Nobel Prize in Chemistry: 
D. Indumathi, The Institute of Mathematical Sciences, Chennai

This year's Nobel Prize in Chemistry 2021 was awarded jointly to Benjamin List and David W.C. MacMillan "for the development of asymmetric organocatalysis."
Here we have to understand the meaning of "asymmetric" and "organo-catalysis". Basically, the work involves building tools that revolutionised the construction of molecules. Benjamin List works in Germany and MacMillan in the USA.
 
A tool for building molecules
Building molecules is a difficult art. Benjamin List and David MacMillan were awarded the Nobel Prize in Chemistry 2021 because of their development of a precise new tool for molecular construction: organocatalysis. This has had a great impact on pharmaceutical research, and has made chemistry greener.
The word organo-catalysis has two parts: one is catalysis, and the other is organic. Hence the process involves catalysis of organic compounds.

What is a catalyst?
Catalysts are substances that control the rate of chemical reactions, without themselves changing in the process. A common example is that of platinum in cars. When fuel burns in a car engine, harmful gases like carbon monoxide (CO) are produced. In the presence of air (which contains oxygen), this is converted to carbon dioxide (CO2), which is less harmful: 2 CO + O2 -> CO2.
However, this process occurs very slowly and so most of the gas that comes out will comprise the harmful monoxide. In the presence of platinum, however, this reaction speeds up. So in the catalytic converter of cars, platinum is used to catalyse the conversion of carbon monoxide to carbon dioxide. The platinum is not used up in the reaction.
Metals are excellent catalysts, but they are very sensitive to oxygen and water. So they work best in an environment free of oxygen and moisture. This is difficult to achieve in large-scale industries. Also, many metal catalysts are heavy metals, which can be harmful to the environment.

What are organo-catalysts?
The second form of catalyst is comprised of the proteins known as enzymes. All living things have thousands of different enzymes that drive the chemical reactions necessary for life. They also work side by side; when one enzyme is finished with a reaction, another one takes over. In this way, they can build complicated molecules with amazing precision, such as cholesterol, chlorophyll or the toxin called strychnine, which is one of the most complex molecules we know of.
Think of organic compounds such as the proteins and enzymes in our body. When any of them function as a catalyst, they are called organo-catalysts. Many thousands of natural enzymes in our body act as catalysts.
Organic catalysts have a stable framework of carbon atoms, to which more active chemical groups containing elements such as oxygen, nitrogen, sulphur or phosphorus, are attached. This means that these catalysts are both environmentally friendly and cheap to produce since metals are costly.
Chemists have discovered several catalysts that can break down molecules or join them together. Using these, we can make thousands of different substances we use in our everyday lives, such as pharmaceuticals, plastics, perfumes and food flavourings. The fact is, it is estimated that 35 per cent of the world’s total GDP in some way involves chemical catalysis.
In principle, all catalysts discovered before the year 2000 belonged to one of two groups: they were either metals or enzymes. But when scientists began to discover how nature uses catalysts, they realised that their understanding was very limited. Whenever they tried to copy these natural molecules, they ended up with a lot of unwanted by-products. It felt like they were using stone-age tools while Nature was using sophisticated ones!
Catalysts are thus fundamental tools for chemists. Many industries depend on chemists’ ability to build new and functional molecules. These could be anything from substances that capture light in solar cells or store energy in batteries, to molecules that can make lightweight running shoes. Or they can even slow down the spread of disease in our body!
Researchers thought that there were just two types of catalysts available: metals such as platinum, and enzymes. Benjamin List and David MacMillan were awarded the Nobel Prize in 2000 they independently developed a third type of catalysis. It is called asymmetric organocatalysis and builds upon small organic molecules. How do we understand "asymmetric"?

Limonene molecules
When molecules are being built, two different types of molecules can form, which – just like our hands – are each other’s mirror image. Chemists will often only want one of these, particularly when producing pharmaceuticals. Hence these molecules are asymmetric. 
These mirror copies often have completely different effects in the body. For example, one version of the limonene molecule has a lemon scent, while its mirror image smells like orange. Many enzymes are specialists in asymmetric catalysis and, in principle, always form one mirror image out of the two that are possible.

