Spirocyclic frameworks are polycyclic structures in which two rings share exactly one carbon atom, known as the spiro centre. Because the two ring systems attached to that atom adopt an orthogonal arrangement, perpendicular to one another in space, the resulting molecules are rigid and distinctly three-dimensional. That geometry is not merely an aesthetic curiosity. It underpins the function of optoelectronic and hole-transporting materials, guides the design of ligands for coordination complexes, and appears repeatedly in the architecture of numerous natural products. Controlling how two molecular fragments are joined at a single shared atom is therefore a central problem for chemists working across these fields.

The most direct conceptual strategy for building a spiro skeleton is to introduce a single carbon atom that joins two components, effectively acting as the linchpin of the spiro centre. In practice, however, that has proven remarkably difficult. Previous carbon-atom-transfer approaches have largely relied on the reactivity of π-bonds, the double and triple bonds that are inherently reactive and easy to engage in chemical transformations. Carbon–carbon σ-bonds, the single bonds that form the backbone of essentially all organic molecules, are far more inert. Controlled insertion of a carbon atom into such σ-bonds has remained a stubborn challenge in synthetic chemistry, and the new report directly addresses that gap.

The key to the breakthrough is a combination of two components: a rhodium catalyst and a reagent called N-isocyanoiminophosphorane, abbreviated PINC, which serves as an atomic carbon equivalent. Isocyanide-based reagents of this type have been developed as sources of bare carbon atoms that can be delivered under catalytic control, and the Osaka team harnessed PINC to supply the single carbon atom that becomes the spiro centre. Rather than attacking a π-bond, the reaction engages carbon–carbon σ-bonds through a sequence of C–C bond activation steps orchestrated by the rhodium catalyst.

The substrates at the heart of the study are biphenylenes, strained polycyclic molecules in which two benzene rings are fused in a way that imposes significant angular strain. That strain makes their carbon–carbon bonds unusually susceptible to activation by transition metals, which is precisely why the researchers chose them as the testing ground for σ-bond spirofusion. In the reported reaction, the rhodium catalyst sequentially activates C–C bonds of the biphenylene framework, and the carbon atom delivered from PINC is inserted so that the two molecular units are joined at a newly formed spiro centre. The net result is the conversion of comparatively simple biphenylene substrates into complex spirocyclic structures.

What makes the transformation striking from a bond-counting perspective is its efficiency: a single catalytic sequence forms four new carbon–carbon bonds at the spiro centre. Constructing four C–C bonds in one operation is rare in organic synthesis, and doing so while installing the defining feature of a spiro framework, the shared orthogonal carbon atom, represents an unusually economical way to build molecular complexity. The single carbon atom delivered by PINC acts as the central linchpin around which the entire three-dimensional architecture is assembled.

The versatility of the method extends beyond joining identical partners. The researchers demonstrated both homo-spirofusion, in which two identical biphenylene units are joined, and cross-spirofusion, in which two different biphenylenes are combined at a single spiro centre. The ability to couple unlike partners greatly expands the structural diversity accessible with the reaction, because chemists can mix and match molecular fragments to tune the properties of the resulting spirocyclic product. Cross-couplings of this kind are typically harder to achieve than homocouplings, since the catalyst must discriminate between different substrates, making this aspect of the work particularly significant for practical applications.

The team also showed that the strategy is not confined to σ-bond activation alone. The reaction can be extended to processes that combine σ-bond and π-bond activation, broadening the scope of the chemistry beyond biphenylene–biphenylene coupling. This flexibility suggests that the catalytic carbon-atom-transfer concept could serve as a general platform for spirocycle construction, with the rhodium catalyst and the PINC carbon source operating together to stitch together molecular fragments through whichever bond types are most appropriate for a given target structure.

The significance of the work lies in establishing a catalytic strategy for constructing structurally complex spirocyclic frameworks through C–C σ-bond activation, a mode of reactivity that had long resisted controlled exploitation. Because spirocyclic motifs appear in optoelectronic and hole-transporting materials, in ligand design for coordination complexes, and in numerous natural products, a method that assembles them directly from σ-bonds could influence fields well beyond synthetic methodology. Rigid, orthogonal three-dimensional scaffolds are increasingly valued in molecular design, and the ability to generate them by inserting a single carbon atom between two preformed fragments offers a concise and modular approach.

The research, conducted in the Department of Applied Chemistry at the Graduate School of Engineering of The University of Osaka, with Fujimoto and Tobisu also affiliated with the Innovative Catalysis Science Division of the Institute for Open and Transdisciplinary Research Initiatives, was published as a peer-reviewed article carrying the DOI 10.1038/s41586-026-11242-8. Correspondence for the study is handled by Hayato Fujimoto and Mamoru Tobisu. As with any newly reported catalytic method, the coming years will show how broadly the rhodium-catalysed, PINC-mediated spirofusion can be applied across different substrate classes, but the conceptual advance is clear: carbon–carbon σ-bonds, the most ubiquitous bonds in organic chemistry, can now serve as entry points for catalytic carbon-atom transfer, and a single carbon atom can serve as the linchpin that locks two molecular worlds together at a right angle.

