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An electrochemical procedure for the α-arylation of ketones has been developed. The method is based on the generation and one-pot anodic oxidation of silyl enol ethers in the presence of the arene. This strategy avoids isolation of the silyl enol intermediate and the utilization of external supporting electrolytes. Intermolecular arylations, which had not been reported so far, are possible when electron-rich arenes are utilized as coupling partners. The method has been demonstrated for a wide variety of aryl ketones and activated arenes, with moderate to good yields (up to 69%) obtained. Mechanistic insights and a theoretical rationale that explains the ketone α-arylation versus dimerization selectivity are also presented.

This study provides a comparative life cycle assessment (LCA) of four different polyurethane dispersion production processes from cradle-to-gate. The environmental performances of the NMP process, the acetone process, the melt process, and a conceptualized continuous flow process were evaluated and compared following the CML 2001 methodology. The LCA revealed that the conceptualized flow process exhibits the lowest environmental impact in all investigated impact categories. Depending on the impact category, the melt process or the acetone process rank second. The NMP process was observed to have the highest impact in all categories. Consequently, the flow process has the lowest carbon footprint (1.13 kg CO2-eq), according to the global warming potential (100 years), followed by the melt (1.45 kg CO2-eq), the acetone (1.95 kg CO2-eq) and the NMP process (3.11 kg CO2-eq).

Continuous flow processing presents a solution for the safe and effective formation of 1,5-tetrazoles due to the small reactive inventory and absence of a reactor headspace. This has been exemplifi...

The oxidation of aldehydes is one of the most prevalent methods for the synthesis of a diverse range of carboxylic acids. We herein present a performic acid generator and its application for aldehy...

The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β2-adrenoceptor agonist that has undergone phase IIa clinical t...

In a rapidly changing environment, such as the current COVID-19 pandemic, continuous flow reactors bear the potential to increase the production of urgently needed active pharmaceutical ingredients (APIs) on demand In the synthesis of remdesivir, the organometallic C-glycosylation step was identified as a limitation for the large-scale production, requiring long addition periods and cryogenic temperatures Previous studies have focused on a Grignard-based protocol, but a flash chemistry approach, using organolithium reagents, has facilitated significant improvements After gaining further understanding of the C-glycosylation, this step was successfully transferred to a five-stream continuous flow process, achieving 60% yield at a moderate temperature (−30 °C) in a total residence time of just 8 s Stable processing was demonstrated for 2 h, providing an exceptionally high space−time yield of 10 4 kg L−1 h−1, in a scalable flow reactor system © XXXX American Chemical Society

A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1-0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.

The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro...

The most challenging step in the preparation of many opioid antagonists is the selective N-demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the N-demethylation step based on the anodic oxidation of the tertiary amine. The ensuing intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.

Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attri...

Noroxymorphone is a pivotal intermediate in the synthesis of important opioid antagonists such as naloxone and naltrexone. The preparation of noroxymorphone from thebaine, a naturally occurring opioate isolated from poppy extract, is a multistep sequence in which oxycodone is first generated and then N- and O-demethylated. Both demethylations are problematic from the safety and sustainability viewpoint, as they involve harmful reagents such as alkyl chloroformates or boron tribromide. Herein, we present a green, safe an efficient telescoped process for the N- and O-demethylation of oxycodone. The method is based on the anodic oxidative intramolecular cyclization of the N-methyl tertiary amine with the 14-hydroxyl group of the morphinan, followed by hydrolysis with hydrobromic acid, which releases the carbon from both heteroatoms. The electrolysis process has been transferred to a scalable flow electrolysis cell, significantly improving the reaction throughput and increasing the space-time yield over 300-fold with respect to batch. The sustainability of the new methodology has been assessed by means of green metrics and qualitative indicators. The sustainability assessment has demonstrated that the new methodology is far superior to the conventional chloroformate process

A greener continuous flow procedure for the synthesis and purification of methyl oximino acetoacetate, a key intermediate for the generation of several heterocyclic scaffolds, has been established....

A safe and scalable continuous flow strategy for Wolff–Kishner reductions that employs methanol as the solvent has been developed. The use of low-cost hydrazine as the reducing agent in combination with a caustic base provides an atom-efficient, environmentally friendly method for the deoxygenation of aldehydes and ketones to alkanes. Because of the required harsh and corrosive reaction conditions (200 °C, 50 bar), reactor materials such as stainless steel, glass, or any type of polymer have compatibility problems, rendering this process problematic on a production scale. The use of corrosion-resistant silicon carbide (SiC) as the reactor material opens up the possibility of performing Wolff–Kishner reductions on scale with a considerably improved safety profile. Methanol as the solvent significantly simplifies the workup procedure compared with the generally employed high-boiling solvents such as diethylene glycol. The continuous flow protocol was applied to a number of substrates and provided the desire...

