The Activating Effect of Strong Acid for Pd-Catalyzed Directed C–H Activation by Concerted Metalation-Deprotonation Mechanism

A computational study on the origin of the activating effect for Pd-catalyzed directed C–H activation by the concerted metalation-deprotonation (CMD) mechanism is conducted. DFT calculations indicate that strong acids can make Pd catalysts coordinate with directing groups (DGs) of the substrates more strongly and lower the C–H activation energy barrier. For the CMD mechanism, the electrophilicity of the Pd center and the basicity of the corresponding acid ligand for deprotonating the C–H bond are vital to the overall C–H activation energy barrier. Furthermore, this rule might disclose the role of some additives for C–H activation.     

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.     

Recent development in transition metal-catalysed C–H olefination

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules. Fine tuning of directing groups, catalysts and ligands has played a crucial role in selective C–H bond (sp² or sp³) activation. Recent developments in these areas have assured a high level of regioselectivity in C–H olefination reactions. In this review, we have summarized the recent progress in the oxidative olefination of sp² and sp³ C–H bonds with special emphasis on distal, atroposelective, non-directed sp² and directed sp³ C–H olefination. The scope, limitation, and mechanism of various transition metal-catalysed olefination reactions have been described briefly.

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules.     

Carbon–hydrogen (C–H) bond activation at PdIV: a Frontier in C–H functionalization catalysis

The direct functionalization of carbon–hydrogen (C–H) bonds has emerged as a versatile strategy for the synthesis and derivatization of organic molecules. Among the methods for C–H bond activation, catalytic processes that utilize a Pd^II/Pd^IV redox cycle are increasingly common. The C–H activation step in most of these catalytic cycles is thought to occur at a Pd^II centre. However, a number of recent reports have suggested the feasibility of C–H cleavage occurring at Pd^IV complexes. Importantly, these latter processes often result in complementary reactivity and selectivity relative to analogous transformations at Pd^II. This mini review highlights proposed examples of C–H activation at Pd^IV centres. Applications of this transformation in catalysis as well as mechanistic details obtained from stoichiometric model studies are discussed. Furthermore, challenges and future perspectives for the field are reviewed.     

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.     

Visible Light-Induced Aerobic Oxidative Dehydrogenation of C–N/C–O to C=N/C=O Bonds Using Metal-Free Photocatalysts: Recent Developments

Performing synthetic transformation using visible light as energy source, in the presence of a photocatalyst as a promoter, is currently of high interest, and oxidation reactions carried out under these conditions using oxygen as the final oxidant are particularly convenient from an environmental point of view. This review summarizes the recent developments achieved in the oxidative dehydrogenation of C–N and C–O bonds, leading to C=N and C=O bonds, respectively, using air or pure oxygen as oxidant and metal-free homogeneous or recyclable heterogeneous photocatalysts under visible light irradiation.     

Ceramic boron carbonitrides for unlocking organic halides with visible light

Photochemistry provides a sustainable pathway for organic transformations by inducing radical intermediates from substrates through electron transfer process. However, progress is limited by heterogeneous photocatalysts that are required to be efficient, stable, and inexpensive for long-term operation with easy recyclability and product separation. Here, we report that boron carbonitride (BCN) ceramics are such a system and can reduce organic halides, including (het)aryl and alkyl halides, with visible light irradiation. Cross-coupling of halides to afford new C–H, C–C, and C–S bonds can proceed at ambient reaction conditions. Hydrogen, (het)aryl, and sulfonyl groups were introduced into the arenes and heteroarenes at the designed positions by means of mesolytic C–X (carbon–halogen) bond cleavage in the absence of any metal-based catalysts or ligands. BCN can be used not only for half reactions, like reduction reactions with a sacrificial agent, but also redox reactions through oxidative and reductive interfacial electron transfer. The BCN photocatalyst shows tolerance to different substituents and conserved activity after five recycles. The apparent metal-free system opens new opportunities for a wide range of organic catalysts using light energy and sustainable materials, which are metal-free, inexpensive and stable.

A metal-free photoredox system was introduced for the transformation of organic halides to afford C–H, C–C, and C–S bonds without the addition of any metals, ligands, extra reductants or additives.     

Ion-molecule reactions catalyzed by a single gold atom

We report that Au atoms within van der Waals complexes serve as catalysts for the first time. This was observed in ionization-induced chemistry of 1,6-hexanediol–Au and 1,8-octanediol–Au complexes formed in superfluid helium nanodroplets, where the addition of Au atom(s) made C₂H₄⁺ the sole prominent product in dissociative reactions. Density functional theory (DFT) calculations showed that the Au atom significantly strengthens all of the C–C bonds and weakens the C–O bonds in the meantime, making the C–C bonds stronger than the two C–O bonds in the ionized complexes. This leads to a preferential cleavage of the C–O bonds and thus a strong catalytic effect of the Au atoms in the reactions.

Single Au atoms within van der Waals complexes are found to serve as catalysts in ionisation-induced chemistry for the first time.     

