UMass Boston Professor Works to Make the Grignard Reaction Greener

Earlier this year, fourteen of the world’s largest pharmaceutical companies, including Pfizer, Eli Lilly, and Novartis, gathered at the annual American Chemical Society/Green Chemistry Institute’s (ACS GCI) Pharmaceutical Roundtable to discuss the most pressing environmental and safety-related issues they face in manufacturing their drugs.

At the top of their list was the Grignard reaction.

A critical chemical reaction that uses the volatile metal magnesium and flammable solvents such as ether to create new carbon bonds, each company depends on the Grignard reaction for production of many of their pharmaceuticals. Each agrees it’s an unsafe and non-environmentally friendly process.

On their behalf, the ACS GCI contacted the best-known academics working in green chemistry to invite them to compete for a $25,000 grant that would support them in attempting to find a new, greener way of initiating this reaction. One of the academics contacted was UMass Boston’s own Associate Professor of Chemistry Wei Zhang.

“They called me and said, ‘We have Pfizer working on this, we have Lilly. Do you want to apply?”, says Zhang. “I did.”

Zhang was chosen out of about 10 finalists to receive the grant this past spring.

“I’d never done very dedicated research on the Grignard reaction,” he says. “This is a big challenge, but it’s very exciting.”

Asha Kadam, a third-year PhD student in Zhang’s lab, is also up for the challenge. Zhang chose her to work on his team, as the grant stipulated that he name a student helper who would also attend the 2011 Annual Green Chemistry and Engineering Conference in Washington, D.C. in June.

Kadam says the conference – which was attended by representatives of pharmaceutical companies from around the world, along with UMass Boston alumni and green chemistry pioneers Paul Anastas (a keynote speaker) and Buzz Cue – was helpful for her research. “I met each member of the pharma companies who supported this grant,” she says. “We could understand exactly what they’re looking for.”

Kadam also had not worked with the Grignard reaction before, but she has experience with pharmaceutical companies. “It’s a big project,” she says. “It’s a good opportunity for me.”

The Grignard reaction is over 100 years old, Zhang says, and although its creator, Francois Grignard, received a Nobel Prize in Chemistry for his work in 1912, it is important to the pharmaceutical industry to find a new way to produce the same result.

“Metal isn’t good to use – it’s difficult to handle,” he says. “Magnesium in particular is very reactive, and easy to get out of control. The common solvents for the system used now are ether or tetrahydrofuran (THF), both of which have a low boiling point. They are very flammable.”

Combining them can be dangerous, he says. “The Grignard reaction now involves a heat-generating metal with a very flammable solvent. It’s a safety issue, so it’s not green. Unsafe is not green; green doesn’t only have to do with pollution.”

The grant extends until December of this year, during which time, Zhang, Kadam, and a team of graduate students will be in the lab, trying out different elements to produce a greener, safer variation on the Grignard reaction. Kadam says the team is “screen[ing] different green solvents. We have six solvents in mind to test. Temperature control is the main issue; we could initiate a critical reaction using overly volatile solvents. And yes, I’m a little nervous.”

While they experiment, they remain in close contact with the ACS GCI and the fourteen Pharmaceutical Roundtable companies.

Zhang, who has been invited to edit Green Processing and Synthesis, a new journal to be published in 2012, says, “This grant isn’t just giving out money to do work. This is collaborative research. This something we’ll build on."