Continuous-flow Setup Research Articles

Oxoammonium-Catalyzed Oxidation of N-Substituted Amines.

We report the development of oxoammonium-catalyzed oxidation of N-substituted amines via a hydride transfer mechanism. Steric and electronic tuning of catalyst led to complementary sets of conditions that can oxidize a broad scope of carbamates, sulfonamides, ureas, and amides into the corresponding imides. The reaction was further demonstrated on a 100-g scale using a continuous flow setup.

Industrial Production of Bioactive Nutrient-Enhanced Extra Virgin Olive Oil under Continuous-Flow Ultrasound and Pulsed Electric Field Treatment.

Extra virgin olive oil (EVOO) is a cornerstone of the Mediterranean diet. Many studies have highlighted its crucial preventive role against cardiovascular disease, neurodegenerative disorders, metabolic syndrome and cancer, with these effects being due to the synergistic anti-inflammatory and antioxidant activities of minor components, such as polyphenols and tocols. The aim of the present study is to implement new technologies for olive oil mills and develop an efficient large-sized industrial process for the continuous extraction of healthier EVOOs that are enriched with these bioactive compounds. Non-thermal technologies, namely ultrasound (US) and pulsed electric field (PEF), have been tested, separately and in combination, to eliminate the need for traditional malaxation. There is extensive literature to support the efficacy of ultrasound-assisted extraction (UAE) and PEF treatments in EVOO production. A newly designed US device and a PEF industrial chamber have been combined into a single, integrated continuous-flow setup, the performance of which in the extraction of EVOO from green Coratina olives has been evaluated herein. Extraction yields, physico-chemical and organoleptic characteristics, and polyphenol and tocol contents were monitored throughout the trials, and the last three were measured at accelerated aging times (AAT) of 15 and 30 days. The US and combined US-PEF processes not only increased daily oil production (ton/day, by nearly 45%), but also eliminated the need for kneading during malaxation, resulting in significant energy savings (approximately 35%). In addition, these innovations enriched the resulting EVOO with nutritionally relevant minor components (8-12% polyphenols, 3-5% tocols), thereby elevating its quality and market value, as well as overall stability. The introduction of continuous-flow US and PEF technologies is a remarkable innovation for the EVOO industry, as they offer benefits to both producers and consumers. The EVOO resulting from non-thermal continuous-flow production meets the growing demand for healthier, nutrient-enriched products.

Visible Light-Driven CO2 Capture and Release Using Photoactive Pyranine in Water in Continuous Flow.

The urgent need to address climate change and its environmental consequences demands innovative carbon capture technologies, given the relationship between rising global temperatures and increased atmospheric CO2 levels. Here, we present a reversible photochemical carbon capture and release strategy and system utilizing photoactive pyranine in an aqueous bicarbonate buffer system. Control experiments suggested that the photoacid effect occurs at the surface which contributes to CO2 release, complemented by the photothermal effect at the surface and in the bulk. A continuous flow setup employing a tube-in-tube configuration with a hollow fiber membrane demonstrates the efficiency and reliability of the visible light-driven carbon capture system, with the release of CO2 captured from a 15% CO2 feed in the dark, at a rate of 0.48 mmol CO2 per hour to a nitrogen sweep stream under light irradiation at 200 W/m2, a level comparable to solar intensity of visible light (150 W/m2 of blue light -250 W/m2 of blue and green light). The robustness and scalability of the system has been demonstrated, with long-term operation over 7 days yielding 60 mmol (1.34 L CO2 at STP) of cumulated CO2 separation. Additionally, we explored the potential for direct air capture, yielding 3 μmol of CO2 separation over 2 h of operation from a bicarbonate buffer solution saturated with ambient air (420 ppm). This work introduces the prospect of photoswing of carbon capture systems, which can avoid external energy input beyond solar irradiation, offering promising avenues for addressing the challenges associated with climate change.

Electrocatalytic continuous flow chlorinations with iodine(I/III) mediators

Electrochemistry offers tunable, cost effective and environmentally friendly alternatives to carry out redox reactions with electrons as traceless reagents. The use of organoiodine compounds as electrocatalysts is largely underdeveloped, despite their widespread application as powerful and versatile reagents. Mechanistic data reveal that the hexafluoroisopropanol assisted iodoarene oxidation is followed by a stepwise chloride ligand exchange for the catalytic generation of the dichloroiodoarene mediator. Here, we report an environmentally benign iodine(I/III) electrocatalytic platform for the in situ generation of dichloroiodoarenes for different reactions such as mono- and dichlorinations as well as chlorocyclisations within a continuous flow setup.

