Nobel in chemistry honors pair for new way to make molecules

Tuesday's Nobel Prize in Chemistry was won by two scientists for their "ingenious" discovery of molecules that can be used for everything, from medicine to food flavors.
Benjamin List from Germany and David W.C. MacMillan, a Scottish-born scientist, developed "asymmetric organocatalysis," which has had a significant impact upon pharmaceutical research, according to Goran Hansson (secretary-general of Royal Swedish Academy of Sciences). Judges said that the tool also makes chemistry "greener".

Pernilla Wittung Stafshede, who is a member the Nobel panel, stated that "it's already greatly benefiting humanity,"

It is a slow and difficult task to make molecules, which requires linking individual atoms in a specific arrangement. The only way for chemists to speed up this process was through catalysts, which were available until the beginning of the millennium.

Wittung-Stafshede said, "But in 2000, everything changed."

List of the Max Planck Institute and MacMillan of Princeton University independently reported that small organic molecules could be used in the same way as large enzymes and metal catalysts to produce reactions that are "exact, cheap, quick, environmentally friendly" she stated. This new toolbox is widely used today in drug discovery as well as fine chemical production.

Johan qvist (chair of the Nobel Committee for Chemistry) stated: "This idea for catalysis seems as simple as it is clever, and many people have wondered why it wasn't thought of earlier."

List spoke after the announcement and said that the award was a "huge shock."

The 53-year old said that he didn't anticipate this and added that he was in Amsterdam on vacation when the call from Sweden arrived.

List stated that he didn't know MacMillan was working in the same area at first and thought his "stupid idea", until it turned out to be true.

He said, "I felt that this could become something significant."

It is not uncommon for scientists working in similar fields to share the prize. The chemistry prize was awarded to Emmanuelle Charpentier, France, and Jennifer A. Doudna, USA, for their contribution to gene-editing tools that revolutionized science.

A Nobel medal is displayed during an event in New York on Tuesday, December 8, 2020. The Nobel Prize for Chemistry in Chemistry will be announced Wednesday, Oct. 6, 2021. Credit to Angela Weiss/Pool Photo via AP. File

This prestigious award includes a gold medal, 10 million Swedish Kronor, and more than $1.14 million in prize money. Alfred Nobel, the Swedish inventor, left the prize money in a bequest. He died in 1895.

The Nobel Committee awarded Monday's prize in physiology/medicine to Ardem Patapoutian and David Julius of the United States for their research into temperature perception and touch.

Three scientists were awarded the Nobel Prize in Physics Tuesday for their work in physics. Their work helped to predict and explain complex forces of nature, which includes our understanding of climate change.

In the days ahead, prizes will be presented for outstanding contributions in the areas of literature, peace, and economics.


Nobel Committee Press Release: The Nobel Prize in Chemistry in 2021

The Nobel Prize in Chemistry 2021 has been awarded by the Royal Swedish Academy of Sciences.

Benjamin List

Max-Planck-Institut fr Kohlenforschung, Mlheim an der Ruhr, Germany

David W.C. MacMillan

Princeton University, USA

"for the advancement of asymmetricorganocatalysis"

An ingenious tool for building molecules

It is difficult to build molecules. The Nobel Prize in Chemistry 2021 is awarded to Benjamin List and David MacMillan for the development of an exact new tool for molecular building: organocatalysis. This has had a significant impact on pharmaceutical research and made chemistry more green.

Many industries and research areas depend on the ability of chemists to create molecules that can be used to form durable and elastic materials, store energy in batteries, or slow down the progression of disease. These chemicals are called catalysts. They control and accelerate chemical reactions without being part of the final product. Catalysts are substances that convert toxic substances from exhaust fumes into harmless molecules. There are also thousands of enzymes that catalyze the creation of the necessary molecules for life.

Although catalysts are fundamental tools for chemists researchers have long believed there were only two types of catalysts: metals or enzymes. The Nobel Prize in Chemistry 2021 is awarded to Benjamin List and David MacMillan because they independently developed a third form of catalysis in 2000. It's called asymmetric ororganocatalysis, and it relies on small organic molecules.

