A cleaner way to make a crucial reagent

How do you make medicinal drugs? The techniques are often highly resource intensive, but chemists are working to make them more environmentally friendly. New research has demonstrated a cleaner way to make Grignard reagents, one of the hallmarks of chemistry.

Grignard reagents can get carbon atoms to bond to one another in very precise ways, which is a difficult thing to do and crucial for making molecules.

Since their discovery 121 years ago by Victor Grignard, these reagents have been used to make a range of important medicines and other substances – including Tamoxifen, one of the most highly-prescribed breast cancer treatments.

Two photos of paste in a metal jar
Two types of Grignard reagent paste made with the new method: on the left, the paste has no organic solvent and a yield of around 6% Grignard reagents, on the right, the paste has a small amount of organic solvent and a 94% yield. Credit: Koji Kubota

Unfortunately, the way to make Grignard reagents demands no exposure to air or moisture, and must be done by dissolving the reagents (magnesium and substances called organohalides) in certain organic (carbon-containing) liquids.

These organic solvents are generally bad for both human and environmental health; so the production of Grignards is expensive, energy intensive, and makes environmentally destructive waste.

But a team of Japanese chemists have updated the Grignard method, finding a simpler way to make the reagents that minimises (but doesn’t eliminate) the hazardous organic solvents. They’ve published their process in Nature Communications.

“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,” says co-author Koji Kubota, an associate professor at Hokkaido University.

This new method employs a technique called ball-milling. The researchers loaded a metal chamber with the solid components of Grignards, along with a small amount of organic solvent (roughly a tenth of the amount used in the traditional reaction) and a stainless-steel ball.

Read more: Changing the shape of water molecules

After spinning the chamber for an hour, the ball successfully mixed the compounds into a paste full of Grignards.

This trick also worked with no solvent at all, but it wasn’t nearly as efficient: the no-solvent method had a 6% yield of Grignard reagents, but the low-solvent method produced a 94% yield.

As well as minimising the solvent required, this reaction was much less sensitive to air and water, meaning it can be done in much simpler conditions.

The researchers were also able to make different types of Grignard reagents, because they could use components that don’t dissolve well in organic solvents. They say that this could open up new areas of drug development.

“Grignard reagents are arguably the most well-known, commonly used reagents in industry,” says Kubota.

“Our work could fundamentally change the way a vast number of chemicals are produced at scale, leading to significantly reduced impact on the environment.”

Diagram depicting two routes of synthesis for grignard reagents
The old and new method for making Grignard reagents. The 1900 method, developed by Victor Grignard, involves steeping reactants in n organci solvent. The newer method, below, creates a paste from a ball milling process. Credit: Rina Takahashi, et al. Nature Communications. November 18, 2021

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