Steering Site-Selectivity in Transition Metal-Catalyzed C−H Bond Functionalization: the Challenge of Benzanilides

Selective C−H bond functionalization catalyzed by metal complexes have completely revolutionized the way in which chemical synthesis is conceived nowadays. Typically, the reactivity of a transition metal catalyst is the key to control the site-, regio- and/or stereo-selectivity of a C−H bond functionalization. Of particular interests are molecules that contain multiple C−H bonds prone to undergo C−H bond activations with very similar bond dissociation energies at different positions. This is the case of benzanilides, relevant chemical motifs that are found in many useful fine chemicals, in which two C−H sites are present in chemically different aromatic fragments. In the last years, it has been found that depending on the metal catalyst and the reaction conditions, the amide motif might behave as a directing group towards the metal-catalyzed C−H bond activation in the benzamide site or in the anilide site. The impact and the consequences of such subtle control of site-selectivity are herein reviewed with important applications in carbon-carbon and carbon-heteroatom bond forming processes. The mechanisms unraveling these unique transformations are discussed in order to provide a better understanding for future developments in the field of site-selective C−H bond functionalization with transition metal catalysts.     

Recent Advances in Carbon-Nitrogen/Carbon-Oxygen Bond Formation Under Transition-Metal-Free Conditions

Carbon-heteroatom bond formation under transition-metal free conditions provides a powerful synthetic alternative for the efficient synthesis of valuable molecules. In particular, C−N and C−O bonds are two important types of carbon-heteroatom bonds. Thus, continuous efforts have been deployed to develop novel C−N/C−O bond formation methodologies involving various catalysts or promoters under TM-free conditions, which enables the synthesis of various functional molecules comprising C−N/C−O bonds in a facile and sustainable manner. Considering the significance of C−N/C−O bond construction in organic synthesis and materials science, this review aims to comprehensively present selected examples on the construction of C−N (including amination and amidation) and C−O (including etherification and hydroxylation) bonds without transition metals. Besides, the involved promoters/catalysts, substrate scope, potential application and possible reaction mechanisms are also systematically discussed.     

Electrocatalytically Activating and Reducing N2 Molecule by Tuning Activity of Local Hydrogen Radical

Decarbonizing N₂ conversion is particularly challenging, but essential for sustainable development of industry and agriculture. Herein, we achieve electrocatalytic activation/reduction of N₂ on X/Fe−N−C (X=Pd, Ir and Pt) dual-atom catalysts under ambient condition. We provide solid experimental evidence that local hydrogen radical (H*) generated on the X site of the X/Fe−N−C catalysts can participate in the activation/reduction of N₂ adsorbed on the Fe site. More importantly, we reveal that the reactivity of X/Fe−N−C catalysts for N₂ activation/reduction can be well adjusted by the activity of H* generated on the X site, i.e., the interaction between the X−H bond. Specifically, X/Fe−N−C catalyst with the weakest X−H bonding exhibits the highest H* activity, which is beneficial to the subsequent cleavage of X−H bond for N₂ hydrogenation. With the most active H*, the Pd/Fe dual-atom site promotes the turnover frequency of N₂ reduction by up to 10 times compared with the pristine Fe site.     

Predictable Selectivity in Remote C−H Oxidation of Steroids: Analysis of Substrate Binding Mode

Predictability is a key requirement to encompass late-stage C−H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp³)−H oxidation, as it requires distinguishing a specific C−H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C−H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host-guest adduct by NMR analysis. These analyses indicate which remote C−H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late-stage C(sp³)−H oxidation of amino-steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.     

