Elementary Steps of Iron Catalysis: Exploring the Links between Iron Alkyl and Iron Olefin Complexes for their Relevance in CH Activation and CC Bond Formation

The alkylation of complexes 2 and 7 with Grignard reagents containing β‐hydrogen atoms is a process of considerable relevance for the understanding of C–H activation as well as C–C bond formation mediated by low‐valent iron species. Specifically, reaction of 2 with EtMgBr under an ethylene atmosphere affords the bis‐ethylene complex 1 which is an active precatalyst for prototype [2+2+2] cycloaddition reactions and a valuable probe for mechanistic studies. This aspect is illustrated by its conversion into the bis‐alkyne complex 6 as an unprecedented representation of a cycloaddition catalyst loaded with two substrates molecules. On the other hand, alkylation of 2 with 1 equivalent of cyclohexylmagnesium bromide furnished the unique iron alkyl species 11 with a 14‐electron count, which has no less than four β‐H atoms but is nevertheless stable at low temperature against β‐hydride elimination. In contrast, the exhaustive alkylation of 1 with cyclohexylmagnesium bromide triggers two consecutive C–H activation reactions mediated by a single iron center. The resulting complex has a diene dihydride character in solution ( 15 ), whereas its structure in the solid state is more consistent with an η³‐allyl iron hydride rendition featuring an additional agostic interaction ( 14 ). Finally, the preparation of the cyclopentadienyl iron complex 25 illustrates how an iron‐mediated C–H activation cascade can be coaxed to induce a stereoselective C? C bond formation. The structures of all relevant new iron complexes in the solid state are presented.     

Elementary Steps of Iron Catalysis: Exploring the Links between Iron Alkyl and Iron Olefin Complexes for their Relevance in C?H Activation and C?C Bond Formation

The alkylation of complexes 2 and 7 with Grignard reagents containing β‐hydrogen atoms is a process of considerable relevance for the understanding of C–H activation as well as C–C bond formation mediated by low‐valent iron species. Specifically, reaction of 2 with EtMgBr under an ethylene atmosphere affords the bis‐ethylene complex 1 which is an active precatalyst for prototype [2+2+2] cycloaddition reactions and a valuable probe for mechanistic studies. This aspect is illustrated by its conversion into the bis‐alkyne complex 6 as an unprecedented representation of a cycloaddition catalyst loaded with two substrates molecules. On the other hand, alkylation of 2 with 1 equivalent of cyclohexylmagnesium bromide furnished the unique iron alkyl species 11 with a 14‐electron count, which has no less than four β‐H atoms but is nevertheless stable at low temperature against β‐hydride elimination. In contrast, the exhaustive alkylation of 1 with cyclohexylmagnesium bromide triggers two consecutive C–H activation reactions mediated by a single iron center. The resulting complex has a diene dihydride character in solution ( 15 ), whereas its structure in the solid state is more consistent with an η³‐allyl iron hydride rendition featuring an additional agostic interaction ( 14 ). Finally, the preparation of the cyclopentadienyl iron complex 25 illustrates how an iron‐mediated C–H activation cascade can be coaxed to induce a stereoselective C C bond formation. The structures of all relevant new iron complexes in the solid state are presented.     

Accelerated Discovery in Photocatalysis using a Mechanism‐Based Screening Method

Herein, we report a conceptually novel mechanism‐based screening approach to accelerate discovery in photocatalysis. In contrast to most screening methods, which consider reactions as discrete entities, this approach instead focuses on a single constituent mechanistic step of a catalytic reaction. Using luminescence spectroscopy to investigate the key quenching step in photocatalytic reactions, an initial screen of 100 compounds led to the discovery of two promising substrate classes. Moreover, a second, more focused screen provided mechanistic insights useful in developing proof‐of‐concept reactions. Overall, this fast and straightforward approach both facilitated the discovery and aided the development of new light‐promoted reactions and suggests that mechanism‐based screening strategies could become useful tools in the hunt for new reactivity.     

(±)‐2‐Aryl‐2,3‐dihydro‐4(1H)‐quinolinones by a tandem reduction–Michael addition reaction

An efficient synthesis of (±)‐2‐aryl‐2,3‐dihydro‐4(1H)‐quinolinones has been developed from chalcones prepared from 2′‐nitroacetophenone and a series of substituted benzaldehydes. The cyclization sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron powder in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid–phosphoric acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discussion and reaction optimization studies are presented. J. Heterocyclic Chem., (2011).     

