Ground-breaking synthesis

Print edition : November 18, 2005

Yves Chauvin. - ALAIN JOCARD/AFP

Yves Chauvin, Robert H. Grubbs and Richard R. Shrock win the Nobel Prize for Chemistry for the development of the metathesis method used in organic synthesis which has great significance for the development of pharmaceuticals to combat a range of diseases including cancer and HIV/AIDS.

THE element carbon is central to life on the earth and much of the chemical substances found in nature. Carbon has the fantastic ability to combine or bond with other carbon atoms as also with elements such as hydrogen, oxygen, chlorine and sulphur Its single, double or triple bonds can form long and small chains, branched structures or rings of different forms and sizes. The chemistry built around the extraordinary versatility of carbon is known as organic chemistry and its reactions basically involve breaking and forming bonds.

Synthetic chemists bring together groups of different molecules in the laboratory in various ways either to reproduce compounds found in nature more efficiently or to produce new compounds by exploiting carbon's versatility cleverly. Thus far they have explored only a small fraction of this huge world of organic compounds. But this science of organic synthesis,which industries use in a big way, has already given us a great variety of drugs, agrochemicals, cosmetics, materials, coatings and so on.

Figure 1 depicts compound A being synthesised from compound B in the presence of a catalyst. (A catalyst is a substance which enables a process to occur quickly and/or more efficiently but itself remains unchanged at the end of the reaction.) Compound B is a long chain of carbon atoms in which one carbon atom has been replaced by an oxygen atom. In compound A, however, the long chain has become a large ring and this ring endows A with anti-cancer activity. This reaction has created two new double bonds (= =) in compound A from the two double bonds (= =) at the terminals of the open chain in compound B . One double bond makes the chain close in on itself by joining the end carbon atoms to form a ring molecule. The other double bond becomes part of the by-product, which in this particular reaction is ethylene.

The above process uses what is called catalytic metathesis, a technique to achieve selective organic synthesis. Synthesising the large ring in any other way is a very complicated process and would involve many more reaction steps. The developers of this method - one French and two American scientists - share this year's Nobel Prize in chemistry. Metathesis - meta (change), thesis (place) - means `change places'. In the metathesis of olefins (also called alkenes, which have a carbon chain with double bonding) the double bonding atom groups exchange places with one another. For example, in the metathesis reaction involving two propylene molecules shown in Figure 2 (known as the Phillips triolefin process), one of the molecules trades its CH{-2} group for the CH{-3}CH group in the other in the presence of a catalyst to form butene and ethylene, a hitherto unknown transformation also called `disproportination' of propylene.

Since the 1950s many such reactions that produced new substances have been discovered but the precise reaction mechanism and the role of the catalyst at the molecular level were not known. Yves Chauvin at the Institut Frane, France, provided an understanding of how the catalyst functioned in metathesis. This provided a basis or recipe for scientists to construct new efficient catalysts. Robert H. Grubbs of the California Institute of Technology and Richard R. Shrock of the Massachusetts Institute of Technology discovered a class of novel compounds of elements known as `transition metals' in the 1970s and 1980s that could selectively catalyse many desired and important metathesis reactions. In particular, these included what are called metal carbenes (also called alkylides, where metal atoms are bound to carbon with double bonds). These catalysts are now available commercially, making metathesis one of organic chemistry's most important reactions. It has opened up new vistas in the industry for producing new molecules; in pharmaceuticals, for example. The catalyst used in the metathesis reaction to produce the anti-cancer compound, in fact, is one of the catalysts discovered by Grubbs.

Robert Grubbs.-GRUBBS FAMILY/AP

Following the discoveries of new catalysts by Grubbs and Shrock, different types of olefin metathesis have become possible: straight exchange of groups between two acyclic olefins (cross metathesis), closure of large rings (ring-closing metathesis), formation of dienes from cyclic and acyclic olefins (ring opening metathesis), polymerisation of cyclic olefins (ring opening metathesis polymerisation), polymerisation of acyclic dienes (acyclic diene metathesis polymerisation) and so on. The power of olefin metathesis, as an article in Chemical and Engineering News put it, is that it transforms the carbon-carbon double bond (C = C), a functional group that is otherwise unreactive towards many reagents that react with many other functional groups. Olefin metathesis now enables the creation of new carbon-carbon double bonds at or near room temperature in aqueous forms from starting materials that bear a variety of functional groups. With constant improvements in the Grubbs-Shrock class of catalysts over the last two decades, use of olefin metathesis in organic synthesis, particularly in industrial applications, has grown rapidly.