Johan qvist (chair of the Nobel Committee for Chemistry) says, "This idea for catalysis seems as simple as it sounds. And the fact is, many people have wondered why it wasn't thought of earlier."

Organic catalysts are composed of stable carbon atoms that can be attached to more active chemical groups. They often contain common elements like oxygen, nitrogen and sulphur. These catalysts are easy to make and both cost-effective.

Organic catalysts are mainly used to accelerate asymmetric catalysis. This is why there has been a rapid increase in their use. Two different molecules can often form when molecules are being made. These molecules, just like our hands, are each other's mirror images. When making pharmaceuticals, chemists often only need one of these.

Since 2000, organocatalysis technology has advanced at an incredible rate. David MacMillan and Benjamin List remain the leaders in this field. They have demonstrated that organic catalysts can drive a multitude of chemical reactions. Researchers can now create anything, from new pharmaceuticals to molecules capable of capturing sunlight in solar cells, more efficiently using these reactions. Organocatalysts bring the greatest benefit to humanity in this way.

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They revolutionized the construction of molecules with their tools

Although chemists can make new molecules by linking small chemical building blocks together, it is difficult to control invisible substances so that they bond in the right way. The Nobel Prize in Chemistry 2021 is awarded to Benjamin List and David MacMillan for developing an innovative tool for molecular building: organocatalysis. It has been used in research to develop new pharmaceuticals, and it has helped to make chemistry more sustainable.

Chemistry is essential for many industries and fields of research. These molecules could include substances that store light in solar cells, or that can be used to make running shoes.

But if you compare the ability of nature to create chemical creations with your own, it is clear that we are still stuck in the Stone Age. The enzymes used to build the molecular structures that give life its forms, colours, and functions have been created by evolution. These chemical marvels were initially looked at in admiration by chemists when they first isolated them. When they tried to copy nature's products, the hammers and chisels they had in their toolboxes were unreliable and blunt.

New tools for finer Chemistry

Every new tool that chemists add to their toolbox increases the precision of molecular constructions. Slowly, but surely, chemistry has moved from being a chiselling in stone process to fine craftsmanship. This has been a great benefit to humanity, and many of these tools have been awarded the Nobel Prize in Chemistry.

The Nobel Prize in Chemistry 2021 was awarded to the discovery of molecular construction. This discovery has made chemistry more efficient and made it easier to create asymmetric molecules. Two molecules can often form during chemical construction. These molecules, just like our hands, are each other's mirror images. In order to produce pharmaceuticals, chemists will often only need one of these mirror images. However, it is difficult to find efficient ways to do this. Benjamin List and David MacMillan's asymmetric organocatalysis concept is simple but brilliant. Many people have wondered why it wasn't thought of earlier.

Why? It is not an easy question to answer. But, before we try to find the right answer, let's take a look at our past. We will discuss the concepts of catalysis, catalyst, and prepare for the Nobel Prize in Chemistry 2021.

Catalysts speed up chemical reactions

Some of the most remarkable discoveries were made by chemists in the nineteenth century when they began to investigate how different chemicals react with one another. One example is that if they placed silver in a container containing hydrogen peroxide (H2O2) the hydrogen peroxide would suddenly begin to dissolve into water (H2O2) and oxygen (O2). The reaction did not appear to affect the silver that started the process. A substance made from sprouting grains can also be used to break down starch and make glucose.

Jacob Berzelius, a well-known Swedish chemist, noticed a pattern in these observations in 1835. He writes in the Royal Swedish Academy of Sciences annual report about the latest advances in physics, chemistry and describes a new force that can "generate chemicals activity". He gave several examples of chemical reactions that were initiated by the mere presence of substances, and explained how they are much more common than previously believed. He believed the substance was catalytic and called it catalysis.

Catalysts make plastic, perfume, and flavoursome food

Since Berzelius' day, a lot of water has flowed through the pipettes of chemists. There are many catalysts that can either break down molecules or combine them. These catalysts allow them to create the many substances that we use every day, including pharmaceuticals, plastics, and food flavourings. It is believed that chemical catalysis accounts for around 35% of the global GDP.

