A look at organocatalysis, which recently earned Drs. Benjamin List and David MacMillan the 2021 Nobel Prize in Chemistry.
When it comes to scientific achievements, the Nobel Prize is the epitome of recognition.
The annual awards were established in 1895 based on instructions in Alfred Nobel’s will to recognize scientists who, “during the preceding year, have conferred the greatest benefit to humankind.” Nobel had accumulated a considerable fortune from his invention of dynamite, but while it had practical uses in construction, he was concerned the explosive could be used to the detriment of humanity. Nobel envisioned that his prizes would stimulate research from which society would profit — which is exactly what Benjamin List of the Max Planck Institute for Coal Research in Germany and David MacMillan of Princeton University have done. The two scientists were recently awarded the 2021 Nobel Prize in Chemistry for their development of “an ingenious tool for building molecules.” That ingenious tool is called organocatalysis.
Life is all about building molecules. Our bodies are constantly linking amino acids to make proteins, synthesizing adenosine triphosphate (ATP) to store energy, and producing neurotransmitters along with a host of other molecules needed to sustain life. In research labs and industrial facilities around the world, chemists synthesize medications, polymers, dyes, paints, agrochemicals, cosmetics, cleaning agents, disinfectants and numerous other substances that have become an integral part of our lives. The chemical reactions that produce many of these materials rely on the use of catalysts, substances that dramatically speed up a reaction without being consumed themselves — a process known as catalysis. List and MacMillan independently developed what they call organocatalysts, a type of catalyst that facilitates the building of molecules while avoiding the hazards of traditional options.
The concept of catalysis is not new. If you dissolve sugar in water, nothing happens, at least not at an observable rate. Add some yeast, however, and the sugar is converted to carbon dioxide and alcohol. This is because yeast produces zymase, an enzyme that acts as a catalyst and speeds up the reaction. In our bodies, enzymes serve as catalysts to help digest fats, synthesize DNA and eliminate toxins. Industries also use enzymes to produce biofuels, stain removers and pharmaceuticals, and to break down waste products. When it comes to the commercial use of catalysts, however, most are metals or their derivatives. For example, one of the most important catalysis processes is the reaction of nitrogen with hydrogen to make ammonia, a fertilizer that has saved millions from starvation. Additionally, catalytic converters on cars, the polymerization of ethylene, the synthesis of vitamin A and the production of drugs such as protease inhibitors to treat hepatitis C all rely on metal catalysts.
But while enzymes and metal catalysts are widely used, there are some issues. Enzymes have a limited temperature and pH range, and although metal catalysts have a wider scope, they must be kept free of moisture and oxygen to function properly. Furthermore, there’s the risk that traces of metal will be left behind during the production of medications or food.
The organocatalysts that Drs. List and MacMillan developed, on the other hand, are simple organic molecules that don’t contain any metal atoms. List wondered how enzymes, which are basically long strings of amino acids, enhance reactions. He determined that it was one particular amino acid in the chain, proline, that attracted the reagents and facilitated their engagement. This led him to try using pure proline as a catalyst, and it worked. Meanwhile, MacMillan, who coined the term “organocatalysis,” independently discovered that another small organic molecule, imidazolidinone, also catalyzed a number of reactions. A version of this molecule has been christened “the MacMillan catalyst” and is now widely used.
Furthermore, organocatalysts have the novel ability to carry out “asymmetric synthesis.” This comes into play when dealing with certain molecules that can exist in non-superimposable mirror-image forms — like our hands. The concept was actually demonstrated by Jacobus van ‘t Hoff, the first-ever recipient of the Nobel Prize for Chemistry in 1901. This molecular feature can be particularly important when synthesizing pharmaceuticals in numerous steps. Some of these steps often yield intermediates that can exist in such dual forms, called “enantiomers.” This can be a problem since one of the mirror-image forms may lead to the desired product, while the other produces an undesired, potentially toxic contaminant. Organocatalysts can be used to synthesize only the desired version, which is crucial for the production of medications such as the anticoagulant warfarin (Coumadin), the cancer drug paclitaxel (Taxol), the antidepressant paroxetine (Paxil) and the antiviral oseltamivir (Tamiflu).
Another area where organocatalysts have made a mark is in the pursuit of “green chemistry” which has the goal of designing chemicals, chemical processes and commercial products in a way that avoids the creation of toxics and waste materials. For example, polymerization reactions, used to produce polystyrene and polyvinyl chloride, have traditionally required high temperatures and the use of expensive metal catalysts that cause environmental toxicity. Organocatalysts, on the other hand, are cheap, non-toxic and work at a lower temperature, thereby saving energy.
It has been estimated that about 35 per cent of all the finished goods and services in the world rely on the use of catalysts. There is no question that the discoveries of Drs. List and MacMillan, first published in 2000, have already impacted our lives and will do so even more in the future.
Joe Schwarcz is the director of McGill University’s Office for Science and Society (mcgill.ca/oss). He hosts The Dr. Joe Show on CJAD 800 every Sunday from 3 p.m. to 4 p.m.
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