In-situ production of Grignard reagents in continuous flow


    A fantastic paper in Organic Letters describes using a Vapourtec R-series to develop a continuous flow protocol for the in-situ production of Grignard reagents that overcomes the often exothermic nature of their creation, and their air and water sensitivity.

    The paper, the product of a collaboration between the Janssen Research Group and Universidad de Castilla-La Mancha, has used a Vapourtec R-series equipped with a column reactor to allow in-situ production of different Grignard reagents as they are required. The column is packed with commercially available magnesium powder which is then activated in-situ by removing the oxide layer from the surface. A range of different Grignard reagents can be produced by passing the relevant organohalide over the reactive magnesium surface.

    The group were able to determine the concentration of the Grignard output using colorimetric titration procedures, and found that the concentration was stable until 60 – 70% of the magnesium had been consumed, at which point the column could be re-packed and re-activated. The insertion reaction that generates the reagent was tolerant of bromo-, chloro- and iodoalkyl and aryl derivatives.

    The approach was applied to a range of insertion substrates including aliphatic halides, piperidines. Even benzotrifluorides – notorious for the potential for runaway reactions – could be used to generate the respective Grignard in high yields. The enhanced heat transfer properties afforded by continuous flow and the inherent protection of the Vapourtec system reduces the risk to the user from potential decomposition reactions using these reagents.

    Using an R-series, multiple reactors can be used in series, so once the Grignard was formed in-situ it was passed into a second reactor where it combined with an electrophile, enabling the continuous synthesis of a wide range of products without the handling challenges that Grignard reagents can pose. The group have also shown how it is also possible to combine this flow technique with a batch protocol were necessary, producing the Grignard as it is needed and feeding into a batch reactor. This approach made it possible to expand the flow protocol yet further to include highly insoluble reagents or reactions needing extended reaction times.

    “Grignard reagents are very useful for the creation of C-C bonds” says Dr Ryan Skilton, Research Scientist at Vapourtec “being able to produce the Grignard reagents in-situ as you need them, and immediately combine them with the electrophile is a very powerful approach, because the very sensitive reagent is never exposed to the atmosphere or moisture. The consistent output of the Grignard reagent as shown by the titration measurements, as well as the wide tolerance of functional groups makes this a really exciting advance for synthetic chemistry in continuous flow”.


    To read more on the original paper click here

    To read more on the R-Series click here

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