Computational Mechanistic Study Research Articles

Molecular Modeling of Mechanisms of Decomposition of Ruthenium Metathesis Catalysts by Acrylonitrile

We report a computational mechanistic study explaining the low stability of Hoveyda–Grubbs catalyst in the presence of acrylonitrile. We show the atomistic and energetic basis of why recently synth...

Inorganic reaction mechanisms. A personal journey.

This review covers highlights of the work performed in the van Eldik group on inorganic reaction mechanisms over the past two decades in the form of a personal journey. Topics that are covered include, from NO to HNO chemistry, peroxide activation in model porphyrin and enzymatic systems, the wonder-world of RuIII(edta) chemistry, redox chemistry of Ru(iii) complexes, Ru(ii) polypyridyl complexes and their application, relevant physicochemical properties and reaction mechanisms in ionic liquids, and mechanistic insight from computational chemistry. In each of these sections, typical examples of mechanistic studies are presented in reference to related work reported in the literature.

Computational Screening of Metal–Organic Framework-Supported Single-Atom Transition-Metal Catalysts for the Gas-Phase Hydrolysis of Nerve Agents

Recent studies have suggested that the gas-phase hydrolysis of nerve agents by Zr-based metal–organic frameworks (MOFs) may be limited by product inhibition resulting from strong bidentate binding of the hydrolysis products to the Zr6-nodes. A potential method to avoid this problem is to deposit single-atom catalysts on the nodes so that the products bind in a more favorable monodentate mode. Such catalytic active sites can be characterized with atomic precision, enabling detailed computational mechanistic studies. Thus, we used density functional theory to perform a comprehensive screening of single-atom transition-metal catalysts, in varying oxidation states, deposited on NU-1000 nodes for the gas-phase hydrolysis of the nerve agent sarin. By calculating the complete reaction pathways for M–NU-1000 systems, we discovered that the highest reaction barrier varies between catalysts, highlighting the need to consider more than a single reaction step when screening a large number of diverse materials. The si...

Gold‐Catalyzed Cross‐Coupling Reactions: An Overview of Design Strategies, Mechanistic Studies, and Applications

Transition-metal-catalyzed cross-coupling reactions are central to many organic synthesis methodologies. Traditionally, Pd, Ni, Cu, and Fe catalysts are used to promote these reactions. Recently, many studies have showed that both homogeneous and heterogeneous Au catalysts can be used for activating selective cross-coupling reactions. Here, an overview of the past studies, current trends, and future directions in the field of gold-catalyzed coupling reactions is presented. Design strategies to accomplish selective homocoupling and cross-coupling reactions under both homogeneous and heterogeneous conditions, computational and experimental mechanistic studies, and their applications in diverse fields are critically reviewed. Specific topics covered are: oxidant-assisted and oxidant-free reactions; strain-assisted reactions; dual Au and photoredox catalysis; bimetallic synergistic reactions; mechanisms of reductive elimination processes; enzyme-mimicking Au chemistry; cluster and surface reactions; and plasmonic catalysis. In the relevant sections, theoretical and computational studies of AuI /AuIII chemistry are discussed and the predictions from the calculations are compared with the experimental observations to derive useful design strategies.

Mechanistic Insight toward Understanding the Role of Charge in Thiourea Organocatalysis.

Pyranylation and glycosylation are pivotal for accessing a myriad of natural products, pharmaceuticals, and drug candidates. Catalytic approaches for enabling these transformations are of utmost importance and integral to advancing this area of synthesis. In exploring this chemical space, a combined experimental and computational mechanistic study of pyranylation and 2-deoxygalactosylation catalyzed by a cationic thiourea organocatalyst is reported. To this end, a thiourea-cyclopropenium organocatalyst was employed as a model system in combination with an arsenal of mechanistic techniques, including 13C kinetic isotope effect experiments, deuterated labeling studies, variable-temperature 1H NMR spectroscopy, and density functional theory calculations. From these studies, two distinct reaction pathways were identified for this transformation corresponding to either dual hydrogen bond (H-bond) activation or Brønsted acid catalysis. The former involving thiourea orchestrated bifurcated hydrogen bonding proceeded in an asynchronous concerted fashion. In contrast, the latter stepwise mechanism involving Brønsted acid catalysis hinged upon the formation of an oxocarbenium intermediate accompanied by subsequent alcohol addition.

Synthesis of α-cyano hydroxylamines via three-component reactions and its computational mechanistic study

In the present report, various α-cyano hydroxylamines were synthesized via a 3-component reaction between aromatic aldehydes, phenylhydroxylamine and trimethylsilyl cyanide at room temperature. In this line, several solvents and catalysts were employed to obtain the best conditions for the reaction. Among the employed solvents and catalysts, methanol (as solvent) and NiCl2 (as catalyst) showed the highest performances. Moreover, the mechanistic details for the both steps of this reaction in the gas phase and explicit solvent (methanol) model have been studied using DFT calculations and the energy profiles for all steps were obtained. The results of these computations are in agreement with the experimental results, which showed the methanol is the best solvent and NiCl2 is the most appropriate catalyst for this reaction.