The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied f...

A continuous process for the on-demand generation, separation, and reaction of hydrogen cyanide (HCN) using membrane separation technology was developed. The inner tube of the reactor is manufactured from a gas-permeable, hydrophobic fluoropolymer (Teflon AF-2400) membrane. HCN is formed from aqueous reagents within the inner tube and then diffuses through the membrane into an outer tubing containing organic solvent. This technique enabled the safe handling of HCN for three different organic transformations without the need for distillation.

Catalytic static mixer (CSM) technology is presented as an industrially-viable solution for an aromatic nitro group reduction in the synthesis of fenebrutinib. Factors effecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR, UHPLC). This facilitated the development of stable and optimal conditions in a system with 4 CSMs positioned inside a thermostated shell-and-tube reactor. Additional care was taken to ensure the control of three key impurities to low levels (< 0.10 area% by offline UHPLC analysis). The optimal conditions (0.4 M concentration, 20 bar, 120 °C, 3.3 equiv H2) were then scaled up to a reactor with 8 CSMs, whereby an improvement in space-time yield was observed. Over 16 h of processing, a stable impurity profile was observed, without metal leaching. Finally, the reaction was performed in a system with 16 CSMs, which also provided an increase in space-time yield (to 26.2 mol/L/h or 6.5 kg/L/h), resulting in 174 g/h throughput, whilst maintaining an excellent impurity profile.

This study provides a comparative life cycle assessment (LCA) of four different polyurethane dispersion production processes from cradle-to-gate. The environmental performances of the NMP process, the acetone process, the melt process, and a conceptualized continuous flow process were evaluated and compared following the CML 2001 methodology. The LCA revealed that the conceptualized flow process exhibits the lowest environmental impact in all investigated impact categories. Depending on the impact category, the melt process or the acetone process rank second. The NMP process was observed to have the highest impact in all categories. Consequently, the flow process has the lowest carbon footprint (1.13 kg CO2-eq), according to the global warming potential (100 years), followed by the melt (1.45 kg CO2-eq), the acetone (1.95 kg CO2-eq) and the NMP process (3.11 kg CO2-eq).

Introduction of acetoxy groups to organic molecules is important for the preparation of many active ingredients and synthetic intermediates. A commonly used and attractive strategy is the oxidative decarboxylation of aliphatic carboxylic acids, which entails the generation of a new C(sp3)-O bond. This reaction has been traditionally carried out using excess amounts of harmful lead(IV) acetate. A sustainable alternative to stoichiometric oxidants is the Hofer-Moest reaction, which relies in the 2-electron anodic oxidation of the carboxylic acid. However, examples showing electrochemical acetoxylation of amino acids are scarce. Herein we present a general and scalable procedure for the anodic decarboxylative acetoxylation of amino acids in batch and continuous flow mode. The procedure has been applied to the derivatization of several natural and synthetic amino acids, including key intermediates for the synthesis of active pharmaceutical ingredients. Good to excellent yields were obtained in all cases. Transfer of the process from batch to a continuous flow cell signficantly increased reaction throughput and space-time yield, with excellent product yields obtained even in a single-pass. The sustainability of the electrochemical protocol has been examined by evaluating its green metrics. Comparison with the conventional method demonstrates that an electrochemical approach has a significant positive effect on the greenness of the process

In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant challenge, but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis, IR and UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine. This synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions, as well as three inline separations. Advanced data analysis models were developed (indirect hard modeling, deep learning and partial least squares regression), to quantify the desired products, intermediates and impurities in real time, at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents a significant step forward in data‐driven continuous flow synthesis., Process analytical technologies hold tremendous promise in multistep continuous flow synthesis. Here, four orthogonal real‐time analytical tools are employed in a three step synthesis, with phase separations. Advanced data processing techniques, such as indirect hard modeling and deep learning, facilitate quantification of up to 9 process components. These analytical capabilities are demonstrated for both steady state and dynamic experiments.

A simple reordering of the reaction sequence allowed the improved synthesis of EIDD-2801, an antiviral with promising activity against the SARS-CoV-2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17% to 61%, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.

