Biomimetic catalytic aerobic oxidation of C–sp(3)–H bonds under mild conditions using galactose oxidase model compound CuIIL

Developing highly efficient catalytic protocols for C–sp(3)–H bond aerobic oxidation under mild conditions is a long-desired goal of chemists. Inspired by nature, a biomimetic approach for the aerobic oxidation of C–sp(3)–H by galactose oxidase model compound Cu^IIL and NHPI (N-hydroxyphthalimide) was developed. The Cu^IIL–NHPI system exhibited excellent performance in the oxidation of C–sp(3)–H bonds to ketones, especially for light alkanes. The biomimetic catalytic protocol had a broad substrate scope. Mechanistic studies revealed that the Cu^I-radical intermediate species generated from the intramolecular redox process of Cu^IILH₂ was critical for O₂ activation. Kinetic experiments showed that the activation of NHPI was the rate-determining step. Furthermore, activation of NHPI in the Cu^IIL–NHPI system was demonstrated by time-resolved EPR results. The persistent PINO (phthalimide-N-oxyl) radical mechanism for the aerobic oxidation of C–sp(3)–H bond was demonstrated.

A biomimetic catalytic approach for the aerobic oxidation of C–sp(3)–H bonds using galactose oxidase model compound was developed. EPR showed that the Cu^I-radical intermediate species was critical for O₂ activation.     

Strategies for switching the mechanism of proton-coupled electron transfer reactions illustrated by mechanistic zone diagrams

The mechanism by which proton-coupled electron transfer (PCET) occurs is of fundamental importance and has great consequences for applications, e.g. in catalysis. However, determination and tuning of the PCET mechanism is often non-trivial. Here, we apply mechanistic zone diagrams to illustrate the competition between concerted and stepwise PCET-mechanisms in the oxidation of 4-methoxyphenol by Ru(bpy)₃³⁺-derivatives in the presence of substituted pyridine bases. These diagrams show the dominating mechanism as a function of driving force for electron and proton transfer (ΔG⁰_ET and ΔG⁰_PT) respectively [Tyburski et al., J. Am. Chem. Soc., 2021, 143, 560]. Within this framework, we demonstrate strategies for mechanistic tuning, namely balancing of ΔG⁰_ET and ΔG⁰_PT, steric hindrance of the proton-transfer coordinate, and isotope substitution. Sterically hindered pyridine bases gave larger reorganization energy for concerted PCET, resulting in a shift towards a step-wise electron first-mechanism in the zone diagrams. For cases when sufficiently strong oxidants are used, substitution of protons for deuterons leads to a switch from concerted electron–proton transfer (CEPT) to an electron transfer limited (ETPT_lim) mechanism. We thereby, for the first time, provide direct experimental evidence, that the vibronic coupling strength affects the switching point between CEPT and ETPT_lim, i.e. at what driving force one or the other mechanism starts dominating. Implications for solar fuel catalysis are discussed.

The mechanism by which proton-coupled electron transfer (PCET) occurs is of fundamental importance and has great consequences for applications, e.g. in catalysis.     

EDOT-based conjugated polymers accessed via C–H direct arylation for efficient photocatalytic hydrogen production

3,4-Ethylene dioxythiophene (EDOT), as a monomer of commercial conductive poly(3,4-ethylene dioxythiophene) (PEDOT), has been facilely incorporated into a series of new π-conjugated polymer-based photocatalysts, i.e., BSO₂–EDOT, DBT–EDOT, Py–EDOT and DFB–EDOT, through atom-economic C–H direct arylation polymerization (DArP). The photocatalytic hydrogen production (PHP) test shows that donor–acceptor (D–A)-type BSO₂–EDOT renders the highest hydrogen evolution rate (HER) among the linear conjugated polymers (CPs) ever reported. A HER up to 0.95 mmol h⁻¹/6 mg under visible light irradiation and an unprecedented apparent quantum yield of 13.6% at 550 nm are successfully achieved. Note that the photocatalytic activities of the C–H/C–Br coupling-derived EDOT-based CPs are superior to those of their counterparts derived from the classical C–Sn/C–Br Stille coupling, demonstrating that EDOT is a promising electron-rich building block which can be facilely integrated into CP-based photocatalysts. Systematic studies reveal that the enhanced water wettability by the integration of polar BSO₂ with hydrophilic EDOT, the increased electron-donating ability by O–C p–π conjugation, the improved electron transfer by D–A architecture, broad light harvesting, and the nano-sized colloidal character in a H₂O/NMP mixed solvent rendered BSO₂–EDOT as one of the best CP photocatalysts toward PHP.

