Search

The structure, function, and dynamics of Earth's terrestrial ecosystems are profoundly influenced by the frequency and duration that they are inundated with water. A diverse array of natural and human engineered systems experience temporally variable inundation whereby they fluctuate between inundated and non-inundated states. Variable inundation spans from extreme flooding and droughts to predictable sub-daily cycles. Variably inundated ecosystems (VIEs) include hillslopes, non-perennial streams, wetlands, floodplains, temporary ponds, tidal systems, storm-impacted coastal zones, and human engineered systems. VIEs are diverse in terms of inundation regimes, water chemistry and flow velocity, soil and sediment properties, vegetation, and many other properties. The spatial and temporal scales of variable inundation are vast, ranging from sub-meter to whole landscapes and from sub-hourly to multi-decadal. The broad range of system types and scales makes it challenging to predict the hydrology, biogeochemistry, ecology, and physical evolution of VIEs. Despite all experiencing the loss and gain of an overlying water column, VIEs are rarely considered together in conceptual, theoretical, modeling, or measurement frameworks/approaches. Studying VIEs together has the potential to generate mechanistic understanding that is transferable across a much broader range of environmental conditions, relative to knowledge generated by studying any one VIE type. We postulate that enhanced transferability will be important for predicting VIE function under future, potentially non-analog, environmental conditions. Here we aim to catalyze cross-VIE science that studies drivers and impacts of variable inundation across Earth's VIEs. To this end, we complement expert mini-reviews of eight major VIE systems with overviews of VIE-relevant methods and challenges associated with scale. We conclude with perspectives on how cross-VIE science can derive transferable understanding via a 'continuum approach' in which the impacts of variable inundation are studied across multi-dimensional environmental space. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Journal of Flow Chemistry has released a special issue titled "Emerging Investigators in Flow Chemistry 2023," which features the work of early career researchers in academia and industry who have made significant contributions to the field. The articles in this issue cover a diverse range of scientific perspectives and approaches, showcasing the wide range of backgrounds and expertise of the contributors. The goal of this special issue is to encourage collaboration and expand the scientific community and readership of the journal. The document provides brief biographical information about the researchers, highlighting their educational background, research interests, and notable achievements. Their work focuses on various aspects of flow chemistry, including the development of new therapeutic options, the application of flow microreactor technology, and the advancement of sustainable methodologies. [Extracted from the article]

Continuous flow chemistry has become the method of choice for the synthesis of toxic and explosive intermediates such as diazo reagents because they can be generated on demand and readily used, eliminating the need to handle hazardous materials. This inherent increase in safety makes it more feasible to use these reagents in day-to-day synthesis. Herein, we describe a continuous flow, metal-free, easy-to-use method for the preparation of semi-stabilized and unstabilized diazo reagents. The scope of the described continuous flow oxidation of hydrazones using a packed bed column with iodosylbenzene includes 13 semi-stabilized and 13 unstabilized diazo reagents in solution in dichloromethane while producing only 1 equivalent of water and iodobenzene as by-products. These otherwise difficult to access compounds are further reacted either in situ or at the reactor outlet to yield esters and ethers in good to excellent yields (47–96%). [ABSTRACT FROM AUTHOR]

Flow chemistry is the future of chemical processing. It represents a significant advance in energy consumption and waste generation regarding operations in batch and continuous flow macroscopic equipment since the transport rate (of mass, heat, photons, electrons, etc.) is tremendously intensified. In parallel, computational fluid dynamics (CFD) is part of engineering's future. Digitalization of transport processes (involving fluid flow and scalar transport, e.g., species, energy, etc.) is the state-of-the-art for designing, optimizing, and scaling chemical reactors, separation and purification units, heat exchangers, etc. This perspective initially presents relevant fundamental CFD concepts applicable to any field. In the sequence, an overview of applications of CFD in flow chemistry reported in the literature over the last two decades is presented, highlighting the evolution of complexity and variety of topics investigated (ranging from single-phase flow optimization to multiphysics cases involving coupling of multiphase flow and external forces—e.g., ultrasound and electric field). Next, the contributions of our research group in CFD in flow chemistry are presented—with a focus on photocatalytic and electrocatalytic systems—and accompanied by highlights about our personal experience. Further discussion about strengths, limitations, and opportunities for CFD in flow chemistry is presented, highlighting to the reader the gaps that should be in the spotlight over the next few years, followed by our final remarks. After reading this perspective, the reader (either a starter in this field or an expert) will be able to identify how CFD has evolved in flow chemistry over the years and what are the next directions from the authors' point of view. [ABSTRACT FROM AUTHOR]

