Asymmetric organocatalysis: why it is a Nobel Prize for Ecological Transition

by Marco Bella – When the chemical industry was born, waste was not considered a problem. Then, it happened as in Minamata, where a factory near a fishing village in Japan threw mercury sulfate directly into the river from 1932 to 1968. There was a higher concentration of mercury in the river sediments than was found in the river. mines. Mercury reached the sea and accumulated in fish and shellfish, humans ate fish and poisoned themselves with mercury. And men were sick and dying and children were born malformed.

The chemical industry has realized that waste is not just “a problem”, it is the problem. And that waste containing heavy metals is an even bigger problem.

On 6 October 2021 the Nobel Prize was awarded to List e MacMillan not for what they have produced, but rather for what they have not obtained: waste. The Nobel Prize for asymmetric organocatalysis.

Let’s look at our hands: they are not the same, but they are the mirror image of each other. All objects that in the mirror are not equal to themselves and therefore exist in pairs (shoes, gloves, but also some shells and even galaxies) are called chirals (from the Greek χείρ, “hand”). It happens that molecules are also objects, and that therefore each chiral molecule exists as non-superimposable mirror images, which from now on for simplicity we will call “hands”.

Chiral molecules exist in two non-overlapping mirror images, such as the right and left hand. (image from wikipedia)

Preparing a single “hand”, but also separating the “hands”, that is, making an “asymmetrical synthesis”, is very difficult. There were drugs of which both “hands” were given, thinking that much did not change much, but our body, however, recognizes the different “hands” and how. The Thalidomide was in fact made up of two “hands”. The “right” hand was an antiemetic, that is a substance that helps fight nausea, and for this reason it was prescribed to pregnant women.

The “left” one, however, was a teratogen, or a substance that caused serious malformations in fetuses such as phocomelia, ie reduced or absent limbs, as in the child in the photo below who has only one leg and no arms.

When Thalidomide was sold in Europe in the late 1950s, there was an explosion of phocomelia cases due to the wrong “hand” of this drug. The United States was spared because FDA pharmacologist Frances Kelsey, not surprisingly a woman, strongly opposed authorizing a new drug for pregnant women without sufficient studies and thus saved her country from much suffering.

The process of obtaining molecules as a single “hand” is called “asymmetric catalysis” when it uses a catalyst, that is, a substance that accelerates the reaction.

Frances Oldham Kelsey awarded by US President John F. Kennedy in 1962

The field of asymmetric catalysis received the Nobel Prize in 2001. The catalysts used contained transition metals (eg palladium, which costs more than gold). Of course: small quantities of metals were used, but even these small quantities were no small problem. In some industrial processes, the costs related to the metal catalyst reach up to 60% of the total, this is because metal catalysts, in addition to being so expensive, are difficult to dispose of. Not only processing waste, but even reactors can be contaminated with metals.

To understand how important the waste problem is in the chemical industry, let’s consider that about 200 kg of other chemical compounds are used to make just one kilo of active ingredient of a drug with an efficient process. One kg is what the tablet you use will become, 199 kg what you throw away and for which you have to find a solution.

Furthermore, to use some metal catalysts you need an environment without air and traces of water, which can be done relatively easily in a chemical laboratory but which becomes much more complex in an industrial reactor weighing hundreds of kg.

What then was the discovery of the Nobel List and MacMillan laureates? That these very difficult asymmetric reactions could be achieved in a much simpler way using some organic molecules as catalysts without using transition metals, and producing the chiral molecules as single hands through asymmetric organocatalysis. As catalysts, compounds containing transition metals were not used, but simpler organic substances, such as proline, an amino acid that can even be eaten. A little water then made the reaction go even better!

Asymmetric organocatalysis has therefore become a new approach to conduct chemical reactions: eliminating transition metals allows for example to put waste in a bioreactor so that the bacteria degrade everything.

Among other things, even from the point of view of efficiency, producing two “hands” of the molecules, separating them and then throwing one away is not too clever a strategy. It is certainly more sensible to produce with the asymmetric organocatalysis only the “hand” that serves, right or left. Respecting the environment and money means producing only what you want to achieve, rather than double it and throw away half of it.

An interesting aspect, however, is that asymmetric organocatalysis was not discovered at all in 2000, when the first articles by List and MacMillan appeared, but there are studies that date back to the 60s-70s and even to the early 1900s. If we go back, however, we can say that asymmetric organocatalysis is actually invented by God: in fact enzymes are highly efficient organocatalysts that produce only the desired “hand” in an almost perfect way. However, it must be said that enzymes are made up of hundreds of amino acids and in order to work they need very specific conditions, for example only a given temperature, while organocatalysts instead of a single amino acid and can operate in many different conditions and solvents.

Thus, asymmetric organocatalysis and its potential were known, yet inexplicably this type of research has been neglected for decades.

I started working in this field in 2003 in Denmark, with Professor Karl Anker Jørgensen, a person who, according to many, also deserved the Nobel. I was one of the first to introduce it in Italy in 2005, amid the skepticism of many colleagues at the time. Among other things, it can be done with very little money, and when I returned to Rome after spending five years between the USA and Denmark, I saw that there was very little money here for research. An asymmetric organocatalytic reaction developed in my laboratory has become an industrial process that allows not only to avoid the use of transition metals but also to decrease the organic solvent used in the original synthesis by a factor of fifty. [J. Org. Chem. 2012, 77, 4765]

What was the decisive impetus for hundreds of researchers around the world to suddenly jump into this field? The awareness that it is important not only what and how you produce but also, if not more, what do you do with waste? Or finally understand that disposing of metals is much more complex than simple organic compounds? I want to believe that it is the set of many things, including the realization by chemists (who are intelligent people) of the importance of the ecological transition.

Ecological transition does not mean going back to the Middle Ages, but it means spending less. It means getting only what you want. It means limiting what you don’t want as much as possible, that is, waste. In one word: ecological transition means efficiency and Nobel research. It means moving towards a world where waste is no longer a problem, because waste simply no longer produces or reuses it.

Source: Il Blog di Beppe Grillo by

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