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The field of C-H bond activation is being revolutionized in a way
that would never have been anticipated five years ago. Influential
papers are appearing which not only challenge existing ideas of what is
possible, but which also offer technical advances. Paper #8 describes
the successful catalytic cross-coupling of two different aromatic
compounds using a palladium catalyst. What is particularly surprising
is the way this catalyst can distinguish between different aromatic C-H
bonds.
The paper comes from Keith Fagnou and David Stuart of the
Center for Catalysis Research and Innovation at
the University of Ottawa, Canada (figure to the left). It promises
to revolutionize synthetic arene chemistry and might well become
important commercially because molecules with linked arene groups
appear in several guises. They are part of light-emitting diodes,
liquid crystals, and pharmaceutical compounds.
Bonding together two molecules with aromatic rings (arenes) is not
easy, and a great deal of effort has gone into ways to do this. These
have involved activating the two rings, for example by the addition of
a halide to the point of contact on one ring and putting an
electropositive group on the other. Even the production of these
preliminary reactants, however, may require several stages, and this
means lower overall yields and the generation of unnecessary waste in
the form of solvents, catalysts, and reagents.
Fagnou and Stuart’s method dispenses with the formation of
activated reactants and uses a catalyst that will do the job directly
and selectively. It results in the desired cross-coupling product and
does not promote the reaction of each arene with itself. The reaction
investigated was the attachment of a benzene ring to an indole
derivative. The type and position of the group attached to the indole
was varied, and this could result in yields as high as 84%. When
microwave heating was used it cut reaction times from 48 to 5 hours.
Various catalytic conditions were tried and an optimal activity was
achieved with palladium(II) trifluoroacetate in combination copper(II)
acetate, 3-nitropyridine and cesium pivalate (aka
2,2-dimethylpropionate). The catalyst appears to be a palladium(II)
species and the 3-nitropyridine is thought to play a role in
stabilizing palladium(0) which is generated at the end of the catalytic
cycle prior to its being re-oxidized to active palladium(II) by the
copper salt. The role of cesium pivalate was less clear, but Fagnou
speculates that it could assist in the formation of a palladium(II)
pivalate complex which might be involved at some stage.
Reaction products were analyzed by gas chromatography-mass
spectrometry, which showed that one product was the dominant one: the
benzene ring attached to the indole carbon at position 3, while the
other product, in which the benzene was attached to the alternative
position 2, accounted for 10% or less. The product with two benzenes
occupying both positions 3 and 2 accounted for at most 4%, and that was
observed only in a few reactions. There was no evidence of the coupling
of indole to indole or benzene to benzene.
As Fagnou tells Science Watch: "One of the biggest challenges
associated with the oxidative arene cross-coupling reaction described
in our paper is that the catalyst must establish regiocontrol at both
of the aromatic coupling partners. We also found that by making minor
modification to the substrate and reaction conditions, a complete
change in regiochemistry could be produced." (See D.R. Stuart, et
al., J. Am. Chem. Soc., 129: 12072, 2007.)
What alerted Fagnou to the potential of palladium(II) catalysts to be
so selective was a study of the direct arylation of perfluorobenzenes;
that work was published in J. Am. Chem. Soc. (M. Lafrance,
et al., 128[27]; 8754-6, 2006). He says his team are now
looking at the fundamental physical parameters governing reactivity,
using newly acquired knowledge to establish new chemical
transformations.
As Fagnou observes, "Instead of asking how we might change the
substrate in order to achieve a desired reaction, we are holding the
organic components as invariable, and striving to modify only the
catalyst and the reaction conditions. My hope is that 20 years from
now, reactions at unactivated C-H bonds will be taken for granted, just
as we take much of the available reactivity at modified substrates for
granted today."
Dr. John Emsley is based at the Department of Chemistry,
Cambridge University, U.K.
KEYWORDS: C-H BOND, ARENE MOLECULES, ARENE CHEMISTRY, ARENES, AROMATIC
COMPOUNDS, CROSS COUPLING, PALLADIUM CATALYST, KEITH FAGNOU, DAVID
STUART.