Solvent Dependence of Ionic Liquid-Based Pt Nanoparticle Synthesis: Machine Learning-Aided In-Line Monitoring in a Flow Reactor.

Colloidal platinum nanoparticles (Pt NPs) possess a myriad of technologically relevant applications. A potentially sustainable route to synthesize Pt NPs is via polyol reduction in ionic liquid (IL) solvents; however, the development of this synthetic method is limited by the fact that reaction kinetics have not been investigated. In-line analysis in a flow reactor is an appealing approach to obtain such kinetic data; unfortunately, the optical featurelessness of Pt NPs in the visible spectrum complicates the direct analysis of flow chemistry products via ultraviolet-visible (UV-vis) spectrophotometry. Here, we report a machine learning (ML)-based approach to analyze in-line UV-vis spectrophotometric data to determine Pt NP product concentrations. Using a benchtop flow reactor with ML-interpreted in-line analysis, we were able to investigate NP yield as a function of residence time for two IL solvents: 1-butyl-1-methylpyrrolidinium triflate (BMPYRR-OTf) and 1-butyl-2-methylpyridinium triflate (BMPY-OTf). While these solvents are structurally similar, the polyol reduction shows radically different yields of Pt NPs depending on which solvent is used. The approach presented here will help develop an understanding of how the subtle differences in the molecular structures of these solvents lead to distinct reaction behavior. The accuracy of the ML prediction was validated by particle size analysis and the error was found to be as low as 4%. This approach is generalizable and has the potential to provide information on various reaction outcomes stemming from solvent effects, for example, differential yields, orders of reaction, rate coefficients, NP sizes, etc.

Photo-reduction facilitated stachydrine oxidative N-demethylation reaction: A case study of Rieske non-heme iron oxygenase Stc2 from Sinorhizobium meliloti.

Rieske-type non-heme iron oxygenases (ROs) are an important family of non-heme iron enzymes. They catalyze a diverse range of transformations in secondary metabolite biosynthesis and xenobiotic bioremediation. ROs typically shuttle electrons from NAD(P)H to the oxygenase component via reductase component(s). This chapter describes our recent biochemical characterization of stachydrine demethylase Stc2 from Sinorhizobium meliloti. In this work, the eosin Y/sodium sulfite pair serves as the photoreduction system to replace the NAD(P)H-reductase system. We describe Stc2 protein purification and quality control details as well as a flow-chemistry to separate the photo-reduction half-reaction and the oxidation half-reaction. Our study demonstrates that the eosin Y/sodium sulfite photo-reduction pair is a NAD(P)H-reductase surrogate for Stc2-catalysis in a flow-chemistry setting. Experimental protocols used in this light-driven Stc2 catalysis are likely to be applicable as a photo-reduction system for other redox enzymes.

Optimization of Lipid-Based Nanoparticles Formulation Loaded with Biological Product Using A Novel Design Vortex Tube Reactor via Flow Chemistry.

Introduction: Lipid-based nanoparticles (LNPs) is increasingly recognized for their potential in drug delivery, offering protection to hydrophobic drugs from degradation. Industrial synthesis of LNPs, exemplified by Pfizer-BioNTech and Moderna mRNA vaccines, utilizes flow chemistry or microfluidics, showcasing its scalability. This study explores the utilization of a novel design reactor, the vortex tube reactor, within flow chemistry for LNPs synthesis, aiming to optimize its conditions and compare them with batch synthesis. Methods: LNPs were synthesized using the vortex tube reactor, incorporating bovine serum albumin (BSA) as a model drug in the aqueous phase, alongside 1.2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol in the organic phase. Design of experiments (DoE), specifically Box-Behnken design, was employed to optimize parameters, including X1: the flow rate ratio (10-100 mL/min), X2: the aqueous-to-organic volumetric ratio (1:1-10:1), and X3: the number of reactor units (1-5 units). Responses evaluated encompassed physical properties and productivity. Optimized conditions were determined by minimizing particle size (Y1), polydispersity index (Y2), and zeta potential (Y3), while maximizing entrapment efficiency (Y4), drug loading (Y5), and productivity (Y5). Results: Results indicated that optimal conditions were achieved at X1 of 100 mL/min, X2 of 5.278, and X3 of 1 unit. LNPs synthesized under these conditions exhibited favorable physical properties and productivity, with uniformity maintained across batches. The vortex tube reactor demonstrated superiority over batch synthesis, yielding smaller particles (166.23 ± 0.98 nm), more uniform nanoparticles (PDI 0.17 ± 0.01), and higher entrapment (67.75 ± 1.55%) and loading capacities (36.39 ± 0.83%), indicative of enhanced productivity (313.4 ± 12.88 mg/min). Conclusion: This study elucidates the potential of flow chemistry, particularly utilizing the vortex tube reactor, for large-scale LNPs formulation, offering insights into parameter relationships and advancing nanoparticle synthesis for drug delivery applications.

