THIS YEAR’S Nobel prize for chemistry was shared by Benjamin List, of the Max Planck Institute for Coal Research, in Germany, and David MacMillan, of Princeton University. Their prize-winning work, published in 2000, was conducted independently, and unknown to each other at the time, but with the same end in mind. This was to break the stranglehold of enzymes and transition metals on the field of catalysis.
Some chemical reactions proceed with alacrity. Most, though—including many that are industrially important—need a helping hand in the form of a catalyst. Evolution has provided a goodly range of these in the form of enzymes, which are large, complicated and sometimes temperamental protein molecules, but have the advantage that they can create pure versions of what are known as optical isomers. These are molecules which have two forms that are mirror images of each other. That is important in the drug industry, for the different versions, known as enantiomers, can have different effects in the body. Also, if you choose the right enzymes, it is often possible to carry out multi-step reactions in only a few stages.
Transition metals are those found in the middle of the periodic table, such as copper, nickel and iron. The structures of their electron shells are complicated, meaning they are chemically versatile, which is what makes them good catalysts. Some transition-metal catalysts are the metals themselves. More often, they are small molecules that include a transition-metal atom. Transition-metal catalysts can be easier to handle than enzymes, but usually fail to distinguish between enantiomers. Also, the metals involved are frequently toxic, with all the environmental consequences that entails. And multi-step reactions involving them can be longwinded.
Dr List and Dr MacMillan found a way to have the best of both worlds: small-molecule catalysts that have no metal atoms in them, can turn out pure enantiomers, and often simplify multi-step reactions. That has significant industrial implications.
Dr List worked on an enzyme called aldolase A, which catalyses what is known as the aldol reaction, an important way of forging molecular bonds between carbon atoms. Aldolase A is made of 350 amino acids, the building blocks of proteins, but the bit that does the work consists of only three of these: lysine, glutamic acid and tyrosine. The rest of the enzyme is, essentially, packaging. He therefore wondered if he could isolate the enzyme’s active centre and yet preserve its activity. In fact, he did better. He showed that the aldol reaction can be catalysed by a single amino acid, proline. And, crucially, this retains the enantiomeric purity of the enzyme-mediated reaction.
Dr MacMillan came from the other end of the problem. He wanted to remove the metal (in this case copper) from the catalyst involved in a different process, the Diels–Alder reaction. This is a way of joining two molecules into a six-carbon ring. One of the reagents contributes four carbon atoms to the ring and the other contributes two. Six-carbon rings are ubiquitous in organic chemistry, and by putting different side groups onto the reagents a vast variety of them can be turned out. Dr MacMillan found he could catalyse Diels-Alder reactions using a type of metal-free molecule called an imidazolidinone to activate the two-carbon component, meaning that it combines enthusiastically with its four-carbon compadre.
The result of these two pieces of work is a field called asymmetric organocatalysis (the asymmetric part of the name referring to its ability to generate pure enantiomers), that is now rippling through industrial chemistry. And, since industrial chemistry, in one form or another, underpins most economic activity, it is also rippling, however invisibly, through life.