Continuous Flow Synthesis in Microstructured Reactors — A New Way of Thinking Chemical Synthesis

Organic chemists usually spend a substantial amount of time on the development of synthetic routes to new materials. The best pathways need to be chosen and reaction conditions must be optimized. Once a product is successful and demand for larger quantities is growing, the whole synthesis process needs to be revised again and readjusted for larger batch sizes.

This general procedure shows a typical problem in conventional batch synthesis: batch synthesis is a space-resolved process. The output of the reaction is determined by the size of the reaction vessel - the larger the vessel the higher the output of the reaction.

In sharp contrast to the batch mode, chemical synthesis becomes a time-resolved process in flow chemistry. Reagent streams are continuously pumped into a flow reactor where they are mixed and allowed to react. The product instantly leaves the reactor as a continuous stream. Therefore, only flow rate and operation time determine the synthesis scale. Identical reactors with an inner volume of less than a milliliter will produce kilogram quantities of material when operated for a whole day at fast flow rates, or small milligram batches if operated for a few minutes.

Rather than size, other parameters define the performance of a microreactor and will decide if it offers better features than a conventional batch reactor. First of all, the reactor material needs to be selected. Microreactors are readily available as metal, glass, or silicon builds. Each material offers specific advantages and disadvantages regarding price and compatibility with reagents or heat conductivity. The preferred material at Sigma-Aldrich is glass. Glass offers the highest compatibility with aggressive media and reagents. The production of glass microreactors is not too cost intensive, and blockages or other possible problems can be located visually through the material.

Independently from the reactor material, microreactors offer two major features that clearly make a difference vis-a-vis classical batch reactors. The neutralization of hydrochloric acid with sodium hydroxide (Scheme 1) can be taken as a simple exothermic model reaction to visualize the superior performance of microreactors compared to batch reactors.

1. Efficient Heat Transfer

Microreactors with their small surface to volume ratios are able to absorb heat created from a reaction much more efficiently than any batch reactor. Figure 2 shows the initial heat distribution for the model reaction (Scheme 1) in a simulated 5 m³ batch reactor stirred at 500 rpm.¹ The batch reactor is heated by the exothermic reaction. Cooling only takes place at the surface of the reactor. As a result, there is a strong temperature gradient from the surface of the reactor to its center. In a microreactor, the heat created by mixing the two reagents is also detectable but the temperature gradient is a lot smaller (Figure 3). Additionally, it only takes a few millimeters of path length for the reagent stream to cool down again to the temperature of the outside cooling medium.

The formation of hot spots or the accumulation of reaction heat may favour undesirable side reactions or fragmentation. Microreactors with their superior heat exchange efficiency present a perfect solution. Precise temperature control affords suppression of undesired by-products (Figure 4).

This becomes even more evident when looking at the scaling-up of a production routine. The surface to volume ratio is a function of reactor size. Bigger reactors have smaller surface to volume ratios (Figure 5). A synthesis procedure that works well in a small glass flask in R&D may pose huge problems when transferred directly to larger vessels in a kilo lab or pilot plant. Time consuming process development is necessary to fit the synthesis to the different parameters of a bigger reactor vessel. In flow chemistry a single microreactor can cover a broad range of production scales from mg to kg. For scaling-up, only the operation time of the system is extended. No further process development is necessary.

Efficient heat transfer is also an important concern regarding safety. In batch reactors highly exothermic reactions require extended dosing times. There’s always a risk that such a reaction might “run away” in a batch reactor. The small inner volume of a microreactor (typically less than a milliliter) combined with its strong heat exchange efficiency guarantees the safe and stable performance of highly exothermic reactions over hours. Even explosive reactants and intermediates can be handled safely in a microreactor.

2. Efficient Mixing

The core part of any microreactor is the mixing regime. Mixing quality is crucial for many reactions where the molar ratio between reactants needs to be controlled precisely in order to suppress side reactions. A sophisticated regime will mix reactants efficiently with a small path length of a few centimeters. The green color in Figure 6 indicates the perfect 1:1 mixture for the same neutralization reaction as in the previous example (Scheme 1). The simulation clearly shows that mechanically stirred batch reactors cannot compete with microreactors with regard to mixing efficiency (Figure 7). Also simple T-joints in very basic flow chemistry systems will not give the same results as the engineered mixing regime of a microreactor.

Benefits from Microreactor Technology and Flow Chemistry

• Scale-independent synthesis
• Product profile improvement
• Accelerated process development
• Enhanced safety
• Constant product output quality
• Cleaner product profile
• Higher yields

Recommended Literature

A couple of excellent reviews and highlight articles explain microreactor technology in detail. They give a comprehensive overview of which reaction types can profit from microfluidics, and describe which considerations should be made when planning a microreaction.

