OLEFIN METATHESIS: BIG-DEAL REACTION
A boon to organic synthetic chemists, olefin metathesis also promises cleaner, cheaper, and more efficient industrial processes
Olefin metathesis is a popular and useful reaction. In the presence of certain transition-metal compounds, including various metal carbenes, olefins exchange the groups around the double bonds, resulting in several outcomes: straight swapping 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), polymerization of cyclic olefins (ring-opening metathesis polymerization), and polymerization of acyclic dienes (acyclic diene metathesis polymerization).
The power of olefin metathesis is that it transforms the carbon-carbon double bond, a functional group that is unreactive toward many reagents that react with many other functional groups. With certain catalysts, new carbon-carbon double bonds are formed at or near room temperature even in aqueous media from starting materials that bear a variety of functional groups. The catalysts are available commercially, making the reaction accessible even to novice researchers.
|LARGE SCALE Olefin metathesis is key in the production of linear olefins at the Geismar, La., facilities of Shell Chemicals.
SHELL CHEMICALS PHOTO
Use of olefin metathesis in organic synthesis has been directly correlated to improvements in metal-carbene catalysts. The chemists most responsible for developing such catalysts are chemistry professors Robert H. Grubbs at California Institute of Technology and Richard R. Schrock at Massachusetts Institute of Technology.
The so-called Grubbs and Schrock catalysts were developed through focused research programs going back to the 1970s. In the mid-1980s, Schrock came up with highly reactive systems based on tungsten and then on molybdenum. The latter were less reactive and therefore more selective in reacting with olefins rather than with other functional groups.
With more-selective catalysts at hand, people began using them in organic chemistry. In 1992, for example, Grubbs and MIT chemistry professor Gregory C. Fu, then a postdoc in Grubbs's lab, used what is now widely known as the Schrock catalyst in ring-closing metathesis to form oxygen and nitrogen heterocycles. In a spectacular example, a team led by Boston College chemistry professor Amir H. Hoveyda used the same catalyst in 1995 in a stereospecific 14-membered macrocyclization in the enantioselective total synthesis of an antifungal compound. This application set the stage for use of olefin metathesis to close big rings carrying many functionalities.
Many people credit the ruthenium catalysts of Grubbs with putting olefin metathesis in the forefront of organic synthesis. The ruthenium compounds have high preference for carbon-carbon double bonds and are indifferent to alcohols, amides, aldehydes, and carboxylic acids. More important, their use does not require stringent conditions, Grubbs says. They can be used by organic chemists applying standard techniques. Vacuum lines and dry boxes, which are needed when working with Schrock's molybdenum catalysts, are not necessary.
The first of Grubbs's ruthenium catalysts was prepared in 1992. It had good functional group tolerance but limited activity. Further refinements led in 1996 to the catalyst (PCy3)2Cl2Ru5CHC6H5 (Cy=cyclohexyl), which is now widely known as the Grubbs catalyst. Three years later, Grubbs introduced an even better ruthenium catalyst, the so-called second-generation Grubbs catalyst. Here, one of the tricyclohexylphosphines of the Grubbs catalyst is replaced with an N-heterocycle ligand.
Since the Grubbs catalyst was introduced in 1996, it has found many uses in organic synthesis. The groups of both Samuel J. Danishefsky, a chemistry professor at Columbia University and director of the Laboratory for Bioorganic Chemistry at Memorial Sloan-Kettering Cancer Center in New York City, and K. C. Nicolaou, a chemistry professor at Scripps Research Institute and the University of California, San Diego, used the catalyst in the synthesis of epothilones.
At the University of Wisconsin, Madison, chemistry professor Laura L. Kiessling is using the Grubbs catalyst to prepare carbohydrate-containing polymers with significant biological activities. At MIT, Peter H. Seeberger, an assistant professor of chemistry, is using the same catalyst to cleave linkers in solid-phase oligosaccharide synthesis. And at Tohoku University in Japan, olefin metathesis catalyzed by the Grubbs catalyst was a key step in the total synthesis of the natural product ciguatoxin by chemistry professor Masahiro Hirama.
"Today, this powerful reaction provides solutions to many synthetic puzzles and has the potential to do so in the future for myriad others."
PHOTO BY ROBERT J. PAZ
PHOTO BY GRETCHEN KAPPELMANN
NEW EXAMPLES continue to appear in the literature. Hoveyda says the ruthenium catalysts are used more often than the molybdenum catalysts because they are easier to handle. He says he works with both: "When we need high reactivity, we go with molybdenum. When we can run reactions under mild conditions, we use ruthenium. They are the two wings of the same angel. The angel can't fly if you clip either one."
At present, one of the most exciting areas in olefin metathesis is enantioselective catalysis. In 1993, Schrock reported the first application of a chiral molybdenum carbene in ring-opening metathesis polymerization. In 1996, Grubbs used a different chiral molybdenum carbene and applied it to a nonpolymeric reaction.
