Marnix van der Kolk

Publication date: February 2026

Source: Journal of Fluorine Chemistry, Volume 290

Author(s): Vivek Kumar, Meenu, M. Shaquiquzzaman, M. Mumtaz Alam, Mymoona Akhter, Darakhshan Parveen, Mohammad Kaleem, Shyama Charan, Md. Khalid Saifullah, Sharba Tasneem

Publication date: February 2026

Source: Journal of Fluorine Chemistry, Volume 290

Author(s): Liam N.D. Beardmore, Alexander J. Hague, Steven L. Cobb, William D.G. Brittain

Nature Chemistry, Published online: 05 January 2026; doi:10.1038/s41557-025-02018-0

Direct enantioselective α-C(sp³)–H functionalization of Lewis-basic N-alkyl anilines has remained a significant challenge in synthetic chemistry. Now it has been shown that a metallaphotoredox-catalysed radical approach, with a sterically hindered aryl ketone photocatalyst, enables site-selective, enantioselective (hetero)arylation with exceptional functional group tolerance.

Reductive cross-couplings have emerged as a powerful strategy for forging C–C bonds directly from electrophiles, circumventing the need for preformed organometallic reagents, yet they often suffer from limitations associated with heterogeneous reductants like Zn (e.g., poor reproducibility and scalability) or costly homogeneous alternatives such as TDAE. Inspired by prior explorations of hydrazide chemistry, we disclose arylhydrazines as inexpensive, readily available homogeneous sacrificial reductants that enable Ni-catalyzed sp²-sp³ cross-coupling of aryl halides with secondary alkyl iodides under mild, operationally simple conditions using a NiII precursor, bipyridine ligand, and hindered amine base. Optimization, substrate scope studies, and direct comparisons reveal superior yields and selectivity relative to Zn-based methods, particularly for heterocyclic and electron-rich partners, while calorimetry-guided safety assessments and decagram-scale demonstrations highlight enhanced thermal control, reproducibility, and practicality. Mechanistic investigations via UV-vis spectroscopy, 19F NMR, and reaction calorimetry support a pathway involving hydrazine-mediated NiII reduction to initiate a NiI/NiIII cycle, with benign byproducts (N₂ and arene), positioning arylhydrazines as versatile reagents for executing reductive coupling on scale.

We have developed a photoinduced synthesis of difluoromethyl compounds using a combined method of fluoride-coupled electron transfer and hydrogen atom transfer. Utilizing benzimidazoline derivatives as photoreductant and hydrogen atom donor, difluoromethylarenes were synthesized through the C–F bond reduction of trifluoromethylarenes.

The difluoromethyl group is a bioisostere of hydroxy and sulfanyl groups. The photocatalytic reduction of trifluoromethyl groups is one of the most important methods for the synthesis of difluoromethyl compounds. We have developed a photoinduced synthesis of difluoromethyl compounds using a combined method of fluoride-coupled electron transfer and hydrogen atom transfer. Utilizing benzimidazoline derivatives as photoreductant and hydrogen atom donor, difluoromethylarenes were synthesized through the C–F bond reduction of trifluoromethylarenes. Mechanistic studies indicated that the photoreduction proceeded via an electron-donor–acceptor complex between trifluoromethylarenes and benzimidazoline derivatives.

Togni reagent I, one of the most used electrophilic trifluoromethylating reagents, has been radiolabeled with fluorine-18 starting from the widely available fluoro-benziodoxole and the [¹⁸F]Ruppert–Prakash reagent. To demonstrate the broad potential for late-stage functionalization, aliphatic carboxylic acids were successfully converted into their ¹⁸F-trifluoromethylated analogs via metallaphotoredox catalysis.

