Oxidations of Allylic and Benzylic Alcohols under Inductively‐Heated Flow Conditions with Gold‐Doped Superparamagnetic Nanostructured Particles as Catalyst and Oxygen as Oxidant

A continuous flow protocol for the oxidation of allylic and benzylic alcohols to aldehydes and ketones, respectively, using oxygen gas or atmospheric air is reported. The key features of this work are gold nanoparticles that are attached to the surface of nanostructured core shell particles composed of an Fe₃O₄‐containing core and a silica shell. These nanostructured particles exert superparamagnetic properties and thus inductively heat up in an external oscillating electromagnetic field, conditions under which the gold catalyst is able to perform these oxidation reactions.

     

Enhanced Reaction Efficiency in Continuous Flow

Continuous flow reactors are enabling tools that can significantly benefit chemical reactions, especially those that are path length dependent (e.g., photochemical), mixing or transport dependent (e.g., gas-liquid), exothermic, or utilize hazardous or unstable intermediates. In this review, it is demonstrated how the nearly instantaneous mixing, exceptionally fast mass transfer, safe access to high temperatures and pressures, and high surface area to volume ratio can be leveraged to improve product yield, reaction rates and/or selectivity. By showcasing five synthetic methodologies examined by our group, it is hoped that the reader will gain an appreciation of the accessible and transformative nature of flow chemistry for improving existing transformations, enabling rapid optimization, and for developing new methodologies that depend on precise parameter controls.     

连续流光反应器中连续制备环丁烷四羧酸二酐

以顺丁烯二酸酐(MA)为原料,乙酸乙酯作溶剂,在连续流光反应器中紫外光照射下连续高效地制备了环丁烷四羧酸二酐(CBDA)。考察了溶液在管路中的停留时间、管路尺寸、反应温度、反应物浓度等对产品收率及单位时间产品产量的影响,对比了连续流光反应器和间歇光反应器对产品收率的影响。实验结果表明,停留时间长、管路内径小、浓度低的反应物溶液对提高产品的收率有利。当停留时间为80 min、管路内径为2.00 mm、反应温度为5℃、反应物质量浓度为0.15g/m L时,产品的收率为51.57%,单位时间产量4.64g/h。与间歇光反应器工艺相比,连续流光反应器具有光子利用率高、光传播过程光子损失量小、光量子通量密度高、照射面积更加充足均匀、比表面积较大、混合效率高、传热快等优点,产品的收率可提高33%以上。     

微管连续流快速合成13个查耳酮

使用壁厚为1~1.5μm,断面内径为0.5~1.5 mm的玻璃毛细管,制作了简易微管连续流反应器。利用该连续流反应器合成了13个查耳酮,并应用IR和1HNMR谱对所合成的化合物进行了结构表征。结果表明,在40kHz的超声波作用下,反应温度26~38℃,使用该反应器合成查耳酮的产率可高达80%~90%,与传统的烧瓶反应相比,反应时间由原来的1~6 h缩短到10 min左右。该法反应产率高、反应时间短,可以连续、大规模合成查耳酮。     

A Palladium Wall Coated Microcapillary Reactor for Use in Continuous Flow Transfer Hydrogenation

Herein we describe the preparation of a novel continuous flow multi‐channel microreactor in which the internal surface has been functionalised with a palladium coating, enabling its use in catalytic heterogeneous liquid‐phase reactions. Simple chemical deposition techniques were used to immobilise palladium(0) on the channel wall surface of a polymeric multi‐capillary extrudate made from ethylene‐vinyl alcohol copolymer. The Pd coating of the microcapillaries has been characterised by mass spectrometry and light and electron microscopy. The functional activity of the catalytic Pd layer was tested in a series of transfer hydrogenation reactions using triethylsilane as the hydrogen source.     

Toward a Continuous‐Flow Synthesis of Boscalid®

A two‐step continuous‐flow protocol for the synthesis of 2‐amino‐4′‐chlorobiphenyl, a key intermediate for the industrial preparation of the fungicide Boscalid^® is described. Initial tetrakis(triphenylphosphine)palladium‐catalyzed high‐temperature Suzuki–Miyaura cross‐coupling of 1‐chloro‐2‐nitrobenzene with 4‐chlorophenylboronic acid in a microtubular flow reactor at 160 °C using the tert‐butanol/water/potassium tert‐butoxide solvent/base system provides 4′‐chloro‐2‐nitrobiphenyl in high yield. After in‐line scavenging of palladium metal with the aid of a thiourea‐based resin, subsequent heterogeneous catalytic hydrogenation is performed over platinum‐on‐charcoal in a dedicated continuous‐flow hydrogenation device. The overall two‐step homogeneous/heterogeneous catalytic process can be performed in a single operation providing the desired 2‐amino‐4′‐chlorobiphenyl in good overall yield and high selectivity.     