Subject of Research: Rhodium-catalysed insertion of atomic carbon into C–C σ-bonds to construct spirocyclic frameworks

Article Title: Catalytic transfer of carbon atoms enables spirofusion of C–C σ-bonds

Article References: Fujimoto, H., Mizutani, M., Imachi, K., Nishioka, T., Ikeda, R., & Tobisu, M. (2026). Catalytic transfer of carbon atoms enables spirofusion of C–C σ-bonds. Nature. https://doi.org/10.1038/s41586-026-11242-8

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11242-8

Keywords: spirocyclic frameworks, carbon atom transfer, C–C σ-bond activation, rhodium catalysis, biphenylene, N-isocyanoiminophosphorane, homogeneous catalysis, synthetic chemistry methodology, cross-spirofusion, organometallic chemistry, molecular architecture, The University of Osaka

The central innovation lies in where the chemistry happens. Traditional approaches to modifying polyethylene either treat the polymer uniformly, which alters its bulk properties, or rely on harsh, unselective surface treatments such as flame or plasma oxidation, which can degrade the material and produce surfaces whose properties fade over time. The Berkeley team instead performed their reaction at a solid–liquid interface, where the solid polyethylene meets a liquid reaction medium containing the catalyst and oxidant. Because the polymer chains are locked in place as a solid while the reagents arrive from the liquid side, the reaction is naturally confined to the surface region. The interior of the plastic, which the reagents cannot easily reach, remains pristine.

The chemistry itself is remarkable for its selectivity and efficiency. The method converts methylene units, the repeating CH2 groups that form the backbone of polyethylene, into ketones, which are carbonyl-containing functional groups that dramatically increase surface polarity. What makes this conversion extraordinary is the catalyst loading: just 0.001 mole percent of an iron catalyst is sufficient, meaning a single catalytic turnover handles an enormous number of polymer C–H bonds. Iron is abundant, inexpensive, and far more benign than many precious metals commonly used in catalysis, which matters enormously for a process aimed at commodity materials. The reaction proceeds below 80 degrees Celsius using inexpensive oxidants, conditions that are mild enough to avoid melting or degrading the polymer.

Selectivity is the word that separates this work from earlier attempts at polyethylene functionalization. When a polymer is functionalized in a uniform medium, functional groups are distributed throughout the material, and even a modest degree of modification can disrupt crystallinity, lower the melting temperature, and weaken tensile strength. The new method sidesteps this trade-off entirely. Because oxidation occurs only where the solid polymer contacts the liquid reagent phase, the resulting materials show enhanced surface properties while maintaining bulk properties such as melting temperature and tensile strength. In practical terms, the plastic becomes sticky on the outside without becoming weak or heat-sensitive on the inside.

The performance gains reported are striking. Polyethylene functionalized at the solid–liquid interface adheres to polar surfaces up to 90 times more strongly than pristine polyethylene. Even more telling is the comparison with conventional bulk functionalization: at a comparable level of modification, the interface-treated material sticks up to four times more strongly than polyethylene functionalized uniformly in solution. This advantage arises because the ketone groups are concentrated exactly where they are needed, at the surface, rather than diluted wastefully through the bulk where they compromise mechanical properties without contributing to adhesion.

The researchers went further, demonstrating that the surface ketones are not merely an endpoint but a versatile chemical handle. Ketones can undergo a variety of subsequent modifications, and the team showed that derivatizing these groups can enhance adhesive strength even further. This opens the door to a modular strategy: first install a uniform layer of carbonyl groups catalytically, then tailor the surface chemistry for specific applications, whether that means bonding to particular adhesives, improving paint adhesion, or enabling compatibility with polar coatings and composites.

Durability is another area where the new approach outperforms alternatives. Surfaces produced by unselective oxidation methods, such as corona, flame, or plasma treatments, are notorious for losing their enhanced properties over time as polar groups migrate into the bulk or as low-molecular-weight oxidized material is rubbed away. The authors report that the augmented surface properties from their catalytic method persist for longer than those achieved by other unselective functionalizations. For industrial applications, where a treated plastic part may sit in a warehouse for weeks before bonding or coating, this longevity could be the difference between a laboratory curiosity and a manufacturable process.

Characterizing a reaction that occurs only at a buried interface is itself a technical challenge, and the team brought substantial analytical firepower to bear. The author list includes researchers from the Advanced Light Source at Lawrence Berkeley National Laboratory and the Advanced Photon Source at Argonne National Laboratory, facilities that provide synchrotron X-ray techniques capable of probing the structure and composition of polymer surfaces with high sensitivity. These methods allowed the team to verify that functionalization was indeed confined to the surface region and that the bulk polymer remained intact, claims that would be difficult to support with conventional bench-top characterization alone.

The broader implications extend across the plastics economy. Polyethylene’s lack of adhesion has long limited its use in multilayer packaging, printed electronics, composite materials, and structural bonding, forcing engineers either to accept weaker assemblies or to resort to energy-intensive surface treatments. A catalytic process that runs below 80 degrees Celsius with inexpensive reagents and vanishingly small amounts of an earth-abundant metal catalyst could, in principle, be scaled to industrial dimensions. It also represents a conceptual advance for the field of polymer functionalization, demonstrating that selective C–H bond activation, a capability usually associated with small-molecule synthesis, can be directed at the surface of a solid commodity plastic with precision.

