Continuous Synthesis Research Articles

Mechanically Driven, Continuous Synthesis of Chiroplasmonic Assemblies.

Chiral plasmonic nanomaterials─with their significant applications in protein detection, drug screening, and enantioselective sensing─necessitate an industrialized fabrication procedure to enhance their commercial viability. However, the prevailing manufacturing of chiral plasmonic nanoparticles and assemblies heavily leans on manual intervention, causing time-consuming and quality-inconsistent concerns. Here, we develop an automated, continuous mechanical synthesis system that consistently sprays metal nanowires to create chiroplasmonic assemblies: a macroscopic twisted layered structure comprising equivalent linear birefringence layers, approximate linear polarizer layers, and a precise angular offset between them. Utilizing the synthesis-with-automation system, we scale up the production of chiral plasmonic films, generating high optical asymmetry (g-factor, with the order of 10-1) across a broadband ranging from ultraviolet to near-infrared wavelengths. We further introduce the portable chiral sensing, expanding plasmonic assemblies into flexible materials and integrating them with wearable real-time display devices. Our mechanically driven, continuous synthesis of chiral plasmonic structures presents an intriguing pathway to facilitate functional chiral structures toward practice.

Catalyst-free and wavelength-tuned glycosylation based on excited-state intramolecular proton transfer

The chemoselectivity of organic reactions is a fundamental topic in organic chemistry. In the long history of chemical synthesis, achieving chemoselectivity is mainly limited to thermodynamic conditions by an exogenous activation strategy. Here, we design an endogenous activation method, which can be used to control the chemoselectivity of phenol and naphthol through the photo-induced excited-state intramolecular proton transfer (ESIPT). A wavelength-tuned glycosylation is developed to showcase the penitential of this new strategy. Traditionally, an exogenous activator (electrophilic promoters) is essential to induce the cleave of a polar single bond, and this strategy has been extensively studied and used in the glycosylation chemistry, for the formation of oxocarbenium cation intermediate. In our systems, the oxocarbenium cation intermediates can be selectively formed from glycosyl donors bearing tunable chromophoric groups under mild conditions of acid-base free and redox neutrality, which enables continuous synthesis of oligosaccharides.

A microfluidic approach for controllable synthesis of TiO2 submicrospheres

TiO2 submicrospheres are used in dye-sensitized solar cells and Li-ion batteries to enhance energy conversion efficiency and volumetric performance. In this study, a microfluidic chip was designed for the realization of the continuous controllable synthesis of TiO2 submicrospheres. The chip utilizes two T-channels to discrete dispersed phases into droplets, and a Y-channel to fuse the two dispersed phase droplets. The droplets generation process, the influencing factors of droplet length and the fusion process of droplets were investigated. The effects of the flow rate ratio of titanium oxysulfate and ammonia solutions, microchannel geometrical profiles including the Y-channel entrance angle on the size of the synthesized TiO2 were studied. The length of the generated droplets was found to decrease with increasing continuous-phase flow rate, and increase with increasing dispersed-phase flow rate and microchannel cross-section area. When the flow rate ratio of titanium oxysulfate solution and ammonia solution was 1:1, the average diameter of TiO2 spheres synthesized was the smallest, around 300 nm. Increasing the microchannel cross-section and Y-channel entrance angle were beneficial in obtaining larger TiO2 submicrospheres. This proposed microfluidic strategy has the potential for applications required continuous synthesis of TiO2 submicrospheres with controllable sizes.

Flowing Forward: Continuous Synthesis of and with Ionic Liquids

AbstractHerein, the developments in the field of continuous ionic liquid synthesis and continuous ionic liquid utilization from the last seven years are reviewed. Starting by discussing recent strategies for the preparation of ionic liquids themselves in different flow reactors, the review will further focus on various continuous strategies employing ionic liquids. The application of ionic liquids in continuous processes, particularly as supported catalytic layers, has drawn significant scientific interest in the last decades. These catalyst frameworks provide a versatile tool in many organic transformations, and their application became an attractive strategy in continuous catalytic approaches.