In the realm of flow chemistry, Do-It-Yourself (DIY) flow setups represent a versatile and cost-effective alternative to expensive commercially available reactors. Not only they are budget friendly, but also unlock a world of possibilities for researchers to explore and create customized setups tailored to their specific needs. This minireview serves as a short compendium of DIY flow systems to assist flow researchers in the challenging task of finding a suitable setup for their experiments and facilitate the transition from batch to flow chemistry. Our goal is to demonstrate that flow chemistry can be affordable, easy-to-build, and reproducible at the same time. Therefore, herein we review and describe selected illustrative examples of easily assembled/constructed DIY flow setups, with a particular emphasis on how to select the most suitable one based on the specific chemistry of interest, ranging from simple homogeneous monophasic reactions to more complex systems for photo-, electrochemistry, and so on. In addition, we briefly comment on the significance of DIY approach on education, particularly its integration into the standard undergraduate curriculum as a key educational tool for young chemists. Ultimately, we hope this mini review will help and encourage the reader to go with the flow and get started with the fine art of flow chemistry. [ABSTRACT FROM AUTHOR]

Photochemistry and continuous flow chemistry are synthetic technology platforms that have witnessed an increasing uptake by chemical industries interested in complex organic molecule synthesis. Simultaneously, automation and data science are prominent targets in organic synthesis and in chemical industries for streamlined workflows, meaning hardware-software interaction between operators and devices is crucial. Since undergraduate teaching labs at public-funded research Universities typically (i) lack budget for commercial, user-friendly continuous flow reactors and (ii) do not teach synthetic chemists how to program or interact with reactors, there is a disparity between the skills undergraduates are equipped with and the skills that future industries need. We report a teaching lab project where undergraduates assemble, program and execute a continuous flow photoreactor to realize a multigram-scale photoredox catalyzed oxidation reaction. A palladium-free synthetic access to the starting material was described to further cut costs. Not only does this exercise introduce useful skills in reactor design, programming and wet chemistry (both photochemical and thermal, both batch and flow), it also accommodates both the typical budget and afternoon timeslot (2-3 h) of a teaching lab and can be followed by thin-layer chromatography/color changes without necessarily requiring access to NMR facilities. [ABSTRACT FROM AUTHOR]

A vicinal diamine motif can be found in numerous natural compounds and pharmaceuticals, making it an important synthetic target. Herein, we report a telescoped synthesis of vicinal diamines under continuous flow conditions. This approach involves the electrochemical aziridination of alkenes with primary amines, followed by the strain-release driven ring-opening using various nitrogen nucleophiles. The efficacy of the developed method was demonstrated through the synthesis of diverse symmetrically and non-symmetrically substituted vicinal diamines, as well as vicinal amino azides, which can be further hydrogenated to diamines in flow. Additionally, O-centered nucleophiles were employed for the ring-opening of aziridines in our telescoped synthesis, yielding vicinal amino ethers and alcohol. This process offers a streamlined and efficient pathway for the direct synthesis of valuable products from readily available starting materials, bypassing the isolation of unstable aziridine intermediates. [ABSTRACT FROM AUTHOR]

In this paper we report a [2 + 2] cycloaddition reaction between ketenes and benzils, characterized by an unusual double photochemical activation triggered by visible light. Employment of a flow system and optimization of reaction conditions through Design of Experiments resulted in moderate to good yields of the corresponding β-lactones. A thorough computational analysis allowed to elucidate the mechanism of the reaction and justify the observed diastereoselectivity. The reaction was also successfully tested with mixed benzils, showing complete regioselectivity. [ABSTRACT FROM AUTHOR]

