Powering up Pyridine

Phosphonium Ions as Activating Groups for the Selective Alkylation of Pyridines and Polyazines

D. A. Brunner, D. C. Thomas, K. R. Steenback, S. D. Rozema & A. McNally*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002373/v1) 🔓

The authors report a strategy to address the poor regio- and site-selectivity of Minisci reactions in pyridines through the use of C4-phosphonium salts as activating groups. These species promote selective radical addition to phosphonium-bearing pyridines over unmodified heterocycles in polypyridine systems, while simultaneously acting as blocking groups to direct alkylation to the 2-position. Under photoredox conditions, alkyl bromides undergo acid-free Minisci coupling, and the resulting C–P bond can be readily cleaved during workup or leveraged as a versatile functional handle for the synthesis of 2,4-disubstituted pyridines. Control over the site of phosphonium installation further enables site-selective switching in complex, drug-like structures.

Chiral S(VI) Platform Unifies Selective C–H Amination of Complex Molecules and Alkane Feedstocks

T. A. Trinh, D. B. Hu, A. J. Kenny, E. M. Warrington, S. Cherempei, I. A. Guzei & J. M. Schomaker*

Science 2026, 392, 421–428 (DOI: 10.1126/science.aee3321)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2025-fqnk2-v2) 🔓

Complex molecules and simple alkanes present distinct challenges in catalyst-controlled C–H functionalisation, requiring either precise site selectivity or activation of inert, undifferentiated bonds. Here, the authors repurpose a classic chiral auxiliary into a unified silver-catalysed platform for C–H amination using chiral sulfur(VI) nitrene precursors. The system enables stereodivergent, late-stage amination of activated C–H bonds with broad functional group tolerance and aqueous compatibility, while also allowing mild, selective functionalisation of simple feedstocks. The sulfur(VI) motif serves as a modular, stereodefined linchpin for rapid library diversification, supporting both target- and diversity-oriented synthesis.

Diverse Radical C–F Functionalizations of Hexa- to Difluoroarenes Using Boryl Radicals as Link-and-Lose Mediators

T. Ye,^† F.-S. Zhang,^† Z.-Y. Xu,^† S.-Q. Zhou,^† Y. L. Phang, Z.-Q. Ding, F.-L. Zhang, W.-C. Yang,* Z.-P. Cai, Y. Peng, B.-Y. Zhou, W.-Q. Suo, X. Guo,* Y. Fu* & Y.-F. Wang*

Nat. Chem. 2026 (DOI: 10.1038/s41557-026-02137-2)

The authors report a “link-and-lose” radical strategy for C–F functionalization of polyfluoroarenes using reactivity-tunable pyridine–boryl radicals. Initial radical addition to the arene (“link”) triggers heterolytic C–F cleavage under non-reductive conditions, generating a polyfluoroaryl radical cation that can be intercepted by diverse coupling partners, with concomitant loss of the boron moiety (“lose”). This enables hydro- and deuterodefluorination, as well as defluorinative arylation and alkylation, and can be applied in a stepwise manner to selectively functionalize multiple C–F bonds across hexa- to difluoroarenes.

👉️ “In the Pipeline” write-up, here.

A Cu(I)-Catalysed Click Reaction Generates ROS-Triggered Cleavable Linkages in Aqueous Media

M. E. Hackey, M. Formica, V. Bauer, N. S. Alavijeh, Y. Fu, E. A. Naudin, A. Nikbakht, D. Yassine, P. H. S. Paioti, J. del Pozo, P. Liu* & A. H. Hoveyda*

Nat. Chem. 2026 (DOI: 10.1038/s41557-026-02100-1)

The authors report copper(I)-catalysed allene–ketone addition (CuAKA), an operationally simple click reaction orthogonal to CuAAC (copper(I)-catalysed azide–alkyne cycloaddition) and CuPDF (copper(I)-catalysed phenoxydiazaborinine formation); together, these strategies enable modular assembly of multifunctional entities. CuAKA facilitates linkage of an allene-bound drug to a ketone-containing derivative of unprotected penetratin in aqueous media. Notably, the resulting linkages are cleavable under mild conditions (37 °C, aq. hydrogen peroxide), highlighting their potential for use in biologically relevant environments.