Electrochemical and bioelectrochemical treatment of steam-assisted gravity drainage water

This study compares electrochemical and bioelectrochemical approaches for treating Steam-Assisted Gravity Drainage (SAGD) water. Electrochemical treatment tests were carried out at applied voltages (Vap) of 1.4, 2.0, and 2.5 V. Bioelectrochemical treatment in a Microbial Electrolysis Cell (MEC) was conducted at the same applied voltages with microaeration of both electrode compartments. The two treatment approaches were thereafter combined in a continuous flow setup that consisted of an electrochemical cell (EC, Vap = 2.5 V) followed by MEC (Vap = 1.4 V). Chemical oxygen demand (COD), naphthenic acid, dissolved metals, and metalloid concentrations of SAGD water were substantially reduced after all treatments, thereby rendering the treated water less toxic according to ecotoxicological tests. However, the MEC treatment was more energy efficient resulting in the lowest specific energy consumption (SEC) value of 5.2 kWh/kgCOD. By replacing a Ti/IrO2-oxide current collector in the MEC with a custom-made Ti/NiCo-oxide mesh, the COD removal efficiency improved by 30%. The results suggest that a MEC equipped with Ti/NiCo-oxide current collector can provide cost-efficient treatment of SAGD water.

Poly(ionic liquid)-based aerogels for continuous-flow CO2 upcycling

The atmospheric concentration of CO2 is rising at an alarming pace, creating a pressing need for new and sustainable materials capable of capture and conversion. Poly(ionic liquid)s (PILs) are particularly effective catalysts for processes at or near atmospheric pressure. PILs industrial application poses challenges due to the low porosity of PIL, the limited batch conversion capacity, and the difficulties in reuse. To overcome these limitations, we herein propose the use of AEROPILs catalysts obtained from the integration of PILs in chitosan-based aerogels. These cost-effective highly porous materials have unique and tuneable porous properties making them not only ideal sustainable CO2 sorbents but also promising heterogeneous catalysts. While AEROPILs show moderate yields for CO2 conversion in batch mode, high catalytic activity was achieved when AEROPILs were used to catalyse the CO2 cycloaddition reaction to epoxides in packed-bed reactors operated under continuous flow. The catalytic activity and stability were maintained over 60 h without activity loss, and high productivity (space-time yield of 21.18 gprod h−1 L−1). This research reveals the pioneering use of AEROPILs to efficiently upcycle CO2 into cyclic carbonate under a continuous flow setup.

In situ Diazonium Salt Formation and Photochemical Aryl-Aryl Coupling in Continuous Flow Monitored by Inline NMR Spectroscopy.

A novel class of diazonium salts is introduced for the photochemical aryl-aryl coupling to produce (substituted) biphenyls. As common diazonium tetrafluoroborate salts fail, soluble and safe aryl diazonium trifluoroacetates are applied. In this mild synthesis route no catalysts are required to generate an aryl-radical by irradiation with UV-A light (365 nm). This reactive species undergoes direct C-H arylation at an arene, forming the product in reasonable reaction times. With the implementation of a continuous flow setup in a capillary photoreactor 13 different biphenyl derivatives are successfully synthesized. By integrating an inline 19F-NMR benchtop spectrometer, samples are reliably quantified as the fluorine-substituents act as a probe. Here, real-time NMR spectroscopy is a perfect tool to monitor the continuously operated system, which produces fine chemicals of industrial relevance even in a multigram scale.

Asymmetric Rh-Catalyzed Reductive Enyne Cyclization Using a Continuous-Flow Setup

Asymmetric Rh-Catalyzed Reductive Enyne Cyclization Using a Continuous-Flow Setup

Oxidation of Alcohols in Continuous Flow with a Solid Phase Hypervalent Iodine Catalyst.

