The development of sustainable trifluoromethylations of enamides is of great interest to the pharmaceutical industry. Herein, we demonstrate a sustainable direct electrochemical trifluoromethylation method in a microflow cell, using Langlois reagent, without the need for a supporting electrolyte, oxidants, or any additive under mild conditions. This method can be applied to various substrates with a yield of up to 84%. Additionally, the batch process yielded significantly less (22%), highlighting the microflow cell's efficiency.

This report presents a rapid, ecofriendly technique for the formation of commonly used -bromo and -iodinating reagents by reacting readily available -chloro derivatives with inorganic bromide and iodide salts. All reagents were easily handled, commercially available, and bench stable. This strategy illustrates the expeditious formation of these halogenating reagents in multigram scale in high-yields and purity with an operationally straightforward recrystallization. The mechanistic details suggest an in situ generation of an interhalogen species.

A catalyst-in-bag system facilitates the recovery and recycling of chiral dirhodium carboxylate catalysts used for enantioselective, intermolecular cyclopropanation. The catalyst-in-bag system incorporates a soluble enantioselective dirhodium complex catalyst within a reusable, commercial dialysis membrane. Dirhodium catalysts of different sizes are examined, and two catalysts with molecular weights above 2400 Da are well-retained by the membrane. The catalyst Rh(-TPPTTL) [TPPTTL = (1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] is explored in enantioselective cyclopropanation reactions under a variety of conditions. The Rh(-TPPTTL) catalyst, when contained in the catalyst-in-bag system, provides high yields and enantioselectivities, akin to the homogeneous catalyst in solution, with negligible rhodium permeation out of the bag over five catalytic cycles. The catalyst-in-bag approach facilitates recovery of the expensive rhodium metal and ligand, with only ppm level Rh detected in the reaction products. The flexible and expandable catalyst-in-bag system can be accommodated in vessels of different shapes and dimensions.

1-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.

The knowledge of the reactivity of -nitrosamines (NSAs) with common organic reagents in synthesis is essential in determining their presence in pharmaceutical products, if formed and retained during synthesis. In this study, we carried out a comprehensive survey of the Reaxys database for all reactions in which the NSA functional group is consumed. Very different reactivities for different classes of NSAs, e.g., ,-dialkylnitrosamines and ,-diphenylnitrosamine, were identified, suggesting substrates which should be included in any future reactivity screening. A classification of NSAs based on their reactivities, and corresponding reagents and transformations, was drawn up based on the data. Furthermore, the survey identified missing areas in the reported reactivities of NSAs with different reagents. This led to an experimental reactivity screening of 8 commercial NSAs with common synthetic reagents in the Mirabilis tool for purge assessment. The results showed NaSO in 1 M aqueous NaOH at 50 °C to be highly effective at destroying NSAs without damaging other organic compounds.

Mixing is one of the most important nonchemical considerations in the design of scalable processes. While noninvasive imaging approaches to deliver a quantifiable understanding of mixing dynamics are well-known, the use of imaging to verify computational fluid dynamics (CFD) models remains in its infancy. Herein, we use colorimetric reactions and our kinetic imaging software, , to explore (i) the correlation of imaging kinetics with pH probe measurements, (ii) feed point sensitivity for Villermaux-Dushman-type competing parallel reactions, and (iii) the use of experimental imaging kinetic data to qualitatively assess CFD models. We report further evidence that the influences of the stirring rate, baffle presence, and feed position on mixing in a tank reactor can be informatively captured with a camcorder and help experimentally verify CFD models. Overall, this work advances scarce little precedent in demonstrating the use of computer vision to verify CFD models of fluid flow in tank reactors.

Perylene diimides (PDI) have an extraordinary ability to activate both energy and electron transfer processes upon light excitation; however, their extremely low solubility has hindered their wide use as photocatalysts. Here, we show that the combination of solid-supported PDIs with continuous flow photochemistry offers a promising strategy for process intensification and a scalable platform for heterogeneous photocatalysis. The photocatalyst immobilized onto glass beads is highly efficient, easy to separate, and extremely reusable, with a broad synthetic application range. Using the photo-oxidation of -butyl sulfide as a benchmark reaction, we demonstrate that immobilized PDI are highly active, outperforming reported homogeneous photosensitizers, and capable of extensive reuse (turnover number (TON) >57,000 over 2 months). Transferring the process from batch to flow results in a 10-fold reduction in irradiation time and an increase in the space-time yield by a factor of 33 (40 vs 1338 mmol h L batch vs flow). What is more, the same catalyst sample can be used for the preparation of a range of sulfoxides, the aza-Henry reaction between nitromethane and N-Ar tetrahydroisoquinolines, and the photo-oxidation of furfural with high catalytic activity. Overall, our work combines the remarkable photocatalytic properties of PDI with inert, easy-to-handle glass beads, producing hybrid materials that are reusable and can be adapted for performing heterogeneous photocatalysis in a range of scalable photochemical reactors.

