Continuous Flow Nitrification
Scope of application of continuous flow nitration
Free radical nitration reactions usually involve high temperature and high pressure. Continuous flow microchannel reactors may be applicable to individual substrates, but they are not universal.
Nitration reactions of substrates with active groups such as hydroxyl and amino groups are often very violent and suitable for continuous flow microchannel reactors.
Nitration of aromatic ring compounds is the most important type of nitration reaction. The applicability of continuous flow microchannel reactors is mainly affected by the activity of aromatic rings caused by different substituents.
Nitration is one of the most studied organic reactions. Both aromatic and aliphatic compounds can be nitrated by various methods, such as heterolytic cleavage (electrophilic and nucleophilic) and free radical nitration. The most common nitration of aromatic compounds is electrophilic, while that of aliphatic compounds is free radical. Nitroaromatic compounds have important uses as intermediates in the synthesis of plastics, drugs, dyes, explosives and pesticides. Nitroaliphatic compounds are used as solvents and synthons in organic synthesis. The most common nitration mixture is a combination of nitric acid and sulfuric acid, and many different methods are provided in the literature.
Nitration is the process of introducing a nitro group (-NO2) into an organic compound molecule. A nitro group is a monovalent group formed by nitric acid losing a hydroxyl group. The reaction mechanism of aromatic compound nitration is: the -OH group of nitric acid is protonated, and then a molecule of water is removed by a dehydrating agent to form a nitroyl cation intermediate, and finally an electrophilic aromatic substitution reaction occurs with the benzene ring and a molecule of hydrogen is removed.
The electron density of the aromatic ring in the nitration reaction determines the reaction rate of the nitration. The higher the electron density of the aromatic ring, the faster the reaction rate. Since the nitro group itself is an electrophile, the electron density of the aromatic ring decreases after the first nitration, which often inhibits the second and subsequent nitration reactions. It must be carried out under more intense reaction conditions (such as high temperature) or stronger nitrating agents.
Dehydrating agents: concentrated sulfuric acid, glacial acetic acid, acetic anhydride, phosphorus pentoxide.
Nitrating agents: nitric acid, nitrogen pentoxide.
Main methods of continuous flow nitration reaction
The main nitration methods are: dilute nitric acid nitration, concentrated nitric acid nitration, nitration with nitric acid in concentrated sulfuric acid, nitration with nitric acid in organic solvents, and heterogeneous mixed acid nitration.
Precautions for continuous flow nitration reaction
1. Dilute nitric acid nitration is generally used for the nitration of aromatic compounds containing strong first-class directing groups. The reaction is carried out in stainless steel or enamel equipment, and the nitric acid is about 10~65% in excess.
2. Nitration with concentrated nitric acid This type of nitration often requires many times more nitric acid, and the excess nitric acid must be used or recovered, which limits its practical application.
3. Homogeneous nitration in concentrated sulfuric acid medium When the nitrated substance or nitration product is solid at the reaction temperature, the nitrated substance is often dissolved in a large amount of concentrated sulfuric acid, and then a mixture of sulfuric acid and nitric acid is added for nitration. This method only requires the use of a small amount of excess nitric acid, and generally has a high yield. The disadvantage is that the amount of sulfuric acid used is large.
4. Heterogeneous mixed acid nitration When the nitrated substance or nitration product is liquid at the reaction temperature, the method of heterogeneous mixed acid nitration is often used. Through strong stirring, the organic phase is dispersed into the acid phase to complete the nitration reaction.
5. Nitration in organic solvents The advantage of this method is that the use of different solvents can often change the ratio of the obtained nitro isomers, avoid the use of a large amount of sulfuric acid as a solvent, and use a near-theoretical amount of nitric acid. Commonly used organic solvents include acetic acid, acetic anhydride, ethylene dichloride, etc.
In addition, the mixed acid nitration method has the following characteristics:
(1) The nitrated substance or nitration product is liquid at the reaction temperature and is insoluble in waste sulfuric acid. Therefore, the waste acid can be recovered by the layering method after nitration;
(2) The amount of nitric acid used is close to the theoretical amount or the excess is not much. The waste sulfuric acid can be used to prepare the mixed acid after concentration, that is, the consumption of sulfuric acid is very small;
(3) Mixed acid nitration is a heterogeneous process, which requires the nitration reactor to be equipped with a good stirring device to ensure full contact between the acid phase and the organic phase;
(4) The composition of the mixed acid is an important factor affecting the nitration capacity. The nitration capacity of the mixed acid is expressed by the sulfuric acid dehydration value (DVS) or the nitration activity factor (FNA). DVS is the calculated mass ratio of sulfuric acid to water in the waste sulfuric acid after the nitric acid in the mixed acid is completely nitrated to produce water. FNA is the calculated mass percentage concentration of sulfuric acid in the waste acid after the nitric acid in the mixed acid is completely nitrated to produce water. High DVS or high FNA indicates strong nitration capacity. For each specific nitration process, the composition of the mixed acid, DVS or FNA must be determined experimentally to determine their suitable range.