Continuous Synthesis of Organozinc Halides Coupled to Negishi Reactions

The Negishi cross‐coupling is a powerful C C bond forming reaction. The method is less commonly used relative to other cross‐coupling methods in part due to lack of availability of organozinc species. While organozinc species can be prepared, problems with reproducibility and handling of these sensitive species can complicate these reactions. Herein, we describe the continuous formation, using an activated packed‐bed of metallic zinc, and subsequent use of organozinc halides. We demonstrate that a single column of zinc can provide excellent yields of organozinc halides and that they can be used downstream in subsequent Negishi cross‐couplings. The preparation of the zinc column and the scope of the reaction are discussed.

     

Continuous Multistep Encapsulation Process for the Generation of Multiple Emulsions

Multiple emulsions (ME) are of interest as carrier of active ingredients that can be released in a controlled way. ME are thermodynamically unstable with a strong tendency to coalesce or flocculate, resulting in a complex emulsion generation and stabilization process. Typical encapsulation procedures utilize individual batch operation steps for the ME production. In this work, a multistep membrane encapsulation process is proposed to allow the generation of ME in a continuous shear‐sensitive processing through different membrane stages. The stages combine the premix generation, followed by the internal phase production, and the final ME encapsulation step. For each step, a tailored membrane with different surface properties is used and combined into the continuous process.     

Electrosynthesis of Aryliminophosphoranes in Continuous Flow

A practical electrochemical method for synthesizing aryliminophosphoranes from widely available nitro(hetero)arenes in a continuous-flow system is presented. The utilization of flow technology offers several advantages to our approach, including the elimination of the need for a supporting electrolyte and enhanced scalability. Our method demonstrates good tolerance towards various functional groups, with electron-deficient nitroarenes being particularly suitable for this strategy. In addition, we have demonstrated the versatility of aryliminophosphoranes as intermediates in synthesizing anilines, amines, and amides. To further enhance the utility of our approach, we have developed a telescoped method that utilizes a tube-in-tube setup for the in-situ production of isocyanates.     

Synthesis of 3‐Arylated 3,4‐Dihydrocoumarins: Combining Continuous Flow Hydrogenation with Laccase‐Catalysed Oxidation

A convenient arylation of diverse 3,4‐dihydrocoumarins with a number of catechols is described leading to a new class of compounds. As key step, a laccase‐catalysed oxidation/Michael addition sequence is applied using commercially available laccase from Agaricus bisporus. 3,4‐Dihydrocoumarins were obtained in a rapid and facile two‐step sequence starting from salicylaldehydes: The corresponding coumarins were synthesised through a Knoevenagel condensation in up to 83% yield followed by a quantitative reduction performed in a flow system. Combining the reductive flow reaction with the laccase‐catalysed arylation also led to successful consecutive one‐pot approaches. Overall, the enzyme‐catalysed arylations were carried out with yields ranging from 63 to 94%.

     

加热炉支路平衡控制中流量控制回路的取舍分析

由于加热炉支路平衡控制是一个带约束的多变量强耦合的控制问题,具有非线性、大滞后及强干扰等的特点,多偏差法的多层串级控制结构会增加系统的复杂性和不确定性。针对上述问题提出了一种改进的多偏差控制方案,通过舍去流量控制回路,避免了回路过多造成的系统稳定性变差的问题,简化了控制结构,改善了控制性能。     

Flow Biocatalysis: A Challenging Alternative for the Synthesis of APIs and Natural Compounds

Biocatalysts represent an efficient, highly selective and greener alternative to metal catalysts in both industry and academia. In the last two decades, the interest in biocatalytic transformations has increased due to an urgent need for more sustainable industrial processes that comply with the principles of green chemistry. Thanks to the recent advances in biotechnologies, protein engineering and the Nobel prize awarded concept of direct enzymatic evolution, the synthetic enzymatic toolbox has expanded significantly. In particular, the implementation of biocatalysts in continuous flow systems has attracted much attention, especially from industry. The advantages of flow chemistry enable biosynthesis to overcome well-known limitations of “classic” enzymatic catalysis, such as time-consuming work-ups and enzyme inhibition, as well as difficult scale-up and process intensifications. Moreover, continuous flow biocatalysis provides access to practical, economical and more sustainable synthetic pathways, an important aspect for the future of pharmaceutical companies if they want to compete in the market while complying with European Medicines Agency (EMA), Food and Drug Administration (FDA) and green chemistry requirements. This review focuses on the most recent advances in the use of flow biocatalysis for the synthesis of active pharmaceutical ingredients (APIs), pharmaceuticals and natural products, and the advantages and limitations are discussed.     

Synthesis of Hyperbranched Polyglycerol in a Continuous Flow Microreactor

Hyperbranched polymers have been synthesized in a microreactor for the first time, employing the known ring‐opening multibranching polymerization of glycidol. Microreactors are well‐known to be beneficial for highly exothermic reactions because of their capability to enhance mass and heat transfer due to short diffusion pathways and large interfacial areas per volume. The characteristics of the microstructured reaction system were utilized to engineer a continuous flow process for the preparation of well‐defined hyperbranched polyglycerols with molecular weights up to 1,000 g/mol. Increased flow rates, as well as the use of highly polar solvents, led to the partial formation of very narrowly distributed (M_w/M_n = 1.05–1.15) high molecular weight fractions (M_n up to 150,000 g/mol). NMR‐ and MALDI‐ToF spectra confirmed incorporation of the multifunctional initiator core into the hyperbranched polymer structure.     

