nitro groups. Substrates include glycol dinitrates: 1,2‐propylene glycol dinitrate (PGDN), ethylene glycol dinitrate (EGDN), diethylene glycol dinitrate (DEGDN), triethylene glycol dinitrate (TEGDN); trinitrates: trimethylolethane trinitrate (TMETN), 1,2,4‐butanetriol trinitrate (BTTN); and tetranitrates: erythritol tetranitrate (ETN). The optimized process for each molecule provided yield >90 % in a short residence time of 1 min corresponding to a space time yield of >18 g/h/mL of reactor volume. [ABSTRACT FROM AUTHOR]

High solubility of active materials is crucial for achieving a high‐energy‐density catholyte/anolyte in redox flow batteries. However, solubility largely depends on the compatibility with electrolyte, limiting the types of redox‐active materials that can be used in aqueous electrolytes. Herein, a universal strategy is introduced to attain a high solubility of active materials regardless of the compatibility with aqueous electrolytes while preserving their intrinsic redox activity via micellar solubilization. Leveraging the amphiphilic nature of surfactant molecules, insoluble redox‐active materials are encapsulated by surfactants to be dissolvable with significant solubility. As a demonstration, it is showed that an order‐of‐magnitude solubility enhancement can be achieved for (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) in aqueous catholyte (≈0.8 m). Consequently, the catholyte performance of TEMPO is fully harnessed, leading to an energy density enhancement of more than ten times compared to that in bare electrolyte. It is also observed that micellar solubilization unexpectedly improves the cycle stability, attributed to the mitigation of intermolecular side reactions and reduced crossover. Finally, the fundamental electrochemical reaction mechanism of micelle‐encapsulated TEMPO is discussed. This strategy offers a new insight regarding the solubility and stability of the catholyte/anolyte, and is expected to be applicable to other redox‐active molecules, opening up an unexplored micellar chemistry in redox flow batteries. [ABSTRACT FROM AUTHOR]

The focus has recently switched to enhancing the safety and sustainability of chemical processes in basic and applied research, pharmaceutical manufacture, and industrial chemical manufacturing. Flow chemistry approaches have attracted a lot of attention as a way to adopt and develop chemical processes to meet the increasing demand for chemical sustainability. Emerging flow chemistry methods are discussed in this mini-review, with applications in environmentally friendly high-value chemical manufacturing and efficient screening of chemical reaction space. The demand for further research and collaboration between chemists and chemical engineers in academia and business is growing as continuous production processes are increasingly being used to reduce material and energy waste. An industrial perspective on present issues is offered to spark interest and urge greater investment in greener advanced synthetic technologies. [ABSTRACT FROM AUTHOR]

The use of microreactors (MRs) in chemical and pharmaceutical industries allows for a series of advantages due to their reduced sizes regarding conventional batch reactors. In the present paper, the transposition of the reaction between 2,4‐thiazolidinedione (TZD) with p‐methoxybenzaldehyde from batch to a continuous capillary MR was carried out. The microdevice performance was evaluated experimentally and numerically by computational fluid dynamics (CFD). The batch process yielded 92% in 480 min using piperidine for equimolar reactant feed, while the pyrrolidine promoted a 100% yield in a 50 min, both using solvent ethanol. Kinetic and thermodynamic parameters of the synthesis using piperidine and pyrrolidine were also obtained from experimental data. In the transposition to flow chemistry, ethanol was also used as solvent and a product yield of 100% (140°C, pyrrolidine) was obtained for a residence time of 20 min, representing a reduction of 24 times in the reaction time. In the numerical simulations by CFD, two mathematical models were elaborated: a transient batch and a steady‐state continuous flow. Both models exhibited good agreement with experimental data. The average relative deviations of TZD conversion and the reaction yields in MRs were, respectively, 0.23% and −7.1% (78°C) and 1.7% and 1.2% (140°C). [ABSTRACT FROM AUTHOR]