N‐Heterocyclic Carbenes: A New Concept in Organometallic Catalysis

N‐Heterocyclic carbenes have become universal ligands in organometallic and inorganic coordination chemistry. They not only bind to any transition metal, be it in low or high oxidation states, but also to main group elements such as beryllium, sulfur, and iodine. Because of their specific coordination chemistry, N‐heterocyclic carbenes both stabilize and activate metal centers in quite different key catalytic steps of organic syntheses, for example, C−H activation, C−C, C−H, C−O, and C−N bond formation. There is now ample evidence that in the new generation of organometallic catalysts the established ligand class of organophosphanes will be supplemented and, in part, replaced by N‐heterocyclic carbenes. Over the past few years, this chemistry has been the field of vivid scientific competition, and yielded previously unexpected successes in key areas of homogeneous catalysis. From the work in numerous academic laboratories and in industry, a revolutionary turning point in oraganometallic catalysis is emerging.     

Transition state docking: a probe for noncovalent catalysis in biological systems. Application to antibody-catalyzed ester hydrolysis

A strategy for pinpointing favorable noncovalent interactions between transition states and active sites of biological catalysts is described. This strategy combines high-level quantum mechanical calculations of transition state geometries with an automated docking procedure using AutoDock. By applying this methodology to antibody-catalyzed hydrolyses of aryl esters (by the 48G7, CNJ206, and 17E8 families of antibodies), varying levels of catalysis are explained in terms of specific hydrogen bonding interactions between combining site residues and transition states. Although these families of antibodies were produced in separate experiments by different researchers using related but different haptens, the mechanism of transition state stabilization appears to be highly conserved. Despite being elicited in response to anionic phosphonate haptens, the best catalysts often utilize hydrogen bond acceptors to stabilize transition states. A mutant of antibody CNJ206, designed based on this observation and predicted to be a better catalyst, is proposed. In the case of antibody 48G7, affinity maturation is shown to produce a catalyst that is highly selective for one of two enantiomeric transition states from a nonselective germline precursor.     

What Is the Catalytic Mechanism of Enzymatic Histone N-Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N-methyl arginine demethylation by human KDM4E and compare the results with those reported for N-methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen-bond between the substrate Ser1 and Tyr178. The calculations imply that in either C−H or N−H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N-methyl arginine demethylation, electron transfer occurs via a σ-channel; the transition state for the N−H pathway is ∼10 kcal/mol higher than for the C−H pathway due to the higher bond dissociation energy of the N−H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier-lowering effect on the C−H pathway, by contrast, such EEFs inhibit the N−H activation rate. The overall results imply that KDM4 catalyzed N-methyl arginine demethylation and N-methyl lysine demethylation occur via similar C−H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates.     

Cooperative Catalysis of Metal and O?H⋅⋅⋅O/sp3‐C?H⋅⋅⋅O Two‐Point Hydrogen Bonds in Alcoholic Solvents: Cu‐Catalyzed Enantioselective Direct Alkynylation of Aldehydes with Terminal Alkynes

Catalyst–substrate hydrogen bonds in artificial catalysts usually occur in aprotic solvents, but not in protic solvents, in contrast to enzymatic catalysis. We report a case in which ligand–substrate hydrogen‐bonding interactions cooperate with a transition‐metal center in alcoholic solvents for enantioselective catalysis. Copper(I) complexes with prolinol‐based hydroxy amino phosphane chiral ligands catalytically promoted the direct alkynylation of aldehydes with terminal alkynes in alcoholic solvents to afford nonracemic secondary propargylic alcohols with high enantioselectivities. Quantum‐mechanical calculations of enantiodiscriminating transition states show the occurrence of a nonclassical sp³‐C? H???O hydrogen bond as a secondary interaction between the ligand and substrate, which results in highly directional catalyst–substrate two‐point hydrogen bonding.     