Toward Continuous Electrochemical Synthesis of Ferrate

AbstractFerrate (Fe(VI)) is of great interest in energy storage solutions, organic synthesis, and wastewater treatment due to its decent oxidation potential and non‐toxic end‐product formation, making it a green oxidizer. The electrochemical generation of ferrate in NaOH at current densities of j ≥ 100 mA cm−2 is presented using low‐cost sacrificial iron anodes, mild steel, and spheroidal graphite cast iron (ductile iron). Under optimized reaction parameters with 40 wt.% (14 m) NaOH and a ZrO2‐based diaphragm, spheroidal graphite cast iron shows no signs of passivation in 5 h experiments even at j = 150 mA cm−2. The results are used in a novel electrolysis cell with a combined geometric anode surface area of 230 cm2, incorporated in a mini‐plant suitable for continuous synthesis. This setup produces a peak ferrate concentration of 10.1 g L−1 (84 mm) after 5 h in 1.6 L anolyte volume, resulting in a total ferrate mass of 16.2 g. Optimal electrolysis temperatures are between 35 and 50 °C. The highest current efficiency is 63.0%, and the lowest specific energy consumption is 9.2 kWh kg−1 ferrate. The presented work is an essential step toward the continuous electrochemical synthesis of ferrate using sacrificial anodes under basic conditions.

An Emerging Solid‐State Electrolyte Reactor to Drive the Future of Electrochemical Synthesis

AbstractElectrochemical reactors, powered by renewable electricity, have garnered widespread attention for chemical synthesis due to their low energy consumption and pollution‐free features. However, the inherent design flaw of traditional electrochemical reactors has persistently hindered the advancement of electrochemical synthesis, as they result in low product concentrations, low purity, and continuous production issues. As a novel electrochemical reactor, the porous solid‐state electrolyte (PSE) reactor is elaborately designed to overcome the limitation by enabling the direct and continuous synthesis of pure products, possessing a modular and scalable structure with high efficiency, safety, and long stability. In this work, first, the distinctive design of the PSE reactor, highlighting its structural features, core components, and variable configurations, is introduced. Furthermore, the configuration‐relevant applications in electrosynthesis, such as formic acid, acetic acid, and hydrogen peroxide (H2O2) production, are summarized. Integrated applications are also discussed, along with potential domains for improvements and optimization. Finally, the future developmental directions of the PSE devices are thoroughly explored. By addressing its unique design attributes, showcasing its capabilities, and envisioning prospective refinements and diverse applications, the aim is to boost the progression of this transformative technology toward widespread commercialization and industrial adoption, thereby revolutionizing sustainable electrochemical synthesis.

Continuous Flow Synthesis of Five‐Membered N‐Heterocycles by Ynone System

In this study, we devised a practical and effective method for synthesizing ynones from terminal alkynes and anhydride utilizing a continuous flow apparatus at ambient temperature. Moreover, we coupled the ynones with hydrazines, and hydroxylamine hydrochloride to synthesize pyrazole and isoxazole derivatives. This protocol's unique characteristics include a metal‐free approach, mild reaction conditions, a short residence time, and a wide range of functional group tolerance. Sustainable strategies are most useful and affordable than conventional benchtop approaches.

Microwave-assisted continuous flow synthesis of propofol

Herein, we present a breakthrough microwave-assisted continuous flow synthesis method for Propofol, an essential anesthetic recognized by the World Health Organization (WHO). This innovative approach exploits the synergistic potential of two cutting-edge technologies in organic synthesis: microwave irradiation and continuous flow. Using this powerful combination, we have developed an enhanced synthesis process for Propofol. Our method achieves Propofol synthesis in only two steps: Friedel-Crafts isopropylation followed by decarboxylation, with a remarkably short total residence time of 21.25 min and an impressive overall yield of 80% over both steps. Of particular note is the decarboxylation step, which is performed in an environmentally friendly solvent, glycerol, and requires a residence time of only 1.25 min. This step yields an impressive 94% with a throughput of 7.07 g h−1, demonstrating the efficiency and sustainability of our approach.

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 Synthesis of Hexyl Laurate Using Immobilized Thermomyces Lanuginosus Lipase from Residual Babassu Mesocarp.

