A Lindau Lecture to Catalyze the Power of Chemistry

Andrei Mihai

The Heidelberg Laureate Forum has a deep connection to the Lindau Nobel Laureate Meetings. Every year, the two sister events “swap lectures.” This year, it was David MacMillan, a Nobel laureate in chemistry, who took the stage at both events, delivering his signature lecture on the power of catalysis. MacMillan’s lecture explored the intricacies of organic catalysis, a field he helped pioneer, and also offered a glimpse into the future of sustainable chemistry.

Catalysis Is Everywhere

MacMillan was awarded the Nobel Prize for his work on asymmetric organocatalysts, which opened up an entirely new range of chemical reactions. But to understand why MacMillan’s work is so revolutionary, we have to first look at the previous state of affairs.

“If you look around you right now, absolutely everything that you can see is made by a chemical reaction,” MacMillan says. From the caffeine in your coffee to the screen you are reading this on, chemical reactions are the invisible architects of the modern world. But some reactions need a bit of “help” to take place. This is where catalysis come in.

A catalyst is a substance that speeds up a chemical reaction without being consumed in the process. Think of it like a person trying to get home every day by walking over a massive hill. A catalyst is like digging a tunnel through that hill. From that long, complex journey that takes up a lot of energy, you can walk through the hill and get to the destination faster and easier. So, in essence, catalysis lowers the energy required for a reaction to happen, making it faster, more efficient, or even making it possible in the first place.

This is not a niche concern. Catalysts are essential because many of the chemical reactions needed to create vital products (from plastics and medicines to the fertilizer that grows our food) are naturally so slow that they are practically impossible on a useful timescale. Catalysts are so widespread that an estimated 35% of the world’s GDP is directly dependent on them, and the number will only get higher in the future. The most striking example is the Haber-Bosch process, a catalytic reaction that converts nitrogen from the air into ammonia for fertilizer. Without it, we could not produce enough food to feed the Earth’s 8 billion people. This process is so widespread that around half of the nitrogen atoms in your body come from synthetic catalysis.

For a hundred years, chemists believed they had only two types of catalysts.

The first was nature’s way: enzymes. These are the catalysts of life, gigantic, intricate proteins that perform every chemical task inside our bodies with remarkable precision. Chemists have harnessed enzymes to create various products and this approach has been widely successful. However, enzymes are often delicate, highly specific, and can be difficult to work with outside of their natural environment.

The second, and far more common in industrial chemistry, was the human-invented method: metal catalysis. Metalocatalysis relies on metals, which are technically elements from the middle of the periodic table. Palladium, rhodium, platinum, and nickel are common examples. These metals are phenomenal catalysts, capable of performing an incredible range of chemical transformations. They are the workhorses that build our plastics, our pharmaceuticals, and our fuels.

But they too have a dark side.

Many of these metals are rare and expensive. Palladium, essential for everything from your car’s catalytic converter to your smartphone, is a prime example. “We’ve been using palladium on Earth for about 90 years,” MacMillan warns, but we don’t have too many years left of palladium on Earth. Furthermore, these metals are also frequently toxic, posing a risk to both human health and the environment. And they are incredibly sensitive. Many metal catalysts are instantly destroyed by contact with air or water, forcing chemists to work in cumbersome “glove boxes,” sealed chambers filled with inert gas.

So, MacMillan looked for a better way.

An Organic Revolution

A key moment for MacMillan started with a question from a graduate student of his. Tristan Lambert walked up to MacMillan and asked about the mechanism of a classic chemical reaction. The Laureate walked to the blackboard and started explaining and that was when he realized something.

A typical metal catalyst has two parts: a central metal atom (the expensive, toxic, and sensitive part) and a surrounding “organic framework.” This framework is a molecule made mostly of carbon, hydrogen, and other common elements, very common elements. In traditional metal catalysis, this organic part was seen as a mere scaffold to hold the important metal atom in place.

Staring at the chalk diagram on the board that day, MacMillan had his eureka moment. He realized the organic molecule in question briefly formed a special state that looked suspiciously similar to the way metal catalysts worked. If an organic molecule could mimic the electronic action of a complex metal catalyst, even for a moment, then couldn’t it be a catalyst on its own? “What if,” he thought, “we just get rid of the metal? Why don’t we just use the organic part to do the catalysis?”

This was the birth of asymmetric organocatalysis. The idea was to use small, simple, robust organic molecules to do the work that had previously required rare, precious metals. These were molecules that are non-toxic, insensitive to air and water, and completely sustainable. It was, in theory, a perfect solution.

