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ACS Catalysis Lectureship Winner Shannon Stahl’s Radical New Tools

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From J. Am. Chem. Soc. 2013, 135, 2357-67

Reprinted with permission from Hoover, J.M.; Ryland, B.L.; Stahl, S.S.  J. Am. Chem. Soc. 2013, 135, 2357-67 Copyright (2013) American Chemical Society

By Ian Mallov, Ph.D., Research Chemist with Inkbox Ink

Here’s a piece of trivia for you: which of the 12 principles of green chemistry has an entire high-impact American Chemical Society (ACS) journal and a lectureship devoted to it?

If you answered principle #9, catalysis, you answered correctly!

In 2011, ACS launched ACS Catalysis, and with it, the ACS Catalysis Lectureship to recognize innovators of this 9th principle in all its myriad forms.

Catalysis is inextricably linked with green chemistry principles 1 and 2: prevention of waste and atom economy. Using a catalyst can often facilitate the choice of a much more atom-economical reactant, reducing waste generated, and present alternatives to toxic or resource-intensive reagents. This is perhaps best exemplified in the simplest redox chemistry: using H2 as a reductant, or O2 as an oxidant.

It is fitting that this past February, the 9th winner of the lectureship honouring advancers of this 9th principle of green chemistry was announced as Professor Shannon Stahl from the University of Wisconsin at Madison. Professor Stahl and his research team were recognized largely for their contributions to oxidation processes using O2 as terminal oxidant, for which Stahl also won a Presidential Green Chemistry Challenge Award in 2014.



Chemical Life Cycle and the Use of Oxidation

“Oxidation reactions are often problematic from a “green” perspective because the reagents often are intrinsically non-green owing to the byproducts they generate,” Stahl says.

Oxidation is, of course, key to a multitude of chemistries at every stage of a chemical life cycle. Every oxygen-containing bulk chemical derived from a petro-feedstock has undergone oxidation. Oxidation is a fundamental tool in fine-tuning chemical structures for use in pharma or materials applications. And, living on earth under our 21% oxygen atmosphere, oxidative degradation mechanisms are ubiquitous.

The contributions of Professor Stahl’s team are, so far, primarily applicable in the middle stages of this chemical life cycle.

To present a classic dilemma: you want to oxidize an alcohol functionality on your molecule to a ketone or aldehyde. As your terminal oxidant, you have several choices commonly available in your organic chemists’ toolbox: classic stoichiometric reagents like chromates and manganates; dimethylsulfoxide via Swern or Parikh-Doering methods; hypervalent iodine reagents. Or, you can use catalytic methods using metals, nitroxyl radicals, or enzymes as catalysts. Some of these use air as terminal oxidant.

The worst of the stoichiometric oxidants both from environmental impact and worker safety perspectives – chromates – are still widely used and taught despite dangers that outweigh their benefits. Hexavalent chromate ions are isostructural to sulfate and phosphate ions. Inside your body, they Trojan-horse their way through sulfate channels into cells, get reduced to trivalent chromium, and complex nucleic acids and proteins, causing mutations that manifest as toxic or cancerous cells.

Kinetic challenges of oxidations often result in the use of strong acids at high concentrations, resulting in dangerous waste that is difficult and resource-intensive to dispose. O2 gas at explosive concentrations, or, where halogenation is desired, toxic chlorine or fluorine gas, pose their own dangers. Literature comparing life cycles of various oxidation agents is scant, but comparing many of these traditional, harsh reagents to, say, air as terminal oxidant offers a stark contrast.

Stahl’s Oxidation Method

Of course, it’s not this simple. However, the thrust of many of Stahl’s oxidation methods is towards using air as a reagent. The aim is for safe, robust, easy and efficient reactions.

A medicinal chemist friend of mine working for a west coast pharmaceutical company told me he actually prefers stoichiometric reagents – “we want something benchtop and weighable” on a small scale, he said. “But I like that there are admixtures (of Stahl’s catalysts) available through MilliporeSigma.”

