Rhodium Complexes in P−H Bond Activation Reactions

The feasibility of oxidative addition of the P−H bond of PHPh₂ to a series of rhodium complexes to give mononuclear hydrido-phosphanido complexes has been analyzed. Three main scenarios have been found depending on the nature of the L ligand added to [Rh(Tp)(C₂H₄)(PHPh₂)] (Tp= hydridotris(pyrazolyl)borate): i) clean and quantitative reactions to terminal hydrido-phosphanido complexes [RhTp(H)(PPh₂)(L)] (L=PMe₃, PMe₂Ph and PHPh₂), ii) equilibria between Rh^I and Rh^III species: [RhTp(H)(PPh₂)(L)]⇄[RhTp(PHPh₂)(L)] (L=PMePh₂, PPh₃) and iii) a simple ethylene replacement to give the rhodium(I) complexes [Rh(κ²-Tp)(L)(PHPh₂)] (L=NHCs-type ligands). The position of the P−H oxidative addition–reductive elimination equilibrium is mainly determined by sterics influencing the entropy contribution of the reaction. When ethylene was used as a ligand, the unique rhodaphosphacyclobutane complex [Rh(Tp)(η¹-Et)(κ^C,P-CH₂CH₂PPh₂)] was obtained. DFT calculations revealed that the reaction proceeds through the rate limiting oxidative addition of the P−H bond, followed by a low-barrier sequence of reaction steps involving ethylene insertion into the Rh−H and Rh−P bonds. In addition, oxidative addition of the P−H bond in OPHPh₂ to [Rh(Tp)(C₂H₄)(PHPh₂)] gave the related hydride complex [RhTp(H)(PHPh₂)(POPh₂)], but ethyl complexes resulted from hydride insertion into the Rh−ethylene bond in the reaction with [Rh(Tp)(C₂H₄)₂].     

Elementary Steps of Iron Catalysis: Exploring the Links between Iron Alkyl and Iron Olefin Complexes for their Relevance in C?H Activation and C?C Bond Formation

The alkylation of complexes 2 and 7 with Grignard reagents containing β‐hydrogen atoms is a process of considerable relevance for the understanding of C–H activation as well as C–C bond formation mediated by low‐valent iron species. Specifically, reaction of 2 with EtMgBr under an ethylene atmosphere affords the bis‐ethylene complex 1 which is an active precatalyst for prototype [2+2+2] cycloaddition reactions and a valuable probe for mechanistic studies. This aspect is illustrated by its conversion into the bis‐alkyne complex 6 as an unprecedented representation of a cycloaddition catalyst loaded with two substrates molecules. On the other hand, alkylation of 2 with 1 equivalent of cyclohexylmagnesium bromide furnished the unique iron alkyl species 11 with a 14‐electron count, which has no less than four β‐H atoms but is nevertheless stable at low temperature against β‐hydride elimination. In contrast, the exhaustive alkylation of 1 with cyclohexylmagnesium bromide triggers two consecutive C–H activation reactions mediated by a single iron center. The resulting complex has a diene dihydride character in solution ( 15 ), whereas its structure in the solid state is more consistent with an η³‐allyl iron hydride rendition featuring an additional agostic interaction ( 14 ). Finally, the preparation of the cyclopentadienyl iron complex 25 illustrates how an iron‐mediated C–H activation cascade can be coaxed to induce a stereoselective C C bond formation. The structures of all relevant new iron complexes in the solid state are presented.     

Chiral Bicyclo[2.2.2]octane-Fused CpRh Complexes: Synthesis and Potential Use in Asymmetric C−H Activation

A new class of chiral cyclopentadienyl rhodium(I) complexes (CpRh^I) bearing C₂-symmetric chiral bridged-ring-fused Cp ligands was prepared. The complexes were successfully applied to the asymmetric C−H activation reaction of N-methoxybenzamides with quinones, affording a series of chiral hydrophenanthridinones in up to 82 % yield with up to 99 % ee. Interestingly, structure analysis reveals that the side wall of the optimal chiral CpRh^I catalyst is vertically more extended, horizontally less extended, and closer to the metal center in comparison with the classic binaphthyl and spirobiindanyl CpRh^I complexes, and may thus account for its superior catalytic performance.     

Size Effects in Gas-phase C−H Activation

The gas-phase clusters reaction permits addressing fundamental aspects of the challenges related to C−H activation. The size effect plays a key role in the activation processes as it may substantially affect both the reactivity and selectivity. In this paper, we reviewed the size effect related to the hydrocarbon oxidation by early transition metal oxides and main group metal oxides, methane activation mediated by late transition metals. Based on mass-spectrometry experiments in conjunction with quantum chemical calculations, mechanistic discussions were reviewed to present how and why the size greatly regulates the reactivity and product distribution.     