As the authors note, selective C–H bond functionalization at the solid–liquid interface produces materials that are inaccessible both by bulk functionalization methods and by traditional surface oxidations. That positioning, between two established but imperfect strategies, is exactly where a transformative technology can take root. If the approach can be adapted to other polyolefins and integrated into existing manufacturing lines, the humble plastic bag’s chemical cousin may soon find itself glued, painted, and bonded into applications its inventors never imagined, all thanks to a whisper of iron catalyst and the quiet power of interfacial chemistry.

Subject of Research: Selective catalytic surface oxidation of polyethylene at a solid–liquid interface to enhance adhesion without altering bulk polymer properties

Article Title: Selective, Catalytic Oxidation of Polyethylene Surfaces

Article References: Woroch, C. P., Klivansky, L., McCarthy, D. P., Miao, H., Fink, Z., Zuo, X., Guthrie, C., Wang, C., Helms, B. A., & Hartwig, J. F. (2026). Selective, Catalytic Oxidation of Polyethylene Surfaces. Nature. https://doi.org/10.1038/s41586-026-11255-3

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11255-3

Keywords: polyethylene, catalysis, C–H functionalization, surface oxidation, iron catalyst, adhesion, polymer chemistry, solid–liquid interface, ketones, plastics, materials science, homogeneous catalysis

The motivation behind the work stems from a striking imbalance in the field. Carbonylative Sonogashira couplings, first demonstrated by Tanaka and coworkers in 1981, have been applied to an impressive range of substrates over the past four decades, including aryl and vinyl triflates, aryl iodides, aryl bromides, alkyl halides, benzyl chlorides, aryl triazenes, and even diazonium salts, with formic acid serving as a carbon monoxide surrogate in the latter case. More recently, aryl thianthrenium salts have opened the door to direct, selective functionalization of aromatic carbon-hydrogen bonds. Yet despite this breadth, arene derivatives have been used almost exclusively as substrates. Given the synthetic utility of alkenyl-alkynyl ketones, the Hungarian research team set out to ask whether iodoalkenes could serve as competent partners, and to map the structure-reactivity and structure-selectivity relationships that govern these transformations.

The investigation began with the direct Sonogashira coupling, using 2-iodobornene as a sterically demanding model iodoalkene and phenylacetylene as the coupling partner. The catalytically active palladium(0) species was generated in situ from palladium(II) acetate and a phosphine ligand, with copper(I) iodide as co-catalyst. As is common in Sonogashira chemistry, an unwanted side reaction loomed: the Glaser homocoupling of the terminal alkyne, which in this case produced 1,4-diphenyl-1,3-butadiyne. Optimizing the reaction therefore meant balancing conversion against selectivity toward the desired enyne product, a delicate dance of solvent, base, ligand, and stoichiometry.

The optimization data reveal how sensitive these couplings are to reaction conditions. In tetrahydrofuran with triphenylphosphine as ligand, conversions hovered around 35 to 37 percent regardless of whether 1.1 or 1.5 equivalents of alkyne were used. Switching the base from triethylamine to potassium carbonate pushed the selectivity toward the enyne to a perfect 100 percent, while omitting the phosphine ligand altogether collapsed the conversion to a mere 12 percent, underscoring its necessity. The decisive breakthrough came with the bidentate ligand Xantphos, which lifted conversion to 72 percent while maintaining complete selectivity. Dimethylformamide, a solvent widely used in such couplings, kept conversion high but came at a steep cost: selectivity plummeted, and with inorganic base the reaction produced essentially none of the desired enyne, the diyne by-product dominating instead.

With the optimized conditions in hand, the team explored the substrate scope across six structurally diverse iodoalkenes, including 2-iodobornene, 1-iodocyclohexene, 1-iodo-4-tert-butylcyclohexene, 1-iodocyclopentene, trans-1-iodo-1-octene, and 17-iodo-androst-16-ene, a steroid-derived substrate. These were paired with five terminal alkynes: phenylacetylene, 1-hexyne, 3-hydroxy-1-butyne, trimethylsilylacetylene, and ethynylferrocene. The resulting conjugated enynes were isolated in moderate to good yields. Aryl alkynes generally outperformed their aliphatic counterparts, while trimethylsilylacetylene consistently delivered the lowest yields across the iodoalkene series. Steric effects were clearly at play, as the more hindered iodoalkenes gave lower yields with bulky alkyne partners. Intriguingly, the hydroxy-functionalized alkyne proved highly effective, particularly with the parent iodoalkene, hinting that substrate-specific effects can override simple reactivity expectations.

The carbonylative variant, the true centerpiece of the study, introduces carbon monoxide as a one-carbon synthon into the catalytic cycle. Under atmospheric pressure of CO, the alkenyl-palladium species formed after oxidative addition undergoes CO insertion to generate an acyl-palladium intermediate, which is then trapped by the alkynyl nucleophile to yield an alkynyl ketone bearing both alkenyl and alkynyl fragments. These alkenyl-alkynyl ketones are valuable building blocks, and accessing them from iodoalkenes under mild conditions represents a meaningful addition to the synthetic repertoire. The optimization, however, revealed an even greater sensitivity to the solvent-base combination than the direct coupling.