Structural Insights into the Very Low Activity of the Homocoenzyme B12 Adenosylmethylcobalamin in Coenzyme B12-Dependent Diol Dehydratase and Ethanolamine Ammonia-Lyase

The X-ray structures of coenzyme B₁₂ (AdoCbl)-dependent eliminating isomerases complexed with adenosylmethylcobalamin (AdoMeCbl) have been determined. As judged from geometries, the Co−C bond in diol dehydratase (DD) is not activated even in the presence of substrate. In ethanolamine ammonia-lyase (EAL), the bond is elongated in the absence of substrate; in the presence of substrate, the complex likely exists in both pre- and post-homolysis states. The impacts of incorporating an extra CH₂ group are different in the two enzymes: the DD active site is flexible, and AdoMeCbl binding causes large conformational changes that make DD unable to adopt the catalytic state, whereas the EAL active site is rigid, and AdoMeCbl binding does not induce significant conformational changes. Such flexibility and rigidity of the active sites might reflect the tightness of adenine binding. The structures provide good insights into the basis of the very low activity of AdoMeCbl in these enzymes.     

Porous Organic Phenanthroline-Based Polymer as an Efficient Transition-Metal-Free Heterogeneous Catalyst for Direct Aromatic C−H Activation

Direct C−H bond transformation has been regarded as one of the most important areas in organic synthesis in both academia and industry. However, the heterogeneous transition-metal-free catalysis of direct C−H bond transformation has remained a contemporary challenge. To tackle this challenge, we designed and constructed a porous phenanthroline-based polymer (namely POP-Phen) via free radical polymerization of vinyl-functionalized phenanthroline monomers. POP-Phen shows excellent catalytic performances in transition-metal-free catalyzed C−H arylation, even better than those of the corresponding homogeneous catalyst, which is mainly attributed to the high density of catalytically active sites in the heterogeneous catalyst. Kinetic isotope experiments and spectral characterizations demonstrate the electron-transfer between the heterogeneous catalyst and the base (t-BuOK), a key step for C−H activation. We believe that this porous organic phenanthroline polymer could open a new door for the design of novel heterogeneous transition-metal-free catalysts for direct C−H activation.     

What factors influence the ratio of C-H hydroxylation versus C=C epoxidation by a nonheme cytochrome P450 biomimetic?

Density functional calculations on a nonheme biomimetic (Fe=O(TMCS+) have been performed and its catalytic properties versus propene investigated. Our studies show that this catalyst is able to chemoselectively hydroxylate C=H bonds even in the presence of C=C double bonds. This phenomenon has been analyzed and found to occur due to Pauli repusions between protons on the TMCS ligand with protons attached to the approaching substrate. The geometries of the rate determining transition states indicate that the steric hindrance is larger in the epoxidation transition states than in the hydroxylation ones with much shorter distances; hence the hydroxylation pathway is favored over the epoxidation. Although, the reactant experiences close lying triplet and quintet spin states, the dominant reaction mechanism takes place on the quintet spin state surface; i.e., Fe=O(TMCS)+ reacts via single-state reactivity. Our calculations show that this spin state selectivity is the result of geometric orientation of the transition state structures, whereby the triplet ones are destabilized by electrostatic repulsions between the substrate and the ligand while the quintet spin transition states are aligned along the ideal axis. The reactivity patterns and geometries are compared with oxoiron species of dioxygenase and monoxygenase enzymes. Thus, Fe=O(TMCS)+ shows some similarities with P450 enzyme reactivity: it chemoselectively hydroxylates C=H bonds even in the presence of a C=C double bond and therefore is an acceptable P450 biomimetic. However, the absolute barriers of substrate oxidation by Fe=O(TMCS)+ are higher than the ones obtained with heme enzymes, but the chemoselectivity is lesser affected by external perturbations such as hydrogen bonding of a methanol molecule toward the thiolate sulfur or a dielectric constant. This is the first oxoiron complex whereby we calculated a chemoselective hydroxylation over epoxidation in the gas phase.     