The trifluoromethyl (CF₃) group is a ubiquitous motif in drug discovery campaigns due to its ability to markedly improve the ADME properties of small molecules while maintaining potency. The isotopologue labeling of CF₃-bearing drugs with fluorine-18 has gained attention for positron emission tomography (PET) imaging. However, their radiolabeling via conventional ¹⁸F-trifluoromethylation methods relies almost completely on nucleophilic and radical [¹⁸F]CF₃-reagents, whereas there remains no general means to incorporate a formal [¹⁸F]CF₃ ⁺ into PET tracer candidates. Herein, we disclose the realization of a novel electrophilic ¹⁸F-labeled trifluoromethylating reagent based on the family of 10-λ-3 hypervalent iodines: [¹⁸F]Togni reagent I. The method uses nucleophilic ligand substitution at iodine by the [¹⁸F]Ruppert–Prakash reagent, providing [¹⁸F]Togni reagent I in a radiochemical yield of 4.3 ± 0.8% and a molar activity of 15 ± 9.6 GBq/μmol. Initial studies on the utility of this reagent demonstrate the direct, late-stage formation of C(sp³)−[¹⁸F]CF₃ bonds via metallaphotoredox-mediated conversion of naturally abundant carboxylic acids. Hence, this work illustrates the potential of the novel electrophilic [¹⁸F]CF₃-reagent as a complementary approach leading to valuable ¹⁸F-trifluoromethylated architectures in PET tracer development.

Nitrogen-centered acridine photocatalysts for direct hydrogen atom transfer have been developed, leveraging dispersion interactions to enhance photocatalytic activity. This approach enables diverse functionalization reactions of strong C─H bonds even under cryogenic conditions and provides a new strategy for boosting the efficiency of direct HAT photocatalysis.

Abstract

The development of structurally distinct and modular photocatalysts for direct hydrogen atom transfer (HAT) has emerged as a key frontier in radical-mediated C–H functionalization of strong carbon–hydrogen bonds. Despite the largely untapped potential across the fields of organic synthesis, medicinal chemistry, and materials science, few classes of direct HAT photocatalysts are currently known, and the approaches to enhancing their photocatalytic activity remain underdeveloped. We report herein the development of nitrogen-centered direct HAT photocatalysts based on the acridine framework, which leverage a C9-ortho-biaryl substituent for enhancing the photocatalytic activity through stabilizing dispersion interactions with the substrate as the key steering effect. The acridine direct HAT photocatalysis enables an array of carbon–carbon and carbon–heteroatom bond-forming reactions in diverse structural and experimental settings, including cryogenic conditions. It also provides a blueprint for enhancing the photocatalytic activity of direct HAT catalysts by leveraging photocatalyst-substrate dispersion interactions.

We develop a copper LMCT photocatalysis/XAT-coupled fluoroalkylation of alkenes using bromodifluoroacetic anhydride (BDFAA) and LiCl to form difluorolactones. Essential aspects include solubility-modulated proximity effect between lithium ion and BDFAA, solvent-mediated propagative radical relay via HAT/XAT, and thermodynamic control of intermediates, enabling reactivity tuning of radical species for efficient reaction.

Ligand-to-metal charge transfer (LMCT) photocatalysis, which utilizes simple transition metal salts to enable redox-potential-independent conversion of anions into radicals, has recently gained significant interest in organic synthesis. Radical relay, which transforms primary radicals generated via LMCT into secondary radicals through atom transfer, expands the synthetic utility of LMCT photocatalysis. However, the high reactivity of LMCT-derived radical species strongly limits the reaction modes and applicable substrates. In this study, we successfully couple copper LMCT photocatalysis with halogen atom transfer (XAT) and demonstrate efficient gem-difluoro-γ-lactone synthesis via difunctionalizing fluoroalkylation of alkenes using bromodifluoroacetic anhydride (BDFAA) and LiCl. Key steps include chlorine radical formation via the LMCT of [CuCl₃]Li and bromine atom transfer from BDFAA to generate a fluoroalkyl radical. Although theoretical calculations suggest that chlorine radical addition to alkenes is significantly faster than XAT, the desired yet energetically unfavorable XAT proceeds through solubility-modulated proximity between the catalyst and BDFAA, as well as a solvent-mediated radical relay involving hydrogen atom transfer from acetonitrile. This study reveals a novel application of LMCT photocatalysis and proposes a general strategy for tuning radical reactivity through the entire reaction system.

Nature Synthesis, Published online: 16 December 2025; doi:10.1038/s44160-025-00925-1

The ambiphilic reactivity of alkyl sulfonyl fluorides in stereoselective cyclopropanation under Pd(II) catalysis is reported. The method provides convenient access to cis-disubstituted cyclopropanes that are otherwise challenging to access. A representative carboxylic acid cyclopropane building block is scaled up to 100 mmol, demonstrating the practicality of this transformation.

Nature, Published online: 17 December 2025; doi:10.1038/d41586-025-03489-4

A chemist faces a classic early-career dilemma: what should they do next, and how do they start?