Finn Moeller

Phenonium ions have frequently been viewed as intermediates of theoretical interest, but whose synthetic utility was limited. This minireview outlines how physical-organic characterization has led to a better understanding of controlling their formation, which has resulted in modern strategies to form phenonium ions straightforwardly and use them in a synthetically useful manner.

Abstract

Whereas phenonium ions have been known for decades, their use in synthesis has been surprisingly scarce. This might be attributed to the difficulty in taming their formation and reactivity. However, by considering the physical-organic properties of phenonium species, through careful design of substrates, or the use of defined reagents/promoter systems, several applications have emerged in recent years to overcome those challenges. This minireview encompasses key recent strategies to generate those highly reactive cationic intermediates in line with their physicochemical properties, with special emphasis on mechanistic aspects, regioselectivity, and functional group compatibility.

Described here is a La^NTMS mediated silylative conversion of primary amides to nitriles under neat reaction conditions. The reaction is highly efficient and selective under such solventless conditions, where all materials are commercially available, demonstrating the robustness and potential of lanthanide heteroatom catalysis.

Abstract

Efficient, selective, and environmentally benign catalytic nitrile synthesis is attractive for pharmaceuticals, specialty chemicals and materials, and large-scale industrial applications. In this regard, metal-catalyzed silylative conversion of primary amides to nitriles is emerging as a promising approach. This contribution reports the utilization of readily available lanthanide-organic amido precatalysts, Ln[N(SiMe₃)₂]₃, Ln = lanthanide, to selectively convert primary alkyl and aryl/heterocyclic amides having diverse functional groups to nitriles, including pharma building blocks, in high yields using the silane reagents PhSiH₃ and TMS-O-[Si(H)(Me)-O-]_n-TMS in a solvent-free process. Kinetic and mechanistic data reveal the role of lanthanide amidates as the catalytically-active species, while DFT analysis indicates a catalytic pathway unlike that found in transition metal complex-catalyzed processes. Thus, the lanthanide amidate resting state actively participates in the catalysis, where rate-determining bound amidate silylation is activated by the metal center and influenced by the bound amidate electronic and steric characteristics. DFT analysis of the catalytic cycle reveals that the relative energies of three intermediate endergonic steps, hence the rate-determining step, depends on the silane concentration.

An electrochemical α-C─H functionalization of nitramines enables the synthesis of molecules containing bifunctional energetic heterocycles with promising properties. A telescoped, HNO₃-free sequence involving nitration and azolation steps offers a safer, modular, and scalable platform for the synthesis of energetic compounds.

Abstract

The synthesis of energetic materials (EMs) often involves hazardous reagents and harsh conditions, raising safety and environmental concerns. We herein present an electrochemical method for the ⍺-C─H azolation of nitramines, enabling the integration of nitramines and various nitrogen-rich azoles as dual energetic components within the same molecule. To enhance the practicality of the overall synthesis, we developed a tandem two-step process that transforms free amines into nitramines using stable and readily available reagents, which was complemented by subsequent electrochemical azolation to complete a streamlined, scalable preparation of bifunctional energetic compounds. Finally, a continuous flow system was employed to further improve the practicality of the electrosynthetic method, which substantially reduced electrolyte usage and increased productivity. Computational and experimental data revealed that the introduction of azoles, particularly those with additional nitro substituents, improves the energy density and thermal stability of nitramines. This work provides a proof of concept that the reported electrochemical azolation reaction may not only offer a safer and more sustainable alternative to traditional approaches for energetic material synthesis, but it will also provide a platform for the discovery of novel compounds with favorable energetic properties.

Nature, Published online: 25 September 2025; doi:10.1038/d41586-025-03143-z

The norbornane-2,6-dione framework can accommodate a carbon-carbon ylide with a zwitterionic σ-bond.

Abstract

Here, we have reported the computational design of a new class of ylides, elusive carbon–carbon ylides featuring zwitterionic σ-bonds, derived from the norbornane-2,6-dione framework. Utilizing the state-of-the-art computational methods, we have demonstrated that appropriate substitutions on this scaffold can stabilize a carbanion at C1 and a carbocation at C7 without orbital overlap, ensuring a zwitterionic electronic structure akin to a CC-ylide. Large singlet–triplet energy gaps guarantee that these species do not adopt a diradical ground state. Time-dependent DFT computations further have revealed small T1–S1 energy gaps, suggesting potential applications of similar scaffolds in thermally activated delayed fluorescence (TADF) materials. Our analyses have identified the cation on C7 as the most reactive site on the molecule toward unwanted reactions, leading to the degradation of the ylides. With their unique electronic structure, CC-ylides present new opportunities for unexplored chemical reactivity and functional material design.

A nickel catalyzed electrochemical cross-electrophile coupling approach for the base-free synthesis of (un)symmetric (hetero)aryl and alkyl sulfides from organic halides and disulfides is described. The reaction is broadly applicable and tolerates water and air atmosphere.

A formal cross-electrophile coupling approach enables the base-free synthesis of (un)symmetric (hetero)aryl and alkyl sulfides from organic halides and disulfides. This water and air-tolerant process utilizes the addition of electrochemically generated thiolate to an in situ-generated reactive nickel species.

The late-stage oxidation of C(sp³ )─H bonds is valuable for modulating properties and diversification. We report that perfluorinated ruthenium porphyrins catalyze the undirected C(sp³ )─H oxidation of various natural products and drugs with high turnover numbers. In combination with directed C─H silylation, alkyl groups remote from existing functionality can be formally dihydroxylated.