Much of Stahl’s group’s most widely applied chemistry using air also relies on nitroxyl radical species as oxidants – TEMPO or ABNO. Radicals are often difficult to control, and many are NMR-silent, making detection of leftovers contaminating your end product difficult.

But TEMPO – 2,2,6,6-tetramethylpiperidine-N-oxyl – is no typical radical. Even the acronym implies control – something capable, perhaps, of imposing regularity, order on an unruly unpaired electron or headstrong reaction. Stahl’s group has developed easy methods using TEMPO, the bicyclic nitroxyl radical ABNO, and occasionally other similar species to aid their oxidations. In 2011, they reported a highly effective alcohol oxidation in acetonitrile using catalytic TEMPO, copper(I), 2,2’-bipyridine (bipy) ligand and N-methylimidazole (NMI) with oxygen from ambient air as terminal oxidant. Two years later, they followed up with another study delineating the rather complex mechanism.

The procedures are indeed safe, robust, easy and efficient. So easy, in fact, I’ve used them successfully myself in oxidations of primary alcohols (and I’m no organic chemist). The reagents are cheap and readily available.


From ACS Catal. 2013, 3, 1652-56

Reprinted with permission from Kim, J.; Stahl, S.S. ACS Catal. 2013, 3, 1652-56 Copyright (2013) American Chemical Society

 “Stahl’s radical-mediated oxidation of amines to nitriles”


Since then, using TEMPO or ABNO, Stahl’s group has extended this methodology to an impressive variety of transformations – oxidation of amines, carbamates, oxidative amide coupling. The group also studies other oxidation methods, including iron- or palladium-based catalyst systems and, recently electrochemical oxidations, which Stahl sees as holding promise to overcome many of the current challenges with catalytic oxidation. But it is the radical oxidant methods using oxygen from the air that have gained the greatest popularity so far. The commercial availability of the admixtures brings this tool from the metaphorical toolbox to the literal toolbox – or at least, the lab fridge. Most crucially, the procedures avoid the bane of every nervous senior researcher or manager: the use of highly explosive pure O2 gas by their colleagues.

Green Catalysts as Alternatives

It bears repeating – in 2020, there is absolutely no reason, given the alternatives available, to teach the use of chromates and other extremely dangerous reagents in academia, or to use them in industry.

OK, you say – no stoichiometric chromium, only catalyst and air. But what of the other leftovers from Stahl’s methods? In the case of the Cu/TEMPO systems, active catalyst requires the presence of all four ingredients above: the nitroxyl radical, copper, ligand, and base. Neither copper nor pyridines are generally benign reagents. But it can reasonably be concluded that catalytic amounts of copper-bipy/NMI complexes are preferable to stoichiometric chromate waste. Nature recently reported a study of copper-bipy complexes as anti-tumour and anti-inflammatory agents.

And what of the solvent? Most solvent guides assess acetonitrile as being a middling solvent – indeed, few polar aprotic solvents fare well in green solvent assessments. But acetonitrile is far from the worst offender.

There is only one full life cycle assessment that I have come across using TEMPO-type oxidation methods. But given the rapid development of these practical, efficient protocols by Stahl’s group, one can see that they are worthy of strong consideration as green alternatives. Stahl’s award is for the development of methodologies. It remains to be seen whether these methodologies will be widely scaled for use in industry. However, as Stahl points out, “the commodity chemical industry has learned to deal with O2 as an oxidant, so I don’t think the challenges here are insurmountable.”

The development from publication to commercially-available reagents bodes well for the replacement of some venerable but environmentally troublesome tools in the organic chemist’s oxidation toolbox.


Reprinted with permission from Steves, J.E.; Preger, Y.; Martinelli, J.R.; Welch, C.J.; Root, T.W.; Hawkins, J.M.; Stahl, S.S. Org. Proc. Res. Dev. 2015, 19, 1548-53 Copyright (2015) American Chemical Society

“Reaction vessel for small-scale aerobic oxidations”