C–H bond activation in the total syntheses of natural products

The transition metal-mediated C–H bond activation has emerged as a powerful and ideal method for the total syntheses of natural products and pharmaceuticals, and has had a significant impact on synthetic planning and strategy in complex natural products.In this review, we describe selected recent examples of the transition metal-mediated C–H bond activation strategies for the rapid syntheses of natural products.     

Cationic iridium-catalyzed enantioselective activation of secondary sp3 C–H bond adjacent to nitrogen atom

A cationic Ir(I)–tolBINAP complex catalyzed an enantioselective C–C bond formation, which was initiated by secondary sp³ C–H bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses. Alkynes were also investigated as coupling partners. The effect of alkyl structure in substrates and directing groups were studied. This transformation represents the first example of a highly enantioselective C–H bond activation of a methylene group, not at allylic or benzylic position.     

Disruptive influence of the host cage C60 on the guest He–H+ bond and bonding in H3+

Although a helium atom prefers to stay at the centre of a fullerene (C₆₀) cage and a proton binds with one of the carbon atoms from inside, DFT(MN15)/cc-pVTZ and DLPNO-MP2/def2-TZVP calculations show that the helium atom and the proton in HeH⁺ prefer to stay away from the centre of the cage, weakening the He–H⁺ covalent bond considerably. Both the helium atom and the proton exhibit noncovalent interactions with the carbon atoms of two pentagons at the opposite ends of the fullerene cage. Our calculations also show that a linear arrangement of H₃⁺ (inside C₆₀), pointing towards the centres of two pentagons opposite to each other, with the proton breaking away from H_2, is energetically more favored over the equilateral triangle geometry of free H₃⁺.     

Allyldialkyl complexes of ruthenium(IV): Preparation and reductive CC bond formation followed by CH bond activation

New η³-allyldimethyl complexes Ru(η⁵-C₅R₅)(η³-C₃H₅)(CH₃)₂, where R = H or CH₃, are prepared from Ru(η⁵-C₅R₅)(η³-C₃H₅)Br₂ by alkylation with trimethyl-aluminium. The Ru^IV dimethyl complex is thermally converted to the Ru^II 1-methylallyl compound, Ru(η⁵-C₅R₅)(η³-CH₂CHCHCH₃)L, where L = CO or t-C₄H₉NC, with evolution of methane. Kinetic and deuteration studies on the reductive process are also discussed.     

Fragmentation of alkoxy radicals: Mechanistic aspects of the tandemβ-fragmentation-intramolecular functionalization reaction

The formation of the β-peroxylactone (4) during the photolysis of lactol (3) with (diacetoxyiodo)-benzene (DIB) and iodine under oxygen atmosphere demostrates the presence of a peroxyradical intermediate in the tandem β-fragmentation-intramolecular functionalization reaction.     

Homolytic dissociation in hydrogen-bonding liquids: energetics of the phenol O–H bond in methanol and the water O–H bond in water

The energetics of the phenol O–H bond in methanol and the water O–H bond in liquid water were investigated by microsolvation modelling and statistical mechanics Monte Carlo simulations. The microsolvation approach was based on density functional theory calculations. Optimised structures for clusters of phenol and the phenoxy radical with one and two methanol molecules are reported. By analysing the differential solvation of phenol and the phenoxy radical in methanol, we predict that the phenol O–H homolytic bond dissociation enthalpy in solution is 24.3±11 kJ/mol above the gas-phase value. The analysis of the water O–H bond dissociation by microsolvation was based on optimised structures of OH–(H₂O)_1–6 and –(H₂O)_1–7 clusters. Microsolvation modelling and statistical mechanics simulations predict that the HO–H bond dissociation enthalpies in the gas phase and in liquid water are very similar. Our results stress the importance of estimating the differences between the solvation enthalpies of the radical species and the parent molecule and the limitations of local models based on microsolvation.Proceedings of the 11th International Congress of Quantum Chemistry satellite meeting in honor of Jean-Louis Rivail     