Natural catalysts
Because enzymes are such efficient catalysts, researchers in the 1990s tried to develop new enzyme variants to drive the chemical reactions needed by humanity.
Benjamin List worked with catalytic antibodies at the Scripps Research Institute in California, USA. Normally, antibodies attach to foreign viruses or bacteria in our bodies: for instance, you must all know by now that the Covid-19 vaccine contains anti-bodies to the Covid-19 virus. But he and his colleagues redesigned them so they could drive chemical reactions instead.
During his work with catalytic antibodies, Benjamin List started to think about how enzymes actually work. They are usually huge molecules that are built from hundreds of amino acids. In addition to these amino acids, a significant proportion of enzymes also have metals that help drive chemical processes. But – and this is the point – many enzymes catalyse 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 out-of-the-box question was: do amino acids have to be part of an enzyme in order to catalyse a chemical reaction? Or could a single amino acid, or other similar simple molecules, do the same job?
He knew that there was research from the early 1970s where an amino acid called proline had been used as a catalyst – but that was more than 25 years ago. Surely, if proline really had been an effective catalyst, someone would have continued working on it?
This is more or less what Benjamin List thought; he assumed that the reason why no one had continued studying the phenomenon was that it had not worked particularly well. Without any real expectations, he tested whether proline could catalyse a particular reaction in which carbon atoms from two different molecules are bonded together. It was a simple attempt that, amazingly, worked straight away.

Proline
With his experiments, Benjamin List not only demonstrated that proline is an efficient catalyst, but also that this amino acid can drive asymmetric catalysis. Of the two possible mirror images, it was much more common for one of them to form than the other.
Unlike the researchers who had previously tested proline as a catalyst, Benjamin List understood the enormous potential it could have. Compared to both metals and enzymes, proline is a dream tool for chemists. It is 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 opportunities.
However, he was not alone in this. In a laboratory at the University of California, Berkeley, David MacMillan was also working towards the same goal.
David MacMillan realised that metals are good catalysts because they can lose or gain electrons easily. He started to design simple organic molecules which – just like metals – could temporarily provide or accommodate electrons. Out of several that he tested, he found the right one, containing a nitrogen atom, which could form a special ion called an iminium ion. He not only found asymmetric organo-catalysts, but also named them so!

Efficiency is the watch-word
Over the years, List and MacMillan have designed multitudes of cheap and stable organocatalysts, which can be used to drive a huge variety of chemical reactions. Previously, in a chemical process, it was necessary to isolate and purify each intermediate product, since many by-products were formed at the same time. Apart from the complexity and loss of time, this also led to the loss of a part of the needed product.
In contrast, with organocatalysts, several steps in a production process can be performed in an unbroken sequence. This is called a cascade reaction, which can considerably reduce waste in chemical manufacturing. One example is the synthesis of the strychnine molecule. Many people will recognise strychnine as a poison used in books by Agatha Christie, queen of the murder mystery. 
When strychnine was first synthesised, in 1952, it required 29 different chemical reactions and only 0.0009 per cent of the initial material formed strychnine. The rest was wasted. In 2011, researchers were able to use organocatalysis and a cascade reaction to build strychnine in just 12 steps, and the production process was 7,000 times more efficient.
Using organocatalysis, researchers can now make large volumes of different asymmetric molecules relatively simply. For example, they can artificially produce potentially curative substances that can otherwise only be isolated in small amounts from rare plants or deep-sea organisms.
At pharmaceutical companies, the method is also used to streamline the production of existing pharmaceuticals. Examples of this include paroxetine, which is used to treat anxiety and depression, and the antiviral medication oseltamivir, which is used to treat respiratory infections and is one of the drugs used to treat Covid. Organocatalysts are thus bringing – right now – the greatest benefit to humankind.