Bond Activation Step Research Articles

Acceleration Mechanisms of C–H Bond Functionalization Catalyzed by Electron-Deficient CpRh(III) Complexes

A rhodium(III) complex bearing a 1,3-bis(ethoxycarbonyl)-substituted or an unsubstituted cyclopentadienyl ligand (CpE or Cp) significantly accelerates a variety of oxidative C–H bond functionalization reactions. However, the driving force of the acceleration compared with a conventionally used Cp*Rh(III) complex has not been elucidated. Herein, we performed density functional theory (DFT) calculations of the rhodium(III)-catalyzed oxidative C–H bond olefination and annulation reactions using Cp*, Cp, and CpE ligands, which revealed that the CpERh(III) complex stabilizes transition states of not only a C–H bond activation step but also rate-determining reductive elimination and insertion steps by strong orbital interactions. For the sterically demanding substrates, the less sterically hindered CpRh(III) complex can stabilize the transition states of the reductive elimination step more than the CpERh(III) complex. Moreover, the whole reaction pathways were calculated to elucidate the mechanism and selectivity of the oxidative [4 + 2] and [2 + 2 + 2] annulation reactions under cationic and neutral conditions, respectively.

Insight into the Mechanism and Regioselectivity of Pd(OAc)2-Catalyzed C-O Bond Activation via a β-O Elimination Approach: A Computational Study.

The density functional theory investigations were carried out to elucidate the mechanism and the origin of regioselectivity for the Pd(OAc)2-catalyzed carbon-oxygen bond activation in the reaction between 4-phenoxy-N-(quinolin-8-yl) butanamide and N-methylindole. The reaction proceeded through four main stages in succession: C-H activation, β-O elimination, nucleo-palladation of the new C-C bond formation, and proto-depalladation steps. A total of six pathways were considered since there were two possible forms of C-O bond breaking in the β-O elimination step and six reaction channels of nucleophilic attack in the crucial nucleo-palladation step. The computational results indicate that the common first step (C-H bond activation step) occurs via a concerted metalation deprotonation (CMD) mechanism. The nucleo-palladation was the rate-determining step for all six reaction pathways. The results also show that the most favorable pathway for the whole reaction is the one (denoted as path b1) in which phenol was removed in the second stage and the hydrogen atom of N-methylindole attacked the oxygen atom of acetate group of the intermediate in the third stage. According to the analyses of noncovalent interaction (NCI) and the reduced density gradient (RDG), the most favored pathway benefits from the strong attractive interaction and weak repulsive interaction in its key transition state. Furthermore, structural, natural bond orbital charge, and energy analyses of the transition states reveal the origin of the regioselectivity. This is a good explanation of the experimental phenomenon and benefits future design of a new strategy for a similar reaction.

Lewis Acid-Promoted Oxidative Addition at a [Ni0 (diphosphine)2 ] Complex: The Critical Role of a Secondary Coordination Sphere.

Oxidative addition represents a critical elementary step in myriad catalytic transformations. Here, the importance of thoughtful ligand design cannot be overstated. In this work, we report the intermolecular activation of iodobenzene (PhI) at a coordinatively saturated 18-electron [Ni0 (diphosphine)2 ] complex bearing a Lewis acidic secondary coordination sphere. Whereas alkyl-substituted diphosphine complexes of Group 10 are known to be unreactive in such reactions, we show that [Ni0 (P2 BCy 4 )2 ] (P2 BCy 4 =1,2-bis(di(3-dicyclohexylboraneyl)-propylphosphino)ethane) is competent for room-temperature PhI cleavage to give [NiII (P2 BCy 4 )(Ph)(I)]. This difference in oxidative addition reactivity has been scrutinized computationally - an outcome that is borne out in ring-opening to provide the reactive precursor - for [Ni0 (P2 BCy 4 )2 ], a "boron-trapped" 16-electron κ1 -diphosphine Ni(0) complex. Moreover, formation of [NiII (P2 BCy 4 )(Ph)(I)] is inherent to the P2 BCy 4 secondary coordination sphere: treatment of the Lewis adduct, [Ni0 (P2 BCy 4 )2 (DMAP)8 ] with PhI provides [NiII (P2 BCy 4 )2 (DMAP)8 (I)]I via iodine-atom abstraction and not a [NiII (Ph)(I)(diphosphine)] compound - an unusual secondary sphere effect. Finally, the reactivity of [Ni0 (P2 BCy 4 )2 ] with 4-iodopyridine was surveyed, which resulted in a pyridyl-borane linked oligomer. The implications of these outcomes are discussed in the context of designing strongly donating, and yet labile diphosphine ligands for use in a critical bond activation step relevant to catalysis.

