Selective molecular recognition, C-H bond activation, and catalysis in nanoscale reaction vessels

Supramolecular chemistry represents a way to mimic enzyme reactivity by using specially designed container molecules. We have shown that a chiral self-assembled M4L6 supramolecular tetrahedron can encapsulate a variety of cationic guests with varying degrees of stereoselectivity. Reactive iridium guests can be encapsulated, and the C-H bond activation of aldehydes occurs with the host cavity controlling the ability of substrates to interact with the metal center based upon size and shape. In addition, the host container can act as a catalyst by itself. By restricting reaction space and preorganizing the substrates into reactive conformations, it accelerates the sigmatropic rearrangement of enammonium cations.     

Catalytic functionalization of arenes and alkanes via C-H bond activation

Several novel synthetic reactions of arenes and alkanes discovered and investigated in our laboratory are summarized here. These include olefin arylation, hydroarylation of alkynes, hydroxylation of arenes, carboxylation of arenes and alkanes, and aminomethylation and acetoxylation of alkanes. Most of these reactions are catalyzed by highly electrophilic transition metal cationic species generated in situ in an acid medium, involving electrophilic metalation of C-H bonds of arenes and alkanes which lead to the formation of aryl-metal and alkyl-metal sigma-complexes.     

Isotope effects in C-H bond activation reactions by transition metals

The activation of alkane C-H bonds by oxidative addition and its reverse reaction, reductive elimination, are believed to occur via transient sigma-alkane complexes. This Account summarizes how isotope effects can be used to probe the nature of these intermediates and points out some pitfalls in interpreting kinetic data. Comparisons are made with arene C-H activation and other activation systems.     

C-H bond activation by oxygen-centered radicals over atomic clusters

Saturated hydrocarbons, or alkanes, are major constituents of natural gas and oil. Directly transforming alkanes into more complex organic compounds is a value-adding process, but the task is very difficult to achieve, especially at low temperature. Alkanes can react at high temperature, but these reactions (with oxygen, for example) are difficult to control and usually proceed to carbon dioxide and water, the thermodynamically stable byproducts. Consequently, a great deal of research effort has been focused on generating and studying chemical entities that are able to react with alkanes or efficiently activate C-H bonds at lower temperatures, preferably room temperature. To identify low-temperature methods of C-H bond activation, researchers have investigated free radicals, that is, species with open-shell electronic structures. Oxygen-centered radicals are typical of the open-shell species that naturally occur in atmospheric, chemical, and biological systems. In this Account, we survey atomic clusters that contain oxygen-centered radicals (O(-?)), with an emphasis on radical generation and reaction with alkanes near room temperature. Atomic clusters are an intermediate state of matter, situated between isolated atoms and condensed-phase materials. Atomic clusters containing the O(-?) moiety have generated promising results for low-temperature C-H bond activation. After a brief introduction to the experimental methods and the compositions of atomic clusters that contain O(-?) radicals, we focus on two important factors that can dramatically influence C-H bond activation. The first factor is spin. The O(-?)-containing clusters have unpaired spin density distributions over the oxygen atoms. We show that the nature of the unpaired spin density distribution, such as localization and delocalization within the clusters, heavily influences the reactivity of O(-?) radicals in C-H bond activation. The second factor is charge. The O(-?)-containing clusters can be negatively charged, positively charged, or neutral overall. We discuss how the charge state may influence C-H bond activation. Moreover, for a given charge state, such as the cationic state, it can be demonstrated that local charge distribution around the O(-?) centers can also significantly change the reactivity in C-H bond activation. Through judicious synthetic choices, spin and charge can be readily controllable physical quantities in atomic clusters. The adjustment of these two properties can impact C-H bond activation, thus constituting an important consideration in the rational design of catalysts for practical alkane transformations.     

Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation

[Reaction: see text]. Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C-H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh- N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh-NHC complexes directly by treating precursors to the intermediate [RhCl(PCy 3)2] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy 3) 2 fragment coordinates to the heterocycle before intramolecular activation of the C-H bond occurs. The resulting Rh-H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy 3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo[4.2.1]nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C-H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations.     

