Computational Mechanistic Study Research Articles

ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism.

The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies imply that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.

Computational mechanistic study of human liver glycerol 3‐phosphate dehydrogenase using ONIOM method

AbstractHuman liver glycerol 3‐phosphate dehydrogenase catalyzes transfer of a hydride anion from NADH to dihydroxyacetone phosphate (DHAP) forming L‐glycerol 3‐phosphate and NAD+ in a single step reaction. It is proposed that a hydride ion is transferred from NADH to the carbonyl carbon of DHAP through a general acid catalysis in which the carbonyl oxygen of DHAP is protonated by a nearby acidic residue. Based on the crystal structure of enzyme, it was suggested that one of the active site lysine residues (Lys120/Lys204) might act as general acid for the protonation of the carbonyl oxygen at DHAP. In this study, we formulated a number of computational systems to study the hydride transfer mechanism including main active site amino acid side chains, NADH cofactor, and DHAP. The calculations involved ONIOM method consisting of DFT and molecular mechanics (MM). We evaluated the energetics of the hydride transfer process in different model systems while probing the roles of active site residues, Lys120/Lys204/Asp260. Based on calculations, protonated Asp260 has more favorable energetics to act as the general acid catalysis as compared to Lys120/204 residues.

Construction of New Azo‐group Containing Polycyclic Imidazole Derivatives: Computational Mechanistic, Structural, and Fluorescence Studies

AbstractThree polycyclic aromatic imidazole derivatives 2‐phenyl‐1‐(4‐(phenyldiazenyl)phenyl)‐1H‐phenanthro[9,10‐d]imidazole (PRO), 2‐(4‐methoxyphenyl)‐1‐(4‐(phenyldiazenyl)phenyl)‐1H‐phenanthro[9,10‐d]imidazole (PRO1), 2‐(2,4‐dichlorophenyl)‐1‐(4‐(phenyldiazenyl)phenyl)‐1H‐phenanthro[9,10‐d]imidazole (PRO2) are synthesized with one‐pot four component fusion reaction using 1,4‐dimethylpyperazinium dihydrosulfate ([Me2pi][HSO4]2) ionic liquid (IL) catalyst (3 mol%). Mechanistic studies are performed with DFT M06 L functional. The utilized IL catalyst holds two moles of HSO4− per one mole of 1,4‐dimethylpyperazinium (cation part), which increases its catalytic performance in a trans form (Figure 1). The IL catalytic effects are determined and described in the optimized transition state structures (Figure 2). Important transition states for the rate‐limiting step (▵G≠=26.56 kcal/mol), the five‐membered imidazole ring formation (▵G≠=6.9 kcal/mol), and the C(sp3)‐H (▵G≠=2.06 kcal/mol) activation are optimized. The PRO fluorescence properties are studied computationally (HOMO and LUMO energy gap=2.41 eV) and experimentally.

Diastereo- and Enantioselective Catalytic Radical Oxysulfonylation of Alkenes in β,γ-Unsaturated Ketoximes

Summary The asymmetric radical-initiated difunctionalization of internal alkenes, which creates two vicinal stereocenters, has been a significant synthetic challenge despite the tremendous progress achieved for terminal alkenes. This is attributable to the common stepwise mechanism that involves an initial free radical addition to the alkene in a nonstereoselective fashion. We report here the first asymmetric radical 1,2-oxysulfonylation of both terminal and internal aryl alkenes in β,γ-unsaturated ketoximes in the presence of copper(I)-cinchona alkaloid-based sulfonamide catalyst. The experimental and computational mechanistic studies collectively support a CuII-CuI mechanism featuring fast, reversible addition of sulfonyl radicals to alkenes and subsequent rate- and stereo-determining C–O bond formation, namely, a scenario under Curtin-Hammett kinetic control. The method provides a robust platform for collective synthesis of a diverse array of valuable chiral sulfonyl-containing building blocks.

Why thermal isomerization of the chromic switch spiropyran-merocyanine is enhance in polar protic solvents. A computational study of the reaction mechanism

Spiropyran (SP) is a chromic material that undergoes isomerization to merocyanine (MC) under irradiation. To extend its applicability as a molecular switch, it would be convenient to be able to induce and control its isomerization also in the dark, what seems to be possible in acidic media. We present here a computational study of the mechanism of isomerization of protonated SP. We have found that protonation induces the stabilization of MC, protonated at O, relative to SP, protonated at N. Given the different site of protonation for both species, the ring-opening reaction must take place together with a proton transfer event. We have shown that the barrier of this process decreases if a protic solvent molecule take part in the reaction. In this way, the rate determining step of the process is the isomerization between different rotamers of protonated MC. The detailed knowledge of the reaction mechanism can help in the design of structural or electronic modifications of SP to improve its switchability.

Synthesis and computational mechanistic studies of copper selective molecular receptor

AbstractAlthough numerous molecular receptors for Cu2+ have been reported, it is not obvious to find a simple molecule as a selective receptor for Cu2+. Here we create a molecular receptor 4MHEB for Cu2+ metal ions. Observation of a new absorption band near 282 nm in UV‐visible spectra and enhancement in fluorescence intensity in emission spectra justify the binding 4MHEB:Cu2+ binding. Inspection in shifting of IR bands, different thermal behavior and oxidation and reduction peaks of complex shows binding of 4MHEB:Cu2+. HRMS m/z 322.0328, Benesi‐Hildebrand method and Job's Plot results 1:1 (4MHEB:Cu2+) binding stoichiometry with the binding affinity K = 1.751×105 M‐1. The docked pose of 4MHEB with Cu2+ ion, Key transitions, % Contribution was calculated by computational studies.