All catalysts that were discovered prior to 2000 fell into one of two categories: metals or enzymes. Because metals have the ability to temporarily hold electrons, or provide them to other molecules in a chemical reaction, they are often great catalysts. This allows bonds to be broken or formed by allowing them to become weaker.

One problem with certain metal catalysts is their sensitivity to oxygen and water. Therefore, these need to be in an environment that is free from moisture and oxygen. This is not possible in large-scale industries. Many metal catalysts contain heavy metals that can cause harm to the environment.

Amazing precision is required for life's catalysts to work.

The proteins, also known as enzymes, are the second type of catalyst. There are thousands of enzymes in all living things that drive chemical reactions. Many enzymes are experts in asymmetric catalysis. They form one mirror image from the two possible. They can also work together; one enzyme will stop working on a reaction and the other one will take over. This allows them to build complex molecules with incredible precision. For example, cholesterol, chlorophyll, or strychnine (a toxin that is among the most complex we know of).

Researchers tried to create new enzyme variants in the 1990s because enzymes are so efficient as catalysts. Carlos F. Barbas III, the late leader of a research group that worked on this topic, was based at Scripps Research Institute in Southern California. Benjamin List was a postdoctoral member of Barbas' research team when the brilliant idea that led the discovery behind the Nobel Prize in Chemistry in Chemistry was born.

Benjamin List thinks out of the box

Benjamin List was a pioneer in the use of catalytic antibodies. The antibodies normally attach to bacteria or viruses in the body, but Scripps researchers redesigned them so that they could be used to drive chemical reactions.

Benjamin List began to wonder how enzymes work during his research with catalytic antibody. These large molecules are often made from hundreds of amino acid compounds. A large number of enzymes contain metals, which help to drive chemical reactions. This is because many enzymes can catalyze chemical reactions without the use of metals. The enzyme's amino acids drive the reactions. Benjamin List asked the question: Do amino acids need to be part an enzyme to catalyze a chemical reaction. Could a single amino acids, or other simple molecules do the same thing?

With a breakthrough result

He was aware that proline, an amino acid known as proline, had been used in research since the 1970s to create a catalyst. However that was over 25 years ago. If proline had really been an effective catalyst someone would have continued to work on it.

Benjamin List believed the same thing. He assumed that the reason no one was continuing to study the phenomenon was because it didn't work well. He tested whether proline could trigger an aldol reaction in which carbon atoms of two different molecules are bonded together. Amazingly, it was a simple experiment that worked immediately.

Benjamin List staked his future

Benjamin List's experiments proved that proline can be used to drive asymmetric catalysis. It was more common for one of the mirror images to form than the others.

Benjamin List, unlike other researchers who had tested proline as an enzyme catalyst, understood its enormous potential. Proline is an ideal tool for chemists. It can be used in place of both metals or enzymes. It is a very simple, cheap and environmentally-friendly molecule. List published his discovery in February 2000. He described it as an innovative concept that offers many possibilities. "The design and screening these catalysts are one of our future goals."

He wasn't the only one doing this. David MacMillan, a scientist further north in California was working toward the same goal.

David MacMillan leaves behind sensitive metals

David MacMillan, a Harvard graduate, had made the move to UC Berkeley two years ago. He had previously worked at Harvard on improving asymmetrical catalysis with metals. While this area was receiving a lot attention from researchers, David MacMillan noticed that the catalysts that had been developed were seldom used in industry. MacMillan began to wonder why. He concluded that sensitive metals were too expensive and difficult to use. It is easy to achieve the oxygen-free, moisture-free conditions required by some metal catalysts in a laboratory. However, it is difficult to conduct large-scale industrial manufacturing under such conditions.

He concluded that, if the chemicals he was creating were to be of any use, he would need to rethink his thinking. He left behind the metals when he moved to Berkeley.

It also develops a simpler type of catalyst

David MacMillan instead designed simple organic molecules that, just like metals, could temporarily provide or accommodate the electrons. In order to understand what organic molecules are, let's say that they are molecules that create all living things. They are composed of stable carbon atoms. This carbon framework is home to active chemical groups, which often contain oxygen, sulphur, or phosphorus.

