Helicenes are ortho-fused polycyclic aromatic molecules whose benzene rings twist into a rigid screw-like backbone, giving rise to two mirror-image forms, labeled P and M for right- and left-handed helices. The longer the helix, the more pronounced its chiroptical behavior, particularly circularly polarized luminescence, in which emitted light preferentially rotates in one direction. Theory predicts that the degree of circular polarization in carbo[n]helicenes increases with the number of fused rings, making long helicenes highly desirable targets. Yet there is a catch: fluorescence quantum yields drop sharply as helicenes grow longer, because the floppy excited-state structures of extended helices relax non-radiatively. Lateral π-extension, adding extra fused benzene rings around the helical periphery, stiffens the framework and suppresses this relaxation, restoring brightness. Combining longitudinal growth with lateral expansion, however, multiplies molecular strain and steric congestion to levels that conventional synthesis simply cannot handle.

The classical workhorse for making carbohelicenes has been oxidative photocyclization of stilbene derivatives. Using this approach, Murase and Fujita reported the racemic synthesis of carbo[16]helicene in 2015 through a remarkable sextuple photocyclization, albeit in low yield. More recently, Jin and coworkers achieved an efficient racemic route to carbo[17]helicene using stilbene precursors containing heteroatom functionalities. But racemic products are only half the story. For applications in circularly polarized light detection, spin filtering and chiral photonics, enantioenriched material is essential, and no one had previously made a long carbohelicene composed solely of carbon and hydrogen in enantioenriched form. Heterohelicenes, which incorporate nitrogen, sulfur or other heteroatoms, are easier to make enantioselectively because the heteroatoms assist reactivity and selectivity; all-carbon helicenes offer no such handles.

The Tokyo group’s alternative strategy centers on the nickel-catalyzed [2+2+2] cycloaddition, a reaction in which three alkyne units cyclotrimerize to form a benzene ring. Chiral nickel catalysts can impose handedness during this ring formation, directly producing helicenes with high enantiomeric purity without the need for chiral chromatography. In 2024, the same laboratory used triple [2+2+2] cycloadditions followed by Scholl reactions, oxidative dehydrogenative cyclizations that fuse peripheral aryl groups, to build π-extended carbo[11] and [13]helicenes. But that earlier approach suffered from partial disordering of the cyclization sequence, which eroded yields and selectivities. Scaling up to a quadruple cyclization, with four separate cyclotrimerizations on a single dodecayne substrate, demanded something new: a way to force the four cyclizations to happen in the right order.

The solution is a sterically differentiated, wavy dodecayne precursor built around a central triphenylene core. The molecule contains two inner triyne units, each destined to form a relatively unhindered [5]helicene, and two outer triyne units that must generate far more sterically demanding [6]helicenes. The triphenylene backbone serves two roles: it elongates the eventual helicene and it increases the distance between the inner triyne units, reducing congestion during their cyclization. Crucially, the inner triynes react faster than the outer ones, so the quadruple cyclization proceeds from the molecular center outward, assembling the two [5]helicenes first and only then tackling the crowded [6]helicene formations. This programmed sequence suppresses dead-end pathways in which an outer triyne cyclizes prematurely and blocks the rest of the cascade.

The experimental route began with iodination of 2,7-dimethoxytriphenylene and demethylation to give a diiodotriphenylenediol, which was coupled by Sonogashira chemistry with pentayne building blocks to form decaynes, then elaborated by triflation and Suzuki–Miyaura coupling into the final dodecaynes. Subjecting dodecayne 1a to the chiral Ni(cod)₂/(R)-Quinap catalyst system under a two-temperature protocol, 72 hours at 0 °C followed by 72 hours at 60 °C, delivered the desired expanded [21]helicene (P,P,P,P)-8a in 31% yield with an outstanding 97:3 enantiomeric ratio, alongside a diastereomeric product. Subsequent Scholl reactions, first with DDQ and triflic acid to fully fuse the backbone and then under harsher conditions to close the peripheral aryl–aryl bonds, converted 8a into the π-extended carbo[17]helicene 2a while preserving the enantiomeric ratio at 98:2. No racemization occurred, mirroring the configurational stability of the smaller [5] and [6]helicene substructures under the same strongly oxidative and acidic conditions.

The importance of sequence control was proven by a series of elegant control experiments. When the team extracted the individual triyne fragments and raced them against each other under the chiral nickel catalyst, the triphenylene-bridged inner triyne produced its [5]helicene in up to 97% yield, roughly four times faster than the naphthalene-bridged triyne that models the outer units. In contrast, a benzene-bridged triyne corresponding to the less hindered analogue dodecayne 1b reacted at nearly the same rate as the inner fragment, meaning no sequence preference existed. Consistently, dodecayne 1b failed to deliver its expanded [19]helicene under the chiral conditions and required a high-temperature achiral catalyst, producing complex mixtures. Density functional theory calculations reinforced the picture: the (P,P) intermediate formed after two inner cyclizations is more stable than its (P,M) diastereomer by 10.9 kcal per mole, and the alternative (M,P,P,M) product is destabilized by 21.9 kcal per mole relative to the desired (P,P,P,P) helicene, explaining why dead-end isomers never appear.

Single-crystal X-ray diffraction confirmed the extraordinary geometry of the products. The π-extended carbo[17]helicene 2a contains a continuous helical backbone of 17 fused benzene rings surrounded by 35 additional benzene rings along its periphery, with 32 overlapping rings compressing the helix to a length of 9.26 Å, among the longest helical nanographenes reported. The precursor 9a displayed interplanar angles as large as 80.6°, among the highest ever measured for helicene derivatives. Thermal studies showed that the kinetically formed (M,P,P,P) isomer is configurationally stable at 60 °C but irreversibly converts to the thermodynamic (P,P,P,P) isomer at 120 °C, with calculated activation barriers of 25.1 and 33.3 kcal per mole for the forward and reverse processes.

Photophysical measurements revealed why the effort was worthwhile. The long helicenes absorb at 465 to 512 nm, red-shifted by roughly 100 nm relative to the precursor, and fluoresce with quantum yields of 14 to 29%, remarkable for helicenes longer than nine rings, which are normally weak or non-emissive. Absorption dissymmetry factors reach 0.017 to 0.040, driven by large magnetic transition dipoles nearly parallel to their electric counterparts. Most strikingly, the luminescence dissymmetry factors of the fully fused long helicenes, 0.038 to 0.043, match or exceed their absorption values, an unusual outcome attributed to the rigid fused framework suppressing excited-state structural relaxation. The resulting circularly polarized luminescence brightness values of 186 to 471 M⁻¹ cm⁻¹ rank among the highest for helical hydrocarbons, and far surpass recently reported donor–acceptor [17]helicenes, underscoring that lateral π-expansion matters as much as helix length. The authors note that future chiral nickel catalysts with even higher stereodiscrimination should suppress the minor diastereomer and push yields and enantioselectivity further, opening a programmable route to ever-larger all-carbon chiral nanocarbons for photonic and spintronic technologies.

Subject of Research: Enantioselective synthesis of a π-extended carbo[17]helicene via sequence-controlled Ni-catalysed quadruple [2+2+2] cycloadditions and Scholl reactions

Article Title: Enantioselective synthesis of π-extended carbo[17]helicene via sequence-controlled quadruple [2+2+2] cycloadditions

Article References: Morita, F., Ichimura, T., Nogami, J., Kishida, Y., Takahashi, K., Shimizu, R., Uekusa, H., & Tanaka, K. (2026). Enantioselective synthesis of π-extended carbo[17]helicene via sequence-controlled quadruple [2+2+2] cycloadditions. Nature Synthesis. https://doi.org/10.1038/s44160-026-01193-3

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01193-3

Keywords: helicene, chiral nanocarbon, [2+2+2] cycloaddition, nickel catalysis, circularly polarized luminescence, enantioselective synthesis, Scholl reaction, polycyclic aromatic hydrocarbon, chiroptical properties, stereochemistry, nanographene, organic synthesis

Allylic amines are everywhere in biologically active chemistry. They appear as substructures in natural products, in pharmaceutical candidates, and in the alkene isosteres used to mimic peptide bonds in drug design. Their appeal as building blocks goes beyond mere prevalence: because an allylic amine carries an alkene, an amine and a stereocentre in close proximity, each of these reactive sites can be manipulated independently, a property chemists describe as orthogonal reactivity. That versatility makes them ideal launch pads for constructing value-added targets, from aza-heterocycles to modified alkaloids. Yet most existing routes to their chiral versions rely on pre-activated substrates such as allylic acetates, on stoichiometric chiral auxiliaries, or on multi-step sequences that erode efficiency.

