Revealing the Mechanistic Features of an Electrosynthetic Catalytic Reaction and the Role of Redox Mediators through DFT Calculations and Microkinetic Modeling.

Organic electrosynthesis is an emerging field that provides original selectivity while adding features of atom economy, sustainability, and selectivity. Electrosynthesis is often enhanced by redox mediators or electroauxiliaries. The mechanistic understanding of organic electrosynthesis is however often limited by the low lifetime of intermediates and its difficult detection. In this work, we report a computational analysis of the mechanism of an appealing reaction previously reported by Mei and co-workers which is catalyzed by copper and employs iodide as redox mediator. Our scheme combines DFT calculations with microkinetic modeling and covers both the reaction in solution and the electrodic steps. A detailed mechanistic scheme is obtained which reproduces well experimental data and opens perspectives for the general treatment of these processes.

Experimental and Computational Studies on the Interaction of DNA with Hesperetin Schiff Base CuII Complexes.

The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or L1H3), isoniazid (HIN or L2H3), or thiosemicarbazide (HTSC or L3H3) and their CuII complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLnH2(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV-Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants (Kb) of the Cu compounds with CT-DNA, in the range (2.3-9.2) × 106, from CuHTSC to CuHHSB, were higher than other copper-based potential drugs, suggesting that π-π stacking interaction due to the presence of the aromatic rings favors the binding. Thiazole orange (TO) assays confirmed that ligands and Cu complexes displace TO from the DNA binding site, quenching the fluorescence emission. DFT calculations allow for an assessment of the equilibrium between [Cu(LnH2)(AcO)] and [Cu(LnH2)(H2O)]+, the tautomer that binds CuII, amido (am) and not imido (im), and the coordination mode of HTSC (O-, N, S), instead of (O-, N, NH2). The docking studies indicate that the intercalative is preferred over the minor groove binding to CT-DNA with the order [Cu(L1H2am)(AcO)] > [Cu(L2H2am)(AcO)] ≈ TO ≈ L1H3 > [Cu(L3H2am)(AcO)], in line with the experimental Kb constants, obtained from the UV-Vis spectroscopy. Moreover, dockings predict that the binding strength of [Cu(L1H2am)(AcO)] is larger than [Cu(L1H2am)(H2O)]+. Overall, the results suggest that when different enantiomers, tautomers, and donor sets are possible for a metal complex, a computational approach should be recommended to predict the type and strength of binding to DNA and, in general, to macromolecules.

Generating Fischer-Type Rh-Carbenes with Rh-Carbynoids.

We describe the first catalytic generation of Fischer-type acyloxy Rh(II)-carbenes from carboxylic acids and Rh(II)-carbynoids. This novel class of transient donor/acceptor Rh(II)-carbenes evolved through a cyclopropanation process providing access to densely functionalized cyclopropyl-fused lactones with excellent diastereoselectivity. DFT calculations allowed the analysis of the properties of Rh(II)-carbynoids and acyloxy Rh(II)-carbenes as well as the characterization of the mechanism.

Comprehensive Mechanistic Scenario for the Cu-Mediated Asymmetric Propargylic Sulfonylation Forging Tertiary Carbon Stereocenters.

Metal-catalyzed propargylic transformations represent a powerful tool in organic synthesis to achieve new carbon-carbon and carbon-heteroatom bonds. However, detailed knowledge about the mechanistic intricacies related to the asymmetric formation of propargylic products featuring challenging heteroatom-substituted tertiary stereocenters is scarce and therefore provides an inspiring challenge. Here, we present a meticulous mechanistic analysis of a propargylic sulfonylation reaction promoted by a chiral Cu catalyst through a combination of experimental techniques and computational studies. Surprisingly, the enantio-discriminating step is not the coupling between the nucleophile and the propargylic precursor but rather the following proto-demetalation step, a scenario further validated by computing enantio-induction levels under other previously reported experimental conditions. A full mechanistic scenario for this propargylic substitution reaction is provided, including a catalyst pre-activation stage, a productive catalytic cycle, and an unanticipated non-linear effect at the Cu(I) oxidation level.

Introducing the Catalytic Amination of Silanes via Nitrene Insertion.