The growing demand for opioid antagonists necessitates the development of more efficient and affordable synthetic routes. The most challenging step in the preparation of these essential medicines is the selective N-demethylation of a 14-hydroxy opioid precursor to the corresponding nor-opioid, which is followed by N-alkylation of the resulting secondary amine. This process is carried out on large scales using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild, reagent- and catalyst-free procedure for the N-demethylation step, based on the anodic oxidation of the tertiary amine. The ensuing iminium cation rapidly undergoes cyclization with the 14-hydroxy group, or acyl transfer from its acetylated derivative, resulting in intermediates that can be readily hydrolyzed to the target nor-opioids. The electrochemical method provides excellent yields and has successfully been transferred to a flow electrolysis cell, thus enabling the potential scale-up of this synthetic strategy.

Zeolitic Imidazolate Framework (ZIF) biocomposites show the capacity to protect and deliver bio-therapeutics. To date, the progress in this research area is based on laboratory batch methods. To further explore the potential of ZIF-biocomposites for application to biomedicine and biotechnology, the continuous production of ZIF-biocomposites of specific particle size is desirable. We report the first continuous flow synthetic method for the encapsulation of a model protein (BSA) and a clinical therapeutic (α1-antitrypsin, AAT) in ZIF-8. We studied the in situ kinetics of nucleation, growth and crystallization of BSA-ZIF-8 by SAXS. By controlling the injection time of ethanol, we could quench the particle growth via ethanol-induced crystallization. The particle size of the biocomposite was tuned in the 40-100 nm range by varying residence time prior to introduction of ethanol.

With ever-evolving light-emitting diode (LED) technology, classical photochemical transformations are becoming accessible with more efficient and industrially viable light sources. In combination with a triplet sensitizer, we report the detailed exploration of [2 + 2] cycloadditions, in flow, of various maleic anhydride derivatives with gaseous ethylene. By the use of a flow reactor capable of gas handling and LED wavelength/power screening, an in-depth optimization of these reactions was carried out. In particular, we highlight the importance of matching the substrate and sensitizer triplet energies alongside the light source emission wavelength and power. Initial triplet-sensitized reactions of maleic anhydride were hampered by benzophenone’s poor absorbance at 375 nm. However, density functional theory (DFT) calculations predicted that derivatives such as citraconic anhydride have low enough triplet energies to undergo triplet transfer from thioxanthone, whose absorbance matches the LED emission at 375...

The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization’s list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup we...

An improved synthetic procedure for the multistep synthesis of aminoimidazole 6, a key intermediate in the preparation of lanabecestat (AZD3293/LY3314814), is described. Under intensified conditions (high temperature and elevated pressure), the overall processing time and required amounts of reagents could be significantly reduced, thus potentially minimizing manufacturing costs and improving the sustainability footprint. Process integration of three sequential steps starting from ketone intermediate 2 has been attempted to set the stage for a potential multistep continuous manufacturing route. The process consists of initial formation of imine 3 by treatment of ketone 2 with ammonia and Ti(iPrO)4, cyclocondensation of 3 with thioamide 4 to form thiol 5, and aminolysis using ammonia and Zn(OAc)2, allowing the target building block 6 to be accessed in 47% overall yield.

A continuous-flow Pd-catalyzed oxidative carbonylation protocol utilizing CO and O2 gas for the synthesis of carbonylated heterocycles is described. The optimization of temperature, pressure, CO/O2 ratio, catalyst loading, and reaction time resulted in process intensified conditions for this transformation. The optimized continuous flow conditions (120 °C, 20 bar pressure, 24 min residence time) were used to prepare a number of benzoxazolone, 2-benzoxazolidinone, and other biologically and synthetically important five- and six-membered carbonylated heterocycles in good overall yield and purity (14 examples). The continuous-flow process enables the safe and scalable oxidative carbonylation using CO/O2 under elevated pressures and temperatures.

The development of a continuous-flow Sonogashira cross-coupling protocol using propyne gas for the synthesis of a key intermediate in the manufacturing of a β-amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, currently undergoing late stage clinical trials for a disease-modifying therapy of Alzheimer’s disease, is described. Instead of the currently used batch manufacturing process for this intermediate that utilizes TMS-propyne as reagent, we herein demonstrate the safe utilization of propyne gas, as a cheaper and more atom efficient reagent, using an intensified continuous-flow protocol under homogeneous conditions. The flow process afforded the target intermediate with a desired product selectivity of ∼91% (vs the bis adduct) after a residence time of 10 min at 160 °C. The continuous-flow process compares favorably with the batch process, which uses TMS-propyne and requires overnight processing, TBAF as an additive, and a significantly higher loading of Cu co-catalyst.

