2021 · Chemistry

Building only one hand: catalysis without metals

Q: In 'asymmetric organocatalysis', what does asymmetric mean?

The reaction makes mainly one of two mirror-image forms. Asymmetric (enantioselective) catalysis favours one enantiomer over its mirror image, which is exactly what you want when only one hand of a drug is useful or safe.

Q: Before 2000, which two kinds of catalyst were thought to be the only options for this work?

Metals and enzymes. Chemists long assumed catalysis needed either a metal or an enzyme. List and MacMillan added small organic molecules as a third kind, called organocatalysis.

Q: Why is an organocatalyst such as proline attractive next to many metal catalysts?

It is cheap, metal-free and tolerant of air and water. Proline is an inexpensive amino acid that works without toxic metals or strict moisture-free, oxygen-free conditions, which makes the chemistry cheaper and greener.

Awarded to Benjamin List and David W.C. MacMillan “for the development of asymmetric organocatalysis”.

What was the 2021 Nobel Prize in Chemistry awarded for?

The 2021 Chemistry prize honours a third kind of catalyst. Many molecules come in two mirror-image forms, like a left and a right hand, and often only one of them is useful or safe. Benjamin List and David MacMillan showed that small, cheap organic molecules can build just the hand you want, without the toxic metals or delicate enzymes chemists had relied on.

Predict first

Your left and right hands are built from exactly the same parts, yet a right glove will not fit your left hand. Many molecules share this quirk. Why would a drug company care which 'hand' of a molecule it makes?

Because the two hands can act completely differently in the body. One mirror image may treat you while its twin does nothing or causes harm. The thalidomide tragedy is the classic case: one form eased nausea, while the mirror image caused severe birth defects. So chemists badly want a way to build just the useful hand.

Predict first

For about a century, chemists believed only two kinds of substance could reliably speed up reactions and pick one mirror image. List and MacMillan added a third. What was it?

Small organic molecules, built mostly from carbon. The first two were metals and enzymes. List and MacMillan showed that a cheap, metal-free molecule such as the amino acid proline can do the same delicate job, an approach they called asymmetric organocatalysis.

A chiral molecule has two mirror-image forms. A small organic catalyst such as proline steers the reaction so that one hand makes up almost all of the product.

A catalyst is a helper. It speeds up the building of a molecule, then walks away unchanged, ready to help again.

Here is the twist. Many molecules come in two versions that are mirror images of each other, exactly like your left and right hands. Same parts, flipped layout. In a medicine, often only one hand heals you, while the mirror-image hand does nothing or can even cause harm.

The big idea in one line

A third kind of helper

For a long time chemists thought only two things could do this delicate building job: metals, or the enzymes inside living cells. Benjamin List and David MacMillan showed that tiny, ordinary organic molecules, the kind made mostly of carbon, can do it too, and build just the hand you want.

These small-molecule helpers are cheap, they need no toxic metals, and they are easy to handle. That makes building the correct hand of a molecule simpler and cleaner.

Many molecules are chiral: they exist as two forms that are mirror images and cannot be laid on top of each other, just like a left and a right hand. The two forms are called enantiomers.

The two enantiomers can behave very differently inside the body. The classic warning is thalidomide: one mirror image can calm nausea while the other can cause severe birth defects. So when chemists build a drug, they usually want one enantiomer, not a 50:50 mixture.

A catalyst speeds up a reaction without being used up. For decades chemists believed only two families of catalyst could do this work: metal complexes and enzymes. Asymmetric (or enantioselective) catalysis means the catalyst favours one enantiomer over its mirror twin.

List, 2000

Proline does the job

Benjamin List used the cheap amino acid L-proline to drive an aldol reaction, a way of joining two carbon fragments. The proline forms a temporary enamine with one partner and steers the new bond so that one enantiomer dominates. No metal, no enzyme, just a small organic molecule.

MacMillan, 2000

Designing the catalyst on purpose

David MacMillan reasoned that a molecule able to form an iminium ion could activate a partner in a similar way. His imidazolidinone catalyst drove a Diels-Alder reaction so that over 90 per cent of the product was a single mirror image. He coined the name organocatalysis.

1970s

Proline is known to catalyse a few special reactions, but chemists treat these as one-off curiosities rather than a general method.

Early 2000

List and MacMillan publish independently, within a month of each other, and frame small organic molecules as a broad new tool for asymmetric synthesis.

After 2000

Organocatalysis grows fast and becomes known as the third pillar of asymmetric catalysis, used to make drugs and light-capturing molecules for solar cells.

Because there is no metal, organocatalysts are cheap, often non-toxic, and friendly to green chemistry. Many of them work on the open bench without the strict moisture-free and oxygen-free conditions that delicate metal catalysts demand.

Asymmetric synthesis turns on a single number: enantiomeric excess (ee), the degree to which one enantiomer outweighs its mirror image. A chiral catalyst lowers the activation energy of one reaction pathway more than the other, so the two enantiomers form in unequal amounts from achiral or prochiral starting materials. Before 2000 the dominant strategies were chiral metal complexes (chiral ligands arranged around a metal centre) and enzymes.

