Continuous Flow Process Research Articles

Intramolecular Photochemical C−H Insertions of α‐Diazocarbonyl Compounds

AbstractIntramolecular photochemical C−H insertion reactions of α‐diazocarbonyl compounds are powerful synthetic transformations leading to carbon‐carbon bond formation. While there are limitations in the scope of C−H bonds amenable to C−H insertion under photochemical conditions relative to metal catalysed C−H insertions, the benefits of conducting these synthetically powerful transformations in a metal‐free approach offers “green” advantages. Recent advances in technology have revolutionised the potential for use of photochemical transformations in synthesis, including the wavelength control enabled by LEDs and the benefits associated with continuous flow processing which overcome many of the traditional challenges associated with synthetic photochemistry including scale‐up. The potential for telescoping the synthesis of α‐diazocarbonyl compounds and downstream photochemical reactions is clear. This review summarises the development of intramolecular photochemical C−H insertions and highlights the benefits of recent technological advances.

Bifunctionalised acid-base hierarchically structured monolithic microreactor for continuous-flow tandem catalytic process of cyanocinnamate synthesis

The results on zirconia-amine bifunctional modification of hierarchically porous silica monoliths for continuous-flow processes ar presented. The study reports the synthesis and properties of the modified porous monoliths and their performance in the tandem process of deacetalization-Knoevenagel condensation reaction. The properties of the materials were studied by thermal analysis, FTIR spectroscopy, XRF and nitrogen adsorption. It was found that both active centres were uniformly distributed along the monolithic cores, and the antagonistic interaction of the acid and base centres was not observed. It was shown that hydrophobicity of the monolith surface has opposite effects on the efficiency of the studied reactions. The overall rate of the tandem process depends on the rate of the condensation reaction. The performance of the bifunctional microreactors was checked and compared with those of cascade-connected monofunctional microreactors and batch reactor. The yield of cyanocinnamate product obtained in both flow systems was ca. 78%; however, pressure drop in the bimodified reactor was only half of that in the cascade. An effective way of water supply to the reaction system has been proposed. The research demonstrates the benefits of using flow-through structured micro-/mesoreactors in tandem reaction processes.

Modelling Approach for the Continuous Biocatalytic Synthesis of N-Acetylneuraminic Acid in Packed Bed Reactors

Continuous flow technologies have become increasingly important for biocatalytic processes. In this study, we present the application and modelling of covalently immobilised N-acetylglucosamine 2-epimerase and N-acetylneuraminic acid lyase in packed bed reactors for the synthesis of N-acetylneuraminic acid. The immobilised enzymes were stable under continuous flow process conditions with half-life times of >28 d (epimerase immobilised on hexamethylamino methacrylate HA403/M) or 58 d (lyase immobilised on dimenthylamino methacrylate ECR8309M), suitable for continuous flow applications. Kinetic studies revealed Michaelis–Menten kinetic behaviour for both enzymes. The kinetic parameters and the inhibitions were analysed under continuous flow conditions and were integrated into a process model using Python. The model was validated by varying flow rates, the mass of immobilised enzymes and the reactor dimensions and shows a low error compared to the measured data. An error accuracy of 6% (epimerase) or 9% (lyase) was achieved. The product concentrations of the enzyme cascade at the end of the packed bed reactor can be predicted with an accuracy of 9% for the calculation of a large column (84.5 mL) or of 24% if several small columns (2.5 mL, 0.8 mL) are connected in series. The developed model has proved to be valid and will be used to optimise the process with respect to substrate concentrations, reactor dimensions and flow rate.

Continuous flow versatile conversion of furfural to valuable end products catalyzed by commercial Pd/C

The conversion of furfural has gained significant attention in recent years due to its potential for transforming this basic chemical into a wide range of valuable end products, such as alcohols, amines, acids, and biopolymers. This contribution aims to demonstrate the versatility and potential of continuous flow processes combined with commercial Pd/C catalysts for converting furfural into high value-added chemicals, including furfuryl alcohol, tetrahydrofurfuryl alcohol, and furfurylimine. By optimizing reaction conditions, high product yields (60–90%) were achieved, marking the first literature example of continuous flow conversion of furfural into diverse products, such as alcohols and imines. This work advances the production of high-value products using propanol as a hydrogen donor, with high yields and selectivity, employing commercial catalysts in a scalable continuous process.

Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis.

