Continuous Flow Process Research Articles

Continuous Flow β‐Zeolite Mediated Regioselective Alkylation of Naphthols Using Alcohols for Peroxynaphthalen‐2(1H)‐one, Azidonaphthalen‐2(1H)‐one and Fluoronaphthalen‐2(1H)‐one

Herein, we demonstrated continuous flow alkylation of α‐ and β‐naphthols by using various primary and secondary benzylic alcohols in the presence of environmentally benign granular β‐zeolite as a reusable catalyst. For a variety of β‐naphthols, the respective alkylated products with good regioselectivity were obtained in high yields under mild reaction conditions and demonstrated with versatile naphthol derivatives (50 and 44 examples in batch and continuous flow process, respectively). Key advantages of this process are that it is rapid and efficient, facilitates gram‐scale synthesis, and generates water as the sole by‐product. The most significant advantage is the continuous reusability of granular β‐zeolite, which further emphasizes the sustainability of the method. The application of alkylated naphthols for quaternary functionalization was demonstrated through peroxidation, azidation, and halogenation reactions under the continuous flow module, which yielded the respective peroxynaphthalen‐2(1H)‐one, azidonaphthalen‐2(1H)‐one and fluoronaphthalen2(1H)‐one derivatives.

Selective Decarboxylative Fluorination of β‐Keto Acids in Aqueous Media: 19F‐NMR‐Assisted Batch Optimization and Transfer to Continuous Flow

AbstractThe selective decarboxylative fluorination of 3‐oxo‐3‐phenylpropionic acid is used as a benchmark reaction to optimize it under biocompatible conditions in batch and to transfer it to continuous flow mode. The reaction conditions are varied with respect to temperature, fluorinating reagents, inorganic base additives, and pH, as these parameters have been identified as having a significant impact on the process. The formation of the products and any by‐products is analyzed using gas chromatography (GC) and 19F nuclear magnetic resonance spectroscopy (NMR). Once optimal conditions have been determined, the reaction is carried out using an automated continuous laboratory synthesis system that features a mesostructured capillary reactor and an integrated 19F‐NMR spectrometer for real‐time monitoring of the reaction. The work presented here represents the initial phase of a multi‐step continuous flow process that will include additional biocatalyzed downstream reactions in future applications.

Depolymerisation of poly(lactide) under continuous flow conditions.

Poly(l-lactic acid) (PLLA) is commercially successful bio-based plastic, where end-of-life materials can undergo industrial composting. To create a circular economy, a desirable alternative to composting is chemical recycling to monomer (CRM), where direct depolymerisation to l-lactide can be achieved. CRM of PLLA is typically impeded by thermal decomposition and side reactions, due to the high ceiling temperate (T c) of PLLA in bulk (>600 °C), which preclude implementation on a large scale, and has led to the development of catalytic strategies, under vacuum or high dilution in high boiling point solvents conditions. In this study, a commercially available Sn(ii) catalyst and low boiling point solvents, at a range of temperatures and concentrations, were explored for the CRM of PLLA in a continuous flow process. The solvent THF was found to produce the best results, where up to 92% conversion of lactide could be achieved, with 92-97% selectivity for l-lactide formation at temperatures 150-170 °C. Further, inline monitoring of monomer and polymer concentrations in flow were used to determine the depolymerisation rate coefficient k depo and the activation energy of k depo was determined to be 129.4 kJ mol-1.

Metal-free [2+2]-photocycloaddition of unactivated alkenes enabled by continuous flow processing.

We report a continuous flow approach generating bicyclic cyclobutanes from unactivated alkenes in a metal-free manner that is inspired by the Kochi-Salomon reaction. A filtered Hg-lamp in combination with a simple flow set-up and acetone as UV light-absorbing co-solvent are crucial for this method thus showcasing attractive features for further exploitations.

Rapid CO2 coupling to propargylic alcohols: unlocking the production of α-alkylidene cyclic carbonates via continuous flow

Silver N-heterocyclic carbene complex unlocks the fast coupling of CO2 to propargylic alcohols to produce α-alkylidene cyclic carbonates through continuous flow process.

Optimization of continuous-flow microwave processing with static mixers for enhanced heating uniformity

Optimization of continuous-flow microwave processing with static mixers for enhanced heating uniformity

Reductive O-alkylation of methanol by ketones using a heterogeneous palladium catalyst under continuous flow conditions

A mild continuous-flow catalytic process for reductive alkylation of methanol with aliphatic ketones. A mechanism is proposed.

Continuous flow synthesis of alkynes from isoxazolones.

