Batch vs. Continuous Flow Chemistry

Research will be limited to:
- Process: Organic Synthesis
- Process Type: Batch vs Continuous Flow Chemistry
- Property: Heat Transfer
- Considerations: Safety and Scalability

Strategy: I will investigate the comparative performance of batch and continuous flow reactors in organic synthesis, specifically focusing on heat transfer coefficients, thermal runaway risks, and scale-up correlations. The search will target quantitative data on surface-area-to-volume ratios and heat removal capacities to provide a technical basis for safety and scalability assessments.
Queries:
- batch vs continuous flow organic synthesis heat transfer coefficient comparison
- flow chemistry safety thermal runaway mitigation organic synthesis
- scale-up heat transfer correlations batch vs microreactor flow chemistry
- exothermic organic reactions batch vs continuous flow safety analysis
- heat transfer efficiency surface-area-to-volume ratio flow vs batch synthesis

Executing 5 concurrent searches:
- batch vs continuous flow organic synthesis heat transfer coefficient comparison
- flow chemistry safety thermal runaway mitigation organic synthesis
- scale-up heat transfer correlations batch vs microreactor flow chemistry
- exothermic organic reactions batch vs continuous flow safety analysis
- heat transfer efficiency surface-area-to-volume ratio flow vs batch synthesis

Found 10 papers. Key excerpts:

Comparative Study of Batch and Continuous Flow Reactors in Selective Hydrogenation of Functional Groups in Organic Compounds: What Is More Effective? — Marina V Bukhtiyarova et al., 2023

Most reactions of petrochemical and commodity chemical industries are heterogeneous catalytic processes, which have been studied in detail. Historically, the manufacturing of fine chemicals has been developed with batch technologies ( Figure 1 a) [ 1 , 2 ]. Mostly, this approach remains the main production technique in industries due to the high profit with low cost and flexibility of batch units to make multiple products. At the present moment, the synthesis of fine chemicals in continuous flow mode ( Figure 1 b) is an interesting challenge for researchers all over the world. On the other hand, developing flow processes can be time consuming.
The batch reactor is a transient reactor. An autoclave uploaded with a reaction mixture and catalyst is commonly used as a batch reactor to perform a reaction at high temperature and high pressure. The main characteristics of batch reactors are the following: the reaction is performed in the liquid phase; temperature control and vigorous stirring is needed to make sure that the temperature and composition are uniform in the whole volume of the reactor; concentrations of reactants and products are changed with the clock time, meaning that the longer the reaction time, the higher the product yield is; long synthesis can result in catalyst deactivation without knowing it has happened; catalyst deactivation is determined by reactivation of the catalyst and repeating the catalytic run with a washed catalyst; catalyst particles disturb the sampling procedure by possibly blocking the sampling port, if it is present in the autoclave; batch synthesis should be repeated several times to produce a high amount of the desired product.
the reaction is performed in the liquid phase;
temperature control and vigorous stirring is needed to make sure that the temperature and composition are uniform in the whole volume of the reactor;
concentrations of reactants and products are changed with the clock time, meaning that the longer the reaction time, the higher the product yield is;
long synthesis can result in catalyst deactivation without knowing it has happened;
catalyst deactivation is determined by reactivation of the catalyst and repeating the catalytic run with a washed catalyst;
catalyst particles disturb the sampling procedure by possibly blocking the sampling port, if it is present in the autoclave;
batch synthesis should be repeated several times to produce a high amount of the desired product.
A continuous flow reactor is a steady-state reactor, in which the reagents are fed constantly to the inlet of the reactor and move through the catalyst bed. After the reaction, the mixture of unreacted reagents

and products flow at the outlet. The main characteristics of continuous flow reactors are the following: the reaction is performed in the gas phase; the composition of the gas at the outlet does not change with the clock time; precise control of the molar ratio of reactants is possible by controlling the flow rates of reactants; the change of residence time without changing the catalyst in the reactor; catalyst deactivation is determined by the long-term stability test with online measurement of the gas mixture; there is no need to start and stop the continuous process for the production of the target product in a high yield.
the reaction is performed in the gas phase;
the composition of the gas at the outlet does not change with the clock time;
precise control of the molar ratio of reactants is possible by controlling the flow rates of reactants;
the change of residence time without changing the catalyst in the reactor;
catalyst deactivation is determined by the long-term stability test with online measurement of the gas mixture;
there is no need to start and stop the continuous process for the production of the target product in a high yield.
Authors [ 3 , 4 ] made an attempt to create a diagram that can help to choose between the batch and continuous flow mode to perform the catalytic reaction with appropriate parameters. The catalytic process is more convenient and reliable in the batch reactors if: there is an acceptable level with respect to yield, scale, and reaction time; the existing synthesis route fits the existing batch equipment; the immediate goal is optimization of discrete variables; there is low market growth (<1 kt/a); precipitate drives the reaction to completion.
there is an acceptable level with respect to yield, scale, and reaction time;
the existing synthesis route fits the existing batch equipment;
the immediate goal is optimization of discrete variables;
there is low market growth (<1 kt/a);
precipitate drives the reaction to completion.
On the other hand, continuous flow reactors are preferred if: one of the reagents is gas; the reaction is performed over a heterogeneous catalyst; there is high marker volume (>10 kt/a); products suffer under catalyst deactivation; heating accelerates the reaction.
one of the reagents is gas;
the reaction is performed over a heterogeneous catalyst;
there is high marker volume (>10 kt/a);
products suffer under catalyst deactivation;
heating acceler

ates the reaction.
Usually, researchers [ 5 , 6 , 7 ] postulate that performing reactions in flow has several advantages in comparison to processes carried out in batch reactors, such as better mixing of reagents, excellent interfacial mass and energy transfer properties, lower operational costs, suppression of byproduct formation through better control over reaction parameters, simplified scaling up, and improved process safety.
Reactants are introduced continuously to the reactor in such a way that only a limited quantity of them react at a given time, meaning well mixing by rapid diffusion in a small reaction space.
A low ratio of reactor inner diameter to catalyst particle diameter is needed for heat management, i.e., sufficient heat removal to the reactor wall for highly exothermic reactions. Moreover, reactor material has an impact on the heat transfer efficiency and needs to be chosen for an exact purpose. It is postulated that dimensions of flow reactors can be smaller than that of batch reactors to obtain the same yield and selectivity [ 4 ]. Small reactors promote efficient heat exchange. It is worth noting that the energy costs are decreased by enhanced heat transfer.
Due to the absence of headspace in flow reactors, there is no accumulation of unstable intermediates. Furthermore, side products, which can block active sites of the catalysts, are removed from the catalyst by the flow. The step of catalyst separation from products is avoided in the case of flow reactors.
In general, scaling up a batch system is easier since batch reactors are mostly available on any required scale. It is only necessary to select the proper stirrer and heating jacket for a batch reactor of high dimensions. For the scale-up of flow reactor kinetic data, reactor modeling and heat and mass transfer information are needed for obtaining the safety process. In addition, clogging issues are greater in the case of flow reactors [ 4 ].
However, as it was mentioned in [ 3 ], these benefits are not always relevant to the topic of the paper. Quite often, researchers try to replace batch reactors with continuous flow reactors due to their better performance, while comparison of the catalytic activity of the same catalytic systems in both reactors is absent in the paper. Readers should believe that the investigated catalysts work better in the continuous flow mode.
There is a lack of literature that has compared the catalytic performance in both batch and continuous flow modes. The aim of the present review is to reveal all publications that consider selective hydrogenation of different functional groups (nitro and carb

