This application note describes using the Vapourtec High Flow rate pump module and Vapourtec Reactor for Rapid Mixing to scale up a liquid/liquid biphasic ester synthesis to over 4.5 kg per day.
In batch, liquid/liquid biphasic oxidation reactions can be challenging because their rate is limited by the reaction being restricted to only taking place at the interface between the two phases. Stirrer mixing can help, but is often not aggressive enough to increase the number of interfaces. Because of this, many biphasic reactions have to make use of a phase-transfer catalyst that is able to shuttle reagents from one phase to the other so they can react, but these catalysts can be challenging to remove from the final product.
In flow chemistry, there is the opportunity to have very intense mixing that would greatly increase the number of interfaces between the two phases in a biphasic reaction, and accelerate the reaction. However, some flow reactors are designed with a short period of intense mixing at the start, followed by a section of reactor that just enables the desired residence time. While this approach works for homogeneous reactions, any biphasic reaction will separate back into two phases as soon as the intense mixing ends.
The Vapourtec large diameter Reactor for Rapid Mixing has been designed with chemical resistant static mixers through its full length (a video of these in action is available here). This ensures that the reaction mixture is being mixed intensely through the full length of the reactor, which in the case of a liquid/liquid biphasic reaction, prevents the two phases from separating. This results in a significant increase in the available interface where the reaction takes place, and can accelerate the reaction considerably. It is also possible, with enough mixing, to remove the need for the phase-transfer catalysts, simplifying the product’s workup.
Using a High Flow rate pump module and a 20 ml reactor for rapid mixing, we have carried out a biphasic Steven’s oxidation of 4-nitrobenzaldehyde using sodium hypochlorite, and because of the very intense mixing, been able to reduce the residence time to just 58 seconds. The reaction was then scaled up using a 60 ml reactor for rapid mixing. After scale-up it was possible to run at 200 g per hour, and producing over 4.5 kg in 24 hours with just the footprint of a Vapourtec R-series.