Enamine catalysis

How L-proline steers an aldol

List, with Lerner and Barbas, showed in 2000 that L-proline catalyses a direct intermolecular aldol reaction. The secondary amine of proline condenses with a ketone to form a nucleophilic enamine, while the carboxylic acid acts as a built-in proton shuttle. This bifunctional transition state delivers the incoming aldehyde to one face and sets the new stereocentre. An early result joined acetone and p-nitrobenzaldehyde with about 30 mol per cent proline to give the aldol product with useful ee.

Iminium catalysis

MacMillan's LUMO-lowering trick

MacMillan's chiral imidazolidinone condenses with an enal to form an iminium ion. Conjugation into the iminium lowers the substrate LUMO and accelerates Diels-Alder and conjugate additions, while a bulky group on the catalyst blocks one face. His first report drove a Diels-Alder reaction to over 90 per cent of one enantiomer. Enamine activation (HOMO-raising) and iminium activation (LUMO-lowering) became the two founding modes of the field.

Together these results established organocatalysis as a third pillar of asymmetric catalysis beside metal and enzyme catalysis. The practical payoff is large. Small organic catalysts are typically cheap, bench-stable, and tolerant of air and water, so they avoid the rigorously anhydrous, oxygen-free handling that many transition-metal catalysts need at scale.

Why industry took notice

No metal residue: a serious advantage for pharmaceuticals, where trace heavy metals must be scrubbed from the final drug.
Lower cost and simpler handling: amino-acid catalysts are inexpensive and need no glove box or inert atmosphere.
Greener processes: avoiding toxic metals and harsh conditions fits the goals of green chemistry.
Breadth: enamine, iminium, hydrogen-bonding and chiral Brønsted-acid catalysts now drive a wide range of bond-forming reactions, from drug intermediates to molecules for solar cells.

Open challenges remain. Organocatalysts often need higher loadings than the best metal catalysts, and extending them to ever more reaction classes is active work. Even so, in roughly two decades the field went from a handful of curiosities to a standard tool, which is why List and MacMillan share the 2021 prize.

Worth knowing

Two papers, one month apart

List and MacMillan hit on the same idea independently and published in early 2000 within about a month of each other. Remarkably, it was List's first paper and MacMillan's second as independent researchers, and between them the two reports launched a whole field.

Check yourself

In 'asymmetric organocatalysis', what does asymmetric mean?

Why: Asymmetric (enantioselective) catalysis favours one enantiomer over its mirror image, which is exactly what you want when only one hand of a drug is useful or safe.

Before 2000, which two kinds of catalyst were thought to be the only options for this work?

Why: Chemists long assumed catalysis needed either a metal or an enzyme. List and MacMillan added small organic molecules as a third kind, called organocatalysis.

Why is an organocatalyst such as proline attractive next to many metal catalysts?

Why: Proline is an inexpensive amino acid that works without toxic metals or strict moisture-free, oxygen-free conditions, which makes the chemistry cheaper and greener.

Key terms

Chirality: The property of a molecule that makes it non-superimposable on its mirror image, just like a left and a right hand.
Enantiomer: One of the two mirror-image forms of a chiral molecule. Two enantiomers share the same atoms and bonds but differ in their 3D arrangement.
Catalyst: A substance that speeds up a chemical reaction without being consumed by it.
Asymmetric (enantioselective) catalysis: Catalysis that produces one enantiomer in excess of its mirror image.
Organocatalyst: A small organic molecule, built mainly from carbon, that acts as a catalyst, with no metal required.
Enamine and iminium catalysis: The two founding activation modes of organocatalysis. An amine catalyst joins the substrate to form either an enamine (more nucleophilic) or an iminium ion (more electrophilic).
Enantiomeric excess (ee): A measure of how strongly one enantiomer outweighs the other in a product mixture.

The laureates

Benjamin List

Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany

List (born 1968, Germany) was working at the Max-Planck-Institut für Kohlenforschung when, in 2000, he showed that the cheap amino acid L-proline could drive an asymmetric aldol reaction and favour one mirror image. He saw that a simple, metal-free organic molecule could be a general catalyst, and framed the idea as a new concept for chemistry.

Photo: Raimond Spekking, CC BY-SA 4.0 (via Wikimedia Commons)

David W.C. MacMillan

Princeton University, Princeton, NJ, USA

MacMillan (born 1968, United Kingdom) had worked on metal catalysis but noticed that sensitive, costly metal catalysts were rarely used in industry. At Princeton and Berkeley he reasoned that a small organic molecule able to form an iminium ion could do the same job. In 2000 his imidazolidinone catalyst drove a reaction to over 90 per cent of one mirror image, and he coined the term organocatalysis.

Sources

Facts are pinned from the official Nobel Prize API. The explanations were written from these sources:

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