Research Progress on Continuous-Flow Nitrification Technology and Equipment

Abstract

The mixture of concentrated nitric and sulfonic acids (mix acid) has been commonly used as a nitration reagent for the preparation of nitro compounds. Compared with the traditional batch reactor, continuous-flow nitrification technology has been recognized by the industry for its higher safety and production efficiency. As a frontier and hot topic in chemical engineering, continuous-flow reactor has gradually become an important platform for the development of new equipment, new processes, and new products for drug synthesis. Combining flow chemistry with real-time process analysis allows the study of reaction kinetics and the monitoring of the chemical synthesis process. In this work, the application of continuous-flow reaction technique in nitrification of aromatic rings, aromatic heterocycles, and aliphatic compounds is summarized. Based on process analysis technology and multistep series continuous-flow reaction to synthesize nitro compounds, the safe technology of nitrification reaction is realized in the green safety process.

 

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Keywords

continuous-flow technology - nitration reaction - process analysis technique

Introduction

The reaction between an organic compound and a nitrifying agent provides a straightforward entry to introduce a nitro group into the carbon, nitrogen, or oxygen atoms of the organic compound, which is called nitration reaction, including the nitration of common compounds such as aromatic hydrocarbons and their derivatives, alcohols, and heterocyclic compounds, etc. The reaction is widely used in the synthesis of pharmaceuticals, pesticides, dyestuffs, and energy-containing materials, and accounts for a very high proportion of the synthesis of fine chemicals. The nitrification reaction belongs to the most critical class of exothermic reactions; however, the kettle reactor cannot transfer the heat in time, and there are local hot spots in the reaction process, which may lead to the loss of control.[1] Nitrification reaction with a continuous and safe production is the current research hotspot.[2]

Continuous-flow technology, also known as flow chemistry, is an emerging interdisciplinary field that has attracted the interest of researchers in the fields of organic synthesis and green chemistry in the past two decades. In recent years, continuous-flow chemistry has made remarkable achievements in both academic research and industrial applications.[3] [4] [5] [6] Compared with the kettle reactors, the advantages of the continuous-flow technology, including the ease of automation, guaranteed reproducibility, improved safety, and process reliability, are now widely recognized.[7]

Process analytical technology (PAT) is a system for designing, analyzing, and controlling production through timely measurements of key quality and performance attributes of raw materials, intermediates, and processes. The combination of continuous-flow technology and PAT enables rapid and accurate determination of key parameters in the production process, improving production efficiency, and product quality.

This paper focuses on introducing several successful cases and the related kinetic studies of continuous-flow reactors in the development and application of nitrification processes in the past decades, elucidating the significant advantages of continuous-flow reaction technology and presenting the challenges and future development direction of continuous-flow technology.

 

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Nitration of Aromatic Compounds

Nitration of Benzene and its Derivatives

Aromatic nitration is arguably one of the most extensively studied transformations in organic synthesis. The reaction typically involves a nitrating mixture of concentrated nitric acid and concentrated sulfuric acid. However, this aromatic nitration still faces some unresolved technical challenges because it is multiphase and highly exothermic, thus requiring careful heat management. Benzene is the simplest aromatic hydrocarbon and is used as a starting material for the synthesis of various organic compounds. Zhao et al reported the synthesis of m-dinitrobenzene via a two-step continuous-flow nitration of benzene.[8] Industrially, m-dinitrobenzene is produced via a two-step nitration process of benzene. In the first nitration stage, the ratio of benzene to nitric acid is 1:1.2, the residence time is 115 seconds, the reaction temperature is 60°C, and the concentration of sulfuric acid is 49.5%. Nitrobenzene was obtained with a 99.5% conversion rate and 99% selectivity. In the second nitration stage, the reaction conditions were 70°C and 1.2 equiv. of nitric acid. The conversion rate of nitrobenzene reached 99.5%, with a 90.88% selectivity in 180 seconds. This makes the process very economical. Compared with the kettle type, the residence time is shortened from 180 to 4 minutes, and the space-time yield increased from 1.07 to 803.1 mol/L/h, a full 800 times.