C−H and C−M Activation,Aromaticity Tuning,and Co⋅⋅⋅Ru Interactions Confined in the Azuliporphyrin Framework

Taking advantage of the specific properties of azuliporphyrin and the reactivity of cobalt(II), activation of an azulene C(sp²)−H bond occurred and organometallic complexes with Co−C bonding were formed. The system allowed for macrocyclic aromaticity tuning through metal coordination and oxidation. Thanks to the Co^II−C and parallel tested Cu^II−C reactivity and the affinity of metal centers to dioxygen, oxygen atom insertion into the M−C bond could be investigated. Insertion starts with an oxygen molecule coordination and leads to monomeric and dimeric complexes of specific electronic structures. Formation of unique paramagnetic σ/π-hybrid bimetallic complexes enabled spectroscopic and theoretical investigations of peculiar Co^II⋅⋅⋅Ru⁰ interactions.     

Catalyst-Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

Rhodium(III)- and cobalt(III)-catalyzed C−H activation of indoles and coupling with 1,6-enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1-regioselectivity with a subsequent type-I intramolecular Diels–Alder reaction (IMDA) to afford [6,5]-fused cycles. When catalyzed by the cobalt(III) congener, 1,2-insertion of the alkyne is preferred, and followed by a rare type-II IMDA, thus leading to bridged [3,3,1]-cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.     

C−H and Si−H Activation Reactions at Ru/Ga Complexes: A Combined Experimental and Theoretical Case Study on the Ru−Ga Bond

Treatment of [Ru(COD)(MeAllyl)₂] and [Ru(COD)(COT)] with GaCp* under hydrogenolytic conditions leads to reactive intermediates which activate Si−H or C−H bonds, respectively. The product complexes [Ru(GaCp*)₃(SiEt₃)H₃] ( 1 ) and [Ru(GaCp*)₃(C₇H₇)H₃] ( 2 ) are formed with HSiEt₃ or with toluene as the solvent, respectively. While 1 was isolated and fully characterized by NMR, MS, IR and SC-XRD, 2 was too labile to be isolated and was observed and characterized in situ by using mass spectrometry, including labelling experiments for the unambiguous assignment of the elemental composition. The structural assignment was confirmed by DFT calculations. The relative energies of the four isomers possible upon toluene activation at the ortho-, meta-, para- and CH₃-positions have been determined and point to aromatic C−H activation. The Ru−Ga bond was analyzed by EDA and QTAIM and compared to the Ru−P bond in the analogue phosphine compound. Bonding analyses indicate that the Ru-GaCp* bond is weaker than the Ru-PR₃ bond.     

Sulfonate N-Heterocyclic Carbene–Copper Complexes: Uniquely Effective Catalysts for Enantioselective Synthesis of C−C,C−B,C−H,and C−Si Bonds

A copper-based complex that contains a sulfonate N-heterocyclic carbene ligand was first reported 15 years ago. Since then, these organometallic entities have proven to be uniquely effective in catalyzing an assortment of enantioselective transformations, including allylic substitutions, conjugate additions, proto-boryl additions to alkenes, boryl and silyl substitutions, hydride-allyl additions to alkenyl boronates, and additions of boron-containing allyl moieties to N-H ketimines. In this review article, we detail the shortcomings in the state-of-the-art that fueled the development of this air stable ligand class, members of which can be prepared on multigram scale. For each reaction type, when relevant, the prior art at the time of the advance involving sulfonate NHC-Cu catalysts and/or subsequent key developments are briefly analyzed, and the relevance of the advance to efficient and enantioselective total or formal synthesis of biologically active molecules is underscored. Mechanistic analysis of the structural attributes of sulfonate NHC-Cu catalysts that are responsible for their ability to facilitate transformations with high efficiency as well as regio- and enantioselectivity are detailed. This review contains several formerly undisclosed methodological advances and mechanistic analyses, the latter of which constitute a revision of previously reported proposals.     

Chiral Catalysts for Pd0-Catalyzed Enantioselective C−H Activation

In the past few decades, processes that involve transition-metal catalysis have represented a major part of the synthetic chemist′s toolbox. Recently, the interest has shifted from the well-established cross-coupling reactions to C−H bond functionalization, thus making it a current frontier of transition-metal-catalyzed reactions. Constant progress in this field has led to the discovery of enantioselective methods to generate and control various types of stereogenic elements, thereby demonstrating its high value to generate scalemic chiral molecules. The present review is dedicated to enantioselective Pd⁰-catalyzed C−H activation, which may be considered as an evolution of Pd⁰-catalyzed cross-couplings, with a focus on the different chiral ligands and catalysts that enable these transformations.     

