Nobel Prize in Chemistry 2021: Asymmetric Organocatalysis and Its Two Discoverers

This note covers the Nobel Prize in Chemistry 2021: who Benjamin List and David W.C.

MacMillan are, what asymmetric organocatalysis means and why chemists had thought no such catalyst could exist, how each laureate found it independently in the year 2000, how the field grew afterwards, why it matters for medicines and green chemistry, and quick facts for exams.

What was the Nobel Prize in Chemistry 2021 awarded for?

The Royal Swedish Academy of Sciences awarded the Nobel Prize in Chemistry 2021 jointly to Benjamin List and David W.C. MacMillan, with the citation:

"for the development of asymmetric organocatalysis"

In plain words, the two chemists discovered, independently of each other in the year 2000, that small, simple organic molecules (molecules built from a carbon skeleton rather than a metal) can act as catalysts, substances that speed up a chemical reaction without being used up themselves.

Before this, chemists believed catalysts came only in two kinds: metals and enzymes. Metal catalysts, used for example inside a car's exhaust system to turn toxic fumes into harmless gases, work by temporarily holding or giving away electrons. Enzymes are the thousands of protein catalysts found inside every living cell, carving out the molecules needed for life with great precision.

List and MacMillan showed a third kind existed, and that it could be made to build only one of the two possible "mirror image" forms of a molecule, a property called asymmetric catalysis. The Nobel Committee for Chemistry noted that catalysis in general is linked to roughly 35 per cent of the world's total economic activity, which gives a sense of how central the idea of a catalyst already was to chemistry before this discovery.

This third kind of catalysis is now called organocatalysis, and the scientific background page describes it as the "third pillar of catalysis," standing alongside metal catalysis and biocatalysis (the use of enzymes). The prize is formally named the Nobel Prize in Chemistry, awarded each year by the Royal Swedish Academy of Sciences.

Who are the laureates?

Benjamin List

Benjamin List was born on 11 January 1968 in Frankfurt-on-the-Main, Germany. He completed his Ph.D. in 1997 at Goethe University Frankfurt, Germany. At the time of the award he was Director of the Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr, Germany. He received one half of the prize.

List had earlier worked as a postdoctoral researcher at the Scripps Research Institute in southern California, in a research group led by Carlos F. Barbas III that redesigned antibodies, the body's infection-fighting proteins, into catalysts able to drive chemical reactions instead of attacking germs.

While thinking about how enzymes work without needing a metal, he noticed that many enzymes rely on only one or a few amino acids in the chain, not the whole protein, to drive a reaction. This led him to ask whether a single amino acid alone, outside any enzyme, could do a catalyst's job.

He tested whether the simple amino acid proline alone could catalyse a reaction called the aldol reaction, which joins carbon atoms from two separate molecules together.

It worked on his first attempt, and he published the discovery in February 2000, showing that proline could also control which mirror-image form of the product formed, a result he described at the time as opening up many future opportunities for designing new catalysts.

David W.C. MacMillan

David W.C. MacMillan was born on 16 March 1968 in Bellshill, United Kingdom. He completed his Ph.D. in 1996 at the University of California, Irvine, USA. At the time of the award he was a Professor at Princeton University, Princeton, NJ, USA. He received the other one half of the prize.

MacMillan had previously worked on asymmetric catalysis using sensitive metal catalysts at Harvard University, but noticed that industry rarely used the catalysts he and others developed, because they needed conditions completely free of oxygen and moisture, which is difficult and expensive to maintain at large manufacturing scale.

After moving to the University of California, Berkeley, he decided to leave metal catalysts behind entirely and design small organic molecules that could copy a metal's key trick of temporarily giving or taking electrons.

He designed a chiral (mirror-image-specific) organic molecule called an imidazolidinone that could drive a reaction called the Diels-Alder reaction, used by chemists to build rings of carbon atoms, and he coined the word organocatalysis for the general method, submitting his paper for publication in January 2000.

What problem were chemists trying to solve?

Many industries depend on the ability to build new molecules: substances that store energy in batteries, form durable or elastic materials, capture light in solar cells, or stop the progress of disease in the body. Building such molecules on purpose, with exactly the shape wanted, is difficult.

A central difficulty is that many molecules can form in two mirror-image versions, much like a left hand and a right hand. These two versions, called the molecule's two "mirror images," often behave very differently in the body.