A novel setup to analyze the heat of reaction of different single- and multiphase reactions carried out in continuous flow is presented. The measurement principle of the calorimetric system is based on true heat flow measurements and therefore ensures precise calorimetric data within 10 mW resolution. In addition to the investigation of simple mixing phenomena (ethylene glycol and water), a number of exothermic, industrially relevant chemical transformations including the nitration of phenol, the reduction of nitrobenzene, as well as several oxidation and reduction processes, were investigated as model systems. For these experiments a commercially available batch calorimeter (ChemiSens CPA202) was equipped with a glass static mixer (250 μL) optionally connected to a tubular microreactor (PFA coil) allowing overall reaction volumes of up to ca. 5.5 mL. Experiments were performed by feeding individual streams with syringe pumps (alternatively substituting one liquid feed with a gaseous feed controlled by a ...

The preparation of a functionalized 4H-benzo-[1,4]-oxazin-3-one was completed via a three-step nitration/hydrogenation/cyclization sequence. The unstable nature of the nitro and amino intermediates, in addition to the hazards associated with the nitration of organic compounds in general, makes this procedure exceedingly difficult to perform on industrial scale. To overcome these limitations, we have developed a fully integrated continuous protocol in which the aromatic starting material (2,2-difluoro-2-(3-fluorophenoxy)-N,N-dimethylacetamide) is subjected to an initial continuous flow dinitration using 20% oleum in combination with 100% HNO3 (2.5 equiv) using a microstructured device heated to 60 °C. This was followed directly by continuous flow hydrogenation of the dinitrointermediate over a Pd/C fixed bed catalyst at 45 °C. The resulting air-sensitive diamino derivative was then directly cyclized to the desired 6-amino-2,2,7-trifluoro-4H-benzo-[1,4]-oxazin-3-one target compound via an acid-catalyzed cyc...

The palladium-catalyzed N-demethylation of the opioid alkaloids oxymorphone 3,14-diacetate and 14-hydroxymorphinone 3,14-diacetate to their nor-derivatives with oxygen as the terminal oxidant has been investigated. Palladium(II) acetate forms colloidal palladium(0) particles upon heating in N,N-dimethylacetamide. The palladium(0) particles are effective catalysts for the aerobic N-demethylation of these opiate alkaloids. Demethylation of 14-hydroxymorphinone 3,14-diacetate with pure oxygen as oxidant in a continuous flow reactor provided the demethylated product with excellent selectivity after residence times of only 10–20 min with 2.5–5 mol % palladium acetate as catalyst on a laboratory scale. Scale-up of the oxidation in a 100 mL flow reactor (combination of FlowPlate A6 and coiled tube to enhance the gas–liquid mass transfer), hydrogenation in a packed bed reactor, and subsequent hydrolysis afforded the desired noroxymorphone in high quality and good yield on a kg scale. The reaction sequence consume...

A continuous process for the synthesis and inline separation of anhydrous trifluoromethyl diazomethane in a single continuous flow process is presented. The diazo building block is generated from the corresponding amine and NaNO2 under acidic, aqueous conditions and subsequently diffuses through a gas-permeable membrane into an organic stream. To avoid storage and transportation of the hazardous compound, a representative downstream process in a packed-bed reactor yielding highly functionalized building blocks was developed.

Hydrocodone, a high value active pharmaceutical ingredient (API), is usually produced in a semisynthetic pathway from morphine, codeine or thebaine. The latter alkaloid is an attractive precursor as it is not used as a remedy itself. The key step in this production route is a selective olefin reduction forming 8,14-dihydrothebaine which can be subsequently hydrolyzed to yield hydrocodone. Unfortunately, standard hydrogenation procedures cannot be applied due to severe selectivity problems. A transfer hydrogenation using in situ generated diimide is the only known alternative to achieve a selective transformation. The most (atom) economic generation of this highly unstable reducing agent is by oxidizing hydrazine hydrate (N2H4·H2O) with O2. In the past, this route was “forbidden” on an industrial scale due to its enormous explosion potential in batch. A continuous high-temperature/high-pressure methodology allows an efficient, safe, and scalable processing of the hazardous reaction mixture. The industriall...

