Electrocatalytic C–H Activation
TL;DR: In this paper, the authors show that electrochemical C-H activation has been identified as a more efficient strategy that exploits storable electricity in place of byproduct-generating chemical reagents.
Abstract: C–H activation has emerged as a transformative tool in molecular synthesis, but until recently oxidative C–H activations have largely involved the use of stoichiometric amounts of expensive and toxic metal oxidants, compromising the overall sustainable nature of C–H activation chemistry. In sharp contrast, electrochemical C–H activation has been identified as a more efficient strategy that exploits storable electricity in place of byproduct-generating chemical reagents. Thus, transition-metal catalysts were shown to enable versatile C–H activation reactions in a sustainable manner. While palladium catalysis set the stage for C(sp2)–H and C(sp3)–H functionalizations by N-containing directing groups, rhodium and ruthenium catalysts allowed the use of weakly coordinating amides and acids. In contrast to these precious 4d transition metals, the recent year has witnessed the emergence of versatile cobalt catalysts for C–H oxygenations, C–H nitrogenations, and C–C-forming [4+2] alkyne annulations. Thereby, the ...
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TL;DR: A comprehensive overview on first row transition metal catalysts for C-H activation until summer 2018 is provided.
Abstract: C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.
1,417 citations
TL;DR: A unique feature of electrochemistry is the simultaneous occurrence of anodic oxidation and cathodic reduction, which allows the dehydrogenative transformations to proceed through H2 evolution without the need for chemical oxidants.
Abstract: N-centered radicals are versatile reaction intermediates that can react with various π systems to construct C-N bonds. Current methods for generating N-centered radicals usually involve the cleavage of an N-heteroatom bond; however, similar strategies that are applicable to N-H bonds prove to be more challenging to develop and therefore are attracting increasing attention. In this Account, we summarize our recent efforts in the development of electrochemical methods for the generation and synthetic utilization of N-centered radicals. In our studies, N-aryl amidyl radical, amidinyl radical and iminyl radical cation intermediates are generated from N-H precursors through direct electrolysis or indirect electrolysis assisted by a redox catalyst. In addition, an electrocatalytic method that converts oximes to iminoxyl radicals has also been developed. The electrophilic amidyl radical intermediates can participate in 5-exo or 6-exo cyclization with alkenes and alkynes to afford C-centered radicals, which can then undergo various transformations such as H atom abstraction, single-electron transfer oxidation to a carbocation, cyclization, or aromatic substitution, leading to a diverse range of N-heterocyclic products. Furthermore, amidinyl radicals, iminyl radical cations, and iminoxyl radicals can undergo intramolecular aromatic substitution to afford various N-heteroaromatic compounds. Importantly, the electrochemical reaction can be channeled toward a specific product despite the presence of other competing pathways. For a successful electrosynthesis, it is important to take into consideration of both the electron transfer steps associated with the electrode and the nonelectrode related processes. A unique feature of electrochemistry is the simultaneous occurrence of anodic oxidation and cathodic reduction, which, as this Account demonstrates, allows the dehydrogenative transformations to proceed through H2 evolution without the need for chemical oxidants. In addition, cathodic solvent reduction can continuously generate a low concentration of base, which facilitates anodic substrate oxidation. Such a mechanistic paradigm obviates the need for stoichiometric strong bases and avoids base-promoted decomposition of sensitive substrates or products. Furthermore, electrode materials can also be adjusted to control the reaction outcome, as demonstrated by the synthesis of N-heteroaromatics and the corresponding N-oxides from biaryl ketoximes.
522 citations
TL;DR: Improved monofunctionalization selectivity is achieved in the Pd-catalyzed C(sp3)-H oxygenation compared to conventional approaches using PhI(OAc)2 as the chemical oxidant.