The conceptual heart of the new method is homologation — the controlled lengthening of a molecular skeleton. Homologation strategies have enjoyed a renaissance in recent years, with one-carbon extensions of carboxylic acids, alkenes and organoboron compounds all demonstrating how growing a carbon chain catalytically can shortcut traditional synthesis. The Shu group applies this logic to enamines, nitrogen-substituted alkenes that are cheap, electron-rich and easily prepared from carbonyl compounds. By coupling an enamine with an alkyne under nickel catalysis, the reaction effectively inserts the alkyne-derived fragment onto the enamine framework, converting it into an allylic amine that is one hydrocarbon unit longer and, crucially, chiral.

Technically, the transformation is an enantioselective C(sp2)–C(sp3) cross-coupling, a class of reaction that has become one of the most competitive arenas in modern catalysis. Nickel is the metal of choice for several reasons: it is earth-abundant compared with palladium, it readily shuttles between oxidation states, and it tolerates the kind of unactivated alkyl intermediates that would decompose on more precious metals. In the reported system, a chiral ligand environment around nickel governs both the regiochemistry — which carbon of the alkyne receives which partner — and the enantioselectivity, delivering products in good yields with excellent enantiomeric excess across a broad substrate scope.

Perhaps the most striking feature is the chemoselectivity that makes the reaction possible at all. Mechanistic investigations by the team revealed that the catalytic cycle hinges on a selective hydrometallation step in which nickel hydride adds preferentially to the electron-rich alkene of the enamine rather than to the more electrophilic linear alkyne present in the same flask. That preference runs counter to what simple electronic intuition might predict, since electrophilic alkynes typically react faster with metal hydrides. By favouring the less obvious partner, the catalyst generates an alkyl-nickel species that then engages the alkyne in the bond-forming event, setting up the stereochemistry-defining step of the cycle.

The scope of the reaction, documented across the paper’s substrate tables and crystallographically confirmed structures, spans a wide range of alkynes and enamines. Six crystal structures deposited with the Cambridge Crystallographic Data Centre underpin the structural assignments, giving the community unambiguous three-dimensional confirmation of the products’ configurations. The breadth matters practically: medicinal chemists rarely work with a single substrate class, and a method that accommodates varied substitution patterns on both coupling partners is far more likely to be adopted in late-stage or discovery settings than one restricted to narrow examples.

The synthetic utility is demonstrated most convincingly in the applications section, where the authors show that the reaction provides a convenient route to a range of bioactive molecules and key intermediates. Among the targets accessible through the chemistry are motifs related to monoamine oxidase inhibitors and CCR3 antagonist scaffolds, compounds whose chiral allylic amine cores have traditionally demanded lengthy asymmetric sequences. Because the products retain multiple reactive handles — the alkene, the amine and any additional functionality inherited from the alkyne — they can be elaborated further, meaning the reaction functions not just as an endpoint but as a strategic gateway within a longer synthesis.

The work also fits into a broader pattern in the Shu group’s research programme, which has focused on nickel-catalysed asymmetric cross-hydrodimerization and hydroalkylation reactions of unsaturated partners. Earlier contributions from the same laboratory include enantioselective alkyl–alkyl couplings of alkenes and cobalt-catalysed cross-hydrodimerizations of dienes with alkynes. The new enamine homologation extends this reactivity-mode thinking to nitrogen-containing substrates, showing how the same mechanistic family — hydrometallation followed by controlled C–C bond formation — can be redirected toward different product classes by changing the coupling partners and ligand design.

For the pharmaceutical industry, the significance is twofold. First, the method converts commodity starting materials into high-value chiral intermediates in a single step, which translates directly into fewer operations, less waste and lower cost in process chemistry. Second, because the products are enantioenriched aliphatic allylic amines rather than aryl-substituted analogues, the chemistry reaches a subclass that asymmetric hydrogenation and classical imine alkenylation methods have served poorly. Homologation itself is increasingly recognised in medicinal chemistry as a powerful strategy for exploring the property space around a lead compound, and a catalytic, enantioselective homologation of amines gives drug hunters a new dial to turn when optimising potency, selectivity and metabolic stability.

The study, supported by the National Natural Science Foundation of China and regional funding bodies in Guangdong and Sichuan, was peer reviewed at Nature Synthesis with crystallographic and mechanistic evidence available in the supplementary materials. As nickel catalysis continues to displace precious-metal chemistry across the synthesis landscape, this enamine-to-allylic-amine homologation stands out as a template for how careful mechanistic insight — here, the counterintuitive selectivity of hydrometallation — can unlock transformations that were previously out of reach, and it is likely to inspire a wave of follow-up work aimed at extending homologation logic to other functional groups and feedstock combinations.

Subject of Research: Nickel-catalysed regio- and enantioselective homologation of enamines with alkynes to synthesize chiral allylic amines

Article Title: Synthesis of chiral allylic amines through regio- and enantioselective homologation of enamines using Ni catalysis

Article References: Du, Y.-M., You, L.-X., Li, Y.-L., Yu, Q., & Shu, W. (2026). Synthesis of chiral allylic amines through regio- and enantioselective homologation of enamines using Ni catalysis. Nature Synthesis. https://doi.org/10.1038/s44160-026-01172-8

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01172-8

Keywords: nickel catalysis, chiral allylic amines, enamines, alkynes, homologation, asymmetric catalysis, cross-coupling, hydrometallation, reaction mechanism, drug discovery, synthetic methodology, Nature Synthesis

The central idea is deceptively simple. Yield data collected across many different reaction conditions are not random; they encode how the amounts of starting materials and products respond to changes in concentration. If one could model that concentration dependence accurately enough, the underlying rate constants, the numbers that describe how quickly individual steps of a reaction occur, could in principle be recovered. The obstacle has always been that optimization datasets are sparse and irregular. Chemists run the experiments that best serve their goal of maximizing yield, not the evenly spaced measurements that classical kinetic analysis demands. CYAN bridges this gap by using machine learning to fill in the gaps between experimental results, creating a denser, more complete picture of how product amounts vary under different conditions. Once that augmented dataset exists, the researchers apply rate equations, the mathematical descriptions chemists have developed over more than a century, to extract rate constants from the data.

Professor Hiroyuki Isobe of the Department of Chemistry, who led the work, described the long-standing division between the two activities that CYAN now unites. For years, he explained, chemists have treated optimization and mechanistic study as separate objectives: reactions are optimized to achieve the highest yield, and if the mechanism matters, another series of time-course experiments is performed. His team’s goal was to bring those two activities together. In the CYAN workflow, machine learning first augments the yield data obtained from the optimization experiments. Chemists then apply rate equations based on their hypotheses about the reaction mechanism to extract rate constants from these data. In this way, a single set of experiments can be used for both reaction optimization and kinetic analysis. The method is therefore not a replacement for chemical thinking but a partnership in which the researcher supplies mechanistic hypotheses and experimental data, while the algorithm supplies a wealth of interpolated yield information.

The project, Isobe admitted, began out of frustration rather than inspiration. His group had previously developed a machine-learning tool that was very good at finding better reaction conditions, but it behaved like a black box, telling the chemists what worked without telling them why. As organic chemists, the team regarded understanding the chemistry as just as important as improving efficiency. CYAN grew from their attempt to interpret those machine-learning results. Isobe characterized the approach as a two-way collaboration between machine learning and organic chemists, in which the researchers contribute the chemical hypotheses and experimental data, while machine learning contributes the augmented yield data. This framing matters because it distinguishes CYAN from purely data-driven approaches that try to learn chemistry from scratch. Instead, the method embeds established physical laws, the rate equations, directly into the analysis, using machine learning only where it is genuinely needed: to interpolate between the experimental points that optimization campaigns produce.