Brazil has one of the greatest biodiversities on the planet, where various crops play a strategic role in the country's economy. Among the highly appreciated biomasses is babassu, whose oil extraction generates residual babassu mesocarp (BM), which still needs new strategies for valorization. This work aimed to use BM as a support for the immobilization of Thermomyces lanuginosus lipase (TLL) in an 8.83 mL packed-bed reactor, followed by its application as a biocatalyst for the synthesis of hexyl laurate in an integrated process. Initially, the percolation of a solution containing 5 mg of TLL at 25 °C and flows ranging from 1.767 to 0.074 mL min-1 was investigated, where at the lowest flow rate tested (residence time of 2 h), it was possible to obtain an immobilized derivative with hydrolytic activity of 504.7 U g-1 and 31.7 % of recovered activity. Subsequent studies of treatment with n-hexane, as well as the effect of temperature on the immobilization process, were able to improve the activities of the final biocatalyst BM-TLLF, achieving a final hydrolysis activity of 7023 U g-1 and esterification activity of 430 U ⋅ g-1 against 142 U g-1 and 113.5 U g-1 respectively presented by the commercial TLIM biocatalyst. Desorption studies showed that the TL IM has 18 mg of protein per gram of support, compared to 4.92 mg presented by BM-TLL. Both biocatalysts were applied to synthesize hexyl laurate, achieving 98 % conversion at 40 °C within 2 h. Notably, BM-TLLF displayed exceptional recyclability, maintaining catalytic efficiency over 12 cycles. This reflects a productivity of 180 mg of product ⋅ h-1 U-1 of the enzyme, surpassing 46 mg h-1 U-1 obtained for TLIM. These results demonstrate the efficacy of continuous flow technology in creating a competitive and integrated process offering an exciting alternative for the valorization of residual lignocellulosic biomass.

Sonication-Assisted Electrochemical Synthesis of Silver Nanoparticles.

In this work, we propose a method for synthesizing silver nanoparticles (Ag NPs) utilizing a sonication-assisted electrochemical approach with a common ultrasonic cleaner. Silver nitrate is employed as the precursor and polyvinylpyrrolidone functions as the ligand. The incorporation of sonication is identified as crucial for achieving several benefits such as enhanced mass transfer, improved dispersion of reactants, and the prevention of electrode fouling. Optimized sonication and electrochemical conditions synergistically contribute to a higher yield of well-dispersed Ag NPs, which are characterized by an average size of 10 nm. Furthermore, the electrode's suitability for the continuous synthesis of Ag NPs over an extended period is highlighted owing to effective electrode surface cleaning facilitated by sonication. This cleaning process proves to be essential in maintaining the electrochemical activity of the electrode, ensuring consistency in the synthesis process. The proposed sonication-assisted electrochemical synthesis method not only addresses challenges associated with electrode fouling but also significantly enhances the dispersity and yield of the resulting particles, making it valuable for scalability and practical applications in various fields, including sensors, catalysis, and nanotechnology.

Protein turnover regulation is critical for influenza A virus infection

The abundance of a protein is defined by its continuous synthesis and degradation, a process known as protein turnover. Here, we systematically profiled the turnover of proteins in influenza A virus (IAV)-infected cells using a pulse-chase stable isotope labeling by amino acids in cell culture (SILAC)-based approach combined with downstream statistical modeling. We identified 1,798 virus-affected proteins with turnover changes (tVAPs) out of 7,739 detected proteins (data available at pulsechase.innatelab.org). In particular, the affected proteins were involved in RNA transcription, splicing and nuclear transport, protein translation and stability, and energy metabolism. Many tVAPs appeared to be known IAV-interacting proteins that regulate virus propagation, such as KPNA6, PPP6C, and POLR2A. Notably, our analysis identified additional IAV host and restriction factors, such as the splicing factor GPKOW, that exhibit significant turnover rate changes while their total abundance is minimally affected. Overall, we show that protein turnover is a critical factor both for virus replication and antiviral defense.

