Concerted Metalation-deprotonation Research Articles

Copper(II)-Catalyzed Regioselective H/D Exchange Based on Reversible C-H Activation.

Despite the increasing use of copper in C-H functionalizations, the Cu-catalyzed direct deuteration of C-H bonds remains a significant challenge due to its inherent low reactivity in inverse C-H bond reconstruction. In this paper, a novel strategy had been developed to reverse the copper-catalyzed concerted metalation-deprotonation process by inhibiting the unexpected disproportionation of Cu(II) to Cu(III). Picolinic acid was identified as a powerful ligand for facilitating this H/D exchange with D2O as deuterium source, and its inhibition activity was supported by preliminary control experiments and DFT studies.

Unactivated Pd-catalyzed oxidative cross-coupling reactions of arenes with benzene: a theoretical and experimental study

Oxidative C–H bond activated palladium-catalyzed aromatic cross-coupling reactions offer advantages of fewer required synthetic steps but disadvantages of loss of inherent regioselectivity and selectivity. In one proposed catalytic cycle, each arene adds to a palladium carboxylate catalyst according to a concerted metalation deprotonation mechanism, followed by reductive elimination to couple the arenes and the replenishment of the catalyst by an oxidant. Using this proposed mechanism, molecular structures and free energy profiles were calculated for coupling of benzene with a range of heteroarenes containing various substituents and with several Pd-carboxylate catalysts. Reaction kinetics were analysed using the energetic span model, predicting turnover frequencies (TOFs) of heterocoupling (HB and BH) and homocoupling (HH and BB) pathways and assessing degrees of turnover frequency control (XTOFs). More electron-withdrawing carboxylate ligands and more electron-donating heteroarene substituents decrease activation and reaction free energies of addition steps, with C-2 more favourable than C-3. When heteroarene and catalyst choice are particularly favourable, the first association can become exergonic, causing a significant change in catalytic kinetics. When not exergonic, free energy for addition of benzene is almost always higher, leading to large energetic spans and slower TOFs (BB < HB < BH < HH). Non-exergonic pathways are also faster with more electron-withdrawing ligands and more electron-donating heteroarene substituents because of lower energy addition steps and a smaller energetic span. For exergonic associations, the low-energy arene–catalyst intermediate creates a larger energetic span, slowing down the HH and HB pathways. More electron-withdrawing ligands and more electron-donating substituents increase the relative TOF for BH, and the reaction requires only small excesses of benzene to induce heterocoupling.

Axial Ligand Enables Synthesis of Allenylsilane through Dirhodium(II) Catalysis.

Described herein is a dirhodium(II)-catalyzed silylation of propargyl esters with hydrosilanes, using tertiary amines as axial ligands. By adopting this strategy, a range of versatile and useful allenylsilanes can be achieved with good yields. This reaction not only represents a SN2'-type silylation of the propargyl derivatives bearing a terminal alkyne moiety to synthesize allenylsilanes from simple hydrosilanes, but also represents a new application of dirhodium(II) complexes in catalytic transformation of carbon-carbon triple bond. The highly functionalized allenylsilanes that are produced can be transformed into a series of synthetically useful organic molecules. In this reaction, an intriguing ON-OFF effect of the amine ligand was observed. The reaction almost did not occur (OFF) without addition of Lewis base amine ligand. However, the reaction took place smoothly (ON) after addition of only catalytic amount of amine ligand. Detailed mechanistic studies and density functional theory (DFT) calculations indicate that the reactivity can be delicately improved by the use of tertiary amine. The fine-tuning effect of the tertiary amine is crucial in the formation of the Rh-Si species via a concerted metalation deprotonation (CMD) mechanism and facilitating β-oxygen elimination.

Axial Ligand Enables Synthesis of Allenylsilane through Dirhodium(II) Catalysis

AbstractDescribed herein is a dirhodium(II)‐catalyzed silylation of propargyl esters with hydrosilanes, using tertiary amines as axial ligands. By adopting this strategy, a range of versatile and useful allenylsilanes can be achieved with good yields. This reaction not only represents a SN2′‐type silylation of the propargyl derivatives bearing a terminal alkyne moiety to synthesize allenylsilanes from simple hydrosilanes, but also represents a new application of dirhodium(II) complexes in catalytic transformation of carbon‐carbon triple bond. The highly functionalized allenylsilanes that are produced can be transformed into a series of synthetically useful organic molecules. In this reaction, an intriguing ON‐OFF effect of the amine ligand was observed. The reaction almost did not occur (OFF) without addition of Lewis base amine ligand. However, the reaction took place smoothly (ON) after addition of only catalytic amount of amine ligand. Detailed mechanistic studies and density functional theory (DFT) calculations indicate that the reactivity can be delicately improved by the use of tertiary amine. The fine‐tuning effect of the tertiary amine is crucial in the formation of the Rh−Si species via a concerted metalation deprotonation (CMD) mechanism and facilitating β‐oxygen elimination.