Although gas-liquid-solid reactions, such as catalytic hydrogenation, have a long history, a fundamental understanding of the flow behavior and its effect on the reaction is lacking for flow chemistry applications using powder catalysts. This study revealed the distinctive effect of gas-solid direct contact on the surface of a powder catalyst. Direct gas–solid contact accelerates the reaction beyond the theoretical maximum of the batch reaction system, where gaseous species are supplied to the catalyst surface after dissolution into the liquid. The benefit of direct contact is further pronounced in systems with low-solubility gaseous species. Liquid holdup analysis revealed that the micro-concavities of the catalyst support is crucial for sustaining the liquid using capillary forces and supplying the liquid substrate to the catalyst surface even under high gas flow rate conditions. The gas-to-liquid flow rate ratio (G/L) is a decisive factor for direct gas–solid contact, whereas the flow direction, whether upflow or downflow, has no impact on powder catalysts with a size of a few hundred microns. Highlights: Utilization of a powder catalyst in flow reactor enables direct gas-solid contact. Accelerated reactions through gas-solid direct contact surpass the maximum rate in the reaction-controlled regime. Micro-concavities of particles retain liquid in reactor and achieve stable reaction rate. [ABSTRACT FROM AUTHOR]

We are currently experiencing a resurgence in the realm of electrochemical organic synthesis, driven by the transformative potential of conducting redox chemistry under mild conditions through the simple use of electrons, thereby circumventing the use of harmful reductants and oxidants. This renaissance is further bolstered by the fusion of electrochemistry with flow chemistry, which not only grants precise control over reaction parameters but also promotes sustainability and heightened reproducibility. Despite these promising advancements, the application of flow electrochemistry to steer asymmetric processes remains in its nascent stage. This perspective delves into the limited contributions to date, shedding light on critical challenges and presenting prospective solutions that are essential for fully unleashing the untapped potential of this field. [ABSTRACT FROM AUTHOR]

Reactive organometallic intermediates present a distinct opportunity for the creation of novel carbon-carbon and carbon-heteroatom bonds. Whereas their utility in synthesis is well-established, the thermal sensitivity of these species often imposes the requirement for stringent reaction conditions, including strict control of reaction temperatures, concentrations, and use of additives. Moreover, their strong reactivity can pose challenges in achieving the desired selectivity. Since pioneering works in the 2000s, the advent of flow microreactor technology has revolutionized this field, expanding the possibilities of reactive organometallic intermediates within synthetic chemistry. In this review, we provide an overview of the recent advancements in this dynamic area, focusing on breakthroughs that have emerged within the past four years. [ABSTRACT FROM AUTHOR]

In a continuous flow microreactor system, a continuous nitration process of 2-(2,4-dichloro-5-nitrophenyl)-4-(difluoromethyl)-5-methyl-1,2,4-triazol-3-one which is the key intermediate for the synthesis of important triazolinone herbicide Sulfentrazone was developed. The effects of molar ratio of mixed acids, molar ratio of nitric acid to substrate, reaction temperature, total flow rate and residence time in the microreactor on nitration reaction were studied. The results showed that when the flow rate of the material was 60 mL/min, the molar ratio of nitrate to sulfur mixed acid was 1:6, the molar ratio of nitric acid to raw material was 1.1:1, the reaction temperature was 60 ℃, and the residence time was 30 s, the product can be obtained in 97% yield. Compared with the results of nitration process using traditional batch reactors, the use of continuous flow microreactors improved reaction efficiency and achieved higher yields. A characterization kinetics study was conducted on this reaction, and the pre-exponential-factor and activation energy for 2-(2,4-dichlorophenyl)-4-(difluoromethyl)-5-methyl-1,2,4-triazol-3-one nitration were obtained. The activation energy of the reaction is 40.204 kJ/mol. The continuous flow microreactor system greatly increased liquid-liquid two phases mass transfer efficiency, while accurately controlling the reaction temperature and residence time in the reactor. [ABSTRACT FROM AUTHOR]

The number of biocatalyzed reactions at industrial level is growing rapidly together with our understanding on how we can maximize the enzyme efficiency, stability and productivity. While biocatalysis is nowadays recognized as a greener way to operate in chemistry, its combination with continuous processes has lately come up as a powerful tool to enhance process selectivity, productivity and sustainability. This perspective aims at describing the recent advances of this technology and future developments leading to smart, efficient and greener strategies for process optimization and large-scale production. [ABSTRACT FROM AUTHOR]

Flow biocatalysis has emerged as an empowering tool to boost the potential of enzymatic reactions towards more automatized, sustainable, and generally efficient synthetic processes. In the last fifteen years, the increasing number of biocatalytic transformations carried out in continuous flow exemplified the benefits that this technology can bring to incorporate biocatalysis into industrial operations. This perspective aims to capture in a nutshell the available methodologies for flow biocatalysis as well as to discuss the current limitations and the future directions in this field. Article highlights: Integration of enzymatic reactions into flow reactors is an exponentially growing technology. Flow biocatalysis can produce valuable molecules for food, cosmetics, and pharmaceuticals in a more eco-friendly manner. An interdisciplinary effort is needed to overcome the current challenges for industrial flow biocatalysis. [ABSTRACT FROM AUTHOR]

