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Nature Chemistry, Published online: 24 March 2026; doi:10.1038/s41557-026-02103-y

Nature Chemistry, Published online: 19 March 2026; doi:10.1038/s41557-026-02105-w

Despite intense interest, the mechanism of iron-catalyzed aryl–aryl cross-coupling remains poorly understood. Combining Mössbauer spectroscopy, kinetics analysis, and DFT computations these studies reveal a novel Fe(I)/Fe(II)/Fe(III) catalytic for aryl–aryl cross-coupling mediated by an Fe(II) PC_NHCP Pincer complex. These findings close a key knowledge gap and offer design principles for sustainable iron-mediated cross-coupling.

ABSTRACT

The widespread use of precious metal catalysts in C–C bond-forming reactions is increasingly challenged by concerns over toxicity, cost, and limited availability. As a sustainable alternative, iron offers distinct advantages in cross-coupling chemistry, but its broader application has been hindered by limited mechanistic understanding. Here, we report a mechanistically driven investigation of aryl–aryl Kumada cross-coupling catalyzed by our previously reported iron complex [(PC_NHCP)FeCl₂] (2). Through a combination of multinuclear NMR, ⁵⁷Fe Mössbauer spectroscopy, single-crystal X-ray diffraction, and reactivity studies, we identify and characterize key in situ formed intermediates, including mono- and bis-arylated iron species, along the catalytic pathway. While PCP-ligated Fe(II) complexes support two-electron chemistry, our findings uncover a distinct radical mechanism responsible for the efficient formation of the biaryl products. Furthermore, we demonstrate that small coordinating molecules, such as N₂, significantly influence the speciation and reactivity of the iron catalyst. These insights advance fundamental understanding of iron-mediated cross-coupling and provide new design principles for sustainable C(sp²)–C(sp²) bond construction.

A data-driven platform integrates curated data and mechanistic modeling to guide catalyst design for N,N′-dioxide/metal-catalyzed Michael additions.

Abstract

Rational catalyst design and accurate selectivity prediction remain major challenges in asymmetric synthesis, which is critical for improving and innovating existing catalytic systems. Among them, chiral N,N′-dioxide/metal complexes have emerged as a powerful and broadly effective class of privileged catalysts, yet systematic tools for understanding and optimizing their performance remain underdeveloped. Here, we present an integrated data platform that unifies literature curation, mechanistic modeling, and predictive analytics to support intelligent catalyst selection for asymmetric N,N′-dioxide/metal-catalyzed Michael additions. We curated over 2,000 reactions from two decades of research into a chemically annotated, machine-readable dataset encompassing catalyst structure, reaction conditions, and stereochemical outcomes. This dataset enabled global statistical analyses of application patterns across metal–ligand–substrate combinations and supported a modeling framework that combines intermediate-informed data augmentation with similarity-weighted tuning, which improved predictive ability on reactions involving previously unseen substrates. Comprehensive experimental validations covering diverse substrates, ligands, and metals confirmed the model's robustness and transferability across a wide selectivity range, including the accurate identification of new highly enantioselective transformations. These findings highlight the value of data-integrated platforms in advancing the development of new reactions within complex asymmetric systems and provide an intelligent framework for future expansion of the N,N′-dioxide catalysis.

Hard-to-access (hetero)aryl sulfonium salts are prepared using stable methoxysulfonium salts in combination with the magnesiation of (hetero)aryl bromides. The approach allows access to aryl sulfonium salts bearing electron-deficient (hetero)aryl rings, or electron-rich aryl motifs in which the sulfonium motif resides at an alternative position on the ring to that delivered by electrophilic sulfenylation. The new sulfonium salts extend the scope of photocatalytic, photochemical, and ligand-coupling processes.

ABSTRACT

Aryl sulfonium salts are indispensable partners in cross-coupling reactions, allowing access to aryl metal or aryl radical intermediates, and offering advantages over aryl halides or other pseudohalides. Routes to aryl sulfonium salts are limited; the standard approach involves activation of arenes using a sulfoxide-derived electrophile. While the activation of non-prefunctionalized arene partners is attractive, the method is limited to arenes that are sufficiently electron-rich to engage with sulfur electrophiles and is often dominated by para-selectivity when monosubstituted benzenes are used. This limited access to aryl sulfonium salts leads to biased substrate scopes and restrictions on accessible chemical space. We describe a route to otherwise hard-to-access (hetero)aryl sulfonium salts that exploits bench-stable alkoxysulfonium salts in combination with the well-established magnesiation of readily available aryl bromides. The approach allows access to aryl sulfonium salts bearing electron-deficient aryl and heteroaryl rings, or electron-rich systems in which the sulfonium motif resides at an alternative position on the ring to that delivered by electrophilic arene sulfenylation. To illustrate their value, the new sulfonium salts have been used to expand the scope of a selection of coupling processes.

This study developed a mild electrochemical method for the efficient synthesis of caprolactam using Ag-Ag₄Sn-SnO₂ catalysts, scaling up the reactor with a CPL productivity of up to 3.41 g h⁻¹ g_cat ⁻¹, highlighting the potential of this technology for large-scale electrosynthesis.