With the increasing awareness of cardiovascular diseases and cancer prevention, the interest in resveratrol and its derivatives, i. e. hydroxylated stilbene compounds, as great antioxidants is growing day by day. The discovery of several other stilbene applications, especially in the treatment of numerous diseases, has further increased interest. Antidiabetic, anti‐inflammatory, antimicrobial, and anti‐neurodegenerative are just a few of the properties attributed to hydroxylated stilbene compounds. It is therefore not surprising that hydroxylated stilbenes are of great importance and frequently researched nowadays. In parallel, research in the field of flow chemistry has been increasing rapidly for years, as it offers many advantages in many different fields, including the synthesis of hydroxylated stilbenes. In this review article, a concise overview of stilbene compounds is given, as well as their properties and biological activity depending on the structure. In addition, various and common synthesis and production methods are described, with emphasis on application of flow chemistry in these processes. [ABSTRACT FROM AUTHOR]

A comprehensive study of the preparation and reactivity of N‐tert‐butanesulfinyl glycosylamines with simple Grignard and organo lithium reagents in batch vs. continuous flow chemistry is reported. As they readily react as latent imine equivalents with a variety of carbon nucleophiles, these carbohydrate derivatives constitute very useful precursors for the diastereoselective synthesis of bioactive compounds such as iminosugar‐C‐glycosides. A hybrid protocol, involving the addition of benzylmagnesium chloride to a (SR)‐arabinofuranosylamine substrate in flow, at room temperature, combined with a cyclization protocol in batch is also described for the first time. Of note, this semi‐continuous flow process shortens the synthesis of imino‐C‐glycoside scaffolds to a single workday. [ABSTRACT FROM AUTHOR]

Amine derivatives, including aniline and allylic amines, can be formed in a single‐step process from benzene and an ammonia plasma in a microreactor. Different process parameters such as temperature, residence time, and plasma power were evaluated to improve the reaction yield and its selectivity toward aminated products and avoid hydrogenated or oligomerized products. In parallel, simulation studies of the process have been carried out to propose a global mechanism and gain a better understanding of the influence of the different process parameters. The exploration of diverse related alkenes showed that the double bonds, conjugation, and aromatization influenced the amination mechanism. Benzene was the best reactant for amination based on the lifetime of radical intermediates. Under optimized conditions, benzene was aminated in the absence of catalyst with a yield of 3.8 % and a selectivity of 49 % in various amino compounds. [ABSTRACT FROM AUTHOR]

Certified reference materials (CRM) of amphetamine derivatives were produced through a simple, rapid and efficient synthesis in both batch and continuous‐flow conditions, accompanied by the development of a comprehensive certification protocol for this class of substances. Our chemistry enabled the synthesis of MDA, MDMA, PMA and PMMA in two steps from safrole and estragole with overall yields of 38–61 % in 48 hours under batch conditions and 61–65 % in 65 minutes under continuous‐flow conditions, followed by the development of a certification protocol for these materials through identity checking, homogeneity, stability, and characterization studies. Furthermore, as result of this work, a very pure CRM of MDA.HCl with 99.1±1.4 g/100 g of certified characterization value was produced. Considering the importance of supplying amphetamine calibrants for public security efforts in Forensic Chemistry, the potential therapeutical applications, and responding to the rising demand for the synthesis of CRM, this work presents a pioneering approach for the production of amphetamine and related compounds. [ABSTRACT FROM AUTHOR]

Enantiomerically pure secondary alcohols are useful in the synthesis of several natural products and as active pharmaceutical intermediates (API). Due to the high demand for these chiral compounds, much progress has been made in the areas of asymmetric synthesis and catalysis. In this context, biocatalysis together with continuous flow technology can be a valuable tool for more versatile and sustainable methods, with lower cost, greater stereoselectivity and less environmental impact. This work aims to obtain an enantiomerically pure alcohol of industrial interest, (4 Fluorophenyl) (furan-2-yl) methanol (3), by performing a kinetic resolution using immobilized Candida antarctica lipase B (Novozyme 435, N435) under continuous-flow conditions. Initial study was carried out to optimize batch reaction conditions. The best results were obtained using isooctane as solvent, 37.7 mg of N435 and three equivalents of isopropenyl acetate as acyl donor at 60 °C for 24 h. Under these conditions, a conversion of 49% and 91 of enantiomeric ratio was obtained. Optimized batch conditions were translated to the continuous flow reactor leading to the desired product in 30 min of residence time, 47% conversion and an enantiomeric ratio of 61. [ABSTRACT FROM AUTHOR]