Palladium-Catalyzed C8-Arylation of Naphthalenes through C−H Activation: A Combined Experimental and Computational Study

Herein, a direct C8-arylation reaction of 1-amidonaphthalenes is described. By using diaryliodonium salts as arylating agents, the palladium-catalyzed C−H activation reaction showed perfect C8 regioselectivity and a wide functional group tolerance. In most cases, the desired polyaromatic compounds were isolated in good to excellent yields. To explain the observed regioselectivity, DFT calculations were performed and highlighted the crucial role of the amide directing group. Finally, the utility of this method is showcased by the synthesis of benzanthrone derivatives.     

Niobium Bis- and Mono(Pentafulvene) Complexes: E−H Bond Cleavage and Insertion Reactions (E=C,N, O)

Bis(η⁵:η¹-(di-para-tolyl)pentafulvene)niobium chloride ( 1 ) reacts with methyl lithium via salt metathesis to the methylated bis(pentafulvene)niobium complex 2 , and with lithium 2,6-diisopropylanilide addition and subsequent N−H bond activation to the imido mono(pentafulvene)niobium complex 3 . Avoiding the competing protonation of the chloride, bis(pentafulvene)niobium complex 2 reacts with primary aromatic and aliphatic amines to form terminal niobocene imido complexes, and with water to form the analog terminal oxo complex. Secondary methyl amines undergo a simultaneous N−H and C−H activation to form niobaaziridines under mild conditions. In contrast to other reported examples, 3 can be employed to investigate the uncontested reactivity of mono(pentafulvene)niobium complexes. Reaction with 4-tert-butylphenol selectively yields a niobocene phenolate complex. Unprecedented for mono(pentafulvene)niobium complexes, treating 3 with multiple-bond-containing substrates (nitriles, isocyanates) smoothly results the insertion into the Nb-C_exo σ-bond, forming the corresponding alkylidene amido and imidato complexes.     

Influence of the Flexibility of Nickel PCP-Pincer Complexes on C−H and P−C Bond Activation and Ethylene Reactivity: A Combined Experimental and Theoretical Investigation

Using a pincer platform based on a bridgehead NHC donor with functional side arms, the combined effect of increased flexibility in six-membered pyrimidine-type heterocycles compared to the more often studied five-membered imidazole, and rigidity of phosphane side arms was examined. The unique features observed include: 1) the reaction of the azolium C_sp2−H bond with [Ni(cod)₂] affording a carbanionic ligand in [NiCl(PC_sp3^HP)] ( 8 ) rather than a carbene; 2) its transformation into the NHC, hydrido complex [NiH(PC^NHCP)]PF₆ ( 9 ) upon halide abstraction; 3) ethylene insertion into the Ni−H bond of the latter and ethyl migration to the N−C−N carbon atom of the heterocycle in [Ni(PC^EtP)]PF₆ ( 10 ); and 4) an unprecedented C−P bond activation transforming the P−C^NHC−P pincer ligand of 8 in a C−C^NHC−P pincer and a terminal phosphanido ligand in [Ni(PPh₂)(CC^NHCP)] ( 15 ). The data are supported by nine crystal structure determinations and theoretical calculations provided insights into the mechanisms of these transformations, which are relevant to stoichiometric and catalytic steps of general interest.     

C−H Bond Activation by Iridium(III) and Iridium(IV) Oxo Complexes

Oxidation of an iridium(III) oxo precursor enabled the structural, spectroscopic, and quantum-chemical characterization of the first well-defined iridium(IV) oxo complex. Side-by-side examination of the proton-coupled electron transfer thermochemistry revealed similar driving forces for the isostructural oxo complexes in two redox states due to compensating contributions from H⁺ and e⁻ transfer. However, C−H activation of dihydroanthracene revealed significant hydrogen tunneling for the distinctly more basic iridium(III) oxo complex. Our findings complement the growing body of data that relate tunneling to ground state properties as predictors for the selectivity of C−H bond activation.     

σ-Holes in Iodonium Ylides: Halogen-Bond Activation of Carboxylic Acids,Phenols and Thiophenols May Enable Their X−H Insertion Reactions

The first systematic evaluation of the electrostatic potential energy maps of iodonium ylides was conducted. We determined that they possess two σ-holes of differing electron deficiencies, with the more electropositive σ-hole located opposite the dative I−C bond to the β-dicarbonyl motif, and the lesser electropositive σ-hole located opposite the iodoarene C−I bond. We also conducted the first systematic evaluation of carboxylic acids, phenols and thiophenols in the O/S-alkylation reaction of iodonium ylides. While carboxylic acids and thiophenols were found to be generally viable, only phenols possessing electron-withdrawing substituents were effective. This high-yielding and highly chemoselective reaction is believed to involve halogen-bond activation of heteroatoms, and nicely complements existing diazo-based methods for alkylation of acidic functional groups.     