A continuous flow approach for the aerobic photo-oxidation of benzylic substrates to ketone and aldehyde products is presented. The resulting process exploits UV-A LEDs (375 nm) in combination with a Corning AFR reactor that ensures effective gas-liquid mixing and leads to short residence times of 1 min. A variety of benzylic substrates are converted to their corresponding carbonyl products, and scalability is demonstrated to produce multigram quantities of products within a few hours. Overall, this continuous flow approach offers several improvements over alternative oxidation methods due to the combined use of air as an oxidant and SAS (sodium anthraquinone-2 sulfonate) as a water-soluble photocatalyst. The use of greener and safer conditions together with process intensification principles renders this flow approach attractive for further industrial applications.

Herein, we describe two practical approaches to synthesize ()-(+)-1,2-epoxy-5-hexene from inexpensive and readily available raw materials and reagents. The first approach is a two-step sequence, involving an epoxidation with -chloroperoxybenzoic acid (mCPBA) and a chiral resolution with (salen)Co(II), producing ()-(+)-1,2-epoxy-5-hexene in 24-30% overall yield. The second approach utilizes readily available ()-epichlorohydrin as the starting material and features an epoxide ring-opening reaction with allylMgCl and the NaOH-mediated ring closure reaction. Development of this two-step process affords -(+)-1,2-epoxy-5-hexene in overall isolated yields of 55-60% with an exceptional purity profile. Both approaches have been successfully demonstrated on 100-200 g scales.

The development of a continuous flow reactor for stereospecific glycosylation reactions with deoxy sugars is described. This apparatus that permits optimizing the selectivity of glycosylation reactions based on the stability of the activated intermediate is described. By coupling a flow apparatus with HPLC analysis, we can optimize the yield of TsCl-mediated -linked deoxy sugar construction in a matter of hours. In all cases, results from continuous flow processing translate into improved results in batch-scale reactions, as demonstrated by competition experiments. This is the result of carrying out optimization to identify the ideal temperature for the reaction of the activated intermediate, as opposed to the initial activation conditions. Such an approach allows for the rapid development of highly selective glycosylation reactions in cases in which classical neighboring group participation is not possible.

The fourth industrial revolution is gaining momentum in the pharmaceutical industry. However, particulate processes and suspension handling remain big challenges for automation and the implementation of real-time particle size analysis. Moreover, the development of antisolvent crystallization processes is often limited by the associated time-intensive experimental screenings. This work demonstrates a fully automated modular crystallization platform that overcomes these bottlenecks. The system combines automated crystallization, sample preparation, and immediate crystal size analysis via online laser diffraction (LD) and provides a technology for rapidly screening crystallization process parameters and crystallizer design spaces with minimal experimental effort. During the LD measurements, to avoid multiple scattering events, crystal suspension samples are diluted automatically. Multiple software tools, i.e., LabVIEW, Python, and PharmaMV, and logic algorithms are integrated in the platform to facilitate automated control of all the sensors and equipment, enabling fully automated operation. A customized graphical user interface is provided to operate the crystallization platform automatically and to visualize the measured crystal size and the crystal size distribution of the suspension. Antisolvent crystallization of ibuprofen, with ethanol as solvent and water with Soluplus (an additive) as antisolvent, is used as a case study. The platform is demonstrated for antisolvent crystallization of small ibuprofen crystals in a confined impinging jet crystallizer, performing automated preplanned user-defined experiments with online LD analysis.

Thermal -Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of -Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl -Boc group in the presence of an alkyl -Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl -Boc group from followed by benzoylation and deprotection of the remaining alkyl -Boc group to form amide proved successful.