Abstract: Electrochemical synthesis of organic compounds has emerged as an attractive and environmentally benign alternative to conventional approaches for oxidation and reduction of organic compounds that utilizes electric current instead of chemical oxidants and reductants. As such, many useful transformations have been developed, including the Kolbe reaction, the Simons fluorination process, the Monsanto adiponitrile process, and the Shono oxidation, to name a few. Electrochemical C-H functionalization represents one of the most promising reaction types among many electrochemical transformations, since this process avoids prefunctionalization of substrates and provides novel retrosynthetic disconnections. However, site-selective anodic oxidation of C-H bonds is still a fundamental challenge due to the high oxidation potentials of C-H bonds compared to organic solvents and common functional groups. To overcome this issue, indirect electrolysis via the action of a mediator (a redox catalyst) is regularly employed, by which the selectivity can be controlled following reaction of said mediator with the substrate. Since the redox potentials of transition metal complexes can be easily tuned by modification of the ligand, the synergistic use of electrochemistry and transition metal catalysis to achieve site-selective C-H functionalization is an attractive strategy. In this Account, we summarize and contextualize our recent efforts toward transition metal-catalyzed electrochemical C-H functionalization proximal to a suitable directing group. We have developed C-H oxygenation, acylation, alkylation, and halogenation reactions in which a Pd(II) species is oxidized to a Pd(III) or Pd(IV) intermediate by anodic oxidation, followed by reductive elimination to form the corresponding C-O, C-C, and C-X bonds. Importantly, improved monofunctionalization selectivity is achieved in the Pd-catalyzed C(sp3)-H oxygenation compared to conventional approaches using PhI(OAc)2 as the chemical oxidant. Physical separators are sometimes used to prevent the electrochemical deposition of Pd black on the cathode resulting from reduction of high valent Pd species. We skirted this issue through the development a Cu-catalyzed electrochemical C(sp2)-H amination using n-Bu4NI as a redox cocatalyst in an undivided cell. In addition, we developed Ir-catalyzed electrochemical vinylic C-H functionalization of acrylic acids with alkynes in an undivided cell, affording various substituted α-pyrones in good to excellent yield. More importantly, chemical oxidants, including Ag2CO3, Cu(OAc)2, and PhI(OAc)2, resulted in much lower yields in the absence of electrical current under otherwise identical conditions. As elaborated below, progress in the area of electrochemical transition metal-catalyzed synthesis provides an effective platform for environmentally friendly and sustainable selective chemical transformations.
391 citations
TL;DR: These studies will stimulate the research interest of chemists and pave the way for the discovery of more electrochemical oxidative cross-coupling with hydrogen evolution reactions, which can not only achieve the oxidativeCross-Coupling under external-oxidant-free conditions, but also release valuable hydrogen gas during the chemical bond formation.
Abstract: Oxidative cross-coupling has proved to be one of the most straightforward strategies for forming carbon-carbon and carbon-heteroatom bonds from easily available precursors. Over the past two decades, tremendous efforts have been devoted in this field and significant advances have been achieved. However, in order to remove the surplus electrons from substrates for chemical bonds formation, stoichiometric oxidants are usually needed. Along with the development of modern sustainable chemistry, considerable efforts have been devoted to perform the oxidative cross-coupling reactions under external-oxidant-free conditions. Electrochemical synthesis is a powerful and environmentally benign approach, which can not only achieve the oxidative cross-couplings under external-oxidant-free conditions, but also release valuable hydrogen gas during the chemical bond formation. Recently, the electrochemical oxidative cross-coupling with hydrogen evolution reactions has been significantly explored. This Account presents our recent efforts toward the development of electrochemical oxidative cross-coupling with hydrogen evolution reactions. (1) We explored the oxidative cross-coupling of thiols/thiophenols with arenes, heteroarenes, and alkenes for C-S bond formation. (2) Using the strategy of electrochemical oxidative C-H/N-H cross-coupling with hydrogen evolution, we successfully realized the C-H amination of phenols, anilines, imidazopyridines, and even ethers. (3) Employing halide salts as the green halogenating reagents, we developed a clean C-H halogenation protocol under electrochemical oxidation conditions. To address the limitation that this reaction had to carry out in aqueous solvent, we also developed an alternative method that uses CBr4, CHBr3, CH2Br2, CCl3Br, and