The activation of aromatic carbon-hydrogen bonds is a complicated but important business, but NMR spectroscopy has now provided new insights into a new approach with wide potential in synthetic organic chemistry.

Aromatic C-H bond activation is used widely in synthetic chemistry for removing the hydrogen atom from a simple, essentially non-functional C-H grouping and swapping it for a C-C connected functional group, whether that's a single element, such as a chlorine atom, an alkyl chain, an amino group, or something more complicated. Key to successful and controlled activation of the C-H groups in an aromatic molecule is regioselectivity.

Regioselectivity is the preference of a reaction to occur at one bond where several similar bonds might otherwise react too. It is an important part of the design of a synthetic reaction scheme and represents a large part of the design process for drug and pesticide synthesis or the synthesis of natural products. Small changes around an aromatic ring system can have a large effect elsewhere around the system perhaps allowing a functional group to be spliced into the wrong place forming an inactive side-product of the reaction.

For example, the acetamino group (NHCOCH₃) on a benzene ring, the parent being acetanilide, will direct C-H activation to the so-called ortho position, i.e. the neighbouring carbon atom in the benzene ring. This happens in preference to activation at the C-H opposite (para) to the acetamino group or at the carbon atoms neighbouring the para position (meta). C-H activation at the ortho positions is not exclusive, but the formation of one isomer is much favoured over the other possibilities. This was already known (de Vries, 2002).

Undergraduate organic chemists learn various rules and mechanisms to explain how different groups direct such reactions. Most organic chemists will admit, however, that there are discrepancies in any explanation, especially when organometallic catalysts are involved, and exceptions to the rules of regioselectivity make predicting the path any given set of starting materials will take to products very difficult.

Now, John Brown, of the University of Oxford, UK, and his colleagues Waqar Rauf and Amber Thompson, have taken a close look at the underpinnings of regioselectivity. They focused on the formation of synthetically important palladocycle intermediates using NMR spectroscopy and X-ray structure determination. As such, they have gained new insights that could offer a "more complete picture" with which synthetic chemists can work to unravel the complexities of regioselectivity. Brown explains that "too much catalytic chemistry is based on empirical approaches, and we need more predictive power so that rational approaches have more value."

The researchers looked at the effect of both acetanilide (an amide group, CH₃CONH, on a benzene ring) and and  a  related  urea directing group on the activation of a neighbouring trimethylsilyl-aryl bond in the formation of palladacycle intermediates. They found that both groups effectively direct the activation of the TMS-aryl bond, which is normally  inert  to  palladium catalysts. However, close studies of the comparative rates of bond activation in the amide and urea substituted derivatives showed that the presence of urea on the ring greatly enhances the rate of bond activation, showing that urea groups are superior to acetanilides for the direction and enhancement of C-H activation reactions.

The team explains that this new insight not only makes a contribution to C-H bond activation but could have direct application in synthetic chemistry, as the rate limiting step of many palladium catalysed C-H activation reactions is the formation of the palladocycle intermediate. They point out that not only does the presence of the urea group on the starting material accelerate the reaction but it is itself hydrolysed and split off from the final product under accessible reaction conditions, so that once it has done its job of directing the reaction it can be removed without harming the final product.

Brown hopes that further studies of this type will give laboratory and industrial synthetic chemists, "the ability to synthesise simple aromatic compounds with full control of substitution pattern and with gentle reagents."

Related links:

• Chem Commun, 2009, in press
• John Brown

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.