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Nature Communications, Published online: 27 October 2023; doi:10.1038/s41467-023-42645-0

Here, the authors investigate frequently observed variations in data between different electrochemical cells using in-situ electronic/electrochemical measurements, developing a vertical microcell strategy to eliminate the conductance issue and enhance measurement reproducibility.

1,4-Dicyanobenzene acts as a substrate and a mediator in an electrochemical C(sp²)−C(sp³) bond-forming reaction with alkyl bromides. The reaction conditions avoid competing alkyl radical homocoupling and allows for the accommodation of alkyl bromides with oxidatively sensitive and acidic functional groups that are difficult to incorporate using alternative C(sp³) precursors.

Abstract

Electrochemical approaches to form C(sp²)−C(sp³) bonds have focused on coupling C(sp³) electrophiles that form stabilized carbon-centered radicals upon reduction or oxidation. Whereas alkyl bromides are desirable C(sp³) coupling partners owing to their availability and cost-effectiveness, their tendency to undergo radical-radical homocoupling makes them challenging substrates for electroreductive cross-coupling. Herein, we disclose a metal-free regioselective cross-coupling of 1,4-dicyanobenzene, a useful precursor to aromatic nitriles, and alkyl bromides. Alkyl bromide reduction is mediated directly by 1,4-dicyanobenzene radical anions, leading to negligible homocoupling and high cross-selectivity to form 1,4-alkyl cyanobenzenes. The cross-coupling scheme is compatible with oxidatively sensitive and acidic functional groups such as amines and alcohols, which have proven difficult to incorporate in alternative electrochemical approaches using carboxylic acids as C(sp³) precursors.

Anti-Stokes fluorescence lifetime imaging in living cells was demonstrated by Rachel C. Evans et al. in their Research Article (e202308602). This was achieved through the design of ultra-small nanoparticle probes based on triplet–triplet annihilation upconversion (TTA-UC) chromophores encapsulated in an organic–inorganic ureasil host. Fluctuations of the UC lifetime in the stained cells suggest that the NPs can be used to map local oxygen diffusion across the subcellular structure.

An enantioselective carbene-catalyzed radical-radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an NHC-derived ketyl radical and a secondary sp3–carbon radical and allows access to chiral α-aryl aliphatic ketones in moderate-to-good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late-stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the NHC controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

A Ni(0/II/III) cycle is uncovered for a Ni-photoredox amide arylation reaction. Identification of a precatalyst-dependent induction period, together with reactivity studies for catalytic intermediates, were key to discerning the mechanism. These findings contrast with other Ni-photoredox C−N couplings that proceed via Ni(I/III) cycles, highlighting how small changes in reaction conditions can lead to alternative pathways.

Abstract

This work demonstrates the dominance of a Ni(0/II/III) cycle for Ni-photoredox amide arylation, which contrasts with other Ni-photoredox C-heteroatom couplings that operate via Ni(I/III) self-sustained cycles. The kinetic data gathered when using different Ni precatalysts supports an initial Ni(0)-mediated oxidative addition into the aryl bromide. Using NiCl₂ as the precatalyst resulted in an observable induction period, which was found to arise from a photochemical activation event to generate Ni(0) and to be prolonged by unproductive comproportionation between the Ni(II) precatalyst and the in situ generated Ni(0) active species. Ligand exchange after oxidative addition yields a Ni(II) aryl amido complex, which was identified as the catalyst resting state for the reaction. Stoichiometric experiments showed that oxidation of this Ni(II) aryl amido intermediate was required to yield functionalized amide products. The kinetic data presented supports a rate-limiting photochemically-mediated Ni(II/III) oxidation to enable C−N reductive elimination. An alternative Ni(I/III) self-sustained manifold was discarded based on EPR and kinetic measurements. The mechanistic insights uncovered herein will inform the community on how subtle changes in Ni-photoredox reaction conditions may impact the reaction pathway, and have enabled us to include aryl chlorides as coupling partners and to reduce the Ni loading by 20-fold without any reactivity loss.

Apparent ligand oxidation enables catalysis by copper in a more stable oxidation state.

Apparent ligand oxidation enables catalysis by copper in a more stable oxidation state.

Nature Chemistry, Published online: 07 September 2023; doi:10.1038/s41557-023-01317-8

Cobalt(II) complexes of porphyrins have dominated the development of metalloradical catalysts. Now it has been shown that five-coordinate iron(III) complexes of porphyrins with an axial ligand are also potent metalloradical catalysts for olefin cyclopropanation. They are shown to react with different classes of diazo compounds via a stepwise radical mechanism.