The excellent reactivity toward C–H direct arylation, water wettability and O–C p–π conjugation endow EDOT to be an attractive electron donor unit for CP photocatalysts, yielding an unprecedented hydrogen evolution rate up to 0.95 mmol h⁻¹/6 mg catalyst.     

A directing group switch in copper-catalyzed electrophilic C–H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole

We present here a copper-catalyzed electrophilic ortho C–H amination of protected naphthylamines with N-(benzoyloxy)amines, cyclization with the pendant amide, and carbon to nitrogen 1,2-directing group migration cascade to access N,N-disubstituted 2-benzimidazolinones. Remarkably, this highly atom-economic tandem reaction proceeds through a C–H and C–C bond cleavage and three new C–N bond formations in a single operation. Intriguingly, the reaction cascade was altered by the subtle tuning of the directing group from picolinamide to thiopicolinamide furnishing 2-heteroaryl-imidazoles via the extrusion of hydrogen sulfide. This strategy provided a series of benzimidazolones and benzimidazoles in moderate to high yields with low catalyst loading (66 substrates with yields up to 99%). From the control experiments, it was observed that after the C–H amination an incipient tetrahedral oxyanion or thiolate intermediate is formed via an intramolecular attack of the primary amine to the amide/thioamide carbonyl. It undergoes either a 1,2-pyridyl shift with the retention of the carbonyl moiety or H₂S elimination for scaffold diversification. Remarkably, inspite of a positive influence of copper in the reaction outcome, from our preliminary investigations, the benzimidazolone product was obtained in good to moderate yields in two steps under metal-free conditions. The N-pyridyl moiety of the benzimidazolone was removed for further manipulation of the free NH group.

A novel directing group switch strategy is explored in a copper-catalyzed divergent synthesis of benzimidazolone via electrophilic C–H amination/cyclization/1,2-C → N directing group migration cascade and benzimidazole through the extrusion of H₂S.     

Combining metal–metal cooperativity,metal–ligand cooperativity and chemical non-innocence in diiron carbonyl complexes

Several metalloenzymes, including [FeFe]-hydrogenase, employ cofactors wherein multiple metal atoms work together with surrounding ligands that mediate heterolytic and concerted proton–electron transfer (CPET) bond activation steps. Herein, we report a new dinucleating PNNP expanded pincer ligand, which can bind two low-valent iron atoms in close proximity to enable metal–metal cooperativity (MMC). In addition, reversible partial dearomatization of the ligand''s naphthyridine core enables both heterolytic metal–ligand cooperativity (MLC) and chemical non-innocence through CPET steps. Thermochemical and computational studies show how a change in ligand binding mode can lower the bond dissociation free energy of ligand C(sp³)–H bonds by ∼25 kcal mol⁻¹. H-atom abstraction enabled trapping of an unstable intermediate, which undergoes facile loss of two carbonyl ligands to form an unusual paramagnetic (S = ) complex containing a mixed-valent iron(0)–iron(i) core bound within a partially dearomatized PNNP ligand. Finally, cyclic voltammetry experiments showed that these diiron complexes show catalytic activity for the electrochemical hydrogen evolution reaction. This work presents the first example of a ligand system that enables MMC, heterolytic MLC and chemical non-innocence, thereby providing important insights and opportunities for the development of bimetallic systems that exploit these features to enable new (catalytic) reactivity.

The PNNP expanded pincer ligand can bind two iron centers in close proximity and display heterolytic and homolytic metal–ligand cooperativity.     

Cobalt-catalyzed chemoselective dehydrogenation through radical translocation under visible light

The transformations that allow the direct removal of hydrogen from their corresponding saturated counterparts by the dehydrogenative strategy are a dream reaction that has remained largely underexplored. In this report, a straightforward and robust cobaloxime-catalyzed photochemical dehydrogenation strategy via intramolecular HAT is described for the first time. The reaction proceeds through an intramolecular radical translocation followed by the cobalt assisted dehydrogenation without needing any other external photosensitizers, noble-metals or oxidants. With this approach, a series of valuable unsaturated compounds such as α,β-unsaturated amides, enamides and allylic and homoallylic sulfonamides were obtained in moderate to excellent yields with good chemo- and regioselectivities, and the synthetic versatility was demonstrated by a range of transformations. And mechanistic studies of the method are discussed.

The dehydrogenative reactions proceeded through selective 1,n-hydrogen atom transfer (n = 5–7) for remote C–H activation by cobaloxime catalysis.     

