We herein report a continuous flow process for the C–H cyanation of quinoline and isoquinoline derivatives. The process was implemented in a fully integrated, enclosed flow system that combined the reaction sequence with in-line quenching of residual cyanide species, thereby enabling a safe and scalable process. The overall flow process consisting of two-stage (cyanation and rearomatization) was completed within a total residence time of 13 min under optimized conditions, which was dramatically improved compared to the batch process (total 21 h). The continuous flow system was operated at a substrate throughput of 3.1 g h-1 and sustained for 3 h without any operational issues on a 10 g scale. Furthermore, this flow process was successfully applied to a broad substrate scope encompassing diverse quinoline and isoquinoline derivatives, affording the corresponding carbonitrile products in 71–96
Continuous-flow nitration in microreactors has attracted increasing attention as a strategy for improving the safety and controllability of highly exothermic nitration processes. This review surveys more than 40 primary studies reported since 2014 and classifies them according to phase behavior into homogeneous, liquid-liquid heterogeneous, and miscellaneous systems; within each category the literature is further organized by nitrating system, principally mixed-acid and nitric-acid-based approaches. Flow operation has compressed residence times from the hours typical of batch nitration to between roughly 2 s and 30 min: the dinitration of o-toluic acid, for example, affords 96
Addressing the challenge of controlling transient oxygen concentration in gas-sensitive photoreactions, this paper reports a microflow process based on a “dual oxygen supply” strategy, successfully applied to the photocatalytic oxidative synthesis of 2-phenylbenzothiazole. This strategy integrated oxygen pre-dissolved in the solvent with oxygen permeating through the microreactor wall, maintaining the dissolved oxygen concentration in the reaction system within a controllable low range, thereby effectively avoiding the severe promotion of oxidation side reaction observed in conventional gas-liquid slug flow where direct gas-liquid contact driven dissolved oxygen close to saturation throughout the reaction. The results revealed the differentiated sensitivity of the main and oxidation side reaction to oxygen concentration: the oxidation side reaction exhibited significantly higher sensitivity than the main reaction. Based on this mechanistic insight, three oxygen supply modes and microflow operation protocols were developed for low (4 mmol/L), medium (20–40 mmol/L), and high (100 mmol/L) initial substrate concentrations, respectively. At a low concentration, relying solely on atmospheric oxygen (O2 at 0.1 MPa absolute pressure) permeation and solvent pre-dissolved oxygen, complete conversion was achieved within 8 min with a yield of 77
This study presents an investigation of hydrogenation reactions in a Corning Advanced-Flow Reactor glass lab scale reactor, designed to facilitate mixing in multiphasic reactions. Using ethyl cinnamate as a model substrate, systematic experiments were performed to understand the reactor potential, reaction performance, and practical operational limits using a Box-Behnken Design of Experiments approach, evaluating the effects of temperature, backpressure, and hydrogen gas flow rate. Under our tested conditions, temperature is the main statistically significant factor affecting yield. Additionally, solvent and solvent mixtures were screened with an aim to understand the minimisation of palladium deposition, with methanol–water identified as the optimal medium for reducing catalyst fouling without compromising yield. Substrate scope extension to alkenes and nitro-compounds showcased the versatility and robustness of consistently achieving near-quantitative conversions except for sterically hindered systems. These results establish the Corning Advanced-Flow Reactor as a fast, scalable, efficient, and sustainable platform for fast hydrogenation, advancing the scope of continuous-flow methodologies for chemical synthesis while addressing key challenges of catalyst blockages and process scale-up. Impact of Flow Chemistry The present research demonstrates the transformative impact of flow chemistry on homogeneous Pd-catalysed continuous hydrogenation overcoming traditional batch limitations. Traditional batch hydrogenation suffers from poor H₂ mass transfer, inconsistent mixing, and heat management challenges, particularly with exothermic hydrogenations prone to runaway reactions. The Corning Advanced Flow Reactor (AFR) eliminates these limitations through its microchannel design, delivering 10–100 × enhanced heat/mass transfer vs. batch systems. The key advantages realized are: A batch equivalent would compromise safety, yield reproducibility, and commercial viability. This work establishes AFR as the scalableplatform for homogeneous hydrogenation directly translating lab discoveries into pharmaceuticals/fine chemicals manufacturing. In shortthis work would not be achievable in a batch reactor setup.