1. “Green Chemistry Articles of Interest to the Pharmaceutical Industry”: Andrews, I. et al. Org. Process Res. Dev. 2009, 13, 397.
2. “Enabling Continuous-Flow Chemistry in Microstructured Devices for Pharmaceutical and Fine-Chemical Production”: Kockmann, N.; Gottsponer, M.; Zimmermann, B.; Roberge, D.M. Chem. Eur. J. 2008, 14, 7470.
3. “Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway?”: Roberge, D.M.; Zimmermann, B.; Rainone, F.; Gottsponer, M.; Eyholzer, M.; Kockmann, N. Org. Process Res. Dev. 2008, 12, 905.
4. “Greener Approaches to Organic Synthesis Using Microreactor Technology”: Mason, B.P.; Price, K.E.; Steinbacher, J.L.; Bogdan, A.R.; McQuade, D.T. Chem. Rev. 2007, 107, 2300.
5. “Advanced organic synthesis using microreactor technology”: Omer, B.A.; Brandt, J.C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733.
6. “Mesoscale Flow Chemistry: A Plug-Flow Approach to Reaction Optimisation”: Wheeler, R.C.; Benali, O.; Deal, M.; Farrant, E.; MacDonald, S.J.F.; Warrington, B.H. Org. Process Res. Dev. 2007, 11, 704.
7. “Continuous Chemistry in Microreaction Systems for Practical Use”: Müller, G; Gaupp, T.; Wahl, F; Wille, G. Chimia 2006, 60, 618.
8. “Chemistry in Microstructured Reactors”; Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew. Chem. Int. Ed. 2004, 43, 406.
9. “Application of Microreactor Technology in Process Development”: Zhang, X.; Stefanick, S.; Villani, F.J. Org. Process Res. Dev. 2004, 8, 455.
10. “Chemical Synthesis in Microreactors”: Schwalbe, T.; Autze, V.; Wille, G. Chimia 2002, 56, 63.

    Further selected application examples can be found in the following publications.

11. “Oxiranyl Anion Methodology Using Microflow Systems”: Nagaki, A.; Takizawa, E.; Yoshida, J.-I. J. Am. Chem. Soc. 2009, 131, 1654.
12. “5-(Pyrrolidin-2-yl)tetrazole-Catalyzed Aldol and Mannich Reactions: Acceleration and Lower Catalyst Loading in a Continuous-Flow Reactor”: Odedra, A.; Seeberger, P.H. Angew. Chem. Int. Ed. 2009, 48, 2699.
13. “The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4-Disubstituted 1,2,3-Triazoles”: Bogdan, A.R.; Sach, N.W. Adv. Synth. Catal. 2009, 351, 849.
14. “MultiStep Synthesis using Modular Flow Reactors: Bestmann- Ohira Reagent for the Formation of Alkynes and Triazoles”: Baxendale, I.R.; Ley, S.V.; Mansfield, A.C.; Smith, C.D. Angew. Chem. Int. Ed. 2009, 48, 4017.
15. “The Use of Diethylaminosulfur-Trifluoride (DAST) for the Fluorination in a Continuous Flow Reactor”: Baumann, M.; Baxendale, I.R.; Ley, S.V. Synlett 2008, 14, 2111.
16. “Rapid Multistep Synthesis of 1,2,4-Oxadiazoles in a Single Continuous Microreactor Sequence”: Grant, D.; Dahl, R.; Cosford, N.D.P. J. Org. Chem. 2008, 73, 7219.
17. “Multistep Continuous-Flow Microchemical Synthesis Involving Multiple Reactions and Separations”: Sahoo, H.R.; Kralj, J.G.; Jensen, K.F. Angew. Chem. Int. Ed. 2007, 46, 5704.
18. “Advantages of Synthesizing trans-1,2-Cyclohexanediol in a Continuous Flow Microreactor over a Standard Glass Apparatus”: Hartung, A.; Keane, M.A.; Kraft, A. J. Org. Chem. 2007, 72, 10235.
19. “A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols”: Baxendale, I.R.; Ley, S.V.; Smith, C.D.; Tranmer, G.K. Chem. Comm. 2006, 4835.
20. “Microreactor Synthesis of β-Peptides”: Flögel, O; Codée, J.D.C.; Seebach, D.; Seeberger, P.H. Angew. Chem. Int. Ed. 2006, 45, 7000.
21. High Energetic Nitration Reactions in Microreactors”: Panke, G.; Schwalbe, T.; Stirner, W.; Taghavi-Moghadam, S.; Wille, G. Synthesis 2003, 18, 2827.

    As MRT becomes widely accepted, fine chemical and pharma companies frequently report utilization of at least one continuous flow step in API manufacturing campaigns and lab synthesis.

22. Eli Lilly: Kopach, M.; Murray, M.; Braden, V.; Kobierski, M.; Williams, O. Org. Process Res. Dev. 2009, 13, 152.
23. Dow: McConnell, J.; Hitt, J.; Daughs, E.; Rey, T. Org. Process Res. Dev. 2008, 12, 940.
24. Neurocrine Bioscience & Irix: Gross, T.; Chou, S.; Bonneville, D.; Gross, R.; Wang, P.; Campopiano, O.; Quellette, M.; Zook, S.; Reddy, J.; Moree, W.; Jovic, F.; Chopade S. Org. Process Res. Dev. 2008, 12, 929.
25. Organon: Linden, J.v.d.; Hilberink, P.; Kronenburg, C.; Kempermann, G. Org. Process Res. Dev. 2008, 12, 911.