Aziridines derived from bioactive molecules may have unique pharmacological activities, making them useful in pharmacology (e.g. mitomycin C). Furthermore, the substitution of the epoxide moiety in epothilone B with aziridine, an analog of epoxides, yielded a pronounced enhancement in its anticancer efficacy. Thus, there is interest in developing novel synthetic technologies to produce aziridines from bioactive molecules. However, known methods usually require metal catalysts, stoichiometric oxidants and/or pre-functionalized amination reagents, causing difficulty in application. A practical approach without a metal catalyst and extra-oxidant for the aziridination of bioactive molecules is in demand, yet challenging. Herein, we report an electro-oxidative flow protocol that accomplishes an oxidant-free aziridination of natural products. This process is achieved by an oxidative sulfonamide/alkene cross-coupling, in which sulfonamide and alkene undergo simultaneous oxidation or alkene is oxidized preferentially. Further anticancer treatments in cell lines have demonstrated the pharmacological activities of these aziridines, supporting the potential of this method for drug discovery. [ABSTRACT FROM AUTHOR]

Professor Rosa Nomen, member of the editorial board of Process Safety and Environmental Protection, and Professor Julià Sempere both from the Institut Químic de Sarrià (IQS), Universitat Ramon Llull (Barcelona, Spain) will be retired in July 2023. They have contributed to the education of more than 1000 chemical engineers around Catalonia for 40 years. In this article, we have revisited the main scientific contributions that they have carried out in the field of chemical engineering. They had diverse research interests covering a wide range of topics in the areas of process safety and environmental protection. These included the utilization of thermal analysis and calorimetry to comprehend chemical reactions, including their safety and chemical and physical kinetics. They also focused on devising new methodologies for industrial safety and implementing flow chemistry to produce fine and specialty chemicals in a more sustainable and safer way. Additionally, they contributed to the advancement of adsorption-based carbon capture technologies as technological strategy for the minimization of the environmental impact of the chemical industry. [ABSTRACT FROM AUTHOR]

Polyglycolic acid (PGA) nanoparticles show promise in biomedical applications due to their exceptional biocompatibility and biodegradability. These nanoparticles can be readily modified, facilitating targeted drug delivery and promoting specific interactions with diseased tissues or cells, including imaging agents and theranostic approaches. Their potential to advance precision medicine and personalized treatments is evident. However, conventional methods such as emulsification solvent evaporation via batch synthesis or tubular reactors via flow chemistry have limitations in terms of nanoparticle properties, productivity, and scalability. To overcome these limitations, this study focuses on the design and development of a 3D-printed vortex tube reactor for the continuous synthesis of PGA nanoparticles using flow chemistry. Computer-aided design (CAD) and the design of experiments (DoE) optimize the reactor design, and computational fluid dynamics simulations (CFD) evaluate the mixing index (MI) and Reynolds (Re) expression. The optimized reactor design was fabricated using fused deposition modeling (FDM) with polypropylene (PP) as the polymer. Dispersion experiments validate the optimization process and investigate the impact of input flow parameters. PGA nanoparticles were synthesized and characterized for size and polydispersity index (PDI). The results demonstrate the feasibility of using a 3D-printed vortex tube reactor for the continuous synthesis of PGA nanoparticles through flow chemistry and highlight the importance of reactor design in nanoparticle production. The CFD results of the optimized reactor design showed homogeneous mixing across a wide range of flow rates with increasing Reynolds expression. The residence time distribution (RTD) results confirmed that increasing the flow rate in the 3D-printed vortex tube reactor system reduced the dispersion variance in the tracer. Both experiments demonstrated improved mixing efficiency and productivity compared to traditional tubular reactors. The study also revealed that the total flow rate had a significant impact on the size and polydispersity index of the formulated PGA nanoparticle, with the optimal total flow rate at 104.46 mL/min, leading to smaller nanoparticles and a lower polydispersity index. Additionally, increasing the aqueous-to-organic volumetric ratio had a significant effect on the reduced particle size of the PGA nanoparticles. Overall, this study provides insights into the use of 3D-printed vortex tube reactors for the continuous synthesis of PGA nanoparticles and underscores the importance of reactor design and flow parameters in PGA nanoparticle formulation. [ABSTRACT FROM AUTHOR]

