The challenge the team set out to solve is one of the deepest in catalysis. Ethane, the second-largest component of natural gas, is held together by carbon–hydrogen bonds that are among the least reactive in chemistry. Breaking one of these bonds selectively, and then persuading the resulting fragment to bond with a carbon monoxide molecule rather than simply burning to carbon dioxide or over-oxidizing into a soup of byproducts, has defeated generations of catalyst designers. Conventional approaches rely on high temperatures that push reactions toward complete combustion, destroying precisely the selectivity that makes a process commercially attractive.

The new work, led by Qi Lu of Tsinghua University together with Bingjun Xu of Peking University and Mu-jeng Cheng of National Cheng Kung University, sidesteps this problem by splitting the catalytic labor between two distinct chemical roles of the same metal. Adsorbed oxygen species on an oxidized copper surface are responsible for activating ethane, abstracting a hydrogen atom to create a surface ethyl species. Meanwhile, copper ions released from the surface oxide into the acidic solution form carbonyl species with dissolved carbon monoxide, and it is at the interface between these two worlds that the crucial carbon–carbon bond forms.

Carbon monoxide plays a double role in this scheme, and that dual function is central to the reaction’s unusual selectivity. It serves as the C1 building block that is inserted into the ethane-derived fragment, ultimately delivering the carboxylic acid functionality of propionic acid. But it also acts as a selectivity-directing agent, intercepting the reactive ethyl intermediates before they can drift into unproductive oxidation pathways. By capturing the C–H activation intermediate quickly, CO essentially funnels the chemistry toward a single desired product rather than the mixture of alcohols, aldehydes and acids that typically plagues partial oxidation of light alkanes.

The experimental evidence for this mechanism is unusually thorough. The team used isotopic labelling to confirm that both the two-carbon skeleton of the product derives from ethane and the single added carbon from carbon monoxide, ruling out alternative carbon sources. In situ surface-enhanced infrared and Raman spectroscopies, techniques the group has refined in earlier studies of carbon monoxide electroreduction on copper, allowed the researchers to watch copper carbonyl species and surface ethyl intermediates directly on the working catalyst. Density functional theory calculations performed by the Cheng group in Tainan provided the energetic underpinning, showing that interfacial coupling between the copper carbonyl and the ethyl species is feasible under the mild conditions of the experiment.

The performance numbers tell a story of deliberate trade-offs. At propionic acid formation rates of up to 120 micromoles per gram of copper per hour, the selectivity settles at around 50 percent. When the team tuned conditions to slow the rate, selectivity climbed to its optimum of 83 percent, indicating that the competing pathways can be suppressed at the cost of throughput. This rate–selectivity relationship is a familiar feature of partial oxidation chemistry, but the fact that both ends of the trade-off are respectable at ambient temperature is what distinguishes the result. The researchers suggest that the strategy establishes CO-mediated alkane carbonylation under mild conditions as a genuine synthetic platform for organic acid production.

The intellectual lineage of the work stretches back decades. Carbonylation, the insertion of carbon monoxide into metal–carbon bonds, is the backbone of some of the largest industrial processes on Earth, most famously the methanol-to-acetic acid route that feeds global demand for one of the most important commodity chemicals. Applying carbonylation to saturated hydrocarbons, however, has required either superacidic media, precious metal catalysts or harsh temperatures. Early hints came from work in the 1970s showing that copper(I) carbonyl cations could carbonylate saturated hydrocarbons in strong acids, and more recent studies have explored carbonylation of alkanes over zeolites and via photocatalytic hydrogen atom transfer. The new study brings these threads together in a heterogeneous, aqueous system that operates at room temperature.

Copper’s starring role is itself notable. The metal has enjoyed a renaissance in catalysis over the past decade, particularly in electrochemistry, where oxide-derived copper electrodes proved capable of converting carbon dioxide and carbon monoxide into multicarbon products such as ethanol and acetate. That literature established that copper carbonyl species on oxidized copper surfaces can engage in carbon–carbon bond formation, and the present work transplants that insight from electrochemistry into a purely chemical, oxygen-driven setting. The researchers’ earlier investigations into how carbon monoxide coverage governs coupling on copper surfaces clearly informed the design of the new reaction, illustrating how mechanistic understanding in one field can seed breakthroughs in another.

