California Institute of Technology (Caltech) chemists in
the laboratory of Nobel laureate Bob Grubbs have developed a new class of
catalysts that will increase the range of chemicals—from pharmaceuticals,
insect pheromones, and perfume musks to advanced plastics—that can be
synthesized using environmentally friendly methods.
“We have been trying to develop this particular
class of catalysts for about 15 years,” says Grubbs, the Victor and
Elizabeth Atkins Professor of Chemistry at Caltech.
Like the catalysts that earned Grubbs the 2005 Nobel
Prize in Chemistry, the new chemicals include the metal ruthenium and help
drive a chemical reaction called olefin metathesis. That reaction has proven
useful and efficient for making chemical products that involve pairs of carbon
atoms connected by double bonds.
“Our original catalysts have found many
applications,” Grubbs notes, “but one of the deficiencies was the
lack of control of the geometry of the double bond.”
And, indeed, what sets the new class of catalysts apart
is their ability to selectively form products that have a particular geometry.
To understand that geometry, think first of trans fats.
Like other fats, trans fats are essentially chains of fatty acids that contain
carbon-carbon double bonds. The “trans” refers to the geometry or
configuration of groups of atoms with relation to those double bonds—they can
be either trans or cis. If the groups of atoms connected to the carbons of the
double bond are located kitty-corner to each other, they exist in the trans
configuration; if they are on the same side, the bonds are cis double bonds. Natural
fats contain cis double bonds. Trans fats are formed during chemical
processing, and the unnatural fats have been found to be unhealthy.
In most circumstances, trans double bonds are much more
stable than their cis counterparts. Since metathesis is a double-bond forming
reaction that tends to form the more stable product, it primarily forms trans
double bonds. But there are many compounds that scientists and manufacturers
would like to make that include pure cis, rather than trans double bonds. Some desired
compounds that contain cis double bonds are pharmaceutical targets; others make
it possible to manufacture polymers with enhanced properties.
“People haven’t been able to make these cis double
bonds using ruthenium-based olefin metathesis before,” says Myles Herbert,
a graduate student in Grubbs’s laboratory who has been working with the new
catalysts. There are alternative methods for making cis double bonds, but the
most popular tend to generate a lot of chemical waste, making them less
economical and less environmentally friendly than metathesis, which is
considered a green chemical reaction.
Herbert has been focusing on one promising application of
the new catalysts—using them to synthesize insect pheromones. Insects such as
the gypsy moth and the Douglas-fir tussock moth are responsible for massive
deforestation around the world, and others destroy acres of crops. Rather than
using poisonous pesticides to control such populations, farmers are beginning
to attack the problem by spraying their fields with female insect sex
pheromones. Male bugs follow pheromones to locate females; raising the
concentration of those chemicals effectively overwhelms their senses, so they
are unable to find mates.
“These pheromones are all nontoxic, so it would be
great if they could be adapted for use on an industrial scale,” Herbert
says. “Since many of them involve cis double bonds, I’m trying to use the
new catalysts and metathesis to find a shorter synthesis that uses cheaper
materials to make these pheromones.”
A serendipitous discovery
The new class of catalysts was discovered largely by chance. Theoretical work
by William Goddard III, Caltech’s Charles and Mary Ferkel Professor of
Chemistry, Materials Science, and Applied Physics, and his group suggested that
one particular catalyst might yield products with cis double bonds. So while
visiting Grubbs’s laboratory, Koji Endo, from Mitsui Chemicals in Japan, set
about trying to synthesize that catalyst, which was later proven to be
ineffective. However, in the process of trying to make that catalyst, Endo
happened across a very unusual reaction that produced an entirely unexpected
compound, which turned out to be the first in this new class of ruthenium
“We had seen complexes that were reminiscent of this
before, but they always decomposed,” says Grubbs’s graduate student Keith
Keitz, a coauthor on several papers published in the past year describing the
new class of catalysts. “So it was really surprising to us that, first of
all, this was stable, and second, that when Koji threw it in with some of our
standard reaction conditions, this catalyst showed an unprecedented selectivity
for cis double bonds.”
The reaction looked promising, but there was room for
improvement. The first-generation catalyst yielded a mix of products containing
roughly half cis and half trans double bonds (previously, the best catalysts
produced mixtures with 10 times as many compounds with trans double bonds). To
convince synthetic chemists to begin regularly using metathesis to create
compounds containing cis double bonds, the researchers would need a catalyst
that generated cis bonds 80% to 100% of the time. And the catalyst would need
to be reusable, without being used up—that is, have a high turnover number.
Endo’s first catalyst had a turnover number around 50. It also tended to
decompose in solution within about two hours of being exposed to air; an ideal
catalyst would be stable in solution or even on the bench top for days at a
The Grubbs team has now made several versions of the
catalyst and found one that can be used at least 1,000 times and is much more
stable than the original. “We can expose a solution of this to oxygen, and
it will stay alive for more than 12 hours,” Keitz says. “If you just
take a vial of this powder and leave it on the bench, it will be good for over
Going forward, the researchers hope to use the new
catalysts to synthesize large chemical rings, or macrocycles. Macrocycles are
common in chemical fragrances (particularly musks) and are found in
pharmaceuticals used to treat cancer and other diseases. Previous metathesis
catalysts have been used to create trans macrocycles for these purposes, but
the catalysts could not make rings that had a high cis double bond content.
“We’re hoping that our new catalysts will make it possible to synthesize
these compounds using metathesis—a proven green reaction,” says Grubbs.
Over the past year and a half,
the Grubbs group has published several papers in the Journal of the American Chemical Society about these new catalysts.