Probing CO2 Reduction Pathways for Copper Catalysis Using an Ionic Liquid as a Chemical Trapping Agent

The key to fully leveraging the potential of the electrochemical CO₂ reduction reaction (CO2RR) to achieve a sustainable solar‐power‐based economy is the development of high‐performance electrocatalysts. The development process relies heavily on trial and error methods due to poor mechanistic understanding of the reaction. Demonstrated here is that ionic liquids (ILs) can be employed as a chemical trapping agent to probe CO2RR mechanistic pathways. This method is implemented by introducing a small amount of an IL ([BMIm][NTf₂]) to a copper foam catalyst, on which a wide range of CO2RR products, including formate, CO, alcohols, and hydrocarbons, can be produced. The IL can selectively suppress the formation of ethylene, ethanol and n‐propanol while having little impact on others. Thus, reaction networks leading to various products can be disentangled. The results shed new light on the mechanistic understanding of the CO2RR, and provide guidelines for modulating the CO2RR properties. Chemical trapping using an IL adds to the toolbox to deduce the mechanistic understanding of electrocatalysis and could be applied to other reactions as well.     

Aromatic Hydroxylation at a Non‐Heme Iron Center: Observed Intermediates and Insights into the Nature of the Active Species

Mechanism of substrate oxidations with hydrogen peroxide in the presence of a highly reactive, biomimetic, iron aminopyridine complex, [Fe^II(bpmen)(CH₃CN)₂][ClO₄]₂ ( 1 ; bpmen=N,N'‐dimethyl‐N,N'‐bis(2‐pyridylmethyl)ethane‐1,2‐diamine), is elucidated. Complex 1 has been shown to be an excellent catalyst for epoxidation and functional‐group‐directed aromatic hydroxylation using H₂O₂, although its mechanism of action remains largely unknown. 1 , 2 Efficient intermolecular hydroxylation of unfunctionalized benzene and substituted benzenes with H₂O₂ in the presence of 1 is found in the present work. Detailed mechanistic studies of the formation of iron(III)–phenolate products are reported. We have identified, generated in high yield, and experimentally characterized the key Fe^III(OOH) intermediate (λ_max=560 nm, rhombic EPR signal with g=2.21, 2.14, 1.96) formed by 1 and H₂O₂. Stopped‐flow kinetic studies showed that Fe^III(OOH) does not directly hydroxylate the aromatic rings, but undergoes rate‐limiting self‐decomposition producing transient reactive oxidant. The formation of the reactive species is facilitated by acid‐assisted cleavage of the O? O bond in the iron–hydroperoxide intermediate. Acid‐assisted benzene hydroxylation with 1 and a mechanistic probe, 2‐Methyl‐1‐phenyl‐2‐propyl hydroperoxide (MPPH), correlates with O? O bond heterolysis. Independently generated Fe^IV?O species, which may originate from O? O bond homolysis in Fe^III(OOH), proved to be inactive toward aromatic substrates. The reactive oxidant derived from 1 exchanges its oxygen atom with water and electrophilically attacks the aromatic ring (giving rise to an inverse H/D kinetic isotope effect of 0.8). These results have revealed a detailed experimental mechanistic picture of the oxidation reactions catalyzed by 1 , based on direct characterization of the intermediates and products, and kinetic analysis of the individual reaction steps. Our detailed understanding of the mechanism of this reaction revealed both similarities and differences between synthetic and enzymatic aromatic hydroxylation reactions.     

