Scale-up Synthesis Research Articles

Highly Diastereoselective [3 + 2] Cycloaddition of Aziridines with Difluorinated Silyl Enol Ethers: Divergent Synthesis of 4,4-Difluoropyrrolidines and 4-Fluoropyrroles.

A highly diastereoselective [3 + 2] cycloaddition of aziridines with difluorinated silyl enol ethers has been developed. This approach provides a facile methodology for highly functionalized gem-difluorinated pyrrolidines in good to excellent yields with good functional group tolerance. A one-pot, two-step approach for synthesis of structurally interesting fluorinated pyrroles has also been developed through a cycloaddition/aromatization/desulfonation sequence. Moreover, readily available substrates, mild reaction conditions, and easy scale-up synthesis show practical advantages.

Synergistic regulation of charge state and electron-donating ability via heterojunctions design for fixation of electronegative greenhouse F-gases

The net-zero greenhouse gas emission has now become a global strategy. In this context, electronegative fluorinated-gases such as sulfur hexafluoride (SF6) and hydrofluorocarbon, have become important emission reduction objects due to their strong global warming potential. In this work, the MnOx@Mn/SiC heterojunction was rationally designed and prepared. Because of the high electron coupling, the positively charged active-site MnOx@Mn (δ+) not only promotes the adsorption of SF6 but also acts as a donor to transport electrons to SF6, so that the adsorption and activation of SF6 are unified in one active site. Therefore, MnOx@Mn/SiC can effectively degrade SF6 above 450°C, and the degradation amount for 12 vol% SF6 can reach 523.8 mL g−1 at 600°C. Furthermore, it also has good degradation performance on hydrofluorocarbons (R-22 and R-410A) even at 100°C. Given the cheap and easy scale-up synthesis, MnOx@Mn/SiC has the potential to reduce the emission of multiple fluorinated-gases in practical applications.

Iron single-atom anchored N-doped carbon: an efficient catalyst for one-pot, scaled-up pentazolate synthesis

An efficient and recyclable iron single-atom catalyst with FeN4 sites has been fabricated, which can facilitate the formation of an Fe(iv)O intermediate and achieve scaled-up pentazolate synthesis via a three-step, one-pot process.

Mechanochemistry enabling highly efficient Birch reduction using sodium lumps and d-(+)-glucose.

In this study, a mechanochemical protocol for highly efficient and ammonia-free sodium-based Birch reduction was developed, leveraging the use of cheap and easy-to-handle sodium lumps. The key to achieving this transformation is the use of d-(+)-glucose as a proton source, which solidifies the reaction mixture in bulk state, enhancing the efficiency of the in situ mechanical activation of sodium lumps through the ball-milling process. Under the developed conditions, a diverse array of aromatic and heteroaromatic compounds were selectively reduced to produce the corresponding 1,4-cyclohexadiene derivatives in high yields within 30 min. Notably, all synthetic operations can be carried out without inert gases or the need for dry or bulk organic solvents. Furthermore, a scaled-up synthesis can be conducted without any yield losses. These results suggest that the present mechanochemical approach offers a more convenient, economically attractive, and sustainable alternative to previously established Birch reduction protocols.

Rh(III)-catalyzed C(sp2)-H functionalization/[4+2] annulation of oxadiazolones with iodonium ylides to access diverse fused-isoquinolines and fused-pyridines.

In this study, a Rh(III)-catalyzed C-H/N-H [4+2] annulation of oxadiazolones with iodonium ylides has been developed, which afforded a series of diverse fused-isoquinolines and fused-pyridines in moderate to high yields. These divergent synthesis protocols featured mild conditions, broad substrate scope, and functional-group compatibility. In addition, scale-up synthesis, related applications and preliminary mechanistic explorations were also accomplished.

Kinetic resolution of 1-(1-alkynyl)cyclopropyl ketones via gold-catalyzed divergent (4 + 4) cycloadditions: stereoselective access to furan fused eight-membered heterocycles.

Chiral eight-membered heterocycles comprise a diverse array of natural products and bioactive compounds, yet accessing them poses significant challenges. Here we report a gold-catalyzed stereoselective (4 + 4) cycloaddition as a reliable and divergent strategy, enabling readily accessible precursors (anthranils and ortho-quinone methides) to be intercepted by in situ generated gold-furyl 1,4-dipoles, delivering previously inaccessible chiral furan/pyrrole-containing eight-membered heterocycles with good results (56 examples, all >20 : 1 dr, up to 99% ee). Moreover, we achieve a remarkably efficient kinetic resolution (KR) process (s factor up to 747). The scale-up synthesis and diversified transformations of cycloadducts highlight the synthetic potential of this protocol. Computational calculations provide an in-depth understanding of the stereoselective cycloaddition process.