The sustainability implications are considerable. Ethane is abundant, cheap and often flared or simply burned as fuel in regions far from petrochemical infrastructure. Converting it directly into propionic acid, a preservative, feed additive and chemical intermediate currently produced largely through petrochemical routes, would add value to a stranded resource while avoiding the energy intensity of steam cracking or high-temperature oxidation. Running the reaction in dilute acid with molecular oxygen as the terminal oxidant, rather than stoichiometric oxidants or precious metals, keeps the reagent palette inexpensive and environmentally benign. The authors acknowledge that the current rates, while scientifically impressive, remain far from industrial scale, and that catalyst durability and reactor engineering will need attention before any commercial translation.

What makes the result resonate beyond its immediate application is the demonstration that the most inert bonds in organic chemistry can be tamed at ambient conditions when activation and functionalization are assigned to different, cooperating chemical environments on a single catalyst. The interfacial coupling concept, in which a surface-bound alkyl fragment meets a solution-phase carbonyl species precisely at the boundary between oxide and liquid, offers a design principle that could extend to methane, propane and other light alkanes. If the strategy generalizes, the humble copper surface, working quietly at room temperature, may become the stage on which natural gas is rewritten into the building blocks of the chemical industry.

Subject of Research: Room-temperature catalytic coupling of ethane and carbon monoxide to synthesize propionic acid over copper

Article Title: Propionic acid synthesis via room-temperature coupling of ethane and CO

Article References: Hou, J., Liu, W., Wang, K.-H., Li, M., Wen, S.-C., Cheng, M.-J., Xu, B., & Lu, Q. (2026). Propionic acid synthesis via room-temperature coupling of ethane and CO. Nature Synthesis. https://doi.org/10.1038/s44160-026-01168-4

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01168-4

Keywords: catalysis, copper catalyst, ethane, carbon monoxide, propionic acid, carbonylation, C–H activation, selectivity, mild conditions, organic acids, sustainability, heterogeneous catalysis

The reaction relies on alkyl sulfonylhydrazides as the alkyl donors, a class of reagents that the team found can release alkyl radicals under remarkably gentle conditions. Conventional directed C–H alkylation protocols typically depend on alkyl halides or other electrophiles that demand elevated temperatures, strong bases, or aggressive activators to enter the catalytic cycle. By swapping in sulfonylhydrazide-derived donors, the researchers sidestepped that energetic barrier entirely. The hydrazide framework fragments to generate the carbon-centred radical directly, which is then captured within the nickel catalytic cycle, allowing the entire sequence to proceed below 50 degrees Celsius while remaining redox-neutral and operationally simple.

Directing groups sit at the heart of the strategy. The substrates carry an amide-type directing group that coordinates to nickel and positions the metal catalyst adjacent to the target C–H bond, enabling selective activation of the C(sp2)–H bond in arenes and heteroarenes. This chelation-assisted approach enforces site selectivity, so the alkylation occurs predictably at the position dictated by the directing group rather than at whichever reactive site happens to be most accessible. The team demonstrated the method on more than seventy examples, spanning simple benzamides through to heavily decorated heterocycles of the kind that populate the internal libraries of pharmaceutical companies.

The heterocycle compatibility is perhaps the feature that will resonate most strongly with practitioners of medicinal chemistry. Nitrogen-containing rings such as pyridines, pyrimidines, and related azines are ubiquitous in approved drugs, yet they are notoriously problematic substrates for metal-catalysed C–H functionalization because the ring nitrogen poisons many catalysts or redirects reactivity in unwanted ways. The Scripps team showed that the sulfonylhydrazide–nickel combination tolerates a wide range of these heteroaromatic systems, opening a practical route to alkylated heterocycles that previously required multi-step sequences or gave poor yields under existing protocols.

Beyond simple primary alkyl groups, the method accepts complex secondary alkyl donors, including fragments derived from elaborated building blocks, which dramatically expands its utility. Late-stage functionalization experiments demonstrated that the reaction can be performed on molecules already bristling with functional groups, appending an alkyl unit to a sophisticated scaffold without disturbing esters, ethers, halides, or other sensitive motifs. The researchers also applied the chemistry in the context of natural product synthesis, underscoring that the transformation is not merely a curiosity of model substrates but a genuinely useful tool for constructing molecules of real structural and biological complexity. The reaction was shown to be scalable, a further indication of its practical character.

