Today’s talk by MIT chemist Richard Schrock was about a discovery that was applied in part to a long-standing chemical problem. There was no efficient method for forming large molecular rings until Robert Grubbs from Caltech and Schrock arrived on the scene. The method that accomplished this was called olefin metathesis. For their achievement, Schrock and Grubbs shared the Nobel Prize in 2005 with French chemist Yves Chauvin. Just as the Nobel Prize for GFP was long anticipated in the community of biochemists, the Nobel Prize for metathesis had been long anticipated in the community of organic chemists. Nobody was surprised when Grubbs and Schrock received it.

To see why the work was so obviously important, imagine a long line of people trying to make ends meet and hold hands. To make the picture much more complicated, imagine that these people are buffeted around by winds blowing at 80 miles an hour. What are the chances that a stable configuration in which they form a ring will arise? Clearly there are many more possibilities for them to not form a circle and assume all kinds of random configurations rather than form a circle. This examples serve as an analogy for the concept of entropy in organic chemistry. The same problems arise when you are trying to get two ends of a long chain of carbons to come together. There are many more ways for them to stay apart and only one way for them to bond to each other, so ordinarily they prefer the latter. The one ordered configuration has much less entropy than the many different disordered ones and is therefore not preferred. In addition the “winds” in this case consist of thermal energy at room temperature and energy from the surrounding solvent that constantly keep the ends of the ring apart from each other.

Schrock and Grubbs’s work dramatically improved this situation. Coming back to our original example of people forming a link, now imagine that Mr. Fantastic from the Fantastic Four suddenly materializes and now extends his remarkably long arms to hold each end of the human link together. Now what are the chances that Mr. Fantastic can hold on to the two ends and tie them together, even when winds are buffeting the assembly? Much better. This is exactly what Schrock and Grubbs did. They used a metal that essentially tied together two ends of the carbon chain. The metal was bound to organic molecules or ligands that carefully controlled the size and orientation of the reactants, leading to specific products. The assembly then underwent a chain of reactions that bonded the two ends of the chain to each other. Essentially the bonds were swapped with a bond that the metal formed with one of the ligands. Yves Chauvin shared the prize with Shrock and Grubbs because even though the fundamental reaction had been known since 1956, nobody had been able to write down the correct mechanism for it; many proposals were put forth, but only Chauvin’s proposal which was written in 1971 turned out to be the correct one.

40 years of chemical research before the 1990s had failed to discover an effective method of making large organic rings, in spite of famous chemists such as Nobel Laureate Vladimir Prelog working on the problem. Of course the earlier chemists also did not have the tools of organometallic chemistry necessary at their disposal. The development of olefin metathesis had to await the development of organometallic chemistry which took place in the last 30 years. And Grubbs and Schrock had to wait Chauvin’s work which actually told them how the reaction proceeds. This is how scientists build on each other’s work.

However the problem is not just limited to making rings. It can be used in case of separate molecules which want to bond to each other. Here the problem is often worse because unlike the ring, there are now two separate entities and it is even more difficult to bring the two in proximity. The metal catalysts that the chemists developed can also be used effectively in this case. The necessary requirement (although by no means sufficient) is simply that the molecules in question contain a carbon-carbon double bond. Another important detail concerns the stereochemistry or ‘handedness’ of the product molecules. Stereochemistry is an integral part of chemical design, and modern drug and polymer development would be unthinkable without considerations of stereochemistry. Both Grubbs and Schrock made it possible to get very high yields of stereochemically pure products using chiral ligands that bound to their metals. These exhaustive studies were critical to the pragmatic utility of the metathesis reaction.

The Russian-born British philosopher and writer Isaiah Berlin classified scientists and thinkers into two categories; hedgehogs and foxes. Hedgehogs drill down deep and stick with one problem for years. Foxes sniff around interesting problems and work in a variety of fields. Both hedgehogs and foxes have made important contributions to science. For instance, Max Perutz who worked on the structure of hemoglobin essentially for his entire fifty-year career was a hedgehog par excellence. Herbert Simon who made major contributions to economics, political science and computer science was an extraordinary fox.

Both Grubbs and Schrock are quintessentially hedgehogs. They stuck with the metathesis problem for twenty years and conducted patient and careful work that dealt with details such as making air and moisture-stable catalysts, improving the yields of the reactions, dealing with a variety of different substrates and modulating the stereochemistry of the products using a wide diversity of ligands of varying size. This was made clear during Schrock’s talk today. Their incremental success was reported in a string of important papers. The incremental progress gradually led to a robust and outstanding paradigm for conducting organic reactions. At the same time their work was helped by foxes like Giulio Natta, J. Osborn and Thomas Katz who had intermittently worked in investigating the reaction during their career

Chavin, Grubbs and Schrock’s work is a model example of scientific discovery. You think of an outstanding problem and stay with it for years, even if it means that you spend most of the time working out details which can seem mundane. It is these mundane details that ultimately will make a significant contribution to the field. Not everyone who follows this path will win a Nobel Prize. But everyone who does it will have the satisfaction of truly applying himself or herself to a problem and experiencing the joy (and frustration!) of facing unexpected challenges that appear in their journey. Every young researcher attending the Lindau meeting should look forward to such a challenge.