Episode 58: Nobel Laureate Dr. Benjamin List on Organocatalysis

Introduction to Dr List

0:00Hi, and welcome back to Let's Talk Chemistry, a science podcast by Chemtalk. I'm one of your co-hosts, Jasmine. And I'm Elizabeth. Today, we are sharing with you the story of Dr. Benjamin List. Dr. Benjamin List won the Nobel Prize in Chemistry in 2021 for his advances in asymmetric organocatalysis. Currently, he serves as one of the directors for the Max Planck Institute for Cool Research and is a professor of organic chemistry at the University of Cologne. List shared that the Max Planck Institute is over 100 years old and the best catalysis institute in the world.

0:36Prior to arriving at the institute, List earned the experience that led him to explore catalysis.

Early Interest in Chemistry

0:42I studied chemistry in Berlin, and at the time, Berlin was a divided city. In the eastern part of Germany, the communist part, but the city itself was also divided into two halves, capitalistic, democratic part, and the other part was the East German part. And I was in this little island, the western part, at the Free University, and that's where I studied chemistry. And I fell in love with organic chemistry pretty early on. Started my PhD there, and then my PhD supervisor moved to the University of Frankfurt, which happens to be my hometown, so I was back home.

1:19I finished my PhD there, and then decided to do something different and moved to the Scripps Research Institute in La Jolla, California. And I worked with Richard Lerner. He has been, unfortunately, he passed away a couple of years ago. He has been a doctor, actually, an MD, and he was a virologist and immunologist, and he had bought antibodies to behave like enzymes. That was something I was really fascinated with at the time. Though the enzyme field is not as vibrant now, it appeared to be very promising when Liszt first began to explore it.

1:53He stayed at Scripps Research Institute as a postdoc of Carlos Barbas and Richard Lerner's labs for one and a half years. While there, he had the opportunity to develop biocatalysts for any kind of reaction one can think of. Though Liszt developed an interest in catalysis during his college education years, he developed an interest in chemistry at a pretty early age. For me, it was really peculiar because I became really interested in chemistry when I was 11 years old. And at the time, we didn't even have that subject in high school.

2:25I had physics and I had biology, but I didn't have chemistry at the time. But somehow, I wanted to do chemistry. And only now, actually, I just realized where I think this interest may have come from. Because I thought chemists understand the entire world. They understand everything. They can control everything also. And it's a weird idea, right? Even for kids actually to think that. But I thought, you know, the world is made of molecules and atoms. And chemists know how molecules and atoms interact.

2:55And they know how to control these interactions. So they are in charge of the universe in a naive way. That's kind of what I thought. I think I was actually different in that I was more interested in humans than in molecules. And this is something I like to say now. Chemists, in fact, somehow decide matter over humans in a way, right? It's a peculiar choice to make to become a chemist. And it's also like IT guys, you know, they like computers and calculate.

3:25But, you know, it's a different choice when you become a lawyer or a businessman or a woman. And, you know, it's different. I thought that chemists understand the world and can control it. This is a new perspective of chemistry that I hadn't really considered before.

Chemistry Expectations

3:40In a way, his expectations of the field were right. Chemists have the ability to manipulate atoms and molecules to develop other molecules. And until we know the specific mechanisms and circumstances of these reactions, it definitely does feel like magic. Chemistry is such an interesting field to explore. And we actually begin to interact with it quite young. I realized where I got this idea from. When I was a really young child, like even before elementary school, I went with my dad into the National Museum in Munich.

4:11It's called das Deutsche Museum, the German Museum. And they had a section there where you could do chemistry experiments. And they were behind a glass wall. So you could just press a bottom. And then some chemicals were mixed. Some colorful precipitates were formed. And some stuff happened. And I don't remember what exactly happened. And unfortunately, they gave up that kind of exhibition. I was there recently. That's when I remembered it, actually. But what impressed me, I think, was sort of this predictableness about chemistry, right?