Recent advances in heterogeneous catalysis for the nonoxidative conversion of methane

The direct conversion of methane to high-value chemicals is an attractive process that efficiently uses abundant natural/shale gas to provide an energy supply. The direct conversion of methane to high-value chemicals is an attractive process that efficiently uses abundant natural/shale gas to provide an energy supply. Among all the routes used for methane transformation, nonoxidative conversion of methane is noteworthy owing to its highly economic selectivity to bulk chemicals such as aromatics and olefins. Innovations in catalysts for selective C–H activation and controllable C–C coupling thus play a key role in this process and have been intensively investigated in recent years. In this review, we briefly summarize the recent advances in conventional metal/zeolite catalysts in the nonoxidative coupling of methane to aromatics, as well as the newly emerging single-atom based catalysts for the conversion of methane to olefins. The emphasis is primarily the experimental findings and the theoretical understanding of the active sites and reaction mechanisms. We also present our perspectives on the design of catalysts for C–H activation and C–C coupling of methane, to shed some light on improving the potential industrial applications of the nonoxidative conversion of methane into chemicals.

The direct conversion of methane to high-value chemicals is an attractive process that efficiently uses abundant natural/shale gas to provide an energy supply.     

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.     

Formation of a C–C double bond from two aliphatic carbons. Multiple C–H activations in an iridium pincer complex

The search for novel, atom-economic methods for the formation of C–C bonds is of crucial importance in synthetic chemistry. Especially attractive are reactions where C–C bonds are formed through C–H activation, but the coupling of unactivated, alkane-type C_sp³–H bonds remains an unsolved challenge. Here, we report iridium-mediated intramolecular coupling reactions involving up to four unactivated C_sp³–H bonds to give carbon–carbon double bonds under the extrusion of dihydrogen. The reaction described herein is completely reversible and the direction can be controlled by altering the reaction conditions. With a hydrogen acceptor present a C–C double bond is formed, while reacting under dihydrogen pressure leads to the reverse process, with some of the steps representing net C_sp³–C_sp³ bond cleavage. Mechanistic investigations revealed a conceptually-novel overall reactivity pattern where insertion or deinsertion of an Ir carbene moiety, formed via double C–H activation, into an Ir–C bond is responsible for the key C–C bond formation and cleavage steps.     

C–H functionalization reactions enabled by hydrogen atom transfer to carbon-centered radicals

Selective functionalization of ubiquitous unactivated C–H bonds is a continuous quest for synthetic organic chemists. In addition to transition metal catalysis, which typically operates under a two-electron manifold, a recent renaissance in the radical approach relying on the hydrogen atom transfer (HAT) process has led to tremendous growth in the area. Despite several challenges, protocols proceeding via HAT are highly sought after as they allow for relatively easy activation of inert C–H bonds under mild conditions leading to a broader scope and higher functional group tolerance and sometimes complementary reactivity over methods relying on traditional transition metal catalysis. A number of methods operating via heteroatom-based HAT have been extensively reported over the past few years, while methods employing more challenging carbon analogues have been less explored. Recent developments of mild methodologies for generation of various carbon-centered radical species enabled their utilization in the HAT process, which, in turn, led to the development of remote C(sp³)–H functionalization reactions of alcohols, amines, amides and related compounds. This review covers mostly recent advances in C–H functionalization reactions involving the HAT step to carbon-centered radicals.

Intramolecular and intermolecular HAT to C-centered radicals enables selective C–H functionalization of organic molecules.     

Catalytic C–H to C–M (M = Al,Mg) bond transformations with heterometallic complexes

C–H functionalisation is one of the cornerstones of modern catalysis and remains a topic of contemporary interest due its high efficiency and atom-economy. Among these reactions, C–H borylation, that is the transformation of C–H to C–B bonds, has experienced a fast development because of the wide utility of organoboron reagents as synthetic intermediates. The mechanistic background is now well-understood and the role of transition metal boryl or σ-borane intermediates in this transformation is well documented. This mini-review focuses on efforts made by our group, and others, to establish palladium- and calcium-catalysed methods for C–H metalation employing heavier main group elements (M = Al, Mg). These are new catalytic reactions first accomplished in our group that we have termed C–H alumination and magnesiation respectively. Unusual heterometallic complexes have been identified as key on-cycle intermediates and their unique reactivity is discussed in the context of new catalytic pathways for C–H functionalisation. Hence, this mini-review summarises the recent progress in the area of C–H metalation reactions as well as the new opportunities that may arise from this concept.

This highlight focuses on recent efforts to establish catalytic methods for C–H functionalisation with main group metals (M = Al, Mg).     