Yang et al studied the nitration of toluene with mixed acid in a continuous-flow microreactor.[9] The preferred reaction condition was 48.8°C and H₂SO₄/HNO₃ (molar ratio 1:1.29). The yield of m-nitrotoluene was 77.85% in 164.84 seconds. Zhao's group has also developed a continuous-flow nitrification process for toluene in an ultrasonic microreactor.[10] The effects of acoustic cavitation and ultrasound assistance on the nitrification reaction were investigated. The results showed that the use of high-viscosity solvents could serve as a better sonication and speed up the reaction. Increasing the temperature, prolonging the residence time, and using ultrasound irradiation all increased the conversion by 9.9 to 36.3%. Later, Song et al studied a nonhomogeneous continuous flow for toluene ([Fig. 1]).[11] The effects of temperature, concentration of H₂SO₄, and residence time on toluene conversion were investigated, and the reaction kinetics were experimentally studied. The activation energy of the toluene nitration reaction was found to be 28.00 ± 1.51 kJ/mol. The activation energies for the formation of 2-nitrotoluene and 4-nitrotoluene were found to be 25.71 ± 2.20 and 31.91 ± 3.36 kJ/mol, respectively.

Fig. 1 Heterogeneous continuous-flow nitration of toluene.

Guo et al studied a continuous-flow nitrification process for o-xylene.[12] The microreactor with a concentration of 94% nitric acid and a temperature of 323 K achieved a conversion rate of 100% in 9 seconds. The volumetric mass transfer coefficient of the microreactor reached 0.33/s. Compared with other conventional liquid–liquid contactors, the device has superior performance in terms of overall mass transfer coefficient and power consumption. Subsequently, a kinetic model of the o-xylene nitration reaction was developed, and the kinetic parameters were obtained, with an activation energy of 53.05 kJ/mol and a finger-forward factor of 1.94 × 10⁷ L/mol/s. Song et al investigated the continuous nitrification pilot process of o-xylene.[13] They used a flow unit consisting of a heat exchanger and fluid modules. Each fluid module produces three flow zones: two heat transfer zones (unit volume area of 788.5/m) and a reaction zone (8.3 mL volume). The maximum flow rate was 200 mL/min, and replenishing the mixed acid midway could improve the conversion from 74.5 to 94.1%. Compared with the kettle type, the amount of phenolic impurities was reduced from 2 to 0.1%, and the yield reached 94.1% with a temporal and spatial yield of 800 g/h.

Prior to the above work, Sagandira et al had reported continuous-flow nonhomogeneous nitration of m-xylene.[14] The team used 1 mL glass plate reactor and a 4.5 mL glass plate reactor. The effective mixing of the reactants was achieved at the residence time of 6 minutes in attribution to the heat transfer in the glass plate reactor. The conversion rate increased to 90% and the selectivity increased to 95%, indicating that mass transfer elimination is very important in the nitrification reaction. Guo et al obtained 1,3-dimethyl-2-nitrobenzene and 2,4-dimethyl-1-nitrobenzene via two-step continuous-flow nitrification of m-xylene ([Fig. 2]).[15] Compared with the conventional one-step nitrification, the unreacted m-xylene can be further nitrated by adding sulfuric acid in the second step. Under the optimum experimental conditions, mono-nitrate product was achieved with a yield of 99% at 1 kg/h. This method effectively reduces the generation of polynitro impurities, with an average content of 0.45%. Meanwhile, the team applied the two-step nitrification method to the continuous-flow nitrification process of mesitylene.[16] Under the reaction temperature of 45°C, the residence time of 60 seconds, nitric acid mass fraction of 65%, and the molar ratio of mesitylene/nitric acid (98%)/sulfuric acid (80%) (1:2.6:1.53), the conversion was >99%, the yield was 95%, and the purity was 97% with a temporal and spatial yield of 1.88 kg/h. Compared with the traditional kettle reaction, the dosage of sulfuric acid was reduced by 7.6 times, and the reaction time was shortened from 4 hours to 60 seconds.

Fig. 2 Two-step continuous-flow mononitration of m-xylene.

In a recent report, Jin et al presented the nonhomogeneous continuous-flow nitrification of nitrobenzene to prepare 1,3-dinitrobenzene ([Fig. 3]).[17] By observing the mixed droplets with a high-speed CCD camera, the segment plug flow and the droplet flow were stable and controllable, which were suitable for the nitrification process. The conversion rate reached 95% and the selectivity was 89% in 600 seconds when the reaction was performed at 65°C in a solution of nitrobenzene/nitric acid/sulfuric acid (1:2:4.3). On this basis, a proposed homogeneous kinetic model was established to determine the kinetic parameters of the reaction, and the activation energy was found to be 71.229 kJ/mol.