Organozinc chemistry is fundamental in the synthesis of highly functionalized molecules, e.g., pharmaceuticals. However, its adaptation to continuous flow has been hindered by an intricate challenge: Reactions involving metallic zinc rely on the presence of an activated metal surface. Conventional protocols depend on chemical zinc activation and, with a few exceptions only, showcase closed processes where redosing the metal, which is consumed in the reaction, is not possible. Here, we present a continuous process that overcomes these limitations by integrating on-demand mechanical surface activation with a continuous flow reactor. A zinc rod is abraded inside a sealed chamber, delivering zinc shavings directly into the reactor under inert conditions. This “from-rod-to-reactor” approach eliminates the need for chemical pre-activation and maintains a reactive surface throughout operation. To demonstrate the viability of this new proposed setup, the Simmons-Smith synthesis, which is used to form cyclopropanes from double bonds, using activated zinc and a dihalomethane as a carbon source, is demonstrated. Using only green solvents and cinnamyl alcohol as a model substrate, we show that the process enables cyclopropanation with high conversion and yield under stable, continuous conditions. Additionally, this study could provide a scalable framework to conduct other stochiometric organometallic reactions, which rely on non-passivated metal surfaces. Continuous flow processing is highly advantageous for managing hazardous, exothermic reactions that utilize reactive starting materials. The classical Simmons-Smith synthesis, a reliable and often used method for the cyclopropanation of alkenes using activated zinc and a dihalomethane, is an ideal candidate for such continuous operations. Furthermore, the economically favorable standard in industrial settings utilizes a Zn/Cu couple, which subsequently requires a cumbersome post-reaction filtration step. This new proposed method uses a novel activation protocol that shifts from chemical to mechanical activation of the zinc, rendering the filtration step unnecessary. Additionally, this approach eliminates the need for copper and avoids the use of large quantities of pyrophoric chemical activators, such as trimethylsilyl chloride (TMSCl). This means that overall, changing from batch to this type of operation eliminates heat transfer limitations, the use of toxic chemicals, as well as the necessity of a downstream operated filtration unit operation.
The deposition of barium sulfate (BaSO4) scale remains a critical operational issue in oil and gas production systems, often requiring chemical removal with chelating agents such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). While most dissolution studies are performed in batch mode, continuous-flow systems provide improved control of hydrodynamics, better representing real well conditions. In this work an integrated continuous-flow methodology that couples in-line ATR-FTIR monitoring with simultaneous pressure measurement to evaluate BaSO4 dissolution and permeability recovery in real-time is presented. Experiments conducted using BaSO4-packed bed stainless-steel columns demonstrated the combined spectroscopic and hydrodynamic data reveal a progressive decoupling between chemical dissolution and permeability restoration, driven by the formation of preferential flow pathways that limit sustained fluid-solid contact. DTPA consistently exhibited faster permeability recovery and higher apparent dissolution under flow and the proposed continuous-flow method as able to quantitatively distinguish the efficiency of DTPA and EDTA solutions (0.125 mol·L−1) at 60 °C. This approach provides a reproducible and non-invasive real-time evaluation of scale dissolvers by capturing the dynamic interplay between dissolution chemistry and transport phenomena. This behavior, inaccessible to batch experiments, highlights the importance of functional performance metrics beyond endpoint conversion and establishes a foundation for future automated screening and kinetic studies of scale removal processes relevant for industrial operations. A novel flow method allows real-time monitoring of scale removal using simultaneous infrared spectroscopy and pressure measurements. The approach integrates chemical dissolution kinetics with hydrodynamic effects for more accurate scale-removal assessment. The experimental setup supports automated testing of future dissolvers under realistic flow conditions.
Handling of solids remains one of the most persistent challenges in continuous-flow chemistry. While the field has achieved remarkable progress in process intensification and scalability, the presence or formation of solids often disrupts smooth operation through clogging, fouling, and hydrodynamic instability. Over the past two decades, an array of reactor concepts and engineering strategies, ranging from improved passive geometries to advanced active systems, have been developed to overcome these issues. This review provides a comprehensive overview of the latest innovations for managing solid–liquid and multiphase mixtures in flow. Technologies discussed include rotating and oscillatory flow reactors, ultrasound-assisted systems, and emerging designs such as liquid-walled reactors. Each strategy is examined in the context of mixing behavior, mass transfer, scalability, and process robustness. By bridging insights from chemical engineering and synthetic methodology, this article aims to guide the rational design of heterogeneous continuous-flow systems that fully exploit the advantages of flow chemistry while embracing its most challenging domain: solid handling.