Continuous Flow Synthesis of Propofol. — Romain Mougeot et al., 2021

Propofol (2,6-diisopropylphenol) is a potent intravenous hypnotic agent, which is widely used for the induction and maintenance of anesthesia and for sedation in the intensive care units [ 1 ]. Propofol is chemically distinct from others intravenous sedative hypnotic such as opioids, barbiturics, halogenated liquids, or benzodiazepines ( Scheme 1 ) [ 2 ]. Propofol is characterized by a rapid onset due to its high lipophilicity, a short duration of action and a low toxicity due to its rapid hepatic and extra-hepatic metabolization into various salts, which are excreted in urine. Moreover, it provides satisfactory sedation and fast recovery time. Hence, Propofol has been recognized as an essential medicine by the World Health Organization since April 2013 [ 3 ].
Importantly, within the context of the COVID-19 pandemic, Propofol is extensively used to avoid cardio-pulmonary injuries for patients, who are mechanically ventilated by minimizing resistance to this mechanical ventilation [ 2 ]. At the early stage of this pandemic, a dramatic shortage of such strategic drugs was witnessed.
Although, most of the drugs are produced under batch conditions, continuous flow chemistry has emerged as a possible alternative for the production of active pharmaceutical ingredients (API) [ 4 , 5 , 6 ], especially since it offers a safer handling of chemicals minimizing the exposition of the operators and allows an easier scale-up [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Thus, following our ongoing research program dedicated toward the synthesis of API under continuous flow [ 14 ], we report our contribution for the first synthesis of the strategic Propofol under continuous flow.
Seminal synthetic approaches to Propofol relied on Friedel–Crafts alkylation of phenol with propylene gas in the presence of a Lewis acid at high temperature (300 °C) and pressure (3000 bar) ( Scheme 2 , path a) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Although isopropanol has been proposed to replace the gaseous propylene, these harsh conditions all led to the production of several impurities (2,4-diisopropyl and 2,4,6-triisopropyl phenol, along with the product ( Scheme 2 , path a)). These side products need to be removed from

the final API (<0.05%) for medical use [ 23 ]. To address the formation of these undesired products in the synthesis of Propofol, another approach was designed using the 4-hydroxybenzoic acid ( 1 ) as the starting material to hamper the undesired alkylation at the para position. [ 23 ] Thus, the alkylation of 1 using isopropyl alcohol (IPA) and H 2 SO 4 followed by a decarboxylation step under alkaline conditions (NaOH) at high temperature, afforded Propofol with a higher purity, matching with the API synthesis standard. However, this procedure suffers from acid–base neutralization at each step, resulting in exothermic quench, a serious drawback for an industrial implementation of the process. This issue was further tackled by Pramanik, who simplifies the isolation and purification steps by getting rid of the acid–base neutralization, using a toluene/water mixture ( Scheme 2 b) [ 23 ].
Inspired by this contribution toward the batch synthesis of Propofol, we started our investigations on a continuous flow process from 4-hydroxybenzoic acid ( 1 ), as starting material, and studied the Friedel–Crafts alkylation with IPA to introduce the two isopropyl substituents. At the outset of our study, we faced a solubility issue with the solvent mixture initially envisioned to introduce the substrate 1 (H 2 SO 4 /IPA/water) by a single inlet in a heated coil reactor. Hence, to avoid any precipitation in the tube reactor, which would jeopardize the development of the continuous flow synthesis of the target, we implemented a set-up composed of two inlets feeding a PFA coil reactor (ID = 1.6 mm) equipped with a T-shaped mixer: inlet A contained the substrate 1 in a homogeneous H 2 SO 4 /H 2 O mixture (9:1, [ 1 ] = 0.4 M) and inlet B was composed of IPA (6 equiv./ 1 ) in a H 2 SO 4 /H 2 O mixture as well (9:1). Importantly, the stock solutions were preheated at 35 °C to avoid any possible clogging before the injection within the reactor.
Then, the influence of the flow rate—and hence the mixing efficiency—was studied by fixing the residence time at t

R = 40 min and adjusting the reactor length accordingly ( Table 1 ). As described in Table 1 , a higher flow rate afforded product 2 with very good isolated yields (entries 1 to 4). An optimum total flow rate of Q T = 2.5 mL·min −1 (Q A = 1.25 mL·min −1 and Q B = 1.25 mL·min −1 , reactor volume V = 100 mL) provided 2 with 84% yield. Importantly, the reaction was scaled up to 200 mmol (27.6 g of 1 , reaction productivity of 2 : 55.95 g·h −1 ), without loss of efficiency and the pure 2 was delivered with a high yield (84%) after a short filtration over a pad of silica gel (entry 4) [ 24 ].
Having optimized the conditions for an efficient bis-alkylation of 1 into 2 , we turned our attention to the final decarboxylation step to access Propofol. This second step, initially performed in batch with a solution of NaOH, 2.3 M in 2-ethoxyethanol at 130 °C for 12 h ( Scheme 2 a), was reinvestigated to fit, here again, with the continuous flow constraints. Thus, we switched from an inorganic base to an organic one; popular triethylamine (TEA), Hünig’s base (DIPEA) and tetramethylene ethylene diamine (TMEDA) were evaluated in various solvents systems ( Table 2 ).
To achieve the synthesis of Propofol, the flow system was composed of a single inlet, containing a premixed solution of 2 with the appropriate base, which was introduced in a tubular copper reactor (ID = 1.0 mm, V = 10 mL) for a better thermal transfer and a putative assistance in the decarboxylation event (150 °C, t R = 3 h). The system was equipped with a back pressure regulator (BPR) set at 9.5 bars to reach high temperatures. Since flow systems offer the possibility to telescope reactions, our studies began with solvent mixtures including toluene, the solvent used to extract 2 from the final the previous step (vide supra). Among bases assessed, TMEDA proved to be efficient, leading to fairly decent NMR yields (entries 1 and 2) compared to DIPEA (entries 3 and

Towards Antibiotic Synthesis in Continuous-Flow Processes. — Marziale Comito et al., 2023

Advances in industrial organic synthesis are essential for the successful commercialization of innovative and efficient chemical–pharmaceutical manufacturing. Achievements, from the discovery of salvarsan to advanced therapy medicinal products (ATMPs), would have been impossible without cutting-edge technology and interdisciplinary collaboration [ 1 , 2 , 3 , 4 ]. The new technologies and modern trends in the synthesis of drugs and natural products that have been developed by academia and industry are opening up opportunities on a scale previously considered unattainable in most laboratories and production lines. The use of high-throughput and breakthrough technology platforms, particularly flow chemistry and process analytics (PAT), is representative of the endless potential in the pharmaceutical field and the improvements over the current state that are possible ( Figure 1 ) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].
In an era where sustainability is driving industrialization and innovation, in accordance with environmental friendliness and green chemistry concepts [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ], the pharmaceutical industry is at the forefront of embracing and leading change. The pharmaceutical industry’s mission is to provide patients with new medicines to help them live longer and healthier lives by creating small molecules in accordance with drug-development protocols. Until not so long ago, drug companies ignored risks to workers and the environment. Today, their approach has changed completely. In 2020, small-molecule drugs accounted for approximately USD 478 billion in sales in the global pharmaceutical markets, and this figure is expected to grow at 7% annually through to 2024 [ 38 ].
In 2005, the American Chemical Society (ACS) Green Chemistry Institute (GCI) and the most important global pharmaceutical corporations set up the ACS GCI Pharmaceutical Roundtable. Their aim was to encourage the integration of green chemistry and green engineering into the synthesis of small molecules [ 39 , 40 , 41 ]. This concept has influenced all phases of drug development over the last twenty years, from preclinical to commercial stages, and has become a successful feature for new molecular entities (NMEs). At the same time, the opportunities presented by renewing old synthetic routes with new technologies have grown into a vast research field.
Of the many emerging technologies available, continuous manufacturing, which is also known as continuous processing or