To test whether the concept could deliver real chemical insight, the researchers applied CYAN to a nickel-mediated reaction used to build large ring-shaped carbon molecules. Macrocyclizations of this kind are notoriously difficult because competing side reactions, particularly the formation of unwanted oligomers and polymers, often overwhelm the desired ring-closing step. When CYAN was applied to the optimization data for this reaction, it successfully extracted kinetic information and uncovered an unexpected feature of the process. Nickel, it turned out, was doing two things at once: it accelerated the formation of the desired molecular ring while simultaneously slowing down a secondary reaction that would otherwise produce unwanted products. That combination steered the reaction toward making a single target molecule rather than a mixture of different ones, explaining the high selectivity that the optimization experiments had revealed.

The nickel finding was a genuine surprise, because slowing part of a reaction sounds like it should make synthesis worse, not better. Isobe offered a vivid analogy: imagine water flowing through a river that splits into two channels. If one channel becomes narrower, more water naturally follows the other route. The team believes nickel creates a similar effect by restricting one competing pathway, allowing the reaction to concentrate its effort on producing the desired ring-shaped molecule. The insight carries broader significance for the field. The so-called template effect, in which a metal ion organizes reacting partners into a favorable geometry, is normally conceived as an effect that accelerates a reaction. The effect found in this study was counterintuitive: the template instead retarded part of the reaction. Isobe suggested that this recognition may prove useful for designing many other metal-templated reactions, where selective inhibition of a competing pathway could be as valuable as acceleration of the desired one.

The technical architecture of CYAN deserves attention because it illustrates a growing trend in physical organic chemistry: hybrid methods that combine machine learning with mechanistic modeling rather than replacing one with the other. Conventional kinetic analysis relies on time-dependent yield data, following a single reaction condition as it evolves from start to finish, and fitting the resulting curves to rate equations to determine rate constants. CYAN instead relies on concentration-dependent yield data, the kind of information naturally accumulated when an optimization campaign varies concentrations across many experiments. Machine learning expands this dataset, effectively reconstructing the reaction landscape between the measured points. Rate equations developed by chemists are then applied to that landscape to extract the rate constants. The result is a method that respects the physics of chemical kinetics while exploiting the statistical power of modern machine learning to compensate for sparse sampling.

The researchers are careful about the limits of their approach. They emphasize that CYAN is intended to complement, not replace, traditional kinetic experiments. When highly precise measurements are required, time-course analysis remains essential, because directly observed concentration profiles over time provide the most rigorous test of a kinetic model. CYAN, by contrast, offers a practical way to extract kinetic and mechanistic information from yield data obtained during reaction optimization, potentially helping researchers design new synthetic methods while making better use of both new and previously published experimental datasets. In other words, CYAN trades some precision for enormous gains in efficiency: the kinetic insight comes essentially for free, extracted from experiments that had to be run anyway.

Perhaps the most striking demonstration of the method’s power lies in its application to historical data. The researchers found that CYAN could be applied to experimental results reported in the older chemical literature, suggesting that countless published datasets could potentially be reexamined to reveal underlying chemical kinetics. In one remarkable case, the team used data from chemistry experiments reported 176 years ago and obtained a rate constant consistent with a modern value. That result is a testament both to the quality of nineteenth-century experimental work and to the robustness of the CYAN pipeline, which could recover physically meaningful kinetics from measurements made with apparatus and techniques utterly different from those of a modern laboratory.

The implications reach well beyond a single laboratory. Synthetic chemistry generates vast quantities of yield data every year, in academic groups, industrial process development and high-throughput screening campaigns, and most of those data are never analyzed for mechanistic content. A method that converts optimization tables into rate constants could change how new reactions are discovered and understood, closing the loop between the practical business of making molecules and the scientific business of explaining why the chemistry works. The study, published in Advanced Science by Xinyi Xiao, Koki Ikemoto, Toshiya M. Fukunaga, Hideaki Nishina and Hiroyuki Isobe, was supported by funding from JSPS KAKENHI and several JST programs. For a discipline in which the gap between knowing what works and knowing why has persisted for generations, CYAN offers a way to walk both paths at once, and it hints that the secrets of many reactions may already be sitting, unnoticed, in the notebooks and databases of chemists everywhere.

Subject of Research: Machine-learning extraction of reaction kinetics from yield-optimization data in organic chemistry

Article Title: Organic chemists harness AI to reveal reaction secrets

Article References: Organic chemists harness AI to reveal reaction secrets. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: organic chemistry, machine learning, reaction kinetics, yield optimization, rate constants, nickel catalysis, template effect, macrocyclization, reaction mechanisms, University of Tokyo, Advanced Science, data-driven chemistry

The significance of the advance becomes clear when one considers how chemists normally activate alcohols for radical chemistry. Classical approaches rely on single-electron transfer (SET) or proton-coupled electron transfer (PCET), both of which depend on the oxidation potential of the substrate or on pre-installed activating groups such as xanthates, oxalates, or N-alkoxyphthalimides. These requirements impose a double penalty: they demand synthetic effort to prepare the activated precursor, and they exclude substrates whose redox potentials fall outside the window accessible to the photocatalyst. A general, redox-neutral method that cleaves the O–H bond directly—without substrate-specific redox tuning or metal pre-activation—has therefore remained an elusive goal in the field.

The Wuhan team’s insight is rooted in computation. Density functional theory calculations revealed that the calculated O–H bond dissociation energy of a representative α-silyl alcohol is only 89.2 kcal/mol, roughly 11.5 kcal/mol lower than that of its non-silylated counterpart. This dramatic bond weakening arises from the β-silicon effect, the well-known ability of a silicon atom positioned beta to a developing radical or cationic center to stabilize that center through hyperconjugative interaction of its σ C–Si bonds with the adjacent orbital. In this case, the effect stabilizes the alkoxy radical formed upon O–H homolysis, rendering direct HAT thermodynamically accessible with a photocatalyst that would be powerless against a normal alcohol.

To translate this computational insight into practice, the researchers selected thioxanthone (TXT) as the HAT photocatalyst. Under mild, redox-neutral conditions, photoexcited thioxanthone abstracts the weakened O–H hydrogen from the α-silyl alcohol, generating an alkoxy radical. What follows is a radical relay of remarkable elegance: the oxygen-centered radical rapidly undergoes a radical Brook rearrangement, a silicon-mediated 1,2-migration that converts the alkoxy radical into a nucleophilic carbon radical. This carbon radical is then intercepted by a nickel catalyst, which performs an enantioconvergent cross-coupling with either acyl chlorides or aryl bromides. The net result is the formation of chiral acyloins and chiral alcohols in high yields with excellent enantioselectivities, all starting from an unactivated O–H bond.

Perhaps the most convincing evidence for the power of the new paradigm comes from a direct experimental comparison with the group’s own earlier work. In a previous study published in Angewandte Chemie, the team had developed SET/PCET conditions for related transformations. Substrates bearing high oxidation potentials—most notably trifluoromethyl-substituted α-silyl alcohols—proved completely inert under those conditions, because the photocatalyst could not oxidize them. Under the new HAT protocol, however, these same stubborn substrates reacted smoothly, delivering the desired product in 84 percent yield. This head-to-head validation demonstrates that the direct HAT pathway operates independently of substrate redox potentials, unlocking a swath of chemical space that electron-transfer-based methods simply cannot reach.

Operational simplicity adds further appeal. The α-silyl alcohol substrates are readily prepared by nucleophilic addition of silyllithium reagents to aldehydes, a straightforward and modular step. After a simple work-up, the crude material can be carried directly into the coupling step without column chromatography, making the entire sequence a one-pot, two-step protocol. Both the acylation with acyl chlorides and the arylation with aryl bromides proceed efficiently under these conditions, furnishing products in good yields and enantioselectivities. The reaction also scales: a 2 millimole-scale run provided product 3a in 72 percent yield with 96 percent enantiomeric excess, with no erosion of stereochemical fidelity as the scale increased.