Flow synthesis is becoming increasingly relevant as a sustainable and safe alternative to traditional batch processes, as reaction conditions that are not usually achievable in batch chemistry can be exploited (for example, higher temperatures and pressures). Telescoped continuous reactions have the potential to reduce waste by decreasing the number of separate unit operations (e.g., crystallization, filtration, washing, and drying), increase safety due to limiting operator interaction with potentially harmful materials that can be reacted in subsequent steps, minimize supply chain disruption, and reduce the need to store large inventories of intermediates as they can be synthesized on demand. Optimization of these flow processes leads to further efficiency when exploring new reactions, as with a higher yield comes higher purity, reduced waste, and a greener synthesis. This project explored a two-step process consisting of a three-phase heterogeneously catalyzed hydrogenation followed by a homogeneous amidation reaction. The steps were optimized individually and as a multistep telescoped process for yield using remote automated control via a Bayesian optimization algorithm and HPLC analysis to assess the performance of a reaction for a given set of experimental conditions. 2-MeTHF was selected as a green solvent throughout the process, and the heterogeneous step provided good atom economy due to the use of pure hydrogen gas as a reagent. This research highlights the benefits of using multistage automated optimization in the development of pharmaceutical syntheses. The combination of telescoping and optimization with automation allows for swift investigation of synthetic processes in a minimum number of experiments, leading to a reduction in the number of experiments performed and a large reduction in process mass intensity values.

A Continuous Flow Process for the Defluorosilylation of HFC-23 and HFO-1234yf.

A continuous flow process has been developed for the defluorosilylation of trifluoromethane (HFC-23) and 2,3,3,3-tetrafluoropropene (HFO-1234yf) through reaction with lithium silanide reagents under inert conditions. Design of experiment optimization improved process conditions, including productivity, yields, reduction of solvent use, and gas destruction. The small chain fluorinated organosilane products R3SiCF2H and R3SiCH2C(F)═CF2 were competent nucleophiles in the fluoride-catalyzed difluoromethylation of aldehydes, and trifluoroallylation of aldehydes, ketones, and imines.

Research progress in the regulation and intensification of continuous-flow liquid-phase polymerization processes

Research progress in the regulation and intensification of continuous-flow liquid-phase polymerization processes

Ultrafast continuous flow-dialysis for nanoparticle-based drug delivery systems via microfluidic-multiple buffer injector

Nanoparticle-based drug delivery systems (NP-DDS) have emerged as promising carriers for bioactive organic molecules due to their potential in enhancing therapeutic effects. However, traditional purification methods like batch dialysis and diafiltration can alter NP-DDS bio-physicochemical properties due to the lengthy process, prolonged coexistence with organic solvents, and external forces. To address this challenge, we developed an ultrafast flow-dialysis microfluidic module with dual channels separated by a membrane layer. The module leverages multiple buffer injectors (MBIs) to accelerate dialysis by injecting fresh buffer into multiple dialysis zones of bottom channel, refreshing the concentration gradients over the mixture sample in the upper channel to maximize mass transfer efficiency. Using this method for a dual drug-loaded liposome sample containing doxorubicin and curcumin, impurities (such as ethanol and un-trapped drugs) removal and buffer exchange were rapidly terminated within 15 min, continuously operating for ∼ 6 hrs with sequential membrane regeneration process. Importantly, unlike traditional methods, the MBI process maintains the initial uniformity in the size and distribution of liposomes with no leakage of the encapsulated drugs. In vitro HeLa cell tests reveal that the liposomes purified by MBI exhibited significantly higher cellular uptake (1.13 ∼ 1.67 fold), presumably due to the small and uniform size of liposomes, leading to improved anti-tumor effects. Notably, the MBI platform’s versatility was further verified by purifying a mixture of laccase enzyme and by removing the used organic solvents from various carriers (e.g., lipid-based, polymeric, and protein nanoparticles). It is envisioned that the outstanding performance of ultrafast dialysis will enables a continuous-flow downstream process for diverse nano-carriers by intensifying with extra steps in the manufacturing of nanomedicnes, including targeted drug delivery and cancer therapy.

Continuous self-circulating up-flow granular sludge fluidized bed process treating low-strength real municipal wastewater at high hydraulic loads

Conditions conducive to aerobic granular sludge (AGS) growth and maintenance are very difficult to realize in continuous-flow biological treatment processes. This study conducted a continuous-flow self-circulating up-flow granular sludge fluidized bed (Zier process) treating real urban wastewater approximately one year. The substantial self-circulating multiple times (RSCMT, 8–15 times) and up-flow velocity (8–15 m/h) generated by aeration, the only power equipment in Zier process, facilitated pollutant removal, particle granulation and stabilization. With hydraulic retention time of 5 h, RSCMT of 9.3–14.4 times and chemical oxygen demand (COD)/total nitrogen (TN) ratio of 5.9 ± 1.0, the effluent COD, ammonia nitrogen and TN were 28.6 ± 7.7, 1.1 ± 1.2, and 13.3 ± 1.7 mg/L, respectively. The median particle size was 150–250 μm and effluent suspended solids concentration was 33.4 ± 14.5 mg/L. It is unnecessary to set up sludge reflux which simplifies the subsequent mud-water separation facilities. The Zier process provides a new process structure for implementation of continuous-flow AGS process.