Versatile Reaction Pathways of 1,1,3,3,3-Pentafluoropropene at Rh(I) Complexes [Rh(E)(PEt3 )3 ] (E=H, GePh3 , Si(OEt)3 , F, Cl): C-F versus C-H Bond Activation Steps.

The reaction of the rhodium(I) complexes [Rh(E)(PEt3)3] (E=GePh3 (1), H (6), F (7)) with 1,1,3,3,3‐pentafluoropropene afforded the defluorinative germylation products Z/E‐2‐(triphenylgermyl)‐1,3,3,3‐tetrafluoropropene and the fluorido complex [Rh(F)(CF3CHCF2)(PEt3)2] (2) together with the fluorophosphorane E‐(CF3)CH=CF(PFEt3). For [Rh(Si(OEt)3)(PEt3)3] (4) the coordination of the fluoroolefin was found to give [Rh{Si(OEt)3}(CF3CHCF2)(PEt3)2] (5). Two equivalents of complex 2 reacted further by C−F bond oxidative addition to yield [Rh(CF=CHCF3)(PEt3)2(μ‐F)3Rh(CF3CHCF2)(PEt3)] (9). The role of the fluorido ligand on the reactivity of complex 2 was assessed by comparison with the analogous chlorido complex. The use of complexes 1, 4 and 6 as catalysts for the derivatization of 1,1,3,3,3‐pentafluoropropene provided products, which were generated by hydrodefluorination, hydrometallation and germylation reactions.

The Emergence of Palladium-Catalyzed C(sp3 )-H Functionalization of Free Carboxylic Acids.

Palladium-catalyzed directing group assisted C-H bond activation has emerged as a powerful tool in synthetic organic chemistry. However, only recently, among various directing groups, widely available carboxylate moiety is recognized as a versatile candidate for the regioselective transformations. Notably, palladium-catalyzed carboxylate directed C(sp3 )-H bond activation and diverse functionalization is highly challenging and has gained huge attention for its versatile applications. Mono- and bidentate ligands have proven to be useful for accelerating the C(sp3 )-H bond activation step, which helps to control reactivity and selectivity (including enantioselectivity). In this Minireview, we discuss the recent progress made in palladium-catalyzed C(sp3 )-H bond functionalization reactions for the construction of C-C and C-Heteroatom bonds with the direction of free carboxylic acid.

Direct Observation of the Microscopic Reverse of the Ubiquitous Concerted Metalation Deprotonation Step in C-H Bond Activation Catalysis.

The ability of carboxylate groups to promote the direct functionalization of C-H bonds in organic compounds is unquestionably one of the most important discoveries in modern chemical synthesis. Extensive computational studies have indicated that this process proceeds through the deprotonation of a metal-coordinated C-H bond by the basic carboxylate, yet experimental validation of these predicted mechanistic pathways is limited and fraught with difficulty, mainly as rapid proton transfer is frequently obscured in ensemble measures in multistep reactions (i.e., a catalytic cycle consisting of several steps). In this paper, we describe a strategy to experimentally observe the microscopic reverse of the key C-H bond activation step underpinning functionalization processes (viz. M-C bond protonation). This has been achieved by utilizing photochemical activation of the thermally robust precursor [Mn(ppy)(CO)4] (ppy = metalated 2-phenylpyridine) in neat acetic acid. Time-resolved infrared spectroscopy on the picosecond-millisecond time scale allows direct observation of the states involved in the proton transfer from the acetic acid to the cyclometalated ligand, providing direct experimental evidence for the computationally predicted reaction pathways. The power of this approach to probe the mechanistic pathways in transition-metal-catalyzed reactions is demonstrated through experiments performed in toluene solution in the presence of PhC2H and HOAc. These allowed for the observation of sequential displacement of the metal-bound solvent by the alkyne, C-C bond formation though insertion in the Mn-C bond, and a slower protonation step by HOAc to generate the product of a Mn(I)-catalyzed C-H bond functionalization reaction.

