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David Bradley ISSUE #66
June 2007
Bonding Solution
Keith Fagnou

The formation of molecular bonds between carbon atoms is fundamental to life on earth as well as the manufacture of countless products on which civilization depends from selective agrochemicals to potent pharmaceuticals and from polymers and plastics to the synthesis of the components of nanotechnology.

However, for a century, chemists have puzzled over how to make unreactive molecules, such as unactivated arenes hook up. Now, Canadian researchers have found the solution.

Vancomycin contains the biaryl unit

Graduate student David Stuart, of the University of Ottawa, working with Keith Fagnou, has devised a novel catalyst to bring together so-called biaryls. These molecules lie at the heart of organic light emitting diodes (OLEDs), electron transport devices that mimic photosynthesis and other natural processes, and the liquid crystals found in modern computer displays and TVs. The biaryl chemical unit is also present in a wide-range of pharmaceuticals, one out of every twenty, approximately, including the last-resort antibiotic vancomycin and the cancer drug Glivec.

The reason it is so difficult to join together unactivated arenes to form a biaryl unit in any given molecule, is that arenes prefer to go it alone because they have an intrinsic stability and so are only very unwilling reactants. In order to make them interact with each other, chemists usually have to modify each individually to reduce their stability and make them more reactive. They must then find the right reaction conditions to make them join in molecular wedlock. Commonly, a halogen atom (a chlorine or fluorine) is added to pull electrons out of one of the pair of stable arene rings and so make it more reactive, and a catalytic metal-containing unit added to the other to make it actively seek out the other potential partner.

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All this modification, destabilization, and functionalization requires numerous additional reaction steps beyond simply getting the two unadulterated arenes to conjoin. It also produces a toxic metal halide byproduct that is difficult to recycle or dispose of. Researchers have for the last several years being finding slicker ways to join arenes together, but until now modification of at least one partner has been required.

Now, Stuart and Fagnou have found a catalyst that will promote the joining of two essentially unmodified arenes without all the fuss and far less waste. This they say will offer industry a much more environmentally friendly and cheaper way to create the ubiquitous biaryl group for the vast range of products for which it is needed.

Stuart describes the technicalities of the development: "We have used palladium, in conjunction with a copper oxidant, to catalyze the cross-coupling of N-acetylindoles and benzenes in high yield and high regioselectivity across a range of indoles without recourse to activating groups." In other words, they can join two simple arenes?an indole and a benzene?without the extraneous reactions and obtain large quantities of exactly the product they were after?the biaryl. The team suggests that their approach could be used to make a wide range of such compounds.

Science, 2007, 316, 1172-1175; http://dx.doi.org/10.1126/science.1141956

Science, 2007, 316, 1131-1132; http://dx.doi.org/10.1126/science.1143373

http://www.chem.uottawa.ca/prof/Fagnou/default.htm

http://www.chemspider.com/RecordView.aspx?id=14253

Inchi for Glivec InChI=1/C29H31N7O/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)
24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,
14-17,20H2,1-2H3,(H,32,37)(H,31,33,34)/f/h32,34H