People have been thinking about why it is difficult to directly synthesize a single mirror molecule? It not only makes chemistry more environmentally friendly, but also makes it easier to produce asymmetric molecules.

Written and compiled by Li Wutu, Gu Shuchen, Wangwang

Swedish Local time on October 6, 2021 (17:55 Beijing time on October 6, 2021), the Nobel Prize in Chemistry was awarded to German scientist Benjamin List and American scientist David MacMillan in recognition of their contribution to "developing asymmetric organic catalysis."

For a long time, people have been thinking about why it is difficult to directly synthesize a single mirror molecule? The reason is that a single mirror molecule often requires "chiral-specific" raw materials to be synthesized, and where does chiral-specific raw materials come from? This puts the synthesis of a single mirror molecule into a logical trap.

Fortunately, the 2021 Nobel Prize in Chemistry was awarded to the discovery that takes asymmetry control in molecular synthesis to a whole new level. It not only makes chemistry more environmentally friendly, but also makes it easier to produce asymmetric molecules. Benjamin List and David MacMillan proposed a new concept - asymmetric organic catalysis. The concept of asymmetric organic catalysis allows people to no longer rely on "chiral-specific" raw materials to obtain a single mirror molecule, which is both simple and wonderful to solve the synthesis problem that has plagued chemists for a long time.

Chemists have created many functional molecules that play an important role in industry and research. These substances can capture the light emitted by the sun and convert it into electricity, store energy efficiently in batteries, and can also be used to make lightweight and elastic running shoes, or to inhibit the development of diseases in the body.

Although chemists designed and synthesized many molecules that had never been born in nature, compared with nature's ability to make molecules, even the best chemists only stayed in the Stone Age. Evolutionary selection and living organisms have produced an incredibly special tool - enzymes, which can exquisitely construct molecules and their complexes of different shapes, colors and functions required by life. Initially, when chemists separate these chemical masterpieces from nature, they only had envy: because the molecular hammers and chisels used for construction in the chemist's toolbox were too rough and unreliable - which made chemists often produce a large number of unnecessary by-products when trying to replicate the exquisite molecules created by nature.

new tool for finer chemistry

With the development of modern science, every new tool added by chemists to the toolbox is gradually improving the accuracy of the synthetic molecular structure. Although the progress is relatively slow, it is certain that chemists have gradually developed the synthesis process from the carving skills of stones into a more refined artistic means. This has greatly promoted the progress of human society, and some of these tools have won the Nobel Prize in Chemistry.

Lemon flavor on the left, orange flavor on the right

The discovery awarded by the Nobel Prize in Chemistry in 2021 has raised the ability to build molecular structure to a whole new level. It not only makes chemistry more environmentally friendly, but also makes it easier to produce asymmetric molecules. During chemical construction, there is often a situation where two molecules can form, just like our hands, mirroring each other. Chemists usually just want a mirror like this, especially when producing drugs, but it has been difficult to find effective ways to do this. The concept proposed by List and Macmillan—asymmetric organic catalysis—is both simple and exciting.

In fact, many people want to know why we didn’t think of it earlier—yes, we don’t use “chiral-specific” raw materials, but instead use “chiral-specific” catalysts to achieve the synthesis of “chiral-specific” molecules. The catalyst is not consumed by chemical reactions, thus helping people continuously obtain the desired product. Johan Åqvist, chairman of the Nobel Committee for Chemistry, said, “The concept of (organic) catalysis is simple and clever, and many people want to know why we didn’t think of it earlier."

Why? This is not an easy question to answer, but before we try, we need to quickly review history. We will define the terms of catalysis and catalysts and lay the foundation for the 2021 Nobel Prize in Chemistry.

Catalyst accelerates chemical reactions

835, the famous Swedish chemist Jakob Berzelius discovered one of the rules. Sciences) 's annual report, he described the latest advances in physics and chemistry and wrote that there is a new "force" that can "produce chemical activities." He cited several examples that only the existence of a substance can trigger chemical reactions, indicating that this phenomenon seems much more common than previously thought. He believed that the substance has catalytic power and called the phenomenon itself a catalysis.

catalyst can produce plastics, perfumes and flavored foods

from Betellius Since the era, a large amount of water has passed through chemists' pipettes. They have discovered a variety of catalysts that can break down molecules or connect molecules together. Thanks to these technologies, they can now carve out thousands of different substances used in our daily lives, such as medicines, plastics, perfumes and food seasonings. In fact, it is estimated that to some extent, 35% of the global GDP involves chemical catalysis.

In principle, all catalysts found before 2000 fall into two categories: either metals or enzymes. Metals are usually good catalysts because they have a special energy Force, can temporarily accommodate electrons or provide electrons to other molecules during chemical processes. This helps loosen the bonds between atoms in the molecule, so that the otherwise firm bonds can be broken and new bonds can be formed.