A fundamental understanding of the process parameters affecting the catalytic hydrodeoxygenation (HDO) of bio-oils is of significance for enabling further progression and improvement of industrial biofuel upgrading methods. Herein, a novel demonstration and evaluation of the effect of temperature, pressure, and weight hourly space velocity in the continuous HDO of vanillin to cresol over a Ni-Mo/δ-Al2O3 catalyst are presented. Response surface methodology was used as a statistical experimental design method, and the application of central composite design enabled the generation of a statistically significant simulation model and a true optimization parametric study. The distribution of Ni and Mo on δ-Al2O3 was confirmed using scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDX). No gradients with EDX mapping could be identified, and the elemental analysis showed well-dispersion of the metals. The mesoporous character of the catalyst-support system was unraveled using N2 physisorption. Experiments were conducted within the parametric range of 250–350 °C, 3–9 bar, and 15–35 h−1. Both temperature and pressure were found to have statistically significant linear and quadratic effects on the selectivity for cresol. The parametric interaction of temperature with pressure and space velocity also had a significant effect on the resulting response. The optimal temperature range becomes more critical at lower space velocities. Optimal selectivity for cresol was established at 314 °C, 5 bar, and 35 h−1. The fitting quality of the generated regression model was statistically confirmed and experimentally validated to describe the specified HDO process within the 95% two-sided confidence interval. [ABSTRACT FROM AUTHOR]

Visible light promoted photoredox catalyzed formation of α-amino radicals from cyclic tertiary amine compounds and their subsequent addition to Michael acceptors performed in flow conditions allowed access to a wide range of functionalized N-aryl-substituted tetrahydroisoquinolines (THIQs) and N-aryl-substituted tetrahydro-β-carbolines (THBCs). Visible light in conjunction with Ru(bpy)3Cl2 photocatalyst allowed the formation and high reactivities of α-amino radicals in flow conditions at room temperature. These reactions gave valuable products with high efficiencies; some previously unavailable reaction pathways photo or thermal reaction conditions; i.e. direct synthesis of 1-substituted (THBCs) via α-amino radical path were successfully realized in flow. The use of custom-made FEP tube microreactor proved to be the key to succesfull α-amino-radical formation and overall reaction performance in flow. Three types of light transparent custom-made microfluidic devices were tested, among them glass/silicon and FEP type reactor showed very good results in the conversion of tested compounds. Plausible reaction mechanism is proposed in accordance with known principles of photo activation of tertiary amines. Visible light promoted C(sp3)-H functionalization of N-aryl-protected tetrahydroisoquinolines and N-aryl-protected tetrahydro-β-carbolines in microflow conditions via a-amino radical pathway with various coupling partners in excellent yields and efficiencies. [ABSTRACT FROM AUTHOR]

Flow chemistry offers several advantages for performing chemical reactions and has become an important area of research. It may seem that sufficient knowledge has already been acquired on this topic to understand how to choose the design of microreactor/micromixer and flow rate in order to achieve the desired outcome of a reaction. However, some experimental data are difficult to explain based on commonly accepted concepts of chemical reactivity and performance of microfluidic systems. In this mini review, we attempt to identify such data and offer a rational explanation of unusual results based on the supramer approach. We demonstrate that variation in flow regime (determined by mixer design and flow rate) can either improve or worsen the reactivity and lead to completely different products, including stereoisomers. It is not necessary to mix the reagents with maximum efficiency. The real challenge is to mix reagents the right way since at a too high or too low flow rate (in the particular mixer), the molecules of reagents are incorrectly presented on the surface of supramers, leading to altered stereoselectivity, or form tight supramers, in which most of the molecules are located inside the supramer core and are inaccessible for attack, leading to low yields. [ABSTRACT FROM AUTHOR]