In dimethylformamide with potassium carbonate, conversions climbed rapidly, reaching 100 percent within three hours, but the direct Sonogashira product and the carbonylative product formed in nearly equal amounts, an unacceptable outcome for chemoselectivity. Replacing the inorganic base with triethylamine slowed the reaction at short times but dramatically improved selectivity toward the alkynyl ketone; at complete conversion after six hours, the ratio of carbonylative product to direct coupling product to diyne stood at an impressive 89 to 9 to 2. Tetrahydrofuran with triethylamine fared far worse, delivering only partial conversion even after 24 hours while the proportion of non-carbonylative and homocoupled by-products steadily grew. Dimethylformamide with triethylamine was therefore selected as the standard for preparative work.

Applying these conditions across the full substrate matrix yielded alkenyl-alkynyl ketones in yields ranging from 19 to 92 percent. Sterically hindered iodoalkenes again lagged behind with the bulky ethynylferrocene partner, while 1-hexyne proved an especially willing participant, its acylation by the acyl-palladium intermediate being more favorable than that of the other alkynes. Not every alkyne cooperated, however. Trimethylsilylacetylene, a reliable partner in many coupling chemistries, took an unexpected detour under the carbonylative conditions: instead of the desired silylated alkynyl ketone, desilylation occurred, followed by addition of diethylamine generated from the triethylamine-containing medium, producing a beta-diethylamino enone or enaminone-type by-product. Switching to potassium carbonate only partially suppressed this pathway and triggered additional side reactions, including a doubly coupled product and a dimethylamino compound derived from dimethylformamide itself, as confirmed by gas chromatography-mass spectrometry. The authors concluded that trimethylsilylacetylene is not a generally reliable partner for the carbonylative protocol under these conditions.

The analytical rigor underpinning the study deserves note. Reaction progress was monitored by gas chromatography with dodecane as an internal standard, using a carefully calibrated single-point relative response factor for the model iodoalkene. Structural assignments rested on nuclear magnetic resonance spectroscopy recorded on a 500-megahertz instrument, complemented by mass spectrometry and infrared spectroscopy with attenuated total reflectance sampling. All isolated compounds were fully characterized, and where products had been reported previously, the analytical data matched the literature values, lending confidence to the reported yields and selectivities.

Taken together, the findings establish iodoalkenes as genuinely useful substrates for accessing two complementary product classes under mild palladium catalysis: conjugated enynes from the direct reaction, performed with a palladium acetate, Xantphos, and copper iodide system in tetrahydrofuran with potassium carbonate, and carbonylated enynone-type products from the carbonylative variant in dimethylformamide with triethylamine under atmospheric carbon monoxide. The study demonstrates that reaction outcome is governed by an interplay of solvent and base, the steric demand of the iodoalkene, and the nature of the terminal alkyne. The successful use of ethynylferrocene as a redox-active alkyne partner adds an intriguing dimension for future materials-oriented applications, while the trimethylsilylacetylene limitation offers a candid map of the protocol’s boundaries. For a transformation whose aryl halide chemistry has been exhaustively catalogued, this systematic exploration of the alkenyl frontier shows that even forty-year-old catalytic reactions still hold surprises worth pursuing.

Subject of Research: Palladium-catalyzed direct and carbonylative Sonogashira coupling reactions of iodoalkenes with terminal alkynes

Article Title: Direct and carbonylative Sonogashira reactions of iodoalkenes

Article References: Jenei, L. B., Zugó, A., Mikle, G., & Kollár, L. (2026). Direct and carbonylative Sonogashira reactions of iodoalkenes. Results in Chemistry, 31, Article 103924. https://doi.org/10.1016/j.rechem.2026.103924

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DOI: 10.1016/j.rechem.2026.103924

Keywords: Sonogashira coupling, carbonylation, iodoalkenes, palladium catalysis, cross-coupling, alkynyl ketones, enynes, Xantphos, carbon monoxide, terminal alkynes, homogeneous catalysis, synthetic chemistry

The central problem in nitrate reduction is well known to anyone who has worked with transition-metal complexes. The nitrate anion is thermodynamically stable and kinetically sluggish; its nitrogen-oxygen bonds are strong, and its negative charge makes it reluctant to bind to negatively charged or electron-rich metal centers. Biological enzymes solve this problem elegantly. In molybdenum- and iron-containing reductases, the primary coordination sphere binds the substrate, while an array of amino acid residues forms a second-shell network of hydrogen bonds that polarizes the substrate, stabilizes charged intermediates, and shuttles protons to the right place at the right time. Synthetic chemists have tried to imitate this architecture for decades, but installing a functional second sphere around a small-molecule catalyst remains a formidable synthetic challenge.