To showcase the synthetic value of the method in more complex settings, the team subjected the chiral acyloin products to a battery of downstream transformations. The products tolerated selective deoxyfluorination, diastereoselective reduction, Wittig olefination, and vinylation, in each case preserving their stereochemical integrity. Because acyloins are versatile intermediates that sit at the intersection of α-hydroxy ketone chemistry, these derivatizations point toward ready application in pharmaceutical synthesis and natural product construction, where chiral α-hydroxy carbonyl motifs are pervasive.

Mechanistic investigations lend strong support to the proposed direct HAT pathway. A radical clock experiment using a cyclopropane-bearing substrate produced the ring-opened product, a classic signature confirming the generation of an oxygen-centered radical intermediate. Cyclic voltammetry measurements showed that the oxidation potentials of the α-silyl alcohols are significantly higher than the excited-state reduction potential of thioxanthone, effectively ruling out a single-electron-transfer mechanism. Meanwhile, proton NMR titration experiments revealed hydrogen-bonding interactions between thioxanthone and the substrate—interactions that likely pre-organize the complex and facilitate the hydrogen atom transfer event itself.

The computational picture completes the story. Density functional theory calculations confirmed that the O–H bond dissociation energy of the α-silyl alcohol is substantially lower than that of the reduced photocatalyst intermediate INT2, and the computed activation barrier for the HAT step is a remarkably low 4.4 kcal/mol—a barrier easily surmounted at room temperature. On the basis of these experimental and computational data, the authors propose a comprehensive catalytic cycle that integrates the initial HAT event, the radical Brook rearrangement, and the nickel-catalyzed enantioconvergent cross-coupling into a single, redox-neutral sequence.

The work, published in National Science Review with DOI 10.1093/nsr/nwag498, lists Professor Xiao Shen and Dr. Xiaoqian He of Wuhan University as corresponding authors, with Dr. Chenyu Jin and Dr. Yunhong Niu as co-first authors. The research was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China, with theoretical calculations performed on the supercomputing system at the Supercomputing Center of Wuhan University. For a field that has long treated the alcohol O–H bond as untouchable by direct HAT, the message of this study is transformative: with a strategically placed silicon atom, one of chemistry’s most stubborn bonds becomes a launch pad for asymmetric radical synthesis.

Subject of Research: Direct hydrogen atom transfer activation of α-silyl alcohols via the β-silicon effect for enantioconvergent nickel-catalyzed cross-couplings

Article Title: β-Silicon effect enables direct HAT for enantioconvergent couplings of α-silyl alcohols

Article References: β-Silicon effect enables direct HAT for enantioconvergent couplings of α-silyl alcohols. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: β-silicon effect, hydrogen atom transfer, α-silyl alcohols, photocatalysis, thioxanthone, Brook rearrangement, nickel catalysis, enantioconvergent coupling, radical chemistry, acyloins, bond dissociation energy, redox-neutral synthesis

The chemistry at the heart of the study is cross-coupling, one of the most widely used strategies in modern synthetic chemistry. In a cross-coupling reaction, two molecular building blocks are joined by a newly formed chemical bond with the help of a metal catalyst. Because most drugs are not harvested from nature but assembled through multistep chemical processes, this bond-forming strategy underpins a huge share of the pharmaceutical industry’s synthetic toolkit. A catalyst, in the strict sense of the term, is a substance that enables or accelerates a chemical reaction without being consumed itself. In practice, many catalysts consist of single metal atoms connected to organic molecules called ligands, which influence how the metal behaves and can be deliberately designed to fine-tune its catalytic properties.

For decades, the metal of choice for many important cross-coupling reactions has been palladium. The significance of palladium-catalyzed cross-coupling in organic synthesis was recognized with the 2010 Nobel Prize in Chemistry, awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki. These reactions have become influential tools for constructing complex molecules, including pharmaceuticals, and palladium catalysts remain highly efficient. The drawback is equally well known: palladium is a noble metal, meaning it is scarce and expensive. Any chemistry that depends on loading large quantities of it into reaction vessels carries a cost, both financial and environmental, that grows uncomfortable at industrial scale.

Roughly a decade ago, researchers demonstrated an intriguing alternative. By combining a nickel catalyst with a second catalyst capable of converting visible light into chemical energy, they could carry out couplings that would otherwise rely on palladium. Nickel is far more abundant and far cheaper than palladium, so the approach promised cheaper and more sustainable reactions. But there was a catch, and it was a serious one. Nickel catalysts of that era were less efficient than their palladium counterparts and did not enable the same breadth of reactions. The promise of light-driven nickel catalysis came wrapped in practical limitations that kept it out of most working chemists’ hands.

The Pieber group has spent years probing those limitations. In their own words, the laboratory tries to understand why contemporary nickel catalysis systems have limitations, and, based on that understanding, designs, makes, and studies alternative candidates and methods. An important step came in 2020, when the researchers showed that nickel catalysts can be destroyed when challenging building blocks are used, and that this destruction can be avoided by carefully controlling the reaction conditions. The demonstration proved that the weaknesses of nickel catalysis were not insurmountable. It was, however, still far from an efficient method, as Pieber himself acknowledges. The reactions ran very slowly and required high amounts of nickel catalyst to deliver their products.

The new study grew out of that accumulating understanding. Aleksander Bena, a PhD student in the group, took the growing mechanistic picture and used it to design possible structures for more efficient and robust nickel catalysts that could be directly activated with visible light, then tested his ideas experimentally in the laboratory. That iterative process of proposing a structure, running the reaction, and learning from each result ultimately led the team to a new ligand, the organic framework wrapped around the nickel atom, that helps the metal overcome many of the remaining limitations of light-driven catalysis. The result is a catalyst system that is broadly applicable and requires substantially less nickel than earlier light-driven approaches.

The technical heart of the breakthrough is that tailor-made ligand, which boosts the catalytic activity of the nickel atom once the system is initiated with visible light. With that boost in place, the catalyst can form bonds between carbon atoms and a strikingly wide range of partner atoms, including nitrogen, oxygen, sulfur, and phosphorus, fusing two molecules into a larger and more complex structure in each case. That breadth matters enormously in practice. Drug molecules and other fine chemicals rarely contain just one kind of heteroatom linkage, so a catalyst that handles carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-phosphorus bonds alike can serve many different synthetic campaigns without bespoke optimization for each one.

The numbers behind the new system are what make it stand out. The researchers reduced the catalyst loading to 100 parts per million, equivalent to 0.01 mol percent. Put plainly, in such an experiment a single molecule of the nickel catalyst produces up to 10,000 molecules of product. Catalyst loadings that low have, until now, typically been achieved only with catalysts based on palladium. Being able to reach that performance threshold with nickel is, according to the team, genuinely exciting, because it suggests that the abundant metal can, with the right ligand design, match one of the key performance benchmarks that has kept palladium entrenched in industrial practice.

To demonstrate that the system was not a one-reaction curiosity, a small task force formed within the Pieber group, consisting of Trisha Banik, Christos Giannoudis, Florian Ortis, Haralds Baunis, and Gayathri Palissery, set out to study the general applicability of the new catalyst. The team showcased its versatility by making more than 150 distinct products. The range stretched from simple building blocks to complex molecules and included derivatives of established drugs, among them fluoxetine, one of the most commonly prescribed antidepressants in the world. Demonstrating the chemistry on drug derivatives is a meaningful signal for pharmaceutical synthesis, since it suggests the method can tolerate the dense, functionalized molecular environments that real medicinal chemistry demands.

The study, which also involved Daniel Bím of the University of Chemistry and Technology in Prague, ultimately makes a broader argument than any single reaction does. It shows that understanding the fundamental reactivity of nickel-based molecules, down to the level of how catalysts fail and how ligands can protect and empower them, can turn an abundant, inexpensive metal into a catalyst with performance once reserved for precious metals. The combination of low catalyst loading and high generality across many building blocks could make the approach particularly interesting for pharmaceutical and fine-chemical synthesis, where every gram of metal saved and every step simplified translates directly into lower costs and cleaner processes. For an industry under pressure to green its supply chains, a blue lamp and a well-designed ligand may prove to be a quietly powerful combination.