4:42You could predict if you mixed, you know, liquid A with solid B, another colorful material will precipitate. And in a reproducible and predictable way. That felt to me like, wow, they're in charge. They understand the universe. I definitely remember experiences like this myself. When I was in elementary school, some of the many science experiments I did involved mixing different solids or liquids together to form something new. Actually, two of my favorites were making crystal art or freezing my own ice cream in plastic bags filled with ice and salt.

5:15I like this lab where you put soap on the toothpick and held it in a petri dish filled with food coloring and different kinds of milk. And see how the colors disperse and swirl around. And a common science for projects is making a volcano with baking soda and vinegar. A lot of our early introductions to science or chemistry, we just aren't always conscious of it. However, when we find inspirations for discovery, we can be led to learn new things. Agreed. Lists shared how his childhood experience led to his current area of research. I built a laboratory when I was 11 years old in the cellar of a friend.

5:49And we started experimenting with the Bunsen burner and concentrated sulfuric acid. And of course, we also make gunpowder and all these things. And then I forgot the initial question that I had and, you know, got excited about, you know, this chemistry world. Do you want to spark interest? I have to admit, chemists do not understand the universe and they're not in charge and control everything, unfortunately. That's what I learned. However, chemistry is pretty powerful when it comes to changing the world.

6:23And typically, you know, improving the world, actually, improving our life, making us healthier and, you know, giving us sort of a longer lifespan, actually, by making vitamins, by making antivirals, antibiotics, vaccines, fertilizers and so on. Like, this is sort of the core power of chemistry, I would argue. And that comes from the ability to create catalysts. And this is also my area of research, catalysis science, where you basically make molecules or substances or materials that facilitate a chemical reaction or basically enable it to occur in the first place without being used up in the chemical reaction itself.

7:14Right. That's where then the magic comes, because it means that one capitalist molecule in principle can do its job an infinite number of times. And that's also where the economic fascination comes from, because it means a small amount of something, a capitalist, can create a huge amount of something else that might be valuable. So that's why chemistry, why catalysis research is sort of so fascinating for chemists as a scientific topic, but also because it's, you know, an economical aspect and it's probably a key technology for our life on Earth.

Catalysts and Chemistry

7:51As Dr. List mentioned, catalysts are very important molecules in the field of chemistry. Catalysts have the potential to make chemical reactions more efficient by increasing the speed at which molecules react. But sometimes these reactions are only able to occur with the catalyst present. That's why developing catalysts is such an important focus in research. Definitely. And there are many kinds of catalysis, but List worked to more greatly develop one kind called organic catalysis. And so we have helped in creating a new field in the area of catalysis, and that's so-called organocatalysis, the catalysis with small organic molecules.

8:29And that is distinguished from what chemists previously had used as catalysts for over 100 years. And those were metals, essentially, and maybe sometimes also enzymes, biological catalysts, you know, isolated from nature, from bacterias or from plants. Basically, my observation was when I was a postdoc at Scripps that the fascinating thing about biocatalysts, about these enzymes, is that sometimes they do have a nectar, but sometimes they don't. And chemists, in contrast, believe they would always need a metal in their catalytic molecules.

9:03And that was the starting point for this question, can we also use organic catalysts? And I answered this question pretty quickly, actually, and these were the very first experiments I did in my independent career. And it was sort of curiosity in the beginning, and everybody was rubbing her eyes, like, wow, this is also possible. But now, during the last two decades or so, this became really a strong and flourishing field that is now not used anywhere. There's no company and no chemistry department in the world that is not utilizing organocatalysis on one or the other level.

9:37So it's kind of like now, in fact, the dominant area when it comes to making viral molecules, you know, mirror image-like molecules, so-called asymmetric synthesis. It's the number one field. Chirality is a very important aspect of organic molecules. Two molecules can have the same chemical formula, but the attachment of the respective atoms may alter how each reacts with other molecules. Two molecules that are mirror images of each other are called enantiomers. There are objects that behave like object and mirror image.