In the new report, the research team designed iron complexes in which hydrogen-bond donors are anchored at the periphery of the ligand framework, close enough to reach nitrate bound at the metal but far enough not to interfere with metal-ligand bonding. The ligands, often described as pendant urea or amide units in related systems, act like a molecular hand that grips the nitrate ion from the outside of the first coordination shell. When the authors compared these second-sphere catalysts with otherwise identical complexes lacking the hydrogen-bond donors, the difference was striking. The decorated systems reduced nitrate at substantially higher rates and with improved selectivity toward nitrogen-containing products, confirming that the rate enhancement is not merely an electronic effect of a modified ligand but a genuine consequence of secondary-sphere interaction.

Mechanistic experiments formed the backbone of the study. Kinetic isotope effects measured with deuterated hydrogen-bond donors revealed that proton transfer participates in the rate-determining step, while spectroscopic monitoring tracked the buildup and decay of iron-bound nitrogen oxo intermediates. The authors observed that the hydrogen-bond network stabilizes the protonated nitrate species and the N-O bond-cleavage transition state, lowering the energetic barrier for the transformation that conventional iron complexes find hardest to accomplish. Density functional theory calculations supported this picture quantitatively: the computed transition states for N-O bond activation sit lower in energy when the second-sphere donors are present, and natural bond orbital analyses showed increased polarization of the nitrate nitrogen-oxygen bonds induced by the surrounding hydrogen-bond framework.

One of the most compelling aspects of the work is the demonstration that the effect is tunable. By systematically varying the acidity and geometry of the pendant donors, the researchers could dial the catalytic activity up or down, an ability that transforms the second sphere from a passive scaffold into an active design element. The geometry matters as much as the acidity. Donors positioned to donate bifurcated or doubly coordinated hydrogen bonds to a single nitrate oxygen produced the largest accelerations, while donors pointing in the wrong direction contributed little. This structure-activity relationship provides a practical roadmap for other laboratories seeking to engineer second-sphere effects into their own catalysts, whether the target is nitrate, carbon dioxide, nitrogen gas, or oxygen reduction.

The implications extend well beyond the walls of a synthetic inorganic laboratory. Nitrate contamination of groundwater is a global health concern, linked to methemoglobinemia in infants and to various cancers in adults, and agricultural runoff keeps the problem growing. Conventional treatment technologies, including ion exchange, reverse osmosis, and biological denitrification, are expensive, energy intensive, or slow. Catalytic conversion of nitrate to ammonia or nitrogen gas under mild conditions would offer an alternative that destroys the pollutant in place and, in the case of ammonia production, recycles the nitrogen into a valuable commodity. The present study does not yet deliver a water-treatment device, but it supplies the mechanistic foundation that such devices will require: a clear picture of how to activate nitrate at an earth-abundant metal without the precious metals that dominate many industrial processes.

Iron is the obvious choice for that vision. It is cheap, abundant, and biocompatible, and it already performs nitrogen chemistry in nature through the enzyme nitrogenase, albeit for the opposite reaction, the reduction of dinitrogen to ammonia. Harnessing iron for selective nitrate reduction in a synthetic setting has proven difficult because the metal tends to bind nitrate weakly and to release reactive intermediates indiscriminately. The second-sphere strategy addresses both weaknesses at once. By enveloping the bound nitrate in a supportive hydrogen-bond pocket, the ligand raises the effective affinity of the complex for the anion and simultaneously organizes the transition states that lead to productive bond cleavage. In effect, the catalyst mimics the reductase active sites that nature has optimized over billions of years, using noncovalent interactions to do work that brute-force electronics cannot.

The study also contributes to a broader intellectual trend in molecular catalysis: the recognition that the region just outside the primary coordination sphere is fertile ground for innovation. Over the past decade, researchers have shown that second-sphere effects can control selectivity in oxygen evolution, enhance carbon dioxide reduction at nickel and cobalt centers, and enable proton-coupled electron transfer sequences that would otherwise be impossible. Each demonstration refines the community’s ability to predict where to place donors and how strongly they should interact with substrates. The nitrate work adds an important data point because it concerns an anionic substrate, the class for which hydrogen-bond assistance is most consequential and also most technically demanding, since electrostatic competition between the ligand framework and the substrate can destabilize the very complexes being engineered.

Questions remain before the chemistry can be scaled. The catalytic turnovers reported in the study, while impressive for a molecular iron complex, still fall short of the durability needed for continuous-flow water treatment or industrial operation. Oxygen and competing anions such as sulfate and carbonate, which are abundant in real wastewater, may challenge the selectivity of the hydrogen-bond pocket. The authors acknowledge these hurdles and point toward future ligand generations with more robust frameworks and tunable pocket sizes. Still, the conceptual advance is unambiguous. A hydrogen-bonded second sphere, carefully installed around an iron center, measurably promotes one of the most stubborn reductions in environmental chemistry, and it does so with the kind of mechanistic clarity that invites reproduction and elaboration by other groups.

For the moment, the study stands as a vivid example of how molecular design can borrow from enzymology to solve practical problems. The nitrate anion that pollutes rivers and aquifers is the same species that enzymes dismantle with ease inside living cells, and the difference between the two situations has always been architecture. By building that architecture, in miniature, into a synthetic iron complex, chemists have shown that the boundary between biology and homogeneous catalysis is not a wall but a design space. The next steps, engineering robustness, testing real water matrices, and coupling the chemistry to renewable electricity, will determine how quickly this laboratory insight matures into technology. What is already clear is that the second coordination sphere, once considered decoration, now belongs among the primary tools of modern catalyst design.