ABSTRACT

Caprolactam (CPL), a monomer of nylon-6 widely used in automotive, machinery, and electronics, is traditionally synthesized from cyclohexanone (CYC) through a complex process that generates low-value ammonium sulfate, leading to environmental pollution. In contrast, electrochemical methods offer a safer, greener one-pot synthesis of CPL from waste NO₃ ^–, but currently, the coupling of CYC and NO₃ ^– primarily produces cyclohexanone oxime (CHO), and the direct generation of CPL is challenging. Here, we report for the first time the electrochemical conversion of CYC and NO₃ ^– to high-value CPL in a one-pot process under ambient conditions. Using Ag-Ag₄Sn-SnO₂ nanoparticle catalysts, we achieved a remarkable 96% yield and 97% selectivity for CPL electrosynthesis. In situ characterizations, control experiments, and theoretical calculations suggested the importance of balanced activation of NO₃ ^– and CYC substrates on the Ag-Ag₄Sn-SnO₂ catalysts for achieving high-efficient CPL electrosynthesis. The method also exhibits broad versatility in synthesizing various amide compounds, including paracetamol for antipyretic. Notably, scaling up the reactor enabled a high CPL production rate of 3.41 g h⁻¹ g_cat ⁻¹ with a 90.5% isolated yield, highlighting the potential of this technique for large-scale electrosynthesis.

Selective electrochemical benzylic C─H pyridination is achieved in an undivided flow cell using a tailored pyridine. Electronic tuning suppresses competing aromatic substitution and enables the formation of versatile benzylic pyridinium intermediates, which undergo diverse downstream transformations to afford primary benzylamines and a wide range of carbon- and heteroatom-functionalized products under practical and scalable conditions.

ABSTRACT

C─H diversification strategies that enable access to various C─X (X = heteroatom) and C─C bonds are of central importance in synthetic chemistry. Here we present a benzylic C─H diversification protocol that merges electrochemical C─H pyridination with subsequent aminolysis or substitution to access unprotected benzylamines and a wide range of benzylic products. The electrochemical transformation proceeds in an undivided flow cell under oxidant- and transition-metal-free conditions and shows broad generality across electron-rich, electron-deficient, and halogenated alkylarenes. A key element is the use of a tailored pyridine with appropriate electronic properties, which suppresses undesired aromatic substitution while facilitating aminolysis and nucleophilic substitution of the pyridinium intermediate. The practicality of this method is underscored by a continuous operation in parallel microreactors, which furnished more than 100 g of benzylamine product.

Photocatalytic cross-coupling: A redox-neutral photochemical method enables direct C(sp²)─C(sp²) bond formation between phenols and heteroaryl halides using an organic dye and base. Complementary radical generation allows efficient cross-coupling in up to 91% yield. Mechanistic studies, DFT, HTE, and machine learning rationalize and predict reactivity, offering a sustainable approach to this challenging transformation.

ABSTRACT

Developing sustainable methods for C(sp²)─C(sp²) bond formation that avoid transition-metals and prefunctionalized substrates remains a central goal in synthetic chemistry. Phenols and N-heteroarenes (azines) are abundantly available, yet their cross-coupling is hindered by mismatched redox properties and chemoselectivity issues. Herein, we report a photochemical strategy that couples phenols with heteroaryl halides under redox-neutral conditions using an organic dye photocatalyst and base. Concurrent oxidation of the phenol component and reduction of the azine component generates complementary radicals that cross-couple efficiently, delivering moderate to high yields (up to 91%) with high functional group tolerance. Mechanistic experiments and density functional theory (DFT) studies elucidate the radical reaction pathways, while substrate clustering, high-throughput experimentation (HTE), and machine learning (ML) enable prediction of C–C versus S_NAr reactivity across broad chemical space.

We develop a computation-guided screening strategy to precisely regulate localized hydrogen affinity on Cu surfaces through site-specific Rh atomic decoration, which demonstrates broad applicability and achieves high electrification efficiencies for diverse aldehydes.

ABSTRACT

Electrifying aldehydes into high-value chemicals presents a sustainable solution for environmental remediation, resource recovery and upgrade, yet its practical implementation has been limited by inefficient electrodes. Here, we develop a computation-guided strategy—localized hydrogen-affinity engineering—to synthesize heteroatom-decorated Cu hydrogenase for aldehydes electrification. Remarkably, the as-prepared Rh-decorated Cu hydrogenase (Rh₁Cu-Hase) achieves a remarkable Faraday efficiency of >99.3% for formaldehyde conversion at an ultrahigh current density of 500 mA cm⁻² with a minimal overpotential of 283 mV. A membrane-free electrolyzer equipped with the Rh₁Cu-Hase operates stably for over 1200 h at 1000 mA cm⁻², continuously producing high-purity potassium diformate (KDF) and hydrogen. Techno-economic analysis reveals a significant $166.1/ton KDF revenue advantage over conventional methods. The paired dehydrogenation mechanism is proposed by a series of operando studies and theoretical calculations, unveiling that the Cu matrix facilitates aldehyde adsorption, while atomic Rh sites activate hydrogen, collectively reducing energy barriers for both C─H cleavage and H─H coupling. Furthermore, the universality of this strategy is demonstrated by its successful application in electrifying a broad range of industrially relevant aldehydes.