Carbon-carbon bond formation is the backbone of organic synthesis, and the reactions that accomplish it define what molecules are practically accessible. Bonds between two sp3-hybridised carbons, the tetrahedral carbons that give molecules their three-dimensional shape, are particularly valuable. Saturated, three-dimensional frameworks are strongly associated with success in drug development, a trend famously described as escaping flatland, because flat, aromatic-rich molecules often suffer from poor solubility and off-target effects. Yet while chemists have become adept at stitching together flat sp2 carbons through classic cross-coupling chemistry, the alkyl-alkyl variant remains far more difficult, because the reactive intermediates involved are short-lived and prone to unproductive side reactions.

One powerful way to make sp3-sp3 bonds is radical chemistry. Radicals, species bearing an unpaired electron, are notoriously reactive, which makes them both useful and dangerous in a synthesis flask. When two radicals meet, they can combine to form a new carbon-carbon bond, a process known as radical-radical cross-coupling. The catch is controlling the encounter. Most successful strategies to date rely on pairing a persistent radical, one that survives long enough to accumulate in solution, with a transient radical, one that lives for only a fleeting moment. The persistent radical effect then steers the chemistry toward selective cross-coupling rather than a chaotic mixture of products. Directly coupling two transient radicals, both generated from separate precursors, has remained a formidable challenge.

There is one venerable exception: Kolbe electrolysis, first described by Hermann Kolbe in 1849. In this electrochemical process, carboxylic acids are oxidised at an anode, losing an electron and releasing carbon dioxide to generate carbon-centred radicals that then dimerise. Kolbe electrolysis is one of the few methods capable of directly coupling two transient radicals, but it works best when both radicals come from the same or very similar carboxylic acids. Getting radicals from two chemically distinct precursors, say a carboxylic acid on one side and a boronic acid on the other, to meet and combine selectively has largely been out of reach, because the two precursors oxidise at different potentials and their radicals tend to react with themselves rather than with each other.

The Northwestern team’s solution rests on two intertwined ideas. The first is redox-matched alternating-polarity electrolysis. Instead of applying a constant current in one direction, the researchers alternate the polarity of the electrodes, so that each half-cycle generates one type of radical under conditions matched to its own oxidation chemistry. This waveform control allows carboxylic acids to be oxidised to alkyl radicals during one polarity phase, while organoboron reagents are activated during the complementary phase, giving both radical pools a chance to coexist and combine. Alternating current electrolysis has been gaining momentum in organic electrosynthesis precisely because it lets chemists run incompatible oxidative and reductive events in the same vessel, and the team’s earlier mechanistic work on alternating-polarity electrolysis for carbon-centred radical generation laid the groundwork for the present advance.

The second idea is controlled activation of redox-active species through fluoride. Organoboron reagents are not normally easy to oxidise directly, but the researchers used controlled fluoride activation to tune the redox behaviour of the boronic acids, making them competent radical precursors under the electrolysis conditions. Cyclic voltammetry studies, an electrochemical technique that maps out at which potentials molecules gain or lose electrons, helped the team identify the redox-matched window in which both precursors could be activated without one simply overwhelming the other. By carefully choreographing electrode polarity and chemical activation, the method achieves what conventional constant-current electrolysis cannot: a productive meeting of two transient radicals born from entirely different functional groups.

The scope of the transformation is what makes the result more than an electrochemical curiosity. The researchers demonstrated the cross-coupling of alkyl carboxylic acids with alkyl boronic acids to form sp3-sp3 carbon-carbon bonds, exactly the connectivity that is prized in drug-like scaffolds but difficult to access. They also showed that the platform extends to homocoupling reactions, in which two identical fragments are joined, and to a net carboxylic acid-alkene cross-coupling. In the latter variant, an alkene is first converted in situ into an alkyl boronic acid through hydroboration, the addition of a boron-hydrogen bond across the double bond, and the resulting boronic acid then enters the electrolytic coupling. This effectively lets chemists use cheap, widely available alkenes as radical precursors without isolating the intermediate.

Perhaps most striking is the way the new chemistry dovetails with established catalytic reactions. The team showcased tandem processes in which the electrochemical radical coupling is combined with Suzuki coupling, the palladium-catalysed workhorse reaction that joins boronic acids with aryl halides, and with Buchwald-Hartwig amination, which forms carbon-nitrogen bonds. This means a single molecular sequence can build a carbon-carbon bond electrochemically and then diversify the product through trusted catalytic steps, multiplying the value of each starting material. For medicinal chemists, who routinely need to prepare families of closely related analogues to optimise a drug candidate, such downstream diversification from a common carboxylic acid-boronic acid coupling product is exactly the kind of flexibility that accelerates discovery.

The significance of the work lies in the feedstocks as much as in the chemistry. Carboxylic acids and organoborons are among the most plentiful and well-behaved functional groups in the synthetic repertoire, stable enough to store and handle, and available in enormous structural variety. Electrochemistry itself has undergone a renaissance in the past two decades, because electricity can serve as a clean, tunable oxidant or reductant, replacing stoichiometric chemical oxidants and offering precise control over reaction outcomes through potential and current. By merging waveform-controlled electrolysis with rational redox matching, the Northwestern group has pushed that renaissance into territory that classical methods, including more than a century and a half of Kolbe chemistry, could not reach.

There remain practical considerations before such methods become routine. Alternating-polarity electrolysis requires equipment and optimisation that many synthetic laboratories are still adopting, and the interplay of electrode material, supporting electrolyte, solvent and waveform parameters demands careful tuning for each new substrate combination. The mechanistic picture, probed through cyclic voltammetry and experimental studies of radical generation, will continue to be refined as the community explores the boundaries of the approach. Nevertheless, the demonstration that two transient radicals from distinct, abundant precursors can be generated in the same pot and persuaded to couple selectively marks a genuine expansion of what electroorganic synthesis can do. For a field whose ultimate goal is to make any desired molecule efficiently, sustainably and in three dimensions, the ability to weld carboxylic acids and organoborons together with nothing more than electrons is a milestone worth watching.

Subject of Research: Electrochemical radical-radical cross-coupling of alkyl carboxylic acids and organoboronic acids

Article Title: The radical-radical cross-coupling of alkyl carboxylic acids and organoborons

Article References: Zhong, J., Boudjelel, M., Evans, J. M., Vanswearingen, I., & Malapit, C. A. (2026). The radical-radical cross-coupling of alkyl carboxylic acids and organoborons. Nature Chemistry. https://doi.org/10.1038/s41557-026-02237-z

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02237-z

Keywords: electrochemistry, radical cross-coupling, carboxylic acids, organoborons, Kolbe electrolysis, C(sp3)-C(sp3) bonds, organic synthesis, alternating polarity electrolysis, Nature Chemistry, synthetic methodology, persistent radical effect, medicinal chemistry

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