Site-selective functionalization of remote aliphatic C–H bonds via C–H metallation

Directing group assistance provided a paradigm for controlling site-selectivity in transition metal-catalyzed C–H functionalization reactions. However, the kinetically and thermodynamically favored formation of 5-membered metallacycles has greatly hampered the selective activation of remote C(sp³)–H bonds via larger-membered metallacycles. Recent development to achieve remote C(sp³)–H functionalization via the C–H metallation process largely relies on employing specific substrates without accessible proximal C–H bonds. Encouragingly, recent advances in this field have enabled the selective functionalization of remote aliphatic C–H bonds in the presence of equally accessible proximal ones by taking advantage of the switch of the regiodetermining step, ring strain of metallacycles, multiple non-covalent interactions, and favourable reductive elimination from larger-membered metallacycles. In this review, we summarize these advancements according to the strategies used, hoping to facilitate further efforts to achieve site- and even enantioselective functionalization of remote C(sp³)–H bonds.

Recent advances in site-selective functionalization of remote aliphatic C–H bonds in organometallic pathways are summarized.     

Pushing the limits of the hydrogen bond enhanced halogen bond—the case of the C–H hydrogen bond

C–H hydrogen bonds have remarkable impacts on various chemical systems. Here we consider the influence of C–H hydrogen bonds to iodine atoms. Positioning a methyl group between two iodine halogen bond donors of the receptor engendered intramolecular C–H hydrogen bonding (HBing) to the electron-rich belt of both halogen bond donors. When coupled with control molecules, the role of the C–H hydrogen bond was evaluated. Gas-phase density functional theory studies indicated that methyl C–H hydrogen bonds help bias a bidentate binding conformation. Interaction energy analysis suggested that the charged C–H donors augment the halogen bond interaction—producing a >10 kcal mol⁻¹ enhancement over a control lacking the C–H⋯I–C interaction. X-ray crystallographic analysis demonstrated C–H hydrogen bonds and bidentate conformations with triflate and iodide anions, yet the steric bulk of the central functional group seems to impact the expected trends in halogen bond distance. In solution, anion titration data indicated elevated performance from the receptors that utilize C–H Hydrogen Bond enhanced Halogen Bonds (HBeXBs). Collectively, the results suggest that even modest hydrogen bonds between C–H donors and iodine acceptors can influence molecular structure and improve receptor performance.

C–H hydrogen bonds to iodine halogen bond donors are shown to improve halogen bonding and molecular preorganization.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Development of Ceria-Supported Ruthenium Catalysts Effective for Various Synthetic Reactions

Our recent results on organic transformations such as C–C bond formation via the activation of stable C–C or C–H bonds and aerobic oxidation of alcohols catalyzed by CeO₂-supported ruthenium are reviewed. A simple, recyclable heterogeneous Ru/CeO₂ catalyst showed excellent activity for sequential transfer-allylation/isomerization of homoallyl alcohols with aldehydes to saturated ketones via the C–C bond activation. While homogeneous ruthenium and rhodium complex catalysts require additives and/or pressurized CO, the reaction with Ru/CeO₂ smoothly proceeded in the absence of any additives. The Ru/CeO₂ catalyst also showed excellent activity for the addition of sp² C–H bonds of aromatic ketones to vinylsilanes. The Ru/CeO₂ catalyst realized the chelation-assisted arylation of stable aromatic C–H bonds with aryl chlorides. The activity of the catalyst was greatly improved by the PPh₃-modification under hydrogen atmosphere prior to the reactions. The catalyst acts heterogeneously without a significant leaching of ruthenium species, indicating that the Ru/CeO₂ catalyst has an advantage over homogeneous catalysts from practical and environmental points of view. The effects of chemical and physical properties of CeO₂ on the activity of CeO₂-supported noble metal catalysts were examined. Porous CeO₂ powders were prepared by the coagulation of solvothermally synthesized colloidal ceria nanoparticles, and the thus-prepared CeO₂ powders showed an oxygen migration ability far superior to the CeO₂ samples prepared by the usual precipitation method. The ruthenium catalysts supported on the former CeO₂ powders showed a high activity for the aerobic oxidation of benzyl alcohol. The effects of the pore structure of CeO₂ powders on the activity of the Ru/CeO₂ catalysts are also discussed.     

Selective cleavage of unactivated arene ring C–C bonds by iridium: key roles of benzylic C–H activation and metal–metal cooperativity

The cleavage of aromatic C–C bonds is central for conversion of fossil fuels into industrial chemicals and designing novel arene functionalisations through ring opening, expansion and contraction. However, the current progress is hampered by both the lack of experimental examples of selective oxidative addition of aromatic C–C bonds and limited understanding of the factors that favour insertion into the C–C rather than the C–H bonds. Here, we describe the comprehensive mechanism of the only reported chemo- and regioselective insertion of a transition metal into a range of substituted arene rings in simple iridium(i) complexes. The experimental and computational data reveal that this ring cleavage requires both reversible scission of a benzylic C–H bond and cooperativity of two Ir centres sandwiching the arene in the product-determining intermediate. The mechanism explains the chemoselectivity and scope of this unique C–C activation in industrially important methylarenes and provides a general insight into the role of metal–metal cooperativity in the cleavage of unsaturated C–C bonds.

The detailed mechanism of iridium-mediated C–C cleavage in unactivated arenes reveals the key factors enabling the process and helps predict the scope of the cleavage reaction.