One version of the molecule limonene smells of lemon, while its mirror image smells of orange.

In medicines the difference can be far more serious: in the thalidomide case in the 1960s, one mirror-image form of the drug caused severe harm to developing embryos, while the sources describe the other as not sharing that effect.

Chemists therefore often want to make only one of the two mirror images, a goal called asymmetric catalysis.

Before 2000, this could be done only with metal catalysts, which are often expensive and sensitive to air and water, or with enzymes, nature's own catalysts, which are highly specific but hard to redesign for new jobs. Researchers assumed no third option existed.

What is a catalyst, and why did chemists think there were only two kinds?

A catalyst is a substance that speeds up a chemical reaction without being consumed or changed itself; it is reused again and again in the reaction cycle.

The idea was first described in 1835 by the Swedish chemist Jacob Berzelius, who noticed that the mere presence of certain substances could start chemical change and named this effect catalysis.

By 2000, chemists used catalysts everywhere, and the popular science background for this prize noted that catalysis is linked to around 35 per cent of the world's total economic activity. Yet, almost every catalyst in use fell into one of two groups:

1. Metal catalysts, which loosen bonds by temporarily holding or giving away electrons, but are often sensitive to oxygen and moisture and can involve heavy metals harmful to the environment.
2. Enzymes, the protein catalysts of living cells, which work with remarkable precision and almost always build only one mirror image of a product, but are large, complex molecules that are difficult to redesign for new industrial reactions.

Both List and MacMillan independently questioned this two-type picture. They asked whether a single small organic molecule, far simpler than a whole enzyme, could do a catalyst's job on its own.

How did Benjamin List discover organocatalysis with proline?

List knew that many enzymes use just one or a few amino acids, not the whole protein chain, to drive a reaction.

He recalled that researchers in the early 1970s had briefly used the amino acid proline as a catalyst, but no one had followed up the idea for over twenty-five years.

List reasoned that if proline had worked brilliantly, someone would have carried on studying it, so he tested it anyway, without expecting much.

He used proline to catalyse an aldol reaction, a reaction that joins carbon atoms from two different molecules together, between acetone and an aldehyde.

The reaction worked straightaway, and proline also directed the reaction so that one mirror-image form of the product formed much more often than the other. List published this result in February 2000.

The scientific background page explains that the mechanism involves the formation of an enamine intermediate between proline's nitrogen and the starting carbonyl molecule, which makes the resulting molecule a better attacker (more "nucleophilic") in the reaction, while proline's acid group helps hold the transition state steady through hydrogen bonding.

Draw proline joining to an aldehyde or ketone to form an enamine intermediate, the enamine attacking a second carbonyl molecule to form a new carbon-carbon bond, and the final step where water is removed to release the aldol product and set proline free to repeat the cycle.

How did David MacMillan develop organocatalysis with iminium ions?

MacMillan had been improving metal-based asymmetric catalysts at Harvard, but he noticed that industry rarely adopted them because the metals needed air-free, moisture-free conditions that are hard to maintain at large scale.

He decided to leave metals behind and design small organic molecules that could copy a metal's key trick: temporarily pulling electrons away from a starting molecule.

He designed a chiral molecule called an imidazolidinone, built in three steps from the methyl ester of the natural amino acid L-phenylalanine.

When this catalyst reacts with an unsaturated aldehyde, it forms an iminium ion, a nitrogen-containing intermediate that lowers the energy of an empty orbital on the molecule, making it react faster with a partner molecule called a diene in a reaction known as the Diels-Alder reaction.

MacMillan tested this on several organic molecules, and the reaction worked well; for one of the two possible mirror images, the catalyst produced over 90 per cent of the product.

He named the whole new approach organocatalysis and submitted his paper for publication in January 2000, just before List's paper appeared.

How did the discovery unfold?

The table below places the main events from the sources in order.

Since the two founding papers in 2000, the Nobel Committee for Chemistry said the field grew so fast it has been likened to a "gold rush," with List and MacMillan continuing to lead the area and design many further organocatalysts for new reactions.

Why does this matter for medicines and green chemistry?

Organocatalysts are usually built from carbon, hydrogen, oxygen, nitrogen, sulphur or phosphorus, elements that are common, cheap and generally less harmful to the environment than heavy metals.

This makes organocatalysis attractive for "greener" chemical manufacturing, because it avoids the toxic metal waste and the strict air-free, moisture-free conditions that some metal catalysts need.