Stereoselective radical C–H alkylation with acceptor/acceptor-substituted diazo reagents via Co(ii)-based metalloradical catalysis

Co(ii)-based metalloradical catalysis has, for the first time, been successfully applied for asymmetric intramolecular C–H alkylation of acceptor/acceptor-substituted diazo reagents. Through the design and synthesis of a new D ₂-symmetric chiral amidoporphyrin as the supporting ligand, the Co(ii)-based metalloradical system, which operates at room temperature, is capable of 1,5-C–H alkylation of α-methoxycarbonyl-α-diazosulfones with a broad range of electronic properties, providing the 5-membered sulfolane derivatives in high yields with excellent diastereoselectivities and enantioselectivities. In addition to complete chemoselectivity toward allylic and allenic C–H bonds, the Co(ii)-based metalloradical catalysis for asymmetric C–H alkylation features a remarkable degree of functional group tolerance.     

Thioether-enabled palladium-catalyzed atroposelective C–H olefination for N–C and C–C axial chirality

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air. Both N–C and C–C axial chiral (hetero)biaryls were successfully constructed, leading to a broad range of axially chiral N-aryl indoles and biaryls with excellent enantioselectivities up to 99% ee. Experimental and computational studies were conducted to unravel the walking mode for the atroposelective C–H olefination. A plausible chiral induction model for the enantioselectivity-determining step was established by detailed DFT calculations.

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air.     

Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group

Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C–H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp³)–H sulfination reaction that can convert abundant aliphatic C–H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C–H functionalization approaches. We report herein a photoinduced C(sp³)–H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp³)–H functionalization.

The photoinduced C–H sulfination of abundant aliphatic C–H bonds provides direct access to all major classes of organosulfur compounds via the intermediacy of synthetically versatile sulfinate salts.     

Direct metal–carbon bonding in symmetric bis(C–H) agostic nickel(i) complexes

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C–H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C–H activation processes and thus are of critical importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d⁹ Ni(i) complexes with symmetric bis(C–H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand–metal donation occurs directly along the C–Ni bond axis, reflecting a novel mode of bis-agostic bonding.

Symmetric Ni(i) agostic complexes reveal an unusual mode of bonding that is dominated by direct carbon-to-metal charge transfer.     

Copper-catalyzed radical cascade reaction of simple cyclobutanes: synthesis of highly functionalized cyclobutene derivatives

Cyclobutenes as versatile and highly valuable synthons have been widely applied in synthesis. Although various methods for their synthesis have been well established, new strategies for the construction of the cyclobutene skeleton from simple substrates are still highly desirable. Starting from simple cyclobutanes, the construction of the cyclobutene skeleton especially introducing multiple functional groups simultaneously had never been achieved. Here, we developed a novel radical cascade strategy for the synthesis of highly functionalized cyclobutenes directly from cyclobutanes involving rare cleavage of four or five C–H bonds and formation of two C–N/C–S or three C–Br bonds. With copper as catalyst and N-fluorobenzenesulfonimide (NFSI) as oxidant, a wide range of diaminated, disulfonylated and tribrominated cyclobutene derivatives were efficiently synthesized.

A novel radical cascade strategy for the synthesis of highly functionalized cyclobutenes directly from cyclobutanes involving rare four or five C–H bonds cleavage and two C–N/C–S or three C–Br bonds formation has been successfully developed.     

Exploring benzylic gem-C(sp3)–boron–silicon and boron–tin centers as a synthetic platform

A stepwise build-up of multi-substituted C_sp³ carbon centers is an attractive, conceptually simple, but often synthetically challenging type of disconnection. To this end, this report describes how gem-α,α-dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an excellent stepping stone towards diverse substitution patterns. These gem-dimetalloids were readily accessed, either by known carbenoid insertion into C–B bonds or by the newly developed scalable deprotonation/metallation approach. Highly chemoselective transformations of either the C–Si (or C–Sn) or the C–B bonds in the newly formed gem-C_sp³ centers have been achieved through a set of approaches, with a particular focus on exploiting the synthetically versatile polarity reversal in organometalloids by λ³-aryliodanes. Of particular note is the metal-free arylation of the C–Si (or C–Sn) bonds in such gem-dimetalloids via the iodane-guided C–H coupling approach. DFT calculations show that this transfer of the (α-Bpin)benzyl group proceeds via unusual [5,5]-sigmatropic rearrangement and is driven by the high-energy iodine(iii) center. As a complementary tool, the gem-dimetalloid C–B bond is shown to undergo a potent and chemoselective Suzuki–Miyaura arylation with diverse Ar–Cl, thanks to the development of the reactive gem-α,α-silyl/BF₃K building blocks.