连续流动注射分析仪测定水体中的阴离子表面活性剂

采用Flow Solution Ⅳ连续流动注射分析仪测定水体中的阴离子表面活性剂,该方法可以快速、自动萃取和测量,水样经亚甲蓝显色、氯仿萃取和膜分离,在640 nm处测量。测量范围：0.03-5.00 mg/L,检出限为0.01 mg/L;不仅节省人力、物力,还能大大减小三氯甲烷对人体的的伤害。     

Continuous Flow Fabrication of Block Copolymer–Grafted Silica Micro‐Particles in Environmentally Friendly Water/Ethanol Media

Polymer‐grafted inorganic particles (PGIPs) are attractive building blocks for numerous chemical and material applications. Surface‐initiated controlled radical polymerization (SI‐CRP) is the most feasible method to fabricate PGIPs. However, a conventional in‐batch reaction still suffers from several disadvantages, including time‐consuming purification processes, low grafting efficiency, and possible gelation problems. Herein, a facile method is demonstrated to synthesize block copolymer–grafted inorganic particles, that is, poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMEMA)‐b‐poly(N‐isopropylacrylamide) (PNIPAM)–grafted silica micro‐particles using continuous flow chemistry in an environmentally friendly aqueous media. Immobilizing the chain transfer agent and subsequent SI‐CRP can be accomplished sequentially in a continuous flow system, avoiding multi‐step purification processes in between. The chain length (MW) of the grafted polymers is tunable by adjusting the flow time or monomer concentration, and the narrower molar mass dispersity (Р< 1.4) of the grafted polymers reveals the uniform polymer chains on the particles. Moreover, compared with the in‐batch reaction at the same condition, the continuous system also suppresses possible gelation problems.     

双氧水氧化乙二醛合成乙醛酸的连续流工艺

以乙二醛和双氧水为原料,在微通道反应器中考察了液相氧化合成乙醛酸的连续流工艺。考察了物料比、催化剂用量、双氧水浓度、停留时间、温度等对反应的影响。确定该法最佳工艺条件为,n(乙二醛)∶n(H_2O_2)∶n(FeSO_4)=1.0∶1.0∶0.13,双氧水浓度1.67 mol/L,停留时间10 min,反应温度30℃。在该条件下,乙二醛转化率达到94.7%,乙醛酸选择性达到85.4%。该工艺充分利用微通道反应器优良的传质传热特点,大大缩短了反应时间,提高了反应速率,扩大了工艺条件选择区间,实现了对氧化反应过程的有效控制,增加了安全系数。     

丙酮液相氨肟化连续流反应

在液相条件下,以丙酮、氨水和双氧水为原料,钛硅分子筛（TS-1）为催化剂,叔丁醇为溶剂,在具有特殊微结构的连续流微通道反应器中一步氧化合成丙酮肟。实验考察了双氧水浓度、氨水用量、双氧水用量、溶剂用量、助催化剂用量以及温度对氨肟化的影响,结果表明：AFR微通道反应器中,反应器出口压力5 bar,温度100 ℃,催化剂浓度8 g/mol（mol为丙酮的单位）,氨水/双氧水/叔丁醇/丙酮摩尔比=3:1.1:6:1,双氧水浓度70 wt.%,氨水浓度25 wt.%,助催化剂浓度3 mg/mol（mol为丙酮的单位）,停留时间72 s,获得丙酮转化率为80%,丙酮肟选择性为97%,丙酮肟的收率为77%。AFR微通道反应系统持液量小、停留时间短、强传质传热等特点,强化了反应物料和催化体系之间的协同效应,提高了氨肟化反应速率,解决了双氧水分解带来的氨肟化反应本质安全问题,实现了丙酮氨肟化的绿色安全高效合成。     

丙酮液相氨肟化连续流反应

液相条件下,以丙酮、氨水和双氧水为原料,钛硅分子筛(TS-1)为催化剂,溴化钠为助催化剂,叔丁醇为溶剂,在具有特殊微结构的连续流微通道反应器(AFR)中一步氧化合成了丙酮肟.考察了双氧水质量分数、氨水/丙酮物质的量比、双氧水/丙酮物质的量比、溶剂/丙酮物质的量比、催化剂和助催化剂用量、温度以及停留时间对氨肟化的影响.结...     

连续流动分析仪测定水中氰化物影响因素的研究

采用AA3连续流动分析仪分光光度法对环境水中的氰化物进行了测定,且对测定水体中氰化物实验的影响因素进行了研究。实验结果表明,蒸馏温度,实验试剂的配制对实验均有较大的影响,蒸馏温度应选在155℃,吡啶巴比妥酸的配制应注意溶解温度和放置时间的影响。