RhRu Bimetallic Oxide Cluster Catalysts for Cross-Dehydrogenative Coupling of Arenes and Carboxylic Acids.

Noble-metal-based bimetallic oxide clusters are promising novel catalysts. In this study, we developed carbon-supported RhRu bimetallic oxide clusters (RhRuOx/C) with a mean diameter of 1.2 nm, which showed remarkable catalytic activity for the cross-dehydrogenative coupling (CDC) of arenes and carboxylic acids with O2 as the sole oxidant. RhRu bimetallic oxide cluster formation was confirmed by aberration-corrected high-angle annular dark-field scanning transmission electron microscopy with energy-dispersive X-ray spectroscopy and synchrotron X-ray absorption spectroscopy. Kinetic isotope and substituent effects indicated that arene C-H bond cleavage was the rate-determining step and proceeded via electrophilic concerted metalation-deprotonation mechanism, with a carboxylate as an internal base. Density functional theory calculations supported the proposed mechanism and indicated that the active center for C-H bond activation was Rh(V) rather than Rh(III), while Ru enhanced the electrophilicity of the Rh(V) site by decreasing the negative charge of the surrounding oxygen atoms. Electron-rich arenes showed relatively high reactivity for the RhRuOx/C-catalyzed CDC reaction, and both aliphatic and aromatic carboxylic acids were applicable to the reaction. The RhRuOx/C catalyst is promising for the CDC reaction of arenes and carboxylic acids to produce aryl esters. This work promotes the development of noble-metal-based bimetallic oxide clusters for C-H bond activation reactions.

Control over Anion Coordination on Pd(II), Cu(I), and Ag(I) with Regioisomeric Phosphine-Carboxylate Ligands.

The coordination of anionic donors is involved at various stages of catalytic cycles in transition-metal catalysis, but control over the spatial positioning of anions around a metal center is a challenge in coordination chemistry. Here we show that regioisomeric phosphine-carboxylate ligands provide spatial anion control on palladium(II) centers by favoring either κ2, cis-κ1, or trans-κ1 coordination of the carboxylate donor. Additionally, the palladium(II) carboxylates, which contain a methyl donor, upon protonation, deliver metal-alkyl complexes that feature a coordinated carboxylic acid. Such complexes can be considered as models for the minima that follow the concerted metalation-deprotonation transition state for C-H activation. The predictability of the coordination modes is further demonstrated on silver(I) and copper(I) centers, for which less common structures of mononuclear and dinuclear complexes can be obtained by using spatial anion control. Our results demonstrate the potential for spatial control over carboxylate anions in coordination chemistry.

Unveiling the Selectivity of Ru(II)-Catalyzed C-H Activation for Defluorinative Cyclization of 2-Arylbenzimidazole and Trifluoromethyl Diazo: A DFT Study.

The synthesis of monofluorinated heterocyclic compounds by C-H activation combined with defluorination is useful. Studies on the reaction mechanism and selectivity have shown that these processes play a positive role in promoting the development of monofluorinated reactions. Density functional theory (DFT) calculations were performed to investigate the mechanism and selectivity of Ru(II)-catalyzed 2-arylbenzimidazole with trifluoromethyl diazo. DFT calculations showed that C-H activation occurs through a concerted metalation/deprotonation (CMD) mechanism. After that, deprotonation and defluorinative cyclization are assisted by acetate and trifluoroethanol (TFE). Further mechanistic insights through noncovalent interaction (NCI) analysis were also obtained to elucidate the origin of the selectivity in the defluorination process.

Palladium(II)-catalyzed annulation of N-methoxy amides and arynes: computational mechanistic insights and substituents effects.

The combined use of transition metal-catalyzed C-H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C-H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C-H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd-C bond formation and a late C-H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent.