Quasi-nature catalysis: developing C-C bond formations catalyzed by late transition metals in air and water

This Account outlines the recent efforts of developing catalysis under the ambient conditions of air and water for synthetic purposes from the author's laboratory. The discussions are focused on catalytic reactions (mostly C-C bond formations) other than oxidations via late transition metals. It includes the following aspects: (1) copper-catalyzed C-C bond formations; (2) palladium-catalyzed C-C bond formations; (3) rhodium-catalyzed C-C bond formations; (4) ruthenium-catalyzed olefin isomerizations and C-H activations. The mechanism, limitations, and synthetic applications of these reactions are also discussed.     

Organometallic-like C-H bond activation and C-S bond formation on the disulfide bridge in the RuSSRu core complexes

C-S bond formations on the disulfide bridge in the dinuclear Ru(III) complexes have been found in the reaction with unsaturated organic molecules, such as alkenes and ketones. The reactions are initiated by the organometallic-like C-H bond activation. Through the mechanistic study of these novel reactions, the specific nature of the disulfide bridging ligand has been unveiled: (i) the double bond character of the sulfur-sulfur bond, which allows the Diels-Alder-type [4 + 2] cycloaddition reaction with butadiene to form a C(4)S(2) ring, (ii) the C-H bond activation on the S-S bond forming a C-S bond. All of the C-H activation reactions and the ensuing C-S bond formation reactions suggest that the disulfide ligand can act in a manner similar to the transition metal centers of the organometallic complexes.     

Molecular surface science of C–H bond activation and polymerization catalysis

Surface science studies of heterogeneous catalysis use model systems ranging from single crystals to monodispersed nanoparticles in the 1–10 nm range. Molecular studies reveal that bond activation (C–H, H–H, C–C, C≡O) occurs at 300 K or below as the active metal sites simultaneously restructure. The strongly adsorbed molecules must be mobile to free up these sites for continued turnover of reaction. Oxide–metal interfaces are also active for catalytic turnover. Examples using C–H and C = O activation are described to demonstrate these properties. Polymerization catalysis demonstrates a strong dependence upon catalyst surface structure, which allows for the selectivity to be tuned by the choice of Ziegler-Natta surface preparation. Novel preparation methods of model catalyst arrays in two and three dimensions are opening the door to a complete understanding of catalytic reaction selectivity.     

N-heterocyclic carbene gold(I) and copper(I) complexes in C-H bond activation

Environmental concerns have and will continue to have a significant role in determining how chemistry is carried out. Chemists will be challenged to develop new, efficient synthetic processes that have the fewest possible steps leading to a target molecule, the goal being to decrease the amount of waste generated and reduce energy use. Along this path, chemists will need to develop highly selective reactions with atom-economical pathways producing nontoxic byproduct. In this context, C-H bond activation and functionalization is an extremely attractive method. Indeed, for most organic transformations, the presence of a reactive functionality is required. In Total Synthesis, the "protection and deprotection" approach with such reactive groups limits the overall yield of the synthesis, involves the generation of significant chemical waste, costs energy, and in the end is not as green as one would hope. In turn, if a C-H bond functionalization were possible, instead of the use of a prefunctionalized version of the said C-H bond, the number of steps in a synthesis would obviously be reduced. In this case, the C-H bond can be viewed as a dormant functional group that can be activated when necessary during the synthetic strategy. One issue increasing the challenge of such a desired reaction is selectivity. The cleavage of a C-H bond (bond dissociation requires between 85 and 105 kcal/mol) necessitates a high-energy species, which could quickly become a drawback for the control of chemo-, regio-, and stereoselectivity. Transition metal catalysts are useful reagents for surmounting this problem; they can decrease the kinetic barrier of the reaction yet retain control over selectivity. Transition metal complexes also offer important versatility in having distinct pathways that can lead to activation of the C-H bond. An oxidative addition of the metal in the C-H bond, and a base-assisted metal-carbon bond formation in which the base can be coordinated (or not) to the metal complexes are possible. These different C-H bond activation modes provide chemists with several synthetic options. In this Account, we discuss recent discoveries involving the versatile NHC-gold(I) and NHC-copper(I) hydroxide complexes (where NHC is N-heterocyclic carbene) showing interesting Br?nsted basic properties for C-H bond activation or C-H bond functionalization purposes. The simple and easy synthesis of these two complexes involves their halide-bearing relatives reacting with simple alkali metal hydroxides. These complexes can react cleanly with organic compounds bearing protons with compatible pK(a) values, producing only water as byproduct. It is a very simple protocol indeed and may be sold as a C-H bond activation, although the less flashy "metalation reaction" also accurately describes the process. The synthesis of these complexes has led us to develop new organometallic chemistry and catalysis involving C-H bond activation (metalation) and subsequent C-H bond functionalization. We further highlight applications with these reactions, in areas such as photoluminescence and biological activities of NHC-gold(I) and NHC-copper(I) complexes.     

