Holy grails: seeking out selective C–H activation

October 1, 2020

Demonstration of complexity of C-H targets

The sheer number of C–H bonds in the precursor to the antibiotic erythromycin shows just how tricky a task it is to target a single one. The oxidation of a single C–H bond (red) makes erythromycin six times more biologically active than its precursor 6-deoxy erythromycin A – this chemical feat is something that bacteria perform with enviable ease. Source Royal Chemical Society.

In a group of articles published in Chemistry World 25 years ago, the "holy grail" paper on the subject of C-H bond activation was penned by Bruce Arndtsen, Andrew Morley, Thomas Peterson and lead author Robert Bergman from UC Berkeley. They described the selective intermolecular C–H bond activation as chemistry’s ultimate prize.

Notoriously stable carbon–hydrogen bonds are commonplace in almost all organic compounds. Being able to home in on individual bonds and replace a hydrogen with a group of one’s choosing is no mean feat, but it would offer chemists huge power to modify organic molecules at will.

In the decades prior to the Accounts issue, many researchers had established that transition metal complexes could cleave ‘unactivated’ C­–H bonds – those bonds not situated near a heteroatom or an electron-rich carbon­–carbon double or triple bond. The big challenge was to do this selectively and efficiently.

"One thing does stand out about our experiences in those days – it was all stoichiometric chemistry," recalls Bergman. "And I talked to lots of people who said, 'I enjoyed your article, but what we really need is catalytic C–H activation, and this will never be catalytic. Nobody will ever be able to turn this into catalytic chemistry.' Which turned out, of course, to be completely wrong."

The first evidence of catalytic C–H activation in alkanes was discovered in 1969 when Alexander Shilov’s lab at the Institute of Problems of Chemical Physics in Chernogolovka, Russia, showed that a simple platinate system could bring about hydrogen–deuterium exchange in methane and ethane.

In 1982, Bergman and his then postdoc Andrew Janowicz reported another major advance when, for the first time, they directly observed a C–H activation of a fully saturated hydrocarbon by a soluble organometallic system. Their discovery of an iridium complex capable of inserting itself into simple alkanes was quickly followed by a report of a similar system by William Graham’s group at the University of Alberta, Canada.

By the time Bergman was asked to write the holy grail article, several metals had been used in C–H activation. For him, the main aim now would be to create a highly active catalyst able to convert cheap and abundant fossil fuel products like methane into more versatile feedstocks like methanol.

Many researchers, for example the Scripps Institute’s Roy Periana (one of Bergman’s former graduate students), have discovered numerous new systems capable of driving these reactions. But 25 years later, we’re still searching for a catalyst with a high enough turnover to make C–H activation chemistry practical on an industrial scale. However, Bergman stresses that important advances have been made in understanding the catalytic cycles involved. ‘And one of the most important, in my view, is Graham Ball’s work where he’s been able to use NMR spectroscopy at very low temperatures to actually identify and observe alkane–metal complexes, and to make extremely specific decisions about what the structures of the complexes really are.’

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