One of the most useful transformations in the synthetic chemist arsenal is the oxidation of alcohols to their corresponding carbonyl congeners. Despite its seemingly straightforward nature, this transformative reaction predominantly relies on the use of metals or hazardous reagents, making these processes highly unsustainable. To address this challenge, we have developed a sustainable metal-free method for the oxidation of alcohols in continuous flow. Using a solid phase hypervalent iodine catalyst and nBu4HSO5 as a phase transfer catalyst and co-oxidant, primary and secondary alcohols were selectively oxidized to the corresponding carbonyl motifs. This operationally simple continuous-flow set-up is highly robust (15 cycles run without significant catalyst leaching or loss of reaction efficiency), uses green solvents, such as acetonitrile or acetic acid, and is readily scalable.

Twisted Intramolecular Charge-Transfer State Addition to Electron-Poor Olefins.

When electron-rich arylpyrrolinium salts are irradiated with ultraviolet light in the presence of Michael acceptors, the pyrrolinyl and aryl fragments add to the activated and polarized double bond in a regioselective manner, forming two C-C bonds and fragmenting the substrate. In this paper, we present a model for this intriguing reaction, supported by spectroscopy and computational analyses, and provide evidence for rectifying previously misassigned structures. We postulate that the photochemical reaction is inefficient because the reaction between the twisted intramolecular charge-transfer state and the olefin competes with fluorescence from this state upon photon absorption. We also discuss the practical advantages of performing this photochemical reaction in a continuous flow setup. Additionally, we explore several subsequent reactions that allow us to further modify the products of the photochemical step, ultimately leading to the creation of new chemical structures.

Continuous flow synthesis and simulation-supported investigation of tunable plasmonic gold patchy nanoparticles.

Plasmonic nanoparticles have intriguing optical properties which make them suitable candidates for sensing or theranostic applications. Anisotropic patchy particles, where metal is locally deposited on the surface of a core particle, exhibit plasmon resonances that can be specifically adjusted for these applications. However, many existing synthesis routes are complex, yield too little material, or provide particles with limited optical tunability. In this work, we present a simple and scalable continuous flow synthesis of gold-on-polystyrene patchy particles with widely adjustable optical properties. By increasing the chloride concentration in the electroless deposition of gold, we slow down the redox reduction kinetics and obtain a dense patch morphology as well as a reduced nucleation rate. The latter is counteracted by introducing a low-level seeding approach where a small number of gold nanocrystals heterocoagulate with the core particles prior to patch growth. Seeding and patch growth are performed in a continuous flow set-up with two T-shaped milli-mixers. The resulting patchy particle samples exhibit a tunable dipolar plasmon peak between 600 nm and 1100 nm. We also investigate the structure-property relationship for our gold patchy particles using finite element method simulations. After identifying a suitable patch shape model, we elucidate the influence of individual geometric parameters on the optical properties and show that the relationship holds true for a large range of patch coverages. Finally, we apply the relationship to explain the time-dependent change in the optical properties of as-synthesized patches by correlating it with the patch shape transformation revealed by electron microscopy.

Development of a solid-compatible continuous flow reactor for the paraformaldehyde slurry mediated α-hydroxymethylation of methyl vinyl ketone

α-Hydroxymethylation reactions often entail safety precautions concerning formaldehyde gas. A paraformaldehyde slurry within a solid-compatible continuous flow setup can now be used with a reduced reaction time and increased productivity.

Nanoprecipitation through solvent-shifting using rapid mixing: Dispelling the Ouzo boundary to reach large solute concentrations

HypothesisThe addition of a non-solvent to a solute in good solvent solution leads to nanoprecipitation, which is the spontaneous formation of nanodomains. Yet, increasing solute concentration usually leads to the formation of macrodomains that quickly separate into a bulk phase, which is a severe process limitation. The corresponding concentration threshold, often termed as the Ouzo boundary, remains a mystery that could find its origin in the complex interplay between nanoprecipitation and mixing. ExperimentsWe performed a systematic investigation of nanoprecipitation thermodynamics and kinetics as well as its interplay with mixing hydrodynamics for the hexadecane-acetone-water system, in the presence of the non-ionic C16EO8 surfactant. The binodal curve and its underlying tie-lines were obtained using Raman spectroscopy, allowing the computation of the spinodal curve. Kinetics were probed using a continuous flow setup that combines two sequential rapid mixers. The impact of mixing efficiency was probed systematically by varying the oil concentration for respectively slow and rapid mixing, while the uncoupling from mixing and nanoprecipitation was quantified by modifying systematically the flow rate in a continuous flow approach. FindingsWe elucidate the nature of the Ouzo boundary that marks the maximal solute concentration leading to nanoobjects. Rather than a thermodynamic boundary, as evidenced by its uncorrelation to the spinodal curve, it results from the coupling of nanoprecipitation and mixing when both processes occur within the same time range, leading to heterogeneous conditions and the escape of some objects to the macroscale. Increasing the solute concentration speeds up nanoprecipitation and thus requires increasingly faster mixing times to uncouple both processes. Accordingly, if the mixing efficiency is large enough, it is possible to dispel the Ouzo boundary and reach very large solute concentrations. Implementing rapid mixing strategies in continuous flow approaches is thus the solution to overcome the most stringent condition of nanoprecipitation and open the way to scale-up, while also providing efficient means to probe its fast mechanism. Overall, the simultaneous control of hydrodynamics and physical chemistry is thus key to boost up the Ouzo effect.