Enantioselective Synthesis of 1,3-Bicyclo[2.1.1]hexanes as meta-Benzene Bioisosteres

C. Pérez-Sánchez, P. Garrido-García, D. Fernández, S. Ortega-Gutiérrez, M. Martín-Fontecha, D. González-Pinardo, I. Fernández, T. Rigotti* & M. Tortosa*

Nat. Synth. 2026 (DOI: 10.1038/s44160-026-01048-x)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv.15000646/v1) 🔓

The authors report an enantioselective copper-catalysed protoborylation to access 1,3-disubstituted bicyclo[2.1.1]hexanes as meta-benzene mimics. These stereodefined frameworks were constructed via desymmetrization of bicyclo[2.1.1]hex-2-enes. The resulting enantioenriched building blocks were incorporated into drug analogues, improving solubility, metabolic stability, and permeability relative to the parent compounds. The analogues retained biological activity by targeting the same molecular receptors, supporting their utility as meta-benzene bioisosteres.

Distance-Dependent, Rate-Accelerating and Diastereoselective Directing Effects in Decatungstate-Mediated Stereoediting Reactions

H. Liang,^† J. Zhu,^† L. Wang & A. E. Wendlandt*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.5c22842)

Excited-state decatungstate (DT) is a widely used hydrogen atom transfer (HAT) reagent, with site- and diastereoselectivity typically governed by steric and bond polarity effects. Here, the authors show that secondary amides can modulate this selectivity by engaging in proximity-dependent, non-covalent interactions with excited-state DT, leading to diastereoselective HAT and ∼10-fold rate acceleration. This effect is leveraged to enable contra-thermodynamic C–H epimerization, providing access to cis-1,2-disubstituted amides from readily available trans-configured starting materials.

Fluoro-Wacker gem-Difluorination of Alkene via Fluoropalladation and Dyotropic Rearrangement

J. Gong, Q. Wang & J. Zhu*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c02970)

The authors report a palladium-catalyzed fluoro-Wacker-type transformation of 1,1-disubstituted alkenes enabled by nucleophilic fluoropalladation using Et₃N·3HF in combination with Selectfluor. The reaction proceeds via oxidation of an alkyl–Pd(II) intermediate to Pd(IV), followed by a key 1,2-Csp³ /Pd(IV) dyotropic rearrangement. This strategy enables migrative 1,1-difluorination, providing access to ring-expanded and chain-extended products bearing gem-difluoromethylene motifs.

Regio- and Stereoselective Deprotonation and Functionalization of Strained 1-Aza[n.1.0]bicycles

T. Xie,^† T. Plowright,^† J. D. Somper, M. Fairchild, J. Soler, J. L. Tyler, F. Duarte* & V. K. Aggarwal*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c03462) 🔓

Strained 1-aza[n.1.0]bicycles are attractive intermediates for the strain-release synthesis of 3D heterocycles but are difficult to functionalize. The authors report a regio- and stereoselective lithiation of azabicyclo[2.1.0]pentane (ABP) and azabicyclo[3.1.0]hexane (ABH), enabling direct functionalization of these frameworks. Lithiation occurs selectively at the exo-C2–H position, challenging conventional acidity-based predictions, and the resulting organolithium intermediates can be trapped with a broad range of electrophiles. This provides access to C2/C3-substituted pyrrolidines with high diastereocontrol upon ring opening. Divergent reactivity is observed upon trapping with boronic esters, with ABH-boronates undergoing strain-promoted migration and ABP-boronates favoring competing elimination pathways.

Overcoming the Barrier to Intermolecular Alkoxy Radical Reactivity: Proton-Coupled Electron Transfer-Mediated Alkene Hydroetherification

L. C. Delgutte,^† Y. Hua,^† J. Lee,^† A. N. Lugo, A. R. Iyengar & D. E. Kim*

J. Am. Chem. Soc. 2026, ASAP (DOI: 10.1021/jacs.6c05777) 🔓

The authors report a proton-coupled electron transfer (PCET)-enabled intermolecular anti-Markovnikov hydroetherification that overcomes the inherent instability of alkoxy radicals. A bifunctional organophotocatalyst, activated via hydrogen bonding with alcohol substrates, enables selective intermolecular trapping of alkoxy radicals generated directly from alcohols, while suppressing competing unimolecular pathways and off-target oxidation of electron-rich olefins. Nucleophilic olefins, including enoxysilanes and enamides, serve as effective bimolecular traps, affording hydroetherification products under mild conditions and low catalyst loadings.