Theoretical study of the gas-phase ethane C–H and C–C bonds activation by bare niobium cation

The potential energy surfaces for the reaction of bare niobium cation with ethane, as a prototype of the C–H and C–C bonds activation in alkanes by transition metal cations, have been investigated employing the Density Functional Theory in its B3LYP formulation. All the minima and key transition states have been examined along both high- and low-spin surfaces. For both the C–H and C–C activation pathways the rate determining step is that corresponding to the insertion of the Nb cation into C–H and C–C bond, respectively. However, along the C–H activation reaction coordinate the barrier that is necessary to overcome is 0.13 eV below the energy of the ground state reactants asymptote, while in the C–C activation branch the corresponding barrier is about 0.58 eV above the energy of reactants in their ground state. The overall calculated reaction exothermicities are comparable. Since the spin of the ground state reactants is different from that of both H–Nb⁺–C₂H₅ and CH₃–Nb⁺–CH₃ insertion intermediates and products, spin multiplicity has to change along the reaction paths. All the obtained results, including Nb⁺–R binding energies for R fragments relevant to the examined PESs, have been compared with existing experimental and theoretical data.     

Iridium pentahydride complex catalyzed formation of CC bond by CH bond activation followed by olefin insertion

The formation of carbon-carbon bond was found to occur by first carbon-hydrogen bond activation followed by olefin insertion under the catalysis of an iridium pentahydride complex.     

Thermochemistry and reaction paths in the oxidation reaction of benzoyl radical: C6H5C•(═O)

Alkyl substituted aromatics are present in fuels and in the environment because they are major intermediates in the oxidation or combustion of gasoline, jet, and other engine fuels. The major reaction pathways for oxidation of this class of molecules is through loss of a benzyl hydrogen atom on the alkyl group via abstraction reactions. One of the major intermediates in the combustion and atmospheric oxidation of the benzyl radicals is benzaldehyde, which rapidly loses the weakly bound aldehydic hydrogen to form a resonance stabilized benzoyl radical (C6H5C(?)═O). A detailed study of the thermochemistry of intermediates and the oxidation reaction paths of the benzoyl radical with dioxygen is presented in this study. Structures and enthalpies of formation for important stable species, intermediate radicals, and transition state structures resulting from the benzoyl radical +O2 association reaction are reported along with reaction paths and barriers. Enthalpies, ΔfH298(0), are calculated using ab initio (G3MP2B3) and density functional (DFT at B3LYP/6-311G(d,p)) calculations, group additivity (GA), and literature data. Bond energies on the benzoyl and benzoyl-peroxy systems are also reported and compared to hydrocarbon systems. The reaction of benzoyl with O2 has a number of low energy reaction channels that are not currently considered in either atmospheric chemistry or combustion models. The reaction paths include exothermic, chain branching reactions to a number of unsaturated oxygenated hydrocarbon intermediates along with formation of CO2. The initial reaction of the C6H5C(?)═O radical with O2 forms a chemically activated benzoyl peroxy radical with 37 kcal mol(-1) internal energy; this is significantly more energy than the 21 kcal mol(-1) involved in the benzyl or allyl + O2 systems. This deeper well results in a number of chemical activation reaction paths, leading to highly exothermic reactions to phenoxy radical + CO2 products.     

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.     

Palladium-catalyzed oxidative cyclopropanation of enamides and norbornenes initiated by C–H activation

A novel palladium-catalyzed oxidative cyclopropanation of enamides and norbornenes has been developed. The reaction proceeded through palladium-catalyzed vinyl C–H bond activation of enamides followed by two migratory insertions, β-(N)H elimination and hydrolyzation cascade steps. The reaction tolerates a range of functional groups and provides an effective method for the synthesis of cyclopropane-fused norbornanes in good yields under mild conditions.     