An Alkanethiol-Surfactant Bilayer To Prevent Shape Conversion of Anisotropic Silver Nanoparticles and Probe Their Formation Mechanisms.

Anisotropic nanoparticles can be synthesized under kinetic control but may undergo subsequent shape changes due to atomic reorganization. Furthermore, their synthesis involves rapid steps, which are challenging to monitor in situ. Here, we show how a nanoemulsion of alkanethiols with an ethoxylated surfactant, easily prepared and metastable for months, can simultaneously prevent shape reorganization and arrest reaction kinetics. We illustrate this generic method on the silver nanoplates synthesized in concentrated acetic acid aqueous solutions, in which rapid shape reorganization occurs. We show that there exists an optimum thiol concentration corresponding to full coverage of all silver surface atoms, which can be simply calculated from particle dimensions. Furthermore, we demonstrate that arresting nanoparticle formation can be achieved within milliseconds using a tandem rapid mixers scheme in a continuous flow setup, allowing ex situ monitoring of the reaction.

Scalable Atroposelective Synthesis of MRTX1719: An Inhibitor of the PRMT5/MTA Complex

MRTX1719 was identified as a potent inhibitor of the PRMT5/MTA complex, designed to selectively target MTAP-deleted cancers. A scalable synthesis of this atropisomeric compound and an efficient isolation of the desired isomer were required to support Phase 1 clinical trials, and this was established through further development of the racemic medicinal chemistry route. In the key step, the desired (M)-atropisomer of MRTX1719 was amplified from racemic API by combining crystallization (20 °C) and racemization (160 °C, 4 min). Concurrent execution of these, ostensibly incompatible, operations was enabled by a continuous flow setup (SPACE = Simultaneous Processing of Antagonistic Chemical Events) providing 98.4% e.e. of (M)-atropisomer in 75% yield from racemic API on 12 kg scale. Process development targeting earlier steps of the API synthesis led to several impactful revisions including desymmetrization of 4-chlorobenzamide to access the 6-substituted-4-(aminomethyl)phthalazin-1(2H)-one ring system, improved borylation conditions (Suzuki–Miyaura or photocatalytic), and demonstration of an economically viable route to the challenging pentasubstituted benzene from 1,4-difluorobenzene and cyclopropyl methyl ketone.

Surface-modified activated carbon for N-nitrosodimethylamine removal in the continuous flow biological activated carbon columns

The carcinogenic nitrogenous disinfection by-product, N-nitrosodimethylamine (NDMA), is challenging to adsorb due to its high polarity and solubility. Our previous research demonstrated that the adsorptive removal of NDMA can be improved using surface-modified activated carbon (AC800). The current study evaluated the efficacy of AC800 in removing NDMA in a continuous-flow column over 75 days, using both granular activated carbon (GAC) and biologically activated carbon (BAC) columns. The AC800 GAC column demonstrated extended breakthrough and exhaustion times of 10 days and 22 days, respectively, compared to the conventional GAC column at 4 days and 10.5 days. The surface modification effect persisted for 25 days before the removal trends became indistinguishable. The AC800 BAC column outperformed the conventional BAC column with a longer breakthrough time of 11.3 days compared to 7.4 days. BAC columns consistently showed greater NDMA removal, emphasizing the role of biodegradation in NDMA removal on carbon. The higher NDMA removal in the inoculated columns was attributed to increased microbial diversity and the dominance of six specific genera, Methylobacterium, Phyllobacterium, Curvibacter, Acidovorax, Variovorax, and Rhodoferax. This study provides new insights into using modified activated carbon as GAC and BAC media in a real-world continuous-flow setup.