Mechanism of Redox‐Active Ligand‐Assisted Nitrene‐Group Transfer in a ZrIV Complex: Direct Ligand‐to‐Ligand Charge Transfer Preferred

The mechanism of the nitrene‐group transfer reaction from an organic azide to isonitrile catalyzed by a Zr^IV d⁰ complex carrying a redox‐active ligand was studied by using quantum chemical molecular‐modeling methods. The key step of the reaction involves the two‐electron reduction of the azide moiety to release dinitrogen and provide the nitrene fragment, which is subsequently transferred to the isonitrile substrate. The reducing equivalents are supplied by the redox‐active bis(2‐iso‐propylamido‐4‐methoxyphenyl)‐amide ligand. The main focus of this work is on the mechanism of this redox reaction, in particular, two plausible mechanistic scenarios are considered: 1) the metal center may actively participate in the electron‐transfer process by first recruiting the electrons from the redox‐active ligand and becoming formally reduced in the process, followed by a classical metal‐based reduction of the azide reactant. 2) Alternatively, a non‐classical, direct ligand‐to‐ligand charge‐transfer process can be envisioned, in which no appreciable amount of electron density is accumulated at the metal center during the course of the reaction. Our calculations indicate that the non‐classical ligand‐to‐ligand charge‐transfer mechanism is much more favorable energetically. Utilizing a series of carefully constructed putative intermediates, both mechanistic scenarios were compared and contrasted to rationalize the preference for ligand‐to‐ligand charge‐transfer mechanism.     

Palladium‐Catalyzed anti‐Markovnikov Oxidation of Terminal Alkenes

The palladium‐catalyzed oxidation of alkenes, the Wacker–Tsuji reaction, is undoubtedly a classic in organic synthesis and provides reliable access to methyl ketones from terminal alkenes under mild reaction conditions. Methods that switch the selectivity of the reaction to provide the aldehyde product are desirable because of the access they provide to a valuable functional group, however such methods are elusive. Herein we survey both the methods which have been developed recently in achieving such selectivity and discuss common features and mechanistic insight which offers promise in achieving the goal of a general method for anti‐Markovnikov‐selective olefin oxidations.     

Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy‐amino‐λ6‐sulfanenitrile Intermediate

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH‐sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. A highly chemoselective and one‐pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, which also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy‐amino‐λ⁶‐sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles.     

Electrochemistry Broadens the Scope of Flavin Photocatalysis: Photoelectrocatalytic Oxidation of Unactivated Alcohols

Riboflavin‐derived photocatalysts have been extensively studied in the context of alcohol oxidation. However, to date, the scope of this catalytic methodology has been limited to benzyl alcohols. In this work, mechanistic understanding of flavin‐catalyzed oxidation reactions, in either the absence or presence of thiourea as a cocatalyst, was obtained. The mechanistic insights enabled development of an electrochemically driven photochemical oxidation of primary and secondary aliphatic alcohols using a pair of flavin and dialkylthiourea catalysts. Electrochemistry makes it possible to avoid using O₂ and an oxidant and generating H₂O₂ as a byproduct, both of which oxidatively degrade thiourea under the reaction conditions. This modification unlocks a new mechanistic pathway in which the oxidation of unactivated alcohols is achieved by thiyl radical mediated hydrogen‐atom abstraction.     

Catalytic and Mechanistic Insights of the Low‐Temperature Selective Oxidation of Methane over Cu‐Promoted Fe‐ZSM‐5

The partial oxidation of methane to methanol presents one of the most challenging targets in catalysis. Although this is the focus of much research, until recently, approaches had proceeded at low catalytic rates (<10 h^?1), not resulted in a closed catalytic cycle, or were unable to produce methanol with a reasonable selectivity. Recent research has demonstrated, however, that a system composed of an iron‐ and copper‐containing zeolite is able to catalytically convert methane to methanol with turnover frequencies (TOFs) of over 14 000 h^?1 by using H₂O₂ as terminal oxidant. However, the precise roles of the catalyst and the full mechanistic cycle remain unclear. We hereby report a systematic study of the kinetic parameters and mechanistic features of the process, and present a reaction network consisting of the activation of methane, the formation of an activated hydroperoxy species, and the by‐production of hydroxyl radicals. The catalytic system in question results in a low‐energy methane activation route, and allows selective C₁‐oxidation to proceed under intrinsically mild reaction conditions.     