Subject of Research: Light-driven nickel-catalyzed cross-coupling reactions using a tailored ligand to achieve low catalyst loadings

Article Title: Efficient catalysis with less metal

Article References: Efficient catalysis with less metal. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: nickel catalysis, cross-coupling, visible light activation, ligand design, palladium alternatives, Nature Catalysis, pharmaceutical synthesis, sustainable chemistry, catalyst loading, heteroatom bonds, ISTA, fluoxetine

The chemistry at stake is one of the most consequential in modern synthesis. Carbon(sp2)–heteroatom bonds — links between an aromatic ring and nitrogen, oxygen, sulfur or phosphorus — appear throughout pharmaceuticals, agrochemicals and functional materials. For decades, forming them reliably has meant palladium catalysis operating through a Pd(0)/Pd(II) cycle. That manifold demands exquisitely tuned ligands, because two steps pull in opposite directions: oxidative addition, in which the metal inserts into the aryl halide bond, favours electron-rich, sterically accessible metal centres, while reductive elimination, the bond-forming step, often benefits from the opposite electronic character. Because these demands are orthogonal, chemists routinely face extensive ligand screening — increasingly assisted by high-throughput experimentation or machine learning — for each new substrate class.

Nickel offers an elegant escape from this tug-of-war. In a Ni(I)/Ni(III) cycle, the bond-forming reductive elimination from Ni(III) is intrinsically favourable, proceeding with a low activation barrier and often without any elaborate ligand at all. The bottleneck shifts instead to the front end of the cycle: Ni(I) is a tempering, highly reactive metalloradical whose oxidative addition into aryl halides is often too sluggish, particularly for electron-rich aryl bromides, the very substrates that palladium struggles with too. Worse, Ni(I) species tend to die in unproductive ways — forming inactive dimers, resting states or insoluble nickel black — which forces chemists to compensate with high catalyst loadings, sometimes several mole percent, undermining the economic appeal of a non-precious metal.

The Pieber group had previously shown that so-called donor–acceptor ligands allow Ni(I) to be generated simply by irradiating a bench-stable Ni(II) precatalyst with blue light, through an intraligand charge-transfer mechanism. But those systems, like other contemporary Ni(I)/Ni(III) protocols, still could not generally couple electron-rich aryl bromides. An alternative strategy developed by Cornella and Ritter sidestepped oxidative addition altogether by using aryl thianthrenium salts that fragment under single-electron transfer — but that approach falters with electron-poor substrates and demands specialized starting materials. Sterically encumbered nucleophiles such as tertiary alcohols remained out of reach for everyone.

The Austrian team’s solution rests on two design decisions, each grounded in mechanism. The first concerns the additive. Earlier work had shown that the amidine base 1,1,3,3-tetramethylguanidine (TMG) helps weak nucleophiles in dual nickel/photoredox couplings, but TMG is itself a nucleophile and competes in the reaction, which likely explains poor results with secondary alcohols and the complete absence of tertiary alcohol couplings. The researchers reasoned that a truly non-nucleophilic additive was needed. They settled on 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), a TMG derivative whose tert-butyl group blocks its nucleophilic site. Experiments showed that BTMG coordinates reversibly to the standard Ni(II) precatalyst Ni(dtbbpy)Cl2, creating a new absorption band reaching into the visible spectrum. Electron paramagnetic resonance measurements then delivered the key observation: a paramagnetic signal consistent with Ni(I) appeared only when the nickel complex, BTMG and an alcohol were combined under irradiation — never when any component was missing. In other words, BTMG enables light absorption, while the nucleophile’s coordination opens the door to Ni(I) formation, all without any exogenous photoredox catalyst.

The second decision concerns the ligand itself. Building on work by Hadt and coworkers showing that oxidative addition rates of Ni(I) into aryl halides correlate with the energy of the metal’s 3d(z2) orbital, the team hypothesized that strongly electron-donating substituents on a 2,2′-bipyridine scaffold would raise that orbital energy and supercharge oxidative addition. Computational comparisons confirmed the trend across a series of bipyridines. But there was a catch: a hyperactive Ni(I) metalloradical is also a fragile one, prone to dimerization and decomposition. The ideal ligand must therefore balance reactivity with stability. The researchers’ answer was a rationally designed ligand they call dpabpy — 4,4′-bis(diphenylamino)-2,2′-bipyridine. Its diphenylamino substituents are powerful electron donors, boosting the nucleophilicity of the Ni(I) centre, while their extended conjugation creates a low-lying π* orbital that can host the unpaired electron as a ligand-centred radical on a square-planar Ni(II) species. Cyclic voltammetry showed that dpabpy’s reduction potential remains comparable to ordinary bipyridines, meaning the ligand can still be readily reduced to generate Ni(I) — the best of both electronic worlds.

The benchmarking experiments were striking. In carbon–nitrogen couplings across a series of para-substituted aryl bromides, the standard ligand dtbbpy showed yields that fell steadily as the aryl bromide became more electron-rich. Methoxy- and dimethylamino-substituted bipyridines improved matters but still struggled with 4-bromoanisole. Dpabpy outperformed every competitor across the board. More remarkably, at catalyst loadings of 0.1 mole percent — and in one case even 0.01 mole percent — dpabpy delivered near-quantitative product formation with challenging aryl bromides, and it retained its advantage when the reaction time was slashed to a single hour. A light on–off experiment revealed that the reaction halts in the dark, indicating that thermal pathways regenerating Ni(II) resting states are fast, and that the ligand’s steric protection is what keeps Ni(I) from sliding into irreversible dimerization and nickel black. Control studies confirmed that BTMG, dpabpy, nickel and light are each essential.

The substrate scope reads like a medicinal chemist’s wish list. With 1 mole percent of Ni(dpabpy)Cl2 and BTMG at 45 degrees Celsius, aryl bromides bearing nitriles, amines, cyclopropyl groups, sulfones, boronic esters and amides all coupled efficiently with benzyl alcohol or benzyl amine. Six-membered heteroaryl bromides performed well, as did a wide range of five-membered heterocycles including thiophenes, indazoles, benzothiazoles, pyrazoles and triazoles — though some electron-poor pyrroles, oxazoles and imidazoles succumbed to protodehalogenation instead. Primary, secondary, benzylic, allylic and aliphatic alcohols gave yields from 51 to 99 percent, and even water could serve as the nucleophile to make phenols. Most strikingly, tertiary alcohols — long considered unreactive in Ni(I)/Ni(III) couplings — participated successfully, as did sterically demanding secondary amines and α,α,α-trisubstituted primary amines. Beyond oxygen and nitrogen, the platform handled phosphine oxides, amides, carbamates, thiols, sulfinate salts, carboxylic acids, chloride, sulfoximines and sulfonamides.

The practical demonstrations are where the chemistry becomes genuinely viral material for the synthesis community. Late-stage functionalizations succeeded on amoxapine, perphenazine, leelamine, linagliptin and cholesterol as nucleophiles, and on derivatives of tocopherol, celecoxib, D-glucose and flumazenil as electrophiles — including a cross-coupling that stitched a tocopherol derivative directly to linagliptin. On scale, two consecutive coupling steps delivered the antipruritic drug pramocaine in a telescoped one-pot sequence with an overall yield of 47 percent, exploiting the selective mono-etherification of 1,4-dibromobenzene at just 0.1 mole percent catalyst. Even more eye-catching, the N-Boc-protected antidepressant fluoxetine was prepared on a 3.65-gram scale in 89 percent isolated yield using only 100 parts per million of nickel — roughly a thousandth of the metal loading typical of many nickel-catalysed couplings.

What makes this work resonate beyond its impressive numbers is the conceptual lesson: in Ni(I)/Ni(III) catalysis, the ligand’s job is not to force reductive elimination, as in palladium chemistry, but to keep a reactive radical in check while feeding it substrates it can actually activate. By tuning donor strength and redox activity in a single bipyridine scaffold, and pairing it with a non-nucleophilic base that turns visible light into a Ni(I) source from a bench-stable precatalyst, the ISTA team has shown that enhancing oxidative addition is the key that unlocks a general, low-loading, photocatalyst-free platform for carbon–heteroatom bond formation. With a patent application filed and gram-scale drug synthesis already demonstrated, the method seems poised to move quickly from journal pages to medicinal chemistry labs — a reminder that sometimes the biggest leaps in catalysis come not from new metals, but from rethinking the molecules that surround them.

