Crush It Safely: Safety Aspects of Mechanochemical Grignard Synthesis

The Grignard reaction has been one of the most versatile workhorses for synthetic organic chemists for more than a century. Typically, the preparation of Grignard reagents and their subsequent reactions require anhydrous solvents and a protective inert atmosphere. A recent report showed that the reactions could be performed under mechanochemical conditions by ball-milling magnesium metal, an organic halide, and a small amount of an ethereal solvent together followed by the addition of an electrophile. Excellent results were reported for a broad range of substrates even when the reaction was performed under the ambient atmosphere, making the process highly appealing to a wide synthetic community. In this commentary, some safety aspects of this mechanochemical Grignard reaction are pointed out so that appropriate risk management plans can be devised to ensure its safe use.