In conventional methods, C−H activations are largely involved in the use of stoichiometric amounts of toxic and expensive metal & chemical oxidants, conceding the overall sustainable nature. Meanwhile, undesired byproducts are generated, that is problematic in the scale up process. However, electrochemical C−H activation via catalyst control strategy using metals as mediators (instead electrochemical substrate control strategy) has been identified as a more efficient strategy toward selective functionalizations. Thus, indirect electrolysis makes the potential range more pleasant, and less side reactions can occur. Herein, we summarize the metalla-electrocatalysis process for activations of inert C−H bonds and functionalization. These Metalla-electrocatalyzed C−H bond functionalizations are presented in term of C−C and C−X (X = O, N, P and halogens) bonds formation. The electrooxidative C−H transformations in the presence of metal catalysts are described by better chemoselectivities with broad tolerance of sensitive functionalities. Moreover, in the future to enhance sustainability and green chemistry concerns, integration of metalla-electrocatalysis with flow and photochemistry will enable safe and efficient scale-up and may even improve reaction times, kinetics and yields.
- C−H bonds activation
- catalyst control strategy
- atom and step economy
The direct functionalization of C–H bonds provides a powerful synthetic pathway for selective C–C and carbon–heteroatom (C–X) bond formation, thus improving atom- and step economy as well as rationalization of chemical synthesis [1, 2]. In the field of conventional C–H activation, prefunctionalization of substrates, generally high temperatures, acidic conditions and/or the use of stoichiometric oxidants (such as a peroxide, a hypervalent iodine) are required due to the high bond dissociation energies, unreactive molecular orbital profiles, low acidities, and ubiquitous nature of the C–H bonds [3, 4]. The stoichiometric amount of reagents/oxidants affect the product’s selectivity, additionally the formation of by-products result in overall low turnover of the reaction. Electrochemical C−H functionalization has advantages as this process avoids prefunctionalization of substrates and offering the direct transformation of a simple substrate to a complex and valuable molecule . However, for C–H functionalization, still need a high oxidation potential for selective C–H bonds activation compared to organic solvents and common functional groups. To overcome this problem, indirect electrolysis via catalysts control strategy (mediators such as redox metal catalysts) is beneficial, makes the potential range more pleasant and has control over selectivity at mild conditions that is not observed through classical catalyst control strategy [6, 7]. From the 90’s, great progress was observed in the evolution of reactions involving control of regioselectivity and enantioselectivity. Much of this merit was achieved by the evolution of catalysts based on high-performance transition metals. Derivatives of organic halides, triflates and several other leaving groups are still applied in reactions of aryl alkylations (Friedel-Crafts) and in cross-coupling reactions with several organometallic reagents. In addition, alkenes are also good substrates for aryl alkylation, alkenylation, or for cross-coupling reactions catalyzed by transition metals, using the corresponding halides or correlated substrates. However, most of the known transition metal catalysts do not meet all the requirements of modern developments, and often the biggest limitation is low efficiency and high costs to obtain efficient ligands. Faced with this challenge, there is an increasing use of new technologies applied concurrently to these catalytic systems, making transition metal catalysts more efficient and cleaner, enabling new mechanistic routes . Additionally, the use of electrochemistry concomitant with the chemistry of transition metals offers a powerful strategy, since it avoids the use of external redox additives .
Electrocatalysis is a field of electrochemistry that has been gaining great growth in recent years due to the several advantages. In indirect electrosynthetic reactions, the exchange of electrons occurs between a mediator and the organic substrate. Therefore, by varying the applied current or voltage of the power source, the oxidation or reduction capacity of the electrochemical system can be manipulated, this being a great advantage in the method. Likewise, the redox mediator alters the applied potential required for electron transfer, making the potential range more pleasant, and fewer side reactions can occur, avoiding overoxidation, dimerization, parallel reactions or electrode passivation (Figure 1). In addition, electrocatalysis deals with the development for energy storage, solar fuels, fuel cells, and also other electrochemical devices with charge transfer reactions interfacial control .