Unravelling the reactivity of metastable molybdenum carbide nanoclusters in the C-H bond activation of methane, ethane and ethylene.

C-H bond activation steps in non-oxidative methane dehydroaromatization (MDA), constitute a key functionalization of the reactant and adsorbed species to form aromatics. Previous studies have focused on studying the energetics of these steps at the most stable active sites involving molybdenum carbide species. Herein, a different paradigm is presented via studying the reactivity of a metastable molybdenum carbide (Mo2C6) nanocluster for the C-H bond activation of methane, ethane, and ethylene and comparing it with the reactivity of the lowest energy Mo2C6 nanocluster. Interestingly, the metastable nanocluster is observed to result in a consistent reduction (by half) in the C-H bond activation barrier of the respective alkane and alkene molecules compared to the global minimum isomer. This specific metastable form of the nanocluster is identified from a cascade genetic algorithm search, which facilitated a rigorous scan of the potential energy surface. We attribute this significant lowering of the C-H bond activation barrier to unique co-planar orbital overlap between the reactant molecule and active centers on the metastable nanocluster. Based on geometrical and orbital analysis of the transition states arising during the C-H bond activation of methane, ethane, and ethylene, a proton-coupled electron transfer mechanism is proposed that facilitated C-H bond cleavage. Motivated by the high reactivity for C-H bond activation observed on the metastable species, a contrasting framework to analyze the elementary-step rate contributions is presented. This is based on the statistical ensemble analysis of nanocluster isomers, where the calculated rates on respective isomers are normalized with respect to the Boltzmann probability distribution. From this framework, the metastable isomer is observed to provide significant contributions to the ensemble average representations of the rate constants calculated for C-H bond activation during the MDA reaction.

Consecutive methane activation mediated by single metal boride cluster anions NbB4.

Cleavage of all C-H bonds in two methane molecules by gas-phase cluster ions at room temperature is a challenging task. Herein, mass spectrometry and quantum chemical calculations have been used to identify one single metal boride cluster anions NbB4- that can activate eight C-H bonds in two methane molecules and release one H2 molecule each time under thermal collision conditions. In these consecutive reactions, the loaded Nb atoms and the support B4 units play different roles but act synergistically to activate CH4, which is responsible for the interesting reactivity of NbB4-. Moreover, there are some mechanistic differences in these two reactions, including the mechanisms for the first C-H bond activation steps, dihydrogen desorption sites, and major electron donors. This study shows that non-noble metal boride species are reactive enough to facilitate thermal C-H bond cleavages, and boron-based materials may be one kind of potential support material facilitating surface hydrogen transport.

Enantioselective Synthesis of Atropisomeric Anilides via Pd(II)-Catalyzed Asymmetric C-H Olefination.

Atropisomeric anilides have received tremendous attention as a novel class of chiral compounds possessing restricted rotation around an N-aryl chiral axis. However, in sharp contrast to the well-studied synthesis of biaryl atropisomers, the catalytic asymmetric synthesis of chiral anilides remains a daunting challenge, largely due to the higher degree of rotational freedom compared to their biaryl counterparts. Here we describe a highly efficient catalytic asymmetric synthesis of atropisomeric anilides via Pd(II)-catalyzed atroposelective C-H olefination using readily available L-pyroglutamic acid as a chiral ligand. A broad range of atropisomeric anilides were prepared in high yields (up to 99% yield) and excellent stereoinduction (up to >99% ee) under mild conditions. Experimental studies indicated that the atropostability of those anilide atropisomers toward racemization relies on both steric and electronic effects. Experimental and computational studies were conducted to elucidate the reaction mechanism and rate-determining step. DFT calculations revealed that the amino acid ligand distortion is responsible for the enantioselectivity in the C-H bond activation step. The potent applications of the anilide atropisomers as a new type of chiral ligand in Rh(III)-catalyzed asymmetric conjugate addition and Lewis base catalysts in enantioselective allylation of aldehydes have been demonstrated. This strategy could provide a straightforward route to access atropisomeric anilides, one of the most challenging types of axially chiral compounds.