The technique is especially useful in pharmaceutical research, because many drugs must be made as a single mirror-image form to avoid unwanted or even harmful side effects, as the thalidomide case showed.

Using organocatalysis, chemists can build large amounts of one desired mirror image relatively simply, rather than relying on tiny amounts isolated from rare plants or deep-sea organisms.

The popular science page names two medicines streamlined using this chemistry: paroxetine, used for anxiety and depression, and oseltamivir, an antiviral used for respiratory infections.

Organocatalysts can also work in sequence, step after step, without needing to purify each intermediate product first, in what is called a cascade reaction. This reduces the waste produced during manufacturing, and the sources point to the 2011 strychnine synthesis as a striking example of the efficiency gained.

The Nobel Committee for Chemistry said this ingenious tool is "as simple as it is ingenious," a view attributed to Johan Åqvist, chair of the committee, reflecting how a concept open to discovery for decades had been overlooked.

The scientific background paper adds that organocatalysis is now a routine part of planning laboratory syntheses in both industry and academic research, used alongside, rather than instead of, metal catalysis and biocatalysis as one of the discipline's three main approaches to speeding up reactions.

How does this connect to what you study?

Asymmetric organocatalysis links directly to basic ideas in school chemistry: chemical reactions, catalysts and the structure of carbon-based (organic) molecules. The idea that a molecule can have two different "mirror-image" forms, called isomers, connects to any chapter on isomerism or three-dimensional molecular structure.

It also connects to everyday chemistry of amino acids: proline, the catalyst at the heart of List's discovery, is one of the twenty standard amino acids that make up proteins, a topic usually met in biology when studying protein structure.

The link between a catalyst and the rate of reaction, a concept in chemical kinetics, is central to understanding why Berzelius first proposed the idea of catalysis in 1835 and why the Nobel Committee for Chemistry has honoured work on catalysis seven separate times.

Thinking about why chemists for decades assumed only metals and enzymes could catalyse reactions is also a useful lesson in how scientific habits of thought can be challenged by a simple experiment.

What new tools did organocatalysis lead to after the year 2000?

Once List and MacMillan had shown that a single small organic molecule could catalyse a reaction, other chemists quickly began designing further organocatalysts, so fast that the growth has been likened to a "gold rush."

Both laureates kept working in the field themselves. List's group went on to use proline-type catalysts for several new reaction types, including the Mannich reaction and the addition of nitrogen groups to aldehydes, while MacMillan's group used imidazolidinone-type catalysts to drive further reaction types, such as Friedel-Crafts reactions and 1,3-dipolar cycloadditions.

In 2005, other chemists introduced an improved catalyst family called diarylprolinol silyl ethers, which proved able to drive both of the main organocatalytic mechanisms, enamine catalysis and iminium ion catalysis, in the same molecule, widening the scope of reactions that organic catalysts could control.

MacMillan's group later showed that an enamine could be made to lose a single electron, forming a reactive radical intermediate that could join onto other molecules while the catalyst still controlled which mirror-image form formed, a method called SOMO activation.

MacMillan's group then combined organocatalysis with photoredox catalysis, in which a separate catalyst absorbs visible light and uses that energy to generate reactive intermediates, letting chemists run new carbon-building reactions using sunlight-like energy rather than heat alone.

1. An organocatalyst first joins to a starting aldehyde to form an enamine intermediate.
2. A light-absorbing photoredox catalyst generates a reactive radical from a separate starting material.
3. The radical joins onto the enamine, forming a new carbon-carbon bond and a new mirror-image centre.
4. The photoredox catalyst removes an electron from the resulting intermediate, and water releases the final product while regenerating the organocatalyst; the photoredox catalyst is regenerated separately, through its own electron-transfer steps.

Organocatalysis was also used in cascade reactions, where several bond-forming steps happen one after another without separating out the product in between, which the sources describe being used in the laboratory synthesis of vitamin E and of the anti-hypertension medicine aliskiren.

Quick facts for exams

The Nobel Prize in Chemistry 2021 was awarded jointly to Benjamin List and David W.C.

MacMillan "for the development of asymmetric organocatalysis." The prize was announced on 6 October 2021 by the Royal Swedish Academy of Sciences, Sweden's body for awarding the chemistry prize each year.

Each laureate received one half of the prize, which totalled 10,000,000 Swedish kronor. List was born in Frankfurt-on-the-Main, Germany, and worked at the Max-Planck-Institut für Kohlenforschung in Germany at the time of the award.

