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Updating a 120-Year-Old Reaction With an Eco-Friendly, Paste-Based Method

A novel, mechanochemical method to create Grignard reagents in a cheaper, simpler, and more environmentally friendly way can potentially revolutionise industrial processes.

Since Grignard reagents were first discovered around 120 years ago, these compounds have been widely used as carbon nucleophiles to facilitate the creation of carbon-carbon bonds to produce various synthetic intermediates and valuable functional molecules in the chemical, food, materials, and pharmaceutical industries. However, despite their versatility, synthesising these compounds is an incredibly complicated, costly, and time-consuming process and requires strict control of reaction temperature and the use of inert-gas-line techniques. Moreover, they result in environmentally hazardous waste since it involves the use of dry, toxic organic solvents.

Sidestepping these limitations, researchers at Hokkaido University have innovated an eco-friendly, efficient, and cost-effective method to synthesise Grignard reagents. By substantially reducing the use of hazardous organic solvents, the new technique also improves the safety of the production process.

To produce Grignard reagents, the scientists proposed minimising the amount of organic solvent used and employing a mechanochemical technique called ball-milling. Their approach involves loading the reactants, magnesium metal and organohalides, into a metal chamber alongside a stainless-steel ball.

A crucial step of the process is adding a small amount of organic solvent – one-tenth of the amount used in conventional methods – to the solid reactants, after which the chamber is spun for an hour. During this time, the ball will tumble around and slam into the solid-state reactants, thoroughly mixing the chemicals together and facilitating the reaction, the end result of which is a paste-like Grignard reagent.

Although organohalides that have poor solubility in organic solvents typically cannot be used to synthesise Grignard reagents, the team succeeded in doing so using their new ball-milling approach. The researchers were also able to overcome solubility problems by avoiding the heavy use of organic solvents. This not only opens up a world of new reactions with Grignard reagents prepared from insoluble compounds, but also a safer path with significantly less hazardous waste.

Since their approach uses fewer organic solvents, the resultant Grignard reagents also become less affected by oxygen or water. Therefore, their procedure can be conducted in air without necessitating special precautions or synthetic techniques such as the use of inert gas to remove oxygen and water from the surrounding air, effectively reducing the complexity and cost of the process. Considering its potential economic and environmental benefits, this new platform is highly promising to reform modern organic synthesis and revolutionise the chemical industry.

“With a growing need to address environmental concerns and reduce CO2 emissions, it is important to develop chemical reactions that don’t require organic solvents,” commented Associate Professor Koji Kubota. “Grignard reagents are arguably the most well-known, commonly used reagents in industry, and so our work could fundamentally change the way a vast number of chemicals are produced at scale, leading to significantly reduced impact on the environment.” [APBN]

Source: Takahashi et al. (2021). Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis. Nature Communications, 12, 6691.