Catalytic enantioselective Strecker reactions on an achiral substrate using sub-stoichiometric amounts of a chiral catalyst represent an evolving key strategy for the effective synthesis of α-amino nitriles. We herein disclosed the set-up of a flow-based methodology for enantioselective Strecker, employing ethyl cyanoformate as a relatively safe cyanide source, a cinchona-based catalyst, and methanol as additive. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, the optimum solvent for the flow synthesis, minimum catalyst loading, additive, temperature, and residence time. The newly developed method allows straightforward reaction channeling towards the fast and complete formation of the α-amino nitrile products, thus reducing the yield drop due to indolenine degradation during long-lasting batch-wise reactions. Moreover, we herein provide preliminary hints for sustainability, by proposing a simple procedure for catalyst recycling, thus opening the way for further optimization of the proposed methodology. [ABSTRACT FROM AUTHOR]

Kinetic modeling of in vitro enzymatic reaction networks is vital to understand and control the complex behaviors emerging from the nonlinear interactions inside. However, modeling is severely hampered by the lack of training data. Here, we introduce a methodology that combines an active learning-like approach and flow chemistry to efficiently create optimized datasets for a highly interconnected enzymatic reactions network with multiple sub-pathways. The optimal experimental design (OED) algorithm designs a sequence of out-of-equilibrium perturbations to maximize the information about the reaction kinetics, yielding a descriptive model that allows control of the output of the network towards any cost function. We experimentally validate the model by forcing the network to produce different product ratios while maintaining a minimum level of overall conversion efficiency. Our workflow scales with the complexity of the system and enables the optimization of previously unobtainable network outputs. Kinetic modeling of in vitro enzymatic reaction networks (ERNs) is severely hampered by the lack of training data. Here, authors introduce a methodology that combines an active learning-like approach and flow chemistry to create optimized datasets for an intricate ERN. [ABSTRACT FROM AUTHOR]

Local anaesthetics such as mepivacaine are key molecules in the medical sector, so ensuring their supply chain is crucial for every health care system. Rapid production of mepivacaine from readily available commercial reagents and (non-dry) solvents under safe conditions using portable, continuous apparatus could make an impactful difference in underdeveloped countries. In this work, we report a continuous platform for synthesising mepivacaine, one of the most widely used anaesthetics for minor surgeries. With a focus on sustainability, reaction efficiency and seamless implementation, this platform afforded the drug in 44% isolated yield following a concomitant distillation–crystallisation on a gram scale after N-functionalisation and amide coupling, with full recovery of the solvents and excess reagents. The use of flow chemistry as an enabling tool allowed the use of "forbidden" chemistry which is typically challenging for preparative and large scale reactions in batch mode. Overall, this continuous platform presents a promising and sustainable approach that has the potential to meet the demands of the healthcare industry. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the offshoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas.[1] Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs.[2] These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America's supply chain resiliency.[3] Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems. [ABSTRACT FROM AUTHOR]

Flow chemistry has recently opened new chemistry windows thanks to the safer use of hazardous and sensitive reagents. Furthermore, flow procedures usually outperform their batch counterparts due to improved mass and heat transfer, offering a good opportunity for industrial application. Herein, a rapid Simmons‐Smith cyclopropanation flow process is presented. Taking advantage of the in situ production of the zinc carbenoid species, several olefins bearing aromatic rings of different electronic nature, aliphatic chains or heterocycles were smoothly cyclopropanated with a residence time of just 15 minutes. In addition, industrial applicability of the protocol is assured thanks to a successful 12‐mmol scale experiment, which represents a 3.59 grams per hour production of a selected example, and to the satisfactory synthesis of pharmaceutical drugs. [ABSTRACT FROM AUTHOR]

This document provides a detailed account of the development of a photocatalyzed reaction for the synthesis of the antifungal drug tavaborole. The researchers optimized the reaction conditions and achieved a yield of up to 81% using a flow reactor. The method has potential applications in the synthesis of other drugs, and the chemical shifts and spectra of the synthesized tavaborole are also included. This research contributes to the advancement of green synthetic methods in pharmaceutical manufacturing. [Extracted from the article]