Ruthenium-Catalyzed Reductive Cleavage of Unstrained Aryl-Aryl Bonds: Reaction Development and Mechanistic Study.

Cleavage of carbon-carbon bonds has been found in some important industrial processes, for example, petroleum cracking, and has inspired development of numerous synthetic methods. However, nonpolar unstrained C(aryl)-C(aryl) bonds remain one of the toughest bonds to be activated. As a detailed study of a fundamental reaction mode, here a full story is described about our development of a Ru-catalyzed reductive cleavage of unstrained C(aryl)-C(aryl) bonds. A wide range of biaryl compounds that contain directing groups (DGs) at 2,2' positions can serve as effective substrates. Various heterocycles, such as pyridine, quinoline, pyrimidine, and pyrazole, can be employed as DGs. Besides hydrogen gas, other reagents, such as Hantzsch ester, silanes, and alcohols, can be employed as terminal reductants. The reaction is pH neutral and free of oxidants; thus a number of functional groups are tolerated. Notably, a one-pot C-C activation/C-C coupling has been realized. Computational and experimental mechanistic studies indicate that the reaction involves a ruthenium(II) monohydride-mediated C(aryl)-C(aryl) activation and the resting state of the catalyst is a η4-coordinated ruthenium(II) dichloride complex, which could inspire development of other transformations based on this reaction mode.

Copper‐Mediated Decarboxylative C–H Arylation of Phenol Derivatives with ortho‐Nitrobenzoic Acids Using Phenanthroline‐Based Bidentate Auxiliary

AbstractA copper‐mediated decarboxylative C–H arylation of phenol derivatives with ortho‐nitrobenzoic acid salts via phenanthroline‐directed C–H cleavage has been developed. The N,N‐bidentate phenanthroline auxiliary uniquely promotes the reaction only in the presence of a copper salt to produce the corresponding biaryls in acceptable yields. Moreover, the directing group can be easily introduced and removed. Additionally, preliminary computational mechanistic studies with DFT have also been performed.

Computational Mechanistic Study of Electro-Oxidation of Ammonia to N2 by Homogenous Ruthenium and Iron Complexes.

A comprehensive DFT study of the electrocatalytic oxidation of ammonia to dinitrogen by a ruthenium polypyridyl complex, [(tpy)(bpy)RuII(NH3)]2+ (a), and its NMe2-substituted derivative (b) is presented. The thermodynamics and kinetics of electron (ET) and proton transfer (PT) steps and transition states are calculated. NMe2 substitution on bpy reduces the ET steps on average 8 kcal/mol for complex b as compared to a. The calculations indicate that N-N formation occurs by ammonia nucleophilic attack/H-transfer via a nitrene intermediate rather than a nitride intermediate. Comparison of the free energy profiles of Ru-b with its first-row Fe congener reveals that the thermodynamics are less favorable for the Fe-b model, especially for ET steps. The N-H bond dissociation free energies (BDFEs) for NH3 to form N2 show the following trend: Ru-b < Ru-a < Fe-b, indicating the lowest and most favorable BDFEs for Ru-b complex.

A Computational Mechanistic Study of Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation: Roles of APAO Ligands.

A computational mechanistic study has been performed on Pd(II)-catalyzed enantioselective reactions involving acetyl-protected aminomethyl oxazolines (APAO) ligands that significantly improved reactivity and selectivity in C(sp3)-H borylation. The results support a mechanism including initiation of C(sp3)-H bond activation generating a five-membered palladacycle and ligand exchange, followed by HPO42--promoted transmetalation. These resulting Pd(II) complexes further undergo sequential reductive elimination by coordination of APAO ligands and protonation to afford the enantiomeric products and deliver Pd(0) complexes, which will then proceed by oxidation and deprotonation to regenerate the catalyst. The C(sp3)-H activation is found to be the rate- and enantioselectivity-determining step, in which the APAO ligand acts as the proton acceptor to form the two enantioselectivity models. The results demonstrate that the diverse APAO ligands control the enantioselectivity by differentiating the distortion and interaction between the major and minor pathways.

Mechanistic Complexity of Asymmetric Transfer Hydrogenation with Simple Mn-Diamine Catalysts.