Schrock and Hoveyda began a collaboration to develop asymmetric catalysts for olefin metathesis in 1997 and within a year reported the first examples of efficient asymmetric olefin metathesis with a chiral catalyst, also based on molybdenum. Last year, Grubbs reported the first chiral ruthenium catalysts. And earlier this year, Hoveyda reported a different chiral ruthenium catalyst that is not only highly selective but also highly recyclable.
Olefin metathesis is "marvelous in the hands of the synthetic chemist," Nicolaou says. "Today, this powerful reaction provides solutions to many synthetic puzzles and has the potential to do so in the future for myriad others."
The buzz of olefin metathesis is heard not only in research labs among chemists applying the reaction to complex syntheses. In industry, olefin metathesis is also causing a stir with its promise of cleaner, cheaper, and more efficient processes.
Industrial interest in olefin metathesis has not waned since the reaction's discovery by industrial chemists (see page 34). Johannes C. Mol, a chemistry professor at the University of Amsterdam, in the Netherlands, has been following the industrial uses of olefin metathesis. He summarizes the current industrial uses of olefin metathesis in a chapter of the book "Novel Metathesis Chemistry," to be published early next year.
Industrial production of olefins is based on cross-metathesis using heterogeneous catalysts. From 1966 to 1972, Phillips Petroleum was making ethylene and 2-butene from propylene, a process known as the Phillips triolefin process. Because olefin metathesis is a reversible reaction, propylene can be produced from ethylene and 2-butene. The process, known as olefins conversion technology (OCT), is currently used by Lyondell Petrochemical and will be operational at BASF Fina Petrochemicals by the end of 2003, according to Mol.
"Global demand for propylene is high," Mol says. For this reason, petrochemical companies are converting ethylene and butene from naphtha crackers to propylene. Mol says Mitsui Chemicals will start up an OCT unit in Japan in August 2004, and Shanghai Secco Petrochemical is scheduled to start up an OCT unit in 2005. Petrochemical Corp. of Singapore is considering use of OCT to increase its propylene capacity.
1-Hexene and neohexene (3,3-dimethyl-1-butene) are also made by cross-metathesis. In the U.S. and England, Shell Chemicals can produce up to 1.2 million tons of linear higher olefins per year from ethylene through the so-called Shell Higher Olefins Process, in which cross-metathesis is a key step.
ON THE OTHER HAND, most olefin-metathesis-derived polymers are made with complex homogeneous systems. Commercial polymers produced industrially by ring-opening metathesis polymerization include polyoctenamer, polynorbornene, and polydicyclopentadiene (PDCP), Mol says.
The new homogeneous catalysts such as those developed by Grubbs and Schrock do not yet play a major role in these industrial scenarios. For PDCP production, however, the Grubbs ruthenium technology is now being made available by Materia, a small company based in Pasadena, Calif., that was founded by Grubbs and others in 1997. The robust catalysts are enabling various applications, and some products are beginning to emerge.
According to Richard A. Fisher, Materia's vice president for marketing and business development, Grubbs's ruthenium catalysts allow polymerization to occur in the presence of fillers, additives, stabilizers, and other ingredients in a polymer formulation. "You can formulate the polymer any way you like," he says. Ruthenium technology also produces castable or moldable polymer formulations, which make it easy to fabricate complex parts.
||STOP A 1.5-inch-thick polydicyclopentadiene resin prepared with ruthenium technology is impenetrableto 9-mm bullets.
PHOTO BY CHRIS CRUCE
Materia has licensed the PDCP-by-ruthenium technology to Easton Sports, a manufacturer of sporting goods based in Van Nuys, Calif. In Japan, Hitachi Chemical is marketing Metathene, a polymer produced by ruthenium technology, for various applications including bathroom fixtures.
The homogeneous catalysts will play a greater role in industry in the future, Mol says. "Many companies are interested in developing processes with preformed carbenes, because they are extremely active," he adds.
Just how active the catalysts are is evident from a recent study by Mol and colleague Maarten B. Dinger using a new Grubbs-type catalyst they developed. They find unprecedented turnover numbers of up to 640,000 in olefin metathesis of neat substrates at room temperature, compared with 21,000 for the Grubbs catalyst and 100,000 for the second-generation Grubbs catalyst [Adv. Synth. Catal., 344, 671 (2002)]. "The technology to develop processes for homogeneous catalysis is more complicated," Mol says, "but if you can make it work, you get far more efficiency."
According to Mol, another area where olefin metathesis may be applied industrially is oleochemistry. The conversion of oleochemical feedstocks into products by olefin metathesis would be environmentally friendly, he notes. Raw materials are from renewable resources. Products, derived from natural oils and fats, would be easily biodegradable. Reactions would be atom efficient because all the metathesis products would be useful. And processes would have not only low energy requirements but also low potential for accidents, because they could proceed under mild conditions.