Droplet microreactor continuous synthesis of hierarchical Rh on CdZnS snowflakes for enhanced photocatalytic hydrogen evolution

Promising droplet microreactor-cation exchange strategy is utilized to construct the unique Rh hierarchical structure (RhHS) and Rh nanoclusters (RhNCs) on CdZnS (CZS) snowflakes. The fabricated RhHS/RhNCs/CZS achieves an optimal hydrogen evolution activity of 926.0μmol h−1 g−1, which is 5.9 and 10.5 folds enhancement that of CZS and CdS, respectively. The enhanced activity for H2 generation can be attributed to the RhHS/RhNCs (accelerating electron transfer), as well as the hierarchical structure of RhHS and CZS, which enhances reflection–absorption of visible light. Theoretical calculations reveal that Rh species can serve as new H* generation-release sites, reducing the energy barrier for hydrogen evolution. Notably, in situ Raman confirmed the Rh (Rh-H) and S (S-H) two main active sites for proton reduction during hydrogen generation. This paper provides a novel approach to constructing hierarchical structure photocatalyst (RhHS/RhNCs/CZS) for enhanced photocatalytic H2 production.

Application of continuous stirring tank reactor for controllable synthesis of Cu7S4 nanocrystals

As a typical model for a chemical reactor in industry, the continuous stirring tank reactor has been widely used in waste-water treatment, industrial catalysis, and biological fermentation as well as great application prospects in the synthesis of nanomaterials. In this report, a convenient lab-scale continuous stirring tank reactor was assembled and utilized to synthesize Cu7S4 nanocrystals by injecting cupric bromide and sulfur solution in the presence of ascorbic acid and polyethyleneimine at 60 °C. The morphology control of Cu7S4 nanocrystals was accomplished by simply adjusting the agitation speed. Cu7S4 nanofibers with an average diameter of 48 ± 4.42 nm and a length of several micrometers were obtained at 80 rpm. Cu7S4 nanoplates with a thickness of 89 ± 13.56 nm and a plane size of 103 ± 16.47 nm were synthesized at 90 rpm, and the size of the nanoplates was regulated by continuously increasing the agitation speed from 90 rpm to 1000 rpm. Furthermore, the influences of two additional conditions (the mean residence time and the concentration of the feed solution) on the morphology of Cu7S4 nanocrystals, were also investigated. Therefore, these results could facilitate the understanding of the behaviors of CSTR in the synthesis of Cu7S4 nanocrystals and could also provide an important reference for the continuous synthesis of other nanoparticles.

Vehicle-Following Control Based on Continuous Synthesis Variable Time Headway Model

Vehicle-Following Control Based on Continuous Synthesis Variable Time Headway Model

Continuous flow synthesis of MOF UTSA-16(Zn), mixed-metal and magnetic composites for CO2 capture – toward scalable manufacture

UTSA-16(Zn) is a zinc and citrate-based metal-organic framework (MOF) which has shown highly promising performance for CO2 capture. However, the transition of this MOF to industrial application has been hindered as a scalable synthesis method has not yet been reported. Herein we report the first scalable continuous flow synthesis of UTSA-16(Zn), demonstrating a production rate of 173 g/h, which is a 77-fold increase compared to previously reported batch methods. Sustainability of the synthesis was maximised using low-cost non-toxic reagents and a low-energy flow reactor operating at atmospheric pressure. Chemical (reactant ratios, Zn/Mg mixed-metal) and process parameters (solvent ratio, flow rate, temperature) were optimised to continuously produce UTSA-16(Zn) which also demonstrated a high CO2 adsorption capacity up to 3.8 mmol/g and conversion yield of up to 66 %. Pristine MOFs are typically thermally insulating, thus thermal regeneration is challenging. To overcome this limitation, magnetic nanoparticles can be embedded within the MOF. This enables fast and energy efficient regeneration through magnetic induction heating. Here, citrate-coated Fe3O4 magnetic nanoparticles (MNP-CA) were successfully incorporated into the flow synthesis process of UTSA-16(Zn) to form UTSA-16(Zn)@MNP-CA magnetic framework composites (MFCs), representing the highest production rate reported of any MFC to date (152 g/h c.f. 13 g/h for MgFe2O4@UiO-66-NH2). UTSA-16(Zn)@MNP-CA MFCs demonstrate rapid heating under a magnetic field (26–150 °C in 60 s). The flow method developed herein is also widely applicable for scalable manufacture of other MOFs and MFCs, enabling their broader transition towards industrial applications.