This work explores divergent reactivity of the benzylic gem-boron–silicon and boron–tin double nucleophiles, including the arylation of the C–B bond with Ar–Cl, along with a complementary oxidative λ³-iodane-guided arylation of the C–Si/Sn moiety.     

Catalyst design in C–H activation: a case study in the use of binding free energies to rationalise intramolecular directing group selectivity in iridium catalysis

Remote directing groups in a bifunctional molecule do not always behave independently of one another in C–H activation chemistries. A combined DFT and experimental mechanistic study to provide enhanced Ir catalysts for chemoselective C–H deuteration of bifunctional aryl primary sulfonamides is described. This provides a pharmaceutically-relevant and limiting case study in using binding energies to predict intramolecular directing group chemoselectivity. Rational catalyst design, guided solely by qualitative substrate–catalyst binding free energy predictions, enabled intramolecular discrimination between competing ortho-directing groups in C–H activation and delivered improved catalysts for sulfonamide-selective C–H deuteration. As a result, chemoselective binding of the primary sulfonamide moiety was achieved in the face of an intrinsically more powerful pyrazole directing group present in the same molecule. Detailed DFT calculations and mechanistic experiments revealed a breakdown in the applied binding free energy model, illustrating the important interconnectivity of ligand design, substrate geometry, directing group cooperativity, and solvation in supporting DFT calculations. This work has important implications around attempts to predict intramolecular C–H activation directing group chemoselectivity using simplified monofunctional fragment molecules. More generally, these studies provide insights for catalyst design methods in late-stage C–H functionalisation.

In C–H activation chemistries, the interpretation of the influence of remote directing groups in a bifunctional molecule depends on the in silico method used to inform catalyst design.     

Ni(0)-promoted activation of Csp2–H and Csp2–O bonds

A dinickel(0)–N₂ complex, stabilized with a rigid acridane-based PNP pincer ligand, was studied for its ability to activate C(sp²)–H and C(sp²)–O bonds. Stabilized by a Ni–μ–N₂–Na⁺ interaction, it activates C–H bonds of unfunctionalized arenes, affording nickel–aryl and nickel–hydride products. Concomitantly, two sodium cations get reduced to Na(0), which was identified and quantified by several methods. Our experimental results, including product analysis and kinetic measurements, strongly suggest that this C(sp²)–H activation does not follow the typical oxidative addition mechanism occurring at a low-valent single metal centre. Instead, via a bimolecular pathway, two powerfully reducing nickel ions cooperatively activate an arene C–H bond and concomitantly reduce two Lewis acidic alkali metals under ambient conditions. As a novel synthetic protocol, nickel(ii)–aryl species were directly synthesized from nickel(ii) precursors in benzene or toluene with excess Na under ambient conditions. Furthermore, when the dinickel(0)–N₂ complex is accessed via reduction of the nickel(ii)–phenyl species, the resulting phenyl anion deprotonates a C–H bond of glyme or 15-crown-5 leading to C–O bond cleavage, which produces vinyl ether. The dinickel(0)–N₂ species then cleaves the C(sp²)–O bond of vinyl ether to produce a nickel(ii)–vinyl complex. These results may provide a new strategy for the activation of C–H and C–O bonds mediated by a low valent nickel ion supported by a structurally rigidified ligand scaffold.

A structurally rigidified nickel(0) complex was found to be capable of cleaving both C(sp²)–H and C(sp²)–O bonds.     

A practical and sustainable two-component Minisci alkylation via photo-induced EDA-complex activation

An operationally simple, open-air, and efficient light-mediated Minisci C–H alkylation method is described, based on the formation of an electron donor–acceptor (EDA) complex between nitrogen-containing heterocycles and redox-active esters. In contrast to previously reported protocols, this method does not require a photocatalyst, an external single electron transfer agent, or an oxidant additive. Achieved under mildly acidic and open-air conditions, the reaction incorporates primary-, secondary-, and tertiary radicals, including bicyclo[1.1.1]pentyl (BCP) radicals, along with various heterocycles to generate Minisci alkylation products in moderate to good yields. Additionally, the method is exploited to generate a stereo-enriched, hetereoaryl-substituted carbohydrate.

An operationally simple, open-air, and efficient light-mediated Minisci C–H alkylation method is described, based on the formation of an electron donor–acceptor (EDA) complex between nitrogen-containing heterocycles and redox-active esters.     