The development of a continuous flow approach for the generation of alkynes from isoxazolones under diazotisation conditions is reported. The underlying transformation has been known for several decades; however, in batch mode, it is plagued by variable yields, excessive use of sodium nitrite and limited scalability due to its exothermic nature and the release of copious amounts of toxic nitroxide gases. The presented flow approach overcomes these limitations and delivers various alkyne products in residence times of less than 1 minute with productivities of ca. 2 g h-1. This demonstrates the value of continuous flow processing in miniaturised devices and renders this alkyne forming method an attractive addition to the limited synthetic toolbox towards this important functional group.

From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir.

Molnupiravir (1) is one among the limited therapeutic options for treating COVID-19 infection and exhibits pan-antiviral potency. Because of urgent demands during the COVID-19 pandemic, a number of methods were developed to offer more efficient routes. In this report, we present a facile 2-step and scalable synthesis of molnupiravir for batch processing and show the implementation of continuous flow biocatalysis to improve the efficiency in synthesis. Our key step entails immobilized lipase and isobutyric anhydride to facilitate regioselective esterification. In batch process, transamination of cytidine (2) provides N4-hydroxycytidine (NHC, 3) with 75 % yield followed by esterification of NHC to give molnupiravir with 64 % yield, providing 48 % overall yield and 99.98 % purity (HPLC). Compared to batch approach in the esterification step, the continuous flow process provides similar product yield and purity and highlights the advantages including 2.42-fold better productivity (mol/day), 2.47-fold improved reaction time, and 30-fold higher space-time-yield. The optimized batch and continuous flow biocatalysis enhance synthesis efficiency and reduce environmental impact, offering a sustainable approach for industrial molnupiravir production.

Hydroformylation of Alkenes by Supported Ionic Liquid Phase (SILP) Catalysis

Hydroformylation of olefins forms aldehydes which are valuable final products as well as intermediates in synthesizing bulk chemicals like alcohols, amines, and esters with a yearly world production of about 12 Mt. Industrial hydroformylation processes are essentially homogeneously catalyzed systems with an economic incitement for improvement by easy separation of products and reuse of catalysts, high reactivity and selectivity by using new catalysts, novel processes and alternative methodologies.One such potential candidate for an alternative catalyst is a Supported Ionic Liquid- Phase (SILP) catalyst comprising “heterogenized” homogeneous ionic liquid (IL) catalyst systems on a porous support. Such catalysts make it possible to apply the much preferred fixed bed continuous flow process design which overcomes the troublesome and energy demanding separation of the products from the reaction mixture obtained in the traditional homogenous batch process.In our previous and very recent studies [1-2], we have prepared SILP catalysts containing immobilized Rh-complexes of TPPTS-Cs3 in 1-butyl-3-methylimidazolium octylsulfate ([BMIM][n-C8H17OSO3]) on SiO2 support and investigated the influence of IL loading on the catalytic activity. The influence of other supports : SBA-15, MCM-41, Al2O3, ZrO2 and TiO2 has also been studied and the catalytic activity compared to the SiO2 SILP catalyst. Finaly we will report on a comparison on the catalytic activity of the SiO2 SILP catalyst by use of the ligand precurser TPPTS-Cs3 and the much cheaper TPPTS-Na3 salt. References. H. N. T. Ha, D. T. Duc, T. V. Dao, M. T. Le, A. Riisager, R. Fehrmann. Catal. Commun. 25, 136-141 (2012)Nguyen, V. C., Do, V. H., Truong, D. D., Pham, T. T., Dinh, P. K., Vu, T. L., Garcia-Suarez, E. J., Riisager, A., Fehrmann, R., Le, M. T. Res. Chem. Int..49, 6, 2383-2398 (2023).

Toward More Sustainable Magnetic Nanoparticle Synthesis Based on Microwave-Assisted Continuous-Flow Processes

Toward More Sustainable Magnetic Nanoparticle Synthesis Based on Microwave-Assisted Continuous-Flow Processes

Batch vs Continuous‐Flow Method to Synthesize N‐(3‐acylamidopropyl)lactams through N‐C Bond Cleavage in Amides with Amidines

The selective N‐C bond cleavage of amides to create value‐added products through a transition metal‐free approach has become a significant challenge. Here, we present a method to convert amides into N‐(3‐acylamidopropyl)lactams through sequential amide chemoselective N‐C bond cleavage and amidine ring opening under mild conditions, applicable in batch and continuous flow processes. These methods utilize bench‐stable reagents and are operationally straightforward and mild, enabling synthesis on a gram scale with excellent functional group tolerance. Additionally, the synthetic feasibility of these reactions under flow conditions has proven to be highly efficient, providing N‐(3‐acylamidopropyl)lactam derivatives with improved yields and shorter reaction time.

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.

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

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.

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 min 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.

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.

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.