Subject of Research: Mechanistically guided ligand design for low-loading Ni(I)/Ni(III)-catalysed C(sp2)–heteroatom cross-coupling of aryl bromides

Article Title: Ligand design broadens NiI-catalysed C(sp2)–heteroatom couplings of aryl bromides at low catalyst loadings

Article References: Bena, A. R., Banik, T., Giannoudis, C., Ortis, F., Bím, D., Baunis, H., Palissery, G. H., & Pieber, B. (2026). Ligand design broadens NiI-catalysed C(sp2)–heteroatom couplings of aryl bromides at low catalyst loadings. Nature Catalysis. https://doi.org/10.1038/s41929-026-01616-6

Image Credits: AI Generated

DOI: 10.1038/s41929-026-01616-6

Keywords: nickel catalysis, cross-coupling, ligand design, bipyridine, photocatalysis, C–N coupling, C–O coupling, aryl bromides, oxidative addition, late-stage functionalization, pharmaceutical synthesis, Nature Catalysis

The appeal of 3,3-diaryloxetanes stems from their role as bioisosteres of diaryl ketones. Bioisosteric replacement is a cornerstone strategy in drug design: chemists swap one functional group for another that mimics its key electronic and spatial characteristics while improving properties such as solubility, stability or potency. Diaryl ketones, the motif in which two aromatic rings flank a central carbonyl group, appear in numerous marketed pharmaceuticals, including the anti-inflammatory drug ketoprofen, the lipid-lowering agent fenofibrate, the antidiabetic compound adiporon and the antiarrhythmic amiodarone. The polarized carbon–oxygen double bond of the ketone generates a substantial dipole moment, typically around 2.7 to 3.0 Debye, which shapes how the molecule interacts with biological targets through electrostatic contacts and molecular recognition.

Oxetanes reproduce much of this electronic character through an entirely different structural principle. The ring oxygen withdraws electron density through sigma-bond polarization, and the two polarized carbon–oxygen bonds of the strained ring collectively generate a dipole of roughly 1.93 Debye, comparable in effect to the carbonyl dipole. Replacing a flat, planar carbonyl with a tetrahedral oxetane therefore preserves overall polarity while introducing a three-dimensional centre into the molecule, a change that can dramatically alter binding geometry and metabolic fate. Crucially, however, oxetanes and ketones differ fundamentally in reactivity. The carbonyl carbon of a ketone is intrinsically electrophilic because of its low-lying pi-star orbital, whereas oxetanes lack a pi system altogether, and their polarity is distributed across the ring. No carbon on an oxetane behaves like a carbonyl carbon, which means the two motifs can be electronically similar yet chemically orthogonal, an ideal combination for drug design.

Despite this conceptual elegance, synthetic access to 3,3-diaryloxetanes has lagged far behind. The dominant approach, pioneered by James Bull and co-workers, relies on Lewis acid-promoted Friedel–Crafts reactions that proceed through oxetanyl cation intermediates. These reactive intermediates are inherently unstable, and the strongly acidic conditions required restrict the method largely to electron-rich arenes, with competing ring-opening and rearrangement pathways eroding yields and selectivity. Recent iron-catalysed variants have broadened the substrate scope somewhat, but the fundamental limitations of cation chemistry remain. An alternative strategy developed by Phil Baran uses decarboxylative coupling of oxetane-3-carboxylic acid derivatives, generating tertiary benzylic radicals that can engage in cross-coupling. However, these radicals are prone to oxidation to carbocations or reduction to carbanions through radical-polar crossover, and the method demands multistep precursor synthesis and costly starting materials, limiting its practicality and scalability.

The Ritter group’s solution reimagines the problem through the lens of transition-metal catalysis. The chemists hypothesized that converting 3-aryl oxetan-3-ols into electrophiles suitable for nickel-catalysed cross-coupling would provide a modular route, provided they could overcome a formidable obstacle: oxidative addition at the sterically congested carbon–oxygen bond of a fully substituted oxetanyl centre. Such bonds combine steric hindrance with limited intrinsic polarization, disfavouring the oxidative addition step that initiates most cross-coupling cycles. Their answer was to install a tetrafluoropyridyl ether as the leaving group. This electron-deficient aromatic unit polarizes the carbon–oxygen bond and stabilizes the departing tetrafluoropyridone through pi delocalization, striking an optimal balance between reactivity and stability. Unlike strongly electron-withdrawing leaving groups such as triflates, which promote elimination and solvolysis when tertiary benzylic cations form, the tetrafluoropyridyl unit enables controlled activation while its low nucleophilicity and weak basicity suppress ring-opening side reactions.

The practical execution is strikingly simple. In the first step, an aryl bromide is lithiated with n-butyllithium and added to 3-oxetanone, and the resulting alkoxide is trapped in the same pot with pentafluoropyridine to form the oxetanyl tetrafluoropyridyl ether. This one-pot sequence delivered a model substrate in 89 percent yield on a 6.2-gram scale, and the addition of sodium hydride before the trapping step boosted yields by roughly 46 percent. The resulting ethers are bench-stable reagents that can be stored at room temperature for at least six months without detectable decomposition, a critical attribute for a method intended for widespread adoption. Grignard reagents can substitute for the aryllithiums, though the ether formation then works better as a separate step.

The second step is a nickel-catalysed Suzuki-type coupling with arylboronic esters. Using 10 mole percent Ni(cod)2, potassium phosphate as base and isobutanol as an additive in tetrahydrofuran at 30 degrees Celsius, the model coupling afforded the 3,3-diaryloxetane product in 99 percent yield. Control experiments confirmed that every component matters: removing the nickel catalyst or the base eliminated product formation entirely, while omitting the alcohol additive dropped the yield to 73 percent, likely because the alcohol promotes transmetalation of the boronic ester. Notably, palladium catalysts and common nitrogen and phosphine ligands such as dtbbpy and dppf suppressed the reaction, suggesting that strongly coordinating ligands inhibit formation of the reactive nickel species, whereas pi-accepting olefin additives such as 4-methoxystilbene maintained efficiency and may stabilize the catalytically active complex.

The substrate scope demonstrates the modularity that has been missing from this field. Both electron-rich and electron-deficient aryl bromides were converted to the ether precursors in 80 to 95 percent yields on 5-millimole scale, and heteroaromatic motifs including indole, benzothiophene, benzofuran, furan and quinoline were all incorporated. On the coupling side, electron-poor arylboronic esters, heteroaryl boronates and even alkenyl boronic esters performed smoothly, a striking contrast to Friedel–Crafts chemistry, where such substrates are typically unreactive because reactivity there depends on arene nucleophilicity rather than metal-catalysed processes. A methyl ester-bearing product was obtained in 95 percent yield on gram scale. Late-stage diversification succeeded on complex molecules including fenbufen, estrone, tocopherol, flurbiprofen and pyriproxyfen, and the method extended to 3,3-diaryl azetidines, although cyclobutane analogues remain out of reach because their tetrafluoropyridyl ethers are too unstable to isolate.

The synthetic payoff is best illustrated through drug analogues. The team prepared oxetane versions of scaffolds related to ketoprofen, oxybenzone, fenofibrate and a tyrosine kinase inhibitor, and assembled an oxetane analogue of adiporon, a drug candidate for type 2 diabetes, in 65 percent yield after deprotection and amide formation. Most dramatically, a KIT inhibitor intermediate was reached in 20 percent overall yield over two steps from 3-oxetanone, whereas a previous route required four steps and delivered only 0.1 percent overall yield. A second intermediate was obtained in 58 percent yield over two steps compared with 22 percent across four steps previously, and it can be advanced to a complement C1s inhibitor by established procedures.