The use of sustainable oxidants is of great interest to the chemical industry, considering the importance of oxidation reactions for the manufacturing of chemicals and society's growing awareness of its environmental impact. Molecular oxygen (O), with an almost optimal atom efficiency in oxidation reactions, presents one of the most attractive alternatives to common reagents that are not only toxic in most cases but produce stoichiometric amounts of waste that must be treated. However, fire and explosion safety concerns, especially when used in combination with organic solvents, restrict its easy use. Here, we use state-of-the-art 3D printing and experimental feedback to develop a miniature continuous stirred-tank reactor (mini-CSTR) that enables efficient use of O as an oxidant in organic chemistry. Outstanding heat dissipation properties, achieved through integrated jacket cooling and a high surface-to-volume ratio, allow for a safe operation of the exothermic oxidation of 2-ethylhexanal, surpassing previously reported product selectivity. Moving well beyond the proof-of-concept stage, we characterize and illustrate the reactor's potential in the gas-liquid-solid triphasic synthesis of an endoperoxide precursor of antileishmanial agents. The custom-designed magnetic overhead stirring unit provides improved stirring efficiency, facilitating the handling of suspensions and, in combination with the borosilicate gas dispersion plate, leading to an optimized gas-liquid interface. These results underscore the immense potential that lies within the use of mini-CSTR in sustainable chemistry.

We describe the optimization and scale-up of two consecutive reaction steps in the synthesis of bio-derived alkoxybutenolide monomers that have been reported as potential replacements for acrylate-based coatings (Sci. Adv.2020, 6, eabe0026). These monomers are synthesized by (i) oxidation of furfural with photogenerated singlet oxygen followed by (ii) thermal condensation of the desired 5-hydroxyfuranone intermediate product with an alcohol, a step which until now has involved a lengthy batch reaction. The two steps have been successfully telescoped into a single kilogram-scale process without any need to isolate the 5-hydroxyfuranone between the steps. Our process development involved FTIR reaction monitoring, FTIR data analysis 2D visualization, and two different photoreactors: (i) a semicontinuous photoreactor based on a modified rotary evaporator, where FTIR and 2D correlation spectroscopy (2D-COS) revealed the loss of the methyl formate coproduct, and (ii) our fully continuous Taylor Vortex photoreactor, which enhanced the mass transfer and permitted the use of near-stoichiometric equivalents of O. The use of in-line FTIR monitoring and modeling greatly accelerated process optimization in the Vortex reactor. This led to scale-up of the photo-oxidation in 85% yield with a projected productivity of 1.3 kg day and a space-time yield of 0.06 mol day mL. Higher productivities could be achieved while sacrificing yield (, 4 kg day at 40% yield). The use of superheated methanol at 200 °C in a pressurized thermal flow reactor accelerated the second step, the thermal condensation of 5-hydroxyfuranone, from a 20 h batch reflux reaction (0.5 L, 85 g) to a space time of <1 min in a reactor only 3 mL in volume operating with projected productivities of >700 g day. Proof of concept for telescoping the two steps was established with an overall two-step yield of 67%, producing a process with a projected productivity of 1.1 kg day for the methoxybutenolide monomer without any purification of the 5-hydroxyfuranone intermediate.

A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored using traditional batch synthesis techniques but suffered from moderate yields, long reaction times, and moderate diastereoselectivities. Here we demonstrate that the process can be greatly improved upon its transfer to continuous flow, which afforded the aziridine targets in high yields, short reaction times, and consistently high diastereoselectivities, with the high-throughput process rendering multigram quantities of product in short periods of time. In addition, flow processing extended the substrate scope including several examples that had failed in batch mode, thus demonstrating the value of this overlooked entry into valuable aziridine species.

Presented here is the design and performance of a coalescing liquid-liquid filter, based on low-cost and readily available meltblown nonwoven substrates for separation of immiscible phases. The performance of the coalescer was determined across three broad classes of fluid mixtures: (i) immiscible organic/aqueous systems, (ii) a surfactant laden organic/aqueous system with modification of the type of emulsion and interfacial surface tension through the addition of sodium chloride, and (iii) a water-acetone/toluene system. The first two classes demonstrated good performance of the equipment in effecting separation, including the separation of a complex emulsion system for which a membrane separator, operating through transport of a preferentially wetting fluid through the membrane, failed entirely. The third system was used to demonstrate the performance of the separator within a multistage liquid-liquid counterflow extraction system. The performance, robust nature, and scalability of coalescing filters should mean that this approach is routinely considered for liquid-liquid separations and extractions within the fine chemical and pharmaceutical industry.

A packed reactor bed incorporating a polymer-supported isothiourea HyperBTM catalyst derivative has been used to promote the enantioselective synthesis of a range of heterocyclic products derived from α-azol-2-ylacetophenones and -acetamides combined with alkyl, aryl, and heterocyclic α,β-unsaturated homoanhydrides in continuous flow via an α,β-unsaturated acyl-ammonium intermediate. The products are generated in good to excellent yields and generally in excellent enantiopurity (up to 97:3 er). Scale-up is demonstrated on a 15 mmol scale, giving the heterocyclic product in 68% overall yield with 98:2 er after recrystallization.