Subject of Research: Second-sphere hydrogen bonding in synthetic iron catalysts for nitrate reduction

Article Title: Secondary-sphere hydrogen bonding promotes catalytic nitrate reduction at iron

Article References: Sarkar, W., LaDuca, A. R., Kazukiewicz, R. W., & Szymczak, N. K. (2026). Secondary-sphere hydrogen bonding promotes catalytic nitrate reduction at iron. Nature Chemistry. https://doi.org/10.1038/s41557-026-02235-1

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02235-1

Keywords: nitrate reduction, iron catalysis, hydrogen bonding, second coordination sphere, homogeneous catalysis, nitrate to ammonia, water treatment, metalloenzymes, proton-coupled electron transfer, earth-abundant metals, ligand design, denitrification

The study, led by Professor Sarah Yunmi Lee of KAIST’s Department of Chemistry and published online on August 3 in the Journal of the American Chemical Society, introduces a ligand-based strategy that tunes the redox behavior of a copper catalyst so that two competing steps of the catalytic cycle proceed in harmony. Ligands are molecules that bind to a metal catalyst and modulate its electronic properties, and the KAIST team turned to an unusual and comparatively underexplored class of them: cyclopropenimines, abbreviated CPI. By attaching a CPI-based ligand to copper, the researchers found they could regulate both how readily the catalyst generates radicals from challenging starting materials and how easily the catalyst is restored to its active form after each turnover. The result is a catalytic system that keeps working smoothly, cycle after cycle, under remarkably mild conditions.

To demonstrate the power of this approach, the team focused on a demanding class of starting materials known as tertiary alkyl halides, compounds in which a bromine or chlorine atom is attached to a tertiary carbon center. When the copper catalyst cleaves the carbon–halogen bond in these substrates, a highly reactive tertiary radical is born. In the reactions developed by the KAIST group, that radical then forms a new carbon–carbon bond with another reactive site within the same molecule, closing a ring in a process called radical cyclization. The transformation is conceptually simple, akin to tying the two loose ends of a string together to form a loop, but carrying it out efficiently with sluggish tertiary substrates has been a longstanding challenge in synthesis.

The crucial insight emerged when the researchers compared several different ligands on the same copper catalyst. Counterintuitively, ligands that were exceptionally good at generating radicals did not necessarily deliver more of the desired product. Some of the most aggressive radical-generating systems produced almost none of the target ring-closed compounds, because the catalyst became trapped in an inactive state and could not continue the cycle. In other words, a flood of radicals with no catalyst regeneration is a dead end. The analogy the team draws is a worker performing a task repeatedly: a catalyst that finishes one job and then cannot reset is useless, no matter how skillful it was at that single task. The CPI ligand acts as the helper that lets the worker move on to the next assignment without pausing after each one.

Redox chemistry sits at the heart of this balancing act. In copper-catalyzed radical reactions, the metal must typically accept an electron to cleave the carbon–halogen bond and generate the radical, and then release or regain electrons in subsequent steps to return to its resting, active oxidation state. If the ligand makes the copper too eager to accept electrons, radical generation is fast but the downstream steps that regenerate the catalyst lag behind, and the cycle jams. If the ligand makes the copper too sluggish, radicals form too slowly and the reaction crawls. The cyclopropenimine ligand occupies a sweet spot, tuning the oxidation-reduction properties of the copper center so that radical generation and catalyst regeneration are matched in rate, allowing each step of the cycle to hand off smoothly to the next.

With this balance achieved, the KAIST team succeeded in synthesizing 3,3-disubstituted oxindoles in high yields. Oxindoles are compounds built around a ring framework that appears repeatedly in medicinal chemistry, and the 3,3-disubstituted variants are structural motifs found in numerous pharmaceuticals and bioactive natural products. Constructing these quaternary carbon centers through radical cyclization of tertiary alkyl halides is exactly the kind of transformation that conventional methods have struggled to accomplish, which makes the new catalytic system a potentially valuable tool for medicinal chemists seeking efficient routes to complex, drug-like molecules.

Perhaps the most striking demonstration of the strategy’s power came from the behavior of the two halogens tested. Substrates bearing carbon–bromine bonds, which are relatively easy to break, reacted efficiently even at room temperature, a testament to how mild the overall conditions are. More impressively, the team also succeeded with substrates containing carbon–chlorine bonds, which are substantially stronger and far less willing to undergo activation. Tertiary alkyl chlorides have previously been difficult or impractical to use in radical cyclizations precisely because their bonds resist cleavage while their radicals, once formed, are so reactive that side reactions tend to dominate. The CPI-enabled copper catalyst overcame both obstacles, opening the door to a range of oxindole products that were previously difficult or impossible to access from chloride starting materials.