A thin-layer approach is presented to bypass the area-volume restrictions of traditional electrolysis cells and perform minute-scale electrolysis reactions. Parallel electrolysis reactions, using multiple thin-layer electrodes (TLE), facilitate the design and study of electrosynthesis reactions. Hosting a microelectrode in the TLE provides an advanced tool for combining electroanalytical and electrosynthetic reactions.

Abstract

Electrochemistry represents unique approaches for the promotion and mechanistic study of chemical reactions and has garnered increasing attention in different areas of chemistry. This expansion necessitates the enhancement of the traditional electrochemical cells that are intrinsically constrained by mass transport limitations. Herein, we present an approach for designing an electrochemical cell by limiting the reaction chamber to a thin layer of solution, comparable to the thickness of the diffusion layer. This thin layer electrode (TLE) provides a modular platform to bypass the constraints of traditional electrolysis cells and perform electrolysis reactions in the timescale of electroanalytical techniques. The utility of the TLE for electrosynthetic applications benchmarked using NHPI-mediated electrochemical C−H functionalization. The application of microscale electrolysis for the study of drug metabolites was showcased by elucidating the oxidation pathways of the paracetamol drug. Moreover, hosting a microelectrode in the TLE, was shown to enable real-time probing of the profiles of redox-active components of these rapid electrosynthesis reactions.

Nickel catalysts promote cyclopropanation reactions of electron-deficient alkenes using dichloromethane as a methylene source. An asymmetric variant using a chiral pyridine-bis(oxazoline) ligand provides access to pharmaceutically relevant 2-aryl cyclopropyl carboxylates in highly enantioenriched form. The proposed mechanism involves the formation of a nucleophilic nickel carbene that reacts by a [2+2]-cycloaddition/C−C reductive elimination pathway.

Abstract

Nickel PyBox catalysts promote nucleophilic cyclopropanation reactions using CH₂Cl₂ as a methylene source and Mn as a stoichiometric reductant. The substrate scope includes a broad range of alkenes bearing electron-withdrawing substituents, including esters, amides, ketones, nitriles, sulfones, phosphonate esters, trifluoromethyl groups, and electron-deficient arenes. Enantioselective cyclopropanations of α,β-unsaturated esters have been developed using chiral PyBox ligands. Mechanistic studies suggest the intermediacy of a (PyBox)Ni=CH₂ species, which adds to the alkene by a stepwise [2+2]-cycloaddition/C−C reductive elimination mechanism. DFT models provide a rationale for the nucleophilic character of the nickel carbene and the sense of enantioinduction.

The electrochemical conversion of unactivated carboxylic acids to olefins under alternating polarity is reported. By modulating electrode surface quality and local acidity, chemoselective Hofer-Moest reactivity is realized on conventionally difficult substrates, including primary and secondary unactivated carboxylic acids. This simple protocol is exceptionally scalable (1 kg) and cost-effective.

Abstract

A mild, scalable (kg) metal-free electrochemical decarboxylation of alkyl carboxylic acids to olefins is disclosed. Numerous applications are presented wherein this transformation can simplify alkene synthesis and provide alternative synthetic access to valuable olefins from simple carboxylic acid feedstocks. This robust method relies on alternating polarity to maintain the quality of the electrode surface and local pH, providing a deeper understanding of the Hofer-Moest process with unprecedented chemoselectivity.

A metal-free natural dye has been developed to selectively convert methane to methyl trifluoroacetate (CH₃TFA) using visible light, probably due to the formation of a chloride-bridged dimer undergoing fast intra-complex charge transfer.

Aromatic isocyanides are able to harvest visible light and promote the oxidative formation of both alkyl and acyl radicals starting from Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. UV-visible absorption and fluorescence experiments, electrochemical measurements along with computational calculations provide key data for mechanistic insights. Furthermore, a direct and easy access to deuterium labeled compounds is reported.

Abstract

The recent disclosure of the ability of aromatic isocyanides to harvest visible light and act as single electron acceptors when reacting with tertiary aromatic amines has triggered a renewed interest in their application to the development of green photoredox catalytic methodologies. Accordingly, the present work explores their ability to promote the generation of both alkyl and acyl radicals starting from radical precursors such as Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. Mechanistic studies involving UV-visible absorption and fluorescence experiments, electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provide key insights to promote a rationale design of a new generation of isocyanide-based organic photoredox catalysts. Importantly, the green potential of the investigated chemistry is demonstrated by a direct and easy access to deuterium labeled compounds.