Catalysed olefin metathesis, like many other discoveries in organic chemistry, was first observed by industrial chemists in the 1950s and 1960s. This was triggered by the observation of polymerisation of ethylene by Ziegler in the early 1950s. In 1956, Herbert S. Eleuterio at DuPont's petrochemical department in Delaware, United States, discovered that a certain molybdenum-on-aluminium catalyst could achieve olefin polymerisation; that is an unsaturated polymer with double bonds. He found that olefin ethylene could be polymerised into olefin polyethylene in this way where earlier attempts had produced only saturated polymers (with no double bonds). In a similar experiment with cyclopentene, Eleuterio told Chemical and Engineering News, "the polymer I got looked like somebody took a pair of scissors, opened up cyclopentene, and neatly sewed it up again."

In 1960, chemists at Standard Oil Company discovered that the use of molybdenum oxide on alumina treated with the catalyst tri-isobutyl aluminium achieved the Phillips process described above. Phillips petroleum itself observed the same process when the catalyst molybdenum hexacarbonyl was used on alumina. Suddenly industry was patenting many such baffling reactions that could not be explained by known chemistry of olefins at that time. Much later, in 1967, Nissim Calderon at Goodyear Tyre and Rubber Company, U.S., saw the connection between the above two processes. They showed that they were essentially the same type of reaction and called it olefin metathesis. However, it was still not clear how the catalyst worked at the molecular level. The race to find newer catalysts entirely by trial and error had begun as it became clear that metathesis had unleashed a great potential in organic synthesis.

Though many explanations were put forward, including one by Grubbs himself in 1972-73, the breakthrough came in 1971 when Chauvin and his student Jean-Louis Herrison suggested that the catalyst was a metal carbene. Chauvin proposed an entirely new mechanism for how the compound functioned as a catalyst in the reaction. In fact, if people had been aware of the French work, other explanations like that of Grubbs, which came later, may not have been made at all. Although it took several years before Chauvin's explanation was experimentally verified and widely accepted, it gave the field "a chance to move away from its state of alchemy", in the words of K.C. Nicolau, a Chemistry Professor at the University of California, San Diego.

According to Chauvin, three papers published in 1964 led him to the hypothesis of a metal carbene. The first was by E.O. Fischer (Nobel laureate, 1973) from the University of Munich who discovered a new type of tungsten-carbon compound, now called tungsten-carbene. The second one was a paper by Giulio Natta (Nobel laureate, 1963) from Milan Polytechnic describing the ring opening polymerisation of cyclopentene with tri-ethyl aluminium and tungsten hexachloride. The third was the disproportionation of propylene by Phillips researchers mentioned earlier. "Apparently these papers had nothing in common," Chauvin told Chemical and Engineering News, "but for me, they were a revelation." Chauvin had the insight that they were the same reaction and, therefore, must involve the same type of intermediate species.The paper of Fischer suggested to him that these species could be metal carbenes.

"It was a Sunday afternoon," Chauvin recalls in his interview to the Nobel Foundation after the announcement of the Prize. "The weather was bad and all of a sudden I said - Oh yes, it is obvious. Voila, as simple as that. But that happens to lots of others in science, that is, while you are resting that great ideas come to you.." Chauvin and his co-workers also presented experimental support for the mechanism, which could not be explained by other proposed mechanisms that were around at the time. However, for several years after Chauvin's paper, there was no consensus on the mechanism as a view prevailed that the available data did not preclude other mechanisms as well.

Many subsequent researches, notably those by Grubbs and Shrock, Thomas J. Katz at Columbia, Michael Lappert at Sussex, C.P. Casey and T.J. Burkhardt at Wisconsin, soon began to provide supportive evidence for Chauvin's hypothesis. The metal carbene mechanism is now generally accepted for metathesis where the exchange between metal carbene and olefin is the fundamental step. It explained at one stroke all earlier outcomes of olefin metathesis.