Whereas the redox potentials and the selectivity of the reaction can be controlled by changing the ligand of the mediators of the complex transition metals. With the use of electrochemistry this process can become more selective, due to the possibility of controlling the electrical potential of the reaction medium by changing the voltage (V) or the electric current (A) through the energy source (Figure 2) .
Considering this, we have prepared an overview of the recent metalla-electrocatalysis process for activation/functionalization of inert C−H bonds. The perspective and limitations together with mechanistic discussions will be presented.
To offer an easy interpretation of the different catalytic systems discussed here, we will use a standardized notation, differentiating the divided cell from the undivided cell, as well as if the reaction follows via constant current or constant potential (Figure 3). Additionally, the different types of electrodes will be added along with other details, offering a better experience for the reader.
2. C-C bond formation
The possibility of extending an organic structure through the formation of new C-C bonds is essential for medicinal chemistry, synthesis of natural products, materials chemistry and even agrochemical synthesis, among others [12, 13, 14]. Synthetic methodologies via carbometallation have been intensively developing in recent decades, and group
Palladium-catalyzed C-H cross-coupling reactions are known to be powerful tool to build new C-C bonds. Considering this, Mei and co-workers reported a C(sp2)-H coupling of ketoximes
Considering experimental results, the authors suggest a mechanism for C(sp2)-H methylation via electrochemical oxidation (Figure 5). Initially, the palladium catalyst coordinates with a nitrogen atom, approaching the ortho-C–H bond, activating the C(sp2)-H bond to form the palladacycle. Transmetallation with MeBF3K under anodic oxidation conditions can provide Pd(III) or Pd(IV), which followed by reductive elimination, delivers the methylated product
Asymmetric catalysis has valuable applications in the synthesis of useful compounds. A greater understanding of the mechanisms involved contributes to expanding its scope, as well as the use of new technologies, which should offer new insights. Ackermann and co-workers reported the very first asymmetric metalla-electrocatalyzed C-H activation . With the aid of a transient directing group (TDG) using graphite felt and platinum electrodes, pallada-electrocatalysis was obtained in high enantioselectivities under moderate reaction conditions, providing the synthesis of highly enantiomerically-enriched biaryls axially chiral scaffolds
C-centered radical cyclization under electrochemical conditions has been used to obtain cyclic structures. These radicals are highly reactive and attractive in organic synthesis, and has received attention. Pan and co-workers reported an electrosynthesis of functionalized 1-naphthols using alkynes and 1,3-dicarbonyl compounds by (4 + 2) annulation of C-centered radical . The reactions were carried out in an undivided cell in the presence of Cp2Fe as a catalyst in THF/EtOH at a constant potential of 1.15 V vs. Ag/AgCl with NaOEt (30 mol%), during 2 h at 100°C (Figure 7). In general, good yield were obtained for compounds with the electron-donating or electron-withdrawing substituents, up to 84%. According to the control experiments, radical intermediates are involved and with absence of Cp2Fe the product was obtained with reduced yield, that is, direct electrolysis results in lower yields. Based on this and cyclic voltammetry experiments, a possible mechanism was proposed (Figure 8). Under electrochemical conditions, it is necessary to form the conjugate base
Ackermann and co-workers reported an electrooxidative C-C alkenylation performed by rhodium(III) catalysis . This reaction proceeded with ample scope and excellent levels of chemo- and position selectivities within an organometallic C-C activation manifold. The reactions were carried out in an undivided cell, in a constant current at 4.0 mA using [Cp*RhCl2]2 as catalyst, in combination with a platinum plate cathode and a reticulated vitreous carbon (RVC) at anode, along with KOAc as additive in H2O at 100°C (Figure 9). According to the examination of leaving group substitution pattern, tertiary and secondary alcohols bearing either aryl or alkyl groups led the product
Mo and co-workers reported a general electrochemical strategy for the combined trifluoromethylation/C(sp2)−H functionalization using Langlois’ reagent as the CF3 source . The reactions were carried out an undivided cell using MnBr2 as the mediator, H3PO4 as the sacrificial oxidant, Pt as the electrodes with a constant electric current of 10 mA for 6 h (Figure 11).
