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October 6, 2021
Two scientists won the Nobel Prize in Chemistry on Wednesday for finding an « ingenious » new way to build molecules that can be used to make anything from drugs to food flavorings.
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Benjamin List from Germany and Scotland born David W.C. MacMillan developed « asymmetric organocatalysis » – work that has already had a significant impact on pharmaceutical research, said Goran Hansson, general secretary of the Royal Swedish Academy of Sciences. According to the jury, the tool has also made chemistry « greener ».
The production of molecules – which requires the linking of individual atoms in a certain arrangement – is a difficult and slow task. Until the beginning of the millennium, chemists had only two methods – or catalysts – at their disposal to speed up the process.
List from the Max Planck Institute and MacMillan from Princeton University independently reported that small organic molecules can be used to do the same job as large enzymes and metal catalysts in reactions that are « precise, cheap, fast and environmentally friendly ». She said. « This new toolkit is now widely used in drug discovery and fine chemical manufacturing, for example. »
Johan Åqvist, Chair of the Nobel Committee for Chemistry, said: « This concept for catalysis is as simple as it is ingenious, and fact is that a lot of people have wondered why we didn’t think about it sooner. «
» I absolutely didn’t expect that, « said the 53-year-old, adding that he was on vacation in Amsterdam when he was Call came in from Sweden.
List said he initially didn’t know MacMillan was working on the same topic and thought his guess might just be a « stupid idea » – until it worked.
It’s common that several scientists working in related fields share the price. Last year, the chemistry award went to Emmanuelle Charpentier from France and Jennifer A. Doudna from the United States for developing a gene editing tool that revolutionized science by providing a way to modify DNA.
The prestigious award is associated with a gold medal and 10 million Swedish crowns (over 1.14 million US dollars). The prize money comes from a legacy of the creator of the prize, the Swedish inventor Alfred Nobel, who died in 1895.
On Monday, the Nobel Committee awarded the prize in Physiology or Medicine to the Americans David Julius and Ardem Patapoutian for their discoveries about how the human body is Senses temperature and touch.
The Nobel Prize in Physics was awarded on Tuesday to three scientists whose work has found order in seeming disorder and helped explain and predict complex natural forces, including expanding our understanding of climate change.
Prizes for outstanding work in the fields of literature, peace and economics will also be awarded in the coming days.
The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2021 to
The construction of molecules is a difficult art. Benjamin List and David MacMillan receive the Nobel Prize in Chemistry 2021 for their development of a precise new tool for molecular assembly: organocatalysis. This has had a huge impact on pharmaceutical research and has made chemistry greener.
Many research areas and industries rely on the ability of chemists to construct molecules that make elastic and durable materials, store energy in batteries, or advance Can inhibit diseases. This work requires catalysts, substances that control and accelerate chemical reactions without becoming part of the end product. Catalysts in cars, for example, convert toxic substances in exhaust gases into harmless molecules. Our bodies also contain thousands of catalysts in the form of enzymes that chisel out the essential molecules.
Catalysts are thus basic tools for chemists, but researchers have long believed that there were basically only two types of catalysts: metals and enzymes. Benjamin List and David MacMillan receive the Nobel Prize in Chemistry 2021 for independently developing a third type of catalysis in 2000. It is known as asymmetric organocatalysis and is based on small organic molecules.
« This concept for catalysis is as simple as it is ingenious, and the fact is that many people have wondered why we didn’t think of it before » says Johan Åqvist, chairman of the Nobel Committee for Chemistry.
Organic catalysts have a stable framework of carbon atoms to which more active chemical groups can attach. These often contain common elements such as oxygen, nitrogen, sulfur or phosphorus. This means that these catalysts are both environmentally friendly and inexpensive to manufacture.
The rapid proliferation of organic catalysts is primarily due to their ability to promote asymmetric catalysis. When building molecules, there are often situations in which two different molecules can form, which – just like our hands – are the mirror image of the other. When it comes to the manufacture of pharmaceuticals, chemists often only want one of them.