The direct functionalization of Si-H bonds by the nitrene insertion methodology is described. A copper(I) complex bearing a trispyrazolylborate ligand catalyzes the transfer of a nitrene group from PhI═NTs to the Si-H bond of silanes, disilanes, and siloxanes, leading to the exclusive formation of Si-NH moieties in the first example of this transformation. The process tolerates other functionalities in the substrate such as several C-H bonds and alkyne and alkene moieties directly bonded to the silicon center. Density functional theory (DFT) calculations provide a mechanistic interpretation consisting of a Si-H homolytic cleavage and subsequent rebound to the Si-centered radical.

Seeking the Optimal Descriptor for SN2 Reactions through Statistical Analysis of Density Functional Theory Results.

Bimolecular nucleophilic substitution is one of the fundamental reactions in organic chemistry, yet there is still knowledge to be gained on the role of the nucleophile and the substrate. A statistical treatment of over 600 density functional theory (DFT)-computed barriers for bimolecular nucleophilic substitution at methyl derivatives (SN2@C) leads to the identification of numerical descriptors that best represent the entering and leaving ability of 26 different nucleophiles. The treatment is based on singular value decomposition (SVD) of a matrix of computed energy barriers. The current work represents the extension to a problem of reactivity of the hidden descriptor methodology that we had previously developed for the thermodynamic problem of bond dissociation energies in transition-metal complexes. The analysis of the results shows that a single descriptor is sufficient. This hidden descriptor has different values for nucleophilic and leaving abilities and, contrary to expectation, does not correlate especially well with either frontier molecular orbital descriptors or solvation descriptors. In contrast, it correlates with other thermodynamic and geometric parameters. This statistical procedure can be in principle extended to additional chemical fragments and other reactions.

An Expanded SET Model Associated with the Functional Hindrance Dominates the Amide-Directed Distal sp3 C-H Functionalization.

The mechanistic understanding of catalytic radical reactions currently lags behind the flourishing development of new types of catalytic activation. Herein, an innovative single electron transfer (SET) model has been expanded by using the nonadiabatic crossing integrated with the rate-determining step of 1,5-hydrogen atom transfer (HAT) reaction to provide the control mechanism of radical decay dynamics through calculating excited-state relaxation paths of a paradigm example of the amide-directed distal sp3 C-H bond alkylation mediated by Ir-complex-based photocatalysts. The stability of carbon radical intermediates, the functional hindrance associated with the back SET, and the energy inversion between the reactive triplet and closed-shell ground states were verified to be key factors in improving catalytic efficiency via blocking radical inhibition. The expanded SET model associated with the dynamic behaviors and kinetic data could guide the design and manipulation of visible-light-driven inert bond activation by the utilization of photocatalysts bearing more or less electron-withdrawing groups and the comprehensive considerations of kinetic solvent effects and electron-withdrawing effects of substrates.

Two Copper-Carbenes from One Diazo Compound.

Many transition-metal complexes MLn decompose diazo compounds N2═CR1R2 generating metal-carbenes LnM═CR1R2 which transfer the carbene group to other substrates, constituting an important tool in organic synthesis. All previous reports have shown that the CR1R2 fragment at the metal-carbene remains intact from the parent diazo compound. Herein we report the detection and isolation of a monosubstituted copper carbene where the CR1R2 ligand has undergone a modification from the initial diazo reagent. When TpMsCu(THF) (TpMs = hydrotris(3-mesityl)pyrazolylborate ligand) was reacted with N,N-diethyl diazoacetamide [N2═C(H)(CONEt2)], the stable copper carbene TpMsCu═C(H)(NEt2) was isolated, resulting from a decarbonylation process, with carbon monoxide being trapped as TpMsCu(CO). The simultaneous observation of products derived from the intramolecular carbene insertion reaction into C-H bonds demonstrates that the expected TpMsCu═C(H)(CONEt2) complex is also formed. Experimental data, DFT calculations, and microkinetic models allow us to propose that the latter undergoes CO loss en route to the former.

Redefining the Mechanistic Scenario of Carbon-Sulfur Nucleophilic Coupling via High-Valent Cp*CoIV Species.

The potential access to CoIV species for promoting transformations that are particularly challenging at CoIII still remains underexploited in the context of Cp*Co-catalyzed C-H functionalization reactions. Herein, we disclose a combined experimental and computational strategy for uncovering the participation of Cp*CoIV species in a Cp*Co-mediated C-S bond-reductive elimination. These studies support the intermediacy of high-valent Cp*Co species in C-H functionalization reactions, under oxidative conditions, when involving nucleophilic coupling partners.