Cyclic Sulfoximines as Methyl and Perdeuteromethyl Transfer Agents and Their Applications in Photoredox Catalysis.

Benzo[1,3,2]dithiazole-1,1,3-trioxides are bench-stable and easy-to-use reagents. In photoredox catalysis, they generate methyl and perdeuteromethyl radicals which can add to a variety of radical acceptors, including olefins, acrylamides, quinoxalinones, isocyanides, enol silanes, and N-Ts acrylamide. As byproduct, a salt is formed which can be regenerated to the original methylating agent. Flow chemistry provides an option for reaction scale-up further underscoring the synthetic usefulness of these methylation reagents. Mechanistic investigations suggest a single-electron transfer (SET) pathway induced by photoredox catalysis.

Flow-Chemistry Based Green Synthesis of Graphene Oxide at Minutes Timescale.

Graphene oxide (GO) is broadly investigated in the electrochemical field. However, for industrial applications, it still suffer from high pollution, low efficiency, poor production quality, and safety concerns associated with traditional synthesis methods. Herein, guided by theoretical analyses, a new oxygen-atom-transfer (OAT) mechanism for periodate oxidizing graphite is revealed, exhibiting controllable reaction activity, strong orbital interaction, and abundant electron transfer. Moreover, a flow chemistry strategy with high mass/heat transfer rates is designed to enhance interlayer diffusion and reaction dynamics between oxidants and graphite, ensuring the efficient synthesis of GO within several minutes. As a result, both low oxygen-content GO with large size, and high oxygen-content GO with adequate active sites can be precisely and safely synthesized. Benefitting from the controllability of oxygen content and lateral size, the as-prepared GO sheets can be facilely assembled into fiber/film electrodes that present high mechanical flexibility, large electrical conductivity, and outstanding electrochemical performance.

Reproducible Green Syntheses Using Hybrid Sol-Gel Catalysts.

Referring to selected examples of reproducible green syntheses using hybrid sol-gel catalysts of the SiliaCat series from different doctoral theses and research works published between 2015 and early 2024, this study briefly illustrates how said catalysts have been applied in a number of green synthetic methods of significant industrial relevance. This shows evidence that the nanochemistry "bottom-up" sol-gel approach based on catalytic species entrapped in organically modified silicas as effective and versatile heterogeneous catalysts developed between the late 1990s and 2010 has succeeded. Subsequent developments will show how the use of said materials in automated syntheses, supplying data to machine learning algorithms actually leads to faster and cheaper optimization of the reaction conditions. Said progress ultimately will further accelerate industrial uptake of heterogeneous catalysis under flow in the fine chemical industry whose reluctance to change processes was due to the need to replace financially amortized (and expensive) production plants.

