More cross-coupling with less metal

Cross-coupling has been one of the most popular types of reactions in organic chemistry for decades. The pharma and agrochemical industries use these methods on a large scale to forge bonds between aromatic rings. One downside of these classic reactions is that they require one of the coupling partners to be fitted with an organometallic group before the coupling step. 

Methods that let chemists bypass that premetalation step in favor of directly stitching together two aryl halides have been gaining momentum. Such methods could shorten syntheses and cut waste. But they often still require a reductant such as zinc or manganese for the catalytic cycle to work, which can pose safety problems on scale-up.

“These are useful reactions at the discovery level, but they're a little challenging to deploy on scale” because metal reductants can plate onto reactors and cause a fire hazard, says Michael J. Krische of the University of Texas at Austin. “You don't want to do ton scale chemistry using elemental zinc or elemental manganese.”

Krische and his team, along with collaborators at Genentech, the University of Minnesota Twin Cities, and the University of Pittsburgh, may have come up with a cost-effective solution to the problem.

They’ve unveiled a new coupling method that joins an aryl bromide with an aryl iodide using inexpensive sodium formate as a reductant, along with a commercially available palladium catalyst and an iodide source (Nat. Chem. 2025, DOI: 10.1038/s41557-024-01729-0).

Sodium formate is “so cheap it's even used for deicing runways at airports,” Krische says. His team previously deployed it to put a new spin on other classic reactions, such as the Grignard (J. Am. Chem Soc. 2019, DOI: 10.1021/jacs.8b13652) and Heck couplings (J. Am. Chem. Soc. 2023, DOI: 10.1021/jacs.3c09876) before setting their sights on cross-coupling.

The reaction can also handle coupling partners that don’t work as well with other cross-couplings, such as nitrogen-containing rings. And it works with anilines and aryl boronates, which can be used for subsequent Buchwald-Hartwig and Suzuki-Miyaura reactions, respectively.

Krische says the reaction works best on electron-rich aryl iodides and aryl bromides with an adjacent nitrogen or other heteroatom.

The mechanism is also somewhat unusual: the catalyst is a negatively charged complex with two palladium atoms and four iodides. The palladiums cycle between the +1 and +2 oxidation states as they shuffle aryl groups and iodines between the metal centers until the aryl groups are next to each other and can bond together to make the cross-coupled product. “People had never really identified any unique reactivity associated with palladium(I). And this is unique,” Krische says.

Harvard University organic chemist Richard Y. Liu, who was not involved in the project, calls the study “very inspiring work” that “will certainly get a lot of attention from the community.” He adds that the ability to use this reaction in tandem with other coupling methods “really improves its potential for chemical discovery.”

Krische says he and his team will continue working to make the reaction as industry-friendly as possible. For example, they would love to figure out how to make it work with cheaper, greener nickel or cobalt catalysts.