continuous-flow chemistry, has become the mainstream in the synthesis of active pharmaceutical ingredients (APIs). Its impact on the life cycles of drugs has been so overwhelming that the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have recently drawn up guidelines for this manufacturing type [ 42 , 43 ]. Although publications on flow chemistry have exponentially grown in number over the last two decades, including assessments of pros and cons [ 11 , 44 , 45 , 46 ], and despite its use being quite commonplace in many industries, the pharmaceutical world is recalcitrant to adopt it, and batch manufacturing remains king. The availability of standard reactors together with the simplicity, versatility and flexibility of their use means that old habits die hard. Although the positive impact of flow mode is now recognized, its application on an industrial scale is still seen as being the game changer that is too volatile to welcome. The industry’s hesitance to embrace continuous-flow processes is understandable precisely because the majority of publications derive from within the academic sphere, many processes are relatively untested and regulatory guidance is too young. In order to extend the scope of these technologies, companies must be sure of their suitability for specific business needs, including an awareness of their operational advantages, as well as the challenges they pose [ 47 , 48 , 49 , 50 , 51 ].
Chemical reactions in discontinuous processes occur in large vessels for a given time before the product is crystallized, discharged, analyzed and, eventually, purified. If a problem emerges during synthesis, or if the product does not comply with standard quality guidelines, production is compromised, causing undesirable losses in money and time. Continuous manufacturing runs constantly until a project is complete, slashing manufacturing times and avoiding breaks between the steps. Given that reactions take place on a much smaller scale, only small amounts of product are lost if the process fails. The automated nature of continuous processes minimizes fluctuations in reaction conditions (e.g., temperature, pressure and reaction time) and reduces human error compared to batch manufacturing, saving assets. For the same reasons, chemists can easily control reactions in continuous flow (also combining photo- and electrochemistry), whereas this is a critical issue in batch mode because of the extreme conditions and the presence of highly reactive and unstable intermediates [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Miniaturization intrinsically improves synthesis due to the excellent

mass and heat transfer that it provides, also meaning that less laboratory and industrial space is required. Modularization allows integrated synchronized operations to be performed, facilitating adaptability to different pharmaceutical processes. The closed architecture of these systems provides safer working conditions as it eliminates direct contact with hazardous chemicals and avoids production-chain incidents. Integration with process analytical technologies (PAT) and purification modules has boosted this technology’s status, making the drug-production process telescopic, increasing production capability while retaining substance quality. Green chemistry concepts are met because the product does not need to be isolated and stored before use in a subsequent step, as it can directly flow into the subsequent reactor for another synthesis or into another module for another operation [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ].
There are many reasons for favoring and adopting continuous manufacturing in the pharmaceutical world ( Figure 2 ), including reasons that support heavy investment in the production of drugs and precursors. In this short review, we present the flow-mode applications of the synthesis of antibiotics and their building blocks. We have covered the period of 2012–2022, as we highlight the key points and merits of applying this new technology for these important drugs. Most of the small molecules studied are off patent, are characterized by chemistry that was developed many years ago and have only been relaunched in some cases [ 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. We hope that flow chemistry can revive them with renewed vigor.
Table 1 lists all of the antibiotics for whose synthesis flow chemistry has been applied. They will be discussed in the subsequent sections.
Cefotaxime ( 1 ) is a β-lactam antibiotic classified as a third-generation cephalosporin, was first synthesized in 1976 and was commercialized by 1980 under the brand name Claforan TM . It was approved by the FDA to treat Gram-positive, Gram-negative and anaerobic bacteria.
Its broad-spectrum activity is useful in treating complicated urinary-tract infections, lower-respiratory-tract infections, bacteremia, meningitis, uncomplicated gonorrhea, skin and soft-tissue infections, and obstetric and gynecological infections. Its activity takes place via linkage to the penicillin-binding proteins (PBPs) via its β-lactam ring and by inhibiting the transpeptidation step

Continuous Flow Synthesis of Anticancer Drugs. — Mara Di Filippo et al., 2021

Drug shortages remain a significant public health issue in the 21st century. All types of drugs are affected by this problem such as anticancer medicines, antimicrobial drugs, analgesics, opioids, cardiovascular drugs, radiopharmaceuticals, and parenteral products. This global problem furthermore has severe economic implications and affects society as a whole [ 1 ]. In the context of anticancer medicines, shortages are even more critical due to the precarious patient situation, which often cannot afford a delay in treatment or a replacement with an alternative drug due to adverse effects such as incompatibility with other medications or higher cost [ 2 , 3 ]. The shortage of a single medicine can have repercussions on many patient cohorts as the same product may be used to treat several conditions. It is therefore of utmost importance to avoid shortages of medicines to ensure patients have the highest survival rate possible.
Recently, both FDA (Food and Drug Administration) and EMA (European Medicines Agency) published updated reports analyzing this situation [ 4 , 5 ]. Drug shortages can occur for many reasons such as manufacturing and shipping problems or price changes and discontinuations of raw materials. The ongoing global pandemic has seen additional supply issues for several drugs due to the disruption of production and distribution networks [ 6 ]. Limited availability of drugs and their building blocks can also result from their production being suspended or disrupted due to contamination of the active pharmaceutical ingredient (API) during the manufacturing process, manufacturing capacity issues, or simply due to the inability to produce as much product as required. Manufacturing issues occur because most pharmaceutical companies strongly rely on traditional batch processing and related supply networks. In this type of discontinuous processing, the raw material is processed in large vessels, in which the chemical reaction is allowed to proceed for a given period of time before the product is discharged and eventually purified ( Figure 1 ). If a problem occurs during this process, all the materials used are compromised and must be discarded, losing a significant amount of chemicals, money, and production time, especially if the issue occurs at the later stages of synthesis. Even when the production process runs smoothly, most of the time the crude product needs to be purified thus rendering batch processes time consuming, labor-intense, and environmentally unfavorable.
To improve the manufacturing process, the chemical industry has started to embrace more advantageous emerging technologies, particularly continuous flow chemistry which allows for various improvements on the manufacturing process as documented previously [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. In the last 20 years, a

growing number of publications have demonstrated the positive impact of continuous manufacturing in industrial applications and now, continuous flow processing is recognized as a game-changer that pharmaceutical companies have largely welcomed [ 14 , 15 , 16 , 17 , 18 ].
Compared to batch manufacturing, continuous manufacturing offers higher quality products and less batch-to-batch variability because of the high control over reaction conditions (e.g., temperature, pressure, and reaction time). For the same reason, flow technology enables chemists to easily perform reactions that would be very challenging in batch mode [ 19 ] due to extreme conditions, such as high- and low-temperature conditions [ 20 , 21 , 22 , 23 ], high pressure [ 24 , 25 , 26 ], the presence of highly reactive and unstable intermediates [ 27 ], as well as photo- or electrochemical processing at scale [ 28 , 29 , 30 , 31 , 32 ]. The modular nature of this technology and the robustness of individual reactor components not only provide flexibility but also facilitate the expansion of the applications of flow reactors to different industrial processes, which can mitigate production-chain incidents [ 7 ]. Additionally, the closed environment of flow reactor systems provides safer working conditions, preventing the operator from being in direct contact with hazardous chemicals [ 33 , 34 ]. The small equipment requires less laboratory space and reactor miniaturization intrinsically improves the quality of the reactions due to the excellent mass and heat transfer. Continuous flow processes can be telescoped and automated [ 35 , 36 ] aided by the integration of suitable process analytical technologies (PAT) and purification modules, which accelerate the production retaining product quality and increase product throughput [ 37 , 38 ]. Telescoped processes also improve the green aspects of the manufactory process because the product of a reaction does not need to be isolated and stored before being used in the following step but can directly flow to the next reactor [ 33 , 39 , 40 , 41 ].
Because of the many advantages ( Figure 2 ) that can be leveraged by developing continuous flow processes over batch routes, many pharmaceutical companies have been investing heavily into this technology to produce fine chemicals, as well as drugs and their precursors. In this review, we wish to highlight the use of flow processes applied to the synthesis of important anticancer drugs and their building blocks as reported within the last five years (2016–2021).
The following Table 1 lists the target molecules discussed in the proceeding sections of the review along with the predominant tumor targets.
Lomustine ( 4 )