The catalytic asymmetric transfer hydrogenation (ATH) of ketones is a powerful methodology for the practical and efficient installation of chiral centers. Herein, we describe the synthesis, characterization, and catalytic application of a series of manganese complexes bearing simple chiral diamine ligands. We performed an extensive experimental and computational mechanistic study and present the first detailed experimental kinetic study of Mn-catalyzed ATH. We demonstrate that conventional mechanistic approaches toward catalyst optimization fail and how apparently different precatalysts lead to identical intermediates and thus catalytic performance. Ultimately, the Mn–N,N complexes under study enable quantitative ATH of acetophenones to the corresponding chiral alcohols with 75–87% ee.

Nickel(IV)-Catalyzed C-H Trifluoromethylation of (Hetero)arenes.

This Article describes the development of a stable NiIV complex that mediates C(sp2)-H trifluoromethylation reactions. This reactivity is first demonstrated stoichiometrically and then successfully translated to a NiIV-catalyzed C-H trifluoromethylation of electron-rich arene and heteroarene substrates. Both experimental and computational mechanistic studies support a radical chain pathway involving NiIV, NiIII, and NiII intermediates.

Oligothiophene Synthesis by a General C–H Activation Mechanism: Electrophilic Concerted Metalation–Deprotonation (eCMD)

Oxidative C-H/C-H coupling is a promising synthetic route for the streamlined construction of conjugated organic materials for optoelectronic applications. Broader adoption of these methods is nevertheless hindered by the need for catalysts that excel in forging core semiconductor motifs, such as ubiquitous oligothiophenes, with high efficiency in the absence of metal reagents. We report a (thioether)Pd-catalyzed oxidative coupling method for the rapid assembly of both privileged oligothiophenes and challenging hindered cases, even at low catalyst loading under Ag- and Cu-free conditions. A combined experimental and computational mechanistic study was undertaken to understand how a simple thioether ligand, MeS(CH2)3SO3Na, leads to such potent reactivity toward electron-rich substrates. The consensus from these data is that a concerted, base-assisted C-H cleavage transition state is operative, but thioether coordination to Pd is associated with decreased synchronicity (bond formation exceeding bond breaking) versus the "standard" concerted metalation-deprotonation (CMD) model that was formalized by Fagnou in direct arylation reaction. Enhanced positive charge build-up on the substrate results from this perturbation, which rationalizes experimental trends strongly favoring π-basic sites. The term electrophilic CMD (eCMD) is introduced to distinguish this mechanism from the standard model, even though both mechanisms locate in a broad concerted continuum. More O'Ferrall-Jencks analysis further suggests eCMD should be a general mechanism manifested by many metal complexes. A preliminary classification of complexes into those favoring eCMD or standard CMD is proposed, which should be informative for studies toward tunable catalyst-controlled reactivity.

Dissociation of the ethyl formate radical cation: A computational mechanistic study

We report a theoretical study of unimolecular dissociation of the ethyl formate radical cation (C2H5OCHO+). The potential energy surface (PES) of its 14 dissociation reactions, including the formation of CH2CHC(OH)2+, CH2CH2CO+, CH3CHCO+, CH2OCHO+, HOCHOH+, HOCO+, CH3CHOH+, HCO2+, CH2OH+, C2H6+, C2H5+, HCO+, and C2H4+, was determined using G4 calculation. A kinetic analysis using RRKM calculations based on the PES obtained adequately explained the results of previous experiments, suggesting that the dissociation occurred statistically from the electronic ground state.

Unraveling Mechanistic Reaction Pathways of the Electrochemical CO2 Reduction on Fe–N–C Single-Site Catalysts

We report a joint experimental–computational mechanistic study of electrochemical reduction of CO2 to CH4, catalyzed by solid-state Fe–N–C catalysts, which feature atomically dispersed, catalytical...

Branched-Selective Direct α-Alkylation of Cyclic Ketones with Simple Alkenes.

Herein, we describe an intermolecular direct branched-selective α-alkylation of cyclic ketones with simple alkenes as the alkylation agents. Through an enamine-transition metal cooperative catalysis mode, the α-alkylation is realized in an atom- and step-economic manner with excellent branched selectivity for preparing β-branched ketones. Employment of a pair of bulky Brønsted acid and base as additives is responsible for enhanced efficiency. Promising enantioselectivity (74 % ee) has been obtained. Experimental and computational mechanistic studies suggest that a pathway through alkene migratory insertion into the Ir-C bond followed by C-H reductive elimination is involved for the high branched selectivity.

Branched‐Selective Direct α‐Alkylation of Cyclic Ketones with Simple Alkenes

AbstractHerein, we describe an intermolecular direct branched‐selective α‐alkylation of cyclic ketones with simple alkenes as the alkylation agents. Through an enamine‐transition metal cooperative catalysis mode, the α‐alkylation is realized in an atom‐ and step‐economic manner with excellent branched selectivity for preparing β‐branched ketones. Employment of a pair of bulky Brønsted acid and base as additives is responsible for enhanced efficiency. Promising enantioselectivity (74 % ee) has been obtained. Experimental and computational mechanistic studies suggest that a pathway through alkene migratory insertion into the Ir−C bond followed by C−H reductive elimination is involved for the high branched selectivity.