The first test was a big one. MacMillan and his students decided to try their idea on one of the most famous and powerful reactions in all of chemistry: the Diels-Alder reaction, a cornerstone of molecular construction so important its discoverers won the Nobel Prize in 1950. They took two simple starting materials, added a small amount of a simple organic molecule as their proposed catalyst, and mixed them.

It worked perfectly.

“I always remember getting this result,” MacMillan recounts with a laugh. “I walked in my office, I closed the door and locked the door. I closed the blinds. Then I jumped up and down for about 10 minutes. I was so excited. I remember calling my wife and I said to my wife, ‘I think we’re going to get tenure!'”

A New Way to Do Chemistry

MacMillan realized he was on to something remarkable. But in his first scientific paper, he made a bold, almost reckless, proclamation. He argued this wasn’t just a one-off trick that worked for a single reaction. He claimed it was a “generic activation mode,” a general principle that should work for hundreds of different reactions.

The only problem was, he could not replicate it in other reactions.

“This was our first-generation catalyst. We said it’s going to work for hundreds of reactions. It went bang, bang, bang … nothing,” he says. “We tried it on three reactions, and then it just stopped.” The catalyst that worked so beautifully for the Diels-Alder reaction was a dud for everything else. “In this moment, I’m starting to have panic attacks. I’ve just told the world this is going to work for hundreds of reactions. We’ve got three.”

Yet again, key inspiration came from graduate students, who suggested a subtle but critical change to the catalyst’s structure. It was a bit of “precision molecular engineering.” MacMillan compares it to a spectacular goal scored against England by Zlatan Ibrahimovic. It’s a goal of sublime, almost impossible precision. The new catalyst, like that goal, was engineered for perfection.

When they tried it, the floodgates opened. “Bang,” MacMillan says, “they started to really work.” Soon, labs around the world jumped in, designing new organocatalysts, and the field exploded.

The impact has been enormous. In everything from fragrances to drugs, organocatalysis is now being routinely used. For MacMillan, seeing his chemistry used to create a medicine that helps millions was a “wonderful” moment.

Perhaps the most profound impact, however, was one he never anticipated. Because the catalysts are so cheap, stable, and easy to use, they don’t require expensive equipment or facilities. This has led to what MacMillan calls the “democratization of catalysis.” For the first time, cutting-edge chemical research could be performed not just in the elite labs of the Western world, but on every continent.

“When people ask me, ‘What is the next big idea coming from catalysis?’,” he says, “I say, ‘Number one, I don’t know. But the second thing is, I know it’s not going to be based on who has the most money but rather on who has the best idea.'” For someone with his values, he says, “that is something which is really, really cool.”

Chemistry in a New Light

After explaining his Nobel-winning work, MacMillan continued with something that he considers just as promising, if not more.

After establishing organocatalysis as the third great pillar of the field, MacMillan’s restless mind turned to a new challenge. This time, he says, the idea was “completely stolen” from a different group of scientists altogether: inorganic chemists who were trying to harness solar energy to power the planet.

Their work involved materials that could absorb visible light. MacMillan wondered if he could take their light-absorbing molecules and merge them with the world of catalysis. This gave rise to a second new field called photoredox catalysis.

Most organic molecules are colorless; they don’t interact with visible light. However, the special photoredox catalysts, often containing a metal atom like iridium or ruthenium, are brightly colored. They act like tiny antennas, specifically designed to absorb the energy from a photon of light like a simple LED.

When the catalyst absorbs that blue light, it enters a highly energized, excited state. MacMillan explains the magnitude of this energy boost with a jaw-dropping analogy: “It basically is the equivalent of being at 32,000 degrees Celsius, while every other molecule in the vessel is still at room temperature.” The catalyst now has a massive surplus of energy, and it is desperate to get rid of it. It does this by either giving an electron to, or snatching one from, a nearby molecule.

This act of electron transfer flips a switch on otherwise inert, unreactive molecules, turning them into highly reactive molecules. Suddenly, chemists could use simple blue light to activate vast classes of abundant, everyday chemicals that were previously thought to be unusable.

The implications are especially important for medicine, enabling researchers to limit the side effects of drugs in the body and create drug candidates with much higher specificity and precision. This branch is now also used routinely by pharmaceutical companies.

David MacMillan’s engaging lecture is a reminder that sometimes, even the most groundbreaking of discoveries start with a blackboard and a seemingly simple question. His work gave chemistry a greener, cheaper, and more democratic way to help build the world. As we face global challenges like climate change and disease, his work is a powerful reminder that the next world-changing idea might just be a matter of looking at an old problem and seeing it in a completely new light.

 

The post A Lindau Lecture to Catalyze the Power of Chemistry originally appeared on the HLFF SciLogs blog.