Today, the topic of nitration is still of great interest and activity, and chemists are constantly researching more efficient and selective nitration methods. Selectivity can be a challenge in nitration, because more than one compound may be produced. But in the end, only one target product may be required, so the unwanted product will become a contaminant or be wasted. Therefore, it is necessary to design a synthesis with suitable selectivity, for example by controlling the reaction conditions.
Continuous flow technology, especially MICROFLU™ continuous flow microchannel reactor, is one of the tools to optimize the current knowledge of nitration process parameters. Due to the advantages of this method, the time-consuming preparation of acid mixtures can be managed in a simple and continuous manner. Reliable control of residence time makes the production of nitration products more selective than before. After adopting microchannel reactors, the entire reaction process can also be switched to a continuous flow production process, and then matched with a continuous post-treatment process, such as the use of continuous separation equipment such as extraction towers and centrifugal extractors, the automation of the entire production line can be greatly improved.
There are many types of products produced by nitration reactions, which are mainly used in medicine, pesticides, dyes, pigments, etc. In the military industry, it is mainly used as gunpowder, propellant and energetic materials. In addition, the strong polarity of the nitro group can be used to activate other substituents on the aromatic ring, making it easier to react chemically. Because of its fast reaction speed and large heat release, which is generally between 150-300KJ/mol, the nitration products are extremely unstable, especially polynitro compounds are extremely easy to explode, posing a great hidden danger to production safety.
Nitration reaction is an important way to introduce nitro groups to aromatic rings to further prepare amino compounds, and then prepare phenols, fluorides and other compounds. The nitration reaction is highly exothermic and fast. If it is not well controlled, it will cause explosion. Therefore, heat removal is one of the outstanding problems in controlling the nitration reaction. The nitration reaction requires maintaining an appropriate reaction temperature to avoid the formation of polynitro substances and oxidation and other side reactions. In order to maintain a certain nitration temperature, the nitration reactor is usually required to have a good heat transfer device.
There are three main purposes for introducing nitro groups on aromatic rings and heterocyclic rings:
1) Converting the introduced nitro groups into other substituents, such as nitro reduction, is an important synthetic route for preparing aromatic primary amines.
2) Using the strong electron-withdrawing property of the nitro group to activate other substituents (especially the chlorine group) on the aromatic ring, it is easy to undergo nucleophilic displacement reactions.
3) Using the characteristics of the nitro group to give fine chemical products certain characteristics, such as deepening the color of dyes, as drugs, explosives or mild oxidants, etc.
Characteristics of nitration reaction: fast speed, large heat release, explosion hazard of the raw materials themselves, explosion hazard of products or by-products.
Advantages of continuous flow microchannel reactor in nitration reaction: precise temperature control, shortened reaction time, improved conversion rate and selectivity. Compared with traditional chemical industry technology, it can achieve more environmental protection and very small footprint, while making rational use of resources without causing high energy consumption. Microchannel reactors are continuous reactors with characteristic dimensions ranging from tens of microns to several millimeters, manufactured using precision machining technology. The special channel structure inside the reactor can greatly enhance the mass transfer effect, providing a feasible solution for the precise, stable and safe conduct of nitration reactions. Due to the high risk of nitration, it is recommended to adopt intrinsically safe microchannel reaction technology, which can solve safety problems from the source and truly achieve "intrinsic safety".
1. Compared with the traditional kettle production process, the use of continuous flow reactors can achieve intrinsic safety for dangerous processes - nitration reactions, with obvious advantages.
(1) Significantly improved safety performance: low liquid holdup, short reaction residence time, and greatly reduced probability of explosive mixture generation.
a. Low total liquid holdup. The continuous flow microchannel reactor has a liquid holdup of less than 10L. In terms of the dangers of dangerous chemicals such as nitration raw materials, products, and nitrifying agents, its total material volume is greatly reduced, so its safety is significantly improved compared with traditional intermittent reactors.
b. High degree of automatic control. On the basis of achieving automatic control, flow, pressure, and temperature detection and control are provided, and overpressure and overtemperature safety interlocks are also set. Strictly control process parameters to avoid unsafe hidden dangers of manual operation, reduce labor intensity, improve the working environment, and better achieve high-yield, high-quality, long-term safe operation.
c. High heat exchange efficiency. The continuous flow microchannel reactor uses precision machining technology to manufacture feature sizes between tens of microns and several millimeters. With the help of local eddy collisions formed by diffusion and structural design, the contact area of the two phases is increased, so that the fluids can fully contact, mix, and transfer mass, thereby improving the reaction efficiency. For highly exothermic reactions, the reaction heat can be removed in time, effectively avoiding safety accidents caused by high reaction heat release.