Fig. 3 Heterogeneous continuous-flow nitration of nitrobenzene.

Li et al studied the nonhomogeneous continuous-flow nitration of 3-[2-chloro-4-(trifluoromethyl)phenoxy]benzoic acid ([Fig. 4]).[18] When the residence time was 220 seconds at 35°C, the conversion was 83.03% and the selectivity was 79.52% at a substance ratio of substrate/nitric acid/sulfuric acid (1:1.6:2.8). The authors also investigated the effect of internal diameter on the reaction. When the internal diameter was increased from 0.5 to 1.59 mm, the conversion was decreased from 80 to 75.5%. The larger the internal diameter and the smaller the flow rate affect the mass transfer, which is not favorable to the reaction rate. Finally, the values of the preexponential factor A and activation energy E_a were obtained and determined to be 3.75 × 10⁴ m³/(mol·s) and 37.9 kJ/mol, respectively.

Fig. 4 Mononitration of 3-[2-chloro-4 -(trifluoromethyl)phenoxyl]benzoic acid.

Xu et al developed a continuous-flow protocol for the preparation of 1-nitronaphthalene from naphthalene ([Fig. 5]).[19] The maximum yield of 94.96% was achieved at a substance ratio of naphthalene/nitric acid (1:1.2) in 120 seconds when the reaction temperature was 30°C. The team studied the apparent reaction rate constants under optimal conditions and combined the energy conservation equation with the mass conservation equation to derive the temperature distribution of the microchannel reaction under optimal conditions. When the conditions were extended to a pilot-scale flow reactor, the proportion of dinitronaphthalene was increased from 3.5 to 8.75% due to the greater limitation of mass transfer. The time was reduced from 80 to 2 minutes, the selectivity could be increased to 88%, and the temporal and annual yields were 50 times higher than the kettle type.

Fig. 5 Mononitration of naphthalene.

Song et al investigated the nitration kinetics of o-nitrotoluene and p-nitrotoluene in a homogeneous microfluidic system, respectively ([Fig. 6]).[20] [21] The team obtained the apparent reaction rate constants based on HNO₃ and NO₂ ⁺, finger front factor and nitrification activation energy, respectively, and established a general method for the kinetic data acquisition of nitrotoluene nitrification, which is a fast and highly exothermic nitrification reaction. The model reports for the first time the finger front factor and activation energy of the nitration reaction of o-nitrotoluene and p-nitrotoluene. The activation energy of o-nitrotoluene nitration was 72.358 ± 2.075 kJ/mol. The activation energy for the formation of 2,4-dinitrotoluene was 70.239 ± 1.808 kJ/mol, that for the formation of 2,6-dinitrotoluene was 78.298 ± 1.252 kJ/mol, and that for the nitration reaction of p-nitrotoluene was 50.207 ± 1.496 kJ/mol.

Fig. 6 Continuous-flow nitration microreactor of o-nitrotoluene and p-nitrotoluene.

3,5-Dinitro-2-methylbenzoic acid is an important raw material for the synthesis of dinitrozolamine, which is a commonly used antiprotozoal agent in poultry farming. Yu et al established a continuous-flow synthesis of 3,5-dinitro-2-methylbenzoic acid from o-toluic acid under isothermal and adiabatic conditions, respectively ([Fig. 7]).[22] Compared with the conventional kettle reaction, this continuous-flow protocol can significantly shorten the reaction time and improve productivity. In addition, the purity of the complex was above 99.5% and the yield was as high as 96% at 1586 g/h.

Fig. 7 A continuous-flow process for the synthesis of 3,5-dinitro-2-methylbenzoic acid.

Picramide is used as a key intermediate in the preparation of energetic materials such as triamino and trinitrobenzene. It is used as a precursor for the preparation of 2,4,6-trinitrophenylhydrazine and has applications in dye chemicals. Maiti et al synthesized picramide from continuous-flow nitration of p-nitroanisole ([Fig. 8]).[23] The yield could reach 98% when the molar ratio of substrate and nitric acid is 1:2.5, the residence time is 2.5 minutes, the reaction temperature is 80°C, and the sulfuric acid intensity is 98%. Compared with the batch process, the flow process has significant advantages in terms of selectivity and yield. The process could achieve a production rate of 25 g/h in a laboratory flow reactor. This method can be used for safe production on a commercial scale.