Current models for inorganic ion transport in porous media describe the adsorption–desorption processes mostly based on empirical adsorption isotherms or simple thermodynamic mechanisms, often overlooking the adsorption kinetics. This study introduces a novel unified reactive solute transport model framework that incorporates well-established surface complexation models to describe the adsorption–desorption of ions in the transport process and takes into full consideration the non-equilibrium adsorption, enabling the use of the same set of thermodynamic-kinetic parameters to accurately describe ion transport under different chemical conditions. To evaluate the constructed model, Cr(VI), P(V), and As(V) column transport experiments were carried out using goethite-coated sand as the porous medium. Kinetic constants derived from single-ion transport experiments accurately predicted the cotransport behaviors of Cr(VI), P(V), and As(V) under various flow chemistry conditions, especially the overshooting phenomena of Cr(VI) under P(V) and As(V) competition. The model framework can be easily incorporated into solute transport models with various surface complexation reactions to predict the fate and transport of ions under complexed chemical conditions without extensive parameterization, and thus is a useful complement to the current reactive transport model. [ABSTRACT FROM AUTHOR]

The Eschenmoser coupling reaction (ECR) of thioamides with electrophiles is believed to proceed via thiirane intermediates. However, little is known about converting the intermediates into ECR products. Previous mechanistic studies involved external thiophiles to remove the sulfur atom from the intermediates. In this work, an ECR proceeding without any thiophilic agent or base is studied by electrospray ionization‐mass spectrometry. ESI‐MS enables the detection of the so‐far elusive polysulfide species Sn, with n ranging from 2 to 16 sulfur atoms, proposed to be the key species leading to product formation. Integrating observations from ion mobility spectrometry, ion spectroscopy, and reaction monitoring via flow chemistry coupled with mass spectrometry provides a comprehensive understanding of the reaction mechanism and uncovers the autocatalytic nature of the ECR reaction. [ABSTRACT FROM AUTHOR]

The acylation of 1,3-benzodioxole was studied in a continuous process using a recyclable heterogeneous substoichiometric catalyst. In a short time period (30 min), at 100 °C, the conversion rate was 73%, with a selectivity of 62% of the desired acylated product; the reaction was run continuously for 6 h, showing excellent stability and selectivity. Moreover, the unreacted starting material, 1,3-benzodioxole, can be easily separated by distillation and recycled. [ABSTRACT FROM AUTHOR]

This article discusses the use of light-emitting diodes (LEDs) in continuous-flow synthesis of cyclobutenes. LEDs have become a popular alternative to traditional light sources in photochemical reactions due to their narrow emission spectra and low cost. The researchers conducted experiments using different light sources and found that the UV-A LED provided the best results, producing the desired cyclobutene product with high yield and without reactor fouling. They also explored the use of different alkynes and maleimides in the synthesis of cyclobutenes and demonstrated the scalability of the process. The article concludes that this LED-based continuous-flow approach offers an efficient and cost-effective method for generating cyclobutenes, which are important building blocks in organic synthesis. [Extracted from the article]

One of the key strategies for radiochemical research facilities is the automation of synthesis processes. Unnecessary manual operations increase the radiation exposure of personnel, while simultaneously threatening the reliability of syntheses. We have previously reported an affordable open‐source system comprising 3D‐printed continuous flow reactors, a custom syringe pump, and a pressure regulator that can be used to perform radiofluorinations. In this paper, we address additional essential processes that are needed for radiotracer development and synthesis, with the aim of making laboratory work safer and research more efficient. We have designed and evaluated a fully automated system for rapidly and effectively processing and drying aqueous [18F]fluoride that can be directly connected to the cyclotron. This process relies on triflyl fluoride gas generation and allows nucleophilic [18F]fluoride to be prepared safely in a hotcell within 10 min and an activity recovery of 91.7 ± 1.6% (n = 5). Owing to the need for convenient radiofluorinated prosthetic ligands, we have adapted our continuous flow system to produce [18F]fluoroethyl tosylate (FEOTs) and [18F]fluoroethyl triflate (FEOTf), prosthetic groups that are widely used for late‐stage fluoroethylation of PET tracers. The processes as well as the radiolabeling of different groups are compared and comprehensively discussed. Having a method providing [18F]fluoroethyl tosylate (FEOTs) as well as [18F]fluoroethyl triflate (FEOTf) quickly and highly efficiently is beneficial for radiochemical research. [ABSTRACT FROM AUTHOR]