is a nitroso urea species widely used in anticancer therapies, especially to treat CNS tumors, throat and larynx tumors, lymphogranulomatosis, Hodgkin’s lymphoma, lung, and gastrointestinal tract tumors. This drug acts as a DNA-alkylating agent that produces chloroethyl carbenium ions and carbamylated intermediates in vivo [ 42 , 43 , 44 ]. The main cytotoxic effect of these species results from their ability to form an adduct via the oxygen atom of guanine causing DNA cross-linking. This adduct interferes with key cellular processes such as DNA replication leading to cell death via apoptosis [ 45 , 46 ].
Lomustine, which is sold under the brand name Gleostine ® , is used orally for treatment every six weeks. Recently, in part due to the new regulatory challenges of handling unstable compounds of this type, the price of Gleostine ® has increased considerably [ 47 ]. The possibility of making this drug via a more convenient on-demand methodology may contribute to reducing its cost in the future.
Thompson et al. published an interesting method for the synthesis of this anticancer compound in continuous flow mode [ 48 ]. This involves a telescoped two-step sequence without isolation of the intermediate. The use of desorption electrospray ionization mass spectrometry (DESI-MS) as an in-line analysis technique was beneficial in the optimization process to evaluate the impact of solvent, concentration, and nitrosation reagent choice on the efficiency of the flow process.
The telescoped approach ( Scheme 1 ) was performed using two microreactors (0.5 mL and 1 mL volume) made from fluorinated ethylene propylene (FEP) tubing. The first carbamylation reaction involved combining both reagent solutions via a microreactor maintained at 50 °C and was achieved with a residence time of only one minute.
The exiting solution was then diluted with a mixed solvent system (H 2 O/DCM) to prevent reactor clogging due to the low solubility of urea intermediate 3 . The resulting stream was directed into a Zaiput liquid-liquid separator to remove the water-soluble base (TEA) from the system and avoid the consumption of the nitrosation agent in the second step. The organic solution was combined with a solution of the nitrosation reagent (

Synthesis of 2,4,6-Trinitrotoluene (TNT) Using Flow Chemistry — Dimitris Kyprianou et al., 2020

1. IntroductionThe synthesis of 2,4,6-trinitrotoluene (TNT) has gained a lot of scientific and industrial interest since it was the first high explosive that was able to fulfil the expectations of producers and the military. It was first synthesized in the 1860s and was later produced in large quantities during World War I and World War II [1]. This explosive is a moderately powerful, high-energy material, with satisfactory thermal stability and reduced mechanical sensitivity. It is still used in many explosive mixtures today by military and special branches of industry. This is facilitated by its low cost and the fact that it is relatively insensitive, as well as readily melt-castable. It is, therefore, still a main component in many explosive mixtures, some of which were developed several decades ago, such as Amatol, Baratol, Comp B, H-6, Tritonal, and Torpex [2].In recent years, considerable progress has been made in the synthesis of high-energy materials, especially in the field of military high explosives or propellants. Some of these high-energy materials can be obtained by novel eco-friendly methods of synthesis or techniques [3,4]. Nevertheless, the traditional approach is still applied, and it involves the use of hazardous concentrated acid mixtures (typically nitric and sulfuric acid as a nitrating mixture [5]). Nitration processes carried out especially at a larger scale are particularly prone to runaway exothermic reactions, and thus are of high safety concern [6].High purity TNT can be obtained after nitration of the dinitrotoluene (DNT) isomers: 2,4-DNT and 2,6-DNT. By applying a conventional synthesis, highly concentrated nitric acid (100%) and oleum (sulfuric acid containing up to 60% SO3) are required to achieve a conversion rate higher than 98% as required for military grade TNT [7,8]. This way of synthesis presents safety concerns since the handling, mixing, and disposal of oleum with anhydrous nitric acid is particularly dangerous [9,10,11].Several methods for TNT synthesis or nitration of aromatic compounds other than the traditional method are patented or reported in the literature [8]. They focus mainly on improving the process by achieving higher purity, faster reaction times, and more environmentally friendly approaches. Some examples include the methods developed by Millar et

al., who performed the nitration of DNT in batch mode by using N2O5/H2SO4 98% as the nitrating mixture, Lagoviyer et al. that used sodium nitrate/molybdenum oxide for nitration of toluene, and Kyler et al. that patented the use of 98–99% nitric acid with trifluoromethanesulfonic acid for the conversion of DNT to TNT [7,11,12].The objective of this work was to develop a safer process for the manufacturing of high purity TNT (>99%) to be used in the preparation of explosives standards at the European Commission’s Joint Research Centre. These standards are used to verify that various explosives detection devices, like explosives trace detection equipment (ETD) used at airports, perform according to the specifications laid down in the EU Commission Implemented Regulation 2015/1998 [13]. In this regard, flow chemistry was chosen as a safer alternative to the conventional method of preparing TNT.Flow chemistry—also known as continuous flow chemistry—is the process of performing chemical reactions in a reactor, which can be a pipe, tube, or more complex microstructure device. The reagents are pumped to a mixing junction and flow into the temperature-controlled reactor. The large surface area facilitates vigorous mixing due to high rates of mass transfer and fast dissipation of heat, which allows for highly exothermic reactions. Consequently, faster, safer, automated, scalable procedures can be developed, and high purity products can be obtained by applying this form of synthesis [14,15,16]. In the pharmaceutical sector, several highly exothermic or hazardous nitration reactions were scaled up using flow chemistry processes [17]. Energetic materials have traditionally been prepared in batch reactors. However, on some occasions, flow chemistry was successfully used as an alternative to batch synthesis [18,19]. Among explosive substances, nitroglycerin, which is also a pharmaceutical substance, attracted a significant scientific interest for translating its conventional batch synthesis into flow process [20].The application of flow chemistry is important for processes associated with large risks. Flow chemistry mainly increases safety with well-controlled pressure, stable temperatures, homogenous mixing, and fast dissipation of heat. Moreover, lesser amounts of energetic materials are present at any time in the reactor due to the continuous flow of reagents and the removal of the synthesis products. Although flow chemistry can be beneficial, the methods