Fig. 8 A continuous-flow nitration process of p-nitroanisole.

Guo et al studied the continuous-flow nitrification and kinetics of (trifluoromethyl)benzene in a microreactor ([Fig. 9]).[24] The nitrification reaction was first carried out using a capillary microreactor. However, the resultant conversion rate was low and did not achieve the expected results. Consequently, a heart-shaped micro-mixer with a barrier was used. The results showed that the volumetric mass transfer coefficient of the heart-type micro-mixer was more than 15 times higher than that of the t-type micro-mixer, and sulfuric acid consumption was significantly reduced by a factor of 3.5 compared with the batch reactor. The temporal and spatial yield of the heart-type micro-mixer was two orders of magnitude higher than that of the batch reactor. Under optimal conditions, a residence time of only 30 seconds was achieved, and the conversion of (trifluoromethyl)benzene could reach 100%. The nitration kinetics of (trifluoromethyl)benzene in a capillary microreactor were reported for the first time, and the activation energy for the nitration of (trifluoromethyl)benzene was 86.33 kJ/mol.

Fig. 9 Nitration of trifluoromethyl benzene.

Nonsmall cell lung cancer accounts for about 87% of lung cancer. Erlotinib is a targeted drug for the treatment of nonsmall cell lung cancer, showing excellent therapeutic efficacy and tolerability. Hui et al developed a novel continuous-flow process for the synthesis of erlotinib ([Fig. 10]).[25] The product was obtained through etherification, nitration, reduction, addition, and cyclization reactions in five continuous-flow units, using inexpensive reagents as starting materials. In the nitrification stage, the reaction solution of 3,4-bis(2-methoxyethoxy)benzonitrile was introduced into a membrane separator at the end of the reaction for online liquid–liquid separation by using an LTF chip reactor. The final optimized process can reach a 99% yield in 5 seconds, which is sufficient to illustrate the unique mixing performance of the chip reactor. Finally, the continuous-flow five-step synthesis of erlotinib was achieved in 83% overall yield with a total residence time of 25.1 minutes.

Fig. 10 A continuous-flow nitration process for the synthesis of the key intermediate of erlotinib in LTF slice reactor.

Sagmeister et al used nuclear magnetic resonance (NMR) to optimize continuous-flow nitration of salicylic acid for the synthesis of mesalazine intermediates ([Fig. 11]).[26] Inline bench-top NMR analysis is a powerful tool for reaction monitoring, but its capabilities are somewhat limited by low spectral resolution, which often leads to peak overlap and quantification difficulties. Processing data using data analysis methods, such as multivariate analysis, overcomes these obstacles and allows for accurate quantification of the different components of complex spectra, enabling the generation of Design of Experiments (DoE) models that are accurately reconciled between online NMR and off-line high-performance liquid chromatography (HPLC) analyses. The power of benchtop NMR can be fully realized in the automated optimization of flow chemistry, mechanistic experiments, and process control.

Fig. 11 Synthesis of mesalazine intermediate using an inline NMR continuous nitration. NMR, nuclear magnetic resonance.

 

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Nitration of Halobenzene

Mesalazine is an anti-inflammatory drug, commonly used in ulcerative colitis, with 5-aminosalicylic acid as the main active ingredient, and is mainly used in the treatment of ulcerative colitis. Kappe' group designed a fully integrated multistep reaction and real-time analysis platform controlled in a single software system.[27] [28] The platform synthesized mesalazine under fully controllable and robust conditions with three synthetic steps of nitration, substitution, hydrogenation, and three-phase separations in a spatiotemporal yield of 1.6 g/h ([Fig. 12]). Mesalazine (5-ASA) was synthesized from 2-chlorobenzoic acid (2ClBA), and each of the following synthetic steps was analyzed in real time by using different PAT tools and UHPLC. In the nitration reaction step, the reaction liquid obtained by membrane separation can be detected by ¹H NMR spectra of the nitrification product using inline NMR (Magritek, Spinsolve Ultra 43 MHz), and quantified using an indirect hard model approach. The hydroxide ion concentration was also quantified based on the NMR data, and the resulting model could help to accurately quantify the components from the process spectra.

