A simpler, greener technique for creating Grignard reagents — one of the most important and widely used types of reagents in the chemical sector — has been formulated by a team of researchers directed by scientists at Hokkaido University.
(Left) Reaction mixture of magnesium metal and organohalide after one hour of ball milling. Use of this material in subsequent reactions led to only a 6% yield of the desired product. (Right) Same process, but with a small amount of organic solvent also added at the beginning. Use of this paste form of Grignard reagent in subsequent reactions led to yields of up to 94% of the desired product ((Image Credit: Koji Kubota).
Grignard reagents significantly minimize the use of unsafe organic solvents and could result in lower production costs. This new process was illustrated in the journal Nature Communications. Grignard reagents are vital components in a widely used technique for making carbon-carbon bonds, the building blocks of organic molecules.
Discovered 120 years ago, these reagents were known for their instability, and therefore the conventional production method still used at present is carried out in lethal organic solvents and with no exposure to oxygen and moisture. This results in a complex, delicate and costly process that creates environmentally harmful waste.
The scientists bypassed these issues by reducing the amount of organic solvent used and by applying a mechanochemical method known as ball-milling to create Grignard reagents.
The reactants, organohalides and magnesium metal were placed into a metal chamber together with a stainless-steel ball. In an important step, a small quantity of organic solvent — about one-tenth the amount used in conventional approaches — was incorporated with the solid reactants.
The chamber was then spun for 1 hour, making the ball tumble around and bang into the solid-state reactants, helping them to blend completely and react, yielding a paste-like Grignard reagent.
The scientists even managed to create new Grignard reagents using organohalides that have weak solubility in organic solvents, which cannot usually be produced by the conventional technique.
Sidestepping heavy use of organic solvents enabled the team to surpass solubility difficulties, which paves the way to a world of new reactions with Grignard reagents made from insoluble compounds. It also leads to a massive reduction in harmful waste.
Furthermore, it is tougher for oxygen or water to impact the Grignard reagents when less organic solvent is employed. This means that eliminating water and oxygen from the immediate air is not necessary, rendering the process easier to carry out and less expensive. Given the possible environmental and economic advantages, this discovery could have a major effect on chemical industries.
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. 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.
Koji Kubota, Associate Professor, Hokkaido University
Funding
This study received support from the Japan Society for the Promotion of Science (JSPS) via KAKENHI grants 17H06370, 20H04795, 18H03907, and 21H01926.
It also received support from a JSPS Research Fellowship for Young Scientists (19J20824); the Japan Science and Technology Agency (JST) via the Core Research for Evolutional Science and Technology (CREST) grant JPMJCR19R1, and the Fusion Oriented Research for disruptive Science and Technology (FOREST) grant JPMJFR201I; as well as by the Institute for Chemical Reaction Design and Discovery (ICReDD), which was set up by the World Premier International Research Initiative (WPI), Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan, and by MEXT (Japan) via the “Program for Leading Graduate Schools” (Hokkaido University “Ambitious Leaders Program”).
Journal Reference:
Takahashi, R., et al. (2021) Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis. Nature Communications. doi.org/10.1038/s41467-021-26962-w.