Understanding the unexpected role of ligands in metal catalysed C-H activation shows that synthetic chemist may need to think quite differently

US researchers have elucidated the unusual reaction kinetics of C-H activation by the palladium(II) catalyst (Pd(OAc)2). Surprisingly, only catalyst concentration appears to affect the reaction rate, while reactant concentration either has no effect or suppresses the reaction. Understanding this mechanism could help the design of more efficient C-H catalysts for industry, including pharmaceuticals. 

C-H bonds in complex molecules are typically unreactive and therefore breaking them easily and efficiently poses a challenge for synthetic chemists. Transition metal catalysts have been shown to selectively activate these bonds with the addition of ligands but a lack of mechanistic studies has restricted the development of catalyst-ligand systems that could improve reactivity and positional selectivity.

"The catalyst seems to be the only variable driving this reaction forward!" - Donna Blackmond

Recently, Jin-Quan Yu and colleagues at The Scripps Research Institute, La Jolla, US, found that Pd(II)-catalyzed olefinations in the presence of mono-N-protected amino acid ligands provided higher yields in significantly shorter reaction times.1 However, it was not understood how this reaction worked.   

In collaboration with Donna Blackmond, also at Scripps, the team has now elucidated the mechanism for one of the reaction steps, namely the ortho-C-H olefination of phenylacetic acids using Pd(OAc)2

’We have shown and rationalized for the first time the unusual concentration dependences in this reaction -  typically reaction rates increase as reaction concentrations are increased (positive order kinetics), and this, along with catalyst concentration, provides the "driving force" for the reaction,’ says Blackmond.    

Using ReactIR spectroscopy and nuclear magnetic resonance spectroscopy, the team monitored the reaction progress in situ and found that the mono-N-protected amino acid ligands activate the metal catalyst by suppressing the substrate from forming of a stable mixed acetate species, which is a sink for catalysis. This accounts for the observed acceleration of the reaction.2     

’Our temporal analysis was able to show that one of the two substrates has no effect on the rate, while the other actually suppresses the rate, as does the reaction product,’ explains Blackmond. ’The catalyst seems to be the only variable driving this reaction forward!  Our combined kinetic and spectroscopic work helps to understand this unusual situation.’    

’Thorough mechanistic studies into Pd(II) catalysed oxidative C-H bond activation processes are particularly welcome,’ comments Ian Fairlamb, a catalysis expert at the University of York, UK. ’This study improves our mechanistic understanding and will greatly influence the design of future ligand scaffolds for Pd(II), particularly in catalytic oxidative C-H bond activation olefination reactions and related processes.’ 

’CH activation is such an important reaction motif in a number of areas of chemistry, so fundamental mechanistic understanding is vital for improving catalysts and designing new reactions for pharmaceuticals, materials, polymers, and other chemicals,’ adds Blackmond. 

James Urquhart