can be complex to develop. The methods and reagents used must in many cases be modified in order to be compatible with a flow chemistry application.In the current work, the possibility of performing the conversion of 2,4-DNT to TNT (third nitration step of TNT synthesis) using flow chemistry and an ordinary 98% sulfuric/65% nitric acid nitrating mixture instead of oleum and anhydrous nitric acid was investigated. This reaction is an electrophilic aromatic substitution and it is depicted in Figure 1 [21].This third step is the most challenging one in order to obtain a high conversion rate because side reactions, oxidations, or other break-down processes can also take place, leading to the formation of several by-products. Several accidents during TNT manufacturing have been reported [8] (p. 349, p. 391).During the development of the flow chemistry method, several challenges were encountered, such as clogging due to precipitation of TNT in the outlet flow stream. After the initial method development, the main factors affecting the purity of the product were identified and optimized using a design of experiments (DoE) approach. The DoE approach presents several advantages compared to the so-called OVAT (one variable at a time) approach and flow chemistry processes are ideally suited for it [22,23]. This is because experimental parameters such as temperature, pressure, flow rate, amount of reagent, and residence time can be easily controlled and finely regulated in a fully automated system. The chromatographic purity of the synthesized products was determined using HPLC-DAD. 1H NMR was used to detect possible by-products and impurities in the final product. 2. Results and Discussion 2.1. Preliminary StudiesPreliminary experiments were performed in order to investigate whether it is feasible to perform the reaction in flow chemistry and if high conversion rates could be achieved. Contrary to reported flow chemistry methods for synthesis of liquid energetic materials [18,19,20], this application was particularly challenging for several reasons. The product, TNT, is a solid substance and can precipitate in the reaction mixture causing clogging. Moreover, long reaction times (usually 4–6 h) and mixtures of oleum-fuming nitric acid are normally required for obtaining military grade TNT (pp. 348–364, [8]), [10,12], and. This range of reaction time is considered too long for continuous processing

A field guide to flow chemistry for synthetic organic chemists. — Luca Capaldo et al., 2023

Flow chemistry is a discipline in synthetic organic chemistry that uses a continuous stream of different reagents, which are introduced by pumps and mixed in a continuous reactor, such as a plug flow reactor (PFR) or continuous-stirred tank reactor (CSTR). 1,2 Compared to conventional batch processing which is often carried out in round-bottom flasks, it offers several advantages such as enhanced mass and heat transfer, improved safety, increased reaction efficiency, reduced waste, better scalability, and improved reproducibility. 3,4 As a consequence, flow chemistry allows for precise control over reaction conditions and enables real-time monitoring and analysis of reaction kinetics, resulting in high-quality products and streamlined processes. These benefits have led to the increasing adoption of flow chemistry in academia and various industries for pharmaceuticals, fine chemicals, and materials science. 5–8
While undoubtedly flow chemistry has numerous advantages, it was received with the skepticism of the synthetic community, 9 therefore its implementation experienced an induction period. This can be attributed to a lack of interdisciplinary knowledge, perceived complexity, and high investment costs (see ESI † ). Indeed, flow chemistry is an interdisciplinary field that requires knowledge from both chemistry and chemical engineering. However, some basic understanding of these principles of flow chemistry should already allow one to begin setting up flow experiments. Furthermore, recent advancements in “Do It Yourself”-assembled flow setups, 10–12 3D-printing technology, 13 and cheap electronic toolkits 14 have made technology more intuitive, accessible and affordable. As a consequence, adoption of flow technology in synthetic organic chemistry has been growing in recent years. With the rise of photo- and electrochemistry, flow technology has become a popular and indispensable choice due to its capability to handle the scalability challenges of these synthetic modes. Flow chemistry is also favored for its ability in safely and effectively conducting reactions with challenging or hazardous reagents, expanding the chemical frontiers.
Frequently, our lab gets asked to help young MSc and PhD students start using the technology. 15,16 Although they may feel intimidated at first, we often see how quickly they grasp the concepts and start reaping the benefits of flow technology for their research. To further increase the adoption of flow chemistry in synthetic organic chemistry, this review seeks to provide some basic guidelines for the use of continuous-flow reactors. The goal is to deliver a concise overview to help researchers gain a basic understanding of the principles behind this

technology, allowing them to get the most out of their experiments. We have highlighted three relevant examples to clarify each fundamental principle. Our aim is not to provide an exhaustive overview of continuous-flow chemistry, 17 but rather to offer simple and easy-to-follow guidelines for readers to determine if flow chemistry is relevant to their research. Consequently, our objective is to educate the broader synthetic community about this innovative technology and demonstrate how and when it can make a difference.
The first, and arguably most potent, advantage of flow chemistry for synthetic organic chemists is the improved mass transfer. Mass transfer is defined as the net movement of one species, e.g. one of the reactants, from one point to another within the reactor due to diffusion and/or convection. In other words, mass transfer defines the degree of mixing in the reaction mixture: the better the mass transfer, the more efficient the mixing.
This parameter is especially crucial in the case of multiphase reactions, e.g. gas–liquid reactions where one of the reagents needs to migrate by diffusion from one phase to another. 18
As an example, Noël and co-workers reported the photocatalytic Giese-type alkylation using gaseous light hydrocarbons ( i.e. , methane, ethane, propane, isobutane) via hydrogen atom transfer photocatalysis in flow ( Fig. 1 ). 19 Hereto, the authors exploited the decatungstate anion (DT, W 10 O 32 4− ) as a versatile and inexpensive polyoxometalate-based hydrogen atom transfer (HAT) photocatalyst: 20 upon activation by UV-light irradiation, this photocatalyst can cleave homolytically C(sp 3 )–H bonds to yield C-centered radicals which can be subsequently exploited for various synthetic purposes. 21 While this chemistry is documented to be efficient in the case of homogeneous solutions ( i.e. , single solution phase), the activation of gaseous alkanes is more challenging due to their limited solubility in common organic solvents. The immediate consequence is that the targeted chemistry is particularly slow due to poor gas-to-liquid mass transfer limitations. The authors tackled this challenge by resorting to flow chemistry: by increasing the pressure in the reactor through use of simple back-pressure regulators, the gaseous alkanes could be forced into the liquid phase, increasing

the odds of C(sp 3 )–H bond activation of the gaseous components. Thus, when a CD 3 CN : H 2 O (7 : 1) solution of olefin 1.1 was irradiated with UV light (365 nm, 150 W) in the presence of tetrabutylammonium decatungstate and methane (20 equiv.) at a pressure of 45 bar, the corresponding methylated product 1.2 was obtained in 42% yield after 6 hours residence time. Intriguingly, flow chemistry allowed to conduct the entire scope (38 examples) at high pressure in a timely and scalable yet safe fashion, which is by no means possible in conventional batch reactors. Very recently, the same authors extended this technology for the C(sp 3 )–H carbonylation with gaseous carbon monoxide (CO), obtaining unsymmetrical ketones (41 examples) in good to excellent yields. 22
Another synthetic discipline that relies heavily on the optimal mass transfer offered by microflow technology is that of flash chemistry. 23,24 Flash chemistry can be considered a subdiscipline of flow chemistry, where extremely fast reactions are conducted in a highly controlled manner to produce the desired compounds with high selectivity. In 2016, Yoshida, Kim and co-workers exploited this concept to outpace the very rapid anionic Fries rearrangement for the chemoselective functionalization of iodophenyl carbamates at the ortho position ( Fig. 2 ). 25 Thus, when compound 2.1 is subjected to iodine/lithium exchange, intermediate 2.2 is obtained; the latter compound rapidly undergoes anionic Fries rearrangement at room temperature to give 2.3. To outpace this rearrangement and functionalize the ortho position of 2.2 with an electrophile, the authors developed a chip microreactor with a 3D serpentine microchannel design made of six layers of UV-laser-ablated fluoroethylene propylene-polyimide films. The chemically inert reactor is capable of withstanding high pressure and low reaction temperatures, while its volume is merely 25 nanoliters. Such reduced internal volume enables exceedingly fast mixing times (as low as 330 ms), which is crucial to quench 2.2 with a suitable electrophile to yield 2.4 before its premature rearrangement. When prolonging the mixing

Green process intensification using microreactor technology for the synthesis of biobased chemicals and fuels — Jun Yue, 2022