An automated high throughput multidimensional reaction screening platform based on an inline Fourier‐transform infrared spectroscopy is presented. By combining flow chemistry, machine automation and inline analysis, the platform is able to screen reactions in multidimensions (residence time, monomer concentration, degree of polymerization, reaction temperature and monomer conversion) rapidly and efficiently way. Kinetic data libraries associated with high data precision (absolute error <4 %), high reproducibility and high data density are built with ease from the platform. To test the method, we screened the reversible addition‐fragmentation chain transfer polymerization of methyl acrylate in unmatched detail, and the ring opening metathesis polymerization of methyl‐5‐norbornene‐2‐carboxylate. The method we introduce is a key step in providing "big data" for data driven research in the future, and already at present allows for precise prediction of reaction outcomes within the high‐dimensional chemical parameter space that is screened. [ABSTRACT FROM AUTHOR]

A very simple Rh‐based catalyst operates under heterogeneous flow conditions for the carbene transfer of methyl diazoacetate (MDA) with several substrates. Two different methods for heterogenizing the catalyst in a column reactor have been applied. Different X−H (X=O, S, Si, CH2) were successfully functionalized by the carbene and cyclopropenation was performed under very mild continuous flow conditions. Following these promising results, catalyst recycling experiments using both methodologies were conducted in which up to 5 catalytic cycles have been achieved for the carbene O−H insertion reaction and interestingly, a sequential transformation of different substrates with up to 10 consecutive runs per reactor were achieved with no loss in the catalytic activity, thus allowing the production of families of compounds. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In this work, we introduce a low-cost open-source flow system that includes a dual syringe pump with implemented pressure sensor and back pressure regulator. The entire system can be built for around 500 €. Commercially available flow systems can be very expensive with equipment starting at, but often greatly exceeding, 10,000 €. This high price of entry makes such technology prohibitively expensive for many research groups. Such systems stand to benefit the emerging academic pharmaceutical field by providing the experience and availability of reliable and affordable solutions. To implement accessible flow chemistry at research facilities, the systems must be made affordable. In addition, space in research laboratories is usually limited and commercially available flow systems can be very bulky. Having a compact and individually adjustable system is thus beneficial, with 3D printing technology offering the solution. Our compact 3D-printed system meets the needs of many applications in flow chemistry research as well as educational requirements for universities. As a proof of concept, we conceptualized, developed, and tested a custom flow system that can be used to synthesize [18F]2-fluoro-2-desoxy-d-glucose ([18F]FDG), the most commonly used PET-tracer. This system was designed to perform the typical functions and operations required in radiotracer production i.e. radiofluorination, dilution, SPE-trapping, deprotection, and SPE-elution. With this proof-of-concept in hand, the system can be easily customized to produce other radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

The design and implementation of flow technique helps organic chemists to resolve numerous challenges that are encountered during various catalytic reactions. Flow technologies, which offer solutions for technical and/or chemical issues, have gained popularity over the last two decades in the field of organic chemistry. The selectivity, efficiency, and safety of the entire process has been accelerated by flow reactors as they improve mass and heat transfer, speeds up the mixing of the reaction, and they offer exact control of the reaction parameters. This review mainly describes the utilization of flow chemistry in reactions involving organiozinc reagent, particularly Negishi coupling. The Negishi coupling of organozinc reagent is a valuable tool for the formation of C-C bond with functional group tolerance and are used extensively in total synthesis. This review also portrays a comparative study of organozinc reagents prepared using different procedures. A study of the effect of different catalysts over the same reaction is also carried out. An overview of different flow techniques that are employed has also been incorporated. [ABSTRACT FROM AUTHOR]