Organocatalysis has developed at an astonishing speed since the year 2000. Benjamin List and David MacMillan continue to lead the way, showing that organic catalysts can be used to drive a wide variety of chemical reactions. Using these reactions, researchers can now design everything from new pharmaceuticals to molecules that can capture light in solar cells more efficiently. This is how organocatalysts bring the greatest benefit to humankind.
Chemists can make new molecules by linking small chemical building blocks together, but controlling invisible substances to combine in the desired way is difficult. Benjamin List and David MacMillan receive the Nobel Prize in Chemistry 2021 for their development of a new and ingenious tool for building molecules: organocatalysis. Its uses include researching new pharmaceuticals and it has also helped make chemistry greener.
Many industries and areas of research depend on chemists’ ability to build new and functional molecules. These can be substances that capture light in solar cells or store energy in batteries, to molecules that make lightweight running shoes or inhibit the progression of diseases in the body.
However, if we use the ability of nature to create chemical creations To compare with our own, we were stuck in the Stone Age for a long time. Evolution has produced incredibly specific tools, enzymes, to construct the molecular complexes that give life its shapes, colors, and functions. When chemists isolated these chemical masterpieces, they initially only viewed them with admiration. The hammers and chisels in their own molecular construction toolboxes were dull and unreliable, so they often had many unwanted byproducts copying nature’s products.
Every new tool chemists have added to their toolbox has the precision their molecular constructions increased. Slowly but surely, chemistry has developed from chiselling in stone to something like fine craft. This was of great benefit to mankind and several of these tools were awarded the Nobel Prize in Chemistry.
The discovery, which was awarded the Nobel Prize in Chemistry 2021, took molecular engineering to a whole new level. Not only has it made chemistry greener, but it also made making asymmetric molecules a lot easier. In the chemical structure, there is often a situation in which two molecules can form, which – like our hands – are the mirror image of the other. Chemists often only want one of these mirror images when producing drugs, but it has been difficult to find efficient methods for doing this. The concept developed by Benjamin List and David MacMillan – asymmetric organocatalysis – is as simple as it is ingenious. The fact is, a lot of people have wondered why we didn’t think of it earlier.
Why actually? This question is not an easy one to answer, but before we even try we need to take a brief look back at history. We’ll define the terms catalysis and catalyst, and set the stage for the Nobel Prize in Chemistry in 2021.
When chemists began exploring the way different chemicals react with each other in the 19th century, they made some strange discoveries. For example, if you put silver with hydrogen peroxide (H2O2) in a beaker, the hydrogen peroxide suddenly began to break down into water (H2O) and oxygen (O2). But the silver – which started the process – did not appear to be affected by the reaction at all. Likewise, a substance obtained from germinating grains could break down starch into glucose.
In 1835 the renowned Swedish chemist Jacob Berzelius began to recognize a pattern in this. In the annual report of the Royal Swedish Academy of Sciences, which describes the latest advances in physics and chemistry, he writes about a new “force” that can “create chemical activity”. He listed several examples in which the mere presence of a substance triggered a chemical reaction, and found that this phenomenon occurs much more frequently than previously thought. He believed that the substance had a catalytic power and called the phenomenon itself catalysis.
A lot of water has run through the pipettes of chemists since Berzelius’ time. They discovered a variety of catalysts that can break down molecules or bind them together. Thanks to this, they can now manufacture thousands of different substances that we use in our daily lives, such as medicines, plastics, perfumes and food flavors. The fact is, an estimated 35 percent of the world’s gross domestic product is due in some way to chemical catalysis.
In principle, all catalysts discovered before 2000 belonged to one of two groups: they were either metals or enzymes. Metals are often excellent catalysts because they have a special ability to temporarily accept electrons or to make them available to other molecules during a chemical process. This helps to break the bonds between the atoms in a molecule so that otherwise strong bonds can be broken and new ones formed.