Nowadays, process intensification (PI) has played a significant role and become more and more a common practice in the execution and optimization of chemical processes in the field of academic research or industrial development [ 1 , 2 ]. It features the use of novel process-intensifying equipment and/or methods based on scientific principles, towards achieving the drastically improved chemical process efficiency, e.g., in terms of the much boosted reaction rate and target product (space time) yield, significantly reduced consumption of energy and raw materials. The substantial intensification often leads to a dramatically reduction of equipment size (and with that the plant size). In this respect, the advent of microreactor technology (also called microreaction technology) in 1990s corresponded well with the ultimate development of PI that entails the use of smaller reaction volumes as a result of the enhanced reaction kinetics through its evolutionary development cycle [3] . As its name suggests, microreactor technology relies on the use of microchannel structures (with its lateral characteristic dimension usually in the range of 0.01 - 1 mm) to perform chemical reactions as well as other unit operations in a continuous flow fashion ( Fig. 1 ) [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] . The miniaturization of channel sizes to typically sub-millimeter or micrometer scale in microreactors brings about distinct advantages in reactor operation and significant potential for PI.
The prevailing laminar flow conditions, and the predominance of surface tension forces or viscous forces (e.g., over buoyant or inertial forces), under wide operational conditions in microreactors facilitates the formation of regular flow patterns ( Fig. 2 ) [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] . For example, a precise manipulation of bubbles, droplets, (single-phase, miscible or immiscible) fluid streams can be easily achieved in microchannel structures where fluid(-fluid) hydrodynamics and fluid-solid interactions are addressed properly. The confinement of such single- or multiphase flow in microchannels renders a very high fluid-fluid or fluid-solid contact area (typically on the order of 10,000 m 2 /m 3 ) [21] . This

, combined with the reduced path for heat conduction and molecular diffusion in microchannels, greatly improves the temperature/concentration uniformity. Such significant heat and mass transfer intensification enables operation of microreactors (largely) under isothermal conditions and kinetic regime towards realizing maximized reaction performance. This makes microreactors well suited for processes that are sensitive to mixing, temperature or interfacial heat/mass transfer limitations as frequently encountered in multiphase systems and conventional macroscale (batch or continuous flow) reactors [20] . The high degree of control over these transport phenomena makes it possible to have not only a precise and fine tuning of the associated process behavior in microreactors (e.g., in terms of the desired mixing or separation efficiency, reaction conversion or selectivity, target product yield), but also a reliable microreactor performance prediction or interpretation. The small reagent inventories and tight temperature control in microreactors further lead to its inherent safety. Microreactors can also handle safely the explosive reaction mixtures (e.g., gaseous hydrogen and oxygen) because the flame propagation is suppressed as the characteristic dimension of microchannels is often below the flame quenching distance [22] . The above features and merits of microreactor technology have spurred enormous research interests over recent two decades in the field of chemical synthesis [ 23 , 24 ].
Various materials (typically glass, silicon, stainless steel and perfluorinated polymers) have been used to fabricate or assemble microreactors in a chip-, plate- or capillary-based configuration ( Fig. 1 ). Chip- or plate-based microreactors are usually custom-made by tailored microfabrication techniques, which allow to integrate different functionalities (e.g., additional channels for heat exchanging [25] , sensors or other mechanisms for the online measurement of reaction parameters [26] ) within the same device for assisting reaction diagnosis, optimization or automation. In comparison, capillary-based microreactors are easily assembled using commercially available polymeric (e.g., made of PTFE, PFA) or metal (e.g., made of stainless steel) tubings, which are relatively cheap and flexible, though with less room to accommodate high functionality. Especially, the latter microreactor type has been widely adopted in the rapid growing field of flow chemistry for accelerated chemistry discovery and optimization in among others fine chemical synthesis [ 27 , 28 ], and the prominent advantages

of flow processing in microreactors have been demonstrated well over conventional batch processing (e.g., bringing new chemical routes, process simplification, fast and effective telescoped synthesis) [26] , [27] , [28] , [29] . A myriad of reactions have benefited from operation in microreactors which can be classified according to phases present, such as gas-solid, biphasic (gas-liquid or liquid-liquid) and triphasic (gas-liquid-liquid, gas-liquid-solid or liquid-liquid-solid) microreactors. A precise manipulation of fluid flow patterns with superior mass transfer properties (e.g., biphasic or triphasic slug flow), coupled with an efficient incorporation of solid catalysts (e.g., as wall coatings, or powders contained in a packed bed or within slurries) in the case of heterogeneous catalysis ( Fig. 2 ), has been realized towards significant transport intensification and reaction performance improvement in microreactors.
So far, microreactors are commonly considered as one important means of PI with broad promising application potentials in chemical industry. Herein, the small volume of microreactors does not hamper process intensification towards larger industrial scale, given the promise of facile production capacity increase with continuous flow processing (e.g., via the flow rate increase) and more importantly, with the modular, flexible and fast scale-up concept. That is, the scale-up of microreactors can be achieved via primarily numbering-up (i.e., the replication of functional microreactor units) and if necessary, combined with the scale-out approach (i.e., by enlarging selectively the reactor dimension while maintaining process intensification merits) [ 30 , 31 ].
Over the last three decades, the concept of designing human health and environmentally benign chemical products and processes to achieve sustainability, especially guided by the 24 principles of green chemistry and green engineering proposed by Anastas and coworkers [ 32 , 33 ], has been widely accepted in both the academia and chemical industry [34] . The emergence of microreactor technology opens up unprecedented opportunities for green and sustainable chemical synthesis, as this technology addresses well many facets of green chemistry and green engineering metrics ( Fig. 3 ).
In terms of alignment with principles of green chemistry, the precise process control (e.g., over reaction temperature and time, mixing and reagent concentration levels) in micro

Thermal Hazard Analysis of Styrene Polymerization in Microreactor of Varying Diameter — Junjie Wang et al., 2020

1. IntroductionChemical safety accidents have occurred frequently in the fields of petrochemical, pharmaceutical and plastic industries [1]. According to statistics, about 26% of chemical industry accidents were mainly caused by thermal runaway of reaction [2]. Reaction thermal runaway is that the reaction system enters the parameter sensitive region, and a small change of operating parameters will lead to an unstable state of the reaction systems [3]. The safety of polymerization, as a typical free radical reaction, is highly dependent on a reliable process control system due to its sensitivity of reaction rate to reaction temperature, material viscosity, and initiator concentration. In addition, local hot spots in the polymerization system could lead to uneven temperature distribution in reactors, which may further cause global thermal runaway. Among all the thermal runaway accidents, polymerization reaction thermal runaway accidents account for the highest proportion, about 48% [4]. Therefore, it was very important to ensure the safety of polymerization reaction at the source by using the principle of inherent safety [5]. In recent years, microreactors have been widely used in organic synthesis as a new type of process intensifier. Microreactors are generally understood as three-dimensional structures with extremely small internal dimensions between 10 and 100 μm (or 1000 μm) [6]. It shares the advantages of high heat transfer, mass transfer, high concentration/temperature gradient, and very large specific surface area [7,8]. These advantages enable microreactors to achieve isothermal operation of exothermic reactions [9]. In addition, the use of microreactors could help reduce the potential hazards of exothermic chemical reactions and toxicity of chemical substances due to their small volume [10]. Moreover, the increasing of the production scale can be easier achieved in microreactors than the traditional scale-up of batch reactors [11].At present, cationic polymerization, anionic polymerization, free-radical polymerization and coordination polymerization have been carried out in microreactor [12]. Iwasaki et al. [13] combined eight microreactors to construct a methyl methacrylate free-radical polymerization micro-chemical pilot plant. The results showed that the polymer microreactor could be applied to relatively large-scale production. Méndez-Portillo et al. [14] studied the continuous free-radical polymerization of styrene in split-and-recombination (SAR) reactor and multilamination microreactor. The