Intermolecular Allene Functionalization by Silver-Nitrene Catalysis.

Under silver catalysis conditions, using [Tp*,BrAg]2 as the catalyst precursor, allenes react with PhI═NTs in the first example of efficient metal-mediated intermolecular nitrene transfer to such substrates. The nature of the substituent at the allene seems crucial for the reaction outcome since arylallenes are converted into azetidine derivatives, whereas methylene aziridines are the products resulting from alkylallenes. Mechanistic studies allow proposing that azetidines are formed through unstable cyclopropylimine intermediates, which further incorporate a second nitrene group, both processes being silver-mediated. Methylene aziridines from alkylallenes derive from catalytic nitrene addition to the allene double bonds. Both routes have resulted to be productive for further synthetic transformations affording aminocyclopropanes.

Photosynthesis of a Dihydroimidazopyridine Chelate Shines Light on the Reactions of a Photoactivated Iron(III) Complex with O2.

The high-spin (S = 5/2) meridional diastereoisomer of [FeIII(tpena)]2+ (tpena = N,N,N'-tris(2-pyridylmethyl)ethylendiamine-N'-acetate), mer-[Fe(tpena)]2+, undergoes photolytic CO2 release to produce an iron(II) intermediate of a radical dihydroimidazopyridine ligand (L•). The structure of this unprecedented transient iron(II)(L•) complex is supported by UV-vis and Mössbauer spectroscopies, DFT calculations, as well as the X-ray structural characterization of an µ-oxo iron(III) complex of the oxidized derivative of L•, namely, [FeIII2O(Cl)2(L+)2](ClO4)4(MeCN)2 (L+ = 2-(2-(bis(pyridin-2-ylmethyl)amino)ethyl)-2,3-dihydro-1H-imidazo[1,5-a]pyridin-4-ium). [FeIII2O(Cl)2(L+)2]4+ is obtained only in the absence of O2. Under aerobic conditions, O2 will intercept the iron(II)(L•) complex to form a putative Fe(III)-alkylperoxide complex which cascades to an iron(II) complex of SBPy3 (SBPy3 = N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-aldimine). Thus, through different oxidative pathways, the unknown ligand L+ or SBPy3 forms by loss of a one-carbon-atom or a two-carbon-atom unit, respectively, from the glycyl arm of tpena. Acceleration of the photodecarboxylation step is achieved by addition of thiocyanate because of transient formation of a more photoreactive NCS- adduct of [Fe(tpena)]2+. This has allowed for kinetic observation of the reaction of [FeII(L•)]2+ with O2 which is, unexpectedly, promoted also by light. We propose that this corresponds to the energy needed for the conversion of the ring-closed radical ligand L• to a ring-opened tautomer to allow for O2 insertion between the C and Fe atoms of the iron(II) complex.

A Quantitative Model for Alkane Nucleophilicity Based on C-H Bond Structural/Topological Descriptors.

A first quantitative model for calculating the nucleophilicity of alkanes is described. A statistical treatment was applied to the analysis of the reactivity of 29 different alkane C-H bonds towards in situ generated metal carbene electrophiles. The correlation of the recently reported experimental reactivity with two different sets of descriptors comprising a total of 86 parameters was studied, resulting in the quantitative descriptor-based alkane nucleophilicity (QDEAN) model. This model consists of an equation with only six structural/topological descriptors, and reproduces the relative reactivity of the alkane C-H bonds. This reactivity can be calculated from parameters emerging from the schematic drawing of the alkane and a simple set of sums.

GARLEEK: Adding an extra flavor to ONIOM.

The ONIOM method, developed in the group of Keiji Morokuma, is one of the most successful examples of quantum mechanics/molecular mechanics (QM/MM) treatments, and of multilayer methods in general. Its implementation in the Gaussian program package is in particular widely used. This implementation has access to the wide variety of QM methods available in Gaussian, but is limited to only three specific force fields. The current article presents the GARLEEK interface, which expands the availability of molecular mechanics methods to the wide variety of force fields available in MM packages. The focus is in the simple installation and use. Two examples of the performance of the interface with selected systems are provided. GARLEEK is MIT-licensed and freely available at https://github.com/insilichem/garleek. © 2018 Wiley Periodicals, Inc.

Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution.

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1'-NR1 R2 and 1'-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.