MacMillan was born in Bellshill, United Kingdom, and worked at Princeton University in the USA.

Both independently discovered, in the year 2000, that small organic molecules can catalyse reactions and control which mirror-image product forms, creating a third type of catalyst beside metals and enzymes.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Catalyst — a substance that speeds up a chemical reaction without being used up or permanently changed itself.
• Organocatalysis — the use of small organic (carbon-based) molecules, rather than metals or enzymes, as catalysts.
• Asymmetric catalysis — catalysis that produces mainly one of two possible mirror-image forms of a product.
• Mirror-image molecules — two versions of the same molecule that are identical except that one is the reflection of the other, like a left and right hand.
• Enamine — an intermediate formed when an amine group, such as that in proline, joins to a carbonyl compound.
• Iminium ion — a nitrogen-containing intermediate formed when an amine joins to an aldehyde or ketone, used in MacMillan's catalysis.
• Aldol reaction — a reaction that forms a new carbon-carbon bond between two carbonyl-containing molecules.
• Diels-Alder reaction — a reaction that builds a ring of carbon atoms from a diene and another unsaturated molecule.
• Proline — a small, naturally occurring amino acid used by Benjamin List as an organocatalyst.
• Imidazolidinone — a type of chiral organic catalyst designed by David MacMillan from the amino acid phenylalanine.
• Cascade reaction — a sequence of reaction steps carried out one after another without separating out each intermediate product.
• Enzyme — a protein catalyst made by living cells that drives biological reactions with high precision.
• Thalidomide — a drug whose two mirror-image forms behaved very differently, with one causing serious harm to developing embryos.

Common errors and misconceptions

• Misconception: Organocatalysts are the same as enzymes. Correct: They are inspired by how enzymes work but are much smaller, simpler molecules without the large protein structure of an enzyme.
• Misconception: List and MacMillan worked together on the discovery. Correct: They worked independently, in separate laboratories, and published their findings separately in 2000, with MacMillan submitting his manuscript in January and List publishing his discovery in February.
• Misconception: Organocatalysis was entirely unknown before 2000. Correct: Isolated examples existed earlier, such as Liebig's 1860 report that an organic molecule (acetaldehyde) could catalyse a reaction and proline being tested as a catalyst in the early 1970s, but no one had generalised it into a method before List and MacMillan.
• Misconception: A catalyst becomes part of the final product. Correct: A catalyst speeds up the reaction and is regenerated at the end, so it is not consumed by the reaction.
• Misconception: Mirror-image molecules always behave identically. Correct: They can have very different effects, as shown by limonene's two forms smelling of lemon and orange, and by thalidomide's two forms.
• Misconception: Metal catalysts have become useless since 2000. Correct: Organocatalysis is described as a third pillar of catalysis alongside, not a replacement for, metal catalysis and enzyme (biocatalysis) methods.

Exam-style questions with model answers

Q1. Name the two laureates of the Nobel Prize in Chemistry 2021 and their shared citation. [2 marks]

1. Benjamin List and David W.C. MacMillan were jointly awarded the prize "for the development of asymmetric organocatalysis."

Q2. What is a catalyst? [2 marks]

1. A catalyst is a substance that speeds up a chemical reaction without being consumed or permanently changed itself.

Q3. Explain why chemists before 2000 believed there were only two kinds of catalysts, and name them. [4 marks]

1. Chemists had long used metal catalysts, which temporarily hold or donate electrons to loosen chemical bonds, and enzymes, the protein catalysts of living cells that work with great precision. Almost every known catalyst fitted one of these two groups, so researchers assumed no third type existed. Metal catalysts, however, were often sensitive to air and moisture and sometimes environmentally harmful, while enzymes were large and hard to redesign, leaving a gap that List and MacMillan independently filled with small organic molecules in the year 2000.

Q4. Describe how Benjamin List discovered that proline can act as an organocatalyst. [4 marks]

1. List had worked on redesigning antibodies into catalysts and began wondering whether a single amino acid, rather than a whole enzyme, could catalyse a reaction. He recalled that proline had briefly been tested as a catalyst in the early 1970s but never followed up. Without strong expectations, he tested proline on an aldol reaction, joining carbon atoms from acetone and an aldehyde. The reaction worked immediately, and proline also directed the reaction so that one mirror-image product formed far more often than the other, which he published in February 2000.