CCl4 as halogenating reagents and the mixture of acetonitrile and methanol as cosolvent. (4) We also developed an approach for constructing C-O bonds in a well-developed electrochemical oxidative cross-coupling with hydrogen evolution manner. (5) Under mild external-oxidant-free electrochemical conditions, we realized the C(sp2)-H and C(sp3)-H phosphonylation with modest to high yields. (6) We successfully achieved the S-H/S-H cross-coupling with hydrogen evolution under electrochemical oxidation conditions. By anodic oxidation instead of chemical oxidants, the overoxidation of thiols and thiophenols was well avoided. (7) The methods for constructing structurally diverse heterocyclic compounds were also developed via the electrochemical oxidative annulations. (8) We have also applied the electrochemical oxidative cross-coupling with hydrogen evolution strategy to the alkenes difunctionalization for constructing multiple bonds in one step, such as C-S/C-O bonds, C-S/C-N bonds, C-Se/C-O bonds, and C-Se/C-N bonds. We hope our studies will stimulate the research interest of chemists and pave the way for the discovery of more electrochemical oxidative cross-coupling with hydrogen evolution reactions.
390 citations
TL;DR: The initial foray into electrocatalytic synthesis led to the development of two generations of alkene diazidation reactions, using transition-metal and organic catalysis, respectively, and a variety of difunctionalization reactions, including halotrifluoromethylation, haloalkylation and azidophosphinoylation, were successfully developed.
Abstract: Electrochemistry has been used as a tool to drive chemical reactions for over two centuries. With the help of an electrode and a power source, chemists are bestowed with an imaginary reagent whose potential can be precisely dialed in. The theoretically infinite redox range renders electrochemistry capable of oxidizing or reducing some of the most tenacious compounds (e.g., F- to F2 and Li+ to Li0). Meanwhile, a granular level of control over the electrode potential allows for the chemoselective differentiation of functional groups with minute differences in potential. These features make electrochemistry an attractive technique for the discovery of new modes of reactivity and transformations that are not readily accessible with chemical reagents alone. Furthermore, the use of an electrical current in place of chemical redox agents improves the cost-efficiency of chemical processes and reduces byproduct generation. Therefore, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis and has seen increasingly broad use in the synthetic community over the past several years.While electrochemical oxidation or reduction can provide access to reactive intermediates, redox-active molecular catalysts (i.e., electrocatalysts) can also enable the generation of these intermediates at reduced potentials with improved chemoselectivity. Moreover, electrocatalysts can impart control over the chemo-, regio-, and stereoselectivities of the chemical processes that take place after electron transfer at electrode surfaces. Thus, electrocatalysis has the potential to significantly broaden the scope of organic electrochemistry and enable a wide range of new transformations. Our initial foray into electrocatalytic synthesis led to the development of two generations of alkene diazidation reactions, using transition-metal and organic catalysis, respectively. In these reactions, the electrocatalysts play two critical roles; they promote the single-electron oxidation of N3- at a reduced potential and complex with the resultant transient N3• to form persistent reactive intermediates. The catalysts facilitate the sequential addition of 2 equiv of azide across the alkene substrates, leading to a diverse array of synthetically useful vicinally diaminated products.We further applied this electrocatalytic radical mechanism to the heterodifunctionalization of alkenes. Anodically coupled electrolysis enables the simultaneous anodic generation of two distinct radical intermediates, and the appropriate choice of catalyst allowed the subsequent alkene addition to occur in a chemo- and regioselective fashion. Using this strategy, a variety of difunctionalization reactions, including halotrifluoromethylation, haloalkylation, and azidophosphinoylation, were successfully developed. Importantly, we also demonstrated enantioselective electrocatalysis in the context of Cu-promoted cyanofunctionalization reactions by employing a chiral bisoxazoline ligand. Finally, by introducing a second electrocatalyst that mediates oxidatively induced hydrogen atom transfer, we expanded scope of electrocatalysis to hydrofunctionalization reactions, achieving hydrocyanation of conjugated alkenes in high enantioselectivity. These developments showcase the generality of our electrocatalytic strategy in the context of alkene functionalization reactions. We anticipate that electrocatalysis will play an increasingly important role in the ongoing renaissance of synthetic organic electrochemistry.