The α-functionalization of unprotected cyclic amines via organolithium reagents presents significant challenges for scale-up due to the extreme reactivity of the intermediates and the requirement for cryogenic control. A continuous-flow platform has been developed that enables the in-situ generation and telescoped use of organolithium reagents for the oxidative C–H functionalization of cyclic amines with organolithium reagents. The lithiation, oxidation, and nucleophilic addition sequence proceeds efficiently at − 10 °C, offering precise thermal management and reproducible steady-state operation. The system furnishes α-aryl-substituted pyrrolidines in up to 54
As a potent and selective gonadotropin-releasing hormone (GnRH) antagonist, linzagolix, has recently been approved for the treatment of uterine fibroids. 6-Methoxy-2,3-difluorobenzaldehyde is the key intermediate during the synthetic process of linzagolix. Conventional batch-scale lithiation of aromatic compounds is inherently associated with considerable thermal hazards, which originates from the exothermic decomposition of reaction intermediates or products. Specifically, the loss of cooling efficiency or rapid reagent addition can readily trigger uncontrolled runaway reactions, a critical safety issue that underscores the need for the development of robust, scalable alternative synthetic protocols. Herein, we developed a novel continuous flow synthesis of 6-methoxy-2,3-difluorobenzaldehyde. Beyond mitigating the inherent safety risks posed by intermediate instability, this approach also establishes a practical, highly efficient protocol amenable to large-scale manufacturing.
“A beaker, in a beaker, in a bucket” – a tuneable photoreactor system that can be rapidly assembled from readily available components is detailed. Involving interchangeable reaction coils and LED light sources, the system is designed to be accessible and affordable, allowing chemists to employ the well documented benefits of (flow) photochemistry to obtain proof-of-concept, without requiring investment in commercial equipment or in house fabrication of components. The flow photoreactor system, which can also be employed for batch reactions, has been characterised, and the visible light (460 nm) isomerisation of trans- to cis-stilbene, employing Ir(ppy)3 as a photosensitiser, has been used as a model reaction to evaluate its performance. It was found that the photostationary state of this reaction could be achieved within just 2 min of irradiation in flow with a 20 mW cm− 2 light source, allowing for reactor throughputs as high as 0.5 mmol min− 1, demonstrating the utility of this easy to access system.
Since their commercialization, packed bed reactors have become a key component of the modern chemical industry. Addressing their shortcomings would yield significant economic benefits and mitigate their negative environmental impact. This is particularly true for ammonia synthesis, a process that is performed globally on a massive scale. Packed bed reactors have a complex internal structure, with catalyst pellets randomly distributed within the reactor vessel with the pore space characteristics clearly impacting the reactor performance. In this work, we develop a three-dimensional model of a packed bed reactor with explicitly resolved catalyst pellets and apply it to ammonia synthesis. After confirming that the simulation results meet expectations, we apply our previously proposed framework to identify the pore-scale characteristics of the reactor that have the largest influence on the flow, described with the hydraulic permeability, and the reaction yield. Reasonably, our methodology indicates that most studied properties are impactful and that their changes have opposite effects on the hydraulic permeability and yield. To complete the analysis, we induce the suggested structural changes by manipulating the pellet size distributions and demonstrate that they lead to the predicted outcomes.