10:10Like our hands, for example, clearly you can tell which one is a left hand and which one is a right hand, right? And this property also exists in the molecular world. And they're the molecules that behave like object and mirror image. In biology, we can distinguish between these two molecules that are mirror image-like, even though they're energetically and physically not distinguishable, other than by their three-dimensional geometry. So there is a need for, for example, in pharmaceuticals to be enantiomerically pure.

10:43That means you have only one form. And that comes from the fact that sometimes the other form is not active or even toxic. And there have been examples in the history of pharmaceuticals where actually the mirror image form was a toxic, very toxic compound sometimes. And so nowadays, actually, it's established that when a new drug enters the market, it has to be stereochemically pure. And therefore, methods to making these compounds are useful and needed. As Dr. Liss stated, two molecules can be similar down to the attachment of two atoms at one position, and this can entirely alter the effects of each molecule.

11:19Before stereochemistry and chirality were fully understood, racemic mixtures, which is a solution containing both enantiomers, of molecules were put on the market without knowing the possible consequences. One such example is the littlemide, which was marketed as a drug for morning sickness. While the R enantiomer of the littlemide achieved this effect, the S enantiomer led to the development of birth defects, so a racemic mixture had to be pulled from the market. What a shocking effect.

11:50That's why the research that chemists are doing is so important. And chirality plays a big part in Dr. Liss's research, which focuses largely on asymmetric catalysts. Even though Dr. Liss won the Nobel Prize in Chemistry in 2021 for developing asymmetric organocatalysts, his journey to that discovery actually started more than 20 years earlier during his time at Scripps Research Institute. Let's hear more from him. I had worked with an enzyme, with one of these antibody enzymes that Richard Lerner had created.

12:23And I had a crystal structure, so on a molecular level, on an atomic level, I knew the structure of that protein. I knew also where the active site was, and there was no metal. That was a surprise. When I really investigated this, what I found was there was an amino group of a lysine residue. That's an amino acid that carries another amino group. And there was another functional group in the active site of that enzyme, a tyrosine phenol that was hydrated. And for me, that quickly suggested how this enzyme actually worked.

12:56It only needed an amino group and an acid group to catalyze this chemical reaction. No metal whatsoever. And that was really fascinating for me. How fascinating. Our body is built of and contains many amino acids. An identifying feature that all amino acids have is an amine group, which is a nitrogen attached to a minimum of one carbon and one hydrogen. Another identifying feature is the acid group, which is a carbon with a doubly bonded oxygen and OH group. Metal catalysts are used because of their strong ability to donate or take electrons.

13:28So catalysts with no metal rely on other groups, such as amine groups and acid groups, to serve as proton donors and acceptors. Well, this experiment stuck with Dr. List as he started his own lab, and it got him sinking. Would it be possible to catalyze similar all the reactions with an amino acid itself instead of an entire enzyme? As it turned out, yes. Dr. List borrowed some proline, which is an asymmetric, non-essential amino acid, from some biologists working next door at Scripps.

13:59Even more interesting is that proline is the only amino acid that has a nitrogen bonded to two carbons rather than one. Dr. List experimented using it as a catalyst for some aldol reactions, which is when two carbon atoms form a bond. Oh, interesting. And he was able to detect his product using TLC, right? Yes. The next day, he performed TLC, or thin layer chromatography, which is a fun method organic chemists use to determine if the reaction actually occurred by dotting the starting reactant along with the assumed product.

14:33The spotting pattern on the TLC plate indicated that he did, in fact, find the product. That's incredible. To think, that one experience working with an antibody enzyme inspired Dr. List to test proline as a catalyst for aldol reactions. In turn, that success led to faster and more efficient pharmaceutical synthesis and numerous environmental benefits, like lower usages of toxic metal, greater energy efficiency, less waste, and more. Looks like his discovery was quite catalytic. Absolutely. Now, winning a Nobel Prize in itself is an immense honor and tribute to the groundbreaking work that Dr. List has done.