Toward the most versatile fluorophore: Direct functionalization of BODIPY dyes via regioselective C–H bond activation

Fluorescent dyes are heavily sought for their potentials applications in bioimaging, sensing, theranostic,and optoelectronic materials. Among them, BODIPY dyes are privileged fluorophores that are now widely used in highly diverse research fields. The increasing success of BODIPY dyes is closely associated with their excellent and tunable photophysical properties due to their rich functionalization chemistry.Recently, growing research efforts have been devoted to the direct functionalization of the BODIPY core,because it allows the facile installation of desired functional groups in a single atom economical step. The challenges of this direct C–H derivation come from the difficulties in finding suitable functionalization agents and proper control of the regioselectivity of the functionalization. The aim of this work is to provide an overview of BODIPY dyes and a summarization of the different synthetic methodologies reported for direct C–H functionalization of the BODIPY framework.     

Challenges in C–C bond formation through direct transformations of sp2 C–H bonds

In the past several decades, organic chemists have made significant contributions to approach direct C–H transformations. However, limited substrate scope and reaction classifications, harsh condition, and the use of noble and toxic late transition-metal catalysts typically with high loadings clogged its applications. This article summarizes our recent efforts to explore new reaction types and develop new catalytic systems in this field, which may open a new channel to consider organic synthesis from easily available chemicals.     

Activation of propane C–H and C–C bonds by a diplatinum cluster: potential energy surfaces and reaction mechanisms

The activation mechanism of C₃H₈ catalyzed by the homonuclear bimetallic Pt₂ cluster has been detailedly explored on the singlet and triplet potential energy surfaces at BPW91/aug-cc-pvtz, Lanl2tz level. The C–H bond cleavage channel (dehydrogenation and the release of propylene) is kinetically predominant, whereas the C–C bond cleavage channel (demethanation and the release of ethane) should be ruled out. Furthermore, the release of propylene channel is kinetically favorable, while the dehydrogenation channel is thermodynamically preferable. Besides, both the C–H cleavage intermediate (Pt₂H₂C₃H₆b) and the C–C cleavage intermediates (CH₃HPt₂CHCH₃ and CH₃PtPtHC₂H₄) are thermodynamically preferred. The C–H cleavage intermediate (Pt₂H₂C₃H₆b) is kinetically favored, while the C–C cleavage intermediates (CH₃HPt₂CHCH₃ and CH₃PtPtHC₂H₄) are kinetically hindered. The homonuclear bimetallic Pt₂ cluster toward propane exhibits higher reactivity than the Pt atom, which is in good agreement with the experimental observation.     

Efficient asymmetric hydrogenation of the C–C double bond of 2-methyl- and 2,3-dimethyl-N-phenylalkylmaleimides by Aspergillus fumigatus

Eight N-phenylalkylmaleimides (four 2-methyl-N-phenylalkylmaleimides and four 2,3-dimethyl-N-phenylalkylmaleimides with an alkyl chain (CH₂)_n (n = 1–4) between the imide N and the benzene ring) were subjected to biotransformation using the fungal strain Aspergillus fumigatus ATCC 26934. All compounds were reduced enantioselectively to their respective succinimides: (R)-2-methyl-N-phenylalkylsuccinimides and (2R,3R)-2,3-dimethyl-N-phenylalkylsuccinimides, with satisfactory conversion rates and high stereoisomeric excesses. NMR analysis using the chiral shift reagent Eu(hfc)₃ showed that enantiomeric excesses were >99%.     

Range,strength and anisotropy of intermolecular forces in atom–molecule systems: an atom–bond pairwise additivity approach

A new method is proposed to calculate bond energies and equilibrium distances in atom–molecule van der Waals complexes which arises from a balancing between long-range attraction and asymptotic tail of the repulsion. The method, based on correlation formulas between the polarizability of the interacting partners and the main interaction parameters, is an extension of an approach originally developed for atom–atom cases. The basic idea exploits the concept of bond polarizability additivity to represent both the molecular repulsion, in terms of a size which is mainly ascribed to the molecular bonds nearest to the probe atom, and the molecular attraction as due to multi-dispersion centers delocalized on the molecular frame. The method, mainly tested on hydrocarbon–rare gas complexes, can be considered as the starting point for the study of systems of higher complexity.     