Computational Mechanistic Study of [MoFe3S4] Cubanes for Catalytic Reduction of Nitrogenase Substrates.

Molybdenum-dependent nitrogenase is the most active biological catalyst for dinitrogen reduction. This reaction is catalyzed by a [MoFe7S9C] cofactor (FeMoco). FeMoco can be described as a double-cubane, with [MoFe3S3] and [Fe4S3] parts, bound via an interstitial carbide and three bridging sulfides. Model compounds have been synthesized since early studies of the enzyme and Coucouvanis and co-workers demonstrated that [MoFe3S4] cubanes are active catalysts for many substrates catalyzed by nitrogenase. These reactions include hydrazine reduction to ammonia and cis-dimethyldiazene reduction to methylamine. Experiments implicated molybdenum as the binding site but the mechanisms have not been studied by theoretical calculations before. Here we present a DFT study of the catalytic reaction mechanisms of hydrazine and cis-dimethyldiazene reduction with a [MoFe3S4] cubane. Like in the experiments, molybdenum is revealed as the likely substrate binding site, likely due to the labile ligand on Mo.For the hydrazine mechanism, a reduction event is centered on Fe, specifically on the Fe antiferromagnetically coupled to the mixed-valence pair. After protonation of the distal hydrazine nitrogen, the N-N bond can be cleaved to yield NH3 and a Mo-bound -NH2 intermediate. This is followed by another protonation/reduction step to give an -NH3 intermediate, and finally substituted by thesubstrate to complete the cycle. The computed mechanisms shed light on the bimetallic cooperativity in these systems where the reduction steps are localized on Fe while the substrate binds to Mo and the reductions require only a free coordination site (onMo) and a favorable reduction event (to Fe). Although both substrates easily displace the weakly bound acetonitrile ligand, one reduction event is required for hydrazine activation and N-N bond cleavage to give an integer-spin -NH2 intermediate. An integer-spin -NH2 intermediate has been observed as a common intermediate for the enzyme reduction of hydrazine and diazene, suggesting a possible link to the enzyme chemistry.

Manganese-Catalyzed Multicomponent Synthesis of Pyrroles through Acceptorless Dehydrogenation Hydrogen Autotransfer Catalysis: Experiment and Computation.

A new base metal catalyzed sustainable multicomponent synthesis of pyrroles from readily available substrates is reported. The developed protocol utilizes an air- and moisture-stable catalyst system and enables the replacement of themutagenic α-haloketones with readily abundant 1,2-diols. Moreover, the presented method is catalytic in base and the sole byproducts of this transformation are water and hydrogen gas. Experimental and computational mechanistic studies indicate that the reaction takes place through a combined acceptorless dehydrogenation hydrogen autotransfer methodology.

Experimental and Computational Mechanistic Studies of the β-Diketiminatoiron(II)-Catalysed Hydroamination of Primary Aminoalkenes.

A comprehensive mechanistic study by means of complementary experimental and computational approaches of the exo-cyclohydroamination of primary aminoalkenes mediated by the recently reported β-diketiminatoiron(II) complex B is presented. Kinetic analysis of the cyclisation of 2,2-diphenylpent-4-en-1-amine (1 a) catalysed by B revealed a first-order dependence of the rate on both aminoalkene and catalyst concentrations and a primary kinetic isotope effect (KIE) (kH /kD ) of 2.7 (90 °C). Eyring analysis afforded ΔH≠ =22.2 kcal mol-1 , ΔS≠ =-13.4 cal mol-1 K-1 . Plausible mechanistic pathways for competitive avenues of direct intramolecular hydroamination and oxidative amination have been scrutinised computationally. A kinetically challenging proton-assisted concerted N-C/C-H bond-forming non-insertive pathway is seen not to be accessible in the presence of a distinctly faster σ-insertive pathway. This operative pathway involves 1) rapid and reversible syn-migratory 1,2-insertion of the alkene into the Fe-Namido σ bond at the monomer {N^N}FeII amido compound; 2) turnover-limiting Fe-C σ bond aminolysis at the thus generated transient {N^N}FeII alkyl intermediate and 3) regeneration of the catalytically competent {N^N}FeII amido complex, which favours its dimer, likely representing the catalyst resting state, through rapid cycloamine displacement by substrate. The collectively derived mechanistic picture is consonant with all empirical data obtained from stoichiometric, catalytic and kinetics experiments.