1. Continuous flow gas-liquid reactions in micro-reactors and its applications in catalytic synthesis
- Author
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Guan, Fanfu, Blacker, John, Zhang, Xumu, Wen, Jialin, and Kapur, Nikil
- Abstract
Efficient amplification of chirality through asymmetric catalysis is one of the fundamental scientific problems. Recent developments in reactor technology, especially micro-reactors, have been creating new opportunities in reaction control. The work reported herein describes studies of (asymmetric) hydrogenation and transfer (de)hydrogenation in different kinds of continuous flow reactors. Catalytic (enantioselective) hydrogenations have been rarely used in lab and industry-scale continuous flow reactions, and this defines much of the novelty of this work. [1] Asymmetric hydrogenation (AH) is one of the most powerful synthetic tools to obtain chiral molecules in pharmaceutical industry.[2] However, practical homogeneous hydrogenation with a low catalyst loading typically requires a long reaction time (more than 24 hours), which poses challenges for continuous operation.[3] Catalyst performance can be improved by adopting high pressure and temperature flow processes. A slug flow reactor system that can hold up to 150 bars was developed. AH of acetophenone can achieve full conversion and >99% ee with 40000 TON in 6.5 minutes residence time. The TOF can reach up to 274000 h-1 . Two multi-step processes of drug synthesis were developed, in which AH was the key step. However, the slug flow reactors have several disadvantages. Firstly, the slug flow tends to be unstable with high linear velocity and gas liquid volume ratio. In addition, the thin tube in which the reactions proceed can be easily clogged. Therefore, a miniature CSTR, fReactor, was employed to overcome these problems. Such active mixing reactors can avoid blocking and decouple mixing with flow rate, which allows the reactor to operate under a wide range of gas and liquid flow rates. A horizontal fReactor system was successfully applied in heterogeneous and homogeneous hydrogenation and to elongate the residence time of reaction medium, a vertical fReactor system was designed and constructed. It is featured with decoupling gas flow rate with liquid flow rate, and was used in hydroformylation reactions. A novel reactor named flashstop reactor was designed and built to obtain kinetic data for the scenario in which ultrafast pressurized reactions such as isomerization is conducted. A continuous reactor system was also designed to solve the problem of diastereomeric as well as enantiomeric control by integrating hydrogenation, transfer hydrogenation and transfer dehydrogenation. A single enantiomer can be selectively oxidized via asymmetric transfer dehydrogenation to produce an unsaturated intermediate. This product can be reduced via asymmetric (transfer) hydrogenation to enrich the desired enantiomer. This strategy can outperform a single reaction, such as AH or ADH, with respect to enantioselectivity, especially tackling some challenging substrates.
- Published
- 2021