Exploring the Role of Coinage Metalates in Trifluoromethylation: A Combined Experimental and Theoretical Study.

Despite the known nucleophilic nature of [M(CF3 )2 ]- (M=Cu, Ag, Au) complexes, their participation in trifluoromethylation reactions of aryl halides remains unexplored. Here, for the first time, selective access to a [Cu(CF3 )2 ]- species is reported, which is ubiquitous in Cu-mediated trifluoromethylations, and we rationalize its complex mechanistic scenario as well as its behavior compared to its silver and gold congeners through a combination of experimental and computational approaches.

On the Use of Thermodynamic Cycles for the Calculation of Standard Potentials for the Oxidation of Solid Metals in Solution.

The performance of a thermodynamic cycle for the calculation of the standard reduction potential (SRP) of a series of metals is examined. It is found that the introduction of simple entropic corrections substantially improves the agreement with experimental data. The accuracy of the estimations is in the range of 0.04 V, which opens the possibility to calculate the SRP for metals in non-aqueous solvents or other unusual situations.

Four Oxidation States in a Single Photoredox Nickel-Based Catalytic Cycle: A Computational Study.

The computational characterization of the full catalytic cycle for the synthesis of indoline from the reaction between iodoacetanilide and a terminal alkene catalyzed by a nickel complex and a photoactive ruthenium species is presented. A variety of oxidation states of nickel, Ni0 , NiI , NiII , and NiIII , is shown to participate in the mechanism. Ni0 is necessary for the oxidative addition of the C-I bond, which goes through a NiI intermediate and results in a NiII species. The NiII species inserts into the alkene, but does not undergo the reductive elimination necessary for C-N bond formation. This oxidatively induced reductive elimination can be accomplished only after oxidation to NiIII by the photoactive ruthenium species. All the reaction steps are computationally characterized, and the barriers for the single-electron transfer steps calculated using a modified version of the Marcus Theory.

Copper-Catalyzed N-F Bond Activation for Uniform Intramolecular C-H Amination Yielding Pyrrolidines and Piperidines.

The dual function of the N-F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C-H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio- and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N-F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.

A Domino Process toward Functionally Dense Quaternary Carbons through Pd-Catalyzed Decarboxylative C(sp3)-C(sp3) Bond Formation.

An efficient protocol was developed to construct functionally dense quaternary carbons with concomitant formation of a new Csp3-Csp3 bond via Pd-catalyzed decarboxylative transformation of vinyl cyclic carbonates. This redox-neutral catalytic system features stereocontrolled formation of multisubstituted allylic scaffolds with an aldehyde functionality generated in situ, and it typically can be performed at room temperature without any additives. DFT calculations provide a rationale toward the selective formation of these compounds and reveal a complex mechanism that with the help of microkinetic models is able to reproduce the nontrivial dependence of the identity of the product on the nature of the substituents in the substrate.

Photoinduced O2-Dependent Stepwise Oxidative Deglycination of a Nonheme Iron(III) Complex.

The iron(III) complex [Fe(tpena)]2+ (tpena = N, N, N'-tris(2-pyridylmethyl)ethylendiamine- N'-acetate) undergoes irreversible O2-dependent N-demethylcarboxylation to afford [FeII(SBPy3)(MeCN)]2+ (SBPy3 = N, N-bis(2-pyridylmethyl)amine- N-ethyl-2-pyridine-2-aldimine), when irradiated with near-UV light. The loss of a mass equivalent to the glycyl group in a process involving consecutive C-C and C-N cleavages is documented by the measurement of the sequential production of CO2 and formaldehyde, respectively. Time-resolved UV-vis absorption, Mössbauer, EPR, and Raman spectroscopy have allowed the spectroscopic characterization of two iron-based intermediates along the pathway. The first of these, proposed to be a low-spin iron(II)-radical ligand complex, reacts with O2 in the rate-determining step to produce a putative alkylperoxide complex. DFT calculations suggest that this evolves into an Fe(IV)-oxo species, which can abstract a hydrogen atom from a cis methylene group of the ligand to give the second spectroscopically identified intermediate, a high-spin iron(III)-hydroxide of the product oxidized ligand, [FeIII(OH)(SBPy3)]2+. Reduction and exchange of the cohydroxo/water ligand produces the crystallographically characterized products [FeII(SBPy3)(X)]2+/3+, X = MeCN, [Zn(tpena)]+.