15:08But one extra benefit of it is that it has given him a certain level of freedom to decide what to research next. This way, he can be more selective and even a bit radical in choosing his next research target. Radical? How so? Well, with each new project he starts, Dr. List has an overarching goal. Make a big breakthrough or solve a major problem. For example, his new objective is to split carbon dioxide. Carbon dioxide absorbs and radiates heat in the atmosphere, and it is one of the primary greenhouse gases contributing to global climate change.

15:42Considering the ever-growing danger of the climate crisis, the ability to split carbon dioxide could change the world. I'm so excited to hear more about this project. This goal that I want to split CO2. This is kind of my topic right now. I mean, I don't have many people in the lab, to be honest, that work on it right now, because I think they're a bit scared of the challenge of this. But it would be, I would argue, and I hope I inspire, if we are not successful, you guys or your listener, it would be really, I guess, one of the biggest chemical discoveries in the history of chemistry, if it would be possible.

16:19Because imagine you could split CO2 into carbon, coal or graphite or diamond, it doesn't matter, and oxygen. It would be sort of the essence of photosynthesis. But in a reductionistic way, I would reduce water on both sides of the equation. I would just take CO2, a catalyst, and light. Of course, you need an energy, because it's thermodynamically uphill, and split it into carbon and oxygen. And photosynthesis is like that. You have, on the one hand, CO2, and then water, and these two other ingredients of photosynthesis. And then there we add, at the present of catalysts and sunlight, to give oxygen and carbohydrates, the hydrates of carbon.

17:02If you know, sort of the essence of that equation is the splitting of CO2. And for some reason, chemists, I think, have overlooked this transformation, even though it would arguably change the world, right? It would be a chemical reaction.

Splitting Carbon Dioxide

17:15Could potentially change the world, right? And I think it's a good opportunity, given the challenges we're facing right now on this planet, to work on this, to use our creativity and our intelligence to potentially solve a big problem with humanity. Of course, I know it's a daunting challenge, but I think it's not impossible. You know, we did the calculations, it's thermodynamically uphill, and it requires 300 nanometers of UV light, but so does photosynthesis. In fact, it requires less energy than photosynthesis. So somehow it must be possible, right?

17:48That's a wonderful idea. Nature has overseen and cultivated the balance of life for billions of years, so it makes sense to take a leaf out of nature's book. Yes. I also love what he said at the end about giving it a try despite existing studies not showing much success in this endeavor. I agree. That can be rather disheartening because it might make you question yourself more and wonder if this is some outlandish idea that won't come to fruition. But in order to achieve innovation and advance science, it's important to overcome those doubts and have the courage to experiment with new ideas.

18:18It's also crucial to surmount doubts from others because some might be a bit scared, like Dr. List mentioned, or even actively deter and criticize you. Actually, Dr. List explained his thought process with regards to overcoming discouragement and setbacks. Let's hear from him. One thing, if you are really interested in science and you want to discover something that changes the world, something that is inherently revolutionary, by definition, you have to go through difficult times because you will face loneliness, by definition, right?

18:50Because if it's revolutionary, nobody is doing what you're doing. And then humans have this tendency then to be, you know, a bit skeptical, right? Of course, you know, this guy is doing something nobody else is doing. You might assume he might be on the wrong path or not very smart, you know, and that I had faced some criticism in the early days. Like people would say that's not a real catalyst because we used quite a large amount of holiness in the early days as a catalyst. It was not a, what I always say, like a single molecule that can produce an infinite amount of new molecules.

19:24It was not like this. I needed several grams of proline to make 10 grams of a product. So it was kind of a medium level catalyst, but it was the first generation. Now, 20 years later, we have catalysts that define the state of the art in asymmetric catalysis in terms of reactivity. Nobody would have expected this in the beginning, right? And now, in fact, a colleague of mine mentioned this to me, very wise words. If you face this kind of skepticism and criticism, it hurts maybe in the moment, but on the long run, it can be a gift.

19:57And for me, it was the gift to try to overcome these limitations, right? It reminded me of what still needs to be done. So it's not easy in the moment, right, when people criticize you, but later on, you can be grateful to your critiques, to the worst critiques, actually, because they encourage you to solve the problems. That's a great way to view criticism. If you're going to try out a new revolutionary idea, you will likely be among the few trailblazers, as most people feel more comfortable on familiar, proven paths.

20:28As a result, you may encounter criticism. However, as long as the fundamentals of your ideas are strong and valid, if you use that criticism as motivation instead of staying dejected, you have a much higher chance of succeeding and making that concept a reality. Definitely. Now, our Time Must Talk list is wrapping up, so let's hear his advice for students. The most important thing is to be happy, and that's what we all want. All eight billion of us want to be happy, right? It can be interpreted as like he makes his life very easy by just only trying to be happy, but I think it's challenging enough.

21:04And ultimately, I think that's what we all want. And a good recipe for happiness is to pursue what you're really interested in. And in my case, it was chemistry, and I can only motivate everybody to go into chemistry because it's like, you know, understanding the world and creating new things. It's, you know, new, beautiful capitalists that change the world. Of course, it's very rewarding and it's fascinating, and you discover stuff that nobody else has seen before. Personally, for me, it's exciting, but others might be interested in other things. And even if they're interested in styling hair or whatever, right, or just surfing, if that is what they truly love, where all their enthusiasm lies, I would really encourage them to pursue that also.

21:47And if you're lucky, then you might have a job, and that, you know, fulfills a big part of your day, like let's say eight hours every day, in which you just do what you love to do, which is by, in my world, the definition of happiness. If it feels painful or if you feel like maybe your parents have pushed you into a career, for example, that you don't really enjoy that much, it's time to have a serious conversation with them and then maybe reconsider. Or whoever gave you, pushed you into a certain world, even if it's your own thinking, for example, right?

22:18You read there's a big need for IT specialists in the future. You go into studying informatics, but then it's actually not your thing, right? It's not a good idea, I think. So follow your enthusiasm. And now, I think, given the challenges humanity faces right now, and global warming, I would say, is a big challenge. And from what I hear, it's maybe one of the biggest challenges humanity has ever faced, right? So I would say, if you are already hooked from chemistry, why not work on solving climate change, you know, contribute to this, to a more sustainable way of transportation and of energy and of chemistry also.

22:59I think that's a formidable and great grand challenge for chemistry right now. So I think it will be rewarding, actually, now to be part of this transformation into a new area of chemistry. I completely agree with him. If you do something you truly enjoy, then you'll be significantly more motivated to work and improve at that job. As a result, you'll have far superior results than if you pursued a career that you didn't have much enthusiasm for, and you'll be happier. Admittedly, it will not be a simple journey, and you may be afraid of taking a chance and falling short or feel pressured by expectations to choose certain career paths.

23:37But your life belongs to you, not to fears and expectations. So why not try to manage the factors within your control and follow your passions? Who knows, perhaps you could eventually win a Nobel Prize yourself, like Dr. Liss. It's certainly a possibility. Also, to those concerned their enthusiasm may be too unrealistic to land a job in, there are likely a wide variety of different career options for whatever your enthusiasm may be. Take chemists, for example. There are environmental chemists, astrochemists, organic chemists, and quite a few more.

24:09Exactly. I also love the part about working on solving climate change. It is a serious issue, continuously growing even more dangerous. But if you choose to tackle this or any other issue plaguing the world, then you will be helping more people than you will ever know and paving a way for future generations to follow and expand on. I agree. Thank you so much to Dr. Liss for sharing your knowledge and advice with us today. And to all our listeners, thank you for joining us. Until next time, I'm Jasmine. And I'm Elizabeth. Bye.

24:39Thank you for listening to Let's Talk Chemistry, a podcast by ChemTalk. We hope you enjoyed it. For more information on today's episode and countless chemistry resources, please visit our website at www.chemistrytalk.org. Thank you.