Complete active space analysis of a reaction pathway: Investigation of the oxygen–oxygen bond formation

Water nucleophilic attack is an important step in water oxidation reactions, which have been widely studied using density functional theory (DFT). Nevertheless, a single-determinant DFT picture may be insufficient for a deeper insight into the process, in particular during the oxygen–oxygen bond formation. In this work, we use complete active space self-consistent field calculations and describe an approach for a complete active space analysis along a reaction pathway. This is applied to the water nucleophilic attack at a Ru-based catalyst, which has successfully been used for efficient water oxidation and in silico design of new water oxidation catalysts recently.     

Recent advances in radical-mediated fluorination through C–H and C–C bond cleavage

The C–H and C–C bonds are abundant in organic compounds, yet generally inert in chemical transformations. Therefore, direct functionalization of inert chemical bonds remains challenging. The fluorine-containing compounds are of special interest for their uses in medicinal chemistry. Direct fluorination of C–H and C–C bonds undoubtedly represents one of the most ideal and attractive approaches to incorporate fluorine atom into complex molecules. Herein, we summarize the recent advances in radical-mediated C–H and C–C bond fluorination. Three types of transformations are discussed: (1) direct C–H abstraction/fluorination of alkanes; (2) decarboxylative fluorination of alkyl carboxylic acids; (3) ring-opening fluorination.     

C–H bond activation versus ring cleavage in the gas phase ion-molecule reactions of Nb+ and Ta+ with toluene and picoline

The reactions of Nb⁺ and Ta⁺ with toluene and picoline and their deuterium-labelled analogues were studied in a Fourier transform ion cyclotron resonance mass spectrometer. Methyl substitution completely changes the reactivities relative to benzene and pyridine. Both metals react to dehydrogenate toluene exclusively. In contrast to benzene, no ring cleavage is observed in the Ta⁺/toluene reaction. A simple explanation for this difference in reactivities is proposed based on the relative energies of the Hückel orbitals of benzene and toluene. The (b₁) symmetric antibonding orbital is higher in energy for toluene. Population of this orbital is necessary for formation of the metallanorbornadiene intermediate and does not occur at thermal energies. Reaction with ring labelled toluene-d₅ shows exclusive H₂ or D₂ elimination in reaction with Nb⁺ and H₂, HD, and D₂ elimination in reaction with Ta⁺. Reactions with the picolines show both dehydrogenation and ring cleavage. Isotope labelling studies show facile H/D scrambling occurs in the intermediate ion-molecule complexes with HCN and DCN both eliminated from the methyl-d₃-2-picoline and 4-picoline. The metals react with picoline and pyridine by different mechanisms. The isotope labelling results suggest a metal-hydrido-azepinium structure for the intermediate complex.     

Theoretical study of the C�CF bond activation in methyl fluoride by alkaline-earth metal monocations

Reactions of methyl fluoride with bare alkaline-earth metal monocations (Mg⁺, Ca⁺, Sr⁺, and Ba⁺) were studied using theoretical methods. Thermochemical data were calculated using density functional theory in conjunction with polarized 3-?? and 4-?? basis sets. Variational/conventional microcanonical transition state theory was used for the calculation of the reaction rate constants over a large range of temperatures. According to our calculations, the Ca⁺, Sr⁺, and Ba⁺ reactions with CH₃F proceed to yield CaF⁺, SrF⁺, and BaF⁺, in agreement with the experimental observation. The theoretically predicted global rate constants are in reasonable agreement with the experimental data. In the case of Mg⁺, the large value of the computed energy barrier associated with the ??inner?? transition structure is fully consistent with the limited progress experimentally observed for this reaction. The importance of bottlenecks other than the ??inner?? transition state is highlighted and its mechanistic implications discussed. Particularly, our calculations suggest that the studied processes proceed through a ??harpoon-like?? mechanism.