Development of a Practical Copper-Catalyzed C–N Cross-Coupling for Heteroaryl Chlorides and Base-Sensitive Substrates

A. McGrath* & D. Lehnherr*

ACS Catal. 2025, ASAP (DOI: 10.1021/acscatal.6c01237)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv.15000029/v1) 🔓

The authors report a copper-catalysed C–N cross-coupling of (hetero)aryl chlorides with a broad range of nitrogen nucleophiles, including primary, secondary, and α-branched amines, amides, hydrazines, ammonia surrogates, NH-heterocycles, and base-sensitive substrates. Both aryl and heteroaryl chlorides, including pyridyl and pyrimidyl derivatives, are effective coupling partners. Reactivity trends of azole methanamines were elucidated as a function of azole identity and isomer through parallel library synthesis comparing heterogeneous and homogeneous conditions across 42 nucleophiles.

Light-Driven Deaminative Nucleophilic Substitution via C(sp³ )-N bond Cleavage: Nucleophilic Transamination of Alkyl Amines

D. Jung,^† J. Y. Park,^† J. U. Kim,^† S. Kim, D. Lee & S. Lee*

ChemRxiv 2026 (DOI: 10.26434/chemrxiv.15002195/v1) 🔓

The authors report a photoredox-catalyzed transamination strategy enabling direct amine-to-amine interconversion without prefunctionalization. The reaction proceeds via polarity inversion, generating an electrophilic iminium intermediate that couples with a second amine nucleophile. The method shows broad scope across benzylic, unactivated, and tertiary amines, with good functional group tolerance. Mechanistic studies support the involvement of α-amino radical and iminium intermediates, with selectivity governed by two key principles: reaction directionality is controlled by relative nucleophilicity, while site-selectivity in C(sp³ )–N bond cleavage is dictated by electronic or steric effects.

Far from Fringe

📊 Far from Fringe. A new global survey suggests that belief in unproven health claims is no longer a fringe phenomenon. Data from over 16,000 people across 16 countries, published by the Edelman Trust Institute, show that 70% of respondents believe at least one claim unsupported by scientific evidence—from vaccine scepticism to fluoride in water, and even raw milk.

Between roughly a quarter and a third of respondents believe each individual claim outright. For example, 32% say fluoride in water is harmful, with a further 33% unsure. 28% believe raw milk is healthier than pasteurised milk, despite long-established evidence that pasteurisation reduces milk borne diseases such as tuberculosis and brucellosis. On vaccines, 31% believe the risks of childhood vaccination outweigh the benefits, although a majority (52%) reject this. More contentious claims attract similar levels of belief: 25% believe vaccines are used for population control, with a further 17% unsure. Even highly specific claims show substantial uncertainty. For instance, 39% of respondents say they don’t know whether paracetamol use during pregnancy causes autism, despite no evidence supporting a link.

One possible explanation could be the success of public health interventions themselves: diseases such as measles and mumps are now rarely seen in many countries due to vaccination, and milk pasteurisation has largely eliminated common food borne infections. As a result, the risks these measures prevent are less visible in everyday life, which may make the interventions easier to question.

At the same time, respondents report navigating an increasingly complex information environment. Nearly 40% of UK respondents in a separate survey say there is now too much information available to know what is true about science. Scientific authority also now exists alongside a wider ecosystem of influencers, commentators, and peer networks operating under less rigorous standards.

Despite this, overall trust in science remains relatively high. In the US, 77% of adults in 2025 said they had confidence in scientists to act in the public interest. This remains higher than confidence in business leaders (37%) or elected officials (27%), although it has declined from 86% in 2019, before the COVID-19 pandemic.