Abstract

The late-stage oxidation of C(sp³ )─H bonds is highly valuable for modulating the solubility and binding of bioactive compounds and for diversification of complex molecules. Undirected methods for C(sp³ )─H oxidation are valuable for the installation of hydroxyl groups at sites remote from other functional groups present in the molecule, but existing catalysts are limited by low turnover numbers and lengthy ligand syntheses. Perfluorinated ruthenium porphyrins are highly active catalysts for the oxidation of alkyl C─H bonds, but the scope of the transformation with complex molecules under conditions of limiting substrate has not been investigated. We report that carbonylruthenium(II) tetrakis(pentafluorophenyl)porphyrin [Ru(TPFPP)(CO)] catalyzes the selective oxidation of tertiary C(sp³ )─H bonds in a broad range of complex natural products and drugs, with turnover numbers as high as 1000, and the tolerance of the reaction to various functional groups was rapidly assessed by performing a model reaction in the presence of additives. We show how the combination of this undirected C(sp³ )─H oxidation and a directed C(sp³ )─H silylation and oxidation provides rapid access to highly oxidized, 1,2-diol derivatives of natural products by a formal dihydroxylation of an alkyl group.

We present a synergistic strategy combining photocatalytic direct C─F borylation of polyfluoroarenes with Suzuki–Miyaura cross-coupling. The high nucleophilicity of amine-ligated boryl radicals enables efficient homolytic aromatic substitution of polyfluoroarenes, forming stable amine–borane adducts that resist protodeboronation and can be directly used in cross-coupling to access functionalized polyfluoroarenes.

Abstract

Polyfluoroarenes are privileged scaffolds in pharmaceutical and materials science, yet their synthesis remains challenging. Aromatic borylation offers a modular entry point for derivatization via Suzuki–Miyaura cross-coupling, but progress is hindered by two persistent issues: the difficulty of direct borylation on electron-deficient polyfluoroarenes, and the pronounced susceptibility of the resulting boron species to rapid protodeboronation under standard cross-coupling conditions. Here, we present an orthogonal strategy that addresses both limitations. Amine-ligated boryl radicals enable direct radical C─F borylation of polyfluoroarenes under visible-light photoredox catalysis. The resulting amine–borane adducts are crystalline, bench-stable, and resistant to protodeboronation, allowing their direct use in Pd-catalyzed Suzuki–Miyaura cross-couplings. This platform provides scalable and broadly applicable access to functionalized polyfluoroarenes and overcomes some of the synthetic constraints associated with these valuable motifs.

Nature, Published online: 17 September 2025; doi:10.1038/d41586-025-02930-y

This work presents the total synthesis of micitide 982. The key advancement lies in the combination of Ni-catalyzed electrochemical cross-electrophile coupling and regioselective Larock macrocyclization, which enables the efficient construction of the highly strained Tyr C6-to-Trp C5′ linkage, as well as the completion of micitide 982.

Abstract

In this study, a facile synthesis method for a highly strained Tyr C6-to-Trp C5′ linkage was developed. This method enables the convergent introduction of arbitrary biaryls to peptide linkers through electrochemically assisted Ni-catalyzed cross-electrophile coupling, followed by regioselective Larock macrocyclization. Additionally, using this approach, the total synthesis of the ribosomally synthesized and post-translationally modified peptide (RiPP) molecule micitide 982 was accomplished. Furthermore, this synthetic strategy allows for the incorporation of various biaryls.

The photoinduced borylation of alkyl bromides via halogen atom transfer is reported. The utility of this strategy is demonstrated with broad functional group tolerance in the borylation of various primary, secondary, and tertiary alkyl bromides. Computational studies provide mechanistic insights into the radical-chain pathway.

Abstract

Alkyl organoboron compounds are versatile synthons in organic synthesis, enabling rapid access to a variety of carbon─carbon and carbon-heteroatom bonds. As such, strategies to efficiently access carbon-boron bonds from simple chemical feedstocks are highly desirable. The radical borylation of alkyl bromides presents an attractive approach. However, the activation of alkyl bromides typically requires strong reductants or transition-metal catalysts. Herein, we report a metal-free radical borylation strategy of various alkyl bromides utilizing a photoinduced silyl radical to mediate a halogen-atom transfer process. This method demonstrates broad utility and functional group tolerance among various primary, secondary, and tertiary unactivated alkyl bromides and can facilitate the functionalization of pharmaceutically relevant motifs. Mechanistic and computational studies support a radical-chain pathway involving a silyl radical-mediated halogen-atom transfer.

This study investigates continuous synthesis of 2-methoxyhydroquinone (MHQ) from vanillin in a Taylor-Couette disc contactor (TCDC). The TCDC, a stirred column reactor utilizing Taylor vortices for intense mixing, achieved efficient phase separation and hydraulic stability. With an 83% yield, 93.8% purity, and a production rate of 0.55 kg h⁻¹ of MHQ, the product proves suitability for redox flow batteries.

Organic redox flow batteries are a promising sustainable technology for large-scale storage of surplus energy in the grid. However, the main challenge lies in scaling up the synthesis of redox-active molecules from sustainable sources, as either the synthesis is complex or renewable feedstock is not available at a large scale. This challenge is addressed by employing vanillin, a fine chemical widely available from lignin, as a starting material for the synthesis of redox-active hydroquinones. The use of a continuously operating column reactor, known as the Taylor-Couette disc contactor, is demonstrated to generate redox-active 2-methoxyhydroquinone in high yields and purity. Production rates of ≈0.55 kg h⁻¹ of 2-methoxyhydroquinone are achieved, with sufficient purity for use in single-cell redox flow battery performance and short-stack stability tests.