Continuous-Flow Chemistry

How Hazardous Reactions Become Safe

  • Fig. 1: Comparison of batch and continuous reactors.Fig. 1: Comparison of batch and continuous reactors.
  • Fig. 1: Comparison of batch and continuous reactors.
  • Fig. 2:  Exothermic reactions: synthesis of adipic acid (a) and reduction of nitroarenes (b).
  • Fig. 3: Explosive intermediates: synthesis of TNPG and TAPG, respectively.
  • Fig. 4: Toxic reagents: Tube-in-flask reactor for CH2N2 generation and consumption.
  • Fig. 5: Toxic reagents: Tube-in-tube reactor set-up for CH2N2 generation and synthesis of α-chloroketones.
Doris Dallinger1 and C. Oliver Kappe1,2
Over the past few years, continuous processing employing flow reactors with channel dimensions in the micro- or millimeter region is flourishing in the academic, pharmaceutical and fine chemical sectors. Owing to these small reactor volumes, the overall safety is considerably enhanced, which is of vital importance when hazardous reagents are operated [1]. Therefore, syntheses that were previously “forbidden” due to safety reasons, or even reactions simply not possible in batch, are feasible with relatively low risk. Toxic intermediates can be generated from benign precursors in situ in the closed environment of a flow reactor and subsequently directly converted to a more advanced, nonhazardous product. In addition, microreactor technology provides a unique way to safely perform exothermic reactions and pathways via highly unstable or even explosive intermediates.
Advantages of Continuous-Flow Reactors
The main benefits of microreactors over their batch counterparts are safety related.  They offer an exceptionally fast heat and mass transfer because of their high surface area-to-volume ratios and small internal dimensions. Thus, heat can be applied and removed efficiently, allowing the precise control of the reaction temperature. In addition, virtually instantaneous mixing can be achieved. Consequently, the formation of hot spots, temperature gradients and thermal runaways – which would lead to a concomitant decrease in reaction selectivity – can be prevented. The microreactor set-up allows a precise control of the residence time of intermediates or products. Furthermore can the reaction temperature be changed rapidly along the reactor channel. Multistep reactions are therefore accomplishable continuously, and the need to handle or store excessive amounts of potentially toxic, reactive, or explosive intermediates is eliminated.
Due to the stability of small-diameter reactors to high pressures, safe operation at extreme reaction conditions at high temperatures (high-T/p) is also guaranteed.

Higher temperatures lead to enhanced reaction rates, which, in turn, increase productivity and result in a more cost-effective overall process (i.e. process intensification). 

