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Nitration and flow chemistry
Abstract
The paper introduced the principle of nitration reaction and flow chemistry, beginning with background information and the reaction mechanism of nitration. Then the correlation between nitration and flow chemistry is further explored by comparing the nitration reaction in conventional batch mode and under continuous flow. As the dangerous corrosive acids and strong exotherms make the reaction especially difficult to increase production scale, flow chemistry is utilized and proved to be a better alternative to the conventional production method to perform nitration. Using flow chemistry to scale up the exothermic and hazardous nitration reactions offer advantages including better yield, higher production rate, enhanced safety, etc.
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This paper describes the nitration of 2,4-dinitrotoluene (DNT) and its conversion to 2,4,6-trinitrotoluene (TNT) at a gram scale with the use of a fully automated flow chemistry system. The conversion of DNT to TNT traditionally requires the use of highly hazardous reagents like fuming sulfuric acid (oleum), fuming nitric acid (90-100%), and elevated temperatures. Flow chemistry offers advantages compared to conventional syntheses including a high degree of safety and simpler multistep automation. The configuration and development of this automated process based on a commercially available flow chemistry system is described. A high conversion rate (>99%) was achieved. Unlike established synthetic methods, ordinary nitrating mixture (65% HNO3/98% H2SO4) and shorter reaction times (10-30 min) were applied. The viability of flow nitration as a means of safe and continuous synthesis of TNT was investigated. The method was optimized using an experimental design approach, and the resulting process is safer, faster, and more efficient than previously reported TNT synthesis procedures. We compared the flow chemistry and batch approaches, including a provisional cost calculation for laboratory-scale production (a thorough economic analysis is, however, beyond the scope of this article). The method is considered fit for purpose for the safe production of high-purity explosives standards at a gram scale, which are used to verify that the performance of explosive trace detection equipment complies with EU regulatory requirements.
As a sustainable alternative for conventional batch-based synthetic techniques, the concept of continuous flow processing has emerged in the synthesis of fine chemicals. Systematic tuning of the residence time, a key parameter of continuous reaction technology, can govern the outcome of a chemical reaction by determining the reaction rate and the conversion and by influencing the product selectivity. This review furnishes a brief insight into flow reactions in which high chemo and/or stereoselectivity can be attained by strategic residencetime control and illustrates the importance of the residence time as a crucial parameter in sustainable method development. Such a fine reaction control cannot be performed in conventional batch reaction set-ups.
This review highlights the state of the art in the field of continuous flow nitration with miniaturized devices. Although nitration has been one of the oldest and most important unit reactions, the advent of miniaturized devices has paved the way for new opportunities to reconsider the conventional approach for exothermic and selectivity sensitive nitration reactions. Four different approaches to flow nitration with microreactors are presented herein and discussed in view of their advantages, limitations and applicability of the information towards scale-up. Selected recent patents that disclose scale-up methodologies for continuous flow nitration are also briefly reviewed.
In this work, continuous flow nitration of trifluoromethoxybenzene (TFMB) was conducted in a microchannel reactor. The effect of process parameters, including temperature, residence time, sulfuric acid strength, flow rate and reactor structure, were systemically investigated. It was found that the aforementioned process parameters had significant effect on TFMB conversion, while the product selectivity was merely sensitive to the reaction temperature. Based on the results of process parameter optimization, a scale up strategy combining microreactor with distributed packed tubular reactor was presented. Consequently, excellent performance was achieved in the combined reactor with a kilogram-scale production.
Over the past two decades, microreaction technology has matured from early devices and concepts to encompass a wide range of commercial equipment and applications. This evolution has been aided by the confluence of microreactor development and adoption of continuous flow technology in organic chemistry. This Perspective summarizes the current state-of-the art with focus on enabling technologies for reaction and separation equipment. Automation and optimization are highlighted as promising applications of microreactor technology. The move towards continuous processing in pharmaceutical manufacturing underscores increasing industrial interest in the technology. As an example, end-to-end fabrication of pharmaceuticals in a compact reconfigurable system illustrates the development of on-demand manufacturing units based on microreactors. The final section provides an outlook for the technology, including implementation challenges and integration with computational tools. AIChE J, 2017 © 2016 American Institute of Chemical Engineers AIChE J, 63: 858–869, 2017.
The paper will describe the use of flow chemistry for scaling up exothermic or hazardous nitration reactions. Such reactions often cause time delays to the delivery of larger batches of intermediates or final compounds for medicinal chemistry projects, because considerable time is required for safety evaluation and, if necessary, modification of the procedure so that it can be scaled-up and run in a safe manner. A commercially available continuous flow reactor was used in the scale up of three challenging nitrations including a reaction involving a potentially explosive mixture of acetic acid and fuming nitric acid, with a productivity of 97 g/h.
1. Nitroglycerine (NG) was discovered in 1847 by Ascanio Sobrero in Turin, following work with Theophile-Jules Pelouze. Sobrero first noted the ‘violent headache’ produced by minute quantities of NG on the tongue.
2. Constantin Hering, in 1849, tested NG in healthy volunteers, observing that headache was caused with ‘such precision’. Hering pursued NG (‘glonoine’) as a homeopathic remedy for headache, believing that its use fell within the doctrine of ‘like cures like’.
3. Alfred Nobel joined Pelouze in 1851 and recognized the potential of NG. He began manufacturing NG in Sweden, overcoming handling problems with his patent detonator. Nobel suffered acutely from angina and was later to refuse NG as a treatment.
4. During the mid-19th century, scientists in Britain took an interest in the newly discovered amyl nitrite, recognized as a powerful vasodilator. Lauder Brunton, the father of modern pharmacology, used the compound to relieve angina in 1867, noting the pharmacological resistance to repeated doses.
5. William Murrell first used NG for angina in 1876, although NG entered the British Pharmacopoeia as a remedy for hypertension. William Martindale, the pharmaceutical chemist, prepared ‘. . . a more stable and portable preparation’: 1/100th of a grain in chocolate.
6. In the early 20th century, scientists worked on in vitro actions of nitrate-containing compounds although little progress was made towards understanding the cellular mode of action.
7. The NG industry flourished from 1900, exposing workers to high levels of organic nitrites; the phenomena of nitrate tolerance was recognized by the onset of ‘Monday disease’ and of nitrate-withdrawal/overcompensation by ‘Sunday Heart Attacks’.
8. Ferid Murad discovered the release of nitric oxide (NO) from NG and its action on vascular smooth muscle (in 1977). Robert Furchgott and John Zawadski recognized the importance of the endothelium in acetylcholine-induced vasorelaxation (in 1980) and Louis Ignarro and Salvador Moncada identified endothelial-derived relaxing factor (EDRF) as NO (in 1987).
9. Glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of NG and its established efficacy make it the mainstay of angina pectoris relief.
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