The mechanism study by cyclic voltammetry showed that combination of MnBr2 and CF3SO2Na exhibits a quasi-reversible anodic CV feature at 0.83 V, that was attributed to the MnII/MnIII redox couple of the CF3-bond complex. When the reagent was added in mixture of MnBr2 and CF3SO2Na, it was observed the presence of two irreversible anodic waves of 0.94 and 1.59 V, which correspond to the formation of the putative MnIII-CF3 and the single electron oxidation leading to the final product. Summarizing, the MnIII-CF3 species is produced by anodic oxidation of MnII in the presence of Langlois reagent. After, Mn-assisted delivery of CF3∙ to the olefin forming a carbon radical. Subsequently, the aromatic ring radical is formed and following by either anode or MnIII-mediated oxidation, then product
3. C-X (X = O, N, P, halogen) bond formation
The organic molecules with C
As an improvement of this transformation, the authors suggest a mechanism for C-H/N-H coupling reaction catalyzed by Pd(II) via electrochemical oxidation (Figure 14). Initially, Pd(II) coordinates with a nitrogen atom of substrate
Cobalt-catalyzed C-H cross-coupling reactions are known to be a strong implement to build new C-N bonds . In this context, Lei and co-workers reported a C(sp2)-H coupling catalyzed by Co of quinoline amide
As an improvement of this methodology, the authors suggest a plausible mechanism (Figure 17). In the path I: Co(II) is oxidized at the anode to give Co(III); which coordinates with N-(quinolin-8-yl)benzamide
The Mn-catalyzed formation of the C-Cl bond was reported by Chen and co-workers (Figure 18) . Electrolyzing styrene derivatives
A mechanistic elucidation in Figure 19 shows that first, Mn(II)Cl oxidized at the anode providing Mn(III)Cl species. Then styrene derivatives
Budnikova and co-workers reported an efficient approach of Ag-catalyzed reaction to a range azole dialkyl phosphonates derivatives
The electrolysis proceeds in a divided cell at a constant voltage, employing AgOAc and Na3PO4 as additives and using acetonitrile as solvent. The proposed mechanism of this methodology is described in Figure 21. The reaction starts by combining dialkyl-
Xu and co-workers reported an efficient method for rhodium (III)-electrocatalyzed to form the C-P bond (Figure 22) . Using a graphite rod as anode and a platinum plates as a cathode, different substituted
A possible mechanism of this strategy is shown in Figure 23. The reaction starts with C-H activation in phenylpyridine
Strekalova and co-workers developed an elegant approach for Co-catalysed electrochemical formation of the C-P bond . By using cobalt complex as a catalyst, different diethyl phosphonates
The plausible mechanism (Figure 25) shows that at the start, Co2+ precursors coordinates with H-phosphonate
The C-O bond formation under Co-catalyst was reported by Ackermann group (Figure 26) . A variety of amides
Presumably, a catalytic cycle commences with the oxidation of CoII precatalyst at the anode to give a CoIII species capable of forming complex
C−H activation/functionalization via metalla-electrocatalysis appears as a valuable tool for organic synthesis. Coupling reactions with hydrogen evolution demonstrate great potential for application in the synthesis of complex molecules. Likewise, electrochemical C−H activation appears to be a greener method, and even more progress is expected in this area of research. However, there are still several challenges, such as the application of other transition metals, the recycling of transition metals and electrolytes, an in-depth study of asymmetric transformations, the application of new ligands, etc. Despite all these challenges, we believe that in the future, the fusion between the transition metal catalysis with electrochemical methods will have a great development, being highly promising for synthetic chemistry, becoming a common tool in all research laboratories.
Support from the EU-COFUND project (Grant No 663830) to Dr. Nisar Ahmed is gratefully acknowledged. We also thank the School of Chemistry, Cardiff Chemistry (N.A), CNPq (G. M. M and G. C. Z) and RUDN University 5–100 Project framework Program (N.S) for their support.
Conflict of interest
The authors declare no conflict of interest.