A robust supported catalyst that is made up of copper nanoparticles on Celite has been successfully prepared for the selective transfer hydrogenation of aromatic nitrobenzenes to anilines under continuous flow. The method is efficient and environmentally benign thanks to the absence of hydrogen gas and precious metals. Long-term stability studies show that the catalytic system is able to achieve very high nitrobenzene conversion (>99%) when working for up to 145 h. The versatility of the transfer hydrogenation system has been tested using representative examples of nitroarenes, with moderate-to-excellent yields being obtained. The packed bed reactor (PBR) permits the use of a setup that can provide products via simple isolation by SPE without the need for further purification. The recovery and reuse of either EG or the ion-exchange resin leads to consistent waste reduction; therefore, E-factor distribution analysis has highlighted the environmental efficiency of this synthetic protocol.

C-Glycosyl compounds (C-glycosides) are a class of saccharide derivatives with improved stability over their O-linked counterparts. This paper reports the synthesis of several -2-(C-glycosyl)acetates via a tandem Wittig-Michael reaction from pyranoses (cyclic hemiacetals) using continuous flow processing, which gave improvements compared to reactions conducted in round-bottom flasks. Products were isolated in yields of >60% from reactions of benzyl-protected xylopyranoses, glucopyranoses, and galactopyranoses at higher temperatures and pressures, which were superior to yields from batch procedures. A two-step procedure involving the Wittig reaction followed by Michael reaction (intramolecular oxa-Michael) of the unsaturated ester obtained in the presence of DBU was developed. Reactions of protected mannopyranose gave low yields in corresponding reactions in flow due to competing C-2 epimerization.

A simple and benign continuous flow oxidation protocol for the selective conversion of primary and secondary alcohols into their respective aldehyde and ketone products is reported. This approach makes use of catalytic amounts of TEMPO in combination with sodium bromide and sodium hypochlorite in a biphasic solvent system. A variety of substrates are tolerated including those containing heterocycles based on potentially sensitive nitrogen and sulfur moieties. The flow approach can be coupled with inline reactive extraction by formation of the carbonyl-bisulfite adduct which aids in separation of remaining substrate or other impurities. Process robustness is evaluated for the preparation of phenylpropanal at decagram scale, a trifluoromethylated oxazole building block as well as a late-stage intermediate for the anti-HIV drug maraviroc which demonstrates the potential value of this continuous oxidation method.

Biocatalytic oxidation is an interesting prospect for the selective synthesis of active pharmaceutical intermediates. Bubbling air or oxygen is considered as an efficient method to increase the gas-liquid interface and thereby enhance oxygen transfer. However, the enzyme is deactivated in this process and needs to be further studied and understood to accelerate the implementation of oxidative biocatalysis in larger production processes. This paper reports data on the stability of NAD(P)H oxidase (NOX) when exposed to different gas-liquid interfaces introduced by N (0% oxygen), air (21% oxygen), and O (100% oxygen) in a bubble column. A pH increase was observed during gas bubbling, with the highest increase occurring under air bubbling from 6.28 to 7.40 after 60 h at a gas flow rate of 0.15 L min. The kinetic stability of NOX was studied under N, air, and O bubbling by measuring the residual activity, the deactivation constants () were 0.2972, 0.0244, and 0.0346 with the corresponding half-lives of 2.2, 28.6, and 20.2 h, respectively. A decrease in protein concentration of the NOX solution was also observed and was attributed to likely enzyme aggregation at the gas-liquid interface. Most aggregation occurred at the air-water interface and decreased greatly from 100 to 14.16% after 60 h of bubbling air. Furthermore, the effect of the gas-liquid interface and the dissolved gas on the NOX deactivation process was also studied by bubbling N and O alternately. It was found that the N-water interface and O-water interface both had minor effects on the protein concentration decrease compared with the air-water interface, whilst the dissolved N in water caused serious deactivation of NOX. This was attributed not only to the NOX unfolding and aggregation at the interface but also to the N occupying the oxygen channel of the enzyme and the resultant inaccessibility of dissolved O to the active site of NOX. These results shed light on the enzyme deactivation process and might further inspire bioreactor operation and enzyme engineering to improve biocatalyst performance.