Underpinning the synthetic scope is a mechanistic picture that the team assembled through a combination of experimental probes and computational analysis. Density functional theory calculations, alongside mechanistic experiments, point to an asynchronous, amine-assisted C–H activation pathway. Rather than proceeding through a single, synchronous transition state in which the C–H bond breaks in concert with metal–carbon bond formation, the activation appears to unfold in a stepwise, nonsynchronous fashion, with an amine component of the catalyst system assisting the deprotonation or proton-shuttling events that accompany metalation. This asynchronous character lowers the energetic cost of C–H cleavage, helping to explain why the reaction succeeds at such low temperatures where classical concerted metalation–deprotonation pathways would stall.

The choice of nickel as the catalyst metal is itself significant. Nickel has earned a reputation as the spirited workhorse of modern cross-coupling, prized for its abundance relative to palladium and its unusual willingness to engage radical intermediates. In this system, the sulfonylhydrazide-derived alkyl radicals are intercepted within the nickel manifold, and the mechanistic studies suggest that radical capture and C–H activation are choreographed within a single catalytic framework. The chemoselectivity observed across the substrate screen—where the reaction finds the directed C–H bond even in the presence of multiple potentially reactive sites—highlights how the interplay between the directing group, the nickel complex, and the gently generated radical donor produces a reaction that is both fast and discerning.

The broader context of this work is the long-running effort in the pharmaceutical industry to escape flatland. Decades of analyses of approved drugs and clinical candidates have shown that molecules richer in three-dimensional character, with more saturated carbon frameworks, tend to enjoy better clinical success rates, improved solubility, and more favourable promiscuity profiles. Yet most robust cross-coupling chemistry remains oriented toward joining flat fragments: aryl to aryl, aryl to vinyl. Methods that reliably weld sp2 ring systems to sp3 alkyl fragments remain comparatively scarce, and those that exist often require photoredox catalysts, electrochemical apparatus, elevated temperatures, or electrophilic alkyl halides that are themselves unstable or difficult to prepare. A thermal, redox-neutral, nickel-catalysed protocol that works below 50 degrees Celsius represents a meaningful addition to that limited toolbox.

The sulfonylhydrazide donor chemistry builds on recent demonstrations that these reagents can serve as a general redox-neutral platform for radical cross-coupling, but the present study extends that logic into the domain of directed C–H activation, where the substrate itself dictates where the new bond forms. The combination is powerful: the directing group provides the site selectivity, the nickel catalyst provides the bond-forming machinery, and the hydrazide reagent provides the alkyl fragment under the mildest possible activation conditions. Because the donors are straightforward to prepare from the corresponding hydrazines and carbonyl or sulfonyl precursors, practitioners can access a diverse panel of alkyl partners without exotic reagent synthesis.

For the synthetic community, the practical implications are immediate. A chemist seeking to methylate, ethylate, or append a branched alkyl group to a pyridine or benzamide scaffold can now contemplate a single-step operation conducted on a warm hotplate rather than a high-thermal or photochemical setup. The demonstrated scalability means medicinal chemistry campaigns can generate gram quantities of alkylated analogues for structure–activity studies, while the late-stage compatibility means proven lead compounds can be diversified without rebuilding them from scratch. As mechanistic understanding of amine-assisted, asynchronous C–H activation deepens, the design principles uncovered here are likely to inform the next generation of mild, selective, and sustainable C–H functionalization methods, bringing the long-promised efficiency of direct C–H chemistry closer to routine practice in laboratories focused on discovering the medicines of tomorrow.

Subject of Research: Mild nickel-catalysed directed C(sp2)–H alkylation of (hetero)arenes using alkyl sulfonylhydrazide radical donors

Article Title: Chemoselective Ni-catalysed directed C(sp2)–H alkylation at low temperature using alkyl sulfonylhydrazides

Article References: Wang, S., Cagan, D. A., Cao, Y., Vokits, B. P., Palkowitz, M. D., Kawamata, Y., Baran, P. S., & Engle, K. M. (2026). Chemoselective Ni-catalysed directed C(sp2)–H alkylation at low temperature using alkyl sulfonylhydrazides. Nature Synthesis. https://doi.org/10.1038/s44160-026-01158-6

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01158-6

Keywords: nickel catalysis, C–H activation, C–H alkylation, sulfonylhydrazides, radical cross-coupling, heterocycles, late-stage functionalization, medicinal chemistry, organometallic chemistry, directing groups, Nature Synthesis, asynchronous mechanism