Although they contain simple elements, organic molecules can also have common elements. However, their properties can be complex depending on how they are assembled. David MacMillan knew from chemistry that organic molecules must be capable of producing an iminium-ion to catalyze the reaction he is interested in. This molecule contains a nitrogen atom that has an intrinsic affinity for electrons.

He chose several organic molecules that had the right properties and tested their ability to drive a DielsAlder react, which is used by chemists to create rings of carbon atoms. It worked exactly as he expected and believed. Asymmetric catalysis was also possible with some organic molecules. One of two mirror images was used, and it made up more than 90% of the final product.

David MacMillan coined the term organocatalysis

David MacMillan realized that the catalysis concept he had developed needed to be named when he was ready for publication. Although researchers had achieved catalysis of chemical reactions with small organic molecules in the past, these were only isolated cases and no one realized that this method could be applied to other chemicals.

David MacMillan sought a term to describe his method to help other researchers understand the fact that there are more organic catalysts. Organocatalysis was his choice.

Just before Benjamin List published his discovery in January 2000, David MacMillan submitted a manuscript to be published in a scientific journal. The introduction says: "Herein we present a new strategy to organocatalysis that will be amenable for a variety of asymmetric transforms."

Organocatalysis is booming

Benjamin List and David MacMillan discovered a completely new method for catalysis independently of each other. The rapid development of this field can be compared to a gold rush. List and MacMillan remain at the forefront of these developments since 2000. Their designs have produced a multitude of stable and cheap organocatalysts that can be used to drive many chemical reactions.

Organocatalysts are often composed of simple molecules. In some cases, they can also work on a conveyor belt just like nature's enzymes. In chemical production, it was important to separate and purify every intermediate product. Otherwise, the amount of byproducts would have been too large. Some of the substance was lost during each stage of chemical construction.

Organocatalysts can tolerate more steps as they are able to perform them in a consistent sequence. This is known as a cascade reaction and can significantly reduce the amount of waste in chemical manufacturing.

Strychnine synthesis is now more efficient than ever at 7,000 times

Organocatalysis has allowed for more efficient molecular constructions. One example is the synthesis natural, but astonishingly complex strychnine molecule. Many will recognize strychnine in Agatha Christie's books, the queen of murder mysteries. For chemists strychnine can be compared to a Rubik’s Cube. This is a problem that you need to solve in the shortest time possible.

In 1952, strychnine was synthesized for the first time. It required 29 chemical reactions. Only 0.0009 percent of the original material could be made strychnine. Rest was thrown away.

2011 was the year that researchers discovered organocatalysis could be combined with a cascade reaction to make strychnine in only 12 steps. The process was also 7,000 times faster.

The most important aspect of pharmaceutical production is organocatalysis

The pharmaceutical industry is dependent on asymmetric catalysis, and organocatalysis has made a huge impact. Before chemists were able to conduct asymmetrical catalysis, pharmaceuticals often contained mirror images of the same molecule. One was active while the other might have undesirable effects. This was illustrated by the thalidomide scandal of 1960s. In which one mirror image caused severe deformities in thousands upon thousands of embryos in human development, this was a tragic example.

Researchers can now produce large quantities of different asymmetric molecules using organocatalysis. They can create potentially curative substances artificially, which can be isolated from rare plants and deep-sea organisms.

The method can also be used by pharmaceutical companies to reduce the time it takes to produce existing pharmaceuticals. This includes paroxetine which can be used to treat anxiety or depression and oseltamivir which is used for respiratory infections.

Sometimes the easiest ideas to visualize are those that are simple.

You could list thousands of ways organocatalysis can be used, but why hasn't anyone come up with a simple, cheap and easy way to do asymmetrical catalysis sooner? There are many ways to answer this question. One answer is that simple ideas can often be the most difficult to visualize. Preconceptions about the world can cloud our view, like the belief that only metals and enzymes can drive chemical reaction. David MacMillan and Benjamin List were able to see past these preconceptions and find a creative solution to a problem that chemists have struggled with for decades. The greatest benefit for humanity is now being provided by organocatalysts.

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