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Photo of David MacMillan // courtesy Princeton University

A U of C connection to the Nobel Prize in chemistry

By Sergio Sharif, January 15 2022—

On Oct. 6, 2021, the Nobel committee announced Professors Benjamin List of the Max Planck Institute and David MacMillan of Princeton University as recipients of the Nobel Prize in Chemistry. Although this was a day of anticipation and excitement for everyone in the chemistry community, it was especially surprising for one member of the University of Calgary community.

Dr. Jeffery Van Humbeck, an assistant professor of organic chemistry in the Faculty of Science, once worked in MacMillan’s laboratory as a Ph.D. student back in Princeton. On the morning of the announcement, with a tone of palpable excitement, he announced to his organic chemistry class that his doctoral advisor won the prize.

In an interview with the Gauntlet, Van Humbeck shared more about the esteemed scientist — and person — that is MacMillan.

When asked about the importance of MacMillan’s work, Van Humbeck answered, “It’s not an exaggeration to say that there are at this exact moment, all over the world, lots of little glass vials creating new chemical structures for the first time using reactions invented in [MacMillan’s] lab. How many vials? You would have to propose a big number before I thought it was too big. More than ten? Definitely. More than a hundred? At this literal instant in time you are seeing these words, dear reader, I would still say yes. A thousand? OK, now we’ve gone too far.”

The field of organic chemistry is largely concerned with how a desired molecule can be synthesized. Beyond the not-so-trivial challenge of how to design such a synthesis, organic chemists are also faced with the task of making it an efficient and high-yield process. 

Many syntheses, such as those designed for producing pharmaceuticals, require the use of a catalyst. Catalysts are substances which allow a reaction that would otherwise take place very slowly. 

“[At] the turn of the century, there were a lot of known catalysts that used metal atoms, like palladium or titanium,” Van Humbeck explained. “There were also many large organic molecules that could act as catalysts — all of the enzymes in your body, for example.”

The breakthrough MacMillan and his group won the Nobel Prize for was in their invention of new chemical reactions that are now widely used, especially in the pharmaceutical industry. These reactions are novel in that they use a small organic molecule as a catalyst, according to Van Humbeck.

Although this new approach to catalysis — dubbed organocatalysis — was recognized by the Nobel Committee as a way to replace metals, Van Humbeck pointed out that what was more interesting and more impactful, was the fact that you could do new things.

“There had been a few select uses of small organic molecules as catalysts before [MacMillan] and [List] — the other recipient. Some of these were quite well known, but I think it is true that very few people were really thinking about how small organic molecules could be used widely for many different applications.”

MacMillan’s new approach to catalysis allowed organic chemists to “create new reactions, [which] can open up entirely new families of molecules that have never been explored before,” says Van Humbeck.  

Importantly, organocatalysis allows for a specific product to be formed when a reaction would otherwise produce two forms of the molecule. This has deep implications in pharmaceutical production. For instance, the drug ketamine follows this principle — termed chirality. One form, (S)-ketamine, has the desired function as an anesthetic. However, the other form — (R)-ketamine — causes undesired hallucinations. Synthesizing drugs with organocatalysis is a new way of ensuring only one form of a chiral molecule is produced. 

Despite winning a Nobel Prize for it, MacMillan’s contributions to organocatalysis may not have been his greatest work. 

“When I was in the lab, David Nicewicz, a postdoctoral student at the time, discovered a new way of catalyzing reactions [called] ‘photoredox’,” Van Humbeck explained. 

Photoredox, which harnesses the power of light to catalyze previously unachievable reactions, also has had an immense impact on the field of organic chemistry and beyond.

“Some chemicals are willing to donate their electrons –– these are called reductants. On the other hand, some chemicals are happy to accept electrons –– these are called oxidants. Normally, if you take a strong oxidant and a strong reductant and mix them together in a flask, that’s a strange-but-effective way of generating a lot of heat, very, very quickly,” said Van Humbeck. 

As Van Humbeck explains, the power of photoredox lies in its ability to permit oxidants and reductants — which normally can’t be mixed — to be present in the same flask.

“This area of research has exploded — pun not intended. Dozens of research groups now use this approach to invent new reactions. There are things that we can force molecules to do that would have seemed like science fiction 20 years ago, that are now quite commonplace. If you were to walk through the labs of a big pharmaceutical company, you would see a lot of blue and green LEDs pointed at rows of little glass vials, doing these types of reactions.”

When asked about which of MacMillan’s innovations were more deserving of winning the Nobel Prize, Van Humbeck said “I think that [his] two big contributions are each worthy of a Nobel prize.”

Van Humbeck also highlighted some of MacMillan’s qualities.

“He had no fear about being wrong, [nothing] was too ambitious or too difficult to think about –– and he would never accept that we couldn’t think up a solution to any given problem –– we just needed to think about it some more,” said Van Humbeck.

In one extraordinary example, Van Humbeck talked about a time when “[MacMillan] basically asked us to figure out how to make fire — combustion — go backwards using a catalyst — not exactly but close enough.”

To put it another way, MacMillan was challenging his students to use catalysts to design a reaction which reverses the near-irreversible process of fire.

“MacMillan had an incredible vision for what he wanted to build and he’s made it real. I had met [him] when he was still at Caltech and [I] had agreed to move to California to work with him there. Then, one day in [around] March 2006, I got a message on my phone. ‘Jeff, it’s Dave MacMillan. When you have a second, do you think you could give me a quick call?’. Everybody in the chemistry world had heard rumours that [MacMillan] was thinking about moving to Princeton –– so I went onto the Princeton Chemistry website and the landing page had a big ‘Welcome Dave MacMillan! Joining the Department in September!’”

Not long after, Van Humbeck decided to go to New Jersey to work with MacMillan at Princeton. 

“When I joined the lab, a lot of the researchers in the group were working on ways to combine organic catalysts with metals and create new reactions that neither catalyst could do on its own. My lab [associates] were in charge of discovering new reactions and I was tasked with figuring out how the organic catalyst and metal were working together after a new reaction was discovered.”

“Princeton has turned into a world leader in catalysis over the last 15 years and [MacMillan] pretty much laid out how it was all going to happen on that phone call and he was good on his word.”

From the time Van Humbeck started his work with MacMillan, to the announcement of the Nobel Prize in the fall, MacMillan has led the way in innovative and clever approaches to the biggest problems in organic chemistry. Not only does Van Humbeck hold him in the highest regard as an academic, but also as a mentor and person of many stories and memories.

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