However, one problem with some metal catalysts is that they are very sensitive to oxygen and water, so in order for them to function, they need an environment without oxygen and moisture. This is difficult to achieve in large-scale industries. In addition, many metal catalysts are heavy metals, which are harmful to the environment.

life Catalysts work with amazing accuracy

The second catalyst is composed of proteins called enzymes. All organisms have thousands of different enzymes that drive the chemical reactions necessary for life. Many enzymes are experts in asymmetric catalysis, and in principle, always form a mirror in the two possible enzymes. They also work side by side; when one enzyme completes the reaction, the other will replace it. In this way, they can build complex molecules with amazing accuracy, such as cholesterol , chlorophyll or toxin called stigin, one of the most complex molecules we know about (We'll go back here).

Because enzymes are such an effective catalyst, researchers were trying to develop new enzyme variants to drive the chemical reactions needed by humans in the 1990s. A team of researchers at the Scripps Research Institute in Southern California, (Scripps research Institute) is studying this issue, led by the late Carlos F. Barbas III (Carlos F. Barbas III) . Benjamin List (Benjamin List) was a postdoctoral fellow in Barbas' research group, a result of this year's Nobel Prize in Chemistry . (Nobel Prize in Chemistry) A brilliant idea behind was born.

Benjamin List jumped out of the box of thinking…

Benjamin List studied catalytic antibodies. Normally, antibodies would attach to foreign viruses or bacteria in our bodies, but researchers at Scripps University redesigned antibodies so that they could drive chemical reactions.

As the process of studying catalytic antibodies, List began to think about how enzymes work. They are usually huge molecules composed of hundreds of amino acids .In addition to these amino acids, a considerable proportion of enzymes also contain metals that help drive chemical processes. But—this is the key—many enzymes catalyze chemical reactions without the help of metals. Instead, the reaction is driven by one or several amino acids in the enzyme. The question for List is: Do amino acids have to be part of the enzyme to catalyze chemical reactions? Or can an amino acid, or other similar simple molecule do the same job?

brought revolutionary results

He knew that as early as the early 1970s, there was a study using an amino acid called proline as a catalyst - but that was already 25 years ago. Of course, if proline is really an effective catalyst, will anyone continue to study it?

This is more or less the idea of ​​List. He believes that the reason why no one continues to study this phenomenon is that its effect is not particularly good. Without any practical expectations, he tested whether proline could catalyze the aldol reaction , in which carbon atoms from two different molecules could bind together. This simple attempt achieved unexpected results.

Benjamin List clarified its direction

Through experiments, List not only proved that proline is an efficient catalyst, but also proved that this amino acid can drive asymmetric catalytic reactions. Among the two mirror isomers, one of the conformation is more common than the other.

Unlike researchers who have tried to use proline as a catalyst, List believes that proline still has huge catalytic potential. Compared with metals and enzymes, proline has a simple structure, cheap and easy to obtain, and is green and environmentally friendly. It is a catalytic tool that chemists dream of. When he published his work in February 2000, List believed that the field of asymmetric catalysis in organic synthesis was still full of opportunities, saying that "continuing to design and screen these catalysts is one of our future goals".

However, he is not the only one who works hard in this field. In a lab in northern California, David MacMillan is working towards the same goal.

David MacMillan bid farewell to the field of sensitive metal catalysis...

Two years ago, David MacMillan transferred from Harvard to University of California, Berkeley . Similar to many researchers, at Harvard University, he has also worked on using metals to improve asymmetric catalytic reactions. But then he found that these developed metal catalysts were difficult to be used in the industry. He began to think about the reason for this: it may be because these sensitive metals are expensive and use harsh conditions, and in the laboratory, the anhydrous and anaerobic conditions required by these metal catalysts can be easily achieved, but large-scale industrial production under such conditions is very difficult.

Therefore, he believes that if he wants to develop a more practical asymmetric catalytic tool, he needs to reconsider the research direction, so he joined Berkeley and bid farewell to the field of metal catalysis.

Homepage of Macmillan team

Develop a simpler catalyst

In contrast, MacMillan began designing simple organic molecules , which are like metals—can temporarily provide or contain electrons. Here we need to define what organic molecules are—in short, these molecules are the molecules that build all living organisms. Organic molecules tend to have a stable carbon atom-based structure. The reactive chemical group (usually contains oxygen, nitrogen, sulfur or phosphorus) is connected to the carbon skeleton.

Therefore, organic molecules are actually composed of simple and common elements, but according to their combination, many complex properties can be achieved. MacMillan's chemistry knowledge tells him that if an organic molecule is needed to catalyze the reaction of interest, it must form imine ions. It contains a nitrogen atom, which has an inherent affinity for electrons.

He selected several organic molecules with characteristic properties and then tested their ability to catalyze the Diels-Alder reaction. Chemists use Diels-Alder reaction to efficiently create carbon atom rings. As he hoped, this move worked very well. In particular, some organic molecules perform quite well in asymmetric catalysis: among the two possible mirror molecules, one of which accounts for more than 90% of the total product.