Mechanistic studies support a conventional but hard-won catalytic cycle. Stoichiometric and catalytic nickel both delivered high yields, and experiments with the one-electron oxidant ferrocenium showed that nickel(I) cannot sustain turnover, implicating nickel(0) as the active species. The radical scavenger BHT had little effect, while TEMPO completely inhibited the reaction with quantitative recovery of starting material, consistent with a polar pathway free of radicals, though TEMPO is also known to oxidize low-valent nickel directly. A Hammett analysis gave a shallow negative reaction constant of minus 0.49, indicating only weak dependence on aryl electronics. Together the data point to a Ni(0)/Ni(II) manifold of oxidative addition, transmetalation and reductive elimination, distinct from the Ni(I)/Ni(III) radical pathways common in modern cross-coupling. The work establishes tetrafluoropyridone as a leaving group worth exploring more broadly and hands medicinal chemists a programmable, two-step entry to benzophenone bioisosteres that were previously among the most difficult scaffolds to access.

Subject of Research: Modular nickel-catalysed synthesis of 3,3-diaryloxetanes as ketone bioisosteres from 3-oxetanone

Article Title: Modular synthesis of 3,3-diaryloxetanes

Article References: Sun, Q., Liu, J., & Ritter, T. (2026). Modular synthesis of 3,3-diaryloxetanes. Nature Synthesis. https://doi.org/10.1038/s44160-026-01183-5

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01183-5

Keywords: oxetanes, bioisosteres, nickel catalysis, cross-coupling, 3-oxetanone, drug discovery, medicinal chemistry, tetrafluoropyridyl ether, oxidative addition, synthetic methodology, diaryl ketones, heterocycles

The difficulty lies in how aziridines are activated. In classical approaches, chemists attach strongly electron-withdrawing groups such as tosyl or nosyl to the ring nitrogen. These groups weaken the carbon-nitrogen bonds, making the ring susceptible to attack by nucleophiles or to activation by transition metals. The problem is that the activating group must then be stripped away and replaced with the desired N-substituent, typically through alkylation or reductive amination, adding steps, waste and cost to every synthesis. For N-alkyl aziridines, which already carry the nitrogen substituent one actually wants, this detour is impossible by definition, and the rings have remained essentially inert under established transition-metal catalytic manifolds.

The Leonori group’s solution, published in Nature Chemistry, begins with a simple Lewis acid-base interaction. Borane, BH3, coordinates to the nitrogen atom of the aziridine, forming a stable aziridine-ligated borane complex. This complex can then be converted into an aziridine-ligated boryl radical, a species in which the unpaired electron sits on the boron centre. That radical undergoes a regioselective beta-scission, cleaving the more substituted carbon-nitrogen bond and releasing the strain of the three-membered ring to generate a beta-aminoalkyl radical. Crucially, this radical intermediate is exactly the kind of species that modern cross-coupling catalysis is built to capture.

The idea has deep roots. In pioneering low-temperature electron paramagnetic resonance studies, Brian Roberts and colleagues showed decades ago that amine-borane complexes could undergo hydrogen-atom abstraction to form amine-ligated boryl radicals, which rapidly fragmented across the aziridine ring. But that reactivity had never been exploited synthetically. The Aachen team recognised that if the fragmentation could be tamed and the resulting radicals funnelled into catalytic cross-couplings, the entire activating-group economy of aziridine chemistry could be rewritten.

Before running a single reaction, the researchers turned to computation to interrogate a subtle stereochemical hazard. Because the aziridine nitrogen is pyramidalised in the borane complex, two diastereomeric boryl radicals, trans and cis, can form. Roberts’ data had suggested these diastereomers fragment across different carbon-nitrogen bonds, which threatened to produce messy mixtures of regioisomeric products. The team’s calculations, performed at the UM06-2X/def2-QZVP level with solvation corrections, told a more encouraging story. For aziridines bearing a beta-phenyl substituent, both diastereomers fragment with complete regioselectivity toward the stabilised benzylic radical, in processes that are highly exothermic and essentially barrierless. For beta-alkyl substrates the picture is more nuanced: the trans diastereomer selectively delivers the desired secondary radical, aided by favourable orbital overlap between the boryl radical’s singly occupied molecular orbital and the sigma-star orbital of the more substituted carbon-nitrogen bond, while the cis isomer risks promiscuous cleavage. Fortunately, borane coordination was found to deliver the trans diastereomer exclusively or predominantly in practice.

With the mechanism mapped, the team built two complementary catalytic platforms. The first is an oxidative copper system. A copper(I) catalyst reacts with a silyl peroxide oxidant, cumylO2TMS, to generate an electrophilic cumyloxyl radical. This radical performs a polarity-matched hydrogen-atom abstraction on the aziridine-borane complex, forging the boryl radical that fragments to the beta-aminoalkyl radical. Meanwhile, a nucleophile such as an aryl boronic acid transmetalates with copper(II) to form an aryl-copper species that captures the radical. Reductive elimination, either through a discrete copper(III) intermediate or by direct carbon-carbon bond formation, delivers the beta-arylated product, which is unmasked to the free N-alkylamine during hydrolytic work-up. A clever design feature is that the arylated intermediate formed before work-up shields the alpha-nitrogen positions from further hydrogen abstraction, protecting the product from over-functionalisation under the oxidative conditions.

The scope of this copper manifold proved impressively broad. Using an N-propyl aziridine and phenylboronic acid as benchmarks, the team obtained the beta-phenylated amine in good yield, including on gram scale. Electron-rich and electron-poor para-substituted boronic acids, meta-substituted and disubstituted reagents, 2-naphthyl, benzofuranyl and even pyridyl boronic acids all coupled successfully. On the aziridine side, both electron-rich and electron-poor beta-aryl groups were tolerated, including a cyclobutane-annulated system, and the N-substituent could be methyl, hexyl, benzyl, isopropyl or cyclohexyl. The same catalytic blueprint also accepted other nucleophiles: trimethylsilyl cyanide delivered beta-nitrile amines, valuable because the nitrile can be hydrolysed to beta-amino acids, while diphenyl disulfide furnished beta-thioether derivatives in high yield, and proof-of-concept azidation and phthalimidooxylation reactions were also demonstrated.

Perhaps the most striking feature of the chemistry is its regioselectivity. In classical aziridine ring openings, the substrate dictates the outcome: benzylic systems cleave at the more substituted position to give branched products, whereas beta-alkyl systems prefer the less substituted bond and deliver linear products. Methods that override this intrinsic bias are exceedingly rare. The boryl radical fragmentation does exactly that, consistently cleaving the more substituted carbon-nitrogen bond across both beta-aryl and beta-alkyl substrates. Every substrate examined in the cyanation series, including derivatives based on the antiarrhythmic drug mexiletine, a glycine derivative, an atorvastatin intermediate and a medicinally relevant N-Boc-piperidinyl motif, delivered the branched product exclusively. Even an unsubstituted aziridine, proceeding through a primary radical, could be opened, and gem-disubstituted systems gave access to alpha,beta-difunctionalised amines and tertiary nitriles.

Where the copper system falters, a second platform picks up the slack. Beta-alkyl aziridines coupled only modestly under copper catalysis, so the team embedded the same hydrogen-atom abstraction and fragmentation steps into a dual photo-nickel manifold. Triplet-excited diaryl ketone photocatalysts, activated by purple light-emitting diodes, abstract the hydrogen atom from the borane complex, while a nickel catalyst handles the cross-coupling with aryl bromides, a widely available class of electrophilic partners. After oxidative addition of the aryl bromide to nickel(0), the beta-aminoalkyl radical is captured by the aryl-nickel(II) complex, and reductive elimination from the resulting nickel(III) intermediate delivers the product, with the ketyl radical by-product closing both catalytic cycles through single-electron transfer. This umpolung variant, pairing the aziridine with electrophiles rather than nucleophiles, lifted the yield of the model beta-alkyl arylation to 54 percent and tolerated a wide panel of aryl and heteroaryl bromides, including pyridyl and thiazole systems, although strongly electron-donating substituents and highly stabilised benzylic radicals proved limiting.