An Unconventional trans - exo -Selective Cyclization of Alkyne-Tethered Cyclohexadienones Initiated by Rhodium(III)-Catalyzed C–H Activation via Insertion Relay

Different from the established trans-endo-selective cyclization of alkyne-tethered electrophiles that involve an E/Z isomerization process, herein, the authors present a novel strategy to allow tra...

DFT study on the mechanism of palladium(II)-catalyzed reaction of allyl-substituted 3,4-dienoate, alkyne and carbon monoxide

The reaction mechanism of palladium-catalyzed allyl-substituted 3,4-dienoate, alkyne and carbon monoxide to form ynone has been theoretically investigated by using density functional theory calculations. Two reaction mechanisms have been calculated. In one reaction mechanism, the C(sp3)–H bond of allyl-substituted 3,4-dienoate is first activated while the C(sp)–H bond of alkyne is first activated in the other reaction mechanism. It is found that the activation of C(sp)–H bond of alkyne is superior to C(sp3)–H bond activation of allyl-substituted 3,4-dienoate. The calculations suggest that the reaction mainly proceeds via C(sp)–H bond activation, CO insertion, alkene insertion, second CO insertion, allene CC insertion and C(sp3)–H bond activation steps. The transition states of alkene insertion and CO insertion into Pd-C(sp3) are competitive as the rate-determining transition state with a free energy barrier of around 23 kcal/mol. Moreover, it is found that the CO molecule does not directly participates in the reaction but also acts as an ancillary ligand. In addition, the reaction mechanisms for formation of other side products have been calculated and compared.

Exploring the Tunability of Trimetallic MOF Nodes for Partial Oxidation of Methane to Methanol.

Density functional theory is used to study the tunability of trigonal prismatic SBUs found in metal-organic frameworks (MOFs) such as MIL-100, MIL-101, and PCN-250/MIL-127 of chemical composition M3+2M2+(μ3-O)(RCOO)6 for the partial oxidation of methane to methanol. We performed a combinatorial screening by varying the composition of the trimetallic node (M13+)2(M22+) (where M1 and M2 = V, Cr, Mn, Fe, Co, and Ni) and calculated the reaction pathway on both M1 and M2 sites. The systematic replacement of metals in the trimetallic cluster allowed us to study the influence of spectator atoms on the catalytic activity of a specific metal site in the cluster toward the N2O activation and C-H bond activation steps of the reaction. In the screening, we identified the top-performing node compositions with predicted barriers lower than those already reported for experimentally tested MOFs with trigonal prismatic SBUs. This work demonstrates the opportunity to tune the catalytic activity of MOFs for redox reactions by changing their metal node composition.

Catalytic Carbon–Carbon Bond Activation of Saturated and Unsaturated Carbonyl Compounds via Chelate-Assisted Coupling Reaction with Indoles