A microfluidic (MF) platform was developed for the controlled synthesis of lanthanide-doped LaF3 nanoparticles (NPs), including co-doped LaF3:Ce,Tb NPs and Rose Bengal (RB)–PEG–LaF3:Ce,Tb@LaF3:Ce core@shell nanocomposites. The structure, composition, and optical properties of the products were comprehensively characterized by XRD, XRF, TEM, HR-TEM, FTIR, UV–vis spectroscopy, and XEOL. The influence of key synthesis parameters such as solvent composition (EG/H2O mixture), reaction temperature, and flow rate on the crystallite size and morphology was systematically investigated. Variation of the EG/H2O ratio led to a pronounced increase in crystallite and particle size from ∼5 to ∼12 nm with increasing water content. By tuning both solvent composition and temperature, the MF synthesis enabled the preparation of LaF3:Ce,Tb NPs with crystallite and particles sizes in the range of ∼ 4 nm to ∼13 nm. For flow rates above 100 μL/s (total synthesis time < 2 min), the crystallite size remained nearly constant, whereas the most pronounced changes were observed at flow rates below 10 μL/s (total synthesis time > 16 min). The MF-synthesized LaF3:Ce,Tb NPs exhibit a compact, pore-free structure, in contrast to NPs obtained by conventional coprecipitation, hydrothermal/solvothermal methods. Moreover, PEG-coated, RB–conjugated LaF3:Ce,Tb@LaF3:Ce core@shell NPs were successfully produced, demonstrating the versatility of the MF platform. These results highlight MF synthesis as an efficient route for fabricating high-quality luminescent LaF3-based nanomaterials with tunable size and morphology for prospective applications in photonics and biomedicine. Ce3+/Tb3+-doped LaF3 nanoparticles were synthesized via microfluidic synthesis. The effects of microfluidic synthesis parameters (solvent, reaction temperature, flow rate) on nanoparticle size and morphology were systematically investigated. Microfluidic synthesis enabled precise control over particle size, yielding uniform nanoparticles with diameters ranging from 4 to 13 nm. Rose Bengal (RB)-conjugated, PEG-coated RB-PEG-LaF3:Ce,Tb@LaF3:Ce core-shell nanocomposite were prepared via microfluidic synthesis.
The development of continuous flow processes for the Staudinger synthesis of β-lactams was investigated in order to provide an alternative to cumbersome batch procedures. First, a model reaction based on acetoxyacetyl chloride and N-(phenylmethylidene)isopropylamine was selected for initial parameter evaluation and optimization. Assessment of a broad set of bases showed that the use of diisopropylethylamine, N-methylpiperidine or tributylamine in acetonitrile is recommended for obtaining the desired 3-acetoxy-1-isopropyl-4-phenyl-β-lactam in high cis diastereoselectivity. Next, the optimized reaction set-up was successfully translated to the continuous flow production of a set of differently substituted β-lactams which are known to be difficult to prepare via batch procedures. Interestingly, an unexpected base-induced diastereoselectivity was observed during this study, allowing for tuning of the reaction conditions to favor the formation of either the cis or the trans isomer in select cases.
4,4’-Diaminodiphenyl ether (ODA) is a key monomer in the synthesis of polyimides and possesses significant application value. However, conventional synthesis methods suffer from notable shortcomings, such as reliance on expensive noble metal catalysts or the requirements for harsh reaction conditions and discontinuous preparation processes when using non-noble metal catalysts. Herein, we employed a dual-membrane micro-dispersion reactor system and low-cost hydrated sodium silicate as the silicon source to achieve green, continuous, and highly efficient synthesis of a bimetallic Ni–Co supported catalyst. The reactor enables precise microscale mixing and mass transfer control, significantly optimizing the catalyst preparation process. Structural characterization results indicated uniform dispersion of metal nanoparticles and strong interactions between the active components and the support, leading to a remarkable enhancement in catalytic performance. In the liquid-phase hydrogenation of 4,4’-dinitrodiphenyl ether (DNDPE) to ODA, the catalyst exhibited excellent activity and stability. The target product yield reached 99.25 A series double-membrane micro-dispersion reactor system was adopted to achieve a continuous, green and economical preparation process. The developed catalyst has low cost and high hydrogenation activity, and has important practical application value. The inorganic silicon source sodium silicate hydrate has replaced the common organic silicon source tetraethyl orthosilicate, reducing the use of organic solvents.
We describe the integration of a minimally modified household air fryer into flow chemistry experiments as a safe and cost-effective platform for conducting esterification reactions at the undergraduate and high school levels. By leveraging the continuous processing principles of flow chemistry alongside the controlled heating capabilities of an air fryer, students can efficiently synthesize esters from readily available carboxylic acids and alcohols in the absence of other solvents and with minimal workup (phase separation from an aqueous solution, washings) in good isolated yields (typically well over 50 The use of air fryer as a heating source for organic chemistry experiments. Introducing flow chemistry at the high school level. Synthesis of commercial fragrances in undergraduate laboratories.
In recent years, electron donor–acceptor (EDA) complexes have emerged as sustainable, cost-effective, and inherently safer alternatives to traditional transition metal-based photocatalysts in photochemical processes. Formed via the association of neutral electron-rich and electron-deficient species, EDAs offer an environmentally benign route to radical generation across a broad spectrum of reactions. Concurrently, flow chemistry has gained prominence as a burgeoning area of scientific inquiry, enhancing reaction control, safety, mixing efficiency, and, critically, light penetration. In this mini review, we highlight recent works that have explored the use of EDA photochemistry with flow methodologies, while assessing both the promising practical advantages and current limitations in bringing these two fields together.