Controlling site selectivity in palladium-catalyzed C-H bond functionalization

Effective methodology to functionalize C-H bonds requires overcoming the key challenge of differentiating among the multitude of C-H bonds that are present in complex organic molecules. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C-H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a number of selectivity trends have emerged for both sp(2) and sp(3) C-H functionalization reactions that hold true for a variety of transformations involving diverse directing groups. Functionalizations tend to occur at the less-hindered sp(2) C-H bond ortho to a directing group, at primary sp(3) C-H bonds that are β to a directing group, and, when multiple directing groups are present, at C-H sites proximal to the most basic directing group. Using approach 2, which exploits electronic biases within a substrate, our group has achieved C-2-selective arylation of indoles and pyrroles using diaryliodonium oxidants. The selectivity of these transformations is altered when the C-2 site of the heterocycle is blocked, leading to C-C bond formation at the C-3 position. While approach 3 (catalyst-based control) is still in its early stages of exploration, we have obtained exciting results demonstrating that site selectivity can be tuned by modifying the structure of the supporting ligands on the Pd catalyst. For example, by modulating the structure of N-N bidentate ligands, we have achieved exquisite levels of selectivity for arylation at the α site of naphthalene. Similarly, we have demonstrated that both the rate and site selectivity of arene acetoxylation depend on the ratio of pyridine (ligand) to Pd. Lastly, by switching the ligand on Pd from an acetate to a carbonate, we have reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. In combination with a growing number of reports in the literature, these studies highlight a frontier of catalyst-based control of site-selectivity in the development of new C-H bond functionalization methodology.     

Remote C-H bond activation/transformations: A continuous growing synthetic tool; Part II

The selective functionalization of inert C-H bonds is always challenging due to their abundance and large bond dissociation energies. Despite recent advancements, the engagement of inert building blocks for distant functionalization is the most appealing approach for the past decade for the construction of complex molecules. Along with the upsurge of proximal C-H bond activation methods, the presence of directing group or participation of ligand surmounts the challenge of regioselective remote C-H bond transformation. Remote C-H functionalization has emerged as an important tool for the direct synthesis of a variety of natural as well as pharmaceutical products. In this area, chemists are continuously designing and exploring new catalysts, ligands and directing group for the functionalization of C-H bonds which are beyond proximity. Earlier success in this area was limited to meta-position, but recently scientists have come out with new templates which can reach even para-position. The developed catalytic transformations provide access for production of a wide range of value-added products without using classical methods such as Friedel-Craft reactions, Heck coupling, etc., providing atom economical alternate and avoiding the toxic waste generation. On this topic, we have recently published a review article entitled “Distant C-H Activation/Functionalization: A New Horizon of Selectivity beyond Proximity” in the same journal, i.e., Catalysis Reviews: Science and Engineering, 2015, 57(3), 345. In continuation of this article, the present review article will cover the catalytic processes on the mentioned topic mainly developed from 2014 to 2017. The main focus will be on mechanistic pathways and the critical role of template as well as ligands. The purpose of this review is to highlight the recent advancements in remote C-H catalysis and a path ahead.     