(2) Improvement of temperature control system
High temperature is conducive to the nitration reaction. Compared with traditional kettle production, nitration reactions in microchannel reactors can generally increase the reaction temperature. Therefore, in terms of the amount of heat exchange medium, the amount of refrigerant is greatly reduced, and about 1/3 of the refrigerant can be saved each year.
(3) Efficiency improvement: After using microreactors, the reaction time is greatly shortened and the efficiency is improved. Generally, it takes only a few minutes to obtain a high conversion rate and selectivity.
In the nitration reaction in the microchannel reactor, the reaction temperature can be precisely controlled. Therefore, the reaction time can be shortened from more than ten hours to a few minutes or even more than ten seconds by heating and direct mixing.
(4) Improved operation method
Compared with the traditional manual feeding and long-term dripping operation of nitric acid, the micro-reactor continuous process simplifies the reaction process. In terms of operation method, the intermittent reaction is changed to a continuous reaction, and the continuous production is realized to reduce the number of operators.
(5) Saving space: The skid-mounted design concept integrates the feeding system, reaction system, and control system, and condenses the traditional reaction device that occupies hundreds of square meters to a space of several square meters, which greatly saves the equipment's floor space.
(6) Stability: After using the microchannel continuous flow reactor, the quality of the prepared compounds is very stable, the types of impurities are reduced, and the content is stable, which is a great advantage for pharmaceutical companies.
Compared with conventional reactors, the internal channel diameter of the microchannel (continuous flow) reactor is very small, and it has a large specific surface area, which can reach hundreds or even thousands of times the specific surface area of conventional reactors. Therefore, it produces great heat exchange efficiency and mass transfer efficiency, can accurately control the reaction temperature, ensure instant mixing of reaction materials, and help improve chemical reaction yield, selectivity, safety, and product quality.
Compared with conventional kettle reactors, microchannel reactors have the following characteristics: ① channel geometry characteristics, ② transfer and macro flow characteristics, ③ enhanced transfer process, ④ improved product yield and selectivity, ⑤ conducive to temperature control, ⑥ high safety performance, ⑦ amplification problems. Compared with traditional chemical intermittent equipment, microchemical equipment can realize continuous production of chemical processes, has a certain production flexibility, and chemical equipment is highly concentrated, saving production space. The powerful heat and mass transfer capabilities of the microreactor itself can not only accurately and safely control the reaction process, but also improve the utilization efficiency of environmental resources and energy, and realize the efficiency, miniaturization and greenness of chemical processes.
Microchannel reactors are suitable for the following reactions: ① reactions with intense heat release; ② reactions with unstable reactants or products; ③ rapid reactions with strict requirements on reactant ratios; ④ dangerous chemical reactions and high-temperature and high-pressure reactions.
2. Dangerous characteristics of nitration reaction process
1. Fast reaction speed and large heat release. Most nitration reactions are carried out in heterogeneous phases, and the uneven distribution of reaction components can easily cause local overheating and lead to danger. Once the stirring is started again in a conventional reactor, a local violent reaction will suddenly occur, releasing a large amount of heat instantly, causing an explosion accident;
2. The reaction materials are explosive;
3. The nitrating agent is highly corrosive and oxidizing, and can cause combustion or explosion when in contact with oils, organic compounds, especially unsaturated organic compounds;
4. Nitration products and by-products are explosive.
3. Continuous nitration process
In order to reduce the risk of production, the traditional nitration process is mostly carried out by adding mixed acid to the reactor. This method has the following characteristics:
(1) The reaction is intermittent production, and the mixed acid addition time is long, usually several hours or even more than ten hours, and the production efficiency is low;
(2) The heat transfer effect of the reactor is limited. If the heat exchange is not timely, it is easy to cause "flying temperature" or "boiling" in the reactor, and the reaction will be out of control;
(3) When the temperature in the reactor rises, the nitrifying agent is prone to oxidation, and the nitration product and by-products are explosive;
(4) The amount of mixed acid is large and post-processing is difficult.