Connecting remote C-H bond functionalization and decarboxylative coupling using simple amines.

Transition metal-catalyzed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the last 30 years. Herein, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway involving an uncommon Pd-catalyzed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements “C–H activation” strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop general para-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of reaction conditions.

Experimental and Computational Insights into the Water‐Mediated Decomposition of N‐Sulfonylhydrazones: A Catalyst‐Free Synthesis of γ‐Keto/Nitrile Sulfones

AbstractThis work is an example of water‐mediated decomposition of N‐sulfonylhydrazones used as sulfonyl‐transferring reagents in the selective sulfa‐Michael reaction in the absence of any base or catalyst. A wide range of substituted N‐sulfonylhydrazones were tested as sources of sulfonyl anions with enones or acrylonitrile, which in turn provided the γ‐ keto/nitrile sulfones in very good yields. Additionally, we have performed a rigorous computational mechanistic study to investigate the role of water which demonstrates the key role of water in the hydrogen abstraction from N‐tosylhydrazone to initiate the reaction.

Dearomative Photocatalytic Construction of Bridged 1,3‐Diazepanes

AbstractThe construction of diverse sp3‐rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7‐diazabicyclo[3.2.1]octanes (bridged 1,3‐diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4‐substituted quinoline substrates, with subsequent Hantzsch ester‐promoted reduction to a dihydropyridine intermediate which undergoes in situ two‐electron ring closure to form the bridged diazepane architecture. A wide scope of N‐arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all‐carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.

Dearomative Photocatalytic Construction of Bridged 1,3-Diazepanes.

The construction of diverse sp3 -rich skeletal ring systems is of importance to drug discovery programmes and natural product synthesis. Herein, we report the photocatalytic construction of 2,7-diazabicyclo[3.2.1]octanes (bridged 1,3-diazepanes) via a reductive diversion of the Minisci reaction. The fused tricyclic product is proposed to form via radical addition to the C4 position of 4-substituted quinoline substrates, with subsequent Hantzsch ester-promoted reduction to a dihydropyridine intermediate which undergoes in situ two-electron ring closure to form the bridged diazepane architecture. A wide scope of N-arylimine and quinoline derivatives was demonstrated and good efficiency was observed in the construction of sterically congested all-carbon quaternary centers. Computational and experimental mechanistic studies provided insights into the reaction mechanism and observed regioselectivity/diastereoselectivity.

Computational mechanistic study on Pd-catalyzed stereoselective synthesis of Z-1,3- and E-1,4-enynes from ligand-controlled regiodivergent hydroalkynylations of allenamides

Density functional theory (DFT) calculations show that regardless of using BrettPhos or (o-OMePh)3P ligand, the Pd-catalyzed synthesis of both 1,3- and 1,4-enynes from hydroalkynylations of allenamides proceeds through the hydropalladation mechanism, rather than the carbopalladation mechanism, as proposed for the formation of 1,4-enyne in the experimental study. BrettPhos ligand favors the formation of 1,4-enyne through anti-Markovnikov addition of PdH bond to the CC double bond, while (o-OMePh)3P ligand leads to the 1,3-enyne through the Markovnikov addition. The palladium catalysis also promotes the isomerization of E-1,3-enyne to its Z-isomer, rationalizing the observed stereoselectivity.

Ullmann-type C-Se Cross-Coupling in the Hydantoin Family: Synthesis, Mechanistic Studies, and Tests of Biological Activity.

An attractive strategy for C-Se bond formation by Ullmann-type copper(I)-promoted cross-coupling is developed. A wide range of aryliodides reacts with various disubstituted 2-selenohydantoins under mild conditions and provides Se-arylated imidazolines in moderate to high yields. Computational mechanistic studies show the oxidative addition/intramolecular reductive elimination likely to be the lowest-energy pathway. Cytotoxic activity of all 43 reaction products has been tested in vitro against MCF7 and A549 cancer cell lines with VA13 and MCF10a control cells.

Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a Meta-Selective Inverse Sonogashira Coupling.

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the β-bromide elimination step.

Rhodium(III)‐Catalyzed Enantio‐ and Diastereoselective C−H Cyclopropylation of N‐Phenoxylsulfonamides: Combined Experimental and Computational Studies

AbstractCyclopropane rings are a prominent structural motif in biologically active molecules. Enantio‐ and diastereoselective construction of cyclopropanes through C−H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing‐group‐assisted C−H activation strategy was used to realize mild and redox‐neutral RhIII‐catalyzed C−H activation and cyclopropylation of N‐phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a RhV nitrenoid intermediate, and Noyori‐type outer sphere concerted proton‐hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.

Rhodium(III)-Catalyzed Enantio- and Diastereoselective C-H Cyclopropylation of N-Phenoxylsulfonamides: Combined Experimental and Computational Studies.

Cyclopropane rings are a prominent structural motif in biologically active molecules. Enantio- and diastereoselective construction of cyclopropanes through C-H activation of arenes and coupling with readily available cyclopropenes is highly appealing but remains a challenge. A dual directing-group-assisted C-H activation strategy was used to realize mild and redox-neutral RhIII -catalyzed C-H activation and cyclopropylation of N-phenoxylsulfonamides in a highly enantioselective, diastereoselective, and regioselective fashion with cyclopropenyl secondary alcohols as a cyclopropylating reagent. Synthetic applications are demonstrated to highlight the potential of the developed method. Integrated experimental and computational mechanistic studies revealed that the reaction proceeds via a RhV nitrenoid intermediate, and Noyori-type outer sphere concerted proton-hydride transfer from the secondary alcohol to the Rh=N bond produces the observed trans selectivity.

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.