Herein, an efficient eco-friendly protocol is reported for the continuous synthesis of enaminones using a microreactor device in the presence of a catalytic amount of cerium (III) trichloride (1 mol%) in Propylene carbonate (PC) as a non-toxic solvent. Moreover, continuous separation of the corresponding product, and recycling of the catalyst-solvent system with water is another promising advantage of this technique. Indeed, the separation of the product by water allows any required catalyst and solvent to be reapplied in the next run. In addition, this microfluidic system enabled turnover frequency (TOF) of up to 2940 h−1 for the corresponding products. The employment of these environment friendly facilitates produce the products with an excellent isolated yield up to 98%. This method performs efficiently, and would extent future applications of continuous organic, inorganic and biochemical reactions in green chemistry. [ABSTRACT FROM AUTHOR]

Herein, we report the first continuous-flow biomimetic cyclization of reticuline derivatives to aporphine alkaloids via ortho-quinol intermediates. The two-step flow process involves an initial oxidative dearomatization of reticuline derivatives to using hypervalent iodine(III) reagents, followed by a TMSOTf-mediated electrophilic cyclization. The high sensitivity of ortho-quinol compounds is mitigated by the mild experimental conditions and fast reaction rates offered by flow reactors. A preliminary structure–reactivity relationship suggests that both steps of the process are favored with strongly electron-rich substrates, similar to what is observed in nature. Article highlights: • A continuous-flow electrophilic cyclization of reticuline derivatives to aporphine alkaloids via ortho-quinol intermediates is developed • The two-step flow process proceeds at room temperature and without protecting group • The high sensitivity of ortho-quinol compounds is mitigated by the assets of flow reactors [ABSTRACT FROM AUTHOR]

The photocatalyzed dearomative reaction between various electron‐deficient aromatic compounds and a non‐stabilized azomethine ylide is successfully performed in a flow system. Whereas the use of supported eosin as organic photocatalyst exhibits limited efficiency, turning to the soluble Rose Bengal allows to transform a broad range of substrates from hetarenes (indole, benzofuran, quinoline, pyridine) to naphthalenes and benzenes. This photocatalyzed (3+2) dearomative cycloaddition under green light irradiation provides a simple and efficient access to tridimensional pyrrolidino scaffolds with a tetrasubstituted carbon center at ring junction and can be performed in the friendly ethyl acetate. Computational studies support the mechanism involving azomethine ylide as reactive species toward the electron‐poor arene. [ABSTRACT FROM AUTHOR]

The ortho‐selective alkynylation of polyhalo‐substituted (hetero)aryl tosylates was investigated using an integrated continuous‐flow/batch protocol. Without the elimination of the tosyloxy group, the regioselective ortho‐metalation of the (hetero)aryl tosylates employing n‐BuLi and ZnCl2 was successfully achieved in continuous‐flow chemistry within 10.92 s (residence time). The Pd‐catalyzed Negishi alkynylations of various iodoethynyl (hetero)arenes and the resulting arylzinc species proceeded at room temperature in yields ranging from 51% to 95%. Finally, the synthetic utility of this strategy was validated by the synthesis of benzofuran and pyridofuran derivatives. [ABSTRACT FROM AUTHOR]

Metal contamination is a waste-generating and serious issue in the synthesis of chemicals, in particular in the case of products with biological activity. The appropriate selection of operating conditions plays a crucial role in the abatement of metal leaching in solution and associated wastes. Herein we report a waste-minimized continuous flow process for the synthesis of 1,4-disubstituted β-keto 1,2,3-triazoles exploiting the use of a copper tube flow reactor (CTFR). The selection of the proper azeotropic mixture allowed an almost quantitative recovery of the reaction medium greatly influencing the E-factor of the protocol. A thorough understanding of the main parameters affecting the waste generation was given by calculation of the E-factor distribution for different work-up tested under batch and flow conditions. Furthermore, the measurement of different green metrics (AE: Atom Economy, SF: Stoichiometric Factor, RME: Reaction Mass Efficiency, and MRP: Mass Recover Parameter) clearly demonstrated the benefits of the flow scale-up that allowed to perform a low environmental footprint CuAAC reaction.