Growth of Smart Microgels in a Flow Reactor Scrutinized by In-Line SAXS.

In this work, a continuous flow setup for in situ investigation of microgel growth with small-angle X-ray scattering (SAXS) is established. Poly(N-n-propylacrylamide) (PNNPAM) and poly(N-isopropylacrylamide) (PNIPAM) microgels are synthesized in H2O at different residence times inside a continuous flow reactor. The microgels are investigated by in situ SAXS and ex situ photon correlation spectroscopy. The size of the microgels was found to be reproducible in independent experiments with run times of up to 7 h. Already the scattering curves of the microgels with a time of residence of 15 min show a well-defined form factor. Further analysis of the scattering profiles confirms the spherical shape of the microgels. At a residence time of 2 min, the scattering intensity is significantly lower corresponding to a smaller particle size. The experimental conditions remain constant over time, which is crucial for long-time experiments. The PNNPAM system is found to be more suitable for the flow reactor experiment with in-line SAXS as it shows less polymer deposition in the tubing and forms particles with lower polydispersity. The presented reactor is characterized by a compact design and offers a plug-and-play setup close to the sample environment. This work paves the way for investigations of microgel growth at e.g. synchrotron X-ray beamlines.

From monomer to micelle: a facile approach to the multi-step synthesis of block copolymers via inline purification.

A one-pass continuous flow strategy to form block copolymer nanoaggregates directly from monomers is presented. A key development towards such a sophisticated continuous flow setup is a significant improvement in continuous flow dialysis. Often impurities or solvent residues from polymerizations must be removed before block extensions or nanoaggregate formation can be carried out, typically disrupting the workflow. Hence, inline purification systems are required for fully continuous operation and eventual high throughput operation. An inline dialysis purification system is developed and exemplified for amphiphilic block copolymer synthesis from thermal and photoiniferter reversible addition fragmentation chain transfer (RAFT) polymerization. The inline dialysis system is found to be significantly faster than conventional batch dialysis and the kinetics are found to be very predictable with a diffusion velocity coefficient of 4.1 × 10-4 s-1. This is at least 4-5 times faster than conventional dialysis. Moreover, the newly developed setup uses only 57 mL of solvent for purification per gram of polymer, again reducing the required amount by almost an order of magnitude compared to conventional methods. Methyl methacrylate (MMA) or butyl acrylate (BA) was polymerized in a traditional flow reactor as the first block via RAFT polymerization, followed by a 'dialysis loop', which contains a custom-built inline dialysis device. Clearance of residual monomers is monitored via in-line NMR. The purified reaction mixture can then be chain extended in a second reactor stage to obtain block copolymers using poly(ethylene glycol) methyl ether acrylate (PEGMEA) as the second monomer. In the last step, nano-objects are created, again from flow processes. The process is highly tuneable, showing for the chosen model system a variation in nanoaggregate size from 34 nm to 188 nm.

Selective oxidation of benzylic alcohols via synergistic bisphosphonium and cobalt catalysis.

A synergistic photocatalytic system using a bisphosphonium catalyst and a cobalt catalyst has been developed, enabling the selective oxidation of benzylic alcohols under oxidant-free and environmentally benign conditions. High efficiencies have been obtained for a variety of alcohol substrates, and exclusive selectivity for aldehyde products has been achieved across the board. Furthermore, this photocatalytic system proved to be efficient when performed under continuous-flow conditions, even using a simple and easily assembled continuous-flow setup.

In Situ Quench Reactions of Enantioenriched Secondary Alkyllithium Reagents in Batch and Continuous Flow Using an I/Li-Exchange.

We report a practical in situ quench (ISQ) procedure involving the generation of chiral secondary alkyllithiums from secondary alkyl iodides (including functionalized iodides bearing an ester or a nitrile) in the presence of various electrophiles such as aldehydes, ketones, Weinreb amides, isocyanates, sulfides, or boronates. This ISQ-reaction allowed the preparation of a broad range of optically enriched ketones, alcohols, amides, sulfides and boronic acid esters in typically 90-98 % ee. Remarkably, these reactions were performed at -78 °C or -40 °C in batch. A continuous flow set-up permitted reaction temperatures between -20 °C and 0 °C and allowed a scale-up up to a 40-fold without further optimization.