Metal-ligand cooperation by aromatization-dearomatization: a new paradigm in bond activation and "green" catalysis

In view of global concerns regarding the environment and sustainable energy resources, there is a strong need for the discovery of new, green catalytic reactions. For this purpose, fresh approaches to catalytic design are desirable. In recent years, complexes based on "cooperating" ligands have exhibited remarkable catalytic activity. These ligands cooperate with the metal center by undergoing reversible structural changes in the processes of substrate activation and product formation. We have discovered a new mode of metal-ligand cooperation, involving aromatization-dearomatization of ligands. Pincer-type ligands based on pyridine or acridine exhibit such cooperation, leading to unusual bond activation processes and to novel, environmentally benign catalysis. Bond activation takes place with no formal change in the metal oxidation state, and so far the activation of H-H, C-H (sp(2) and sp(3)), O-H, and N-H bonds has been demonstrated. Using this approach, we have demonstrated a unique water splitting process, which involves consecutive thermal liberation of H(2) and light-induced liberation of O(2), using no sacrificial reagents, promoted by a pyridine-based pincer ruthenium complex. An acridine pincer complex displays unique "long-range" metal-ligand cooperation in the activation of H(2) and in reaction with ammonia. In this Account, we begin by providing an overview of the metal-ligand cooperation based on aromatization-dearomatization processes. We then describe a range of novel catalytic reactions that we developed guided by these new modes of metal-ligand cooperation. These reactions include the following: (1) acceptorless dehydrogenation of secondary alcohols to ketones, (2) acceptorless dehydrogenative coupling of alcohols to esters, (3) acylation of secondary alcohols by esters with dihydrogen liberation, (4) direct coupling of alcohols and amines to form amides and polyamides with liberation of dihydrogen, (5) coupling of esters and amines to form amides with H(2) liberation, (6) selective synthesis of imines from alcohols and amines, (6) facile catalytic hydrogenolysis of esters to alcohols, (7) hydrogenolysis of amides to alcohols and amines, (8) hydrogenation of ketones to secondary alcohols under mild hydrogen pressures, (9) direct conversion of alcohols to acetals and dihydrogen, and (10) selective synthesis of primary amines directly from alcohols and ammonia. These reactions are efficient, proceed under neutral conditions, and produce no waste, the only byproduct being molecular hydrogen and/or water, providing a foundation for new, highly atom economical, green synthetic processes.     

Borylation and silylation of C-H bonds: a platform for diverse C-H bond functionalizations

Methods that functionalize C-H bonds can lead to new approaches for the synthesis of organic molecules, but to achieve this goal, researchers must develop site-selective reactions that override the inherent reactivity of the substrates. Moreover, reactions are needed that occur with high turnover numbers and with high tolerance for functional groups if the C-H bond functionalization is to be applied to the synthesis of medicines or materials. This Account describes the discovery and development of the C-H bond functionalization of aliphatic and aromatic C-H bonds with borane and silane reagents. The fundamental principles that govern the reactivity of intermediates containing metal-boron bonds are emphasized and how an understanding of the effects of the ligands on this reactivity led us to broaden the scope of main group reagents that react under mild conditions to generate synthetically useful organosilanes is described. Complexes containing a covalent bond between a transition metal and a three-coordinate boron atom (boryl complexes) are unusually reactive toward the cleavage of typically unreactive C-H bonds. Moreover, this C-H bond cleavage leads to the formation of free, functionalized product by rapid coupling of the hydrocarbyl and boryl ligands. The initial observation of the borylation of arenes and alkanes in stoichiometric processes led to catalytic systems for the borylation of arenes and alkanes with diboron compounds (diborane(4) reagents) and boranes. In particular, complexes based on the Cp*Rh (in which Cp is the cyclopentadienyl anion) fragment catalyze the borylation of alkanes, arenes, amines, ethers, ketals, and haloalkanes. Although less reactive toward alkyl C-H bonds than the Cp*Rh systems, catalysts generated from the combination of bipyridines and iridium(I)-olefin complexes have proven to be the most reactive catalysts for the borylation of arenes. The reactions catalyzed by these complexes form arylboronates from arenes with site-selectivity for C-H bond cleavage that depends on the steric accessibility of the C-H bonds. These complexes also catalyze the borylation of heteroarenes, and the selectivity for these substrates is more dependent on electronic effects than the borylation of arenes. The products from the borylation of arenes and heteroarenes are suitable for a wide range of subsequent conversions to phenols, arylamines, aryl ethers, aryl nitriles, aryl halides, arylboronic acids, and aryl trifluoroborates. Studies of the electronic properties of the ancillary ligand on the rate of the reaction show that the flat structure and the strong electron-donating property of the bipyridine ligands, along with the strong electron-donating property of the boryl group and the presence of a p-orbital on the metal-bound atom, lead to the increased reactivity of the iridium catalysts. Based on this hypothesis, we studied catalysts containing substituted phenanthroline ligands for a series of additional transformations, including the silylation of C-H bonds. A sequence involving the silylation of benzylic alcohols, followed by the dehydrogenative silylation of aromatic C-H bonds, leads to an overall directed silylation of the C-H bond ortho to hydroxyl functionality.     