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

This work applied BM as support for immobilization of lipase TLL in packed-bed reactor and its application for the synthesis of hexyl laurate. Initially, the percolation of a solution containing 5 mg of TLL at 25 oC generated an immobilized derivative with hydrolytic activity of 504.7 U/g and 31.7% of recovered activity. Subsequent treatment with n-hexane, as well as the effect of temperature on the immobilization process were able to improve the activities of the final BM-TLLF, achieving a hydrolysis activity of 7023 U/g and esterification activity of 430 U/g against 142 U/g and 113.5 U/g respectively presented by commercial TLIM. 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 a residence time of 2 hours. Notably, BM-TLLF displayed exceptional recyclability, maintaining catalytic efficiency over 12 cycles. This reflects a productivity of 180 mg of product/h/U of the enzyme, surpassing 46 mg/h/U 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.

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications.

Amino acids are vital motifs in the domain of biochemistry, serving as the foundational unit for peptides and proteins, while also holding a crucial function in many biological processes. Due to their bifunctional character, they have been also used for combinatorial chemistry purposes, such as the preparation of DNA-encoded chemical libraries. We developed a practical synthesis for α-heteroaryl-α-amino acids starting from an array of small heteroaromatic halides. The reaction sequence utilizes a photochemically enhanced Negishi cross-coupling as a key step, followed by oximation and reduction. The prepared amino esters were validated for on-DNA reactivity via a reverse amidation-hydrolysis-reverse amidation protocol.

Nanogels: Recent Advances in Synthesis and Biomedical Applications.

In the context of advanced nanomaterials research, nanogels (NGs) have recently gained broad attention for their versatility and promising biomedical applications. To date, a significant number of NGs have been developed to meet the growing demands in various fields of biomedical research. Summarizing preparation methods, physicochemical and biological properties, and recent applications of NGs may be useful to help explore new directions for their development. This article presents a comprehensive overview of the latest NG synthesis methodologies, highlighting advances in formulation with different types of hydrophilic or amphiphilic polymers. It also underlines recent biomedical applications of NGs in drug delivery and imaging, with a short section dedicated to biosafety considerations of these innovative nanomaterials. In conclusion, this article summarizes recent innovations in NG synthesis and their numerous applications, highlighting their considerable potential in the biomedical field.

C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow.

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C-H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp2)-C(sp3) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate-determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate.

A flow photochemical reaction system for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence was developed, which utilizes in situ-generated 2-benzopyrylium intermediates as the photoredox catalyst and electrophilic substrates. The key 2-benzopyrylium intermediates were generated in the flow reaction system through the intramolecular cyclization of ortho-carbonyl alkynylbenzene derivatives by the π-Lewis acidic metal catalyst AgNTf2 and the subsequent proto-demetalation with trifluoroacetic acid. The 2-benzopyrylium intermediates underwent further photoreactions with benzyltrimethylsilane derivatives as the donor molecule in the flow photoreactor to provide 1H-isochromene derivatives in higher yields in most cases than the batch reaction system.

Dynamics of pH Oscillators in Continuous Stirred Tanks in Series.

Complex reaction networks with positive and negative feedback can produce diverse nonlinear phenomena in open reactors, such as multistability and oscillations. pH oscillators driven by hydrogen or hydroxide autocatalytic processes show sustained oscillations in continuously stirred tank reactors (CSTR) but only a sharp pH switch in batch. Here, we present a numerical study on the dynamics of pH oscillators in a series of CSTRs. We show a critical residence time under which bistability and above which oscillations develop. The dynamics of the CSTR cascade show the cross-shaped phase diagram of nonlinear activatory inhibitory systems. In the domain of oscillations, one reactor starts to oscillate autonomously and induces forced complex oscillations in the following tanks with damped amplitudes. These results, with their practical implications, may contribute to understanding the recent experimental observations of nonlinear phenomena in the presence of a residence time ramp and inspire further research in this area.

Synthesis of Cs3Cu2I5 Nanocrystals in a Continuous Flow System.