2-Pyridone-Directed CuII-Catalyzed General Method of C(sp2)-H Activation for C-S, C-Se, and C-N Cross-Coupling: Easy Access to Aryl Thioethers, Selenide Ethers, and Sulfonamides and DFT Study.

We have demonstrated N-substituted 2-pyridones as an N,O-directing group for selective C(sp2)-H-activated thiolation, selenylation, and sulfonamidation of ortho C-H bonds of benzamides. This method utilizes a cost-effective Cu(II)-salt catalyst instead of precious metal catalysts, achieving high yields, including gram-scale synthesis and excellent functional group tolerance. We applied this protocol to access 30 different compounds with high yields, demonstrating thiolation of fluorine-substituted benzamides as well. Density functional theory (DFT) calculations support the mechanism, including acetate-supported concerted metalation deprotonation (CMD) steps and the unique role of dimethyl sulfoxide (DMSO) solvent. The facile synthesis of pharmaceutically important sulfonamides and other compounds highlights the method's potential in chemistry and medicinal chemistry.

Density Functional Theory Study on the Mechanism of Nickel-Catalyzed 3,3-Dialkynylation of 2-Aryl Acrylamides Via Double Vinylic C-H Bond Activation.

The mechanisms of Ni-catalyzed 3,3-dialkynylation of 2-aryl acrylamide have been investigated by using density functional theory calculations. The result shows that this reaction includes double alkynylation, which involves sequential key steps of vinylic C-H bond activation, successive oxidative addition, and reductive elimination, with the second C-H bond activation being the rate-determining step. C-H and N-H bond activation occurs via the concerted metalation-deprotonation mechanism. The calculations show that no transition state exists in the first reductive elimination process, and a negative free energy barrier in the second reductive elimination process though a transition state is identified, indicating that the nickel-catalyzed vinylic C(sp2)-C(sp) bond formation does not require activation energy. Z-E isomerization is the prerequisite for the second alkynylation. In addition, our spin-flip TDDFT (SF-TDDFT) computational result discloses that the actual process of Z-E isomerization occurs on the potential energy surface of the first excited singlet state S1.

Towards Catalytic C–H Activation Using Main Group Elements

AbstractCatalytic C–H activation reactions are now established as a means to directly transform organic molecules and are commonly associated with metals such as palladium, rhodium, ruthenium and iridium. This Account will describe a short number of reports demonstrating that structures containing main group elements can facilitate C–H activation processes. In particular, boron-based catalysts can promote catalytic arene C–H borylation reactions, and an emerging approach using phosphenium ions can also cleave sp2 C–H bonds. These processes use a Lewis acidic main group atom combined with a pendant base to cleave C–H bonds, which compares with metal-catalyzed reactions that proceed via concerted metalation deprotonation mechanisms.1 Introduction2 Metal-Catalyzed C–H Activation via CMD/AMLA Mechanisms3 C–H Borylation via Boron-Based Catalysts4 C–H Activation Using Phosphenium Ions5 Conclusions

Accessing Benzoazepine Derivatives via Photoinduced Radical Relay Formal [5 + 2] Reaction of Amide/Alkyne Enabled by Palladium Catalysis.

A novel class of alkyne-tethered amides facilitates an unprecedented photoinduced palladium-catalyzed radical relay formal [5 + 2] reaction. This innovative strategy allows for the rapid construction of diverse fused benzoazepine structures, yielding structurally novel and compelling compounds. With a broad substrate scope and excellent functional group tolerance, the methodology synthesizes biologically active compounds. Notably, the resulting tricyclic benzo[b]azepines offer diversification opportunities through simple transformations. DFT calculations elucidate a seven-membered ring closure mechanism involving the alkenyl radical and Pd(I) rebound alongside a concerted metalation-deprotonation (CMD) process.

Pd-Catalyzed Oxidative C-H Arylation of (Poly)fluoroarenes with Aryl Pinacol Boronates and Experimental and Theoretical Studies of its Reaction Mechanism.