Direct C-H difluoroallylation of α,β-unsaturated amides and aryl amides by rhodium catalysis.

Herein, we report the first example of Rh-catalyzed C(sp2)-H difluoroallylation of α,β-unsaturated amides with 3-bromo-3,3-difluoropropene under mild conditions. The features of this protocol for difluoroallylation are unprecedented vinylic substrates, ethanol as a green solvent, good functional group and air compatibility, and scale-up synthesis with low catalyst loading.

Rh(III)-catalyzed oxidative [4+2] annulation of 2-arylquinoxalines and 2-aryl-2H-indazoles with allyl alcohols.

Synthesis of functionalized benzo[a]phenazines and indazolo[2,3-a]quinolines has been developed through Rh(III)-catalyzed oxidative annulation of 2-arylquinoxalines and 2-aryl-2H-indazoles with allyl alcohols, respectively. The method features a broad substrate scope, excellent functional group tolerance, good to high yields of annulated products, and scaled-up synthesis capability. Based on a preliminary mechanistic investigation, a tentative mechanism of annulation reaction has been proposed.

Recent advances and applications in high-throughput continuous flow.

High-throughput continuous flow technology has emerged as a revolutionary approach in chemical synthesis, offering accelerated experimentation and improved efficiency. With the aid of process analytical technology and automation, this system not only enables rapid optimisation of reaction conditions at the millimole to the picomole scale, but also facilitates automated scale-up synthesis. It can even achieve the self-planning and self-synthesis of small drug molecules with artificial intelligence incorporated in the system. The versatility of the system is highlighted by its compatibility with both electrochemistry and photochemistry, and its significant applications in organic synthesis and drug discovery. This highlight summarises its recent developments and applications, emphasising its significant impact on advancing research across multiple disciplines.

A review of the synthetic strategies toward the antiviral drug tecovirimat.

This review provides a comprehensive analysis of synthetic routes for tecovirimat, an antiviral drug used to treat orthopoxvirus infections, including monkeypox and smallpox. We focus on the scale-up synthesis of key intermediates, including cycloheptatriene, as documented in the published literature and patent records. The review highlights the efficiency, yield, and purity of these approaches, as well as the minimization of genotoxic and in-process impurities. Furthermore, we critically evaluate the recently reported optimized industrial-scale synthesis process, highlighting its advantages and limitations, and identifying avenues for further improvement. By obtaining insights from the published literature and patent records, this review elucidates the current state of knowledge regarding key synthesis parameters influencing tecovirimat production and emphasizes the critical importance of optimizing synthesis techniques to achieve remarkable improvements in safety and environmental impact. This review serves as a valuable resource for researchers and industry professionals in the field of R&D and production of APIs, particularly in expediting the safe and efficient industrial production of tecovirimat.

N-Benzylhydroxylamine as a novel synthetic block in "C1N1" embedding reaction via α-C(sp3)-H activation strategy.

A novel process using N-benzylhydroxylamine hydrochloride as a "C1N1 synthon" in [2+2+1] cyclization for the construction of 1,2,5-trisubstituted imidazoles has been described for the first time. The key to realizing this process lies in capturing arylamines by in situ generated novel acyl ketonitrone intermediates. Subsequent tautomerization activates the α-C(sp3)-H of N-benzylhydroxylamines, and thus breaks through its inherent reaction mode and achieves N, α-C site-selective cyclization. Furthermore, this method enables scale-up synthesis and late-stage modification of complex molecules.

Aryl ether-free polymer electrolytes for electrochemical and energy devices.

Anion exchange polymers (AEPs) play a crucial role in green hydrogen production through anion exchange membrane water electrolysis. The chemical stability of AEPs is paramount for stable system operation in electrolysers and other electrochemical devices. Given the instability of aryl ether-containing AEPs under high pH conditions, recent research has focused on quaternized aryl ether-free variants. The primary goal of this review is to provide a greater depth of knowledge on the synthesis of aryl ether-free AEPs targeted for electrochemical devices. Synthetic pathways that yield polyaromatic AEPs include acid-catalysed polyhydroxyalkylation, metal-promoted coupling reactions, ionene synthesis via nucleophilic substitution, alkylation of polybenzimidazole, and Diels-Alder polymerization. Polyolefinic AEPs are prepared through addition polymerization, ring-opening metathesis, radiation grafting reactions, and anionic polymerization. Discussions cover structure-property-performance relationships of AEPs in fuel cells, redox flow batteries, and water and CO2 electrolysers, along with the current status of scale-up synthesis and commercialization.