David MacMillan coined the word "organocatalysis"

When MacMillan was preparing to publish his results, he realized that the concept of catalytic he discovered needed a name. In fact, researchers have previously successfully used small organic molecules to catalyze chemical reactions, but these are often isolated cases, and no one realizes that this approach can be further generalized.

MacMillan wanted to find a term to describe this approach so that other researchers will understand that there are more organic catalysts to be discovered. His choice is "organocatalysis (organocatalysis) ".

In January 2000, just before List published his discovery, MacMillan submitted his manuscript to a scientific journal for publication. He mentioned in the introduction: "Here, we introduce a new organic catalysis strategy, which we hope will adapt to a series of asymmetric transformations." The application of organic catalysis is booming

List and Macmillan each independently discovered a brand new catalytic concept. The development in this field can almost be compared to the gold rush since 2000, and the two have maintained a leading position in this field. They designed a large number of cheap and stable organic catalysts to drive a wide variety of chemical reactions.

Organocatalysts not only usually consist of simple molecules, but in some cases, like enzymes in nature, they can work on conveyor belts. Previously, during chemical production, each intermediate product needed to be separated and purified to remove a large amount of by-products: this resulted in the loss of matter and additional energy consumption of each step of synthesis.

organic catalyst is much more tolerant because relatively speaking, the production steps can be carried out continuously without interruption. This is called the cascade reaction , which can greatly reduce the waste of matter and energy in chemical manufacturing.

Silin synthesis efficiency has been increased by 7000 times

Natural, surprisingly complex moleculeSilin synthesis is a typical case of efficient construction of organic matter. Many people will know Sidening from the book "Mysterious Murder Queen " by Agatha Christie" (Agatha Christie) . However, for chemists, Sidening is like a Rubik's Cube: a challenge you want to try to solve in as few steps as possible.

When the first synthesis of Shidening in 1952, 29 different chemical reactions were required, and only 0.0009% of the initial substance formed Shidening, and the rest were wasted.

In 2011, researchers used organic catalysis and cascade reactions to produce Shide Ning in just 12 steps, and the production efficiency increased by a full 7,000 times.

Organocatalysis is the most important in pharmaceutical production

Organocatalysis has had a huge impact on drug research, and drug research often requires asymmetric catalysis. Before chemists were able to perform asymmetric catalysis, many drugs contained mirror images of molecules, one of which was active, while the other sometimes had negative effects. A catastrophic example is the thalidomide scandal in the 1960s, where a molecule that mirrors thalidomide caused severe malformations in thousands of human embryos.

Using organic catalysis, researchers can now relatively simply create a large number of different asymmetric molecules. For example, they can artificially produce molecules with potential efficacy instead of being able to separate only small amounts from rare plants or deep-sea organisms.

In pharmaceutical companies, this method is also used to simplify the production of existing drugs. Examples of this include paroxetine for the treatment of anxiety and depression , and oseltamivir for the treatment of respiratory infection .

The simple idea is often the most difficult to imagine how

How to use organic catalysis, we can list thousands of examples, but why hasn't anyone proposed this simple, green and cheap asymmetric catalysis concept before? There are many answers to this question. First, simple ideas are often the hardest to imagine. Our viewpoints about how the world should work are obscured by strong preconceived ideas, such as the belief that only metals or enzymes can drive chemical reactions for a long time. List and Macmillan succeeded in transcending these preconceptions and found a clever solution to the problems that chemists struggled for decades. Therefore, organic catalysts are bringing huge benefits to humans.

Benjamin List (1968-)

Benjamin List, a German organic chemist, is currently a professor at the Max-Planck-Institut für Kohlenforschung, Germany. In 1997, he obtained his Ph.D. from the University of Frankfurt , and later conducted postdoctoral research at the Scripps Institute in the United States and remained as an assistant professor. Since 2003, he has joined the Coal Research Institute of Maxford, Germany and was promoted to professor in 2005. Professor Benjamin List is mainly engaged in organic chemistry and synthesis. He is one of the pioneers in the field of asymmetric organic catalysis. He used L-proline as an organic small molecule catalyst for catalyzing asymmetric aldol reactions for the first time, setting a precedent for the catalysis of organic small molecule and leading the development of organic small molecule catalysts.

David W. C. MacMillan (1968-)

David MacMillan, Princeton University James S. McDonnell Distinguished University Professor of Chemistry, American Academy of Sciences . He was born in Scotland in 1968 and received a bachelor's degree in chemistry from Glasgow University; in 1996, he received his doctorate from UC Irving ; in 1998, he started his independent career at the University of California, Berkeley, and moved to Caltech in 2000. He taught at Princeton University since 2006, and served as the chair of the Department of Chemistry at Princeton from 2010 to 2015. MacMillan is committed to studying the development of asymmetric organic molecular catalysts and the development of new synthesis methods. He has won the 2015 Harrison Howe Award, the 2017 Ryoji Noyori Award and other awards.