One problem with some metal catalysts, however, is that they are very sensitive to oxygen and water, so they need an oxygen- and moisture-free environment for their function. This is difficult to achieve in large-scale industries. Also, many metal catalysts are heavy metals that can be harmful to the environment.
The second form of catalyst is made up of proteins known as enzymes. All living things have thousands of different enzymes that drive the chemical reactions necessary for life. Many enzymes are specialists in asymmetric catalysis and in principle always form a mirror image of the two possible ones. They also work side by side; When one enzyme is done with one reaction, another takes over. In this way, they can build complex molecules like cholesterol, chlorophyll or the toxin called strychnine, which is one of the most complex molecules we know (we’ll come back to that) with amazing precision.
Because enzymes are such efficient catalysts, In the 1990s, researchers attempted to develop new variants of enzymes to drive the chemical reactions needed by mankind. A research group that worked on it was based at the Scripps Research Institute in Southern California and was led by the late Carlos F. Barbas III. Benjamin List was doing a postdoctoral position in Barbas’ research group when the brilliant idea was born that led to one of the discoveries behind this year’s Nobel Prize in Chemistry.
Benjamin List worked with catalytic antibodies. Antibodies normally attach to foreign viruses or bacteria in our bodies, but Scripps researchers redesigned them so that they could trigger chemical reactions instead.
While working with catalytic antibodies, Benjamin List began to think about how enzymes actually do function. They are usually huge molecules made up of hundreds of amino acids. In addition to these amino acids, a significant proportion of the enzymes also contain metals that drive chemical processes. But – and that’s the point – many enzymes catalyze chemical reactions without the help of metals. Instead, the reactions are driven by one or a few individual amino acids in the enzyme. Benjamin List’s unconventional question was: Do amino acids have to be part of an enzyme in order to catalyze a chemical reaction? Or could a single amino acid or other similar simple molecule do the same job?
He knew there had been research since the early 1970s that used an amino acid called proline as a catalyst – but that was more than 25 years ago Years. If proline had really been an effective catalyst, surely someone would have continued to work on it?
That was more or less what Benjamin List thought; he assumed that no one had investigated the phenomenon further because it hadn’t worked very well. With no real expectations, he tested whether proline could catalyze an aldol reaction in which carbon atoms from two different molecules are bonded together. It was a simple experiment that surprisingly worked straight away.
With his experiments, Benjamin List not only showed that proline is an efficient catalyst, but also that this amino acid can drive asymmetric catalysis. Of the two possible mirror images, one formed much more frequently than the other.
In contrast to the researchers who had previously tested proline as a catalyst, Benjamin List understood the enormous potential it could have. Compared to metals and enzymes, proline is a chemists dream tool. It’s a very simple, cheap, and environmentally friendly molecule. When he published his discovery in February 2000, List described asymmetric catalysis with organic molecules as a new concept with many possibilities: « The design and screening of these catalysts is one of our future goals ».
But he was not alone. In a laboratory further north in California, David MacMillan was also working towards the same goal.
Two years earlier, David MacMillan had moved from Harvard to UC Berkeley. At Harvard, he worked on improving asymmetric catalysis with metals. This was an area that attracted a lot of researcher attention, but David MacMillan noted that the catalysts developed were rarely used in industry. He wondered why and assumed that the sensitive metals were simply too difficult and expensive to use. Achieving the oxygen and moisture-free conditions required by some metal catalysts is relatively straightforward in a laboratory, but performing large-scale manufacture under such conditions is complicated chemical tools should be useful. When he moved to Berkeley, he left the metals behind.
Instead, David MacMillan began designing simple organic molecules that – just like metals – can temporarily provide or accept electrons. Here we need to define what organic molecules are – in short, these are the molecules that make up all living things. They have a stable structure made of carbon atoms. Active chemical groups, which often contain oxygen, nitrogen, sulfur or phosphorus, are attached to this carbon structure.