Aldolase Cascade Facilitated by Self-Assembled Nanotubes from Short Peptide Amphiphiles

Early evolution benefited from a complex network of reactions involving multiple C−C bond forming and breaking events that were critical for primitive metabolism. Nature gradually chose highly evolved and complex enzymes such as lyases to efficiently facilitate C−C bond formation and cleavage with remarkable substrate selectivity. Reported here is a lipidated short peptide which accesses a homogenous nanotubular morphology to efficiently catalyze C−C bond cleavage and formation. This system shows morphology-dependent catalytic rates, suggesting the formation of a binding pocket and registered enhancements in the presence of the hydrogen-bond donor tyrosine, which is exploited by extant aldolases. These assemblies showed excellent substrate selectivity and templated the formation of a specific adduct from a pool of possible adducts. The ability to catalyze metabolically relevant cascade transformations suggests the importance of such systems in early evolution.     

Origin of enantioselectivity in the asymmetric Ru-catalyzed metathesis of olefins

The mechanism of enantioselectivity in the asymmetric Ru-catalyzed metathesis of olefins is investigated with a theoretical approach. The models are based on the chiral N-heterocyclic (NHC)-based catalysts developed by Grubbs. Our analysis indicates that the origin of enantioselectivity in the ring-closing metathesis of achiral trienes is correlated to the chiral folding of the N-bonded aromatic groups, which is imposed by the Ph groups in positions 4 and 5 of the imidazole ring of the NHC ligand. This chiral folding of the catalyst imposes a chiral orientation around the Ru=C bond, which, in turn, selects between the two enantiofaces of the substrate. In the ring-closing transition state, the geometry in which additional groups on the forming ring are in pseudoequatorial positions is favored over transition states in which this additional group is in a pseudoaxial position. These combined effects rationalize the enantiomeric excesses experimentally obtained.     

Aryne-Enabled C−N Arylation of Anilines

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C−N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C−N bond.     

Mechanism of activation of a hafnium pyridyl-amide olefin polymerization catalyst: ligand modification by monomer

We have investigated the olefin polymerization mechanism of hafnium catalysts supported by a pyridyl-amide ligand with an ortho-metalated naphthyl group. Ethylene-alpha-olefin copolymers from these catalysts have broad molecular weight distributions that can be fit to a bimodal distribution. We propose a unique mechanism to explain this behavior involving monomer modification of the catalyst, which generates multiple catalyst species when multiple monomers are present. More specifically, we present evidence that the hafnium alkyl cation initially undergoes monomer insertion into the Hf-naphthyl bond, which permanently modifies the ligand to generate new highly active olefin polymerization catalysts. Under ethylene/octene copolymerization conditions, a plurality of new catalysts is formed in relative proportion to the respective monomer concentrations. Due to the asymmetry of the metal complex, two "ethylene-inserted" and eight "octene-inserted" isomers are possible, but it is a useful approximation to consider only one of each in the polymerization behavior. Consequently, gel permeation chromatography data for the polymers can be fit to a bimodal distribution having a continuous shift from a predominantly low molecular weight fraction to predominantly higher molecular weight fraction as [octene]/[ethylene] is increased. Theoretical calculations show that such insertions into the Hf-aryl bond have lower barriers than corresponding insertions into the Hf-alkyl bond. The driving forces for this insertion into the Hf-aryl bond include elimination of an eclipsing H-H interaction and formation of a stabilizing Hf-arene interaction. These new "monomer-inserted catalysts" have no beta-agostic interaction, very weak olefin binding, and olefin-insertion transition states which differ on the two sides by more than 4 kcal/mol. Thus, the barrier to site epimerization is very low and high polymerization rates are possible even when the chain wags prior to every insertion. Experimental evidence for aryl-insertion products is obtained from reactions of ethylene (13C2H4 NMR studies) or 4-methyl-1-pentene (4M1P) using relatively low monomer/catalyst ratios. Quantitative generation of monomer-inserted products is complicated by slow initiation kinetics followed by fast polymerization kinetics. However, NMR evidence for reaction with 13C2H4 was observed in situ at low temperature, and the attachment of monomer to ligand was confirmed by GC/MS and 13C NMR after quenching. Furthermore, a 4M1P-appended ligand was isolated from a polymerization reaction (50:1 monomer:catalyst) by column chromatography followed by multiple recrystallizations. One isomer was characterized by X-ray crystallography, which unequivocally shows a 4-methylpentyl substituent at the 2-position of the naphthyl, consistent with 1,2-insertion into the Hf-aryl bond. NMR suggests a second diastereomer (not isolated) is formed from a 1,2-insertion of opposite stereoselectivity.     