Mechanism of Phosphine‐Catalyzed Allene Coupling Reactions: Advances in Theoretical Investigations

Organocatalysis has emerged as an effective strategy for chemical synthesis. Within this area, phosphine‐catalyzed coupling reactions have attracted considerable attention because of their versatility and wide range of applications in the construction of new C?C bonds. Recently, various experimental studies on the phosphine‐catalyzed coupling reaction of allenes have been reported, and mechanistic and computational studies have also progressed considerably. As a nucleophile, phosphine can react with an allene to form a zwitterionic phosphoniopropenide intermediate. After stepwise cycloaddition and proton transfer, the phosphine catalyst can be regenerated by C?P bond cleavage. Alternatively, the zwitterionic phosphoniopropenide intermediate could also be protonated by a Brønsted acid to generate a phosphonium intermediate, which can be used to construct new C?C bonds by electrophilic addition. In this review, we have summarized details of mechanistic studies of phosphine‐catalyzed allene coupling reactions that follow these two reaction modes. In addition to detailing the reaction pathway, the regioselectivity and diastereoselectivity of the phosphine‐catalyzed allene coupling reaction are also discussed in this review.     

Synthesis of New 1‐Hydroxyindole‐2‐Carboxylates and Mechanistic Studies on Reaction Pathways

Synthesis of new 1‐hydroxyindole‐2‐carboxylates 1 and mechanistic studies on the reaction pathways were described. The substrates 2 , prepared through two‐step synthetic sequences, were treated with nucleophiles in the presence of SnCl₂ · 2H₂O to obtain compounds 1 . In particular, the mechanistic studies led to a significant finding that reactions with thiol nucleophiles occur through a newly proposed pathway (path B: 1,4‐addition followed by reduction/condensation) rather than through a previously assumed pathway (path A: reduction/condensation followed by 1,5‐addition). Further mechanistic investigations revealed steric effects of o‐substituents in 2 governing the ratio of products ( 1i / 7 ).     

Iron‐Catalyzed C−H Activation with Propargyl Acetates: Mechanistic Insights into Iron(II) by Experiment,Kinetics, Mössbauer Spectroscopy,and Computation

An iron‐catalyzed C?H/N?H alkyne annulation was realized by using a customizable clickable triazole amide under exceedingly mild reaction conditions. A unifying mechanistic approach combining experiment, spectroscopy, kinetics, and computation provided strong support for facile C?H activation by a ligand‐to‐ligand hydrogen transfer (LLHT) mechanism. Combined Mössbauer spectroscopic analysis and DFT calculations were indicative of high‐spin iron(II) species as the key intermediates in the C?H activation manifold.     

The Nickel‐Catalyzed Carbonylative Cycloaddition of Allyl Halides and Acetylenes: An Efficient Tool for Cyclopentane Annelation

From a practical synthetic point of view, the nickel‐mediated carbonylative cycloaddition of alkynes and allyl halides is a straightforward method for obtaining the cyclopentane skeleton in high yields and with controlled stereochemistry, especially when considering the efficiency of the intermolecular version of the reaction. The efforts to make the previously stoichiometric process catalytic in nickel, after experimental mechanistic observations, are reported herein. The unexpected intervention of iron as a reductant and the isolation of a final dimeric species that exhibits interesting tautomeric behavior are also presented. An extension of the reaction to new substrates has led to the conclusion that, although the steric and electronic effects of the alkyne substituents are generally irrelevant in relation to the adducts and their yields, those of the allylic counterpart may have a significant influence on the outcome of the reaction. However, the presence of the amine moiety in the alkyne completely inhibited the reaction. The feasibility of a multicentered reaction was verified with a triacetylene in which up to 12 bonds were created at once and in good yield.     

Nanostructured Ni2P as a Robust Catalyst for the Hydrolytic Dehydrogenation of Ammonia–Borane

Ammonia–borane (AB) is a promising chemical hydrogen‐storage material. However, the development of real‐time, efficient, controllable, and safe methods for hydrogen release under mild conditions is a challenge in the large‐scale use of hydrogen as a long‐term solution for future energy security. A new class of low‐cost catalytic system is presented that uses nanostructured Ni₂P as catalyst, which exhibits excellent catalytic activity and high sustainability toward hydrolysis of ammonia–borane with the initial turnover frequency of 40.4 mol_(H2) mol_(Ni2P)^?1 min^?1 under air atmosphere and at ambient temperature. This value is higher than those reported for noble‐metal‐free catalysts, and the obtained Arrhenius activation energy (E_a=44.6 kJ mol^?1) for the hydrolysis reaction is comparable to Ru‐based bimetallic catalysts. A clearly mechanistic analysis of the hydrolytic reaction of AB based on experimental results and a density functional theory calculation is presented.     