This work unveils a T-shaped organoboron system with three stable oxidation states, which allowed for the isolation of geometrically constrained superacidic boron dication, ambiphilic boron radical cation and superbasic borylene.

Abstract

This report unveils an advancement in the formation of a Lewis superacid (LSA) and an organic superbase by the geometrical deformation of an organoboron species towards a T-shaped geometry. The boron dication [2]²⁺ supported by an amido diphosphine pincer ligand features both a large fluoride ion affinity (FIA>SbF₅) and hydride ion affinity (HIA>B(C₆F₅)₃), which qualifies it as both a hard and soft LSA. The unusual Lewis acidic properties of [2]²⁺ are further showcased by its ability to abstract hydride and fluoride from Et₃SiH and AgSbF₆ respectively, and effectively catalyze the hydrodefluorination, defluorination/arylation, as well as reduction of carbonyl compounds. One and two-electron reduction of [2]²⁺ affords stable boron radical cation [2]⋅⁺ and borylene 2, respectively. The former species has an extremely high spin density of 0.798e at the boron atom, whereas the latter compound has been demonstrated to be a strong organic base (calcd. pK _BH ⁺ (MeCN)=47.4) by both theoretical and experimental assessment. Overall, these results demonstrate the strong ability of geometric constraining to empower the central boron atom.

The identity of alkali metal cations plays a paramount role in tuning the activity and selectivity of hydrogen evolution reaction, oxygen evolution reaction, and electrochemical reduction of CO₂. From the chemical and/or electrostatic interactions with adsorbed intermediates to the redistribution of interfacial water layer and buffering the interfacial pH, cations greatly influence the crucial steps of electrocatalytic reactions.

Abstract

The identity of alkali metal cations in the electrolyte of electrocatalysis systems has been recently introduced as a crucial factor to tailor the kinetics and Faradaic efficiency of many electrocatalytic reactions. In this Minireview, we have summarized the recent advances in the molecular-level understanding of cation effects on relevant electrocatalytic processes such as hydrogen evolution (HER), oxygen evolution (OER), and CO₂ electroreduction (CO₂RR) reactions. The discussion covers the effects of electrolyte cations on interfacial electric fields, structural organization of interfacial water molecules, blocking the catalytic active sites, stabilization or destabilization of intermediates, and interfacial pHs. These cation-induced interfacial phenomena have been reported to impact the performance (activity, selectivity, and stability) of electrochemical reactions collaboratively or independently. We describe that although there is almost a general agreement on the relationship between the size of alkali cations and the activities of HER, OER, and CO₂RR, however, the mechanism by which the performance of these electrocatalytic reactions is influenced by alkali metal cations is still in debate.

A metal-free intramolecular benzylic sp³ C−H amination is disclosed using aryl nitro compounds as aryl nitrene precursors. Organosilicon reagent N,N’-bis(trimethylsilyl)-4,4’-bipyridinylidene (Si-DHBP) served as an efficient reductant in the transformation, enabling the in situ generation of aryl nitrene species for the synthesis of 2-arylindolines from the corresponding nitroarene compounds.

Abstract

Given the prevalence of molecules containing nitro groups in organic synthesis, innovative methods to expand the reactivity of this functional group are of interest in both industrial and academic settings. In this report, a metal-free intramolecular benzylic sp³ C−H amination is disclosed using aryl nitro compounds as aryl nitrene precursors. Organosilicon reagent N,N’-bis(trimethylsilyl)-4,4’-bipyridinylidene (Si-DHBP) served as an efficient reductant in the transformation, enabling the in situ generation of aryl nitrene species for the direct, metal-free synthesis of unprotected 2-arylindolines from the corresponding nitroarene compounds.

By the combination of an Ugi-4CR and a transition metal-free selective N−S bond cleavage and C−N bond activation, diverse primary amides and α-ketoamides were simultaneously obtained in a highly efficient, rapid, and step-economical manner. The reaction features broad substrate scope, excellent functional-group tolerance, and exclusive selectivity. Primary amides derived from the pharmaceuticals probenecid and febuxostat are also prepared.

Abstract

A novel method of transition metal-free N−S bond cleavage and subsequent C−N bond activation of Ugi-adducts was developed. Diverse primary amides and α-ketoamides were prepared in a rapid, step-economical and highly efficient manner in two steps. This strategy features excellent chemoselectivity, high yield and functional-group tolerance. Primary amides derived from the pharmaceuticals probenecid and febuxostat were prepared. This method opens a new pathway for the simultaneous synthesis of primary amides and α-ketoamides in an environmentally friendly manner.