The oleochemical industry should seriously consider olefin metathesis, Mol suggests in a paper published earlier this year [Green Chem., 4, 5 (2002)]. Examples of products that could be made more efficiently with olefin metathesis are macrocyclic compounds such as civetone, the ingredient in musk perfumes; 1-triacontanol, a plant growth stimulant; intermediates such as unsaturated diesters or dicarboxylic acids and v-unsaturated esters; and various polymers.
In the fine chemicals arena, use of olefin metathesis technology is also being spearheaded by Materia. The company was originally called Advanced Sports Materials, to reflect the goal of developing commercial applications of ring-opening metathesis polymerization in sporting goods and recreational equipment. The company's name was changed in 1998 to reflect the wider commercial opportunities for olefin metathesis, says Richard L. Pederson, Materia's director of fine chemicals R&D.
Materia's technology platform includes the olefin metathesis catalysts of Grubbs, Schrock, and Hoveyda. In addition, Materia is commercializing technology based on organic catalysts developed by Caltech chemistry professor David W. C. MacMillan for enantioselective transformations. The four academics are scientific advisers of Materia.
"OUR GOAL is to use metathesis technology in current applications where the traditional methods have been unable to perform well," Pederson says. A good example is synthesis of insect pheromones, which are useful as environmentally friendly pest-control agents.
Pheromones are chemical signals. Through a sex attractant pheromone, female insects attract mating partners. If the compounds are introduced in the field at concentrations that saturate the sensory organs of the males, the males are confused and mating is prevented. Disruption of the normal mating cycle leads to a decline in the target insect's population without harming other insects.
However, pheromones have been very expensive to produce by traditional synthetic methods, Pederson says. "You could not make them less expensive without a whole new approach," he tells C&EN. And that's when he turned to olefin metathesis. With the help of Grubbs, he invented olefin-metathesis-based routes to various pheromones.
Materia now has registered with the Environmental Protection Agency three insect pheromones: (E)-5-decenyl acetate, a pheromone of peach twig borer (Anarsia lineatella); a mixture of (E)- and (Z)-11-tetradecenyl acetate, of omnivorous leafroller (Platynota stultana); and a different mixture of (E)- and (Z)-11-tetradecenyl acetate, of Sparganothis fruit worm, a pest of cranberries and blueberries.
Materia also has commenced field-testing (5R,6S)-6-acetoxy-5-hexadecanolide, the mosquito oviposition pheromone. Female mosquitoes of the genus Culex release this compound when they lay eggs to attract other pregnant females to the site. The pheromone may help combat the spread of West Nile virus, which is transmitted by Culex mosquitoes. The pheromone will be used in traps that will kill ensnared insects.
According to Pederson, olefin metathesis offers efficient routes to these compounds from cheap raw materials, such as low-molecular-weight alkenes and plant oils. "Because metathesis is an equilibrium reaction, you use an excess of the inexpensive starting material to force the equilibrium to the product side," he explains. "Any starting materials that don't react, we isolate and reuse in the next reaction."
The metathesis reactions do not usually give ratios of the E- and Z-isomers that are effective in the field. Enrichment is achieved through a proprietary crystallization technique, Pederson says. In the case of the omnivorous leafroller pheromone, however, metathesis produces the ratio that the insect requires.
Sales of some pheromones can reach up to 2,000 kg per year, Pederson says. "Materia can produce these quantities at its Pasadena facilities. In two years, we project annual pheromone sales of about $2.5 million."
In the pharmaceutical field, Materia is working on active ingredients that can be made through the complementary capabilities of olefin metathesis and MacMillan's chemistry. MacMillan has developed asymmetric, metal-free molecules that catalyze a broad range of reactions, producing chiral products in high yields and high enantiomeric excess. The key substrate in these reactions is an ,-unsaturated aldehyde.
,-Unsaturated aldehydes are easily made through olefin metathesis. "Give me an olefin and crotonaldehyde, and we can make exotic and novel substrates for MacMillan that are laborious to make by other methods," Pederson says. "The synergism is very nice. MacMillan's chemistry takes us beyond the double-bond exchange, allowing us to make more-value-added compounds."
For example, MacMillan has demonstrated this synergy in a route to (S)-ketorolac. Ketorolac is an anti-inflammatory drug that has been used as a racemic mixture. An efficient route to only the active enantiomer could prove profitable to drug companies. A key pyrrole intermediate is prepared by MacMillan chemistry from an ,-unsaturated aldehyde produced by cross-metathesis between crotonaldehyde and allyl benzoate [Adv. Synth. Catal., 344, 728 (2002)].
Materia has begun developing a route to Paxil, GlaxoSmithKline's blockbuster antidepressant that is susceptible to generic competition (C&EN, Sept. 23, page 37). The key intermediate p-fluorocinnamaldehyde has been prepared efficiently through cross-metathesis of p-fluorostyrene and crotonaldehyde.
Other projects are under way. For example, Materia now offers chiral indole building blocks and will soon launch a line of chiral heterocyclic derivatives. "We have many other ideas. We're trying to grow with the revenue we generate so that we can go after other opportunities with this technology," Pederson says.