Fig. 12 Continuous-flow nitration of 2-chlorobenzoic acid using an inline NMR. NMR, nuclear magnetic resonance.

As a basic organic synthetic raw material, chlorobenzene is widely used in chemical, pharmaceutical, and pesticide fields. Chlorobenzene is also used as a solvent and catalyst in organic synthesis reactions. Further, dichlorobenzene and trichlorobenzene are widely used in pesticides and pharmaceuticals. Cui et al studied the processes of nitrification of chlorobenzene in a continuous-flow microreactor system ([Fig. 13]).[29] A kinetic model was developed based on the conversion rates at different times, and an apparent reaction rate constant was obtained, with an activation energy of chlorobenzene nitration of 25.98 kJ/mol. The results showed that the nitrification rate was closely related to the temperature and the concentration of sulfuric acid. The k_obs value was increased with the increase in temperature. At the same temperature, the k_obs value enhanced significantly as the mass fraction of sulfuric acid increased from 85 to 95%.

Fig. 13 Nitration of chlorobenzene in a continuous-flow microreactor system.

Lan and Lu studied a continuous-flow nitrification process for o-dichlorobenzene.[30] The team combined a scheme of adiabatic nitrification, a microfilled bed reactor, and partial product recirculation. Under adiabatic conditions, the microfilled bed reactor was able to maintain a better two-phase dispersion, the reaction was carried out thoroughly with a residence time of 5 seconds or less, and the selectivity was maintained at more than 89%, and the activation energy E_a for the nitration reaction of o-dichlorobenzene was found to be 30.96 ± 0.87 kJ/mol.

Sulfentrazone is the first triazolinone herbicide successfully developed and launched by FMC in 1996. Cao et al developed a continuous-flow nitrosation process for the synthesis of 2-(2,4-dichloro-5-nitrophenyl)-4-(difluoromethyl)-5-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one, a key intermediate of the triazolinone herbicide sulfentrazone ([Fig. 14]).[31] When the molar ratio of feedstock/H₂SO₄/ HNO₃ was 1:1.1:6.6, the product yield was up to 97% at 60°C with a residence time of 30 seconds, which was higher than that of the conventional kettle type of 75%. The activation energy E_a of the reaction was 40.204 kJ/mol.

Fig. 14 A continuous flow for the synthesis of sulfentrazone intermediates.

Chen's group prepared 5-fluoro-2-nitro-1-(trifluoromethyl) benzene using 3-fluoro- 1-(trifluoromethyl) benzene as the raw material.[32] When the molar ratio of C₇H₄F₄/HNO₃/H₂SO₄ was 1:3.77:0.82, the yield of the desired product was up to 96.4% at 0°C. Compared with the traditional nitrification method, the continuous-flow process was mild and stable with high mass and heat transfer efficiency, which effectively suppressed the generation of impurities and improved production efficiency.

Guo et al investigated the homogeneous continuous-flow nitrification reaction of 2,4-difluoro-1-nitrobenzene and the kinetics.[33] The results showed that the mixing limited the conversion rate of 2,4-difluoro-1-nitrobenzene, suggesting that mixing was the main factor affecting the low conversion of the T-type microreactor. Then, a heart-shaped microreactor with a mixing efficiency three orders of magnitude higher than a T-shaped microreactor was used. As a result, an intrinsic kinetic model was developed based on NO₂ ⁺ with an activation energy of 60.44 kJ/mol for the nitration of 2,4-difluoro-1-nitrobenzene ([Fig. 15]).

Fig. 15 Heart-shaped microreactor.

 

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Nitration of Anilines

In November of 2015, ositinib was approved by the Food and Drug Administration as the first third-generation lung cancer-targeted drug to be marketed in the United States. Köckinger et al investigated a continuous-flow synthesis process of N-(4-fluoro-2-methoxy-5-nitrophenyl)acetamide, a key intermediate of ositinib ([Fig. 16]).[34] The raw material is reacted with acetic anhydride and then proceeded to nitration using a modular flow platform and the online liquid phase that allows for rapid data acquisition. The purity of the reaction liquid was greater than 99% with 82% yield. The spatiotemporal yield was 25 mmol/h when the molar ratio of HNO₃/H₂SO₄ was 1:1. At the same time, the team conducted a pilot scale using a larger-scale flow reactor that allowed for more efficient heat and mass transfer, with flow rates of up to 600 mL/min, and fluxes of up to 5 mol/h. The final yield was 83%, with a purity greater than 99%, and a spatiotemporal yield of 2 mol/h, which was 80 times higher than the previous laboratory protocol.

