Researchers have upped the ante on carbon-hydrogen bond activation by transforming two adjacent C–H bonds in one reaction. Tristan Lambert and Tao Shen at Cornell University used a mix of light and electrochemistry to convert neighboring C–H bonds on simple hydrocarbons to cyclic amine and diamine derivatives, molecules often found in useful drug compounds (Science, 2021, DOI: 10.1126/science.abf2798). This rare double activation method offers a new path to synthesizing valued molecules and a relatively simple way to create powerful catalysts.
Very few double C–H functionalizations are known, mainly because activating one C–H bond tends to make the surrounding C–H bonds less reactive. The key was turning on the trisaminocyclopropenium ion catalyst first through electrochemical oxidation, then with white light, Lambert says. This oxidation-first approach makes the catalyst energetic enough to activate both C–H neighbors but allowed the researchers to apply a current below the threshold that would oxidize the ethane reactants. “This gives you the potency of this massively oxidizing, excited state intermediate,” Lambert says.
The team can also control its products by changing the electrolyte. In lithium perchlorate, the compound adds an acetonitrile from solution, then reacts internally to form a cyclic aziridine compound (shown, bottom). If the electrolyte is tetrabutylammonium fluoride, the ethane adds first one, then a second acetonitrile to form a dihydroimidazole (shown, top). With its strategy, the team was able to synthesize over 65 compounds, including a variety of drug-molecule analogues. This suggests that the technique is useful for late-stage functionalization, a way to add functional groups to existing molecules instead of making them from scratch.
The reaction does a 4-electron oxidation of the ethane, which shows the true power of using electrochemistry, says David Nicewicz, a photochemist at the University of North Carolina at Chapel Hill. If the team had used a chemical oxidant, “they would need a truckload,” he says. “In this case, they just need a current.”