Continuous Microreactor‐Based Synthesis of SnO2 Nanoparticles for Sensor Applications

Tin oxide nanoparticles are well‐established materials with a wide range of applications, including optoelectronic devices and solid‐state gas sensors. Conventional synthesis methods of these systems are often based on batch processes. In this study, we compare batch and continuous synthesis methods for tin dioxide nanoparticles using precipitation and sol‐gel processes. For the continuous processes we applied the so called microjet reactor method. The nanoparticles were characterized by TEM, elemental analysis and XRD and exhibited particle sizes of 1.7‐3.0 nm and crystallite sizes of 1.7‐2.3 nm, consisting of tetragonal (P42/mnm) and orthorhombic (Pbcn) phases. We have evaluated different post‐synthesis purification methods to remove impurities such as chlorides and carbon‐hydrogen species. Each purification method exhibited unique advantages and side effects, providing insight into selecting the most appropriate method for specific applications. We also demonstrated the potential of these SnO2 nanoparticles as ethanol gas sensing materials and compared their performance with a commercial sensor.

Continuous flow synthesis of the antiviral drug tecovirimat and related sp3-rich scaffolds.

Herein we report a 2-step continuous flow synthesis of the antiviral drug tecovirimat, which is used for the treatment of monkeypox and smallpox. This work exploits a high-temperature pericyclic cascade process between cycloheptatriene and maleic anhydride generating a key sp3-rich scaffold, which affords the desired API after further condensation with an acyl hydrazide. Additional investigations of the key intermediate in reactions with different hydrazines revealed the accessibility of different heterocyclic chemotypes, depending on the substitution pattern of the hydrazine used. Ultimately, the streamlined and scalable access to these sp3-rich scaffolds enables improved access to tecovirimat and structurally related entities with high drug-like character.

Continuous Synthesis and Processing of Covalent Organic Frameworks in a Flow Reactor.

Covalent organic frameworks (COFs) are typically prepared in the form of insoluble microcrystalline powders using batch solvothermal reactions that are energy-intensive and require long annealing periods (>120 °C, >72 h). Thus, their wide-scale adoption in a variety of potential applications is impeded by complications related to synthesis, upscaling, and processing, which also compromise their commercialization. Here we report a strategy to address both the need for scalable synthesis and processing approaches through the continuous, accelerated synthesis, and processing of imine- and hydrazone-linked COFs using a flow microreactor. The flow microreactor is capable of unprecedented COF productivities, up to 61,111 kg m-3 day-1, and provides control over key stages of COF formation, including nanoparticle growth, self-assembly, and precipitation. Additionally, the technique successfully yields highly crystalline and porous COFs in versatile macroscopic structures such as monoliths, membranes, prints, and packed beds. We also show that a COF synthesized using the flow microreactor acts as an excellent photocatalyst for the photocatalytic degradation of perfluorooctanoic acid (PFOA) outperforming the degradation efficiency of its batch analogue and other classical photocatalysts such as titanium dioxide (TiO2).

Perfluoroalkyl-modified covalent organic frameworks for continuous photocatalytic hydrogen peroxide synthesis and extraction in a biphasic fluid system

H2O2 photosynthesis represents an appealing approach for sustainable and decentralized H2O2 production. Unfortunately, current reactions are mostly carried out in laboratory-scale single-phase batch reactors, which have a limited H2O2 production rate (<100 μmol h−1) and cannot operate in an uninterrupted manner. Herein, we propose continuous H2O2 photosynthesis and extraction in a biphasic fluid system. A superhydrophobic covalent organic framework photocatalyst with perfluoroalkyl functionalization is rationally designed and prepared via the Schiff-base reaction. When applied in a home-built biphasic fluid photo-reactor, the superhydrophobicity of our photocatalyst allows its selective dispersion in the oil phase, while formed H2O2 is spontaneously extracted to the water phase. Through optimizing reaction parameters, we achieve continuous H2O2 photosynthesis and extraction with an unprecedented production rate of up to 968 μmol h−1 and tunable H2O2 concentrations from 2.2 to 38.1 mM. As-obtained H2O2 solution could satisfactorily meet the general demands of household disinfection and wastewater treatments.