Sustainable, Upscaled Synthesis of Pinene-Derived (Meth)acrylates and their Application as High Tg Monomers in Styrene/Acrylic-Based Bioderived Copolymer Coatings

The improved synthesis of the pinene-derived monomers (3-pinanyl acrylate 1 and 3-pinanyl methacrylate 2), replacing hazardous and/or expensive reagents from established methods with cheaper, more innocuous and sustainable reagents is...

Rapid removal of decabromodiphenyl ether by mechanochemically prepared submicron zero-valent iron with FeC2O4·2 H2O layers: Kinetics, mechanisms and pathways

The utilization of nano zero-valent iron (nZVI) in polybrominated diphenyl ethers remediation has been studied extensively. However, challenges in balancing cost and reactivity have been encountered. A submicron zero-valent iron coated with FeC2O4·2 H2O layers (OX-smZVI) was synthesized via a mechanochemical method, aiming to resolve this contradiction. Characterization via SEM, TEM, and XPS confirmed the structure as FeC2O4·2 H2O coated iron lamellate with a surface area 24-fold higher than ball-milled zero-valent iron (smZVI). XRD highlighted an Fe/C eutectic in OX-smZVI, boosting its electron transfer capacity. Decabromodiphenyl ether degradation by OX-smZVI follows a two-stage process, with initial degradation by FeC2O4·2 H2O and a subsequent phase dominated by electron transfer. OX-smZVI exhibits a 4.52–34.40 times faster BDE209 removal rate than nZVI and scaled-up OX-smZVI displayed superior reactivity with preparation costs only 1/680 of nZVI. Given its enhanced reactivity and cost-efficiency, OX-smZVI emerges as a promising replacement for nZVI.

Mechanism study and preparing (hetero)arylidene malononitriles through a greener and scalable catalytic strategy

One of the important concerns in the field of catalysis is to find a reliable route to reduce the transition energies to reach the corresponding product. The mechanism of Knoevenagel condensation of 2-chlorobenzaldehyde and malononitrile in the presence of imidazole, an organocatalyst, is investigated through control experiments. In this study, the interactions and intermediates in synthesizing 2-chlorobenzylidenemahmonitrile (CS) are studied by FTIR and NMR analyses. First, a screen activity of seven nitrogen-based organocatalysts for preparing 2-chlorobenzylidenemahmonitrile (CS) was conducted in ethanol, an eco-friendly medium. The conversion of 100 % and excellent yields were obtained in a short reaction time. The products could be crystallized directly from the reaction solution. After separating pure products, the residue solution was employed directly in the next run without any concentration, activation, purification, or separation. Then, the generality and substrate scope of the new strategy were investigated in the presence of imidazole as a selected nitrogen-based organocatalyst. In addition, the scale-up synthesis of 2-chlorobenzylidenemahmonitrile (CS) was carried out, afforded crystalline products with 95 ± 2 % yield in five consecutive runs. Energy efficiency, cost saving, greener conditions, the use of catalytic loading organocatalyst and its high recyclability, prevention of waste, and recycling extractant by a rotary evaporator for non-crystallized products, demonstrate the newly developed metal-free and halogen-free catalytic methodology as a more sustainable process for the synthesis of (hetero-)arylidene malononitriles in the laboratory and industrial scale.

Scaled-up Synthesis and Characterization of Oxytocin Trisulfide

Scaled-up Synthesis and Characterization of Oxytocin Trisulfide

Enhancing the Hydrogen-Air Fuel Cell Performance of Octahedral Ptni Nanoalloys with Rational Design of Dopants, Layering and Support in the PEM Fuel Cells

This study focuses on the scale-up synthesis of carbon-supported octahedral PtNiX nanoparticles to improve their oxygen reduction reaction electrocatalytic activity, stability, and high current density for fuel cell applications. Octahedral PtNiX nanoparticles doped with different elements such as Rh or Ir and with high Pt loading on carbon supports were synthesized, characterized by physio-chemical methods and tested in single MEA-based fuel cells after rotating disk electrode (RDE) pre-screening measurements. Different carbon supports were compared, including N-doped carbon. We investigated the sensitivity of the I/C ratio for the ink on the performance of the nanoparticles in RDE, and show that it is an important parameter to consider during synthesis. Our study shows that the sensitivity of the I/C ratio is more pronounced for PtNi alloy octahedra than for pure Pt catalyst. Moreover, we also use in-situ measurement techniques, such as X-ray Absorption Spectroscopy (XAS) in a liquid cell, to study the impact of the dopants during the operation. In the MEA, we achieve a state-of-the-art current density of around 1500 mA/cm2 at 0.6V for octahedral PtNiX nanoparticles in fuel cell applications. This high current density is attributed to the superior electrocatalytic activity and stability of the doped nanoparticles, as well as their high loading of Pt. Overall, our results demonstrate the potential of octahedral PtNiX nanoparticles as highly efficient electrocatalysts for fuel cell applications. The study highlights the importance of considering the I/C ratio during catalyst ink preparation, and the use of in-situ measurement techniques to improve the fundamental understanding of catalyst structure-activity and -stability for the design of future electrocatalysts.