Seasonality plays a critical role in cold mountain regions as variation in air temperature, ground thermal status, and precipitation phase alter the rate, timing and magnitude of hydrological and chemical transport. Additionally, cold mountain catchments can have highly variable topography, geology, permafrost, and landcover, which intrinsically add to this irregularity. Understanding how external and internal variability act to control mass fluxes requires sampling at a high spatial resolution over time, which rarely occurs in cold remote regions. In this work, we conduct five snapshot sampling surveys across 34 subcatchments during the ice‐free period in Wolf Creek Research Basin (a mesoscale montane subarctic catchment) and two additional winter surveys across a subset of sites to assess the drivers of variability in stream chemistry and discharge. We sampled for specific conductance (SpC), major ions, and dissolved organic carbon (DOC) and used statistical metrics and Bayesian mixing analysis to quantify patterns of flow and chemistry across space and time. Our results indicate patterns in both flow and chemistry remain largely consistent across seasons for all solutes. However, there was weaker correlation of chemistry between sites, suggesting asynchronous behaviour within the catchment. There was evidence of increasing production of ions and DOC along the stream network during high spring flows but not during low flows. Although concentrations and flows exhibit high seasonality in subarctic mountains, this seasonal variability does not alter spatial patterns that arise from highly variable catchment characteristics. [ABSTRACT FROM AUTHOR]

Kinetic data is most commonly collected through the generation of time‐series data under either batch or flow conditions. Existing methods to generate kinetic data in flow collect integral data (concentration over time) only. Here, we report a method for the rapid and direct collection of differential kinetic data (direct measurement of rate) in flow by performing a series of instantaneous rate measurements on sequential small‐scale reactions. This technique decouples the time required to generate a full kinetic profile from the time required for a reaction to reach completion, enabling high throughput kinetic experimentation. In addition, comparison of kinetic profiles constructed at different residence times allows the robustness, or stability, of homogeneously catalysed reactions to be interrogated. This approach makes use of a segmented flow platform which was shown to quantitatively reproduce batch kinetic data. The proline mediated aldol reaction was chosen as a model reaction to perform a high throughput kinetic screen of 216 kinetic profiles in 90 hours, one every 25 minutes, which would have taken an estimated continuous 3500 hours in batch, an almost 40‐fold increase in experimental throughput matched by a corresponding reduction in material consumption. [ABSTRACT FROM AUTHOR]

The use of micro/meso‐fluidic reactors has resulted in both new scenarios for chemistry and new requirements for chemists. Through flow chemistry, large‐scale reactions can be performed in drastically reduced reactor sizes and reaction times. This obvious advantage comes with the concomitant challenge of re‐designing long‐established batch processes to fit these new conditions. The reliance on experimental trial‐and‐error to perform this translation frequently makes flow chemistry unaffordable, thwarting initial aspirations to revolutionize chemistry. By combining computational chemistry and machine learning, we have developed a model that provides predictive power tailored specifically to flow reactions. We show its applications to translate batch to flow, to provide mechanistic insight, to contribute reagent descriptors, and to synthesize a library of novel compounds in excellent yields after executing a single set of conditions. [ABSTRACT FROM AUTHOR]

Molecular solar thermal (MOST) energy storage systems are getting increased attention related to renewable energy storage applications. Particularly, 2,3‐difunctionalized norbornadiene‐quadricyclane (NBD‐QC) switches bearing a nitrile (CN) group as one of the two substituents are investigated as promising MOST candidates thanks to their high energy storage densities and their red‐shifted absorbance. Moreover, such NBD systems can be prepared in large quantities (a requirement for MOST‐device applications) in flow through Diels‐Alder reaction between cyclopentadiene and appropriately functionalized propynenitriles. However, these acetylene precursors are traditionally prepared in batch from their corresponding acetophenones using reactive chemicals potentially leading to health and physical hazards, especially when working on a several‐grams scale. Here, we develop a multistep flow‐chemistry route to enhance the production of these crucial precursors. Furthermore, we assess the atom economy (AE) and the E‐factor showing improved green metrics compared to classical batch methods. Our results pave the way for a complete flow synthesis of NBDs with a positive impact on green chemistry aspects. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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.

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.

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]

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]

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]

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 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]

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]