Transient Directing Groups in Metal−Organic Cooperative Catalysis

The direct functionalization of C−H bonds is among the most fundamental chemical transformations in organic synthesis. However, when the innate reactivity of the substrate cannot be utilized for the functionalization of a given single C−H bond, this selective C−H bond functionalization mostly relies on the use of directing groups that allow bringing the catalyst in close proximity to the C−H bond to be activated and these directing groups need to be installed before and cleaved after the transformation, which involves two additional undesired synthetic operations. These additional steps dramatically reduce the overall impact and the attractiveness of C−H bond functionalization techniques since classical approaches based on substrate pre-functionalization are sometimes still more straightforward and appealing. During the past decade, a different approach involving both the in situ installation and removal of the directing group, which can then often be used in a catalytic manner, has emerged: the transient directing group strategy. In addition to its innovative character, this strategy has brought C−H bond functionalization to an unprecedented level of usefulness and has enabled the development of remarkably efficient processes for the direct and selective introduction of functional groups onto both aromatic and aliphatic substrates. The processes unlocked by the development of these transient directing groups will be comprehensively overviewed in this review article.     

Carbon–Carbon Bond Formation in a Weak Ligand Field: Leveraging Open‐Shell First‐Row Transition‐Metal Catalysts

Unique features of earth‐abundant transition‐metal catalysts are reviewed in the context of catalytic carbon–carbon bond‐forming reactions. Aryl‐substituted bis(imino)pyridine iron and cobalt dihalide compounds, when activated with alkyl aluminum reagents, form highly active catalysts for the polymerization of ethylene. Open‐shell iron and cobalt alkyl complexes have been synthesized that serve as single‐component olefin polymerization catalysts. Reduced bis(imino)pyridine iron and cobalt dinitrogen compounds have also been discovered that promote the unique [2+2] cycloaddition of unactivated terminal alkenes. Studies of the electronic structure support open‐shell intermediates, a deviation from traditional strong‐field organometallic compounds that promote catalytic C−C bond formation.     

Metal–Organic Framework (MOF)-Based Materials as Heterogeneous Catalysts for C−H Bond Activation

Converting light hydrocarbons such as methane, ethane, propane, and cyclohexane into value-added chemicals and fuel products by means of direct C−H functionalization is an attractive method in the petrochemical industry. As they emerge as a relatively new class of porous solid materials, metal–organic frameworks (MOFs) are appealing as single-site heterogeneous catalysts or catalytic supports for C−H bond activation. In contrast to the traditional microporous and mesoporous materials, MOFs feature high porosity, functional tunability, and molecular-level characterization for the study of structure–property relationships. These virtues make MOFs ideal platforms to develop catalysts for C−H activation with high catalytic activity, selectivity, and recyclability under relatively mild reaction conditions. This review highlights the research aimed at the implementation of MOFs as single-site heterogeneous catalysts for C−H bond activation. It provides insight into the rational design and synthesis of three types of stable MOF catalysts for C−H bond activation, that is, i) metal nodes as catalytic sites, ii) the incorporation of catalytic sites into organic struts, and iii) the incorporation of catalytically active guest species into pores of MOFs. Here, the rational design and synthesis of MOF catalysts that lead to the distinct catalytic property for C−H bond activation are discussed along with the post-synthesis of MOFs, intriguing functions with MOF catalysts, and microenvironments that lead to the distinct catalytic properties of MOF catalysts.