The chelate assistance strategy was devised to promote a highly regioselective catalytic C–C bond activation reaction of saturated and unsaturated carbonyl compounds. The cationic Ru–H complex 1 was found to be an effective catalyst for mediating the coupling reaction of 1,2-disubstituted indoles with α,β-unsaturated aldehydes and ketones, in which the regioselective Cα–Cβ activation of the carbonyl substrates has been achieved in forming the 3-alkylindole products. The analogous coupling reaction of indoles with saturated aldehydes and ketones directly led to the Cα–Cβ cleavage of the carbonyl substrates in forming the 3-alkylindole products. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one and 2-propanol-d8 showed 20–22% of deuterium incorporation to both α- and β-CH2 of the 3-alkylindole product. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one exhibited the most significant carbon kinetic isotope effect on the α-carbon of the product (Cα = 1.046). The Hammett plot constructed from the reaction of 1,2-dimethylinole with a series of para-substituted enones p-X-C6H4CH═CHCOCH3 (X = OMe, Me, H, Cl, CF3) showed a modest promotional effect by an electron-donating group (ρ = −0.2 ± 0.1). Several catalytically relevant Ru–H species were detected by NMR from a stoichiometric reaction mixture of the Ru–H complex 1 with 1,2-dimethylindole and (E)-3-nonen-2-one in CD2Cl2. These results support a mechanism of the catalytic coupling reaction via conjugate addition of indoles to enones followed by the C–C bond activation and hydrogenolysis steps.

Mechanistic Study of Pd/Ag Dual-Catalyzed Cross-Dehydrogenative Coupling of Perfluoroarenes with Thiophenes

The mechanism of the Pd/Ag dual-catalyzed cross-dehydrogenative coupling (CDC) between perfluoroarenes and thiophenes was clarified. The exact role of the catalytic resting state of the homo-biaryl-Pd(II) complex, which was previously overlooked in Pd/Ag dual-catalyzed CDC, was carefully investigated. Detailed experimental studies indicated that a homo-biaryl-Pd(II) complex occurred in the catalytic off-cycle as a resting state and prevented the homocoupling of perfluoroarenes. In addition, these studies indicated that the C–H bond activation steps of perfluoroarenes and thiophenes proceeded by different mechanisms. While the C–H bond of perfluoroarenes was immediately activated by Ag(I) salts, the C–H bond of thiophenes was activated by the Pd(II) catalyst. Kinetic studies revealed that the Pd(II)–C–H activation of thiophenes is most likely the rate-determining step.

Atroposelective Synthesis of Axially Chiral Styrenes via an Asymmetric C–H Functionalization Strategy

<h2>Summary</h2> Axially chiral styrenes, which exhibit a chiral axis between a substituted alkene and an aromatic ring, have been largely overlooked. The hurdle is the lower barriers to rotation compared with that of their biaryl counterparts, rendering their asymmetric synthesis more difficult. We report herein the highly atroposelective synthesis via a C−H functionalization strategy of axially chiral styrenes with an open-chained alkene. Various axially chiral styrenes were produced by Pd(II)-catalyzed C−H alkenylation and alkynylation in good yields (up to 99%) and enantioselectivities (up to 99% ee) by using L-pyroglutamic acid as an inexpensive chiral ligand. The potent application of the styrene atropisomers is demonstrated by a Co(III)-catalyzed enantioselective C−H amidation of ferrocene with axially chiral styrene-type acid as chiral ligand. Experimental and computational studies were conducted to elucidate the reaction mechanism. The chiral induction model of the enantioselectivity-determining C−H bond activation step was also provided based on DFT calculations.

Base-Assisted C-H Bond Cleavage in Cross-Coupling: Recent Insights into Mechanism, Speciation, and Cooperativity.

This review analyzes recent mechanistic studies that have provided new insights into how the structure of a metal complex influences the rate and selectivity of base-assisted C-H cleavage. Partitioning a broader mechanistic continuum into classes delimited by the polarization between catalyst and substrate during C-H cleavage is postulated as a method to identify catalysts favoring electrophilic or nucleophilic reactivity patterns, which may be predictive based on structural features of the metal complex (i.e., oxidation state, d-electron count, charge). Multi-metallic cooperativity and polynuclear speciation also provide new avenues to affect energy barriers for C-H cleavage and site selectivity beyond the limitations of single metal catalysts. An improved understanding of mechanistic nuances and structure-activity relationships on this important bond activation step carries important implications for efficiency and controllable site selectivity in non-directed C-H functionalization.

B-B Cleavage and Ring-Expansion of a 1,4,2,3-Diazadiborinine with N-Heterocyclic Carbenes.