Organic molecules therefore consist of simple and common elements, but depending on their composition they can also have complex properties. David MacMillan’s knowledge of chemistry told him that in order for an organic molecule to catalyze the reaction he was interested in, it must be able to form an iminium ion. This contains a nitrogen atom that has an inherent affinity for electrons.
He selected several organic molecules with the right properties and then tested their ability to drive a Diels-Alder reaction, which chemists use to create rings of carbon atoms. As he had hoped and believed, it worked brilliantly. Some of the organic molecules were also excellent in asymmetric catalysis. Of two possible mirror images, one comprised more than 90 percent of the product.
When David MacMillan was ready to publish his results, he realized that the concept of catalysis he had discovered needed a name. The fact was that researchers had previously succeeded in catalyzing chemical reactions with small organic molecules, but these were isolated examples and no one had realized that the method could be generalized.
David MacMillan wanted to find a term to describe the method so that other researchers understand that there are more organic catalysts to be discovered. His choice fell on organocatalysis.
In January 2000, just before Benjamin List published his discovery, David MacMillan submitted his manuscript for publication in a scientific journal. The introduction states: « Here we present a new strategy for organocatalysis that we expect to be suitable for a number of asymmetric transformations ».
Independently of one another, Benjamin List and David MacMillan came up with a completely new concept discovered for catalysis. Since the year 2000 one can almost compare the development in this area with a gold rush in which List and MacMillan occupy leading positions. They have developed a large number of cheap and stable organocatalysts with which a large number of chemical reactions can be promoted.
Organocatalysts not only often consist of simple molecules, but can in part – similar to nature’s enzymes – work on an assembly line. Until now it was necessary in chemical production processes to isolate and purify every intermediate product, otherwise the amount of by-products would be too large. As a result, part of the substance was lost at every step of a chemical construction.
Organocatalysts are much more forgiving, since quite often several steps in a production process can be carried out in an uninterrupted sequence. This is known as the cascade reaction, which can significantly reduce the waste in chemical manufacturing.
An example of how organocatalysis has led to more efficient molecular constructions is the synthesis of the natural and amazingly complex molecule of strychnine. Many people will recognize strychnine from books by Agatha Christie, the queen of crime fiction. For chemists, however, strychnine is like a magic cube: a challenge that one would like to solve in as few steps as possible.
When strychnine was first synthesized in 1952, 29 different chemical reactions were required and only 0.0009 percent of the starting material was strychnine. The rest was wasted.
In 2011, using organocatalysis and a cascade reaction, researchers were able to build strychnine in just 12 steps, and the manufacturing process was 7,000 times more efficient.
Organocatalysis has a significant impact on pharmaceutical research, which often requires asymmetric catalysis. Until chemists could perform asymmetric catalysis, many pharmaceuticals contained both mirror images of a molecule; one of them was active while the other could sometimes have undesirable effects. A disastrous example of this was the thalidomide scandal in the 1960s, in which a reflection of the thalidomide drug caused severe malformations in thousands of developing human embryos . For example, you can artificially produce potentially healing substances that can otherwise only be isolated in small quantities from rare plants or deep-sea organisms.
The process is also used by pharmaceutical companies to rationalize the production of existing drugs. Examples include paroxetine, which is used to treat anxiety and depression, and the antiviral drug oseltamivir, which is used to treat respiratory infections.
There are thousands of examples of organocatalysis in use – but no one had why earlier developed this simple, green and inexpensive concept for asymmetric catalysis? There are many answers to this question. One of them is that the simple ideas are often the hardest to imagine. Our perspective is clouded by strong prejudices about how the world should work, such as the idea that only metals or enzymes can drive chemical reactions. Benjamin List and David MacMillan managed to overcome these prejudices and come up with an ingenious solution to a problem that chemists had struggled with for decades. Organocatalysts thus bring – currently – the greatest benefit for mankind.
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