C-F and C-H bond activation of fluorobenzenes and fluoropyridines at transition metal centers: how fluorine tips the scales

In this Account, we describe the transition metal-mediated cleavage of C-F and C-H bonds in fluoroaromatic and fluoroheteroaromatic molecules. The simplest reactions of perfluoroarenes result in C-F oxida tive addition, but C-H activation competes with C-F activation for partially fluorinated molecules. We first consider the reactivity of the fluoroaromatics toward nickel and platinum complexes, but extend to rhenium and rhodium where they give special insight. Sections on spectroscopy and molecular structure are followed by discussions of energetics and mechanism that incorporate experimental and computational results. We highlight special characteristics of the metal-fluorine bond and the influence of the fluorine substituents on energetics and mechanism. Fluoroaromatics reacting at an ML(2) center initially yield η(2)-arene complexes, followed usually by oxidative addition to generate MF(Ar(F))(L)(2) or MH(Ar(F))(L)(2) (M is Ni, Pd, or Pt; L is trialkylphosphine). The outcome of competition between C-F and C-H bond activation is strongly metal dependent and regioselective. When C-H bonds of fluoroaromatics are activated, there is a preference for the remaining C-F bonds to lie ortho to the metal. An unusual feature of metal-fluorine bonds is their response to replacement of nickel by platinum. The Pt-F bonds are weaker than their nickel counterparts; the opposite is true for M-H bonds. Metal-fluorine bonds are sufficiently polar to form M-F···H-X hydrogen bonds and M-F···I-C(6)F(5) halogen bonds. In the competition between C-F and C-H activation, the thermodynamic product is always the metal fluoride, but marked differences emerge between metals in the energetics of C-H activation. In metal-fluoroaryl bonds, ortho-fluorine substituents generally control regioselectivity and make C-H activation more energetically favorable. The role of fluorine substituents in directing C-H activation is traced to their effect on bond energies. Correlations between M-C and H-C bond energies demonstrate that M-C bond energies increase far more on ortho-fluorine substitution than do H-C bonds. Conventional oxidative addition reactions involve a three-center triangular transition state between the carbon, metal, and X, where X is hydrogen or fluorine, but M(d)-F(2p) repulsion raises the activation energies when X is fluorine. Platinum complexes exhibit an alternative set of reactions involving rearrangement of the phosphine and the fluoroaromatics to a metal(alkyl)(fluorophosphine), M(R)(Ar(F))(PR(3))(PR(2)F). In these phosphine-assisted C-F activation reactions, the phosphine is no spectator but rather is intimately involved as a fluorine acceptor. Addition of the C-F bond across the M-PR(3) bond leads to a metallophosphorane four-center transition state; subsequent transfer of the R group to the metal generates the fluorophosphine product. We find evidence that a phosphine-assisted pathway may even be significant in some apparently simple oxidative addition reactions. While transition metal catalysis has revolutionized hydrocarbon chemistry, its impact on fluorocarbon chemistry has been more limited. Recent developments have changed the outlook as catalytic reactions involving C-F or C-H bond activation of fluorocarbons have emerged. The principles established here have several implications for catalysis, including the regioselectivity of C-H activation and the unfavorable energetics of C-F reductive elimination. Palladium-catalyzed C-H arylation is analyzed to illustrate how ortho-fluorine substituents influence thermodynamics, kinetics, and regioselectivity.     

On transient species and activation energies in heterogeneous catalysis

A discussion is presented on the relation between true and apparent activation energies found in heterogeneous catalysis. The possibility of a transient species defining the rate determining step is emphasized. In such a case, the difference between apparent and true activation energies can be quite small. Such a condition is of importance for the understanding of phenomena involving the activation energy, such as the isokinetic effect.