Development of an ion exchange process for ammonium removal and recovery from municipal wastewater using a metakaolin K-based geopolymer

Ion exchange represents a promising process for ammonium removal from municipal wastewater (MWW), in order to recover it for fertilizer production. Previous studies on ammonium ion exchange neglected the assessment of process robustness and the optimization the desorption/recovery step. This study aimed at developing a continuous-flow process of ammonium removal/recovery based on a metakaolin K-based geopolymer, named G13. Process robustness was assessed by operating 7 adsorption/desorption cycles with two types of MWW. These tests resulted in satisfactory and constant performances: operating capacity at 40 mgN L-1 in the inlet = 12 mgN gdry sorbent-1, bed volumes of treated MWW at the selected breakpoint = 199 - 226, ammonium adsorption yield = 88 - 91%. Empty bed contact time (EBCT) was decreased from 10 to 5 minutes without any reduction in performances. The NH4+ adsorption process was effectively simulated by the Thomas model, allowing a model-based assessment of the effect of EBCT reductions on process performances. An innovative desorption procedure led to high ammonium recovery yields (86 - 100%) and to a desorbed product composed primarily of KNO3 (54%w) and NH4NO3 (39%w), two salts largely used in commercial fertilizers. The energy consumption of ammonium removal/recovery with G13 resulted 0.027 kWh m-3treated WW, with a relevant reduction in comparison to traditional nitrification/denitrification, whereas the operational cost resulted equal to 60-110% of the cost of the benchmark process. These results show that G13 is a promising material to recover ammonium in a circular economy approach.

Electro-peroxone process for triclocarban and triclosan removal and reclaimed water disinfection

Water reclamation is a known solution to the water scarcity problem; however, concern over water contamination by emerging contaminants and pathogens is growing. This study investigates the simultaneous removal of emerging contaminants and pathogens by applying the continuous-flow electro-peroxone process. Triclocarban (TCC) and triclosan (TCS) were selected as model contaminants of emerging concern, while Escherichia coli strain DH5α was chosen as a representative pathogen. The effects of the initial concentration, water flow rate, and water matrices (direct reclaimed water (treated wastewater), indirect reclaimed water (groundwater), and natural surface water) on TCC, TCS, and E. coli removal were examined. The removal efficiency of TCC (2 mg/L) was up to 92.54 % in 120 min. TCS (non-ozone-resistant compound) was effectively removed in 15 min, while E. coli was instantly inactivated in 3 min. The increase in flow rate decreased the electrical energy per order (EEO) of TCC removal, with the lowest EEO of 19 kWh/m3 at 45 mL/min. The dissolved organic carbon content in water matrices (consuming O3 and H2O2) markedly inhibited the TCC removal, and the kinetic rate as well as reduced 3,4-dichloroaniline (intermediate product) formation. Overall, these findings show the use of the electro-peroxone process is effective in mitigating ozone- and non-ozone-resistant emerging contaminants (TCC and TCS) and pathogens with consideration of water matrices for reclaimed water application.

A Green and Efficient Electrocatalytic Route for the Highly-Selective Oxidation of C-H Bonds in Aromatics over 1D Co3O4-Based Nanoarrays.

Electrocatalytic oxidation of C-H bonds in hydrocarbons represents an efficient and sustainable strategy for the synthesis of value-added chemicals. Herein, a highly selective and continuous-flow electrochemical oxidation process of toluene to various oxygenated products (benzyl alcohol, benzaldehyde, and benzyl acetate) is developed with the electrocatalytic membrane electrodes (ECMEs). The selectivity of target products can be manipulated via surface and interface engineering of Co3O4-based electrocatalysts. We achieved a high benzaldehyde selectivity of 90% at a toluene conversion of 47.6% using 1D-Co3O4 nanoneedles (NNs) loaded on a microfiltration (MF) titanium (Ti) membrane, i.e, Co3O4 NNs/Ti. In contrast, the main product shifted to benzyl alcohol with a selectivity of 90.1% at conversion of 32.1% after modifying MnO2 nanosheets (NSs) on Co3O4 NNs/Ti (Co3O4@MnO2/Ti) catalyst. Moreover, benzyl acetate product can be obtained withselectivity of 92% at a conversion of 58.5% at high current density (> 1.5mA cm-2), demonstrating that the pathway of toluene oxidation is readily maneuvered. DFT results reveal that modifying MnO2 on Co3O4 optimizes the electron structure of Co3O4@MnO2/Ti and modulates the adsorption behavior of intermediate species. This work demonstrates a sustainable,and continuous-flow process for precise control over production selectivity of value-added oxygenated derivatives in electrochemical oxidation of aromatic hydrocarbons.