heat transfer coefficient of the SAR reactor and multilamination microreactor were 3.02 and 2.8 kW/(m2·k), respectively, and the mixing efficiency was up to 0.95. Yadav et al. [15] performed emulsion polymerization in a microreactor and determined that the emulsion had a considerable effect on the stability of the process operating conditions. Moreover, the microreactor exhibited a better emulsion mixing effect than the batch reactor. These results showed that the microreactors have the advantages of regulating the molecular weight distribution and improving the heat transfer performance, which makes the microreactor more attractive in industrial production. However, the thermal hazard of exothermic polymerization in microreactors has not been discussed.The computational fluid dynamics (CFD) method was widely used to optimize the design of reactors and simulate reactions under harsh experimental conditions, which are difficult to be conducted in practice. For instance, CFD could simulate reactions under adiabatic conditions with extremely high reaction rates. The results can be served as a reference for process safety assessment. The local data of parameters, such as concentration and temperature, can be determined, and the mixing behavior of fluids in the reactor can be studied thoroughly. Mandal et al. [16] performed a numerical simulation of free-radical polymerization of styrene in a spiral tube microreactor; Their results were compared with that obtained in a straight tube microreactor of the same length under the same reaction conditions. It showed that the monomer conversion rate in the spiral tube microreactor was higher than that in the straight tube microreactor. Jiang et al. [17] established a batch reactor model, and the effects of cooling temperature, cooling flow rate and stirring speed on thermal runaway were discussed in detail. The temperature monitoring position and inhibitor injection position were optimized. Soleymani et al. [18]. Established a three-dimensional model to study the effects of different process parameters on flow dynamics and mixing efficiency. The simulation results indicated that the development of vortices was essential to achieve high mixing performances. Furthermore, the generation and development of vortices were closely related to the geometrical parameters of the mixer. These results indicated that CFD is an effective and reliable tool, which could be used for heat transfer, mass transfer, fluid flow, and reaction process analysis of polymerization in microreactors.In the present study, a three-dimensional steady-state

model of a batch reactor and that of a continuous flow microchannel reactor for thermal polymerization of styrene were established. The thermal runaway in a “millimeter” grade microreactor was studied, and the internal size of the microreactor was appropriately enlarged so that the results of the study were more suitable for industrial application and production. The reaction mechanism was introduced using user-defined functions (UDF) with the source terms of the component transport equations and the energy equations. The reaction kinetics of thermal polymerization of styrene was verified through a comparison of the simulation results with those in the literature. The risk of thermal runaway in microchannel reactors and batch reactors were discussed. The effects of wall insulation, inlet velocity, residence time, microreactor tube diameter and jacket temperature on the polymerization process were studied. A chaos criterion was included to provide early warning of a reaction runaway, which provides the basis for formulating the critical criterion of thermal runaway in a microreactor. The analysis of the thermal hazard of styrene thermal polymerization in the microreactor may be served as a reference for the design of the polymerization process and improve the reliability of microreactors in the production process. 2. Model Establishment 2.1. Modeling of the Batch ReactorA computational fluid dynamics (CFD) model of thermal polymerization of styrene was established based on a 2L batch reactor (RC1e). The batch model was established (Figure 1), and the mesh was generation by using Ansys software.Figure 1 illustrates the geometric model of the batch reactor. The total height of the reactor was 245 mm, the inner diameter was 115 mm, and the wall thickness was 5 mm, and the liquid level was 80.00 mm. The reactor was equipped with a four-blade propeller of 60 mm diameter, with 30° tilted blade impeller type. The reactor was divided into four parts, comprised of a form inside to outside, the stirring propeller, reaction fluid system, inner reactor wall, and outer cooling jacket. To ensure the accuracy of the numerical simulation, the reaction liquid system was assumed to be completely mixed during the simulation process, and the method of multiple reference frames (MRF) was used to solve the problem associated with using stirring blades. Several models were adopted, comprising the standard k-ε turbulence model, the enhanced wall model for the near-wall flow field. The fluid–solid coupling boundary conditions were used for the

Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds. — Antonella Ilenia Alfano et al., 2023

The increasing need for safer
and more sustainable practices has prompted chemists to re-evaluate
and re-design several synthetic protocols and strategies. Accordingly,
the pharmaceutical industry is in search of enabling technologies
to reduce process footprint, minimize lead time, and accelerate scale-up.
Flow chemistry allows the development of protocols for single chemical
reactions or multi-step synthesis in a continuous fashion in flow
set-ups of different scales. 1 The general
continuous-flow chemistry set-up involves different elements ( Figure 1 ). 2
A) General representation and B) main elements of a flow chemistry
set-up. BPR = back-pressure regulator.
Key advantages of flow technologies are summarized below: i) Faster reactions :
Flow reactors are easily pressurized, thus allowing increased heating
capability, which in turn can speed-up reactions. ii) Cleaner products :
Flow reactors enable excellent reaction selectivity; rapid diffusion
mixing avoids the issues found in batch reactors. 3 iii) Safer reactions :
Flow chemistry allows only a small amount of hazardous intermediate
to be formed at any instant; thus a flow reaction is intrinsically
safer with respect to the batch counterpart due to the lower reactor
volume. 4 iv) Integrated work-up and analysis : Reaction
products can be flowed into an aqueous work-up system
or a solid-phase scavenger column and then either be analyzed in line
or, using a sampler and diluter, be injected into an LCMS. v) Rapid reaction
optimization : Automated flow chemistry enables the quick
variation of reaction
conditions even on very small scales. vi) Easy scale-up : Scale-up
issues are minimized due to maintaining excellent mixing and heat
transfer. Three main strategies can be considered for scaling-up the
flow reaction, i.e., increase the number of reactors, increase the
channel length, and/or increase the channel diameter. 5 vii) Higher heat and mass transfer : This is mainly due to the
small dimensions, high interfacial surface
of reactors, and efficient reagent mixing. 6
Faster reactions :
Flow reactors are easily pressurized, thus allowing increased heating
capability, which in turn can speed-up reactions.
Cleaner products :
Flow reactors enable excellent reaction selectivity; rapid diffusion
mixing avoids the issues found in batch reactors. 3
S

afer reactions :
Flow chemistry allows only a small amount of hazardous intermediate
to be formed at any instant; thus a flow reaction is intrinsically
safer with respect to the batch counterpart due to the lower reactor
volume. 4
Integrated work-up and analysis : Reaction
products can be flowed into an aqueous work-up system
or a solid-phase scavenger column and then either be analyzed in line
or, using a sampler and diluter, be injected into an LCMS.
Rapid reaction
optimization : Automated flow chemistry enables the quick
variation of reaction
conditions even on very small scales.
Easy scale-up : Scale-up
issues are minimized due to maintaining excellent mixing and heat
transfer. Three main strategies can be considered for scaling-up the
flow reaction, i.e., increase the number of reactors, increase the
channel length, and/or increase the channel diameter. 5
Higher heat and mass transfer : This is mainly due to the
small dimensions, high interfacial surface
of reactors, and efficient reagent mixing. 6
Often, when conducting batch chemistry,
the use of hazardous reagents
and/or the generation of high-risk intermediates requires either a
work-around or the devising of a new route to avoid issues of potential
toxicity or extreme exothermic processes. 7 , 8 This
is particularly true when dealing with classical chemical rearrangements
(e.g., Curtius, Hoffmann, and Schmidt rearrangements) which encompass
the handling of hazardous, toxic, and/or pollutant chemicals as well
as high-risk intermediates. In this context, flow chemistry can provide
unique control over reaction parameters, enhancing the overall reactivity,
efficiency, and safety; it can also allow to in situ intercept the generated intermediates, thus allowing the generation
of more complex molecular architectures through multi-step transformations.
In this Technology Note we highlight recent advances in the field
of flow chemistry protocols for Curtius, Hofmann, and Schmidt rearrangements
applied to the synthesis of prominent functional units in several
active pharmaceutical ingredients.
The Curtius rearrangement
(CR) involves the thermal decomposition
of an acyl azide derived from carboxylic acid to produce an isocyanate
as the initial product; the latter then can easily undergo further
reactions

