# 2021 Nobel Prize in Chemistry: Building only one hand: catalysis without metals > 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. - Laureates: Benjamin List (share 1/2, Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany); David W.C. MacMillan (share 1/2, Princeton University, Princeton, NJ, USA) - Official citation: “for the development of asymmetric organocatalysis” - Course page: https://nobelexplained.com/chemistry/2021-asymmetric-organocatalysis - Last updated: 2026-06-21 ## Explained simply (ELI5) 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. > **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. ## Explained for undergraduates 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. > **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. > **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. ## Explained for experts 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. > **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. > **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. ## Think first **Q:** 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? **A:** **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. **Q:** 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? **A:** **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. ## 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. ## 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. ## Check yourself 1. In 'asymmetric organocatalysis', what does asymmetric mean? - The catalyst is heated unevenly - **The reaction makes mainly one of two mirror-image forms** (correct) - The equipment is lopsided - The molecule has no symmetry of any kind - 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. 2. Before 2000, which two kinds of catalyst were thought to be the only options for this work? - Acids and bases - **Metals and enzymes** (correct) - Light and heat - Salts and gases - 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. 3. Why is an organocatalyst such as proline attractive next to many metal catalysts? - It glows in the dark - **It is cheap, metal-free and tolerant of air and water** (correct) - It needs a sealed glove box to work - It only works at very high pressure - 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. ## The laureates ### Benjamin List 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. ### David W.C. MacMillan 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 - [The Nobel Prize in Chemistry 2021, popular information (NobelPrize.org)](https://www.nobelprize.org/prizes/chemistry/2021/popular-information/) - [The Nobel Prize in Chemistry 2021, press release (NobelPrize.org)](https://www.nobelprize.org/prizes/chemistry/2021/press-release/) - [Organocatalysis (Wikipedia)](https://en.wikipedia.org/wiki/Organocatalysis) --- From Nobel Explained (https://nobelexplained.com), a free, independent course on every Nobel Prize since 2020. Not affiliated with the Nobel Foundation. Facts are pinned from the official Nobel Prize API.