The broader lesson the authors draw from the work extends well beyond a single reaction class. Generating radicals well, they emphasize, is not sufficient on its own. Rather than simply maximizing the reactivity of one step in a catalytic cycle, catalyst designers should consider the entire cycle, including radical generation, bond-forming events, and catalyst regeneration, as an integrated system whose steps must remain in balance. This systems-level view suggests a general design principle for future radical-based catalytic reactions: instead of hunting for ever more reactive radical sources, chemists can achieve better outcomes by choosing ligands that harmonize the redox demands of every stage of the process. Such a principle could expand the range of challenging substrates available for chemical synthesis and guide the development of new reactions that were previously out of reach.

The practical implications are considerable. Milder reaction conditions mean less energy input, fewer protecting groups, and greater compatibility with sensitive functional groups, all of which matter when the goal is efficiently constructing complex molecules relevant to pharmaceuticals and other bioactive compounds. If the balancing principle generalizes, chemists may be able to recruit entire families of inexpensive, abundant alkyl chlorides as building blocks for drug discovery, substrates that have historically been sidelined in favor of their more reactive bromide and iodide counterparts. Professor Lee summarized the significance of the finding, stating that the study shows efficient radical generation alone is not sufficient and that the different processes within a catalytic cycle must proceed in balance. She added that the team expects the approach can be applied to the development of new radical-based catalytic reactions that make use of challenging substrates that have previously been difficult to activate.

Behind the publication stands a collaborative effort. Sarah Jang, a student in the integrated master’s–PhD program in KAIST’s Department of Chemistry, and Seongryeol Jeung, who earned a master’s degree at Yonsei University, served as co-first authors, with Sumin Kim, also an integrated master’s and PhD student in the Department of Chemistry at KAIST, participating as a third author. Professor Sarah Yunmi Lee is the corresponding author. The research was supported by the Samsung Science and Technology Foundation under Project SSTF-BA2202-06. As radical chemistry continues to expand its role in building the molecules of modern medicine, the KAIST team’s message is likely to resonate across the field: the fastest catalyst is not the one that generates radicals most aggressively, but the one that keeps every step of its cycle moving in step, turning the once-recalcitrant bonds of tertiary alkyl chlorides into reliable handles for molecular construction.

Subject of Research: Ligand-controlled redox balancing in copper-catalyzed radical cyclization of tertiary alkyl halides to synthesize 3,3-disubstituted oxindoles

Article Title: KAIST develops a strategy to balance radical generation and catalyst regeneration, enabling challenging chemical reactions

Article References: KAIST develops a strategy to balance radical generation and catalyst regeneration, enabling challenging chemical reactions. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: copper catalysis, radical cyclization, cyclopropenimine ligand, redox control, tertiary alkyl chlorides, oxindoles, carbon-carbon bond formation, catalyst regeneration, KAIST, medicinal chemistry, homogeneous catalysis, alkyl halide activation

The stakes are enormous. Many of the most biologically active molecules in medicine and agriculture exist as two enantiomers, mirror-image structures that can behave completely differently in living systems. One form of a drug may heal while the other causes harm, which is why regulatory agencies and pharmaceutical manufacturers demand enantiomerically pure products. Asymmetric catalysis answers that demand by using chiral metal complexes to steer bond formation toward one stereoisomer with high stereoselectivity, enantioselectivity, and regioselectivity. The field traces its origins to 1968, when Knowles and Horner, together with their coworkers, performed the first asymmetric catalytic reaction. Since then, the interplay between metal identity and ligand design has defined progress across pharmaceuticals, agrochemicals, and medicinal chemistry.

At the heart of the review sits BINAP, or 2,2′-bis(diarylphosphino)-1,1′-binaphthyl, the landmark chiral ligand discovered by Ryoji Noyori and Hidemasa Takaya. BINAP supplies axial chirality, conformational flexibility, and strong steric and electronic asymmetry, and its complexes with ruthenium and rhodium catalyze an extraordinarily broad set of hydrogenations of olefins, ketones, and allylic alcohols with enantioselectivities that typically exceed ninety percent. The review emphasizes that these catalysts combine large turnover numbers with practical scalability, a combination that has made them workhorses in the industrial production of medicines and derivatives of natural products. Precise stereochemical control, the authors stress, emerges from the conjunction of ligand design, catalyst-substrate interactions, and carefully tuned reaction conditions rather than from any single factor.

One particularly striking line of research surveyed involves rhodium nanoparticles stabilized by chiral BINAP ligands, prepared in a one-pot synthesis alongside their silica-supported analogues. Characterization by transmission electron microscopy, phosphorus-31 magic-angle spinning NMR, and infrared spectroscopy of adsorbed carbon monoxide revealed highly dispersed nanoparticles with narrowly distributed core sizes. In the asymmetric hydroformylation of styrene, the chiral stabilization of the nanoparticle surface produced a regioselectivity of 99:1 and enantioselectivities of up to fifty-nine percent, markedly outperforming conventional systems. The chelated (R)-BINAP ligand carves out a rigid chiral pocket on the nanocatalyst surface, demonstrating that chirality can be effectively imposed even on nanoparticulate metal clusters.

