Clean, Green Chemistry

<p>Nicholas Leadbeater outside UConn's Chemistry building. Photo courtesy of Nicholas Leadbeater.</p>
Nicholas Leadbeater outside UConn's Chemistry Building. Photo courtesy of Nicholas Leadbeater

Nicholas Leadbeater has a reputation. People call him a microwave chemist, because he – you guessed it – is a chemist who uses microwaves in his laboratory.

But even though these humble machines have enabled him to develop chemical techniques that are faster, cleaner, and “greener” than many similar methods before them, the associate professor of chemistry doesn’t give them too much credit.

“There’s nothing magical to microwaves,” he says. “We use microwaves to facilitate what we do, and that’s chemistry – chemistry with a purpose and a use.” He likens his work to playing with molecules until he finds new ways to bond them together – “like Lego bricks.”

Using two of the chemical reactions that earned the Nobel Prize in chemistry earlier this month, Leadbeater has over the past decade discovered techniques for making natural products, pharmaceuticals, polymers, and other advanced materials with a fraction of the waste, in a fraction of the time, and at a fraction of the cost. The techniques he has developed allow scientists to quickly and easily create products, such as potential new medicines, to be tested for use in the marketplace.

“Our work builds on what these famous Nobel Prize winners [Richard Heck, Ei-ichi Negishi, and Akira Suzuki] did: we’re developing new ways to get molecules to get together,” says Leadbeater. “We’re climbing on their coattails.”

Microwave ovens rose to prominence in American kitchens in the 1960s, using electric fields called microwave radiation to cook food. But it wasn’t until the late 1990s that specialized microwave ovens began showing up in chemistry laboratories. Leadbeater was intrigued, and over the next several years borrowed microwave equipment from CEM Corp. in North Carolina and began to experiment with it. That’s when, he says, things started to change.

A Clean Water Act

Conventional chemistry often uses a combination of high temperature, a high level of pressure, a catalyst, and a liquid chemical solvent to make a chemical reaction happen. But the appeal of microwaves was that they allowed chemists like Leadbeater to reach higher temperatures and pressures more safely and easily than conventional heating methods. This led to his first discovery.

Chemical reactions generally need to occur in some sort of fluid, and the standard approach is to use organic chemicals as solvents. But at these high temperatures and pressures, Leadbeater looked to a simpler fluid, namely, water, which was desirable because it is non-toxic, inexpensive, and easy to dispose of.

Using water and his microwave, Leadbeater shortened the famous Suzuki reaction – the procedure named for Akira Suzuki that won him a share of this year’s Nobel Prize – from several hours down to just five minutes. Not only did this procedure save chemists immense amounts of time, but it also greatly reduced the waste byproducts created when using organic solvents. Now, instead of having to incinerate their waste, Leadbeater found that much of it was clean enough to reuse.

Leadbeater then turned his attention to the other part of the equation: chemical catalysts. The element palladium was traditionally thought to be the best catalyst for these Suzuki reactions, but wasn’t as readily available as other more common metals. When Leadbeater found that the reactions worked just as well using copper or lead, he says, “alarm bells started going off in my head.”

And then when he tried to do the impossible – run the reaction with no catalyst at all – the reaction instead worked beautifully.

“We thought we had discovered that you could make the reaction go without a catalyst,” says Leadbeater.

After investigating further, however, he and his students found that in fact, their samples were contaminated with trace amounts of palladium.

Even though the reactions apparently still needed this particular metal, Leadbeater set about describing the minimum amount of palladium needed to run a Suzuki reaction. He found that the metal was necessary in only trace amounts: 50 parts per billion, or the equivalent of 50 drops of ink in a tanker truck full of water.

Scaling Up

Creating amounts of newly-discovered products large enough to be tested for commercial use meant that chemists would now need to scale up their research. Reactions that produced a milligram would need instead to produce a kilogram of product.

Getting to this level of scaling was a big leap because of engineering and safety issues, says Leadbeater. Microwaves not only afford greater heating and pressure, but need to be constructed with a cavity that protects the reaction from the outside world – and vice versa.

“If you have a small test tube and it fails, it goes ‘pop,’ and you clean it up and off you go,” says Leadbeater. But if you’re making larger amounts, and they explode, he says, that can be dangerous. However, with the right microwave equipment, Leadbeater and his recently graduated students William Devine, Chad Kormos, and Jason Schmink showed that it is possible to easily scale up these reactions.

Leadbeater says these discoveries are also an invaluable tool in the classroom. Microwaves have made it possible to complete a reaction in the laboratory that once took hours in mere minutes, a feat that allows students much more flexibility and time to actually experiment in the lab. This flexibility is key to students’ understanding of basic chemistry, he says.

“If you screw up a reaction, you can do it again,” he says. Students also have time to tweak reactions and try concocting new things.

Leadbeater’s microwave chemistry techniques have been included in one of the major organic chemistry lab manuals in the country (Clean, Fast Organic Chemistry: Microwave-assisted Laboratory Experiments, 2006). Although not all chemistry teaching labs have access to microwaves, a growing number are investing in them, he says.

Going with the Flow

Despite using microwaves extensively in his lab, Leadbeater is now turning his attention to another new technique that could be the next wave of chemistry innovation.

Called flow chemistry, this new idea uses a metal or plastic tube coiled tens or hundreds of times around a central heating apparatus, much like a spool of thread the size of a blender. Reaction mixtures are flushed through these coils, which heats the liquid evenly and effectively. Using this approach allows much greater control over the time a reaction is exposed to heat, which Leadbeater says can eliminate unwanted byproducts.

For example, a particular anti-cancer drug can be made in water, but its reaction creates an unwanted byproduct that’s difficult to extract. By using the flow approach and limiting the amount of time the chemicals are exposed to heat to about five minutes, Leadbeater and one of his undergraduate interns, Elizabeth Pedrick, were able to prevent the byproduct from forming.

Leadbeater and many of his colleagues think that flow chemistry is the field’s next big thing.

“Seeing what we can do with flow chemistry is a hot topic at the moment,” he says. “We’re starting to feel excitement now about flow. It’s the same kind of excitement we were feeling with microwaves 10 years ago.”

Although microwaves have contributed greatly to Leadbeater’s success over the last decade, he firmly believes that technology is simply a tool to do more interesting chemistry, and he’ll never be wed to just one technique.

“We want to be the early adopters when new equipment becomes available,” he adds. “You’ve got to recognize an opportunity and just jump.”