Together, the two manifolds offer chemists a choice of partner and catalyst matched to the radical at hand, all flowing from a single mechanistic blueprint. By eliminating the historical dependence on electron-withdrawing N-activating groups, the work streamlines access to beta-functionalised N-alkylamines, compounds that sit at the heart of countless bioactive molecules, and establishes aziridine-ligated boryl radicals as a genuinely useful class of synthetic intermediates. The Aachen team anticipates that the generality of the activation mode will accelerate the synthesis of biologically relevant targets and inspire broader exploration of amine-ligated boryl radicals, a reactivity logic that sat dormant in the literature for four decades before finally being put to work.

Subject of Research: Radical ring-opening and divergent functionalization of N-alkyl aziridines via aziridine-ligated boryl radicals

Article Title: Divergent ring opening and functionalization of N-alkyl aziridines via boryl radical fragmentation

Article References: Peng, P., Roure, B., Lulli, T., Stavagna, C., Lonardi, G., & Leonori, D. (2026). Divergent ring opening and functionalization of N-alkyl aziridines via boryl radical fragmentation. Nature Chemistry, 18(10), 1755-1762. https://doi.org/10.1038/s41557-026-02247-x

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02247-x

Keywords: aziridines, boryl radicals, ring opening, copper catalysis, nickel catalysis, photocatalysis, cross-coupling, beta-aminoalkyl radicals, regioselectivity, borane coordination, organic synthesis, medicinal chemistry

The bond at the heart of the work is the C(sp3)–C(sp3) linkage, the connection between two tetrahedral, saturated carbon atoms. These bonds form the skeletal framework of the vast majority of drugs, agrochemicals and natural products, yet they remain among the hardest bonds for synthetic chemists to forge selectively. Conventional cross-coupling methods, which earned the Nobel Prize in Chemistry in 2010, excel at joining flat, sp2-hybridized carbons but struggle with the stubborn, unreactive sp3 carbons that dominate three-dimensional molecular architecture. Radical approaches — in which two carbon-centred radicals recombine — offer an appealing alternative, but they come with a fundamental catch.

That catch is diffusion control. When two free radicals meet in solution, they combine at essentially the rate at which random molecular motion brings them together. The chemistry offers no inherent preference for coupling two different radicals over two identical ones, so reactions tend to produce statistical mixtures: the desired cross-coupled product alongside wasteful homodimers of each partner. Compounding the problem, the transition-metal catalysts typically used to impose order on this chaos are exquisitely sensitive to the redox environment of the reaction. Radical generation is inherently a redox process, and the reactive intermediates it creates can push a delicate nickel or iron catalyst into inactive oxidation states, collapsing the very selectivity the catalyst is meant to provide.

The Harbin team’s solution is an elegant act of chemical bookkeeping: decoupling radical generation from catalytic redox maintenance. Instead of asking a single catalytic system to both create radicals and keep the cross-coupling catalyst in its productive state, the researchers split the labour. Light handles the first job through photoinduced ligand-to-metal charge transfer, a process in which a photon excites an electron from a ligand — here, a carboxylate or alkoxide bound to an iron centre — up to the metal, tearing the bond apart and releasing an alkyl radical under remarkably mild conditions. Electricity handles the second job, continuously regulating the redox balance of the catalytic cycle through the applied potential at the electrode, so that the metal catalyst neither accumulates in an over-reduced state nor burns out through over-oxidation.

Bringing these two energy inputs together with a dual-metal catalyst — iron for radical generation and nickel for selective bond formation — the system accomplishes an impressive range of transformations. Double decarboxylative couplings join two carboxylic acids by expelling carbon dioxide from both partners. Dehydroxymethylative couplings convert alcohols into alkyl radicals by cleaving a C–C bond adjacent to the hydroxyl group. Deformylative couplings do the same for aldehydes, stripping the formyl group to reveal the underlying alkyl fragment. In every case, the starting materials are native functional groups — the very handles already present in feedstock chemicals, metabolites and drug candidates — requiring no conversion into redox-active esters or other activated derivatives.

The substrate scope reported in the study is strikingly broad. The method accommodates primary, secondary and even sterically hindered tertiary carbon centres, and it works across every pairing: primary-to-primary, primary-to-secondary, secondary-to-secondary, primary-to-tertiary and even tertiary-to-tertiary couplings. Quaternary carbon centres — carbons bonded to four other carbons, a structural motif that confers biological potency but that synthetic chemists find notoriously difficult to construct — fall within reach. The authors also demonstrated applications to the synthesis of pharmaceutically relevant intermediates, suggesting the chemistry could shorten routes to drug candidates by allowing medicinal chemists to couple molecular fragments at late stages rather than building complex scaffolds from scratch.

How does the system avoid the statistical chaos that plagues ordinary radical recombination? The mechanistic studies point to a process called SH2 radical sorting, or bimolecular homolytic substitution at a metal centre. Rather than letting two radicals find each other freely in solution, the nickel catalyst captures one radical to form a high-valent organonickel species, and the second radical then attacks that complex directly, displacing the coupled product in a single, ordered step. This pathway imposes selectivity that diffusion-controlled recombination cannot, channelling the reaction toward the cross-coupled product. Electron paramagnetic resonance spectroscopy and cyclic voltammetry provided experimental support for this picture, tracking the radical intermediates and the oxidation states of the nickel catalyst as the reaction proceeded.

One of the most intriguing mechanistic findings concerns a seemingly humble additive: a sacrificial alkyl bromide. Mechanistic analysis indicated that this reagent prevents over-reduction of nickel, sustaining a Ni(II)/Ni(III) catalytic cycle — the oxidation-state shuttle that mediates the selective radical cross-coupling. In an electrochemical setting, where the electrode continuously pumps electrons into the system, keeping the catalyst from sliding into an inactive low-valent state is a genuine challenge. The sacrificial bromide acts as a redox buffer, preferentially accepting electrons that would otherwise reduce the nickel catalyst beyond its productive cycle. It is a small molecular chaperone with an outsized role in keeping the entire catalytic machine running.

The significance of the work extends beyond any single reaction. It sits at the confluence of three rapidly advancing fields: photocatalysis, electrocatalysis and first-row transition-metal catalysis. By using earth-abundant iron and nickel rather than precious metals, and by drawing energy from light and electricity rather than stoichiometric chemical oxidants and reductants, the approach aligns with the growing demand for sustainable synthesis. The electrochemical component also offers something batch chemistry rarely can: a tunable dial. By adjusting the applied potential, chemists can influence which intermediates form and which oxidation states persist, effectively programming the reaction’s selectivity through waveform control — a concept that has already transformed related electrochemical transformations such as modern versions of the century-old Kolbe electrolysis.

For the broader chemistry community, the study offers a template for taming radical reactions that were previously considered too promiscuous to be useful. If two carbon radicals can be generated from the most ordinary functional groups and then sorted selectively into a single cross-coupled product under mild conditions, the retrosynthetic imagination of chemists expands considerably: complex molecules could be conceived as combinations of simple carboxylic acid, alcohol or aldehyde fragments, joined where needed by a photon, an electron and a pair of cheap metal catalysts. The Harbin team’s data, including raw NMR, cyclic voltammetry and EPR datasets deposited openly on Zenodo, will allow other groups to scrutinize and build upon the mechanism. What remains to be seen is how far the platform can stretch — whether it can be rendered enantioselective, extended to heteroatom-bearing fragments, and scaled from milligram demonstrations to the gram and kilogram quantities that industrial synthesis demands. For now, the message is clear: the once-chaotic world of radical coupling is being brought under disciplined control, one photon and one electron at a time.

Subject of Research: Photoelectrochemical C(sp3)–C(sp3) radical cross-coupling of native functional groups using iron–nickel dual catalysis

Article Title: Photoelectrochemical C(sp3)–C(sp3) cross-coupling using native functional groups

Article References: Zhong, P.-F., Yang, C., Guo, L., & Xia, W. (2026). Photoelectrochemical C(sp3)–C(sp3) cross-coupling using native functional groups. Nature Synthesis. https://doi.org/10.1038/s44160-026-01162-w

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01162-w

Keywords: photoelectrochemistry, cross-coupling, C(sp3)–C(sp3) bonds, radical sorting, nickel catalysis, iron catalysis, ligand-to-metal charge transfer, decarboxylation, SH2 mechanism, electrocatalysis, photocatalysis, organic synthesis

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