The review also dissects how counterions, often dismissed as chemical spectators, reshape the behavior of rhodium-BINAP hydrogenation catalysts. Combining single-crystal X-ray crystallography, NMR spectroscopy, and catalytic testing, researchers showed that different counterions yield distinct pseudo-first-order rate constants and enantioselectivities, and that solvent choice further modulates both kinetics and selectivity. Intriguingly, for the hydrogenation of dimethyl itaconate in propylene carbonate, the anion exerted no effect at all on either activity or enantioselectivity, underscoring that counterion influence is complex and substrate-dependent. Alongside this, ruthenium(II)-BINAP complexes, notably Ru(CH3COO)2[(R)- or (S)-BINAP], achieve nearly quantitative yields of saturated isoquinoline alkaloid precursors from 2-acyl-1-alkylidene-1,2,3,4-tetrahydroisoquinolines with high optical purity—and, remarkably, in the stereochemical sense opposite to that delivered by the analogous rhodium catalyst, a reversal that highlights how metal identity alone can flip asymmetric induction.

Beyond phosphines, the review turns to the oxazoline family, where bis-oxazoline ligands have earned a reputation for delivering good to high enantioselectivities across many catalytic asymmetric reactions. New C2-symmetric Isbut-Box ligands, synthesized from substituted bis(oxazolin-2-yl)methylpropene frameworks, were evaluated in copper(I)-catalyzed cyclopropanation of olefins, with density functional theory calculations illuminating solvent effects and the structure of the copper(I) complex. These systems achieve up to seventy percent enantioselectivity and seventy-two percent diastereoselectivity, while a copper complex derived from a tert-butyl bisoxazoline showed promising activity in the enantioselective cyclopropanation of styrene. The authors note that the enormous early promise of bis-oxazolines has spurred extensive modification of the framework, including stiff, cyclic 1,4-box backbones in both C2- and C1-symmetric variants designed to tighten stereochemical control further.

Oxazolines are also proving valuable beyond traditional solution-phase transformations. C2-symmetric bis(oxazoline) ligands serve as transient chiral auxiliaries for constructing enantiomerically pure bis-cyclometalated rhodium(III) complexes, which act as configurationally stable stereogenic catalysts in asymmetric photocatalysis. Using inexpensive beta-amino alcohols and a symmetrically disubstituted diethyl malonimidate salt, the chiral auxiliary complexes formed within a single hour at room temperature. In a parallel effort, a new class of triazolyl-oxazoline ligands combining a chiral 2-oxazoline with a 1,2,3-triazol-4-yl moiety was shown by X-ray diffraction to coordinate palladium(II) either as monodentate ligands through the oxazoline nitrogen or as N,N-chelators, generating cationic allyl complexes, neutral dimers, and mononuclear dichloro species—an adaptable coordination chemistry that widens the design space for chiral palladium catalysis.

Perhaps the most forward-looking section concerns BINOL, 1,1′-bi-2-naphthol, paired with abundant main-group metals. Recent work revealed an unusual chiral-at-metal mechanism in BINOL-aluminum asymmetric catalysis: an octahedral chiral aluminum complex, thermodynamically more favorable than the previously proposed aluminum hydride, operates through ligand-assisted hydride transfer. In the catalytic hydroboration of heteroaryl ketones with pinacolborane, the optimized conditions delivered ninety-nine percent yield and ninety-nine percent enantiomeric excess, producing chiral alcohols prized in pharmaceutical synthesis. Meanwhile, bifunctional BINOL and H8BINOL ligands catalyze the addition of diphenylzinc to aldehydes at room temperature without additives, and a related ligand promotes highly enantioselective TMSCN additions when combined with Me2AlCl, with yields spanning seventy-five to ninety-six percent across optimized solvent systems.

The review closes with bis(imine) systems, where a bidentate chiral bis(imine)-copper(II) triflate complex drives the 1,3-dipolar cycloaddition of nitrones to electron-deficient dipolarophiles with endo/exo ratios of up to 95:5 and enantioselectivities reaching ninety-nine percent—performance that outshines established TADDOL-titanium, bis-oxazoline magnesium, and BINAP-palladium systems for this transformation. Together, the authors argue, these results show that rational ligand design and metal-ligand cooperation are the twin engines of progress in asymmetric catalysis. They call for sustainable synthesis built on eco-friendly oxidants, solvents, and reaction conditions, and for deeper integration of mechanistic studies and computational chemistry to design the next generation of rigid, electronically tunable chiral catalysts capable of tackling the most demanding reactions in organic synthesis.

Subject of Research: Innovative chiral metal ligand architectures for asymmetric catalysis

Article Title: Review on innovative metal ligand architectures for asymmetric catalysis

Article References: Patel, S. P., Shaikh, R. S., Patel, N. C., & Savant, S. S. (2026). Review on innovative metal ligand architectures for asymmetric catalysis. Discover Green Chemistry, 1(1), Article 32. https://doi.org/10.1007/s44509-026-00035-x

Image Credits: AI Generated

DOI: 10.1007/s44509-026-00035-x

Keywords: asymmetric catalysis, chiral ligands, BINAP, BINOL, bis-oxazoline, enantioselectivity, hydrogenation, hydroformylation, rhodium nanoparticles, green chemistry, homogeneous catalysis, cyclopropanation