Scale-up is generally easier for a continuous process than for a batch process. Flow routes developed in the laboratory often can be scaled to production quantities without major changes in the synthetic path. Numbering-up of flow devices or scaling-up of the reactor volume increases the throughput, while the performance of the reactor can be essentially conserved by keeping certain characteristics of the system constant (“smart dimensioning”). 
Exothermic Reactions
Highly exothermic reactions are limited by their mass and heat transfer. Due to the high surface area-to-volume ratio of flow reactors and the accompanied improved heat removal, it is ensured that these reactions can be safely controlled.
In the synthesis of adipic acid from cyclohexene using hydrogen peroxide (H2O2) as green oxidizing agent, the decomposition of H2O2 to H2O and O2 is very exothermic. Additionally, the rise in temperature from the exotherm increases the rate of decomposition. By performing the synthesis via a continuous-flow procedure (fig.2a), where the heat is effectively dissipated, complete oxidation of cyclohexene to adipic acid in a perfluoroalkoxy (PFA) tube at a reaction temperature of 140 °C was achieved [2]. Another example is the selective reduction of nitroarenes to anilines where the exothermicity of the hydrazine-based reduction limits the safe scale-up in batch format [3]. This method relies on the rapid in situ generation of colloidal Fe3O4 nanocrystals with high catalytic activity, which, after the reduction process, agglomerate and can be removed using a simple magnet. By employing this environmentally benign, safe, scalable, and extremely efficient protocol, a precursor of Boscalid (a fungicide produced on a scale of 1000 t/y) could be synthesized with a productivity of 60 g/h (fig. 2b).
Explosive Intermediates
Nitrations belong to the most hazardous and thus challenging transformations for the chemical industry since serious accidents have been experienced. Not only are nitration reactions highly exothermic but also many (poly)nitrated products − such as trinitrotoluene (TNT), picric acid or nitroglycerine − are highly explosive. In addition, nitric acid (the most common nitration agent) is highly corrosive and a powerful oxidant. The better control of the reaction conditions in microreactors in combination with a reduced total volume of processed material due to minimized reactor volumes, improves safety and therefore, continuous-flow nitrations have found quite considerable usage [1].
Toward the synthesis of triaminophloroglucinol (TAPG), an intermediate in the synthesis of powerful cation chelating agents, three successive nitrations are required to generate trinitrophloroglucinol (TNPG) [4]. The first nitration step of the strongly electron-rich phloroglucinol is extraordinary fast and exothermic. Further, TNPG is a highly unstable and explosive compound and hence, a telescoped flow process was designed: the first residence coil dissipates the heat generated in the initial nitration and prevents a thermal runaway, whereas the slower subsequent nitrations were performed in a second residence coil heated to 40 °C (fig. 3). The solution was finally directly hydrogenated with H2 over PtO2 in a high-pressure hydrogenator.
Toxic Reagents
By applying the concept of the in situ on-demand generation of chemicals using continuous-flow processes, potentially toxic intermediates, which are preferably produced from benign precursors, can be utilized directly for further transformations without any human exposure. 
One such example is diazomethane (CH2N2), a compound intensively used in contemporary organic synthesis but notoriously dangerous to handle, since it is volatile, toxic, carcinogenic and highly explosive. It is an exceptionally potent and versatile C1-building block in organic synthesis and reactions with CH2N2 are typically fast and clean, often with nitrogen as the sole byproduct. Diazomethane is produced by base-mediated decomposition of commercially available Diazald or phased-out N-nitroso-N-methylurea, which – to increase safety – can also be generated in situ from harmless and cheap N-methyl urea. By utilizing a semi-permeable membrane which selectively allows CH2N2 to cross, anhydrous CH2N2 can be generated in continuous flow systems. With a semi-batch reactor, where the membrane tubing is wrapped inside a flask (tube-in-flask reactor, fig. 4), CH2N2 selectively separates from the tubing into the solvent- and substrate-filled flask and hence, reactions with CH2N2 can be performed directly in the flask. This concept has been employed for the methylation of carboxylic acids, the synthesis of α-chloroketones and pyrazoles, and palladium-catalyzed cyclopropanation reactions on laboratory scale [5]. A similar strategy using a tube-in-tube reactor was applied to generate α-chloroketones via a modified Arndt-Eistert reaction starting from the corresponding protected α-amino acids (fig. 5) [6]. This transformation is of particular interest because of its use in the synthesis of modern HIV protease inhibitors such as Atazanavir.
Traditionally, the elimination of safety concerns by avoiding hazardous reaction conditions is the primary objective in the design of chemical processes. Nevertheless, the most time- and atom-efficient routes frequently demand the use of hazardous, highly reactive, often low-molecular weight, compounds. For decades, such chemistry was excluded from the organic synthesis repertoire (in particular on a larger scale), and costly and long alternative routes were chosen instead. But nowadays, with the application of flow/microreactors, the safe operation range of synthetic processes can drastically be expanded toward syntheses employing reagents that would otherwise be too reactive, explosive, toxic or even too short-lived.
1 Institute of Chemistry, University of Graz, NAWI Graz, Austria
2 Research Center Pharmaceutical Engineering GmbH (RCPE), Graz, Austria
C. Oliver Kappe
Institute of Chemistry,
University of Graz, 
Graz, Austria
More articles:
More about flow chemistry:

[1] B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54, 6688, DOI: 10.1002/anie.201409318
[2] M. Damm, B. Gutmann, C. O. Kappe, ChemSusChem 2013, 6, 978, DOI: 10.1002/cssc.201300197
[3] D. Cantillo, M. Baghbanzadeh, C. O. Kappe, Angew. Chem. Int. Ed. 2012, 51, 10190, DOI: 10.1002/anie.201205792
[4] D. Cantillo, M. Damm, D. Dallinger, M. Bauser, M. Berger, C. O. Kappe, Org. Process Res. Dev. 2014, 18, 1360, DOI: 10.1021/op5001435
[5] D. Dallinger, V. D. Pinho, B. Gutmann, C. O. Kappe, J. Org. Chem. 2016, accepted.
[6] V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A. de Souza, C. O. Kappe, J. Org. Chem. 2014, 79, 1555, DOI: 10.1021/jo402849z




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