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Grignard Reactions in Flow

The Grignard reaction is a highly prominent process to form carbon-carbon bonds. This organometallic reaction involves the addition of an alkyl, allyl, vinyl or aryl-magnesium halide (known as the Grignard reagent) to the carbonyl group of an aldehyde or ketone. Grignard reagents are highly reactive and both air- and moisture-sensitive thus making it preferential to form the reagent shortly before any subsequent Grignard reaction.

To successfully translate Grignard reactions from batch to flow, it is therefore desirable to form the Grignard reagent in-situ through reaction of magnesium powder with the desired organic halide. This therefore results in the requirement of a flow reactor to be able to handle a heterogenous magnesium slurry.

Internal testing performed by the chemists and engineers at AMT has looked to assess the suitability of Coflore systems towards magnesium slurry handling, with a view to indicating suitability for Grignard reaction applications with emphasis on the simplest peripheral equipment set up possible. Throughout April, we carried out internal testing whereby we recycled a 10 wt% slurry of magnesium powder in petroleum-ether through a Coflore ATR using only a standard peristaltic pump.

Coflore ATR and ReactoMate feed vessel
A close-up of our Coflore ATR testing set up

For this testing, LS18 Masterflex tubing was used, which has an ID of 7.9mm. When handling solids in flow, it is important to appreciate that the larger the ID of the pump tubing, the slower the fluid velocity is to achieve a certain flowrate. This can have large implications as to whether the solid remains suspended or settles out in the reagent transfer lines.

A render of the Coflore ATR
The Coflore ATR Flow Reactor

With this simple equipment set up, we were able to successfully and easily recirculate the 10 wt% slurry through the Coflore ATR without blocking or noticeable accumulation at flow rates of 700 mL/min and 1,000 mL/min which equates to 10-minute and 14.4-minute residence times in a 10 L Coflore ATR system (for the purposes of this testing, a 1.6 L ATR system was used to minimise volumes required). Furthermore, we were able to shutdown the system whilst full, allowing the suspension to fully settle out overnight, and then restart the system, successfully re-suspending the slurry, highlighting the vital importance of the mechanical agitation employed by the Coflore ATR in solids handling in flow.

A summary technical note (AMT TN-09) of this initial testing is available for download from our technical notes section here. Stay tuned for further testing as we look to evaluate a range of peripheral equipment set ups of varying complexity over the coming weeks and months!


“One of today's most important tools for modernizing the pharmaceutical industry is a process known as continuous manufacturing”

Director of the FDA’s Centre for Drug Evaluation and Research,

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