355 citations
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TL;DR: An overview of the basic photophysics and electron transfer theory is presented in order to provide a comprehensive guide for employing this class of catalysts in photoredox manifolds.
Abstract: In this review, we highlight the use of organic photoredox catalysts in a myriad of synthetic transformations with a range of applications. This overview is arranged by catalyst class where the photophysics and electrochemical characteristics of each is discussed to underscore the differences and advantages to each type of single electron redox agent. We highlight both net reductive and oxidative as well as redox neutral transformations that can be accomplished using purely organic photoredox-active catalysts. An overview of the basic photophysics and electron transfer theory is presented in order to provide a comprehensive guide for employing this class of catalysts in photoredox manifolds.
3,550 citations
TL;DR: A review of palladium-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle can be found in this paper.
Abstract: Pick your Pd partners: A number of catalytic systems have been developed for palladium-catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle are discussed (see scheme), and the versatility and practicality of this new mode of catalysis are presented. Unaddressed questions and the potential for development in the field are also addressed.
In the past decade, palladium-catalyzed CH activation/CC bond-forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross-coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming CC bonds from CH bonds: PdII/Pd0, PdII/PdIV, Pd0/PdII/PdIV, and Pd0/PdII catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.
3,533 citations
TL;DR: This review focuses on Rh-catalyzed methods for C-H bond functionalization, which have seen widespread success over the course of the last decade and are discussed in detail in the accompanying articles in this special issue of Chemical Reviews.
Abstract: Once considered the 'holy grail' of organometallic chemistry, synthetically useful reactions employing C-H bond activation have increasingly been developed and applied to natural product and drug synthesis over the past decade. The ubiquity and relative low cost of hydrocarbons makes C-H bond functionalization an attractive alternative to classical C-C bond forming reactions such as cross-coupling, which require organohalides and organometallic reagents. In addition to providing an atom economical alternative to standard cross - coupling strategies, C-H bond functionalization also reduces the production of toxic by-products, thereby contributing to the growing field of reactions with decreased environmental impact. In the area of C-C bond forming reactions that proceed via a C-H activation mechanism, rhodium catalysts stand out for their functional group tolerance and wide range of synthetic utility. Over the course of the last decade, many Rh-catalyzed methods for heteroatom-directed C-H bond functionalization have been reported and will be the focus of this review. Material appearing in the literature prior to 2001 has been reviewed previously and will only be introduced as background when necessary. The synthesis of complex molecules from relatively simple precursors has long been a goal for many organic chemists. The ability to selectively functionalize a molecule with minimal pre-activation can streamline syntheses and expand the opportunities to explore the utility of complex molecules in areas ranging from the pharmaceutical industry to materials science. Indeed, the issue of selectivity is paramount in the development of all C-H bond functionalization methods. Several groups have developed elegant approaches towards achieving selectivity in molecules that possess many sterically and electronically similar C-H bonds. Many of these approaches are discussed in detail in the accompanying articles in this special issue of Chemical Reviews. One approach that has seen widespread success involves the use of a proximal heteroatom that serves as a directing group for the selective functionalization of a specific C-H bond. In a survey of examples of heteroatom-directed Rh catalysis, two mechanistically distinct reaction pathways are revealed. In one case, the heteroatom acts as a chelator to bind the Rh catalyst, facilitating reactivity at a proximal site. In this case, the formation of a five-membered metallacycle provides a favorable driving force in inducing reactivity at the desired location. In the other case, the heteroatom initially coordinates the Rh catalyst and then acts to stabilize the formation of a metal-carbon bond at a proximal site. A true test of the utility of a synthetic method is in its application to the synthesis of natural products or complex molecules. Several groups have demonstrated the applicability of C-H bond functionalization reactions towards complex molecule synthesis. Target-oriented synthesis provides a platform to test the effectiveness of a method in unique chemical and steric environments. In this respect, Rh-catalyzed methods for C-H bond functionalization stand out, with several syntheses being described in the literature that utilize C-H bond functionalization in a key step. These syntheses are highlighted following the discussion of the method they employ.