Q5. What is asymmetric catalysis, and why does it matter for medicines? [3 marks]

1. Asymmetric catalysis is catalysis that produces mainly one of the two possible mirror-image forms of a molecule, rather than an equal mixture of both. It matters for medicines because the two mirror images of a drug can behave very differently in the body; in the thalidomide case, one form caused serious harm while the other did not, so being able to make only the safe, effective form is important for drug safety and manufacturing.

Q6. Compare the catalytic routes developed by Benjamin List and David MacMillan. [5 marks]

1. Both routes use small organic molecules rather than metals or enzymes, and both achieve asymmetric catalysis. List's route uses the amino acid proline, which forms an enamine intermediate with a carbonyl compound; this raises the energy of a filled molecular orbital, making the molecule react readily as an attacker, as demonstrated in the aldol reaction. MacMillan's route uses a chiral imidazolidinone catalyst built from phenylalanine, which forms an iminium ion with an unsaturated aldehyde; this lowers the energy of an empty molecular orbital, making the molecule react faster with a partner, as demonstrated in the Diels-Alder reaction. List's paper was published in February 2000, after MacMillan submitted his manuscript in January 2000, but the two worked entirely independently.

Q7. Discuss why organocatalysis is described as environmentally friendly, with examples from the sources. [5 marks]

1. Organocatalysts are usually built from common, non-metallic elements such as carbon, hydrogen, oxygen, nitrogen, sulphur and phosphorus, which are cheap and generally less environmentally harmful than heavy metals used in some metal catalysts. Unlike many sensitive metal catalysts, organocatalysts often do not need strict oxygen-free and moisture-free conditions, which simplifies large-scale manufacturing. Organocatalysts can also drive several reaction steps in sequence, called cascade reactions, without purifying each intermediate separately, reducing waste. One example given is the synthesis of the complex molecule strychnine, which needed 29 separate reactions in 1952 but could be made in just 12 steps, about 7,000 times more efficiently, using organocatalysis and a cascade reaction by 2011.

Q8. State the prize amount for the Nobel Prize in Chemistry 2021 and how it was shared. [1 mark]

1. The prize amount was 10,000,000 Swedish kronor, shared equally between the two laureates.

Key takeaways

• The Nobel Prize in Chemistry 2021 went jointly to Benjamin List and David W.C. MacMillan for developing asymmetric organocatalysis.
• Before 2000, chemists recognised only two types of catalysts: metals and enzymes.
• Both laureates independently discovered that small organic molecules can act as a third type of catalyst, in the year 2000.
• List showed the amino acid proline alone can catalyse an asymmetric aldol reaction, forming an enamine intermediate.
• MacMillan designed an imidazolidinone catalyst that forms an iminium ion to drive an asymmetric Diels-Alder reaction.
• Asymmetric catalysis lets chemists build mainly one of two possible mirror-image forms of a molecule.
• Organocatalysis is generally cheaper and more environmentally friendly than many metal-based methods.
• The technique has streamlined the manufacture of medicines such as paroxetine and oseltamivir.
• Organocatalysis made the synthesis of complex natural molecules such as strychnine thousands of times more efficient.

Test yourself

Who were the two laureates of the Nobel Prize in Chemistry 2021?

Benjamin List and David W.C. MacMillan shared the prize for developing asymmetric organocatalysis.

What two types of catalyst did chemists know of before 2000?

Chemists recognised only metal catalysts and enzymes before List and MacMillan showed organic molecules could also work as catalysts.

Which amino acid did Benjamin List use as a catalyst?

Benjamin List used proline, a simple naturally occurring amino acid, to catalyse an asymmetric aldol reaction.

What catalyst did David MacMillan design, and from what was it built?

David W.C. MacMillan designed a chiral imidazolidinone catalyst, built in three steps from the amino acid L-phenylalanine.

Why do chemists often want only one mirror-image form of a molecule?

Because the two mirror-image forms can behave very differently, as shown by thalidomide, where one form caused serious harm while the other did not.

How much more efficient did organocatalysis make the synthesis of strychnine by 2011?

Organocatalysis and a cascade reaction made strychnine synthesis about 7,000 times more efficient than the original 1952 method.

When was the Nobel Prize in Chemistry 2021 announced, and by whom?

The Royal Swedish Academy of Sciences announced the prize on 6 October 2021.