Investing in Nobel Prize Achievements – Asymmetric Organocatalysis

Nobel Prize History

The Nobel Prize is the most prestigious award in the scientific world. It was created according to Mr. Alfred Nobel’s will to give a prize “to those who, during the preceding year, have conferred the greatest benefit to humankind” in physics, chemistry, physiology or medicine, literature, and peace.

A sixth prize would be later on created for economic sciences by the Swedish central bank, officially called the Prize in Economic Sciences, often better known as the Nobel Prize in Economics.

The decision of who to attribute the prize to belongs to multiple Swedish academic institutions.

Legacy Concerns

The decision to create the Nobel Prize came to Alfred Nobel after he read his own obituary, following a mistake by a French newspaper that misunderstood the news of his brother’s death. Titled “The Merchant of Death Is Dead”, the French article hammered Nobel for his invention of smokeless explosives, of which dynamite was the most famous one.

His inventions were very influential in shaping modern warfare, and Nobel purchased a massive iron and steel mill to turn it into a major armaments manufacturer. As he was first a chemist, engineer, and inventor, Nobel realized that he did not want his legacy to be one of a man remembered to have made a fortune over war and the death of others.

Nobel Prize

These days, Nobel’s Fortune is stored in a fund invested to generate income to finance the Nobel Foundation and the gold-plated green gold medal, diploma, and monetary award of 11 million SEK (around $1M) attributed to the winners.

Source: Britannica

Often, the Nobel Prize money is divided between several winners, especially in scientific fields where it is common for 2 or 3 leading figures to contribute together or in parallel to a groundbreaking discovery.

Over the years, the Nobel Prize became THE scientific prize, trying to strike a balance between theoretical and very practical discoveries. It has rewarded achievements that built the foundations of the modern world, like radioactivity, antibiotics, X-rays, or PCR, as well as fundamental science like the power source of the sun, the electron charge, atomic structure, or superfluidity.

The Quest For More Catalysts

From the early era of chemistry, scientists have looked at ways to speed up chemical reactions or make molecules react in unusual ways. Sometimes, it can be achieved by changing the physical conditions, like using heat or pressure. However, for other chemical reactions, special products called catalysts are needed.

Catalysts are usually boosting the chance of a chemical reaction to happen, therefore increasing its speed and/or its efficiency.

What makes catalysts unique is that while they are involved in the chemical reaction, they are left unchanged at the end of it – the only “facilitate” the reaction.

This makes catalysts an often forgotten keystone of the modern world and absolutely essential in the manufacturing of everyday goods like refined oil, plastics, air filters, water purification, pharmaceuticals, perfume, flavoring, foodstuff, etc.

Altogether, catalysts contribute in one way or another to the production of as much as 35% of the world’s GDP.

Many Types Of Catalysts

The first catalytic activity to be discovered was from metals like silver, nickel, platinum, palladium, etc. However, these catalysts are expensive. Metal catalysts also have a low selectivity, meaning that they can catalyze many different reactions.

While this can sometimes be an advantage, it is not the case when only one precise reaction is desired, like in the production of pharmaceuticals.

Another type of catalyst is enzymes. These proteins are able to accelerate very specific chemical reactions and are essentially the gears and machines powering life itself.

The preparation of pure enzymes was a significant scientific breakthrough and was awarded a Nobel Prize in 1946. Today, enzymes are routinely used in countless chemical processes.

The limit of enzymes is that they were designed by nature to perform specific tasks in living cells. So when the catalysis required is for something unrelated to biology, such as the production of plastics, it can be rather hard or even impossible to find a matching enzyme for the task.

Enzymes can also be fragile and not work in conditions of extreme acidity, for example. So, there was a strong need for non-metallic, custom-designed catalysts. This is where organocatalysts enter the scene. They are made of ordinary carbon, hydrogen, nitrogen, sulphur, and phosphorus but no metals.

Organocatalysts

In 2021, the Nobel Prize in Chemistry was attributed to Benjamin List and David W.C. MacMillan, for the development of asymmetric organocatalysis.

As explained, organocatalysts are made of cheap and abundant elements forming the basis of organic chemistry (centered around carbon). The “asymmetric” part is important, as for most chemical and biological processes, molecules can display different versions, depending on their symmetry.

Such changes in the molecule orientation, also called “chirality”, have often important consequences for its functionality. For example, the same molecule of limonene will smell differently depending on which side it is oriented.

Source: Nobel Prize

List & MacMillan were not the first to discover organocatalysts. Some were found by accident as early as 1912 with quinine catalysis of cyanohydrins production. Later on, a quinine-derived catalyst would be used to perform asymmetric catalysis.

Source: Nobel Prize

However, for a long time, there was no framework to properly analyze organocatalysts, even less custom design new ones.

How Does Catalysis Work?

Most chemical reactions need some level of energy to be reached at the molecule levels, to make the 2 compounds “bump into each other” and react. Catalysts bring the reagents closer together, reducing the energy required and making the reaction quicker and more likely to happen.

Source: Byjus

So while specific metallic elements are able to cause this lowering of energy levels due to their inherent atomic properties, the amino acids of enzymes are able to do it through the combination of their 3D configuration and chemical properties.

Often, it is only a few amino acids that actually perform the catalytic reaction, with the rest of the enzyme providing stability, activation from biochemical signals, or other functions.

Source: Nobel Prize

This was the starting point for Benjamin List, who wanted to investigate if a small number of amino acids, or even just one could perform catalysis the way entire enzymes do.

List Catalysts: Proline & Chirality

List started to work with a single amino acid called proline, which had been demonstrated to be a potential catalyst more than 25 years ago in the 1970s. Not expecting a very strong reaction, but still curious to learn more about it, he ran the experiment to check on it.

Not only did proline work as a catalyst, but it did so very strongly. Looking at the reaction further, List found that the catalysis was asymmetrical, with one of the 2 possible images of the newly formed molecule a lot more likely to be formed.

This would form the base for a new category of catalyst, called by chemists enamine catalysis, or Lewis base catalysis.

In it, a nitrogen atom reduces the energy required, and a carboxylic acid stabilizes the transition state in the intermediary steps of the chemical reaction catalyzed.

Source: Nobel Prize

MacMillan Catalysts: Iminium Ion

MacMillan had been working on metal-based asymmetrical catalysts but realized the conditions for these to work were rarely workable in an industrial setting, causing the discoveries in labs to be rarely useful for chemical production at scale.

Instead, he looked at how to replicate the basic mechanisms these metals use with organic chemistry.

Metal catalysts are especially active thanks to their ability to temporarily provide or accommodate electrons, reducing the barrier for a chemical reaction to occur.

To replicate such ability with organic molecules (made of a carbon backbone), MacMillan guessed from his chemistry knowledge that the perfect one would be an iminium ion.

As a result, this type of organocatalyst would become known as iminium ion catalysis/Lewis acid catalysis.

The idea here is that the nitrogen atom, with an inherent affinity for electrons, can play the role of the metal atom in a metal catalyst. Large chemical groups around the nitrogen atoms force the reaction to be asymmetrical.

Source: Nobel Prize

The Rise Of Organocatalysts

MacMillan and List would publish their parallel findings almost at the same time in 2000, with the word to describe this new class of catalysts coined by MacMillan.

By fully explaining and investigating how they work, the two researchers and their teams opened the way for the systematic development of organocatalysts, where previous works were done more in a piecemeal fashion or through accidental discoveries.