Achieving the goal of generating all of the world's energy via renewable sources and significantly reducing the energy usage will require the development of novel, abundant, nontoxic energy conversion materials. Here, a cost-efficient and scalable continuous flow synthesis of Cs3Cu2I5 nanocrystals is developed as a basis for the rapid advancement of novel nanomaterials. Ideal precursor solutions are obtained through a novel batch synthesis, whose product served as a benchmark for the subsequent flow synthesis. Realizing this setup enabled a reproducible fabrication of Cs3Cu2I5 nanocrystals. The effect of volumetric flow rate and temperature on the final product's morphology and optical properties are determined, obtaining 21% quantum yield with the optimal configuration. Consequently, the size and morphology of the nanocrystals can be tuned with far more precision and in a much broader range than previously achievable. The flow setup is readily applicable to other relevant nanomaterials. It should enable a rapid determination of a material's potential and subsequently optimize its desired properties for renewable energy generation or efficient optoelectronics.

Facile scalable one-flow synthesis of ionizable cationic lipid library as precursors of nanoparticle carriers.

A variety of ionizable and cationic lipids have been synthesized as precursors for nanoparticle carriers. However, the laborious synthetic routes in batch reactors often involve the use of toxic and carcinogenic agents, as well as challenge of removing gaseous byproducts. In this study, we present facile one-flow micro-reaction process that enables the synthesis of 11 ionizable lipids as well as 7 cationic lipids, including the well-known DODAP and DOTAP. These lipids can be scaled up to produce approximately ∼10g/h by using a straightforward size-up approach. The development of the lipid library was involved generating highly moisture-sensitive acyl chloride at 25 °C for 1.5 min. The toxic byproducts such as HCl, CO2 and CO were subsequently removed using a liquid-gas separator. The esterification with dimethylamino-1,2-diol at 25 °C for 3 min, monitored in-line with FTIR, completed the process. Additionally, the synthesized ionizable lipids were converted to cationic lipids with methyl sulfate, chloride ions via dimethyl sulfate and Steglich esterification in a continuous flow system. Finally, the produced DODAP was transformed into a uniform-sized LNPs (64 nm, PDI 0.07) and liposomal nanoparticles (72 nm, PDI 0.05) while DOTAP was converted to liposomes (55 nm, PDI 0.08) using a custom micro-mixer. This efficient platform for lipid synthesis significantly contributes to the practical applications of lipid-based nanomedicines.

Design, Synthesis, and Evaluation of Antifungal Activity of Pyrazoleacetamide Derivatives.

BACKGROUND: Fungal infections have posed a big challenge in the management of their treatment. Due to the resistance and toxicity of existing drug molecules in the light of pandemic infections, like COVID-19, there is an urgent need to find newer derivatives of active molecules, which can be effective in fungal infections. OBJECTIVE: In the present study, we aimed to design pyrazole derivatives using molecular modeling studies against target 1EA1 and synthesize 10 molecules of pyrazole derivatives using a multi-step synthesis approach. METHODS: Designed pyrazole derivatives were synthesized by conventional organic methods. The newly synthesized pyrazole molecules were characterized by using FT-IR, 1HNMR, 13CNMR, and LC-MS techniques. Molecular docking studies were also performed. The antifungal activity of newly synthesized compounds was assessed in vitro against Candida albicans and Aspergillus niger using the well plate method. RESULTS: Two of the compounds, OK-7 and OK-8, have been found to show significant docking interaction with target protein 1EA1. These two compounds have also been found to show significant anti-fungal activity against Candida albicans and Aspergillus nigra when compared to the standard fluconazole. The Minimum Inhibitory Concentration (MIC) value of these two compounds has been found to be 50 µg/ml. CONCLUSION: Pyrazole derivatives with -CH3, CH3O-, and -CN groups have been found to be active against tested fungi and can be further explored for their potential as promising anti-fungal agents for applications in the field of medicinal chemistry.

Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol.

This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new pharmaceutical for treatment of antibiotic-resistant Pseudomonas aeruginosa biofilm infections. The potentially hazardous diazotisation step in the lab-scale synthesis was transformed to a safe and easy-to-handle flow chemistry step. Additionally, the paper presents an OSHA-recommended safety assessment of active compound E, as performed by Fauske and Associates, LLC, Burr Ridge, IL, USA.

Recent advances in catalytic asymmetric synthesis.

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature's most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow.