The preparation of pyridine N-oxides plays a critical role in functionalization of pyridines, which enhances the physical, chemical and biological properties of pyridine derivatives. And, the corresponding N-oxides are usually generated easily from the oxidation of pyridines by peracids. However, the peracids are extremely explosive even though they are used via preparation in situ. In this context, we developed a highly safe, economical and practical strategy to produce pyridine N-oxides using the cheap and environmentally friend H2O2 as terminal oxidation in continuous flow system. The solid-supported polyacrylic acid was used as catalyst which improved the reaction stability and operational safety and was reusable. In addition, the mixing efficiency was also enhanced by the solid-supported catalyst and made the scale-up synthesis achievable. Specifically, the output of this continuous flow synthesis could be increased to 67.93 kg/d and 24.8 t/a using a thicker tube reactor which was 200 m long, 1 cm thick and filled with solid-supported acid catalyst to give 10 L volume. A highly safe strategy to produce pyridine N-oxides was developed using H2O2 as terminal oxidation in continuous flow. Reusable solid-supported polyacrylic acid catalyst was used and improved the reaction stability and safety. The output of this continuous flow synthesis could be increased to 67.93 kg/d and 24.8 t/a using a thicker tube reactor.
Boron-containing compounds are essential building blocks in organic synthesis. A significant advancement in the preparation of alkyl boranes relied on the use of B2Cat2 with competent radical precursors under chemical, photochemical, and electrochemical conditions. However, these molecules are unstable and require one-pot formation of corresponding pinacol boranes to be isolated. In this work, we present a continuous flow electrochemical decarboxylative borylation approach telescoped with the exchange from unstable catechol boranes intermediates to isolable pinacol boranes. The study encompassed the optimization of a single-pass protocol employing an electrochemical microreactor, followed by the telescoped pinacol addition. No supporting electrolyte was necessary to successfully execute the process. The continuous-flow approach was validated across 11 examples comprising primary, secondary, and tertiary alkyl carboxylic acids.
A Continuous Flow Photochemistry (CFP) - based protocol has been developed for the synthesis of a complex isomeric API impurity, Sulindac E-Isomer (2), which is a USP reference standard. The reported flow photochemical E/Z isomerization reaction is more efficient than metal catalyzed multistep batch process (residence time of 3 min in flow vs overall reaction time of 20 h in batch process; 44
Flow chemistry provides a new method for medicinal chemistry education owing to its continuous operation, improved reaction efficiency, and safety. In the improved experiment, dioxane was used as a solvent to dissolve salicylic acid and acetic anhydride; this helped reduce the corrosion of the equipment by the reaction solution, prevent injuries, and ensure good fluidity. Simultaneously, a feeding system under nitrogen protection was designed and applied to avoid the hydrolysis of acetic anhydride and deterioration of salicylic acid. The entire experiment included dissolution pre-experiments, energy-saving and consumption reduction experiment. Paracetamol was synthesized using a technique that had also been applied in undergraduate teaching experiments. Compared to previously reported aspirin synthesis experiments, this method enhances the safety of the experiment and diversity of cultivation abilities. This experiment not only improves the teaching effect but also provides an example of the application of flow chemistry and medicinal chemistry in teaching. The microchannel continuous-flow technology is an advanced technology that uses microscale channels to perform efficient and controllable chemical reactions. We developed a new process for the synthesis of aspirin and paracetamol using this technology. Before the formal experiment, dissolution pre-experiments were conducted to cultivate students’ pre-experimental consciousness. After screening and analysis, dioxane was determined as the reaction solvent in the formal experiment. This innovative measure not only effectively reduces the corrosion risk of the reaction liquid to the equipment and minimizes potential personal injuries, but also enables the reaction to achieve continuous crystallization. In this study, the nitrogen-protected feeding system was designed and applied, and the energy-saving and consumption reduction experiment was conducted. This device is easy to assemble, inexpensive, and conducive to popularization and application, which is helpful for the cultivation of applied talents. We hope that this research will provide valuable insights into the teaching of flow chemistry and medicinal chemistry.