Herein we present a high-temperature/high-pressure continuous flow synthesis of 1H-4-substituted imidazoles starting from α-bromoacetophenones and carboxylic acids. 1H-4-aryl imidazoles are key building blocks in the synthesis of NS5A inhibitors, including daclatasvir as the most prominent example. The reaction sequence started with the generation of the α-acyloxy ketone from α-bromoacetophenone and the carboxylic acid. The subsequent condensation to the 1H-4-substituted imidazole was performed with ammonium acetate in a high-temperature stainless steel coil reactor. High-temperature operation (> ∼ 150 °C) was essential for this reaction to form the desired imidazole in high purity. Intensification of chemical reactions in continuous flow reactors has emerged as key enabling technology for process enhancement and for reducing the environmental impact of chemical processes. The continuous flow setup allowed rapid heating of the reaction mixture to the desired temperature. Furthermore, operation at elevated...

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key step in the preparation of certain ATR kinase inhibitors. Reactions with NaN3 or TMSN3 and concentrated sulfuric acid under literature conditions provided low conversions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ∼90% after a reaction time of only 10–15 min at 50 °C. The imidation reaction using TMSN3 as reagent was successfully performed in a flow reactor utilizing CH2Cl2/H2SO4 biphasic conditions. The mixture was subsequently quenched in-line with H2O. Phase separation, neutralization, and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.

The development of a continuous flow multistep strategy for the synthesis of linear peptoids and their subsequent macrocyclization via Click chemistry is described. The central transformation of this process is an Ugi four-component reaction generating the peptidomimetic core structure. In order to avoid exposure to the often toxic and malodorous isocyanide building blocks, the continuous approach was telescoped by the dehydration of the corresponding formamide. In a concurrent operation, the highly energetic azide moiety required for the subsequent intramolecular copper-catalyzed azide-alkyne cycloaddition (Click reaction) was installed by nucleophilic substitution from a bromide precursor. All steps yielding to the linear core structures can be conveniently coupled without the need for purification steps resulting in a single process generating the desired peptidomimetics in good to excellent yields within a 25 min reaction time. The following macrocyclization was realized in a coil reactor made of copper without any additional additive. A careful process intensification study demonstrated that this transformation occurs quantitatively within 25 min at 140 °C. Depending on the resulting ring strain, either a dimeric or a monomeric form of the cyclic product was obtained.

A continuous-flow process for the synthesis of triaminophloroglucinol has been developed. The synthetic procedure is based on a sequential nitration/reduction protocol which uses phloroglucinol as an inexpensive substrate. During the initial exothermic nitration step employing a combination of ammonium nitrate and sulfuric acid, the temperature was controlled through the enhanced heat transfer derived from the high surface-to-volume ratio of the utilized capillary tubing. Clogging of the tubing due to precipitation of trinitrophloroglucinol (TNPG) was avoided by immersing the tubular reactor in an ultrasound bath during the process. The nitration mixture was diluted with water and immediately subjected to catalytic hydrogenation of the nitro groups using a commercially available continuous-flow reactor and PtO2 as heterogeneous catalyst, thus avoiding the isolation of the highly unstable and explosive TNPG intermediate.

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield).

The oxidation of ethylbenzene with hydrogen peroxide and molecular oxygen catalyzed by cobalt and bromide ions in acetic acid as solvent was studied. The oxidation of ethylbenzene with hydrogen peroxide provided a mixture of ethylbenzene hydroperoxide, acetophenone, 1-phenylethanol, and 1-phenylethyl acetate. After rapid initial oxidation, the reaction rate decreased steadily so that full conversion of ethylbenzene and reaction intermediates to acetophenone could not be achieved. In contrast, no catalyst deactivation was observed for oxidations using atmospheric oxygen. Ethylbenzene was oxidized to acetophenone in 74% selectivity after a reaction time of 150 min at 80 °C. The reaction conditions were translated to a continuous flow process using a tubular gas–liquid reactor. At temperatures of 110 to 120 °C and an oxygen pressure of ∼12 bar, the reaction time necessary for complete oxidation of ethylbenzene was reduced to 6 to 7 min. The acetophenone was formed in 80 to 84% selectivity, and virtually pure...

A continuous process for generation, separation, and reactions of anhydrous diazomethane in a tube-in-tube reactor was developed. The inner tube of the reactor is made of hydrophobic, gas-permeable Teflon AF-2400. The diazomethane is formed in the inner tube and then diffuses through the permeable membrane into the outer chamber and subsequently reacts in the solution carried within. This technique allows safe and scalable reactions with dry diazomethane to be performed on a laboratory scale.