3,210 citations
TL;DR: This review summarizes the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010 and proposes new acronyms, such as CMD (concerted metalationdeprotonation), IES (internal electrophilic substitution), or AMLA (ambiphilic metal ligand activation), which describe related mechanisms.
Abstract: The site-selective formation of carbon-carbon bonds through direct functionalizations of otherwise unreactive carbon-hydrogen bonds constitutes an economically attractive strategy for an overall streamlining of sustainable syntheses. In recent decades, intensive research efforts have led to the development of various reaction conditions for challenging C-H bond functionalizations, among which transition-metal-catalyzed transformations arguably constitute thus far the most valuable tool. For instance, the use of inter alia palladium, ruthenium, rhodium, copper, or iron complexes set the stage for chemo-, site-, diastereo-, and/or enantioselective C-H bond functionalizations. Key to success was generally a detailed mechanistic understanding of the elementary C-H bond metalation step, which depending on the nature of the metal fragment can proceed via several distinct reaction pathways. Traditionally, three different modes of action were primarily considered for CH bond metalations, namely, (i) oxidative addition with electronrich late transition metals, (ii) σ-bond metathesis with early transition metals, and (iii) electrophilic activation with electrondeficient late transition metals (Scheme 1). However, more recent mechanistic studies indicated the existence of a continuum of electrophilic, ambiphilic, and nucleophilic interactions. Within this continuum, detailed experimental and computational analysis provided strong evidence for novel C-H bond metalationmechanisms relying on the assistance of a bifunctional ligand bearing an additional Lewis-basic heteroatom, such as that found in (heteroatom-substituted) secondary phosphine oxides or most prominently carboxylates (Scheme 1, iv). This novel insight into the nature of stoichiometric metalations has served as stimulus for the development of novel transformations based on cocatalytic amounts of carboxylates, which significantly broadened the scope of C-H bond functionalizations in recent years, with most remarkable progress being made in palladiumor ruthenium-catalyzed direct arylations and direct alkylations. These carboxylate-assisted C-H bond transformations were mostly proposed to proceed via a mechanism in which metalation takes place via a concerted base-assisted deprotonation. To mechanistically differentiate these intramolecular metalations new acronyms have recently been introduced into the literature, such as CMD (concerted metalationdeprotonation), IES (internal electrophilic substitution), or AMLA (ambiphilic metal ligand activation), which describe related mechanisms and will be used below where appropriate. This review summarizes the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010. Moreover, experimental and computational studies on stoichiometric metalation reactions being of relevance to the mechanism of these catalytic processes are discussed as well. Mechanistically related C-H bond cleavage reactions with ruthenium or iridium complexes bearing monodentate ligands are, however, only covered with respect to their working mode, and transformations with stoichiometric amounts of simple acetate bases are solely included when their mechanism was suggested to proceed by acetate-assisted metalation.
2,820 citations
TL;DR: P palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners--including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations.
Abstract: The area of transition-metal-catalyzed direct arylation through cleavage of CH bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations
2,408 citations