Upscale Synthesis of Magnetic Mesoporous Silica Nanoparticles and Application to Metal Ion Separation: Nanosafety Evaluation.

The synthesis of core-shell magnetic mesoporous nanoparticles (MMSNs) through a phase transfer process is usually performed at the 100-250 mg scale. At the gram scale, nanoparticles without cores or with multicore systems are observed. Iron oxide core nanoparticles (IO) were synthesized through a thermal decomposition procedure of α-FeO(OH) in oleic acid. A phase transfer from chloroform to water was then performed in order to wrap the IO nanoparticles with a mesoporous silica shell through the sol-gel procedure. MMSNs were then functionalized with DTPA (diethylenetriaminepentacetic acid) and used for the separation of metal ions. Their toxicity was evaluated. The phase transfer procedure was crucial to obtaining MMSNs on a large scale. Three synthesis parameters were rigorously controlled: temperature, time and glassware. The homogeneous dispersion of MMSNs on the gram scale was successfully obtained. After functionalization with DTPA, the MMSN-DTPAs were shown to have a strong affinity for Ni ions. Furthermore, toxicity was evaluated in cells, zebrafish and seahorse cell metabolic assays, and the nanoparticles were found to be nontoxic. We developed a method of preparing MMSNs at the gram scale. After functionalization with DTPA, the nanoparticles were efficient in metal ion removal and separation; furthermore, no toxicity was noticed up to 125 µg mL-1 in zebrafish.

Rapid Postgrafting Reaction to Prepare Quaternized Polycarbazoles.

We report a rapid postgrafting reaction to prepare alkyl ammonium functionalized polycarbazoles from a commercially available monomer. This novel synthetic approach provides benefit to preparing the high molecular weight quaternized polycarbazoles within 1 h of Friedel-Crafts polycondensation, avoiding the synthesis and purification step to prepare a functionalized monomer. The postgrafting reaction produces hexyl alkyl ammonium functionalized polycarbazole with 100% grafting degree. However, the postgrafting reaction produced only 60% grafting with propyl alkyl ammonium due to the competitive elimination reaction because of the higher acidity of β-hydrogen in the propyl alkyl group resulting from the proximity of the bromide and ammonium groups. The hexyl alkyl ammonium functionalized polycarbazole has a high hydroxide conductivity of 103 mS cm-1 at 80 °C and showed excellent alkaline stability with less than 3% loss of ion group after 1 M NaOH treatment at 80 °C for 500 h. This study highlights that the postgrafting reaction provides a pathway for the scale-up synthesis of quaternized aryl ether-free polyaromatics.

Integrating Hybrid Perovskite Nanocrystals into Metal-Organic Framework as Efficient S-Scheme Heterojunction Photocatalyst for Synergistically Boosting Controlled Radical Photopolymerization under 980 nm NIR Light.

S-scheme heterojunction photocatalyst MAPbI3@PCN-222 with light absorption extending to the NIR region is constructed by embedding organic-inorganic hybrid perovskite (MAPbI3) into porphyrinic Zr-MOF (PCN-222). Both in situ X-ray photoelectron spectroscopy, ultraviolet photoelectron spectral characterization, and photocatalytic polymerization experiment prove the formation of S-scheme heterojunction. MAPbI3@PCN-222 with a low dosage (90 ppm) displays an impressive photocatalytic ability for 980 nm light-mediated photoinduced electron/energy-transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization in air. The well-defined controllable-molecular weight polymers including block copolymers and ultrahigh-molecular weight polymers can be achieved with narrow distributions (Mw/Mn < 1.20) via rapid photopolymerization. The industrial application potential of the photocatalyst also has been proved by scale-up synthesis of polymers with low polydispersity under NIR light-induced photopolymerization in a large-volume reaction system (200 mL) with high monomer conversion up to 99%. The penetration photopolymerization through the 5 mm polytetrafluoroethylene plate and excellent photocontrollable behavior illustrate the existence of long-term photogenerated electron transfer of heterojunction and abundant free radicals in photopolymerization. The photocatalyst still retains high catalytic activity after 10 cycles of photopolymerization in air. It is revealed for the first time that the special PET-RAFT polymerization pathway is initiated by the aldehyde-bearing α-aminoalkyl radical derived from the oxidization of triethanolamine (TEOA) by the heterojunction photocatalyst. This research offers a new insight into understanding the NIR-light-activated PET-RAFT polymerization mechanism in the presence of TEOA.