A 1,4,2,3‐diazadiborinine derivative was found to form Lewis adducts with strong two‐electron donors such as N‐heterocyclic and cyclic (alkyl)(amino)carbenes. Depending on the donor, some of these Lewis pairs are thermally unstable, converting to sole B,N‐embedded products upon gentle heating. The products of these reactions, which have been fully characterized by NMR spectroscopy, elemental analysis, and single‐crystal X‐ray diffraction, were identified as B,N‐heterocycles with fused 1,5,2,4‐diazadiborepine and 1,4,2‐diazaborinine rings. Computational modelling of the reaction mechanism provides insight into the formation of these unique structures, suggesting that a series of B−H, C−N, and B−B bond activation steps are responsible for these “intercalation” reactions between the 1,4,2,3‐diazadiborinine and NHCs.

A Reaction-Induced Localization of Spin Density Enables Thermal C-H Bond Activation of Methane by Pristine FeC4.

The reactivity of the cationic metal‐carbon cluster FeC4 + towards methane has been studied experimentally using Fourier‐transform ion cyclotron resonance mass spectrometry and computationally by high‐level quantum chemical calculations. At room temperature, FeC4H+ is formed as the main ionic product, and the experimental findings are substantiated by labeling experiments. According to extensive quantum chemical calculations, the C−H bond activation step proceeds through a radical‐based hydrogen‐atom transfer (HAT) mechanism. This finding is quite unexpected because the initial spin density at the terminal carbon atom of FeC4 +, which serves as the hydrogen acceptor site, is low. However, in the course of forming an encounter complex, an electron from the doubly occupied sp‐orbital of the terminal carbon atom of FeC4 + migrates to the singly occupied π*‐orbital; the latter is delocalized over the entire carbon chain. Thus, a highly localized spin density is generated in situ at the terminal carbon atom. Consequently, homolytic C−H bond activation occurs without the obligation to pay a considerable energy penalty that is usually required for HAT involving closed‐shell acceptor sites. The mechanistic insights provided by this combined experimental/computational study extend the understanding of methane activation by transition‐metal carbides and add a new facet to the dizzying mechanistic landscape of hydrogen‐atom transfer.

Synthesis of the Madangamine Alkaloid Core by a C-C Bond Activation Cascade.

The diazatricyclic core of the madangamine alkaloids was synthesized from a densely functionalized cyclohexane derivative. An alkene and two cyanoformamide groups are used to form two new rings and a new quaternary stereocenter in a cascade reaction, which involves two Pd-catalyzed C-C bond activation steps. The synthesis of the cascade precursor involves an intramolecular Staudinger reaction of a vicinal diester that gives a [3.2.1]azabicyclooctane derivative, allowing the regioselective introduction of a monosubstituted alkene.

Mixed Electron–Proton Conductors Enable Spatial Separation of Bond Activation and Charge Transfer in Electrocatalysis

Electrochemical energy conversion requires electrodes that can simultaneously facilitate substrate bond activation and electron-proton charge transfer. Traditional electrodes co-localize both functions to a single solid|liquid interface even though each process is typically favored in a disparate reaction environment. Herein, we establish a strategy for spatially separating bond activation and charge transfer by exploiting mixed electron-proton conduction (MEPC) in an oxide membrane. Specifically, we interpose a MEPC WOx membrane between a Pt catalyst and aqueous electrolyte and show that this composite electrode is active for the hydrogen oxidation reaction (HOR). Consistent with H2 activation occurring at the gas|solid interface, the composite electrode displays HOR current densities over 8-fold larger than the diffusion-limited rate of HOR catalysis at a singular Pt|solution interface. The segregation of bond activation and charge separation steps also confers excellent tolerance to poisons and impurities introduced to the electrolyte. Mechanistic studies establish that H2 activation at the Pt|gas interface is coupled to the electron-proton charge separation at the WOx|solution interface via rapid H-diffusion in the bulk of the WOx. Consequently, the rate of HOR is principally controlled by the rate of H-spillover at the Pt|WOx boundary. Our results establish MEPC membrane electrodes as a platform for spatially separating the critical bond activation and charge transfer steps of electrocatalysis.