Condensation of β‐Diester Titanium Enolates with Carbonyl Substrates: A Combined DFT and Experimental Investigation

The condensation of dialkyl β‐diesters with various aldehydes promoted by TiCl₄ has been studied by DFT approaches and experimental methods, including NMR, IR and UV/Vis spectroscopy. Various possible reaction pathways have been investigated and their energy profiles evaluated to find out a plausible mechanism of the reaction. Theoretical results and experimental evidence point to a three‐step mechanism: 1) Ti‐induced formation of the enolate ion; 2) aldol reaction between the enolate ion and the aldehyde, both coordinated to titanium; and 3) intramolecular elimination that leads to a titanyl complex. The presented mechanistic hypothesis allows one to better understand the pivotal role of titanium(IV) in the reaction.     

Catalyst‐Controlled 1,2‐ and 1,1‐Arylboration of α‐Alkyl Alkenyl Arenes

Two methods are reported for the 1,2‐ and 1,1‐arylboration of α‐methyl vinyl arenes. In the case of 1,2‐arylboration, the formation of a quaternary center occurred through a rare cross‐coupling reaction of a tertiary organometallic complex. 1,1‐Arylboration was enabled by catalyst optimization and occurred through a β‐hydride elimination/reinsertion cascade. Enantioselective variants of both processes are presented as well as mechanistic investigations.     

Revisiting the Molecular Roots of a Ubiquitously Successful Synthesis: Nickel(0) Nanoparticles by Reduction of [Ni(acetylacetonate)2]

The widely used preparation of Ni⁰ nanoparticles from [Ni(acac)₂] (acac=acetylacetonate) and oleylamine, often considered to be a thermolysis or a radical reaction, was analyzed anew by using a combination of DFT modeling and designed mechanistic experiments. Firstly, the reaction was followed up by using TGA to evaluate the energy barrier of the limiting step. Secondly, all the byproducts were identified using NMR spectroscopy, mass spectrometry, FTIR, and X‐ray crystallography. These methods allowed us to depict both main and side‐reaction pathways. Lastly, DFT modeling was utilized to assess the validity of this new scheme by identifying the limiting steps and evaluating the corresponding energy barriers. The oleylamine was shown to reduce the [Ni(acac)₂] complex not through a one‐electron radical mechanism, as often stated, but as an hydride donor through a two‐electron chemical reduction route. This finding has strong consequences not only for the design of further nanoparticles syntheses that use long‐chain amine as a reactant, but also for advanced understanding of catalytic reactions for which these nanoparticles can be employed.     

The Development of Copper‐Catalyzed Aerobic Oxidative Coupling of H‐Tetrazoles with Boronic Acids and an Insight into the Reaction Mechanism

The development of a highly efficient and practical protocol for the direct C?N coupling of H‐tetrazole and boronic acid was presented. A careful and patient optimization of a variety of reaction parameters revealed that this conventionally challenge reaction could indeed proceed efficiently in a very simple system, that is, just by stirring the tetrazoles and boronic acids under oxygen in the presence of different Cu^I or Cu^II salts with only 5 mol % loading in DMSO at 100 °C. Most significantly, the reaction could proceed very smoothly in a regiospecific manner to afford the 2,5‐disubstituted tetrazoles in high to excellent yields. A mechanistic study revealed that both tetrazole and DMSO are crucial for the generation of catalytically active copper species in the reaction process in addition to their role as reactant and solvent, respectively. It is demonstrated that in the reaction cycle, the Cu^I catalyst could be oxidized to Cu^II by oxygen to form a [CuT₂D] complex (T=tetrazole anion; D=DMSO) through an oxidative copper amination reaction. The Cu^II complex thus formed was confirmed to be the real catalytically active copper species. Namely, the Cu^II complex disproportionates to aryl Cu^III and Cu^I in the presence of boronic acid. Facile elimination of the Cu^III species delivers the C?N‐coupled product. The results presented herein not only provide a reliable and efficient protocol for the synthesis of 2,5‐disubstituted tetrazoles, but most importantly, the mechanistic results would have broad implications for the de novo design and development of new methods for Cu‐catalyzed coupling reactions.