Within the realm of organic synthesis, photocatalysis has blossomed since the beginning of the last decade. A plethora of classical reactivities, such as selective oxidation of alcohol and amines, redox radical formation of reactive species in situ, and indirect activation of an organic substrate for cycloaddition by EnT, have been revised in a milder and more sustainable fashion via photocatalysis. However, even though the spark of creativity leads scientists to explore new reactions and reactivities, the urgency of replacing the toxic and critical metals that are involved as catalysts has encouraged chemists to find alternatives in the branch of science called organocatalysis. Unfortunately, replacing metal catalysts with organic analogues can be too expensive sometimes; however, this drawback can be solved by the reutilization of the catalyst if it is heterogeneous. The aim of this review is to present the recent works in the field of heterogeneous photocatalysis, applied to organic synthesis, enabled by continuous flow. In detail, among the heterogeneous catalysts, g-CN, polymeric photoactive materials, and supported molecular catalysts have been discussed within their specific sections, rather than focusing on the types of reactions.

Microfluidic chemistry assisted synthesis of cobalt quantum dot embedded nitrogen doped carbon with oxidase-like properties toward ascorbic acid detection.

Ascorbic acid (AA) is a powerful antioxidant in food safety and disease treatment. It is of great significance to develop a low-cost, high-stability, and easy-to-operate colorimetric method for quantitative detection of AA in food or human body. Although various nanozymes have been developed for the colorimetric detection of AA, the size regulation of the catalytic center of nanozymes remains a challenge. In this work, we propose a combined strategy of flow chemistry synthesis and pyrolysis to realize the controllable adjustment of the catalytic center size of nanozymes. Zinc-cobalt zeolitic imidazole frameworks (ZnCo-ZIFs) with different sizes are synthesized by flow chemistry. Nitrogen-doped carbon materials with different Co catalytic centers (80 nm-10 nm) are then obtained by pyrolysis of ZnCo-ZIFs precursors. Among them, cobalt quantum dot embedded nitrogen-doped carbon (Co QDs/N-C) exhibits excellent oxidase activity, with Vmax and Km of 4.19 × 10-7 M s-1 and 0.12 mM. Therefore, a simple, low-cost, and stable colorimetric method for the detection of AA is established with a good linear relationship (3-500 µM) and low detection limit (0.40 µM). This work has certain guiding significance for the size regulation of catalytic center of nanozyme, and the detection method has broad application prospects in biochemical sensing field.

Flow-based bioconjugation of coumarin phosphatidylethanolamine probes: Optimised synthesis and membrane molecular dynamics studies.

A series of phosphatidylethanolamine fluorescent probes head-labelled with 3-carboxycoumarin was prepared by an improved bioconjugation approach through continuous flow synthesis. The established procedure, supported by a design of experiment (DoE) set-up, resulted in a significant reduction in the reaction time compared to the conventional batch method, in addition to a minor yield increase. The characterization of these probes was enhanced by an in-depth molecular dynamics (MD) study of the behaviour of a representative probe of this family, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine labelled with 3-carboxycoumarin (POPE-COUM), in bilayers of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (SLPC) 2:1, mimicking the composition of the egg yolk lecithin membranes recently used experimentally by our group to study POPE-COUM as a biomarker of the oxidation state and integrity of large unilamellar vesicles (LUVs). The MD simulations revealed that the coumarin group is oriented towards the bilayer interior, leading to a relatively internal location, in agreement with what is observed in the nitrobenzoxadiazole fluorophore of commercial head-labelled NBD-PE probes. This behaviour is consistent with the previously stated hypothesis that POPE-COUM is entirely located within the LUVs structure. Hence, the delay on the oxidation of the probe in the oxygen radical absorbance capacity (ORAC) assays performed is related with the inaccessibility of the probe until alteration of the LUV structure occurs. Furthermore, our simulations show that POPE-COUM exerts very little global and local perturbation on the host bilayer, as evaluated by key properties of the unlabelled lipids. Together, our findings establish PE-COUM as suitable fluorescent lipid analogue probes.