Sequential-Flow Synthesis of Donepezil: A Green and Sustainable Strategy Featuring Heterogeneous Catalysis and Hydrogenation.

An atom-economical sequential-flow synthesis of donepezil, a widely prescribed drug for Alzheimer's disease, was accomplished using inexpensive, commercially available precursors. This achievement was made possible by reconfiguring the synthetic route to include only heterogeneous catalytic addition and condensation reactions, with a particular emphasis on skeletal transformation and bond formation through hydrogenation processes. Notably, water was the sole byproduct in this synthesis. A crucial aspect of this work was the development of appropriate continuous-flow processes to achieve a one-flow synthesis. This was accomplished by implementing in-line treatments of the main reaction stream to eliminate inhibitory factors that could affect catalyst performance in the hydrogenation steps.

Development of a Safer Continuous Flow Process for B2(OH)4-Mediated Chemoselective Reduction of Nitroarenes to Anilines

Development of a Safer Continuous Flow Process for B₂(OH)₄-Mediated Chemoselective Reduction of Nitroarenes to Anilines

Study on Continuous-Flow Process for Direct Synthesis of p-Aminophenol from Nitrobenzene

Study on Continuous-Flow Process for Direct Synthesis of <i>p</i>-Aminophenol from Nitrobenzene

Coupling photocatalytic trifluoromethylation with biocatalytic stereoselective ketone reduction in continuous flow

Photocatalysis and biocatalysis represent powerful efficient tools in synthetic chemistry. While, both have individually shown promising results, their integration remains challenging, particularly in continuous flow processes. This work presents a semicontinuous setup, combining photo- and biocatalysis in a multistep synthesis for the production of optically pure (S)-3,3,3-trifluoro-1-phenylpropan-1-ol. Initially, a photocatalytic trifluoromethylation of a methyl ketone in α-position in a self-made photoreactor was tested in flow, followed by enzymatic ketone reduction catalyzed by an alcohol dehydrogenase (variant of an ADH from Lactobacillus kefir). The study addresses the challenge of enzyme stability in aggressive solvents, developing a robust immobilization approach for the selected ADH with a PVA/PEG cryogel matrix. This strategy has been investigated in this work to ensure enzyme stability in THF, marking a notable advance in compatibility for continuous cascades. The separate process steps were finally combined in a semicontinuous flow system, achieving a space–time yield for the photocatalytic step of 39.8 g L−1 h−1 and of 1.12 g L−1 h−1 for the enzymatic step. The study signifies one of the first instances of combining photo- and biocatalysis in continuous cascades, offering an innovative approach to synthesizing chiral 3,3,3-trifluoro-1-phenylpropan-1-ol.Graphical abstract

Efficient reduction-oxidation coupling degradation of nitroaromatic compounds in continuous flow processes

Nitroaromatic compounds (NACs) with electron-withdrawing nitro (-NO2) groups are typical refractory pollutants. Despite advanced oxidation processes (AOPs) being appealing degradation technologies, inefficient ring-opening oxidation of NACs and practical large-scale applications remain challenges. Here we tackle these challenges by designing a reduction-oxidation coupling (ROC) degradation process in LaFe0.95Cu0.05O3@carbon fiber cloth (LFCO@CFC)/PMS/Vis continuous flow system. Cu doping enhances the photoelectron transfer, thus triggering the -NO2 photoreduction and breaking the barriers in the ring opening. Also, it modulates surface electronic configuration to generate radicals and non-radicals for subsequent oxidation of reduction products. Based on this, the ROC process can effectively remove and mineralize NACs under the environmental background. More importantly, the LFCO catalyst outperformed most of the recently reported catalysts with lower cost (13.72 CNY/ton) and higher processing capacity (3600 t/month). Furthermore, the high scalability, material durability, and catalytic activity of LFCO@CFC under various realistic environmental conditions prove the potential ability for large-scale applications.

