Safe, efficient and selective synthesis of dinitro herbicidesvia a multifunctional continuous-flow microreactor: one-step dinitration with nitric acid as agent

Abstract

A continuous and selective method for synthesis of dinitro herbicides through one-step dinitration approach has been successfully developed in microreactor systems. Compared to a conventional two-step batch process, reaction can be conducted without the need to separate intermediates and much less solvent or solventfree condition has been employed.Dinitroaniline derivatives are an important class of compounds with wide applications in herbicides and pesticides. 1 For example, pendimethalin, N-(1-ethylpropyl)-3,4-dimethyl-2,6-dinitroaniline, is a widely-used selective herbicide in agricultural industry. 2 Dinitroaniline derivatives are generally produced by nitration of aniline derivatives. These nitration reactions are extremely hazardous due to highly exothermic thermodynamics as well as possible decomposition and explosion of nitro compounds. 3 The reaction heat of direct dinitration can be twice as much as that of mononitration. In the chemical industry, to carry out the reaction in a mild way, a two-step process is generally conducted, in which one mononitration step is followed by subsequent mononitration. 4 Moreover, large quantities of solvents or diluents are used in each nitration step since nitration reactions are usually fast for reactive species such as phenol and aniline derivatives. Thus, it requires long reaction time and large amounts of waste solvents. Also, selectivity is not satisfying due to easy oxidation or over-nitration of aniline derivatives when reagents and products are exposed to the reaction conditions over a long residence time, and protection of the amino group by acetylation may be required prior to nitration. 5 Still, the safety risk is not eliminated owing to mass and heat transfer limitations in conventional batch reactors.The broad applications of dinitroaniline herbicides provide enormous impetus for extensive study of nitration reactions. The well-established mechanisms for nitration of reactive species, such as aniline and phenol compounds, include both electrophilic and charge-transfer processes. 6 Recently, one solution complementary to the conventional batch or semibatch mode is to employ a continuous and selective nitration mode. The continuous process can offer much small reaction volume and relatively large surface-to-volume ratio; thus process safety is improved and both temperature and residence time can be precisely controlled, which may improve selectivity by suppression of side reactions. 7 Microreactors have been demonstrated as an effective tool in continuous processes for mononitration of some aromatic compounds, for instance benzene, toluene and chlorobenzene. 8 Beneficial for its characteristic submillimeter dimensions, microreactors have much short diffusion paths and large surface-to-volume ratios compared with batch reactors, which are beneficial to realize excellent heat and mass transfer. So far, most academic and industrial attention has been focused on mononitration processes, and the straightforward one-step dinitration in continuous-flow reactors...

Managing Hazardous Reactions and Compounds in Process Chemistry

“…The aniline, 3,4-dimethyl-N-(pentan-3-yl)aniline was mixed with nitric acid in mixing micropores, which were directed connected to residence microchannels to give 3,4-dimethyl-2,6-dinitro-N-(pentan-3-yl)aniline. The product, N- (3,4-dimethyl-2,6-dinitrophenyl)-N-(pentan-3-yl)nitrous amide, from trinitration was also formed, but at a lower level than for other reaction parameters monitored (42).…”

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

“…[130] For the flow process in a0.2 mL multichannel microreactor,both nitrations were conducted with 65 %n itric acid at temperatures of 60 8 8Ct o8 08 8 Ca nd residence times of less than two seconds without isolation of the intermediate. [130] Ac ontinuous run for 1hprovided 0.54 kg of the products 79 a and 79 b in 97 %o verall yield. This corresponds to ad aily output of approximately 13 kg for as ingle microreactor with at otal internal volume of approximately 200 mL.…”

Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen

“…Chen und Mitarbeiter demonstrierten, dass unter Anwendung der Mikroreaktortechnologie die Konzentration des Nitrierungsgemischs sicher erhçht werden kann. [130] Beim Durchflussverfahreni ne inem 0.2-mL-Mehrkanalmikroreaktor wurden beide Nitrierungen ohne Isolierung des Zwischenprodukts mit 65-proz. Salpetersäure bei Te mperaturen von 60-80 8 8Cu nd Verweilzeiten von weniger als 2s durchgeführt.…”

“…Salpetersäure bei Te mperaturen von 60-80 8 8Cu nd Verweilzeiten von weniger als 2s durchgeführt. [130] Der kontinuierliche Durchlauf über 1h lieferte 0.54 kg der Produkte 79 a und 79 b in einer Gesamtausbeute von 97 %. Das entspricht einem Tagesausstoß von ca.…”

“…13 kg bei einem einzelnen Mikroreaktor mit einem Gesamtinnenvolumen von etwa 200 mL. [130] Sogar drei aufeinanderfolgende Nitrierungen sind für die Synthese von Tr initrophloroglucin (TNPG) erforderlich. Die nachfolgende Hydrierung führt zur Bildung von Tr iaminophloroglucin (81) …”