We report the synergistic combination of Pd(OAc)2 and Ag2O for the oxidative C-H arylation of (poly)fluoroarenes with aryl pinacol boronates (Ar-Bpin) in DMF as the solvent. This procedure can be conducted easily in air, and without using additional ligands, to afford the fluorinated unsymmetrical biaryl products in up to 98 % yield. Experimental studies suggest that the formation of [PdL2(C6F5)2] in DMF as coordinating solvent does not take place under the reaction conditions as it is stable to reductive elimination and thus would deactivate the catalyst. Thus, the intermediate [Pd(DMF)2(ArF)(Ar)] must be formed selectively to give desired arylation products. DFT calculations predict a low barrier (5.87 kcal/mol) for the concerted metalation deprotonation (CMD) process between C6F5H and the Pd(II) species formed after transmetalation between the Pd(II)X2 complex and aryl-Bpin which forms a Pd-Arrich species. Thus a Pd(Arrich)(Arpoor) complex is generated selectively which undergoes reductive elimination to generate the unsymmetrical biaryl product.

Regio- and Chemoselective Palladium-Catalyzed Additive-Free Direct C─H Functionalization of Heterocycles with Chloroaryl Triflates Using Pyrazole-Alkyl Phosphine Ligands.

A series of new pyrazole-alkyl phosphine ligands with varying cycloalkyl ring sizes that enable additive-free regio- and chemoselective C─H arylation of heterocycles are reported. Excellent α/β selectivity of various heterocycles such as benzo[b]thiophene, thiophene, furan, benzofuran, and thiazole can be achieved using these ligands, along with excellent chemoselectivity of C─Cl over C─OTf of chloroaryl triflates. Mechanistic studies supported by both experimental findings and density functional theory calculations indicate that the pyrazole phosphine ligands with optimal ring sizes allow the reaction to proceed with a lower energy barrier via a concerted metalation-deprotonation pathway.

Unveiling Mechanistic Complexity in Manganese-Catalyzed C-H Bond Functionalization Using IR Spectroscopy Over 16 Orders of Magnitude in Time.

ConspectusAn understanding of the mechanistic processes that underpin reactions catalyzed by 3d transition metals is vital for their development as potential replacements for scarce platinum group metals. However, this is a significant challenge because of the tendency of 3d metals to undergo mechanistically diverse pathways when compared with their heavier congeners, often as a consequence of one-electron transfer reactions and/or intrinsically weaker metal-ligand bonds. We have developed and implemented a new methodology to illuminate the pathways that underpin C-H bond functionalization pathways in reactions catalyzed by Mn-carbonyl compounds. By integrating measurements performed on catalytic reactions with in situ reaction monitoring and state-of-the-art ultrafast spectroscopic methods, unique insight into the mode of action and fate of the catalyst have been obtained.Using a combination of time-resolved spectroscopy and in situ low-temperature NMR studies, we have shown that photolysis of manganese-carbonyl precatalysts results in rapid (<5 ps) CO dissociation─the same process that occurs under thermal catalytic conditions. This enabled the detection of the key states relevant to catalysis, including solvent and alkyne complexes and their resulting transformation into manganacycles, which results from a migratory insertion reaction into the Mn-C bond. By systematic variation of the substrates (many of which are real-world structurally diverse substrates and not simple benchmark systems) and quantification of the resulting rate constants for the insertion step, a universal model for this migratory insertion process has been developed. The time-resolved spectroscopic method gave insight into fundamental mechanistic pathways underpinning other aspects of modern synthetic chemistry. The most notable was the first direct experimental observation of the concerted metalation deprotonation (CMD) mechanism through which carboxylate groups are able to mediate C-H bond activation at a metal center. This step underpins a host of important synthetic applications. This study demonstrated how the time-resolved multiple probe spectroscopy (TRMPS) method enables the observation of mechanistic process occurring on time scales from several picoseconds through to μs in a single experiment, thereby allowing the sequential observation of solvation, ligand substitution, migratory insertion, and ultimate protonation of a Mn-C bond.These studies have been complemented by an investigation of the "in reaction flask" catalyst behavior, which has provided additional insight into new pathways for precatalyst activation, including evidence that alkyne C-H bond activation may occur before heterocycle activation. Crucial insight into the fate of the catalyst species showed that excess water played a key role in deactivation to give higher-order hydroxyl-bridged manganese carbonyl clusters, which were independently found to be inactive. Traditional in situ IR and NMR spectroscopic analysis on the second time scale bridges the gap to the analysis of real catalytic reaction systems. As a whole, this work has provided unprecedented insight into the processes underpinning manganese-catalyzed reactions spanning 16 orders of magnitude in time.

Versatile Palladium-catalyzed intramolecular cyclization to access new luminescent azaphosphaphenalene motifs.