Co-immobilization of amine dehydrogenase and glucose dehydrogenase for the biosynthesis of (S)-2-aminobutan-1-ol in continuous flow

Reductive amination by amine dehydrogenases is a green and sustainable process that produces only water as the by-product. In this study, a continuous flow process was designed utilizing a packed bed reactor filled with co-immobilized amine dehydrogenase wh84 and glucose dehydrogenase for the highly efficient biocatalytic synthesis of chiral amino alcohols. The immobilized amine dehydrogenase wh84 exhibited better thermo-, pH and solvent stability with high activity recovery. (S)-2-aminobutan-1-ol was produced in up to 99% conversion and 99% ee in the continuous flow processes, and the space-time yields were up to 124.5 g L-1 d-1. The continuous reactions were also extended to 48 h affording up to 91.8% average conversions. This study showcased the important potential to sustainable production of chiral amino alcohols in continuous flow processes.

Growth Kinetics and Porous Structure of Surfactant-Promoted Gas Hydrate.

Surfactants present in tiny amounts in the aqueous phase are known to be efficient gas hydrate promoters; yet, the promotion mechanisms are still not fully understood. Understanding and directing those mechanisms is key to the implementation of gas-hydrate-based applications such as gas storage and separation, secondary refrigeration or water treatment, and desalination. In this work, the growth at the water/gas interface and the porous structure of surfactant-promoted methane hydrate are observed by optical microscopy and Raman imaging in glass capillaries used as optical cells. Hollow crystals are continuously generated and expelled from the methane/water meniscus into the water or surfactant solution, where they ultimately form the skeleton of a porous medium filled with the solution. Unprecedented information is gathered over a range of scales from the molecular scale (crystal structure and cage filling) to the mesoscale (crystal morphologies, growth habits and pore sizes) and macroscale (rates and amounts of water and gas converted into hydrate and hydrate porosity). Following an early steady-state growth regime, a sudden order-of-magnitude increase of the conversion rate occurs, which is related to gaseous methane microbubbles being directly incorporated across the meniscus in the aqueous solution and later converted to methane hydrate. An assessment and comparison are made of the mechanisms and performance of two common anionic surfactants known to be efficient gas hydrate promoters, SDS (sodium dodecyl sulfate) and AOT (dioctylsulfosuccinate sodium or AerosolOcTyl). AOT provides a quicker but more limited conversion into hydrate than SDS, suggesting that it is more appropriate for continuous flow processes while SDS is better suited for gas storage applications. Raman spectra reveal that cage filling by methane of structure I methane hydrate is not affected by surfactants.

Rapid Start-up of Continuous Autotrophic Nitrogen Removal Reactor by Hybrid-inoculating PN and PN/A Granular Sludges

The rapid cultivation of partial nitritation/ANAMMOX （PN/A） granular sludge in a continuous-flow mode is one of the key technologies for efficient biological nitrogen removal in domestic wastewater treatment. Compared with that in PN/A granular sludge, PN granular sludge demonstrates a shorter incubation period and suitability for batch culture. It is also a good carrier for enriching ANAMMOX （AMX） bacteria. In this study, we established a continuous-flow autotrophic nitrogen removal process in three continuously stirred tank reactors （CSTR） （R1-R3） by hybrid-inoculating PN/A and PN granular sludge at the mass ratios of 3∶1, 1∶1, and 1∶3, respectively. By implementing high ammonium nitrogen loading and short hydraulic retention time, continuous autotrophic nitrogen removal processes were successfully started up in the three CSTRs. The results showed that compared with that of R1 and R2, R3 had a longer start-up time but a similar steady-state nitrogen removal performance. The total nitrogen removal load of R3 could be more than 2.6 kg·（m3·d）-1. Intriguingly, the inoculated PN granular sludge served as a precursor for PN/A granular sludge cultivation. This approach facilitated the enrichment of anaerobic ammonia-oxidizing bacteria （AMX） by introducing abundant ammonium-oxidizing bacteria （AOB） and nitrite nitrogen substrates into the CSTR. According to the results of high-throughput sequencing, the microbial abundance and diversity of the mature granules in R1-R3 were significantly higher than those of the inoculation sludge. AOB （genus Nitrosomonas）, AMX （genera Candidatus Kuenenia and Candidatus Brocadia）, and symbiotic heterotrophs, such as Chloroflexi, Bacteroidetes, and Chlorobi, drove the autotrophic nitrogen removal process and maintained the stability of the granular structure. In summary, a novel start-up strategy of hybrid-inoculating granular sludge was provided for a continuous-flow autotrophic nitrogen removal in engineering application.