The Chauvin mechanism suggests that one could just synthesise metal carbene compounds and let them react as catalysts with olefins. For instance, Lappert discovered rhodium-based catalysts and Casey developed tungsten-based catalysts. Chauvin, however, left the scene soon after. It was the subsequent work of people like Grubbs and Shrock that has had such a dramatic impact on modern organic synthesis, a process that is ongoing.

Early on, while the tremendous potential of metathesis could be seen, its exploitation was proving to be difficult. Traditional catalysts were sensitive to air and moisture. Their usefulness was limited by side-reactions and relatively short lifetimes. Realising the promise of metathesis required identifiable, relatively stable compounds that would serve as longlife catalysts and, more importantly, whose reactivity could be "tweaked" for the desired task. In addition, they had to be selective - only react with double bonds and leave other parts of the molecule intact. The problem was that none of the well-defined metal carbenes acted as catalysts in olefin metathesis.

Enter Shrock and Grubbs. Shrock had begun research on metal carbene complexes in the 1970s. His systematic studies using different metals such as tantalum, tungsten and molybdenum led to an understanding of what metals could be used and how they functioned. He identified molybdenum and tungsten as the most suitable metals, but zeroing in on the appropriate groups that would bind with the metals to yield stable and active catalysts required a long-drawn search. He achieved the breakthrough in 1990 when he found a whole family of very active, well-defined and practicable molybdenum and tungsten carbene complexes that acted as catalysts for metathesis.

Richard Schrock.-BRIAN SNYDER /REUTERS

With this discovery and the catalysts' commercial availability, widespread use of olefin metathesis in general-purpose organic synthesis started to happen as it could replace many of the traditional methods of synthesis. At the same time, it permitted entirely novel approaches to the synthesis of new molecules. Molybdenum catalysts are sensitive to oxygen and moisture but properly treated ones, as exemplified by Shrock's, have become very powerful tools in organic synthesis.

Grubbs came up with his breakthrough finding in 1992 when he and associates discovered a catalyst with the metal ruthenium. It was stable in air and showed higher selectivity but lower reactivity than Shrock's catalysts. Grubbs' catalysts could also initiate metathesis in the presence of other functional groups like alcohols, water and carboxyl acids. The 1992 catalyst was further improved upon to arrive at very effective metathesis catalysts that are easy to fabricate. Indeed, Grubbs' catalysts have become the first well-defined catalysts for general metathesis applications in ordinary laboratories.

His latter ruthenium catalyst - named Grubbs' catalyst - has become a standard with which all new catalysts are compared. The general applicability of this catalyst has given rise to immense future possibilities of organic synthesis, in research as well as in industry. With its greater thermal stability, this new ruthenium catalyst is also available commercially. Grubbs has continued the development of ruthenium-based catalysts - whose designs are based on detailed mechanistic studies - into more powerful tools for synthesis, including that of polymers with special properties.

Further refinements, which go by the name of Second Generation Grubbs' catalysts, have given higher reactivity and are the most used catalysts for efficient cross-metathesis reactions. In fact, the vibrancy field opened up by these two is such that rarely a month passes without the announcement of a new catalyst for metathesis applications.

In the short span of about a decade of their development, the breadth of applications that the catalysts discovered by Shrock and Grubbs have spawned is indeed remarkable. Metathesis has great potential in the pharmaceutical industry, the biotechnology industry and in the food-processing industry. Novel applications include synthesis of insect pheromones (traditional methods are very expensive), herbicides, additives for polymers and fuels, and special-property polymers. There is new research aimed at developing pharmaceuticals for a wide array of diseases such as bacterial infection, hepatitis C, cancer, Alzheimer's disease, Down's Syndrome, osteoporosis, arthritis, inflammation, fibrosis, HIV/AIDS, migraine and so on, in which metathesis has become a major tool for synthesis.

The development of these new catalysts has meant that processes in the chemical industry can be made more efficient. Metathesis applications now involve fewer reaction steps, fewer resources and less wastage. The methods are also simpler to use because they are stable in air and at normal temperatures and pressures and environmentally friendlier as the processes now use non-injurious solvents, and less hazardous waste products are produced. Thus the work of the laureates is equally significant for paving the way of the future towards `green chemistry'.

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