• The San Juan Daily Star

Nobel Prize in Chemistry awarded to scientists for tool that builds better catalysts

David W.C. MacMillan at his Princeton University office in 2012. His research has focused on innovative concepts in synthetic organic chemistry.

By Sabrina Imbler, Marc Santora and Cora Engelbrecht

The Nobel Prize in chemistry was awarded Wednesday to Benjamin List and David W.C. MacMillan for their development of a new tool to build molecules, work that has spurred advances in pharmaceutical research and allowed scientists to construct catalysts with considerably less impact on the environment.

The process developed by List and MacMillan, while unseen by consumers, has led to a “gold rush” in the field, the Nobel Committee wrote. Known as organocatalysis, it has helped those who apply chemistry to real world problems to build more precise catalysts that reduce waste and streamline the production of existing pharmaceuticals.

Peter Somfai, a member of the Nobel Committee, compared the tool to a new player on a chessboard. “You can think about the game in a different way, and you can execute the game in a different way,” he said after the Nobel conference Wednesday.

H.N. Cheng, president of the American Chemical Society, said List and MacMillan’s tool goes beyond a new player. “It’s more than just a chess piece. They have opened up the board,” Cheng said. “Now it is up to you to play the game.”

MacMillan’s phone started buzzing early Wednesday, but he ignored it. When it buzzed again later, he saw List had texted, saying the Royal Swedish Academy had tried to reach him.

He looked back at the earlier message, but it misspelled his name, so he dismissed the text as a prank. MacMillan wrote back to List and bet him $1,000 that the text was not real and went back to sleep.

Later, he woke up and saw his name on the website of The New York Times.

“Now I am $1,000 down but a very happy person,” MacMillan said.

In 1835, Swedish chemist Jacob Berzelius described a phenomenon in which certain substances could galvanize a chemical reaction. These substances were named catalysts, and the process was called catalysis. Since then, scientists have discovered many catalysts that can build up and break down molecules, enabling inventions such as plastics, perfumes and pharmaceuticals.

Before 2000, scientists assumed all catalysts were either a metal or an enzyme. Metal catalysts, which can temporarily accommodate electrons or offer them to other molecules during chemical processes, can be toxic and environmentally taxing. Precious metals used as catalysts, such as platinum, must be mined.

Enzymes, which are proteins found in nature, are the catalysts that form complicated and vital molecules, like cholesterol and chlorophyll. Because enzymes are so efficient, researchers in the 1990s tried to develop enzyme variants as catalysts to drive the chemical reactions needed by industry and in manufacturing. But “enzymes are cumbersome,” Cheng said, and the process led to vast amounts of waste.

In 2000, List and MacMillan — working independently of each other — developed a new type of catalysis that used organic molecules called asymmetric organocatalysis.

Organic molecules, such as carbohydrates, are called that because they build all living things. The researchers discovered “cheaper, smaller and safer” catalysts that used organic molecules had the same rich chemistry as metal compounds, according to Tehshik Yoon, a chemist at the University of Wisconsin-Madison. Their technique was also simpler and more environmentally friendly.

List was working on enzymes at the Scripps Research Institute in San Diego, in a research group run by Carlos F. Barbas III. He knew of research from the 1970s that used a simple amino acid called proline as a catalyst. The studies had garnered little attention at the time.

He tested whether proline could catalyze an aldol reaction, in which carbon atoms from two different molecules bond together. The reaction worked, proving that proline was an excellent catalyst and that an amino acid can drive what is known as asymmetric catalysis.

Many organic molecules exist in two, mirrored variants like human hands — what is known as chirality. For example, one version of the molecule limonene — the right-handed one — smells like lemon, and its mirror image, which is left-handed, smells like orange.

“Organic molecules that play a role in life have this important feature of being handed — a right-handed and left-handed version that can have very different chemistry and very different biological consequences,” said Dr. Francis Collins, director of the National Institutes of Health, which has funded both List’s and MacMillan’s work, the latter continuously since 2000.

Chemists and pharmaceutical researchers often only want one version of a molecule, and typical catalysis produced both versions. Having both can lead to disastrous effects; in the 1950s and 1960s, one mirror image of the molecule thalidomide caused severe birth defects in thousands of babies.

But asymmetric catalysis can produce just one of these asymmetric molecules, the left or the right, a boon for safety and for reducing chemical waste.

Two years earlier, MacMillan had left a position at Harvard University, where he was researching asymmetric catalysis in metals. He noticed these metal catalysts were rarely used in the real world, as they were expensive and difficult to maintain. Some metal catalysts need to be in an environment free of oxygen and moisture, which is hard to achieve at a larger scale.

So MacMillan, now working for the University of California, Berkeley, developed a more durable catalyst from organic molecules that, like metals, could temporarily accommodate or provide electrons. He tested the organic molecule’s ability to drive a Diels-Alder reaction, which can build rings of carbon atoms.

Like List’s experiment, MacMillan’s reaction worked perfectly. He said he remembers jumping up and down and telling himself, “I think I’m going to get tenure.”

His results showed that some of these organic molecules were excellent at asymmetric catalysis, producing more than 90% of the desired mirror image.

In 2000, List and MacMillan each published their papers. MacMillan’s paper coined the term for this new catalysis — organocatalysis — so that other researchers might seek out new organic catalysts.

“It was a watershed moment,” Yoon said. “This idea was so obvious and so elegant that it was very easy for other people to apply that central concept to other kinds of reactions.”

Echoing that point Wednesday when delivering the prize, Johan Aqvist, chairman of the Nobel Committee for Chemistry, said that “many people have wondered why we didn’t think of it earlier.”

Jon Lorsch, director of the National Health Institute’s National Institute of General Medical Sciences, called the process “molecular carpentry.”

“You can imagine if you’re trying to build houses of different shapes and sizes, if all you had were boards and a hammer and a nail, it would be difficult and slow,” Lorsch said. “They developed a whole different suite of tools that allow you to join different kinds of materials together in all sorts of different ways in rapid fashion to build different kinds of structures.”

Since List’s and MacMillan’s concurrent discoveries, the two scientists and other researchers have designed a plethora of molecules used in drugs, agrochemicals and efficient, durable materials. Their research has also sped up the production of existing pharmaceuticals, such as the antidepressant paroxetine and the antiviral oseltamivir, which treats respiratory infections, the committee wrote.

List, calling in to the Nobel Conference from a vacation in Amsterdam, said he originally worried his idea was “stupid.”

“I literally felt like I was the only one working on this,” he said. “When I saw it worked, I did feel that this could be something big.”