Using a straightforward sequence of diphosphonylation and a Pd-catalysed concerted-metalation-deprotonation (CMD), a synthetic strategy towards polyaromatic phosphorus containing heterocycles was developed. Herein, we report the synthesis and characterization of new azaphosphaphenalenes, using easily accessible palladium catalysts and starting materials. The key tetrahydroquinoline intermediates of the reaction were synthesised via a fast and effective procedure and could be isolated as such, or further reacted towards the target polyaromatic structures. The obtained products showed interesting luminescent properties and their emission, excitation and quantum yields were evaluated.

Synthesis of Heptagon-Containing Polyarenes by Catalytic C-H Activation.

Nanocarbons incorporating non-hexagonal aromatic rings - such as five-, seven-, and eight-membered rings - have various intriguing physical properties such as curved structures, unique one-dimensional packing, and promising magnetic, optical, and conductivity properties. Herein, we report an efficient synthetic approach to polycyclic aromatics containing seven-membered rings via a palladium-catalyzed intramolecular Ar-H/Ar-Br coupling. In addition to all-hydrocarbon scaffolds, heteroatom-embedded heptagon-containing polyarenes can be efficiently constructed with this method. Rhodium- and palladium-catalyzed sequential six- and seven-membered ring formations also afford complex heptagon-containing molecular nanocarbons from readily available arylacetylenes and biphenyl boronic acids. Detailed mechanistic analysis by DFT calculations showed the feasibility of seven-membered ring formation by a concerted metalation-deprotonation mechanism. This reaction can serve as a template for the synthesis of a wide range of seven-membered ring-containing molecular nanocarbons.

Study on the Mechanism of Ru-Catalyzed Cyclization of Aromatic Amides with Allylphosphine Oxides.

The mechanism of Ru-catalyzed cyclization of aromatic amides with allylphosphine oxides is studied by density functional theory calculation (DFT). The results show that, first, a 5-membered Ru ring intermediate is formed by N-H and C-H diprotons via the concerted metalation-deprotonation mechanism (CMD) and then the allylphosphine oxide is inserted through the ring-extending reaction to form a 7-membered ring intermediate. Next, reduction elimination is followed via intramolecular hydrogen transfer isomerization. At last, with the assistance of acetic acid, Ru (II) → Ru (IV) → Ru (II) complexes occur from the 7-membered Ru ring intermediate, and the final product is formed by reduction elimination and protonation reaction, while the catalyst is released to participate in the next cycle.

Access to Electron‐Rich Dibenzofurans through NBu4OAc‐Mediated Palladium Catalysis

AbstractDibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron‐rich aryl rings. Forming the key intramolecular Ar−Ar bond using traditional cross‐coupling is difficult. The C−H functionalisation (C−H activation) approach is, in principle, far more useful. However, we previously found that the well‐established conditions, which promote C−H functionalisation through Concerted Metalation‐Deprotonation (CMD), proved unsatisfactory. Herein, we report a Pd‐catalysed C−H functionalisation protocol that works with electron‐rich arenes. We use tetrabutylammonium acetate (NBu4OAc), which we suspect can act as base, ligand and solvent, rendering this protocol a simple and efficient route to electron‐rich dibenzofurans.

Mechanistic insights to define the directional role of hydrogen-bonding network between aryl oximes and propargyl alcohols in Rh(III) catalysis

The mechanism of the Cp*Rh(OAc)2-catalyzed C−H activation/annulation of acetophenone oxime and secondary propargyl alcohol was studied theoretically. Four elementary steps are involved as follows: C−H activation via concerted-metalation-deprotonation (CMD) mechanism, regioselective alkyne insertion, β-OH elimination and metal-free 6π electrocyclization. Importantly, density functional theory (DFT) calculations reveal that β-H elimination is inferior to β-OH elimination that is assisted by the directional hydrogen-bonding network between the two hydroxyl groups of the substrates. This noncovalent interaction also contributes to tuning the regioselectivity of alkyne insertion. Furthermore, the metal-free 6π electrocyclization rather than Rh-assisted cyclization gave the final product, isoquinoline N-oxides. The computationally supported mechanistic features were further validated by exploring substrate effects via replacing acetophenone oxime with O-methyl oxime and secondary propargyl alcohol with allyl alcohol, allenol and tertiary propargyl alcohol, respectively.