Atropoenantioselective palladaelectro-catalyzed anilide C–H olefinations viable with natural sunlight as sustainable power source

Enantioselective electrocatalyzed transformations represent a major challenge. We herein achieved atropoenantioselective pallada-electrocatalyzed C–H olefinations and C–H allylations with high efficacy and enantioselectivity under exceedingly mild reaction conditions. With (S)-5-oxoproline as the chiral ligand, activated and non-activated olefins were suitable substrates for the electro-C–H activations. Dual catalysis was devised in terms of electro-C–H olefination, along with catalytic hydrogenation. Challenging enantiomerically-enriched chiral anilide scaffolds were thereby obtained with high levels of enantio-control in the absence of toxic and cost-intensive silver salts. The resource-economy of the transformation was even improved by directly employing renewable solar energy.

Asymmetric pallada-electrocatalyzed C–H activation of achiral anilides were accomplished by catalyst control with high levels of enantioselectivity. Dual catalysis was devised, while photovoltaic cells could be used to empower the electrocatalysis.     

Hydrogen and proton exchange at carbon. Imbalanced transition state and mechanism crossover

A recent remarkable study of the C–H oxidation of substituted fluorenyl-benzoates together with the transfer of a proton to an internal receiving group by means of electron transfer outer-sphere oxidants, in the noteworthy absence of hydrogen-bonding interactions, is taken as an example to uncover the existence of a mechanism crossover, making the reaction pass from a CPET pathway to a PTET pathway as the driving force of the global reaction decreases. This was also the occasion to stress that considerations based on “imbalanced” or “asynchronous” transition states cannot replace activation/driving force models based on the quantum mechanical treatment of both electrons and transferring protons.

Using the remarkable study of C–H oxidation of substituted fluorenyl-benzoates as an example, we have shown that a mechanism crossover takes place upon decreasing the driving force, from a CPET pathway to a PTET pathway.     

RhodiumIII-catalyzed remote difunctionalization of arenes assisted by a relay directing group

Rhodium-catalyzed diverse tandem twofold C–H bond activation reactions of para-olefin-tethered arenes have been realized, with unsaturated reagents such as internal alkynes, dioxazolones, and isocyanates being the coupling partner as well as a relay directing group which triggers cyclization of the para-olefin group under oxidative or redox-neutral conditions. The reaction proceeded via initial ortho-C–H activation assisted by a built-in directing group in the arene, and the ortho-incorporation of the unsaturated coupling partner simultaneously generated a relay directing group that allows sequential C–H activation at the meta-position and subsequent cyclization of the para-olefins. The overall reaction represents C–C or N–C difunctionalization of the arene with the generation of diverse 2,3-dihydrobenzofuran platforms. The catalytic system proceeded with good efficiency, simple reaction conditions, and broad substrate scope. The diverse transformations of the products demonstrated the synthetic utility of this tandem reaction.

Rhodium-catalyzed twofold C–H bond activation of para-olefin-tethered arenes has been realized using diverse unsaturated reagents. The overall reaction represents C–C or N–C difunctionalization of arenes with the generation of diverse 2,3-dihydrobenzofurans.     

Magnesium-mediated sp3 C–H activation in cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes: efficient synthesis of carborane-fused cyclopentanes

This work reports an unprecedented cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes promoted by magnesium-mediated sp³ C–H activation. Treatment of 1-arylethynyl-2-alkyl-o-carboranes with MeMgBr gives a series of carborane-fused cyclopentanes in very good yields. Deuterium labelling and control experiments suggest that HMgBr, resulting in situ from the nucleophilic substitution of cage B–H bonds with Grignard reagent, initiates the reaction, in which magnesium-promoted intramolecular sp³ C–H activation serves as a key step. This work not only offers a new route for the synthesis of carborane-fused cyclopentanes, but also sheds some light on Mg-mediated C–H activation and functionalization.

An unprecedented cascade cyclization of 1-arylethynyl-2-alkyl-o-carboranes with Grignard reagent for synthesizing carborane-fused cyclopentanes has been disclosed, in which magnesium-mediated intramolecular sp³ C–H activation serves as a key step.     

Site-selective coupling of remote C(sp3)–H/meta-C(sp2)–H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies

Construction of C(sp²)–C(sp³) bonds via regioselective coupling of C(sp²)–H/C(sp³)–H bonds is challenging due to the low reactivity and regioselectivity of C–H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp³)–H bonds in amides and meta-C(sp²)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp³)–H bonds and meta-C(sp²)–H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

A novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp³)–H bonds in amides and meta-C(sp²)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished.