Nobel Laureate Says Development of Efficient, Environmentally Friendly Catalysts Is Already Underway
The following article is the first half of Prof. David MacMillan’s keynote presentation at the Twenty-eighth International Conference on the Unity of the Sciences (ICUS XXVIII) in 2022, entitled “New Catalytic Strategies for a Sustainable Future.”
“Everything you can see—and even almost everything you cannot see—is made from chemical reactions. ... But how do chemical reactions work? It turns out that chemical reactions usually do not happen spontaneously: In order to convert a starting material into the product you want, you often need to input a significant amount of energy. The process of catalysis can dramatically lower the amount of energy needed to power a chemical reaction.”
Catalysis impacts nearly every aspect of the modern world. Today, at least 90% of industrial-scale chemical reactions employ catalysis, and fully 35% of the world’s gross domestic product is based on catalytic processes.
Industrial-scale catalytic processes provide many of modern society’s staples, including food, medicines, solar cells, diagnostic tools, and even polymers and materials.
Over the next century, catalysis will provide solutions to many pressing societal challenges, such as alternative energy, environmental remediation, inexpensive pharmaceuticals, sustainable agriculture, and renewable soft materials. The development of efficient, environmentally friendly catalysts will be key to our common goal of creating a more sustainable future. That is why, over the past two decades, my research group has been dedicated to inventing powerful and environmentally friendly catalytic processes.
It was my great honor to share the 2021 Nobel Prize in Chemistry for the development of asymmetric organocatalysis. Since winning the prize, many people have asked me just one basic question: What exactly is asymmetric organocatalysis? This is a rather technical term, so it is good to begin by explaining the concepts of asymmetry, catalysis, and more specifically, organocatalysis.
What Is Catalysis?
Everything you can see—and even almost everything you cannot see—is made from chemical reactions. Our food, medicines, clothing, electronics, and even the cells of our bodies are created through chemical reactions. We can appreciate that chemical reactions are absolutely essential to our existence. But how do chemical reactions work?
It turns out that chemical reactions usually do not happen spontaneously: In order to convert a starting material into the product you want, you often need to input a significant amount of energy. The process of catalysis can dramatically lower the amount of energy needed to power a chemical reaction.
Here is an analogy to explain the power of catalysis I give to my students:
Imagine that every evening, you have to climb a large hill to get from class back to your dorm. Your daily trek up and over this hill clearly requires a lot of energy.
Now, imagine that, one day, you find a tunnel that leads directly through the hill. You walk through the tunnel and straight home with hardly any effort. In this analogy, catalysis represents the tunnel, as it provides a new path for chemical reactions to follow with minimal input of energy.
Catalysis … allows chemical reactions to proceed quickly, efficiently, and often with relatively little cost.
An important feature of catalysts is that they are not used up in chemical reactions. In fact, a very small amount of a potent catalyst can be used to convert large quantities of starting materials to products. Catalysis therefore allows chemical reactions to proceed quickly, efficiently, and often with relatively little cost.
These unique attributes help explain why so much of our modern society relies on catalysis. As an example, we can consider the real-world impact of perhaps the most revolutionary catalytic process of our age: nitrogen fixation (Figure 3). Invented in the early twentieth century by the German chemist Fritz Haber, catalytic nitrogen fixation is an industrial-scale process that converts nitrogen (N2) to ammonia (NH3).
Ammonia is an essential component of farming, and modern agriculture depends on the ammonia produced through catalytic nitrogen fixation to grow an abundance of food crops. This increased crop productivity, in turn, has fueled the exponential growth of Earth’s population over the past century. Without this one catalytic process, it would be very difficult—if not impossible—to produce the food needed to sustain Earth’s eight billion people. To visualize how this process impacts you, consider that about half of the nitrogen atoms in your body were likely derived from industrial-scale nitrogen fixation.
What Is Asymmetry?
The property of asymmetry is easy to visualize. Most of us have two hands, and our hands are mirror images of one another. These mirror images are almost identical, but they are not exactly identical. That is, your right-handed glove does not fit on your left hand. Two mirror-image objects, like hands and feet, that are almost identical but not superimposable are called asymmetric.
Interestingly, molecules can also exhibit this property of asymmetry. In other words, organic molecules can exist in one of two nonsuperimposable mirror image forms, each of which is called an enantiomer. As you might expect, the two mirror images of an organic molecule have almost identical physical properties and behavior, and it can be difficult to distinguish one from the other in a laboratory. In fact, two enantiomers will behave in very similar ways to one another except when they are interacting with other asymmetric molecules. Much like your two mirror-image hands can distinguish between two mirror-image gloves, each enantiomer of an organic molecule will interact differently with other asymmetric molecules.
Here is an example that may be familiar to those of you who took organic chemistry in college: (R)-carvone and (S)-carvone are enantiomers of one another. Since the carvone mirror images are almost identical, it is very difficult to distinguish (R)-carvone from (S)-carvone in the lab unless you have access to fairly specialized and expensive equipment. However, if you were to hand a sample of each carvone enantiomer to a very small child, the child would immediately be able to differentiate between the two mirror images. Why is that? The reason is that, to us, (R)-carvone smells like spearmint and (S)-carvone smells of caraway.
Why is it that our smell receptors can so readily perform a task that is so challenging for the most sophisticated lab equipment?
Why is it that our smell receptors can so readily perform a task that is so challenging for the most sophisticated lab equipment? The answer is that the human body is made of building blocks (proteins, DNA, carbohydrates, and hormones) that themselves exist as asymmetric molecules. Therefore, just as your left-hand glove interacts differently with your left and right hands, your asymmetric smell receptors interact differently with each carvone enantiomer, recognizing different and easily distinguishable scents.
This property of asymmetry that infuses your body has important implications beyond the actions of your smell receptors. Perhaps most impactful is the role of asymmetry in determining how medicines behave in the body (Figure 6).
Many medicines are small organic molecules that can exist as two mirror images. Not surprisingly, your body typically responds differently to each of these mirror images. One of these mirror images will interact with your body in the desired way, perhaps by blocking the activity of a problematic overactive enzyme. However, the other mirror image will likely not play a productive role and might even interact with your body in dangerous ways.
A long-standing priority of organic chemistry is to invent new strategies that employ catalysis to construct molecules in single–mirror image form.
It is easy to see why we need technologies that allow us to selectively prepare only the desired mirror image of a medicinal compound. A long-standing priority of organic chemistry is to invent new strategies that employ catalysis to construct molecules in single–mirror image form. This field of research is known as asymmetric catalysis.
What is Organocatalysis?
Today, organocatalysis represents a major field of asymmetric catalysis, and I am proud to have played a role in pioneering this exciting, sustainable new technology. To place organocatalysis into historical context, we must consider the state of the field of asymmetric catalysis at the dawn of my career, over two decades ago.
In 1996, there were two major modes of asymmetric catalysis: biocatalysis and metal catalysis. Biocatalysis employs naturally occurring enzymes to construct single enantiomers of organic molecules. This strategy leverages the fact that enzymes are themselves massive asymmetric molecules. Metal-based asymmetric catalysis, on the other hand, is a man-made field that uses catalysts composed of metals paired with single-enantiomer organic molecules.
My Part in this Story
Here is where my part in this story begins. On finishing my PhD studies under the great Prof. Larry Overman at the University of California at Irvine, it was my privilege to undertake postdoctoral research with Prof. David Evans at Harvard University. Dave is one of the most influential chemists in the world and an absolute master of asymmetric metal catalysis. My time in the group provided me invaluable exposure to this field of research.
While in the Evans group, I grew to fully appreciate both the power and the drawbacks of asymmetric metal catalysis. The reality was that most of my days were spent working in a rather uncomfortable and bulky contraption called a glovebox.
A glovebox is a special piece of equipment designed to rigorously eliminate moisture, oxygen, and air from a chemical reaction. In the Evans group, we needed to work in the glovebox, as the metal component of the asymmetric metal catalyst can be difficult to handle. Often, metals cannot be exposed to the atmosphere; moreover, they can be toxic, unsustainable, and expensive. Organic molecules, on the other hand, are usually quite easy to handle and are typically safe, sustainable, recyclable, and inexpensive.
What if? Catalysis with Organic Molecules
During my time in the group, I began to wonder whether it would be possible to develop a new kind of asymmetric catalyst that only used the single-enantiomer organic component and eliminated the metal altogether. I believed that an asymmetric catalyst based solely on organic molecules could have revolutionary potential, for several reasons. Organic catalysts should be easily and inexpensively constructed from Nature’s building blocks. Organic catalysts would not be sensitive to moisture or air and could be handled without special equipment. Additionally, organic molecules are sustainable, recyclable, and nontoxic. Finally—and most exciting to me—I recognized the possibility of developing a single general platform for organic catalysis that could be used to promote not just one but hundreds of different reactions. I imagined that, if I could achieve this goal, then perhaps one day organic molecule catalysis could ultimately mature into a third major pillar of asymmetric catalysis.
As I was formulating this grand vision, I unfortunately had no idea of exactly how we might leverage simple organic molecules as asymmetric catalysts. I could not know at the time that, within two years of the start of my independent career at the University of California at Berkeley, we would invent a general platform for asymmetric catalysis that completely eliminated the metal component. In our seminal 2000 publication, we gave this new field of asymmetric catalysis a name: organocatalysis.
Be sure to enjoy the second half of David MacMillan’s presentation in our Dec/Jan issue of The Earth & I. The professor recalls his path to the Nobel Prize in Chemistry and ponders the exciting role of organocatalysis in a sustainable future.
Prof. MacMillan is the James S. McDonnell Distinguished University Professor of Chemistry at Princeton University. He shares the 2021 Nobel Prize in Chemistry with Dr. Benjamin List for the “development of asymmetric organocatalysis.”