to provide amino, urea, or urethane functionalities (see Figure S1 for details). 9 The CR has found widespread application in the synthesis of privileged
scaffolds and approved drugs; 10 however,
it suffers from significant limitations related to the generation
and the use of potentially explosive and highly toxic azide promoters
and the corresponding acyl azide counterpart. In recent years, the
application of continuous-flow protocols for CR has been explored
for minimizing the use or generation of hazardous reagents, thus enabling
safer, high-yielding, and environmentally friendly processes.
In 2007, Jensen et al. used the CR as a model reaction to demonstrate
multi-step microchemical synthesis with in-line purification steps. 11 Micro-separators were specifically designed
to conduct liquid–liquid extraction and liquid–gas separation.
Acyl azides were prepared in situ upon mixing of
the acyl chloride with aqueous sodium azide in a microreactor, followed
by a liquid/liquid micro-separator. The organic phase containing the
azides was then flowed into another microreactor and heated to 90
°C to prompt CR. A gas/liquid separator was added to remove the
generated nitrogen, and the final carbamates were obtained upon reaction
between the generated isocyanates and the desired alcohols inserted
through a third microreactor ( Scheme 1 A).
In a follow-up paper by Baumann et al., an azide ion-exchange monolith
reactor was developed for the conversion of acyl chlorides into their
corresponding isocyanates via the acyl azide intermediate, to increase
the safety profile of the reaction. 12 The
azide-exchange monolith was prepared directly in the flow reactor
column and used in the following flow reactions. 1 mmol of a 1 M solution
of the acyl chloride in MeCN was passed through a column with an azide
monolith (15 mmol) for a residence time of 13 min, to guarantee complete
and fast conversion. The monolith-containing column was followed by
another column packed with Na 2 SO 4 as the dehydrating
agent, thus avoiding side-reactions. Subsequently, the solution was
passed through a tubular flow reactor and heated to 120 °C to
enable CR. The output isocyanate stream was collected

Translation of Batch to Continuous Flow in Photoredox Reactions. — Tomohiro Yasukawa et al., 2021

The vast majority of chemical syntheses are carried
out by either batch or flow methods ( Figure 1 ). Batch methods are commonly used for fine
chemical synthesis in fields such as active pharmaceutical ingredients
(APIs), agrochemicals, and fragrances; in this approach, all reagents
are charged into a reaction vessel where they react. In the flow method,
materials are continuously introduced from one end into a hollow loop
or column as reactors, and products are continuously eluted from the
other end. The continuous-flow method has several advantages over
the batch method in terms of efficiency, safety, and scalability,
and is suitable for on-demand synthesis. 1 Another advantage can be seen in photoredox catalysis, in which
photon-harvesting molecules convert light energy into chemical energy.
Photoredox catalysis is currently being studied very extensively because
it is environmentally friendly and can be used to achieve unique reactions
via high-energy intermediates. 2 However,
most of these processes have been developed as batch methods, which
pose a problem for scale-up. This is because, as known by the Beer–Lambert
law, when the volume of the reaction vessel is increased, insufficient
light intensity may reach the interior of the reaction mass. Flow
reactions, which utilize a narrow tubular space, can be used to overcome
this problem. 3 Despite the many advantages,
research on the synthesis of fine chemicals by flow reactions has
lagged far behind that of batch reactions, and a method to develop
flow reactions more rapidly is desired. In this issue of ACS
Central Science , MacMillan et al. describe an approach in
which microscale high-throughput experimentation (HTE) is used to
identify optimal reaction conditions that can be directly translated
to flow systems. 4
Batch
reactions vs flow reactions.
There are several issues that make rapid optimization of flow reactions
difficult: (1) each reaction requires a pump and a reactor, and thus
experiments are not possible to perform in parallel with a single
flow system; (2) the size of the flow reactors often influences the
optimal reaction conditions; (3) compared with microscale batch reactions,
flow reactions require much larger amounts of reagents; and (4) generation
of precipitation causes clogging. To overcome these problems in optimizing

flow reactions, MacMillan et al. developed the flow simulation (FLOSIM)
HTE setup, which matches the path length of irradiation under flow
conditions. The platform consists of a multienvironment 96-well glass
plate device, two Kessil LEDs (PR160), two ThorLabs concave lenses,
and a fan ( Figure 2 ). After examining the position and number of LEDs and fans, the
homogeneity of the system was confirmed. The general workflow for
the translation of a photoredox reaction from batch to flow is that
(1) HTE screening is performed on a 96-well glass plate, where it
is exposed to light irradiation for a short period of time equivalent
to the desired residence time in the flow system; (2) the crude reaction
mixtures are analyzed by ultraperformance liquid chromatography (UPLC,
4 min per sample); and (3) the optimal conditions determined by the
platform can be directly reproduced in a commercial flow system.
FLOSIM device reproduced with permission
from ref ( 4 ). Copyright
2021 The Authors. Published by the American Chemical Society.
The platform enables several hundreds to 1000 “flow-type”
reactions to be performed in short order to examine the effect of
residence time, solvent, concentration, organic base, photocatalyst,
catalyst loading, and the transition-metal complex. The authors achieved
several reactions, optimized by the HTE systems, in multigram flow
conditions, such as decarboxylative C–C coupling ( Figure 3 a), 5 decarboxylative C–N coupling ( Figure 3 b), 6 cross-electrophile
coupling ( Figure 3 c), 7 and C–O coupling ( Figure 3 d) reactions. 8 In all cases, the low, moderate, and high yield results under HTE
conditions could be reproduced under flow conditions and multigram
synthesis in flow. One of limitations is that conditions that generate
precipitation during the reaction cannot be applied to flow because
it causes clogging of the tube reactor. In cross-electrophile coupling,
the initial optimized conditions using 2,6-lutidine failed to translate
to the flow reaction because the poorly soluble lutidine salt formed.
In this case, the authors performed approximately 1000 experiments
to

identify homogeneous conditions. Finally, decreasing the amount
of base and switching to N , N -dimethylacetamide
as a more polar solvent enabled the precipitation issue to be overcome,
and the high efficiency of the new conditions could be translated
to the flow reaction. MacMillan et al. also demonstrated that HTE
FLOSIM optimization was applicable to various commercial flow reactors.
Achieved
reactions under multigram flow conditions.
High-throughput screening of flow reactions, especially at the laboratory
level, is difficult because of the cost and size of the equipment.
The platform described herein solves these problems with an approach
in which batch reactions can reproduce the results of flow reactions.
Although flow reactions are very compatible with automated control
by machines combined with autosamplers, the authors’ method
is efficient and can be applied not only to photoredox reactions but
also to various homogeneous reactions. However, the current approach
is not considered to be easily translatable to flow reactions in which
the liquid is pumped into a column packed with a heterogeneous catalyst.
If organic reactions can be developed and optimized rapidly using
flow methods, it could be a revolution in fine chemical synthesis.