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New in Grignards

New in Grignards
20 November 2021 - Orgo

Koij Kubota and Haijme Ito of Hokkaido University report an improved method for the synthesis of Grignard reagents (Rina Takahashi et al. DOI). As every organic chemistry student will remember from practical lab sessions, Grignard reactions are notoriously difficult to get started. Grignards also react with oxygen to form hydroperoxides and therefore degassing solvents with nitrogen is recommended and a nitrogen blanket is required.
The Kubota / Ito solution for this problem is counter-intuitive because it is driven by mechanosynthesis and with relaxed reaction conditions. They found that ball milling bromobenzene, THF and magnesium turnings results in an light-orange mud without any of the metal visibly left and with interesting properties. It can withstand an oxygen environment and will react with a range of carbon nucleophiles in high yield in a second milling run. Additional advantage of a paste is that substrates that otherwise have solubility issues can also be handled.

Grignards in a ball mill have been investigated before but for the yield the use of THF was found to be key. An explanation is not given but a theoretical study suggests R-Mg-X compounds aggregate to form cubes at the atomic level and the the presence of THF rings forces the cubes to become a more open. Grignard formation was confirmed by deuteration experiments (R-MgX conversion to R-D in presence of deuterated acetic acid) and X-ray absorption near edge structure (presence of divalent magnesium).

More researchers are on the Grignard mechanosynthesis track. Beating the Hokkaido team by a month (chemrxiv can work wonders), the group of Carsten Bolm of Aachen University published very similar work (Victoria Pfennig et al. DOI).
Their winning brew: ball-milling the aromatic bromide with magnesium and THF in presence of lithium hydroxide. They do not think much of the THF in the equation, in their words the positive effect was already observed by Grignard himself. The LiOH is reminiscent of LiBr in turbo Grignards. The best combination was just 2-methyltetrahydrofuran and no salt. Oddly enough the Bolm group did not detect any tolerance for oxygen in the procedure, on the contrary they insist on carefully flushing equipment with argon.

If there is an annual Grignard award, a third contender would be the group of Jingbo Yu of the Zejiang University of Technology who a month before the Germans published an article on mechanomechanical Minisci reaction (DOI). Not a Grignard but a radical reaction but the components in this particular mix are the same: an alkyl halide (2-bromopropanol), magnesium turnings and a substrate (2-phenylpyrimidine). And be prepared for another surprise, the key additional ingredient here was TMEDA, which the authors suspect helps to prevent Grignard formation. Adding THF or any solvent did nothing, a water and oxygen free environment again a must.

Also see work done by Fraunhofer IMM in 2020 and featured in this blog on a continuous reactor with mechanical magnesium activation.