Fig. 16 A continuous-flow process for the synthesis of N-(4-fluoro-2-methoxy-5-nitrophenyl)acetamide, an intermediate of ositinib.

Dimethoate, chemically named “N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitroaniline,” is a widely used selective herbicide for the control of weeds and grasses in cotton, soybeans, rice, barley, and other crops. Hussain investigated the scale-up of the dinitrosation reaction for the selective synthesis of the herbicide dimethoate by using nitric acid in continuous flow ([Fig. 17]).[35] The authors developed a model to predict the outcome of the high-volume reaction by determining the reaction kinetics. The model predictions indicated that 1/4-inch SS316 tubing was sufficient to dissipate heat efficiently under scale-up conditions and was suitable for obtaining the desired yield. The efficient mixing and mass transfer requirements of the reaction were realized using a clamped tube reactor and a pilot reactor was fabricated. Finally, the authors analyzed measurements of residence time distributions, heat transfer coefficients, and mass transfer coefficients based on a laboratory-scale flow reactor and a pilot-scale reactor for the production of dimethenolide in a pilot plant (clamped tube flow reactor) with a production capacity of 50 kg/d.

Fig. 17 Continuous-flow dinitration of dimethylpentalin.

 

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Nitration of Aromatic Heterocyclic Compounds

In recent work, Zhou et al realized a continuous nitrifying–quenching–neutralization–extraction full continuous-flow process for the synthesis of 4-nitropyrazole from pyrazole ([Fig. 18]).[36] When the molar flux ratio of pyrazole, fuming nitric acid, and concentrated sulfuric acid was 1.0:1.1:6.0, the total residence time was 33.5 minutes, and the reaction temperature was 60°C, the final product yield was 96.9%, the purity was 99.3%, and the yield of 4-nitropyrazole was 381 g/h. The activation energy of the nitration reaction was obtained as 72.65 kJ/mol. The process significantly suppressed denitrification side reaction and overcame the problems of hydrolysis of extraction solvents and solids plugging. The process applies not only to the same type of products but also to liquid–liquid two-phase reactions where immediate separation of the products is required and can be easily scaled up by running multiple high-throughput reactors in parallel.

Fig. 18 Continuous nitrifying–quenching–neutralization–extraction of 4-nitropyrazole in a fully continuous-flow process.

Several companies such as Jiangsu Kanglejia Material Co., Ltd. have applied for a patent ([Fig. 19]).[37] 2-Methyl-5-nitroimidazole was synthesized using a SiC microchannel reactor, with a yield of 74%, and a process production of 316 kg. The whole operation was in the continuous-flow reactor, and the reaction was safe and controllable. The patent claims to use a superacid catalyst based on sulfate Fe₃O₄-Al₂O₃, which minimizes the amount of acid required for the reaction.

Fig. 19 A continuous-flow nitration process for the synthesis of 2-methyl-5-nitroimidazole.

Duchuang Medical Development Co., Ltd. applied for a patent on continuous-flow nitration of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde ([Fig. 20]).[38] They used potassium nitrate as the nitrification agent, producing 3,5- dimethyl -4 -nitropyrrole -2- carbaldehyde through a liquid–liquid two-phase nitrification reaction in a microreactor. The molar equiv. ratio of raw material to potassium nitrate was 1:1.05, the product purity was 96.69%, and the yield was 98.75%. By using two stages of nitration, the continuous operation of the nitration process was realized, thereby greatly reducing the amount of sulfuric acid, and the danger level of the nitration reaction.

Fig. 20 A continuous-flow nitration process for synthesis of 3,5-dimethyl-4-nitro-1H-pyrrole-2-carbaldehyde.