Preparative Scale Applications of C−H Activation in Medicinal Chemistry

C−H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well-established cross-coupling methods, C−H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C−H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C−H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in-depth understanding of the challenges and potential of C−H activation methodologies in the production of pharmaceuticals.     

Direct C−H Borylation of Arenes Catalyzed by Saturated Hydride-Boryl-Iridium-POP Complexes: Kinetic Analysis of the Elemental Steps

The saturated trihydride IrH₃{κ³-P,O,P-[xant(PiPr₂)₂]} ( 1 ; xant(PiPr₂)₂=9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene) activates the B−H bond of two molecules of pinacolborane (HBpin) to give H₂, the hydride-boryl derivatives IrH₂(Bpin){κ³-P,O,P-[xant(PiPr₂)₂]} ( 2 ) and IrH(Bpin)₂{κ³-P,O,P-[xant(PiPr₂)₂]} ( 3 ) in a sequential manner. Complex 3 activates a C−H bond of two molecules of benzene to form PhBpin and regenerates 2 and 1 , also in a sequential manner. Thus, complexes 1 , 2 , and 3 define two cycles for the catalytic direct C−H borylation of arenes with HBpin, which have dihydride 2 as a common intermediate. C−H bond activation of the arenes is the rate-determining step of both cycles, as the C−H oxidative addition to 3 is faster than to 2 . The results from a kinetic study of the reactions of 1 and 2 with HBpin support a cooperative function of the hydride ligands in the B−H bond activation. The addition of the boron atom of the borane to a hydride facilitates the coordination of the B−H bond through the formation of κ¹- and κ²-dihydrideborate intermediates.     

Stoichiometric and Catalytic Aryl−Cl Activation and Borylation using NHC-stabilized Nickel(0) Complexes

NHC-nickel (NHC=N-heterocyclic carbene) complexes are efficient catalysts for the C−Cl bond borylation of aryl chlorides using NaOAc as a base and B₂pin₂ (pin=pinacolato) as the boron source. The catalysts [Ni₂(ICy)₄(μ-(η²:η²)-COD)] ( 1 , ICy=1,3-dicyclohexylimidazolin-2-ylidene; COD=1,5-cyclooctadiene), [Ni(ICy)₂(η²-C₂H₄)] ( 2 ), and [Ni(ICy)₂(η²-COE)] ( 3 , COE=cyclooctene) compare well with other nickel catalysts reported previously for aryl-chloride borylation with the advantage that no further ligands had to be added to the reaction. Borylation also proceeded with B₂neop₂ (neop=neopentylglycolato) as the boron source. Stoichiometric oxidative addition of different aryl chlorides to complex 1 was highly selective affording trans-[Ni(ICy)₂(Cl)(Ar)] (Ar=4-(F₃C)C₆H₄, 11 ; 4-(MeO)C₆H₄, 12 ; C₆H₅, 13 ; 3,5-F₂C₆H₃, 14 ).     

Transition Metal-Free Aromatic C−H,C−N,C−S and C−O Borylation

Aromatic organoboron compounds are highly valuable building blocks in organic chemistry. They were mainly synthesized through aromatic C−H and C−Het borylation, in which transition metal-catalysis dominate. In the past decade, with increasing attention to sustainable chemistry, numerous transition metal-free C−H and C−Het borylation transformations have been developed and emerged as efficient methods towards the synthesis of aromatic organoboron compounds. This account mainly focuses on recent advances in transition metal-free aromatic C−H, C−N, C−S, and C−O borylation transformations and provides insights to where further developments are required.     

On-Surface Synthesis of One-Dimensional Carbon-Based Nanostructures via C−X and C−H Activation Reactions

The past decades have witnessed the emergence of low-dimensional carbon-based nanostructures owing to their unique properties and various subsequent applications. It is of fundamental importance to explore ways to achieve atomically precise fabrication of these interesting structures. The newly developed on-surface synthesis approach provides an efficient strategy for this challenging issue, demonstrating the potential of atomically precise preparation of low-dimensional nanostructures. Up to now, the formation of various surface nanostructures, especially carbon-based ones, such as graphene nanoribbons (GNRs), kinds of organic (organometallic) chains and films, have been achieved via on-surface synthesis strategy, in which in-depth understanding of the reaction mechanism has also been explored. This review article will provide a general overview on the formation of one-dimensional carbon-based nanostructures via on-surface synthesis method. In this review, only a part of the on-surface chemical reactions (specifically, C−X (X=Cl, Br, I) and C−H activation reactions) under ultra-high vacuum conditions will be covered.