 

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Aliphatic Nitration

Nitration of aliphatic compounds with continuous-flow protocol has also been investigated. For example, Guo et al synthesized 2-ethylhexyl nitrate through a continuous-flow nitrification process ([Fig. 21]).[39] A quadratic correlation model between four factors and yield was developed by the design of the Box–Behnken response surface method. The model can predict the yield of 2-ethylhexyl nitrate within the range of four factors of experimental design. The calculations resulted in a purity of 99.6% and a yield of 99%. The team then used computational fluid dynamics methods to simulate the mixing effect of a liquid–liquid nonhomogeneous phase system in the microreactor. The experiment demonstrated that the microreactor had a good mixing efficiency in terms of mass and heat transfer. Finally, a scaled-up microreactor was designed for the intensive preparation of 2-ethylhexyl nitrate at a flux of 16 kg/h.

Fig. 21 A continuous-flow nitration process for the synthesis of 2-ethylhexyl nitrate.

Nitrites are a kind of important organic compounds as they have a wide range of applications in energy-containing materials, pharmaceuticals, and fuel additives. Mittal et al developed a continuous-flow nitration process of olefins via a tert-butyl nitrite ([Fig. 22]).[40] tert-Butyl nitrite has been prepared at a residence time of 1 minute with 95% yield and a spatiotemporal yield of 13 g/h/mL, then, metal-free stereoselective nitration of olefins was carried out. According to the fixed-bed column reactor, the reaction time was reduced from 12 hours to 3 minutes due to better liquid–air contact, which was applied to a range of styrene derivatives, demonstrating good tolerance.

Fig. 22 A continuous-flow nitration process of olefin.

Jiang et al combined a self-designed heart-shaped channel-integrated chip microreactor with a tracked microreactor to develop a two-step continuous nitrification process for the synthesis of BuNENA, a new type of high-performance energetic plasticizer ([Fig. 23]).[41] The reaction conditions including two-stage reaction temperature, volume flow rate, and nitrating agent dosage were screened. When the flow rate of n-butylethanolamine was 1.00 mL/min, the temperature of the heart-shaped channel microreactor was 10°C, the temperature of the caterpillar microreactor was 35°C, the molar ratios of ZnCl₂ to n-butylethanolamine was 0.02, nitric acid to n-butylethanolamine was 2.4, and acetic anhydride to n-butylethanolamine was 2.5, BuNENA was obtained in 87.1% yield with 98.1% purity.

Fig. 23 BuNENA's two-step continuous nitrification process.

 

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Summary and Outlook

Nitrification reaction is widely used in the synthesis of dyes, pesticides, pharmaceuticals, optical materials, and other fine chemicals. However, due to the potentially strong exothermic effects, the nitration process system is prone to local “hot spots,” incurring uncontrolled reactions, rapid decomposition of organic nitrates, and the rapid rise in the temperature of the system, resulting in safety accidents. For the nitrification of an aromatic ring, aromatic heterocycles, and aliphatic compounds, a continuous-flow reactor could effectively reduce the risk of nitrification and improve the selectivity and productivity of the reaction with a small amount of online materials.

Although continuous-flow reaction has significant advantages, it solves only some problems of traditional kettle reactions. It still faces some technical difficulties. On the one hand, a continuous-flow reactor has a small diameter, the fluid flow is usually in a laminar flow state, the surface tension is significant, and the slurry with large solid content is very easy to plug, which makes the cleaning of the reactor inconvenient. Therefore, it is necessary to use a reactor suitable for solid–liquid reactions for follow-up studies. On the other hand, the PAT tool is mainly used to monitor changes in components, which is beneficial for reaction monitoring and process control. When calculating the nitrification kinetics, it is necessary to introduce online monitoring equipment to monitor changes in concentration in real time to obtain more accurate kinetic data, as the nitrification reaction is very rapid.

As an emerging reaction technology, continuous-flow reaction has been widely used in the synthetic research of pharmaceuticals, pesticides, chemical products, and their intermediates in recent years, demonstrating its great practical application potential. With the advancement of flow chemistry theory and continuous-flow reaction technology, more and more continuous-flow reaction devices have been continuously developed, and it can be envisaged that the application of continuous-flow microreaction technology will gradually become common in the chemical–pharmaceutical industry in the near future.

 

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Conflict of Interest

None declared.

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Publication History

Received: 20 November 2024

Accepted: 08 April 2025

Article published online:
19 May 2025